palti

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>
> ---
>
>
>
> **Yoram PALTI**
>
> **Tumor-Curing Electric Fields**
>
> ---
>
> **<http://www.technologyreview.com/Biotech/19195/>**
>
> ***MIT Technology Review* (Wednesday, August 08, 2007)**
>
> **Electric Fields Kill Tumors**
>
> ***A promising device uses electric fields to destroy
> cancer cells in the brain.***
>
> **By Katherine Bourzac**
>
> An Israeli company is conducting human tests for a device
> that uses weak electric fields to kill cancer cells but has no
> effect on normal cells. The device is in late-stage clinical
> trials in the United States and Europe for glioblastoma, a
> deadly brain cancer. It is also being tested in Europe for its
> effectiveness against breast cancer. In the lab and in animal
> testing, treatment with electric fields has killed cancer
> cells of every type tested.
>
> The electric-field therapy was developed by Yoram Palti, a
> physiologist at the Technion-Israel Institute of Technology,
> in Haifa, who founded the company NovoCure to commercialize the treatment.
> Palti's electric fields cause dividing cancer cells to explode
> while having no significant impact on normal tissues. The
> range of electric fields generated by the device harms only
> dividing cells. And since normal cells divide at a much slower
> rate than cancer cells, the electric fields target cancer
> cells. "An Achilles' heel of cancer cells is that they have to
> divide," says Herbert Engelhard, chief of neuro-oncology in
> the department of neurosurgery at the University of Illinois,
> Chicago.
>
> Even after chemotherapy, radiation therapy, and surgery,
> about 85 to 90 percent of glioblastoma patients' cancer still
> progresses, and their survival rates are low, says Engelhard.
> He has about 10 glioblastoma patients enrolled in the trial,
> which is testing the unusual treatment in patients for whom
> all other approaches have failed. Engelhard says that the
> results are encouraging but that it's too early to comment on
> the treatment's efficacy.
>
> The electric fields' different effects on normal and dividing
> cells mostly have to do with geometry. A dividing cell has
> what Palti calls "an hourglass shape rather than a round
> shape." The electric field generated by the NovoCure device
> passes around and through round cells in a uniform fashion.
> But the narrow neck that pinches in at the center of a
> dividing cell acts like a lens, concentrating the electric
> field at this point. This non-uniform electric field wreaks
> havoc on dividing cells. The electric field tears apart
> important biological molecules, such as DNA and the structural
> proteins that pull the chromosomes into place during cell
> division. Dividing cells simply "disintegrate," says Palti.
>
> Palti, who for years has been studying the effect of electric
> fields on cancer and normal cells, says that he has verified
> this mechanism in computer models and experiments in the lab.
> "The physics are solid," says David Cohen, associate professor
> of radiology at Harvard Medical School.
>
> Patients in the glioblastoma clinical trial wear the device
> almost constantly, carrying necessary components in a
> briefcase. A wire emerging from the briefcase connects to
> adhesive electrodes covering the skull. Alternating electric
> fields pass through the scalp, into the skull, and on to the
> brain. The Food and Drug Administration approved the device
> for late-stage clinical trials for glioblastoma following
> promising results from a pilot study in 10 patients, one of
> whom had a complete recovery.
>
> ![](divcell.jpg)  
> **A dividing cell in an electric field**
>
> ![](06027txt.jpg)
>
> ---
>
>
>
> **Yoram PALTI Patents**
>
> **Method for Selectively Destroying Dividing Cells**   
> **US7136699**   
> **2007-02-08**
>
> An apparatus is provided for selectively destroying dividing
> cells in living tissue formed of dividing cells and
> non-dividing cells. The dividing cells contain polarizable
> intracellular members and during late anaphase or telophase,
> the dividing cells are connected to one another by a cleavage
> furrow. The apparatus includes a generator and insulated
> electrodes for subjecting the living tissue to electric field
> conditions sufficient to cause movement of the polarizable
> intracellular members toward the cleavage furrow in response
> to a non-homogeneous electric field being induced in the
> dividing cells. The non-homogeneous electric field produces an
> increased density electric field in the region of the cleavage
> furrow. The movement of the polarizable intracellular
> intracellular members towards the cleavage furrow causes the
> breakdown thereof which results in the destruction of the
> dividing cells, while the non-dividing cells of the living
> tissue remain intact.
>
> ![](71366txt.jpg)
>
> **Treating Cancer with Electric Fields...**   
> **US2006282122**   
> **2006-12-14**
>
> Electric fields with certain characteristics have been shown
> to be effective at inhibiting the growth of cancer cells (and
> other rapidly dividing cells). However, when the cancer is
> located in a target region beneath the surface of a body, it
> can be difficult to deliver the beneficial fields to the
> target region. This difficulty can be surmounted by
> positioning a biocompatible field guide between the surface of
> the body and the target region, positioning electrodes on
> either side of the field guide, and applying an AC voltage
> with an appropriate frequency and amplitude between the
> electrodes. This arrangement causes the field guide to route
> the beneficial field to the target region. In an alternative
> embodiment, one of the electrodes is positioned directly on
> top of the field guide.
>
> **Apparatus & Method for Preventing the Spread of
> Cancerous Metastases...**   
> **US2006276858**   
> **2006-12-07**
>
> AC electric fields at certain frequencies and field strengths
> disrupt dividing cells, but leave undividing cells
> substantially unharmed. Since cancer cells divide much more
> often than normal cells, those AC fields have been shown to be
> effective at inhibiting tumor growth and shrinking tumors.
> Because certain body parts (e.g., the lungs and the liver) are
> at high risk for developing metastases in patients with some
> forms of cancer, treating those body parts with those AC
> fields can prevent metastases from growing in those body
> parts. This treatment may be used both after a metastasis has
> reached a detectable size and prophylactically (to prevent
> such metastases from ever reaching a detectable size in the
> first place). It may also be used to prevent cancer in people
> with a high probability of developing cancer (e.g., based on
> family history).
>
> **Probe for Treating a Tumor or the Like**   
> **US6868289**   
> **2006-10-26**
>
> An article of clothing is provided for selectively destroying
> dividing cells in living tissue formed of dividing cells and
> non-dividing cells. The dividing cells contain polarizable
> intracellular members and during late anaphase or telophase,
> the dividing cells are connected to one another by a cleavage
> furrow. The article of clothing includes insulated electrodes
> to be coupled to a generator for subjecting the living tissue
> to electric field conditions sufficient to cause movement of
> the polarizable intracellular members toward the cleavage
> furrow in response to a non-homogeneous electric field being
> induced in the dividing cells. The non-homogeneous electric
> field produces an increased density electric field in the
> region of the cleavage furrow. The movement of the polarizable
> intracellular intracellular members towards the cleavage
> furrow causes the breakdown thereof which adversely impacts
> the multiplication of the dividing cells.
>
> **Treating a tumor or the like with electric fields at
> different orientations**   
> **US2006167499**   
> **2006-07-27**
>
> Cells that are in the late anaphase or telophase stages of
> cell division are vulnerable to damage by AC electric fields
> that have specific frequency and field strength
> characteristics. The selective destruction of rapidly dividing
> cells can therefore be accomplished by imposing an AC electric
> field in a target region for extended periods of time. Some of
> the cells that divide while the field is applied will be
> damaged, but the cells that do not divide will not be harmed.
> This selectively damages rapidly dividing cells like tumor
> cells, but does not harm normal cells that are not dividing.
> Since the vulnerability of the dividing cells is strongly
> related to the alignment between the long axis of the dividing
> cells and the lines of force of the electric field, improved
> results are obtained when the field is sequentially imposed in
> different directions. The field may also be rotated through
> 360 DEG by applying AC waveforms with different phases to the
> electrodes.
>
> **Electrodes for applying an electric field in-vivo over an
> extended period of time**   
> **US2006149341**   
> **2006-07-06**
>
> As compared to conventional electrodes, the electrode
> configurations disclosed herein minimize irritation and damage
> to the skin when they are placed in contact with a patient's
> body over extended of time. The electrodes are formed from a
> conductive substrate coated with a thin dielectric material,
> and a plurality of open spaces pass through the electrodes.
> Those open spaces are distributed and sized to permit moisture
> on the surface of the patient's body to escape when the
> electrode is placed in contact with the patient's body. One
> intended use for the electrodes is for treating tumors by
> applying an AC electric field with specific frequency and
> field strength characteristics over an extended period of
> time.
>
> **Treating a tumor or the like with electric fields at
> different orientations**   
> **US2005209642**   
> **2005-09-22**
>
> Cells that are in the late anaphase or telophase stages of
> cell division are vulnerable to damage by AC electric fields
> that have specific frequency and field strength
> characteristics. The selective destruction of rapidly dividing
> cells can therefore be accomplished by imposing an AC electric
> field in a target region for extended periods of time. Some of
> the cells that divide while the field is applied will be
> damaged, but the cells that do not divide will not be harmed.
> This selectively damages rapidly dividing cells like tumor
> cells, but does not harm normal cells that are not dividing.
> Since the vulnerability of the dividing cells is strongly
> related to the alignment between the long axis of the dividing
> cells and the lines of force of the electric field, improved
> results are obtained when the field is sequentially imposed in
> different directions.
>
> **Treating a tumor or the like with an electric field**   
> **US2005209640**   
> **2005-09-22**
>
> Cells that are in the late anaphase or telophase stages of
> cell division are vulnerable to damage by AC electric fields
> that have specific frequency and field strength
> characteristics. The selective destruction of rapidly dividing
> cells can therefore be accomplished by imposing an AC electric
> field in a target region for extended periods of time. Some of
> the cells that divide while the field is applied will be
> damaged, but the cells that do not divide will not be harmed.
> This selectively damages rapidly dividing cells like tumor
> cells, but does not harm normal cells that are not dividing.
> Since the vulnerability of the dividing cells is strongly
> related to the alignment between the long axis of the dividing
> cells and the lines of force of the electric field, improved
> results are obtained when the field is sequentially imposed in
> different directions.
>
> **Treating a tumor or the like with an electric field that
> is focused at a target region**   
> **US2005240173**   
> **2005-10-27**
>
> An apparatus is provided for selectively destroying dividing
> cells in living tissue formed of dividing cells and
> non-dividing cells. The dividing cells contain polarizable
> intracellular members and during late anaphase or telophase,
> the dividing cells are connected to one another by a cleavage
> furrow. The apparatus includes insulated electrodes to be
> coupled to a generator for subjecting the living tissue to
> electric field conditions sufficient to cause movement of the
> polarizable intracellular members toward the cleavage furrow
> in response to a non-homogeneous electric field being induced
> in the dividing cells. The movement of the polarizable
> intracellular members towards the cleavage furrow causes the
> breakdown thereof which adversely impacts the multiplication
> of the dividing cells, but does not damage non-dividing cells.
> In some embodiments, the electric field is guided to a desired
> target region by varying the sizes of the electrodes that are
> used to apply the electric field. In other embodiments, the
> electric field is guided to a desired target region (and/or
> away from other regions) by positioning one or more conductors
> in appropriate positions within the patient's body.
>
> **Apparatus and method for optimizing tumor treatment
> efficiency by electric fields**   
> **US7146210**   
> **2004-09-09**
>
> The apparatus and method are designed to compute the optimal
> spatial and temporal characteristics for combating tumor
> growth within a body on the basis of cytological (as provided
> by biopsies, etc.) and anatomical data (as provided by CT,
> MRI, PET, etc.), as well as the electric properties of the
> different elements. On the basis of this computation, the
> apparatus applies the fields that have maximal effect on the
> tumor and minimal effect on all other tissues by adjusting
> both the field generator output characteristics and by optimal
> positioning of the insulated electrodes or isolects on the
> patient's body.
>
> ![](7146txt.jpg)
>
> **Method and apparatus for destroying dividing cells**   
> **US7016725**   
> **2003-05-22**
>
> The present invention provides a method and apparatus for
> selectively destroying dividing cells in living tissue formed
> of dividing cells and non-dividing cells. The dividing cells
> contain polarizable intracellular members and during late
> anaphase or telophase, the dividing cells are connected to one
> another by a cleavage furrow. According to the present method
> the living tissue is subjected to electric field conditions
> sufficient to cause movement of the polarizable intracellular
> members toward the cleavage furrow in response to a
> non-homogenous electric field being induced in the dividing
> cells. The non-homogenous electric field produces an increased
> density electric field in the region of the cleavage furrow.
> The movement of the polarizable intracellular members towards
> the cleavage furrow causes the break down thereof which
> results in destruction of the dividing cells, while the
> non-dividing cells of the living tissue remain intact.
>
> **Method and apparatus for destroying dividing cells**   
> **US2003150372**   
> **2003-08-14**
>
> The present invention provides a method and apparatus for
> selectively destroying dividing cells in living tissue formed
> of dividing cells and non-dividing cells. The dividing cells
> contain polarizable intracellular members and during late
> anaphase or telophase, the dividing cells are connected to one
> another by a cleavage furrow. According to the present method
> the living tissue is subjected to electric field conditions
> sufficient to cause movement of the polarizable intracellular
> members toward the cleavage furrow in response to a
> non-homogenous electric field being induced in the dividing
> cells. The non-homogenous electric field produces an increased
> density electric field in the region of the cleavage furrow.
> The movement of the polarizable intracellular members towards
> the cleavage furrow causes the break down thereof which
> results in destruction of the dividing cells, while the
> non-dividing cells of the living tissue remain intact.
>
> ---
>
>   
>
> TREATING
> TUMOR OR THE LIKE WITH ELECTRIC FIELDS AT DIFFERENT
> FREQUENCIES  
>  JP2011078804  
>  WO2005115535
>
>   
> TECHNICAL FIELD  
>   
>  [0002] This invention concerns selective destruction of
> rapidly dividing cells in a localized area, and more
> particularly, selectively destroying dividing cells without
> destroying nearby non-dividing cells by applying an electric
> field with specific characteristics to a target area in a living
> patient.   
>   
> BACKGROUND   
>   
> [0003] All living organisms proliferate by cell division,
> including cell cultures, microorganisms (such as bacteria,
> mycoplasma, yeast, protozoa, and other single-celled organisms),
> fungi, algae, plant cells, etc. Dividing cells of organisms can
> be destroyed, or their proliferation controlled, by methods that
> are based on the sensitivity of the dividing cells of these
> organisms to certain agents. For example, certain antibiotics
> stop the multiplication process of bacteria.  
>   
>  [0004] The process of eukaryotic cell division is called
> "mitosis", which involves nice distinct phases (see Darnell et
> al. , Molecular Cell Biology, New York: Scientific American
> Books, 1986, p. 149). During interphase, the cell replicates
> chromosomal DNA, which begins condensing in early prophase. At
> this point, centrioles (each cell contains 2) begin moving
> towards opposite poles of the cell. In middle prophase, each
> chromosome is composed of duplicate chromatids. Microtubular
> spindles radiate from regions adjacent to the centrioles, which
> are closer to their poles. By late prophase, the centrioles have
> reached the poles, and some spindle fibers extend to the center
> of the cell, while others extend from the poles to the
> chromatids. The cells then move into metaphase, when the
> chromosomes move toward the equator of the cell and align in the
> equatorial plane. Next is early anaphase, during which time
> daughter chromatids separate from each other at the equator by
> moving along the spindle fibers toward a centromere at opposite
> poles. The cell begins to elongate along the axis of the pole;
> the pole-to-pole spindles also elongate. Late anaphase occurs
> when the daughter chromosomes (as they are now called) each
> reach their respective opposite poles. At this point,
> cytokinesis begins as the cleavage furrow begins to form at the
> equator of the cell. In other words, late anaphase is the point
> at which pinching the cell membrane begins. During telophase,
> cytokinesis is nearly complete and spindles disappear. Only a
> relatively narrow membrane connection joins the two cytoplasms.
> Finally, the membranes separate fully, cytokinesis is complete
> and the cell returns to interphase.   
>   
> [0005] In meiosis, the cell undergoes a second division,
> involving separation of sister chromosomes to opposite poles of
> the cell along spindle fibers, followed by formation of a
> cleavage furrow and cell division. However, this division is not
> preceded by chromosome replication, yielding a haploid germ
> cell. Bacteria also divide by chromosome replication, followed
> by cell separation. However, since the daughter chromosomes
> separate by attachment to membrane components; there is no
> visible apparatus that contributes to cell division as in
> eukaryotic cells.  
>   
>  [0006] It is well known that tumors, particularly
> malignant or cancerous tumors, grow uncontrollably compared to
> normal tissue. Such expedited growth enables tumors to occupy an
> ever-increasing space and to damage or destroy tissue adjacent
> thereto. Furthermore, certain cancers are characterized by an
> ability to transmit cancerous "seeds", including single cells or
> small cell clusters (metastases), to new locations where the
> metastatic cancer cells grow into additional tumors.  
>   
>  [0007] The rapid growth of tumors, in general, and
> malignant tumors in particular, as described above, is the
> result of relatively frequent cell division or multiplication of
> these cells compared to normal tissue cells. The distinguishably
> frequent cell division of cancer cells is the basis for the
> effectiveness of existing cancer treatments, e. g., irradiation
> therapy and the use of various chemo-therapeutic agents. Such
> treatments are based on the fact that cells undergoing division
> are more sensitive to radiation and chemo-therapeutic agents
> than non-dividing cells. Because tumors cells divide much more
> frequently than normal cells, it is possible, to a certain
> extent, to selectively damage or destroy tumor cells by
> radiation therapy and/or chemotherapy. The actual sensitivity of
> cells to radiation, therapeutic agents, etc. , is also dependent
> on specific characteristics of different types of normal or
> malignant cell types. Thus, unfortunately, the sensitivity of
> tumor cells is not sufficiently higher than that many types of
> normal tissues. This diminishes the ability to distinguish
> between tumor cells and normal cells, and therefore, existing
> cancer treatments typically cause significant damage to normal
> tissues, thus limiting the therapeutic effectiveness of such
> treatments. Furthermore, the inevitable damage to other tissue
> renders treatments very traumatic to the patients and, often,
> patients are unable to recover from a seemingly successful
> treatment. Also, certain types of tumors are not sensitive at
> all to existing methods of treatment.  
>   
>  [0008] There are also other methods for destroying cells
> that do not rely on radiation therapy or chemotherapy alone. For
> example, ultrasonic and electrical methods for destroying tumor
> cells can be used in addition to or instead of conventional
> treatments. Electric fields and currents have been used for
> medical purposes for many years. The most common is the
> generation of electric currents in a human or animal body by
> application of an electric field by means of a pair of
> conductive electrodes between which a potential difference is
> maintained. These electric currents are used either to exert
> their specific effects, i. e., to stimulate excitable tissue, or
> to generate heat by flowing in the body since it acts as a
> resistor. Examples of the first type of application include the
> following: cardiac defibrillators, peripheral nerve and muscle
> stimulators, brain stimulators, etc. Currents are used for
> heating, for example, in devices for tumor ablation, ablation of
> malfunctioning cardiac or brain tissue, cauterization,
> relaxation of muscle rheumatic pain and other pain, etc.  
>   
>  [0009] Another use of electric fields for medical purposes
> involves the utilization of high frequency oscillating fields
> transmitted from a source that emits an electric wave, such as
> an RF wave or a microwave source that is directed at the part of
> the body that is of interest (i. e., target). In these
> instances, there is no electric energy conduction between the
> source and the body; but rather, the energy is transmitted to
> the body by radiation or induction. More specifically, the
> electric energy generated by the source reaches the vicinity of
> the body via a conductor and is transmitted from it through air
> or some other electric insulating material to the human body.  
>   
>  [0010] In a conventional electrical method, electrical
> current is delivered to a region of the target tissue using
> electrodes that are placed in contact with the body of the
> patient. The applied electrical current destroys substantially
> all cells in the vicinity of the target tissue. Thus, this type
> of electrical method does not discriminate between different
> types of cells within the target tissue and results in the
> destruction of both tumor cells and normal cells.  
>   
>  [0011] Electric fields that can be used in medical
> applications can thus be separated generally into two different
> modes. In the first mode, the electric fields are applied to the
> body or tissues by means of conducting electrodes. These
> electric fields can be separated into two types, namely (1)
> steady fields or fields that change at relatively slow rates,
> and alternating fields of low frequencies that induce
> corresponding electric currents in the body or tissues, and (2)
> high frequency alternating fields (above 1 MHz) applied to the
> body by means of the conducting electrodes. In the second mode,
> the electric fields are high frequency alternating fields
> applied to the body by means of insulated electrodes.  
>   
>  [0012] The first type of electric field is used, for
> example, to stimulate nerves and muscles, pace the heart, etc.
> In fact, such fields are used in nature to propagate signals in
> nerve and muscle fibers, central nervous system (CNS), heart,
> etc. The recording of such natural fields is the basis for the
> ECG, EEG, EMG, ERG, etc. The field strength in these
> applications, assuming a medium of homogenous electric
> properties, is simply the voltage applied to the
> stimulating/recording electrodes divided by the distance between
> them. These currents can be calculated by Ohm's law and can have
> dangerous stimulatory effects on the heart and CNS and can
> result in potentially harmful ion concentration changes. Also,
> if the currents are strong enough, they can cause excessive
> heating in the tissues. This heating can be calculated by the
> power dissipated in the tissue (the product of the voltage and
> the current).  
>   
>  [0013] When such electric fields and currents are
> alternating, their stimulatory power, on nerve, muscle, etc. ,
> is an inverse function of the frequency. At frequencies above
> 1-10 KHz, the stimulation power of the fields approaches zero.
> This limitation is due to the fact that excitation induced by
> electric stimulation is normally mediated by membrane potential
> changes, the rate of which is limited by the RC properties (time
> constants on the order of 1 ms) of the membrane. [0014]
> Regardless of the frequency, when such current inducing fields
> are applied, they are associated with harmful side effects
> caused by currents. For example, one negative effect is the
> changes in ionic concentration in the various "compartments"
> within the system, and the harmful products of the electrolysis
> taking place at the electrodes, or the medium in which the
> tissues are imbedded. The changes in ion concentrations occur
> whenever the system includes two or more compartments between
> which the organism maintains ion concentration differences. For
> example, for most tissues, [Ca@] in the extracellular fluid is
> about 2#10-3 M, while in the cytoplasm of typical cells its
> concentration can be as low as 10-7 M. A current induced in such
> a system by a pair of electrodes, flows in part from the
> extracellular fluid into the cells and out again into the
> extracellular medium. About 2% of the current flowing into the
> cells is carried by the Ca@ ions. In contrast, because the
> concentration of intracellular Ca@ is much smaller, only a
> negligible fraction of the currents that exits the cells is
> carried by these ions. Thus, Ca++ ions accumulate in the cells
> such that their concentrations in the cells increases, while the
> concentration in the extracellular compartment may decrease.
> These effects are observed for both DC and alternating currents
> (AC). The rate of accumulation of the ions depends on the
> current intensity ion mobilities, membrane ion conductance, etc.
> An increase in [Ca++] is harmful to most cells and if
> sufficiently high will lead to the destruction of the cells.
> Similar considerations apply to other ions. In view of the above
> observations, long term current application to living organisms
> or tissues can result in significant damage. Another major
> problem that is associated with such electric fields, is due to
> the electrolysis process that takes place at the electrode
> surfaces. Here charges are transferred between the metal
> (electrons) and the electrolytic solution (ions) such that
> charged active radicals are formed. These can cause significant
> damage to organic molecules, especially macromolecules and thus
> damage the living cells and tissues. [0015] In contrast, when
> high frequency electric fields, above 1 MHz and usually in
> practice in the range of GHz, are induced in tissues by means of
> insulated electrodes, the situation is quite different. These
> type of fields generate only capacitive or displacement
> currents, rather than the conventional charge conducting
> currents. Under the effect of this type of field, living tissues
> behave mostly according to their dielectric properties rather
> than their electric conductive properties. Therefore, the
> dominant field effect is that due to dielectric losses and
> heating. Thus, it is widely accepted that in practice, the
> meaningful effects of such fields on living organisms, are only
> those due to their heating effects, i. e., due to dielectric
> losses.  
>   
> [0016] In U. S. Pat. No.
> 6,043,066 ('066) to Mangano, a method and device are
> presented which enable discrete objects having a conducting
> inner core, surrounded by a dielectric membrane to be
> selectively inactivated by electric fields via irreversible
> breakdown of their dielectric membrane. One potential
> application for this is in the selection and purging of certain
> biological cells in a suspension. According to the '066 patent,
> an electric field is applied for targeting selected cells to
> cause breakdown of the dielectric membranes of these tumor
> cells, while purportedly not adversely affecting other desired
> subpopulations of cells. The cells are selected on the basis of
> intrinsic or induced differences in a characteristic electroporation threshold.
> The differences in this threshold can depend upon a number of
> parameters, including the difference in cell size.   
>   
> [0017] The method of the '066 patent is therefore based on the
> assumption that the electroporation threshold of tumor cells is
> sufficiently distinguishable from that of normal cells because
> of differences in cell size and differences in the dielectric
> properties of the cell membranes. Based upon this assumption,
> the larger size of many types of tumor cells makes these cells
> more susceptible to electroporation and thus, it may be possible
> to selectively damage only the larger tumor cell membranes by
> applying an appropriate electric field. One disadvantage of this
> method is that the ability to discriminate is highly dependent
> upon cell type, for example, the size difference between normal
> cells and tumor cells is significant only in certain types of
> cells. Another drawback of this method is that the voltages
> which are applied can damage some of the normal cells and may
> not damage all of the tumor cells because the differences in
> size and membrane dielectric properties are largely statistical
> and the actual cell geometries and dielectric properties can
> vary significantly.   
>   
> [0018] What is needed in the art and has heretofore not been
> available is an apparatus for destroying dividing cells, wherein
> the apparatus better discriminates between dividing cells,
> including single-celled organisms, and non-dividing cells and is
> capable of selectively destroying the dividing cells or
> organisms with substantially no effect on the non-dividing cells
> or organisms.   
>   
> SUMMARY   
>   
> [0019] While they are dividing,
> cells are vulnerable to damage by AC electric fields that have
> specific frequency and field strength characteristics.
> The selective destruction of rapidly dividing cells can
> therefore be accomplished by imposing an AC electric field in a
> target region for extended periods of time. Some of the cells
> that divide while the field is applied will be damaged, but the
> cells that do not divide will not be harmed. This selectively
> damages rapidly dividing cells like tumor cells, but does not
> harm normal cells that are not dividing. Improved results may be
> achieved by using a field with two or more frequencies.   
>   
> [0020] A major use of the present apparatus is in the treatment
> of tumors by selective destruction of tumor cells with
> substantially no effect on normal tissue cells, and thus, the
> exemplary apparatus is described below in the context of
> selective destruction of tumor cells. It should be appreciated
> however, that for purpose of the following description, the term
> "cell" may also refer to a single-celled organism (eubacteria,
> bacteria, yeast, protozoa), multi- celled organisms (fungi,
> algae, mold), and plants as or parts thereof that are not
> normally classified as "cells". The exemplary apparatus enables
> selective destruction of cells undergoing division in a way that
> is more effective and more accurate (e. g., more adaptable to be
> aimed at specific targets) than existing methods. Further, the
> present apparatus causes minimal damage, if any, to normal
> tissue and, thus, reduces or eliminates many side-effects
> associated with existing selective destruction methods, such as
> radiation therapy and chemotherapy. The selective destruction of
> dividing cells using the present apparatus does not depend on
> the sensitivity of the cells to chemical agents or radiation.
> Instead, the selective destruction of dividing cells is based on
> distinguishable geometrical characteristics of cells undergoing
> division, in comparison to non-dividing cells, regardless of the
> cell geometry of the type of cells being treated.   
>   
> [0021] According to one exemplary embodiment, cell
> geometry-dependent selective destruction of living tissue is
> performed by inducing a non-homogenous electric field in the
> cells using an electronic apparatus.  
>   
>  [0022] It has been observed by the present inventor that,
> while different cells in their non-dividing state may have
> different shapes, e. g., spherical, ellipsoidal, cylindrical,
> "pancake-like", etc. , the division process of practically all
> cells is characterized by development of a "cleavage furrow" in
> late anaphase and telophase. This cleavage furrow is a slow
> constriction of the cell membrane (between the two sets of
> daughter chromosomes) which appears microscopically as a growing
> cleft (e. g., a groove or notch) that gradually separates the
> cell into two new cells. During the division process, there is a
> transient period (telophase) during which the cell structure is
> basically that of two sub-cells interconnected by a narrow
> "bridge" formed of the cell material. The division process is
> completed when the "bridge" between the two sub-cells is broken.
> The selective destruction of tumor cells using the present
> electronic apparatus utilizes this unique geometrical feature of
> dividing cells.   
>   
> [0023] When a cell or a group of cells are under natural
> conditions or environment, i. e., part of a living tissue, they
> are disposed surrounded by a conductive environment consisting
> mostly of an electrolytic inter-cellular fluid and other cells
> that are composed mostly of an electrolytic intra-cellular
> liquid. When an electric field is induced in the living tissue,
> by applying an electric potential across the tissue, an electric
> field is formed in the tissue and the specific distribution and
> configuration of the electric field lines defines the direction
> of charge displacement, or paths of electric currents in the
> tissue, if currents are in fact induced in the tissue. The
> distribution and configuration of the electric field is
> dependent on various parameters of the tissue, including the
> geometry and the electric properties of the different tissue
> components, and the relative conductivities, capacities and
> dielectric constants (that may be frequency dependent) of the
> tissue components.   
>   
> [0024] The electric current flow pattern for cells undergoing
> division is very different and unique as compared to
> non-dividing cells. Such cells including first and second
> sub-cells, namely an "original" cell and a newly formed cell,
> that are connected by a cytoplasm "bridge" or "neck". The
> currents penetrate the first sub-cell through part of the
> membrane ("the current source pole") ; however, they do not exit
> the first sub-cell through a portion of its membrane closer to
> the opposite pole ("the current sink pole"). Instead, the lines
> of current flow converge at the neck or cytoplasm bridge,
> whereby the density of the current flow lines is greatly
> increased. A corresponding, "mirror image", process that takes
> place in the second sub-cell, whereby the current flow lines
> diverge to a lower density configuration as they depart from the
> bridge, and finally exit the second sub-cell from a part of its
> membrane closes to the current sink.   
>   
> [0025] When a polarizable object is placed in a non-uniform
> converging or diverging field, electric forces act on it and
> pull it towards the higher density electric field lines. In the
> case of dividing cell, electric forces are exerted in the
> direction of the cytoplasm bridge between the two cells. Since
> all intercellular organelles and macromolecules are polarizable,
> they are all forced towards the bridge between the two cells.
> The field polarity is irrelevant to the direction of the force
> and, therefore, an alternating electric having specific
> properties can be used to produce substantially the same effect.
> It will also be appreciated that the concentrated and
> inhomogeneous electric field present in or near the bridge or
> neck portion in itself exerts strong forces on charges and
> natural dipoles and can lead to the disruption of structures
> associated with these members.   
>   
> [0026] The movement of the cellular organelles towards the
> bridge disrupts the cell structure and results in increased
> pressure in the vicinity of the connecting bridge membrane. This
> pressure of the organelles on the bridge membrane is expected to
> break the bridge membrane and, thus, it is expected that the
> dividing cell will "explode" in response to this pressure. The ability to break the membrane
> and disrupt other cell structures can be enhanced by applying
> a pulsating alternating electric field that has a frequency
> from about 50 KHz to about 500 KHz. When this type of
> electric field is applied to the tissue, the forces exerted on
> the intercellular organelles have a "hammering" effect, whereby
> force pulses (or beats) are applied to the organelles numerous
> times per second, enhancing the movement of organelles of
> different sizes and masses towards the bridge (or neck) portion
> from both of the sub-cells, thereby increasing the probability
> of breaking the cell membrane at the bridge portion. The forces
> exerted on the intracellular organelles also affect the
> organelles themselves and may collapse or break the organelles.
>   
>   
> [0027] According to one exemplary embodiment, the apparatus for
> applying the electric field is an electronic apparatus that
> generates the desired electric signals in the shape of waveforms
> or trains of pulses. The electronic apparatus includes a
> generator that generates an alternating voltage waveform at
> frequencies in the range from about 50 KHz to about 500 KHz. The
> generator is operatively connected to conductive leads which are
> connected at their other ends to insulated conductors/electrodes
> (also referred to as isolects)
> that are activated by the generated waveforms. The insulated
> electrodes consist of a conductor in contact with a dielectric
> (insulating layer) that is in contact with the conductive
> tissue, thus forming a capacitor. The electric fields that are
> generated by the present apparatus can be applied in several
> different modes depending upon the precise treatment
> application.   
>   
> [0028] In one exemplary embodiment, the electric fields are
> applied by external insulated electrodes which are incorporated
> into an article of clothing and which are constructed so that
> the applied electric fields are of a local type that target a
> specific, localized area of tissue (e. g., a tumor). This
> embodiment is designed to treat tumors and lesions that are at
> or below the skin surface by wearing the article of clothing
> over the target tissue so that the electric fields generated by
> the insulated electrodes are directed at the tumors (lesions,
> etc.).   
>   
> [0029] According to another embodiment, the apparatus is used in
> an internal type application in that the insulated electrodes
> are in the form of a probe or catheter etc. , that enter the
> body through natural pathways, such as the urethra or vagina, or
> are configured to penetrate living tissue; until the insulated
> electrodes are positioned near the internal target area (e.g.,
> an internal tumor).   
>   
> [0030] Thus, the present apparatus utilizes electric fields that
> fall into a special intermediate category relative to previous
> high and low frequency applications in that the present electric
> fields are bio-effective fields that have no meaningful
> stimulatory effects and no thermal effects. Advantageously, when
> non-dividing cells are subjected to these electric fields, there
> is no effect on the cells; however, the situation is much
> different when dividing cells are subjected to the present
> electric fields. Thus, the present electronic apparatus and the
> generated electric fields target dividing cells, such as tumors
> or the like, and do not target non-dividing cells that is found
> around in healthy tissue surrounding the target area.
> Furthermore, since the present apparatus utilizes insulated
> electrodes, the above mentioned negative effects, obtained when
> conductive electrodes are used, i. e., ion concentration changes
> in the cells and the formation of harmful agents by
> electrolysis, do not occur with the present apparatus. This is
> because, in general, no actual transfer of charges takes place
> between the electrodes and the medium, and there is no charge
> flow in the medium where the currents are capacitive.   
>   
> [0031] It should be appreciated that the present electronic
> apparatus can also be used in applications other than treatment
> of tumors in the living body. In fact, the selective destruction
> utilizing the present apparatus can be used in conjunction with
> any organism that proliferates by division, for example, tissue
> cultures, microorganisms, such as bacteria, mycoplasma,
> protozoa, fungi, algae, plant cells, etc. Such organisms divide
> by the formation of a groove or cleft as described above. As the
> groove or cleft deepens, a narrow bridge is formed between the
> two parts of the organism, similar to the bridge formed between
> the sub- cells of dividing animal cells. Since such organisms
> are covered by a membrane having a relatively low electric
> conductivity, similar to an animal cell membrane described
> above, the electric field lines in a dividing organism converge
> at the bridge connecting the two parts of the dividing organism.
> The converging field lines result in electric forces that
> displace polarizable elements and charges within the dividing
> organism.   
>   
> [0032] The above, and other objects, features and advantages of
> the present apparatus will become apparent from the following
> description read in conjunction with the accompanying drawings,
> in which like reference numerals designate the same elements.   
>   
> BRIEF DESCRIPTION OF THE
> DRAWINGS  
>   
> [0033] FIGS. 1A-1E are
> simplified, schematic, cross-sectional, illustrations of
> various stages of a cell division process;   
>   
> [0034] FIGS. 2A and 2B are
> schematic illustrations of a non-dividing cell being subjected
> to an electric field;   
>   
> [0035] FIGS. 3A, 3B and 3C are
> schematic illustrations of a dividing cell being subjected to
> an electric field according to one exemplary embodiment,
> resulting in destruction of the cell (FIG. 3C) in accordance
> with one exemplary embodiment;   
>   
> [0036] FIG. 4 is a schematic
> illustration of a dividing cell at one stage being subject to
> an electric field;   
>   
> [0037] FIG. 5 is a schematic
> block diagram of an apparatus for applying an electric
> according to one exemplary embodiment for selectively
> destroying cells;   
>   
> [0038] FIG. 6 is a simplified
> schematic diagram of an equivalent electric circuit of
> insulated electrodes of the apparatus of FIG. 5;   
>   
> [0039] FIG. 7 is a
> cross-sectional illustration of a skin patch incorporating the
> apparatus of FIG. 5 and for placement on a skin surface for
> treating a tumor or the like;   
>   
> [0040] FIG. 8 is a
> cross-sectional illustration of the insulated electrodes
> implanted within the body for treating a tumor or the like;   
>   
> [0041] FIG. 9 is a
> cross-sectional illustration of the insulated electrodes
> implanted within the body for treating a tumor or the like;   
>   
> [0042] FIGS. 10A-10D are
> cross-sectional illustrations of various constructions of the
> insulated electrodes of the apparatus of FIG. 5;  
>   
>  [0043] FIG. 11 is a front
> elevational view in partial cross-section of two insulated
> electrodes being arranged about a human torso for treatment of
> a tumor container within the body, e. g., a tumor associated
> with lung cancer;   
>   
> [0044] FIGS. 12A-12C are
> cross-sectional illustrations of various insulated electrodes
> with and without protective members formed as a part of the
> construction thereof;   
>   
> [0045] FIG. 13 is a schematic
> diagram of insulated electrodes that are arranged for focusing
> the electric field at a desired target while leaving other
> areas in low field density (i. e., protected areas);   
>   
> [0046] FIG. 14 is a
> cross-sectional view of insulated electrodes incorporated into
> a hat according to a first embodiment for placement on a head
> for treating an intra-cranial tumor or the like;  
>   
>  [0047] FIG. 15 is a
> partial section of a hat according to an exemplary embodiment
> having a recessed section for receiving one or more insulated
> electrodes;   
>   
> [0048] FIG. 16 is a
> cross-sectional view of the hat of FIG. 15 placed on a head
> and illustrating a biasing mechanism for applying a force to
> the insulated electrode to ensure the insulated electrode
> remains in contact against the head;   
>   
> [0049] FIG. 17 is a
> cross-sectional top view of an article of clothing having the
> insulated electrodes incorporated therein for treating a tumor
> or the like;   
>   
> [0050] FIG. 18 is a
> cross-sectional view of a section of the article of clothing
> of FIG. 17 illustrating a biasing mechanism for biasing the
> insulated electrode in direction to ensure the insulated
> electrode is placed proximate to a skin surface where
> treatment is desired;   
>   
> [0051] FIG. 19 is a
> cross-sectional view of a probe according to one embodiment
> for being disposed internally within the body for treating a
> tumor or the like;   
>   
> [0052] FIG. 20 is an
> elevational view of an unwrapped collar according to one
> exemplary embodiment for placement around a neck for treating
> a tumor or the like in this area when the collar is wrapped
> around the neck;   
>   
> [0053] FIG. 21 is a
> cross-sectional view of two insulated electrodes with
> conductive gel members being arranged about a body, with the
> electric field lines being shown;   
>   
> [0054] FIG. 22 is a
> cross-sectional view of the arrangement of FIG. 21
> illustrating a point of insulation breakdown in one insulated
> electrode;   
>   
> [0055] FIG. 23 is a
> cross-sectional view of an arrangement of at least two
> insulated electrodes with conductive gel members being
> arranged about a body for treatment of a tumor or the like,
> wherein each conductive gel member has a feature for
> minimizing the effects of an insulation breakdown in the
> insulated electrode;   
>   
> [0056] FIG. 24 is a cross-sectional view of another
> arrangement of at least two insulated electrodes with
> conductive gel members being arranged about a body for
> treatment of a tumor or the like, wherein a conductive member
> is disposed within the body near the tumor to create a region
> of increased field density;  
>   
> [0057] FIG. 25 is a cross-sectional view of an arrangement of
> two insulated electrodes of varying sizes disposed relative to
> a body; and   
>   
> [0058] FIG. 26 is a cross-sectional view of an arrangement of
> at least two insulated electrodes with conductive gel members
> being arranged about a body for treatment of a tumor or the
> like, wherein each conductive gel member has a feature for
> minimizing the effects of an insulation breakdown in the
> insulated electrode.   
>   
> [0059] FIGS. 27A-C show a configuration of electrodes that
> facilitates the application of an electric field in different
> directions.   
>   
> [0060] FIG. 28 shows a three-dimensional arrangement of
> electrodes about a body part that facilitates the application
> of an electric field in different directions.   
>   
> [0061] FIGS. 29A and 29B are graphs of the efficiency of the
> cell destruction process as a function of field strength for
> melanoma and glioma cells, respectively.   
>   
> [0062] FIGS. 30A and 30B are graphs that show how the cell
> destruction efficiency is a function of the frequency of the
> applied field for melanoma and glioma cells, respectively.   
>   
> [0063] FIG. 31A is a graphical representation of the
> sequential application of a plurality of frequencies in a
> plurality of directions.   
>   
> [0064] FIG. 31B is a graphical representation of the
> sequential application of a sweeping frequency in a plurality
> of directions.   
>   
> DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS   
>   
> [0065] Reference is made to FIGS. 1A-1E which
> schematically illustrate various stages of a cell division
> process. FIG. 1A illustrates a cell 10 at its normal geometry,
> which can be generally spherical (as illustrated in the
> drawings), ellipsoidal, cylindrical, "pancake- like" or any
> other cell geometry, as is known in the art. FIGS. 1B-1D
> illustrate cell 10 during different stages of its division
> process, which results in the formation of two new cells 18 and
> 20, shown in FIG. 1E. [0066] As shown in FIGS. 1B-1D, the
> division process of cell 10 is characterized by a slowly growing
> cleft 12 which gradually separates cell 10 into two units,
> namely sub-cells 14 and 16, which eventually evolve into new
> cells 18 and 20 (FIG. 1E). A shown specifically in FIG. 1D, the
> division process is characterized by a transient period during
> which the structure of cell 10 is basically that of the two
> sub-cells 14 and 16 interconnected by a narrow "bridge" 22
> containing cell material (cytoplasm surrounded by cell
> membrane). [0067] Reference is now made to FIGS. 2A and 2B,
> which schematically illustrate non-dividing cell 10 being
> subjected to an electric field produced by applying an
> alternating electric potential, at a relatively low frequency
> and at a relatively high frequency, respectively. Cell 10
> includes intracellular organelles, e. g., a nucleus 30.
> Alternating electric potential is applied across electrodes 28
> and 32 that can be attached externally to a patient at a
> predetermined region, e. g., in the vicinity of the tumor being
> treated. When cell 10 is under natural conditions, i. e., part
> of a living tissue, it is disposed in a conductive environment
> (hereinafter referred to as a "volume conductor") consisting
> mostly of electrolytic inter- cellular liquid. When an electric
> potential is applied across electrodes 28 and 32, some of the
> field lines of the resultant electric field (or the current
> induced in the tissue in response to the electric field)
> penetrate the cell 10, while the rest of the field lines (or
> induced current) flow in the surrounding medium. The specific
> distribution of the electric field lines, which is substantially
> consistent with the direction of current flow in this instance,
> depends on the geometry and the electric properties of the
> system components, e. g., the relative conductivities and
> dielectric constants of the system components, that can be
> frequency dependent. For low frequencies, e. g., frequencies
> lower than 10 KHz, the conductance properties of the components
> completely dominate the current flow and the field distribution,
> and the field distribution is generally as depicted in FIG. 2A.
> At higher frequencies, e. g., at frequencies of between 10 KHz
> and 1 MHz, the dielectric properties of the components becomes
> more significant and eventually dominate the field distribution,
> resulting in field distribution lines as depicted generally in
> FIG. 2B.  
>   
>  [0068] For constant (i. e., DC) electric fields or
> relatively low frequency alternating electric fields, for
> example, frequencies under 10 KHz, the dielectric properties of
> the various components are not significant in determining and
> computing the field distribution. Therefore, as a first
> approximation, with regard to the electric field distribution,
> the system can be reasonably represented by the relative
> impedances of its various components. Using this approximation,
> the intercellular (i. e., extracellular) fluid and the
> intracellular fluid each has a relatively low impedance, while
> the cell membrane 11 has a relatively high impedance. Thus,
> under low frequency conditions, only a fraction of the electric
> field lines (or currents induced by the electric field)
> penetrate membrane 11 of the cell 10. At relatively high
> frequencies (e. g., 10 KHz-1 MHz), in contrast, the impedance of
> membrane 11 relative to the intercellular and intracellular
> fluids decreases, and thus, the fraction of currents penetrating
> the cells increases significantly. It should be noted that at
> very high frequencies, i. e., above 1 MHz, the membrane
> capacitance can short the membrane resistance and, therefore,
> the total membrane resistance can become negligible.  
>   
>  [0069] In any of the embodiments described above, the
> electric field lines (or induced currents) penetrate cell 10
> from a portion of the membrane 11 closest to one of the
> electrodes generating the current, e. g., closest to positive
> electrode 28 (also referred to herein as "source"). The current
> flow pattern across cell 10 is generally uniform because, under
> the above approximation, the field induced inside the cell is
> substantially homogeneous. The currents exit cell 10 through a
> portion of membrane 11 closest to the opposite electrode, e.g.,
> negative electrode 32 (also referred to herein as "sink").   
>   
> [0070] The distinction between field lines and current flow can
> depend on a number of factors, for example, on the frequency of
> the applied electric potential and on whether electrodes 28 and
> 32 are electrically insulated. For insulated electrodes applying
> a DC or low frequency alternating voltage, there is practically
> no current flow along the lines of the electric field. At higher
> frequencies, the displacement currents are induced in the tissue
> due to charging and discharging of the electrode insulation and
> the cell membranes (which act as capacitors to a certain
> extent), and such currents follow the lines of the electric
> field. Fields generated by non-insulated electrodes, in
> contrast, always generate some form of current flow,
> specifically, DC or low frequency alternating fields generate
> conductive current flow along the field lines, and high
> frequency alternating fields generate both conduction and
> displacement currents along the field lines. It should be
> appreciated, however, that movement of polarizable intracellular
> organelles according to the present invention (as described
> below) is not dependent on actual flow of current and,
> therefore, both insulated and non-insulated electrodes can be
> used efficiently. Advantages of insulated electrodes include
> lower power consumption, less heating of the treated regions,
> and improved patient safety.   
>   
> [0071] According to one exemplary embodiment of the present
> invention, the electric fields that are used are alternating
> fields having frequencies that are in the range from about 50
> KHz to about 500 KHz, and preferably
> from about 100 KHz to about 300 KHz. For ease of
> discussion, these type of electric fields are also referred to
> below as "TC fields",
> which is an abbreviation of "Tumor Curing electric fields",
> since these electric fields fall into an intermediate category
> (between high and low frequency ranges) that have bio-effective
> field properties while having no meaningful stimulatory and
> thermal effects. These frequencies are sufficiently low so that
> the system behavior is determined by the system's Ohmic
> (conductive) properties but sufficiently high enough not to have
> any stimulation effect on excitable tissues. Such a system
> consists of two types of elements, namely, the intercellular, or
> extracellular fluid, or medium and the individual cells. The intercellular fluid is mostly
> an electrolyte with a specific resistance of about 40-100
> Ohm\*cm. As mentioned above, the cells are characterized
> by three elements, namely (1) a thin, highly electric resistive
> membrane that coats the cell; (2) internal cytoplasm that is
> mostly an electrolyte that contains numerous macromolecules and
> micro-organelles, including the nucleus; and (3) membranes,
> similar in their electric properties to the cell membrane, cover
> the micro-organelles.   
>   
> [0072] When this type of system is subjected to the present TC fields (e. g., alternating
> electric fields in the frequency range of 100 KHz-300 KHz) most
> of the lines of the electric field and currents tend away from
> the cells because of the high resistive cell membrane and
> therefore the lines remain in the extracellular conductive
> medium. In the above recited frequency range, the actual fraction of electric
> field or currents that penetrates the cells is a strong
> function of the frequency.   
>   
> [0073] FIG. 2 schematically depicts the resulting field
> distribution in the system. As illustrated, the lines of force,
> which also depict the lines of potential current flow across the
> cell volume mostly in parallel with the undistorted lines of
> force (the main direction of the electric field). In other
> words, the field inside the cells is mostly homogeneous. In
> practice, the fraction of the field or current that penetrates
> the cells is determined by the cell membrane impedance value
> relative to that of the extracellular fluid. Since the
> equivalent electric circuit of the cell membrane is that of a
> resistor and capacitor in parallel, the impedance is a function
> of the frequency. The higher the frequency, the lower the
> impedance, the larger the fraction of penetrating current and
> the smaller the field distortion (Rotshenker S. & Y. Palti,
> Changes infraction of current penetrating an axon as a function
> of duration of stimulating pulse, J. Theor. Biol. 41; 401-407
> (1973).   
>   
> [0074] As previously mentioned, when cells are subjected to
> relatively weak electric fields and currents that alternate at
> high frequencies, such as the present TC fields having a
> frequency in the range of 50 KHz-500 KHz, they have no effect on
> the non-dividing cells. While the present TC fields have no
> detectable effect on such systems, the situation becomes
> different in the presence of dividing cells.   
>   
> [0075] Reference is now made to FIGS. 3A-3C which schematically
> illustrate the electric current flow pattern in cell 10 during
> its division process, under the influence of alternating fields
> (TC fields) in the frequency range from about 100 KHz to about
> 300 KHz in accordance with one exemplary embodiment. The field
> lines or induced currents penetrate cell 10 through a part of
> the membrane of sub-cell 16 closer to electrode 28. However,
> they do not exit through the cytoplasm bridge 22 that connects
> sub-cell 16 with the newly formed yet still attached sub-cell
> 14, or through a part of the membrane in the vicinity of the
> bridge 22. Instead, the electric field or current flow
> lines--that are relatively widely separated in sub- cell
> 16--converge as they approach bridge 22 (also referred to as
> "neck" 22) and, thus, the current/field line density within neck
> 22 is increased dramatically. A "mirror image" process takes
> place in sub-cell 14, whereby the converging field lines in
> bridge 22 diverge as they approach the exit region of sub-cell
> 14.   
>   
> [0076] It should be appreciated by persons skilled in the art
> that homogeneous electric fields do not exert a force on
> electrically neutral objects, i. e., objects having
> substantially zero net charge, although such objects can become
> polarized. However, under a non-uniform, converging electric
> field, as shown in FIGS. 3A-3C, electric forces are exerted on
> polarized objects, moving them in the direction of the higher
> density electric field lines. It will be appreciated that the
> concentrated electric field that is present in the neck or
> bridge area in itself exerts strong forces on charges and
> natural dipoles and can disrupt structures that are associated
> therewith. One will understand that similar net forces act on
> charges in an alternating field, again in the direction of the
> field of higher intensity.   
>   
> [0077] In the configuration of FIGS. 3A and 3B, the direction of
> movement of polarized and charged objects is towards the higher
> density electric field lines, i. e., towards the cytoplasm
> bridge 22 between sub-cells 14 and 16. It is known in the art
> that all intracellular organelles, for example, nuclei 24 and 26
> of sub-cells 14 and 16, respectively, are polarizable and, thus,
> such intracellular organelles are electrically forced in the
> direction of the bridge 22. Since the movement is always from
> lower density currents to the higher density currents,
> regardless of the field polarity, the forces applied by the
> alternating electric field to organelles, such as nuclei 24 and
> 26, are always in the direction of bridge 22. A comprehensive
> description of such forces and the resulting movement of
> macromolecules of intracellular organelles, a phenomenon
> referred to as "dielectrophoresis" is described extensively in
> literature, e. g., in C. L. Asbury & G. van den Engh,
> Biophys. J. 74, 1024-1030, 1998, the disclosure of which is
> hereby incorporated by reference in its entirety.   
>   
> [0078] The movement of the organelles 24 and 26 towards the
> bridge 22 disrupts the structure of the dividing cell, change
> the concentration of the various cell constituents and,
> eventually, the pressure of the converging organelles on bridge
> membrane 22 results in the breakage of cell membrane 11 at the
> vicinity of the bridge 22, as shown schematically in FIG. 3C.
> The ability to break membrane 11 at bridge 22 and to otherwise
> disrupt the cell structure and organization can be enhanced by
> applying a pulsating AC electric field, rather than a steady AC
> field. When a pulsating field is applied, the forces acting on
> organelles 24 and 26 have a "hammering" effect, whereby pulsed
> forces beat on the intracellular organelles towards the neck 22
> from both sub-cells 14 and 16, thereby increasing the
> probability of breaking cell membrane 11 in the vicinity of neck
> 22.   
>   
> [0079] A very important element, which is very susceptible to
> the special fields that develop within the dividing cells is the
> microtubule spindle that plays a major role in the division
> process. In FIG. 4, a dividing cell 10 is illustrated, at an
> earlier stage as compared to FIGS. 3A and 3B, under the
> influence of external TC fields (e. g., alternating fields in
> the frequency range of about 100 KHz to about 300 KHz),
> generally indicated as lines 100, with a corresponding spindle
> mechanism generally indicated at 120. The lines 120 are
> microtubules that are known to have a very strong dipole moment.
> This strong polarization makes the tubules, as well as other
> polar macromolecules and especially those that have a specific
> orientation within the cells or its surrounding, susceptible to
> electric fields. Their positive charges are located at the two
> centrioles while two sets of negative poles are at the center of
> the dividing cell and the other pair is at the points of
> attachment of the microtubules to the cell membrane, generally
> indicated at 130. This structure forms sets of double dipoles
> and therefore they are susceptible to fields of different
> directions. It will be understood that the effect of the TC
> fields on the dipoles does not depend on the formation of the
> bridge (neck) and thus, the dipoles are influenced by the TC
> fields prior to the formation of the bridge (neck).   
>   
> [0080] Since the present apparatus (as will be described in
> greater detail below) utilizes insulated electrodes, the
> above-mentioned negative effects obtained when conductive
> electrodes are used, i. e., ion concentration changes in the
> cells and the formation of harmful agents by electrolysis, do
> not occur when the present apparatus is used. This is because,
> in general, no actual transfer of charges takes place between
> the electrodes and the medium and there is no charge flow in the
> medium where the currents are capacitive, i. e., are expressed
> only as rotation of charges, etc.   
>   
> [0081] Turning now to FIG. 5, the TC fields described above that
> have been found to advantageously destroy tumor cells are
> generated by an electronic apparatus 200. FIG. 5 is a simple
> schematic diagram of the electronic apparatus 200 illustrating
> the major components thereof. The electronic apparatus 200
> generates the desired electric signals (TC signals) in the shape
> of waveforms or trains of pulses. The apparatus 200 includes a
> generator 210 and a pair of conductive leads 220 that are
> attached at one end thereof to the generator 210. The opposite
> ends of the leads 220 are connected to insulated conductors 230
> that are activated by the electric signals (e. g., waveforms).
> The insulated conductors 230 are also referred to hereinafter as
> isolects 230. Optionally and according to another exemplary
> embodiment, the apparatus 200 includes a temperature sensor 240
> and a control box 250 which are both added to control the
> amplitude of the electric field generated so as not to generate
> excessive heating in the area that is treated.   
>   
> [0082] The generator 210 generates an alternating voltage
> waveform at frequencies in the range from about 50 KHz to about
> 500 KHz (preferably from about 100 KHz to about 300 KHz) (i. e.,
> the TC fields). The required voltages are such that the electric
> field intensity in the tissue to be treated is in the range of
> about 0.1 V/cm to about 10 V/cm. To achieve this field, the
> actual potential difference between the two conductors in the
> isolects 230 is determined by the relative impedances of the
> system components, as described below.   
>   
> [0083] When the control box 250 is included, it controls the
> output of the generator 210 so that it will remain constant at
> the value preset by the user or the control box 250 sets the
> output at the maximal value that does not cause excessive
> heating, or the control box 250 issues a warning or the like
> when the temperature (sensed by temperature sensor 240) exceeds
> a preset limit.  
>   
>  [0084] The leads 220 are standard isolated conductors with
> a flexible metal shield, preferably grounded so that it prevents
> the spread of the electric field generated by the leads 220. The
> isolects 230 have specific shapes and positioning so as to
> generate an electric field of the desired configuration,
> direction and intensity at the target volume and only there so
> as to focus the treatment.   
>   
> [0085] The specifications of the apparatus 200 as a whole and
> its individual components are largely influenced by the fact
> that at the frequency of the present TC fields (50 KHz-500 KHz),
> living systems behave according to their "Ohmic", rather than
> their dielectric properties. The only elements in the apparatus
> 200 that behave differently are the insulators of the isolects
> 230 (see FIGS. 7-9). The isolects 200 consist of a conductor in
> contact with a dielectric that is in contact with the conductive
> tissue thus forming a capacitor.  
>   
>  [0086] The details of the construction of the isolects 230
> is based on their electric behavior that can be understood from
> their simplified electric circuit when in contact with tissue as
> generally illustrated in FIG. 6. In the illustrated arrangement,
> the potential drop or the electric field distribution between
> the different components is determined by their relative
> electric impedance, i. e., the fraction of the field on each
> component is given by the value of its impedance divided by the
> total circuit impedance. For example, the potential drop on
> element A VA=A/(A+B+C+D+E). Thus, for DC or low frequency AC,
> practically all the potential drop is on the capacitor (that
> acts as an insulator). For relatively very high frequencies, the
> capacitor practically is a short and therefore, practically all
> the field is distributed in the tissues. At the frequencies of
> the present TC fields (e. g., 50 KHz to 500 KHz), which are
> intermediate frequencies, the impedance of the capacitance of
> the capacitors is dominant and determines the field
> distribution. Therefore, in order to increase the effective
> voltage drop across the tissues (field intensity), the impedance
> of the capacitors is to be decreased (i. e., increase their
> capacitance). This can be achieved by increasing the effective
> area of the "plates" of the capacitor, decrease the thickness of
> the dielectric or use a dielectric with high dielectric
> constant.   
>   
> [0087] In order to optimize the field distribution, the isolects
> 230 are configured differently depending upon the application in
> which the isolects 230 are to be used. There are two principle
> modes for applying the present electric fields (TC fields).
> First, the TC fields can be applied by external isolects and
> second, the TC fields can be applied by internal isolects.  
>   
>  [0088] Electric fields (TC fields) that are applied by
> external isolects can be of a local type or widely distributed
> type. The first type includes, for example, the treatment of
> skin tumors and treatment of lesions close to the skin surface.
> FIG. 7 illustrates an exemplary embodiment where the isolects
> 230 are incorporated in a skin patch 300. The skin patch 300 can
> be a self-adhesive flexible patch with one or more pairs of
> isolects 230. The patch 300 includes internal insulation 310
> (formed of a dielectric material) and the external insulation
> 260 and is applied to skin surface 301 that contains a tumor 303
> either on the skin surface 301 or slightly below the skin
> surface 301. Tissue is generally indicated at 305. To prevent
> the potential drop across the internal insulation 310 to
> dominate the system, the internal insulation 310 must have a
> relatively high capacity. This can be achieved by a large
> surface area; however, this may not be desired as it will result
> in the spread of the field over a large area (e. g., an area
> larger than required to treat the tumor). Alternatively, the
> internal insulation 310 can be made very thin and/or the
> internal insulation 310 can be of a high dielectric constant. As
> the skin resistance between the electrodes (labeled as A and E
> in FIG. 6) is normally significantly higher than that of the
> tissue (labeled as C in FIG. 6) underneath it (1-10 K# vs. 0.1-1
> K#), most of the potential drop beyond the isolects occurs
> there. To accommodate for these impedances (Z), the
> characteristics of the internal insulation 310 (labeled as B and
> D in FIG. 6) should be such that they have impedance preferably
> under 100 K# at the frequencies of the present TC fields (e. g.,
> 50 KHz to 500 KHz). For example, if it is desired for the
> impedance to be about 10 K Ohms or less, such that over 1% of
> the applied voltage falls on the tissues, for isolects with a
> surface area of 10 mm, at frequencies of 200 KHz, the capacity
> should be on the order of 10-10 F. , which means that using
> standard insulations with a dielectric constant of 2-3, the
> thickness of the insulating layer 310 should be about 50-100
> microns. An internal field 10 times stronger would be obtained
> with insulators with a dielectric constant of about 20-50.   
>   
> [0089] Using an insulating material with a high dielectric
> constant increases the capacitance of the electrodes, which
> results in a reduction of the electrodes' impedance to the AC
> signal that is applied by the generator 1 (shown in FIG. 5).
> Because the electrodes A, E are wired in series with the target
> tissue C, as shown in FIG. 6, this reduction in impedance
> reduces the voltage drop in the electrodes, so that a larger
> portion of the applied AC voltage appears across the tissue C.
> Since a larger portion of the voltage appears across the tissue,
> the voltage that is being applied by the generator 1 can be
> advantageously lowered for a given field strength in the tissue.
>   
>   
> [0090] The desired field strength in the tissue being treated is
> preferably between about 0.1 V/cm and about 10 V/cm, and more
> preferably between about 2 V/cm and 3 V/cm or between about 1
> V/cm and about 5 V/cm. If the dielectric constant used in the
> electrode is sufficiently high, the impedance of the electrodes
> A, E drops down to the same order of magnitude as the series
> combination of the skin and tissue B, C, D. One example of a
> suitable material with an extremely high dielectric constant is
> CaCu3Ti4O12, which has a dielectric constant of about 11,000
> (measured at 100 kHz). When the dielectric constant is this
> high, useful fields can be obtained using a generator voltage
> that is on the order of a few tens of Volts.   
>   
> [0091] Since the thin insulating layer can be very vulnerable,
> etc. , the insulation can be replaced by very high dielectric
> constant insulating materials, such as titanium dioxide (e. g.,
> rutile), the dielectric constant can reach values of about 200.
> There a number of different materials that are suitable for use
> in the intended application and have high dielectric constants.
> For example, some materials include: lithium niobate (LiNb03),
> which is a ferroelectric crystal and has a number of
> applications in optical, pyroelectric and piezoelectric devices;
> yttrium iron garnet (YIG) is a ferromagnetic crystal and
> magneto- optical devices, e. g., optical isolator can be
> realized from this material; barium titanate (BaTi03) is a
> ferromagnetic crystal with a large electro-optic effect;
> potassium tantalate (KTa03) which is a dielectric crystal
> (ferroelectric at low temperature) and has very low microwave
> loss and tunability of dielectric constant at low temperature;
> and lithium tantalate (LiTa03) which is a ferroelectric crystal
> with similar properties as lithium niobate and has utility in
> electro-optical, pyroelectric and piezoelectric devices.
> Insulator ceramics with high dielectric constants may also be
> used, such as a ceramic made of a combination of Lead Magnesium
> Niobate and Lead Titanate. It will be understood that the
> aforementioned exemplary materials can be used in combination
> with the present device where it is desired to use a material
> having a high dielectric constant.   
>   
> [0092] One must also consider another factor that affects the
> effective capacity of the isolects 230, namely the presence of
> air between the isolects 230 and the skin. Such presence, which
> is not easy to prevent, introduces a layer of an insulator with
> a dielectric constant of 1.0, a factor that significantly lowers
> the effective capacity of the isolects 230 and neutralizes the
> advantages of the titanium dioxide (rutile), etc. To overcome
> this problem, the isolects 230 can be shaped so as to conform
> with the body structure and/or (2) an intervening filler 270 (as
> illustrated in FIG. 10C), such as a gel, that has high
> conductance and a high effective dielectric constant, can be
> added to the structure. The shaping can be pre-structured (see
> FIG. 10A) or the system can be made sufficiently flexible so
> that shaping of the isolects 230 is readily achievable. The gel
> can be contained in place by having an elevated rim as depicted
> in FIGS. 10C and 10C'. The gel can be made of hydrogels,
> gelatins, agar, etc. , and can have salts dissolved in it to
> increase its conductivity. FIGS. 10A-10C' illustrate various
> exemplary configurations for the isolects 230. The exact
> thickness of the gel is not important so long as it is of
> sufficient thickness that the gel layer does not dry out during
> the treatment. In one exemplary embodiment, the thickness of the
> gel is about 0.5 mm to about 2 mm. Preferably, the gel has high
> conductivity, is tacky, and is biocompatible for extended
> periods of time. One suitable gel is AG603 Hydrogel, which is
> available from AmGel Technologies, 1667 S. Mission Road,
> Fallbrook, CA 92028-4115, USA.  
>   
>  [0093] In order to achieve the desirable features of the
> isolects 230, the dielectric coating of each should be very
> thin, for example from between 1-50 microns. Since the coating
> is so thin, the isolects 230 can easily be damaged mechanically
> or undergo dielectric breakdown. This problem can be overcome by
> adding a protective feature to the isolect's structure so as to
> provide desired protection from such damage. For example, the
> isolect 230 can be coated, for example, with a relatively loose
> net 340 that prevents access to the surface but has only a minor
> effect on the effective surface area of the isolect 230 (i. e.,
> the capacity of the isolects 230 (cross section presented in
> FIG. 12B). The loose net 340 does not effect the capacity and
> ensures good contact with the skin, etc. The loose net 340 can
> be formed of a number of different materials; however, in one
> exemplary embodiment, the net 340 is formed of nylon, polyester,
> cotton, etc. Alternatively, a very thin conductive coating 350
> can be applied to the dielectric portion (insulating layer) of
> the isolect 230. One exemplary conductive coating is formed of a
> metal and more particularly of gold. The thickness of the
> coating 350 depends upon the particular application and also on
> the type of material used to form the coating 350; however, when
> gold is used, the coating has a thickness from about 0.1 micron
> to about 0.1 mm. Furthermore, the rim illustrated in FIG. 10 can
> also provide some mechanical protection.   
>   
> [0094] However, the capacity is not the only factor to be
> considered. The following two factors also influence how the
> isolects 230 are constructed. The dielectric strength of the
> internal insulating layer 310 and the dielectric losses that
> occur when it is subjected to the TC field, i. e., the amount of
> heat generated. The dielectric strength of the internal
> insulation 310 determines at what field intensity the insulation
> will be "shorted" and cease to act as an intact insulation.
> Typically, insulators, such as plastics, have dielectric
> strength values of about 100V per micron or more. As a high
> dielectric constant reduces the field within the internal
> insulator 310, a combination of a high dielectric constant and a
> high dielectric strength gives a significant advantage. This can
> be achieved by using a single material that has the desired
> properties or it can be achieved by a double layer with the
> correct parameters and thickness. In addition, to further
> decreasing the possibility that the insulating layer 310 will
> fail, all sharp edges of the insulating layer 310 should be
> eliminated as by rounding the comers, etc., as illustrated in
> FIG. 10D using conventional techniques.   
>   
> [0095] FIGS. 8 and 9 illustrate a second type of treatment using
> the isolects 230, namely electric field generation by internal
> isolects 230. A body to which the isolects 230 are implanted is
> generally indicated at 311 and includes a skin surface 313 and a
> tumor 315. In this embodiment, the isolects 230 can have the
> shape of plates, wires or other shapes that can be inserted
> subcutaneously or a deeper location within the body 311 so as to
> generate an appropriate field at the target area (tumor 315).   
>   
> [0096] It will also be appreciated that the mode of isolects
> application is not restricted to the above descriptions. In the
> case of tumors in internal organs, for example, liver, lung,
> etc. , the distance between each member of the pair of isolects
> 230 can be large. The pairs can even by positioned opposite
> sides of a torso 410, as illustrated in FIG. 11. The arrangement
> of the isolects 230 in FIG. 11 is particularly useful for
> treating a tumor 415 associated with lung cancer or
> gastro-intestinal tumors. In this embodiment, the electric
> fields (TC fields) spread in a wide fraction of the body.   
>   
> [0097] In order to avoid overheating of the treated tissues, a
> selection of materials and field parameters is needed. The
> isolects insulating material should have minimal dielectric
> losses at the frequency ranges to be used during the treatment
> process. This factor can be taken into consideration when
> choosing the particular frequencies for the treatment. The
> direct heating of the tissues will most likely be dominated by
> the heating due to current flow (given by the I\*R product). In
> addition, the isolect (insulated electrode) 230 and its
> surroundings should be made of materials that facilitate heat
> losses and its general structure should also facilitate head
> losses, i. e., minimal structures that block heat dissipation to
> the surroundings (air) as well as high heat conductivity. Using
> larger electrodes also minimizes the local sensation of heating,
> since it spreads the energy that is being transferred into the
> patient over a larger surface area. Preferably, the heating is
> minimized to the point where the patient's skin temperature
> never exceeds about 39 C.   
>   
> [0098] Another way to reduce heating is to apply the field to
> the tissue being treated intermittently, by applying a field
> with a duty cycle between about 20% and about 50% instead of
> using a continuous field. For example, to achieve a duty cycle
> of 33%, the field would be repetitively switched on for one
> second, then switched off for two seconds. Preliminary
> experiments have shown that the efficacy of treatment using a
> field with a 33% duty cycle is roughly the same as for a field
> with a duty cycle of 100%. In alternative embodiments, the field
> could be switched on for one hour then switched off for one hour
> to achieve a duty cycle of 50%. Of course, switching at a rate
> of once per hour would not help minimize short-term heating. On
> the other hand, it could provide the patient with a welcome
> break from treatment.   
>   
> [0099] The effectiveness of the treatment can be enhanced by an
> arrangement of isolects 230 that focuses the field at the
> desired target while leaving other sensitive areas in low field
> density (i. e., protected areas). The proper placement of the
> isolects 230 over the body can be maintained using any number of
> different techniques, including using a suitable piece of
> clothing that keeps the isolects at the appropriate positions.
> FIG. 13 illustrates such an arrangement in which an area labeled
> as "P" represents a protected area. The lines of field force do
> not penetrate this protected area and the field there is much
> smaller than near the isolects 230 where target areas can be
> located and treated well. In contrast, the field intensity near
> the four poles is very high.   
>   
> [00100] The following Example serves to illustrate an exemplary
> application of the present apparatus and application of TC
> fields; however, this Example is not limiting and does not limit
> the scope of the present invention in any way.   
>   
> EXAMPLE   
>   
> [00101] To demonstrate the effectiveness of electric fields
> having the above described properties (e. g., frequencies
> between 50 KHz and 500 KHz) in destroying tumor cells, the
> electric fields were applied to treat mice with malignant
> melanoma tumors. Two pairs of isolects 230 were positioned over
> a corresponding pair of malignant melanomas. Only one pair was
> connected to the generator 210 and 200 KHz alternating electric
> fields (TC fields) were applied to the tumor for a period of 6
> days. One melanoma tumor was not treated so as to permit a
> comparison between the treated tumor and the non-treated tumor.
> After treatment for 6 days, the pigmented melanoma tumor
> remained clearly visible in the non-treated side of the mouse,
> while, in contrast, no tumor is seen on the treated side of the
> mouse. The only areas that were visible discemable on the skin
> were the marks that represented the points of insertion of the
> isolects 230. The fact that the tumor was eliminated at the
> treated side was further demonstrated by cutting and inversing
> the skin so that its inside face was exposed. Such a procedure
> indicated that the tumor has been substantially, if not
> completely, eliminated on the treated side of the mouse. The
> success of the treatment was also further verified by
> histopathological examination.   
>   
> [00102] The present inventor has thus uncovered that electric
> fields having particular properties can be used to destroy
> dividing cells or tumors when the electric fields are applied to
> using an electronic device. More specifically, these electric
> fields fall into a special intermediate category, namely
> bio-effective fields that have no meaningful stimulatory and no
> thermal effects, and therefore overcome the disadvantages that
> were associated with the application of conventional electric
> fields to a body. It will also be appreciated that the present
> apparatus can further include a device for rotating the TC field
> relative to the living tissue. For example and according to one
> embodiment, the alternating electric potential applies to the
> tissue being treated is rotated relative to the tissue using
> conventional devices, such as a mechanical device that upon
> activation, rotates various components of the present system.   
>   
> [00103] Moreover and according to yet another embodiment, the TC
> fields are applied to different pairs of the insulated
> electrodes 230 in a consecutive manner. In other words, the
> generator 210 and the control system thereof can be arranged so
> that signals are sent at periodic intervals to select pairs of
> insulated electrodes 230, thereby causing the generation of the
> TC fields of different directions by these insulated electrodes
> 230. Because the signals are sent at select times from the
> generator to the insulated electrodes 230, the TC fields of
> changing directions are generated consecutively by different
> insulated electrodes 230. This arrangement has a number of
> advantages and is provided in view of the fact that the TC
> fields have maximal effect when they are parallel to the axis of
> cell division. Since the orientation of cell division is in most
> cases random, only a fraction of the dividing cells are affected
> by any given field. Thus, using fields of two or more
> orientations increases the effectiveness since it increases the
> chances that more dividing cells are affected by a given TC
> field.   
>   
> [00104] In vitro experiments have shown that the electric field
> has the maximum killing effect when the lines of force of the
> field are oriented generally parallel to the long axis of the
> hourglass-shaped cell during mitosis (as shown in FIGS. 3A-3C).
> In one experiment, a much higher proportion of the damaged cells
> had their axis of division oriented along the field: 56% of the
> cells oriented at or near 0 with respect to the field were
> damaged, versus an average of 15% of cells damaged for cells
> with their long axis oriented at more than 22 with respect to
> the field.   
>   
> [00105] The inventor has recognized that applying the field in
> different directions sequentially will increase the overall
> killing power, because the field orientation that is most
> effectively in killing dividing cells will be applied to a
> larger population of the dividing cells. A number of examples
> for applying the field in different directions are discussed
> below.   
>   
> [00106] FIGS. 27A, 27B, and 27C show a set of 6 electrodes
> E1-E6, and how the direction of the field through the target
> tissue 1510 can be changed by applying the AC signal from the
> generator 1 (shown in FIG. 1) across different pairs of
> electrodes. For example, if the AC signal is applied across
> electrodes El and E4, the field lines F would be vertical (as
> shown in FIG. 27A), and if the signal is applied across
> electrodes E2 and E5, or across electrodes E3 and E6, the field
> lines F would be diagonal (as shown in FIGS. 27B and 27C,
> respectively). Additional field directions can be obtained by
> applying the AC signal across other pairs of electrodes. For
> example, a roughly horizontal field could be obtained by
> applying the signal across electrodes E2 and E6.   
>   
> [00107] In one embodiment, the AC signal is applied between the
> various pairs of electrodes sequentially. An example of this
> arrangement is to apply the AC signal across electrodes E1 and
> E4 for one second, then apply the AC signal across electrodes E2
> and E5 for one second, and then apply the AC signal across
> electrodes E3 and E6 for one second. This three-part sequence is
> then repeated for the desired period of treatment. Because the
> efficacy in cell-destruction is strongly dependant on the cell's
> orientation, cycling the field between the different directions
> increases the chance that the field will be oriented in a
> direction that favors cell destruction at least part of the
> time.   
>   
> [00108] Of course, the 6 electrode configuration shown in FIGS.
> 27A-C is just one of many possible arrangement of multiple
> electrodes, and many other configurations of three or more
> electrodes could be used based on the same principles.   
>   
> [00109] Application of the field in different directions
> sequentially is not limited to two dimensional embodiments, and
> FIG. 28 shows how the sequential application of signals across
> different sets of electrodes can be extended to three
> dimensions. A first array of electrodes Al-A9 is arranged around
> body part 1500, and a last array of electrodes N1-N9 is arranged
> around the body part 1500 a distance W away from the first
> array. Additional arrays of electrodes may optionally be added
> between the first array and the last array, but these additional
> arrays are not illustrated for clarity (so as not to obscure the
> electrodes A5- A9 and B5-B8 on the back of the body part 1500).
>   
>   
> [00110] As in the FIG. 27 embodiment, the direction of the field
> through the target tissue can be changed by applying the AC
> signal from the generator 1 (shown in FIG. 1) across different
> pairs of electrodes. For example, applying the AC signal between
> electrodes A2 and A7 would result in a field in a front-to-back
> direction between those two electrodes, and applying the AC
> signal between electrodes A5 and A9 would result in a roughly
> vertical field between those two electrodes. Similarly, applying
> the AC signal across electrodes A2 and N7 would generate
> diagonal field lines in one direction through the body part
> 1500, and applying the AC signal across electrodes A2 and B7
> would generate diagonal field lines in another direction through
> the body part.  
>   
>  [00111] Using a three-dimensional array of electrodes also
> makes it possible to energize multiple pairs of electrodes
> simultaneously to induce fields in the desired directions. For
> example, if suitable switching is provided so that electrodes A2
> through N2 are all connected to one terminal of the generator,
> and so that electrodes A7 through N7 are all connected to the
> other terminal of the generator, the resulting field would be a
> sheet that extends in a front-to-back direction for the entire
> width W. After the front-to-back field is maintained for a
> suitable duration (e. g., one second), the switching system (not
> shown) is reconfigured to connect electrodes A3 through N3 to
> one terminal of the generator, and electrodes A8 through N8 to
> the other terminal of the generator. This results in a sheet-
> shaped field that is rotated about the Z axis by about 40 with
> respect to the initial field direction. After the field is
> maintained in this direction for a suitable duration (e. g., one
> second), the next set of electrodes is activated to rotate the
> field an additional 40 to its next position. This continues
> until the field returns to its initial position, at which point
> the whole process is repeated.   
>   
> [00112] Optionally, the rotating sheet-shaped field may be added
> (sequentially in time) to the diagonal fields described above,
> to better target cells that are oriented along those diagonal
> axes.   
>   
> [00113] Because the electric field is a vector, the signals may
> optionally be applied to combinations of electrodes
> simultaneously in order to form a desired resultant vector. For
> example, a field that is rotated about the X axis by 20 with
> respect to the initial position can be obtained by switching
> electrodes A2 through N2 and A3 through N3 all to one terminal
> of the generator, and switching electrodes A7 through N7 and A8
> through N8 all to the other terminal of the generator. Applying
> the signals to other combinations of electrodes will result in
> fields in other directions, as will be appreciated by persons
> skilled in the relevant arts. If appropriate computer control of
> the voltages is implemented, the field's direction can even be
> swept through space in a continuous (i. e., smooth) manner, as
> opposed to the stepwise manner described above.   
>   
> [00114] FIGS. 29A and 29B depict the results of in vitro
> experiments that show how the killing power of the applied field
> against dividing cells is a function of the field strength. In
> the FIG. 29A experiment, B16F1 melanoma cells were subjected to
> a 100 kHz AC field at different field strengths, for a period of
> 24 hours at each strength. In the FIG. 29B experiment, F-98
> glioma cells were subjected to a 200 kHz AC field at different
> field strengths, for a period of 24 hours at each strength. In
> both of these figures, the strength of the field (EF) is
> measured in Volts per cm. The magnitude of the killing effect is
> expressed in terms of TER, which is which is the ratio of the
> decrease in the growth rate of treated cells (GRT) compared with
> the growth rate of control cells (GRc). EMI29.1 The experimental
> results show that the inhibitory effect of the applied field on
> proliferation increases with intensity in both the melanoma and
> the glioma cells. Complete proliferation arrest (TER = 1) is
> seen at 1.35 and 2.25 V/cm in melanoma and glioma cells,
> respectively.  
>   
>  [00115] FIGS. 30A and 30B depict the results of in vitro
> experiments that show how the killing power of the applied field
> is a function of the frequency of the field. In the experiments,
> B16F1 melanoma cells (FIG. 30A) and F-98 glioma cells (FIG. 30B)
> were subjected to fields with different frequencies, for a
> period of 24 hours at each frequency. FIGS. 30A and 30B show the
> change in the growth rate, normalized to the field intensity
> (TER/EF). Data are shown as mean + SE. In FIG. 30A, a window
> effect is seen with maximal inhibition at 120 kHz in melanoma
> cells. In FIG. 30B, two peaks are seen at 170 and 250 kHz. Thus,
> if only one frequency is available during an entire course of
> treatment, a field with a frequency of about 120 kHz would be
> appropriate for destroying melanoma cells, and a field with a
> frequency on the order of 200 kHz would be appropriate for
> destroying glioma cells.   
>   
> [00116] Not all the cells of any given type will have the exact
> same size. Instead, the cells will have a distribution of sizes,
> with some cells being smaller and some cells being larger. It is
> believed that the best frequency for damaging a particular cell
> is related to the physical characteristics (e. g., the size) of
> that particular cell. Thus, to best damage a population of cells
> with a distribution of sizes, it can be advantageous to apply a
> distribution of different frequencies to the population, where
> the selection of frequencies is optimized based on the expected
> size distribution of the target cells. For example, the data on
> FIG. 30B indicates that using
> two frequencies of 170 kHz and 250 kHz to destroy a population
> of glioma cells would be more effective than using a single
> frequency of 200 kHz.  
>   
>  [00117] Note that the optimal field strengths and
> frequencies discussed herein were obtained based on in vitro
> experiments, and that the corresponding parameters for in vivo
> applications may be obtained by performing similar experiments
> in vivo. It is possible that relevant characteristics of the
> cell itself (such as size and/or shape) or interactions with the
> cell's surroundings may result in a different set of optimal
> frequencies and/or field strengths for in vivo applications.  
>   
>  [00118] When more than one frequency is used, the various
> frequencies may be applied sequentially in time. For example, in
> the case of glioma, field frequencies of 100, 150,170, 200, 250,
> and 300 kHz may be applied during the first, second, third,
> fourth, fifth, and sixth minutes of treatment, respectively.
> That cycle of frequencies would then repeat during each
> successive six minutes of treatment. Alternatively, the
> frequency of the field may be swept in a stepless manner from
> 100 to 300 kHz.  
>   
>  [00119] Optionally, this frequency cycling may be combined
> with the directional cycling described above. FIG. 31A is an
> example of such a combination using three directions (D1, D2,
> and D3) and three frequencies (F1, F2, and F3). Of course, the
> same scheme can be extended to any other number of directions
> and/or frequencies. FIG. 31B is an example of such a combination
> using three directions (D1, D2, and D3), sweeping the frequency
> from 100 kHz to 300 kHz. Note
> that the break in the time axis between tl and t2 provides the
> needed time for the sweeping frequency to rise to just under 300
> kHz. The frequency sweeping (or stepping) may be synchronized
> with directional changes, as shown in FIG. 31A. Alternatively,
> the frequency sweeping (or stepping) may be asynchronous with
> respect to the directional changes, as shown in FIG. 31B.  
>   
>  [00120] In an alternative embodiment, a signal that
> contains two or more frequencies components simultaneously (e.
> g., 170 kHz and 250 kHz) is applied to the electrodes to treat a
> populations of cells that have a distribution of sizes. The
> various signals will add by superposition to create a field that
> includes all of the applied frequency components.  
>   
>  [00121] Turning now to FIG. 14 in which an article of
> clothing 500 according to one exemplary embodiment is
> illustrated. More specifically, the article of clothing 500 is
> in the form of a hat or cap or other type of clothing designed
> for placement on a head of a person. For purposes of
> illustration, a head 502 is shown with the hat 500 being placed
> thereon and against a skin surface 504 of the head 502. An
> intra-cranial tumor or the like 510 is shown as being formed
> within the head 502 underneath the skin surface 504 thereof. The
> hat 500 is therefore intended for placement on the head 502 of a
> person who has a tumor 510 or the like.  
>   
>  [00122] Unlike the various embodiments illustrated in
> FIGS. 1-13 where the insulated electrodes 230 are arranged in a
> more or less planar arrangement since they are placed either on
> a skin surface or embedded within the body underneath it, the
> insulated electrodes 230 in this embodiment are specifically
> contoured and arranged for a specific application. The treatment
> of intra-cranial tumors or other lesions or the like typically
> requires a treatment that is of a relatively long duration, e.
> g., days to weeks, and therefore, it is desirable to provide as
> much comfort as possible to the patient. The hat 500 is
> specifically designed to provide comfort during the lengthy
> treatment process while not jeopardizing the effectiveness of
> the treatment.  
>   
>  [00123] According to one exemplary embodiment, the hat 500
> includes a predetermined number of insulated electrodes 230 that
> are preferably positioned so as to produce the optimal TC fields
> at the location of the tumor 510. The lines of force of the TC
> field are generally indicated at 520. As can be seen in FIG. 14,
> the tumor 510 is positioned within these lines of force 520. As
> will be described in greater detail hereinafter, the insulated
> electrodes 230 are positioned within the hat 500 such that a
> portion or surface thereof is free to contact the skin surface
> 504 of the head 502. In other words, when the patient wears the
> hat 500, the insulated electrodes 230 are placed in contact with
> the skin surface 504 of the head 502 in positions that are
> selected so that the TC fields generated thereby are focused at
> the tumor 510 while leaving surrounding areas in low density.
> Typically, hair on the head 502 is shaved in selected areas to
> permit better contact between the insulated electrodes 230 and
> the skin surface 504; however, this is not critical.  
>   
>  [00124] The hat 500 preferably includes a mechanism 530
> that applies a force to the insulated electrodes 230 so that
> they are pressed against the skin surface 502. For example, the
> mechanism 530 can be of a biasing type that applies a biasing
> force to the insulated electrodes 230 to cause the insulated
> electrodes 230 to be directed outwardly away from the hat 500.
> Thus, when the patient places the hat 500 on his/her head 502,
> the insulated electrodes 230 are pressed against the skin
> surface 504 by the mechanism 530. The mechanism 530 can slightly
> recoil to provide a comfortable fit between the insulated
> electrodes 230 and the head 502. In one exemplary embodiment,
> the mechanism 530 is a spring based device that is disposed
> within the hat 500 and has one section that is coupled to and
> applies a force against the insulated electrodes 230.  
>   
>  [00125] As with the prior embodiments, the insulated
> electrodes 230 are coupled to the generator 210 by means of
> conductors 220. The generator 210 can be either disposed within
> the hat 500 itself so as to provide a compact, self-sufficient,
> independent system or the generator 210 can be disposed external
> to the hat 500 with the conductors 220 exiting the hat 500
> through openings or the like and then running to the generator
> 210. When the generator 210 is disposed external to the hat 500,
> it will be appreciated that the generator 210 can be located in
> any number of different locations, some of which are in close
> proximity to the hat 500 itself, while others can be further
> away from the hat 500. For example, the generator 210 can be
> disposed within a carrying bag or the like (e. g., a bag that
> extends around the patient's waist) which is worn by the patient
> or it can be strapped to an extremity or around the torso of the
> patient. The generator 210 can also be disposed in a protective
> case that is secured to or carried by another article of
> clothing that is worn by the patient. For example, the
> protective case can be inserted into a pocket of a sweater, etc.
> FIG. 14 illustrates an embodiment where the generator 210 is
> incorporated directly into the hat 500.  
>   
>  [00126] Turning now to FIGS. 15 and 16, in one exemplary
> embodiment, a number of insulated electrodes 230 along with the
> mechanism 530 are preferably formed as an independent unit,
> generally indicated at 540, that can be inserted into the hat
> 500 and electrically connected to the generator (not shown) via
> the conductors (not shown). By providing these members in the
> form of an independent unit, the patient can easily insert
> and/or remove the units 540 from the hat 500 when they may need
> cleaning, servicing and/or replacement.   
>   
> [00127] In this embodiment, the hat 500 is constructed to
> include select areas 550 that are formed in the hat 500 to
> receive and hold the units 540. For example and as illustrated
> in FIG. 15, each area 550 is in the form of an opening (pore)
> that is formed within the hat 500. The unit 540 has a body 542
> and includes the mechanism 530 and one or more insulated
> electrodes 230. The mechanism 530 is arranged within the unit
> 540 so that a portion thereof (e. g., one end thereof) is in
> contact with a face of each insulated electrode 230 such that
> the mechanism 530 applies a biasing force against the face of
> the insulated electrode 230. Once the unit 540 is received
> within the opening 550, it can be securely retained therein
> using any number of conventional techniques, including the use
> of an adhesive material or by using mechanical means. For
> example, the hat 500 can include pivotable clip members that
> pivot between an open position in which the opening 550 is free
> and a closed position in which the pivotable clip members engage
> portions (e. g., peripheral edges) of the insulated electrodes
> to retain and hold the insulated electrodes 230 in place. To
> remove the insulated electrodes 230, the pivotable clip members
> are moved to the open position. In the embodiment illustrated in
> FIG. 16, the insulated electrodes 230 are retained within the
> openings 550 by an adhesive element 560 which in one embodiment
> is a two sided self-adhesive rim member that extends around the
> periphery of the insulated electrode 230. In other words, a
> protective cover of one side of the adhesive rim 560 is removed
> and it is applied around the periphery of the exposed face of
> the insulated electrode 230, thereby securely attaching the
> adhesive rim 560 to the hat 500 and then the other side of the
> adhesive rim 560 is removed for application to the skin surface
> 504 in desired locations for positioning and securing the
> insulated electrode 230 to the head 502 with the tumor being
> positioned relative thereto for optimization of the TC fields.
> Since one side of the adhesive rim 560 is in contact with and
> secured to the skin surface 540, this is why it is desirable for
> the head 502 to be shaved so that the adhesive rim 560 can be
> placed flushly against the skin surface 540.   
>   
> [00128] The adhesive rim 560 is designed to securely attach the
> unit 540 within the opening 550 in a manner that permits the
> unit 540 to be easily removed from the hat 500 when necessary
> and then replaced with another unit 540 or with the same unit
> 540. As previously mentioned, the unit 540 includes the biasing
> mechanism 530 for pressing the insulated electrode 230 against
> the skin surface 504 when the hat 500 is worn. The unit 540 can
> be constructed so that side opposite the insulated electrode 230
> is a support surface formed of a rigid material, such as
> plastic, so that the biasing mechanism 530 (e. g., a spring) can
> be compressed therewith under the application of force and when
> the spring 530 is in a relaxed state, the spring 530 remains in
> contact with the support surface and the applies a biasing force
> at its other end against the insulated electrode 230. The
> biasing mechanism 530 (e. g., spring) preferably has a contour
> corresponding to the skin surface 504 so that the insulated
> electrode 230 has a force applied thereto to permit the
> insulated electrode 230 to have a contour complementary to the
> skin surface 504, thereby permitting the two to seat flushly
> against one another. While the mechanism 530 can be a spring,
> there are a number of other embodiments that can be used instead
> of a spring. For example, the mechanism 530 can be in the form
> of an elastic material, such as a foam rubber, a foam plastic,
> or a layer containing air bubbles, etc.   
>   
> [00129] The unit 540 has an electric connector 570 that can be
> hooked up to a corresponding electric connector, such as a
> conductor 220, that is disposed within the hat 500. The
> conductor 220 connects at one end to the unit 540 and at the
> other end is connected to the generator 210. The generator 210
> can be incorporated directly into the hat 500 or the generator
> 210 can be positioned separately (remotely) on the patient or on
> a bedside support, etc. [00130] As previously discussed, a
> coupling agent, such as a conductive gel, is preferably used to
> ensure that an effective conductive environment is provided
> between the insulated electrode 230 and the skin surface 504.
> Suitable gel materials have been disclosed hereinbefore in the
> discussion of earlier embodiments. The coupling agent is
> disposed on the insulated electrode 230 and preferably, a
> uniform layer of the agent is provided along the surface of the
> electrode 230. One of the reasons that the units 540 need
> replacement at periodic times is that the coupling agent needs
> to be replaced and/or replenished. In other words, after a
> predetermined time period or after a number of uses, the patient
> removes the units 540 so that the coupling agent can be applied
> again to the electrode 230.  
>   
>  [00131] FIGS. 17 and 18 illustrate another article of
> clothing which has the insulated electrodes 230 incorporated as
> part thereof. More specifically, a bra or the like 700 is
> illustrated and includes a body that is formed of a traditional
> bra material, generally indicated at 705, to provide shape,
> support and comfort to the wearer. The bra 700 also includes a
> fabric support layer 710 on one side thereof. The support layer
> 710 is preferably formed of a suitable fabric material that is
> constructed to provide necessary and desired support to the bra
> 700.   
>   
> [00132] Similar to the other embodiments, the bra 700 includes
> one or more insulated electrodes 230 disposed within the bra
> material 705. The one or more insulated electrodes are disposed
> along an inner surface of the bra 700 opposite the support 710
> and are intended to be placed proximate to a tumor or the like
> that is located within one breast or in the immediately
> surrounding area. As with the previous embodiment, the insulated
> electrodes 230 in this embodiment are specifically constructed
> and configured for application to a breast or the immediate
> area. Thus, the insulated electrodes 230 used in this
> application do not have a planar surface construction but rather
> have an arcuate shape that is complementary to the general
> curvature found in a typical breast.   
>   
> [00133] A lining 720 is disposed across the insulated electrodes
> 230 so as to assist in retaining the insulated electrodes in
> their desired locations along the inner surface for placement
> against the breast itself. The lining 720 can be formed of any
> number of thin materials that are comfortable to wear against
> one's skin and in one exemplary embodiment, the lining 720 is
> formed of a fabric material. [00134] The bra 700 also preferably
> includes a biasing mechanism 800 as in some of the earlier
> embodiments. The biasing mechanism 800 is disposed within the
> bra material 705 and extends from the support 710 to the
> insulated electrode 230 and applies a biasing force to the
> insulated electrode 230 so that the electrode 230 is pressed
> against the breast. This ensures that the insulated electrode
> 230 remains in contact with the skin surface as opposed to
> lifting away from the skin surface, thereby creating a gap that
> results in a less effective treatment since the gap diminishes
> the efficiency of the TC fields. The biasing mechanism 800 can
> be in the form of a spring arrangement or it can be an elastic
> material that applies the desired biasing force to the insulated
> electrodes 230 so as to press the insulated electrodes 230 into
> the breast. In the relaxed position, the biasing mechanism 800
> applies a force against the insulated electrodes 230 and when
> the patient places the bra 700 on their body, the insulated
> electrodes 230 are placed against the breast which itself
> applies a force that counters the biasing force, thereby
> resulting in the insulated electrodes 230 being pressed against
> the patient's breast. In the exemplary embodiment that is
> illustrated, the biasing mechanism 800 is in the form of springs
> that are disposed within the bra material 705.   
>   
> [00135] A conductive gel 810 can be provided on the insulated
> electrode 230 between the electrode and the lining 720. The
> conductive gel layer 810 is formed of materials that have been
> previously described herein for performing the functions
> described above.   
>   
> [00136] An electric connector 820 is provided as part of the
> insulated electrode 230 and electrically connects to the
> conductor 220 at one end thereof, with the other end of the
> conductor 220 being electrically connected to the generator 210.
> In this embodiment, the conductor 220 runs within the bra
> material 705 to a location where an opening is formed in the bra
> 700. The conductor 220 extends through this opening and is
> routed to the generator 210, which in this embodiment is
> disposed in a location remote from the bra 700. It will also be
> appreciated that the generator 210 can be disposed within the
> bra 700 itself in another embodiment. For example, the bra 700
> can have a compartment formed therein which is configured to
> receive and hold the generator 210 in place as the patient wears
> the bra 700. In this arrangement, the compartment can be covered
> with a releasable strap that can open and close to permit the
> generator 210 to be inserted therein or removed therefrom. The
> strap can be formed of the same material that is used to
> construct the bra 700 or it can be formed of some other type of
> material. The strap can be releasably attached to the
> surrounding bra body by fastening means, such as a hook and loop
> material, thereby permitting the patient to easily open the
> compartment by separating the hook and loop elements to gain
> access to the compartment for either inserting or removing the
> generator 210.  
>   
>  [00137] The generator 210 also has a connector 211 for
> electrical connection to the conductor 220 and this permits the
> generator 210 to be electrically connected to the insulated
> electrodes 230  
>   
>  [00138] As with the other embodiments, the insulated
> electrodes 230 are arranged in the bra 700 to focus the electric
> field (TC fields) on the desired target (e. g., a tumor). It
> will be appreciated that the location of the insulated
> electrodes 230 within the bra 700 will vary depending upon the
> location of the tumor. In other words, after the tumor has been
> located, the physician will then devise an arrangement of
> insulated electrodes 230 and the bra 700 is constructed in view
> of this arrangement so as to optimize the effects of the TC
> fields on the target area (tumor). The number and position of
> the insulated electrodes 230 will therefore depend upon the
> precise location of the tumor or other target area that is being
> treated. Because the location of the insulated electrodes 230 on
> the bra 700 can vary depending upon the precise application, the
> exact size and shape of the insulated electrodes 230 can
> likewise vary. For example, if the insulated electrodes 230 are
> placed on the bottom section of the bra 700 as opposed to a more
> central location, the insulated electrodes 230 will have
> different shapes since the shape of the breast (as well as the
> bra) differs in these areas.  
>   
>  [00139] FIG. 19 illustrates yet another embodiment in
> which the insulated electrodes 230 are in the form of internal
> electrodes that are incorporated into in the form of a probe or
> catheter 600 that is configured to enter the body through a
> natural pathway, such as the urethra, vagina, etc. In this
> embodiment, the insulated electrodes 230 are disposed on an
> outer surface of the probe 600 and along a length thereof. The
> conductors 220 are electrically connected to the electrodes 230
> and run within the body of the probe 600 to the generator 210
> which can be disposed within the probe body or the generator 210
> can be disposed independent of the probe 600 in a remote
> location, such as on the patient or at some other location close
> to the patient.  
>   
>  [00140] Alternatively, the probe 600 can be configured to
> penetrate the skin surface or other tissues to reach an internal
> target that lies within the body. For example, the probe 600 can
> penetrate the skin surface and then be positioned adjacent to or
> proximate to a tumor that is located within the body.  
>   
>  [00141] In these embodiments, the probe 600 is inserted
> through the natural pathway and then is positioned in a desired
> location so that the insulated electrodes 230 are disposed near
> the target area (i. e., the tumor). The generator 210 is then
> activated to cause the insulated electrodes 230 to generate the
> TC fields which are applied to the tumor for a predetermined
> length of time. It will be appreciated that the illustrated
> probe 600 is merely exemplary in nature and that the probe 600
> can have other shapes and configurations so long as they can
> perform the intended function. Preferably, the conductors (e.
> g., wires) leading from the insulated electrodes 230 to the
> generator 210 are twisted or shielded so as not to generate a
> field along the shaft.  
>   
>  [00142] It will further be appreciated that the probes can
> contain only one insulated electrode while the other can be
> positioned on the body surface. This external electrode should
> be larger or consist of numerous electrodes so as to result in
> low lines of force-current density so as not to affect the
> untreated areas. In fact, the placing of electrodes should be
> designed to minimize the field at potentially sensitive areas.
> Optionally, the external electrodes may be held against the skin
> surface by a vacuum force (e.g., suction).  
>   
>  [00143] FIG. 20 illustrates yet another embodiment in
> which a high standing collar member 900 (or necklace type
> structure) can be used to treat thyroid, parathyroid, laryngeal
> lesions, etc. FIG. 20 illustrates the collar member 900 in an
> unwrapped, substantially flat condition. In this embodiment, the
> insulated electrodes 230 are incorporated into a body 910 of the
> collar member 900 and are configured for placement against a
> neck area of the wearer. The insulated electrodes 230 are
> coupled to the generator 210 according to any of the manner
> described hereinbefore and it will be appreciated that the
> generator 210 can be disposed within the body 910 or it can be
> disposed in a location external to the body 910. The collar body
> 910 can be formed of any number of materials that are
> traditionally used to form collars 900 that are disposed around
> a person's neck. As such, the collar 900 preferably includes a
> means 920 for adjusting the collar 900 relative to the neck. For
> example, complementary fasteners (hook and loop fasteners,
> buttons, etc. ) can be disposed on ends of the collar 900 to
> permit adjustment of the collar diameter.  
>   
>  [00144] Thus, the construction of the present devices are
> particularly well suited for applications where the devices are
> incorporated into articles of clothing to permit the patient to
> easily wear a traditional article of clothing while at the same
> time the patient undergoes treatment. In other words, an extra
> level of comfort can be provided to the patient and the
> effectiveness of the treatment can be increased by incorporating
> some or all of the device components into the article of
> clothing. The precise article of clothing that the components
> are incorporated into will obviously vary depending upon the
> target area of the living tissue where tumor, lesion or the like
> exists. For example, if the target area is in the testicle area
> of a male patient, then an article of clothing in the form of a
> sock-like structure or wrap can be provided and is configured to
> be worn around the testicle area of the patient in such a manner
> that the insulated electrodes thereof are positioned relative to
> the tumor such that the TC fields are directed at the target
> tissue. The precise nature or form of the article of clothing
> can vary greatly since the device components can be incorporated
> into most types of articles of clothing and therefore, can be
> used to treat any number of different areas of the patient's
> body where a condition may be present.  
>   
>  [00145] Now turning to FIGS. 21-22 in which another aspect
> of the present device is shown. In FIG. 21, a body 1000, such as
> any number of parts of a human or animal body, is illustrated.
> As in the previous embodiments, two or more insulated electrodes
> 230 are disposed in proximity to the body 1000 for treatment of
> a tumor or the like (not shown) using TC fields, as has been
> previously described in great detail in the above discussion of
> other embodiments. The insulated electrode 230 has a conductive
> component and has external insulation 260 that surrounds the
> conductive component thereof. Each insulated electrode 230 is
> preferably connected to a generator (not shown) by the lead 220.
> Between each insulated electrode 220 and the body 1000, a
> conductive filler material (e. g., conductive gel member 270) is
> disposed. The insulated electrodes 230 are spaced apart from one
> another and when the generator is actuated, the insulated
> electrodes 230 generate the TC fields that have been previously
> described in great detail. The lines of the electric field (TC
> field) are generally illustrated at 1010. As shown, the electric
> field lines 1010 extend between the insulated electrodes 230 and
> through the conductive gel member 270.   
>   
> [00146] Over time or as a result of some type of event, the
> external insulation 260 of the insulated electrode 230 can begin
> to breakdown at any given location thereof. For purpose of
> illustration only, FIG. 22 illustrates that the external
> insulation 260 of one of the insulated electrodes 230 has
> experienced a breakdown 1020 at a face thereof which is adjacent
> the conductive gel member 270. It will be appreciated that the
> breakdown 1020 of the external insulation 260 results in the
> formation of a strong current flow-current density at this point
> (i. e., at the breakdown 1020). The increased current density is
> depicted by the increased number of electric field lines 1010
> and the relative positioning and distance between adjacent
> electric field lines 1010. One of the side effects of the
> occurrence of breakdown 1020 is that current exists at this
> point which will generate heat and may burn the tissues/skin
> which have a resistance. In FIG. 22, an overheated area 1030 is
> illustrated and is a region or area of the tissues/skin where an
> increased current density exits due to the breakdown 1020 in the
> external insulation 260. A patient can experience discomfort and
> pain in this area 1030 due to the strong current that exists in
> the area and the increased heat and possible burning sensation
> that exist in area 1030.  
>   
> [00147] FIG. 23 illustrates yet another embodiment in which a
> further application of the insulated electrodes 230 is shown. In
> this embodiment, the conductive gel member 270 that is disposed
> between the insulated electrode 230 and the body 1000 includes a
> conductor 1100 that is floating in that the gel material forming
> the member 270 completely surrounds the conductor 1100. In one
> exemplary embodiment, the conductor 1100 is a thin metal sheet
> plate that is disposed within the conductor 1100. As will be
> appreciated,,if a conductor, such as the plate 1100, is placed
> in a homogeneous electric field, normal to the lines of the
> electric field, the conductor 1100 practically has no effect on
> the field (except that the two opposing faces of the conductor
> 1100 are equipotential and the corresponding equipotentials are
> slightly shifted). Conversely, if the conductor 1100 is disposed
> parallel to the electric field, there is a significant
> distortion of the electric field. The area in the immediate
> proximity of the conductor 1100 is not equipotential, in
> contrast to the situation where there is no conductor 1100
> present. When the conductor 1100 is disposed within the gel
> member 270, the conductor 1100 will typically not effect the
> electric field (TC field) for the reasons discussed above,
> namely that the conductor 1100 is normal to the lines of the
> electric field.  
>   
>  [00148] If there is a breakdown of the external insulation
> 260 of the insulated electrode 230, there is a strong current
> flow-current density at the point of breakdown as previously
> discussed; however, the presence of the conductor 1100 causes
> the current to spread throughout the conductor 1100 and then
> exit from the whole surface of the conductor 1100 so that the
> current reaches the body 1000 with a current density that is
> neither high nor low. Thus, the current that reaches the skin
> will not cause discomfort to the patient even when there has
> been a breakdown in the insulation 260 of the insulated
> electrode 230. It is important that the conductor 1100 is not
> grounded as this would cause it to abolish the electric field
> beyond it. Thus, the conductor 1100 is "floating" within the gel
> member 270.  
>   
>  [00149] If the conductor 1100 is introduced into the body
> tissues 1000 and is not disposed parallel to the electric field,
> the conductor 1100 will cause distortion of the electric field.
> The distortion can cause spreading of the lines of force (low
> field density-intensity) or concentration of the lines of field
> (higher density) of the electric field, according to the
> particular geometries of the insert and its surroundings, and
> thus, the conductor 1100 can exhibit, for example, a screening
> effect. Thus, for example, if the conductor 1100 completely
> encircles an organ 1101, the electric field in the organ itself
> will be zero since this type of arrangement is a Faraday cage.
> However, because it is impractical for a conductor to be
> disposed completely around an organ, a conductive net or similar
> structure can be used to cover, completely or partially, the
> organ, thereby resulting in the electric field in the organ
> itself being zero or about zero. For example, a net can be made
> of a number of conductive wires that are arranged relative to
> one another to form the net or a set of wires can be arranged to
> substantially encircle or otherwise cover the organ 1101.
> Conversely, an organ 1103 to be treated (the target organ) is
> not covered with a member having a Faraday cage effect but
> rather is disposed in the electric field 1010 (TC fields).  
>   
>  [00150] FIG. 24 illustrates an embodiment where the
> conductor 1100 is disposed within the body (i. e., under the
> skin) and it is located near a target (e. g., a target organ).
> By placing the conductor 1100 near the target, high field
> density (of the TC fields) is realized at the target. At the
> same time, another nearby organ can be protected by disposing
> the above described protective conductive net or the like around
> this nearby organ so as to protect this organ from the fields.
> By positioning the conductor 1100 in close proximity to the
> target, a high field density condition can be provided near or
> at the target. In other words, the conductor 1100 permits the TC
> fields to be focused at a particular area (i. e., a target).  
>   
>  [00151] It will also be appreciated that in the embodiment
> of FIG. 24, the gel members 260 can each include a conductor as
> described with reference to FIG. 23. In such an arrangement, the
> conductor in the gel member 260 protects the skin surface
> (tissues) from any side effects that may be realized if a
> breakdown in the insulation of the insulated electrode 230
> occurs. At the same time, the conductor 1100 creates a high
> field density near the target.   
>   
> [00152] There are a number of different ways to tailor the field
> density of the electric field by constructing the electrodes
> differently and/or by strategically placing the electrodes
> relative to one another. For example, in FIG. 25, a first
> insulated electrode 1200 and a second insulated electrode 1210
> are provided and are disposed about a body 1300. Each insulated
> electrode includes a conductor that is preferably surrounded by
> an insulating material, thus the term "insulated electrode".
> Between each of the first and second electrodes 1200, 1210 and
> the body 1300, the conductive gel member 270 is provided.
> Electric field lines are generally indicated at 1220 for this
> type of arrangement. In this embodiment, the first insulated
> electrode 1200 has dimensions that are significantly greater
> than the dimensions of the second insulated electrode 1210 (the
> conductive gel member for the second insulated electrode 1210
> will likewise be smaller).  
>   
>  [00153] By varying the dimensions of the insulated
> electrodes, the pattern of the electric field lines 1220 is
> varied. More specifically, the electric field tapers inwardly
> toward the second insulated electrode 1210 due to the smaller
> dimensions of the second insulated electrode 1210. An area of
> high field density, generally indicated at 1230, forms near the
> interface between the gel member 270 associated with the second
> insulated electrode 1210 and the skin surface. The various
> components of the system are manipulated so that the tumor
> within the skin or on the skin is within this high field density
> so that the area to be treated (the target) is exposed to
> electric field lines of a higher field density.  
>   
>  [00154] FIG. 26 also illustrates a tapering TC field when
> a conductor 1400 (e.g., a conductive plate) is disposed in each
> of the conductive gel members 270. In this embodiment, the size
> of the gel members 270 and the size of the conductors 1400 are
> the same or about the same despite the differences in the sizes
> of the insulated electrodes 1200, 1210. The conductors 1400
> again can be characterized as "floating plates" since each
> conductor 1400 is surrounded by the material that forms the gel
> member 270. As shown in FIG. 26, the placement of one conductor
> 1400 near the insulated electrode 1210 that is smaller than the
> other insulated electrode 1200 and is also smaller than the
> conductor 1400 itself and the other insulated electrode 1200 is
> disposed at a distance therefrom, the one conductor 1400 causes
> a decrease in the field density in the tissues disposed between
> the one conductor 1400 and the other insulated electrode 1200.
> The decrease in the field density is generally indicated at
> 1410. At the same time, a very inhomogeneous tapering field,
> generally indicated at 1420, changing from very low density to
> very high density is formed between the one conductor 1400 and
> the insulated electrode 1210. One benefit of this exemplary
> configuration is that it permits the size of the insulated
> electrode to be reduced without causing an increase in the
> nearby field density. This can be important since electrodes
> that having very high dielectric constant insulation can be very
> expensive. Some insulated electrodes, for example, can cost
> $500.00 or more; and further, the price is sensitive to the
> particular area of treatment. Thus, a reduction in the size of
> the insulated electrodes directly leads to a reduction in cost.
> [00155] As used herein, the term "tumor" refers to a malignant
> tissue comprising transformed cells that grow uncontrollably.
> Tumors include leukemias, lymphomas, myelomas, plasmacytomas,
> and the like; and solid tumors. Examples of solid tumors that
> can be treated according to the invention include sarcomas and
> carcinomas such as, but not limited to: fibrosarcoma,
> myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma,
> chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
> lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's
> tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma,
> pancreatic cancer, breast cancer, ovarian cancer, prostate
> cancer, squamous cell carcinoma, basal cell carcinoma,
> adenocarcinoma, sweat gland carcinoma, sebaceous gland
> carcinoma, papillary carcinoma, papillary adenocarcinomas,
> cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma,
> renal cell carcinoma, hepatoma, bile duct carcinoma,
> choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,
> cervical cancer, testicular tumor, lung carcinoma, small cell
> lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma,
> astrocytoma, medulloblastoma, craniopharyngioma, ependymoma,
> pinealoma, hemangioblastoma, acoustic neuroma,
> oligodendroglioma, meningioma, melanoma, neuroblastoma, and
> retinoblastoma. Because each of these tumors undergoes rapid
> growth, any one can be treated in accordance with the invention.
> The invention is particularly advantageous for treating brain
> tumors, which are difficult to treat with surgery and radiation,
> and often inaccessible to chemotherapy or gene therapies. In
> addition, the present invention is suitable for use in treating
> skin and breast tumors because of the ease of localized
> treatment provided by the present invention. [00156] In
> addition, the present invention can control uncontrolled growth
> associated with non-malignant or pre-malignant conditions, and
> other disorders involving inappropriate cell or tissue growth by
> application of an electric field in accordance with the
> invention to the tissue undergoing inappropriate growth. For
> example, it is contemplated that the invention is useful for the
> treatment of arteriovenous (AV) malformations, particularly in
> intracranial sites. The invention may also be used to treat
> psoriasis, a dermatologic condition that is characterized by
> inflammation and vascular proliferation; and benign prostatic
> hypertrophy, a condition associated with inflammation and
> possibly vascular proliferation. Treatment of other
> hyperproliferative disorders is also contemplated. [00157]
> Furthermore, undesirable fibroblast and endothelial cell
> proliferation associated with wound healing, leading to scar and
> keloid formation after surgery or injury, and restenosis after
> angioplasty or placement of coronary stents can be inhibited by
> application of an electric field in accordance with the present
> invention. The non-invasive nature of this invention makes it
> particularly desirable for these types of conditions,
> particularly to prevent development of internal scars and
> adhesions, or to inhibit restenosis of coronary, carotid, and
> other important arteries. [00158] In addition to treating tumors
> that have already been detected, the above- described
> embodiments may also be used prophylactically to prevent tumors
> from ever reaching a detectable size in the first place. For
> example, the bra embodiment described above in connection with
> FIGS. 17 and 18 may be worn by a woman for an 8 hour session
> every day for a week, with the week-long course of treatment
> being repeated every few months to kill any cells that have
> become cancerous and started to proliferate. This mode of usage
> is particularly appropriate for people who are at high risk for
> a particular type of cancer (e. g., women with a strong history
> of breast cancer in their families, or people who have survived
> a bout of cancer and are at risk of a relapse). The course of
> prophylactic treatment may be tailored based on the type of
> cancer being targeted and/or to suit the convenience of the
> patient. For example, undergoing a four 16 hour sessions during
> the week of treatment may be more convenient for some patients
> than seven 8 hour session, and may be equally effective. [00159]
> Thus, the present invention provides an effective, simple method
> of selectively destroying dividing cells, e. g., tumor cells and
> parasitic organisms, while non-dividing cells or organisms are
> left affected by application of the method on living tissue
> containing both types of cells or organisms. Thus, unlike many
> of the conventional methods, the present invention does not
> damage the normal cells or organisms. In addition, the present
> invention does not discriminate based upon cell type (e. g.,
> cells having differing sizes) and therefore may be used to treat
> any number of types of sizes having a wide spectrum of
> characteristics, including varying dimensions. [00160] While the
> invention has been particularly shown and described with
> reference to preferred embodiments thereof, it will be
> understood by those skilled in the art that various changes in
> form and details can be made without departing from the spirit
> and scope of the invention. ==   
>   
>
>
> ---
>
>   
>
> Apparatus for destroying dividing cells   
> US2004068295
>
>   
> TECHNICAL FIELD   
>   
> [0001]   
>   
> This invention concerns selective destruction of rapidly
> dividing cells, and more particularly, to an apparatus for
> selectively destroying dividing cells by applying an electric
> field having certain prescribed characteristics.   
>   
> BACKGROUND   
>   
> [0002] All living organisms proliferate by cell division,
> including cell cultures, microorganisms (such as bacteria,
> mycoplasma, yeast, protozoa, and other single-celled organisms),
> fungi, algae, plant cells, etc. Dividing cells of organisms can
> be destroyed, or their proliferation controlled, by methods that
> are based on the sensitivity of the dividing cells of these
> organisms to certain agents. For example, certain antibiotics
> stop the multiplication process of bacteria.   
>   
> [0003] The process of eukaryotic cell division is called
> "mitosis", which involves nice distinct phases (see Darnell et
> al., Molecular Cell Biology, New York: Scientific American
> Books, 1986, p. 149). During interphase, the cell replicates
> chromosomal DNA, which begins condensing in early prophase. At
> this point, centrioles (each cell contains 2) begin moving
> towards opposite poles of the cell. In middle prophase, each
> chromosome is composed of duplicate chromatids. Microtubular
> spindles radiate from regions adjacent to the centrioles, which
> are closer to their poles. By late prophase, the centrioles have
> reached the poles, and some spindle fibers extend to the center
> of the cell, while others extend from the poles to the
> chromatids. The cells then move into metaphase, when the
> chromosomes move toward the equator of the cell and align in the
> equatorial plane. Next is early anaphase, during which time
> daughter chromatids separate from each other at the equator by
> moving along the spindle fibers toward a centromere at opposite
> poles. The cell begins to elongate along the axis of the pole;
> the pole-to-pole spindles also elongate. Late anaphase occurs
> when the daughter chromosomes (as they are not called) each
> reach their respective opposite poles. At this point,
> cytokinesis begins as the cleavage furrow begins to form at the
> equator of the cell. In other words, late anaphase is the point
> at which pinching the cell membrane begins. During telophase,
> cytokinesis is nearly complete and spindles disappear. Only a
> relatively narrow membrane connection joins the two cytoplasms.
> Finally, the membranes separate fully, cytokinesis is complete
> and the cell returns to interphase.   
>   
> [0004] In meisosis, the cell undergoes a second division,
> involving separation of sister chromosomes to opposite poles of
> the cell along spindle fibers, followed by formation of a
> cleavage furrow and cell division. However, this division is not
> preceded by chromosome replication, yielding a haploid germ
> cell.   
>   
> [0005] Bacteria also divide by chromosome replication, followed
> by cell separation. However, since the daughter chromosomes
> separate by attachment to membrane components; there is no
> visible apparatus that contributes to cell division as in
> eukaryotic cells.   
>   
> [0006] It is well known that tumors, particularly malignant or
> cancerous tumors, grow uncontrollably compared to normal tissue.
> Such expedited growth enables tumors to occupy an
> ever-increasing space and to damage or destroy tissue adjacent
> thereto. Furthermore, certain cancers are characterized by an
> ability to transmit cancerous "seeds", including single cells or
> small cell clusters (metastasises), to new locations where the
> messastatic cancer cells grow into additional tumors.   
>   
> [0007] The rapid growth of tumors, in general, and malignant
> tumors in particular, as described above, is the result of
> relatively frequent cell division or multiplication of these
> cells compared to normal tissue cells. The distinguishably
> frequent cell division of cancer cells is the basis for the
> effectiveness of existing cancer treatments, e.g., irradiation
> therapy and the use of various chemo-therapeutic agents. Such
> treatments are based on the fact that cells undergoing division
> are more sensitive to radiation and chemo-therapeutic agents
> than non-dividing cells. Because tumors cells divide much more
> frequently than normal cells, it is possible, to a certain
> extent, to selectively damage or destroy tumor cells by
> radiation therapy and/or chemotherapy. The actual sensitivity of
> cells to radiation, therapeutic agents, etc., is also dependent
> on specific characteristics of different types of normal or
> malignant cell types. Thus, unfortunately, the sensitivity of
> tumor cells is not sufficiently higher than that many types of
> normal tissues. This diminishes the ability to distinguish
> between tumor cells and normal cells, and therefore, existing
> cancer treatments typically cause significant damage to normal
> tissues, thus limiting the therapeutic effectiveness of such
> treatments. Furthermore, the inevitable damage to other tissue
> renders treatments very traumatic to the patients and, often,
> patients are unable to recover from a seemingly successful
> treatment. Also, certain types of tumors are not sensitive at
> all to existing methods of treatment.   
>   
> [0008] There are also other methods for destroying cells that do
> not rely on radiation therapy or chemotherapy alone. For
> example, ultrasonic and electrical methods for destroying tumor
> cells can be used in addition to or instead of conventional
> treatments. Electric fields and currents have been used for
> medical purposes for many years. The most common is the
> generation of electric currents in a human or animal body by
> application of an electric field by means of a pair of
> conductive electrodes between which a potential difference is
> maintained. These electric currents are used either to exert
> their specific effects, i.e., to stimulate excitable tissue, or
> to generate heat by flowing in the body since it acts as a
> resistor. Examples of the first type of application include the
> following: cardiac defibrillators, peripheral nerve and muscle
> stimulators, brain stimulators, etc. Currents are used for
> heating, for example, in devices for tumor ablation, ablation of
> malfunctioning cardiac or brain tissue, cauterization,
> relaxation of muscle rheumatic pain and other pain, etc.   
>   
> [0009] Another use of electric fields for medical purposes
> involves the utilization of high frequency oscillating fields
> transmitted from a source that emits an electric wave, such as
> an RF wave or a microwave source that is directed at the part of
> the body that is of interest (i.e., target). In these instances,
> there is no electric energy conduction between the source and
> the body; but rather, the energy is transmitted to the body by
> radiation or induction. More specifically, the electric energy
> generated by the source reaches the vicinity of the body via a
> conductor and is transmitted from it through air or some other
> electric insulating material to the human body.   
>   
> [0010] In a conventional electrical method, electrical current
> is delivered to a region of the target tissue using electrodes
> that are placed in contact with the body of the patient. The
> applied electrical current destroys substantially all cells in
> the vicinity of the target tissue. Thus, this type of electrical
> method does not discriminate between different types of cells
> within the target tissue and results in the destruction of both
> tumor cells and normal cells.   
>   
> [0011] Electric fields that can be used in medical applications
> can thus be separated generally into two different modes. In the
> first mode, the electric fields are applied to the body or
> tissues by means of conducting electrodes. These electric fields
> can be separated into two types, namely (1) steady fields or
> fields that change at relatively slow rates, and alternating
> fields of low frequencies that induce corresponding electric
> currents in the body or tissues, and (2) high frequency
> alternating fields (above 1 MHz) applied to the body by means of
> the conducting electrodes. In the second mode, the electric
> fields are high frequency alternating fields applied to the body
> by means of insulated electrodes.   
>   
> [0012] The first type of electric field is used, for example, to
> stimulate nerves and muscles, pace the heart, etc. In fact, such
> fields are used in nature to propagate signals in nerve and
> muscle fibers, central nervous system (CNS), heart, etc. The
> recording of such natural fields is the basis for the ECG, EEG,
> EMG, ERG, etc. The field strength in these applications,
> assuming a medium of homogenous electric properties, is simply
> the voltage applied to the stimulating/recording electrodes
> divided by the distance between them. These currents can be
> calculated by Ohm's law and can have dangerous stimulatory
> effects on the heart and CNS and can result in potentially
> harmful ion concentration changes. Also, if the currents are
> strong enough, they can cause excessive heating in the tissues.
> This heating can be calculated by the power dissipated in the
> tissue (the product of the voltage and the current).   
>   
> [0013] When such electric fields and currents are alternating,
> their stimulatory power, on nerve, muscle, etc., is an inverse
> function of the frequency. At frequencies above 1-10 KHz, the
> stimulation power of the fields approaches zero. This limitation
> is due to the fact that excitation induced by electric
> stimulation is normally mediated by membrane potential changes,
> the rate of which is limited by the RC properties (time
> constants on the order of 1 ms) of the membrane. [0014]
> Regardless of the frequency, when such current inducing fields
> are applied, they are associated with harmful side effects
> caused by currents. For example, one negative effect is the
> changes in ionic concentration in the various "compartments"
> within the system, and the harmful products of the electrolysis
> taking place at the electrodes, or the medium in which the
> tissues are imbedded. The changes in ion concentrations occur
> whenever the system includes two or more compartments between
> which the organism maintains ion concentration differences. For
> example, for most tissues, [Ca<++>] in the extracellular
> fluid is about 2\*10<-3 >M, while in the cytoplasm of
> typical cells its concentration can be as low as 10<-7 >M.
> A current induced in such a system by a pair of electrodes,
> flows in part from the extracellular fluid into the cells and
> out again into the extracellular medium. About 2% of the current
> flowing into the cells is carried by the Ca<++> ions. In
> contrast, because the concentration of intracellular
> Ca<++> is much smaller, only a negligible fraction of the
> currents that exits the cells is carried by these ions. Thus,
> Ca<++> ions accumulate in the cells such that their
> concentrations in the cells increases, while the concentration
> in the extracellular compartment may decrease. These effects are
> observed for both DC and alternating currents (AC). The rate of
> accumulation of the ions depends on the current intensity ion
> mobilities, membrane ion conductance, etc. An increase in
> [Ca<++>] is harmful to most cells and if sufficiently high
> will lead to the destruction of the cells. Similar
> considerations apply to other ions. In view of the above
> observations, long term current application to living organisms
> or tissues can result in significant damage. Another major
> problem that is associated with such electric fields, is due to
> the electrolysis process that takes place at the electrode
> surfaces. Here charges are transferred between the metal
> (electrons) and the electrolytic solution (ions) such that
> charged active radicals are formed. These can cause significant
> damage to organic molecules, especially macromolecules and thus
> damage the living cells and tissues.   
>   
> [0015] In contrast, when high frequency electric fields, above 1
> MHz and usually in practice in the range of GHz, are induced in
> tissues usually by means of insulated electrodes or transmission
> of e.m. waves, the situation is quite different. These type of
> fields generate only capacitive or displacement currents, rather
> than the conventional charge conducting currents. Under the
> effect of this type of field, living tissues behave mostly
> according to their dielectric properties rather than their
> electric conductive properties. Therefore, the dominant field
> effect is that due to dielectric losses and heating. Thus, it is
> widely accepted that in practice, the meaningful effects of such
> fields on living organisms, are only those due to their heating
> effects, i.e., due to dielectric losses.   
>   
> [0016] In U.S. Pat. No. 6,043,066 ('066) to Mangano, a method
> and device are presented which enable discrete objects having a
> conducting inner core, surrounded by a dielectric membrane to be
> selectively inactivated by electric fields via irreversible
> breakdown of their dielectric membrane. One potential
> application for this is in the selection and purging of certain
> biological cells in a suspension. According to the '066 patent,
> an electric field is applied for targeting selected cells to
> cause breakdown of the dielectric membranes of these tumor
> cells, while purportedly not adversely affecting other desired
> subpopulations of cells. The cells are selected on the basis of
> intrinsic or induced differences in a characteristic
> electroporation threshold. The differences in this threshold can
> depend upon a number of parameters, including the difference in
> cell size.   
>   
> [0017] The method of the '066 patent is therefore based on the
> assumption that the electroporation threshold of tumor cells is
> sufficiently distinguishable from that of normal cells because
> of differences in cell size and differences in the dielectric
> properties of the cell membranes. Based upon this assumption,
> the larger size of many types of tumor cells makes these cells
> more susceptible to electroporation and thus, it may be possible
> to selectively damage only the larger tumor cell membranes by
> applying an appropriate electric field. One disadvantage of this
> method is that the ability to discriminate is highly dependent
> upon cell type, for example, the size difference between normal
> cells and tumor cells is significant only in certain types of
> cells. Another drawback of this method is that the voltages
> which are applied can damage some of the normal cells and may
> not damage all of the tumor cells because the differences in
> size and membrane dielectric properties are largely statistical
> and the actual cell geometries and dielectric properties can
> vary significantly.   
>   
> [0018] What is needed in the art and has heretofore not been
> available is an apparatus for killing dividing cells, wherein
> the apparatus better discriminates between dividing cells,
> including single-celled organisms, and non-dividing cells and is
> capable of selectively destroying the dividing cells or
> organisms with substantially no affect on the non-dividing cells
> or organisms.   
>   
> SUMMARY   
>   
> [0019] An apparatus for use in a number of different
> applications for selectively destroying cells undergoing growth
> and division is provided. This includes, cell, particularly
> tumor cells, in living tissue and single-celled organisms. The
> apparatus can be incorporated into a number of different
> configurations (e.g., as a skin patch or embedded internally
> within the body) to eliminate or control the growth of such
> living tissue or organisms.   
>   
> [0020] A major use of the present apparatus is in the treatment
> of tumors by selective destruction of tumor cells with
> substantially no affect on normal tissue cells, and thus, the
> exemplary apparatus is described below in the context of
> selective destruction of tumor cells. It should be appreciated
> however, that for purpose of the following description, the term
> "cell" may also refer to a single-celled organism (eubacteria,
> bacteria, yeast, protozoa), multi-celled organisms (fungi,
> algae, mold), and plants as or parts thereof that are not
> normally classified as "cells". The exemplary apparatus enables
> selective destruction of cells undergoing division in a way that
> is more effective and more accurate (e.g., more adaptable to be
> aimed at specific targets) than existing methods. Further, the
> present apparatus causes minimal damage, if any, to normal
> tissue and, thus, reduces or eliminates many side-effects
> associated with existing selective destruction methods, such as
> radiation therapy and chemotherapy. The selective destruction of
> dividing cells using the present apparatus does not depend on
> the sensitivity of the cells to chemical agents or radiation.
> Instead, the selective destruction of dividing cells is based on
> distinguishable geometrical and structural characteristics of
> cells undergoing division, in comparison to non-dividing cells,
> regardless of the cell geometry of the type of cells being
> treated.   
>   
> [0021] According to one exemplary embodiment, cell
> geometry-dependent selective destruction of living tissue is
> performed by inducing a non-homogenous electric field in the
> cells using an electronic apparatus.   
>   
> [0022] It has been observed by the present inventor that, while
> different cells in their non-dividing state may have different
> shapes, e.g., spherical, ellipsoidal, cylindrical,
> "pancake-like", etc., the division process of practically all
> cells is characterized by development of a "cleavage furrow" in
> late anaphase and telophase. This cleavage furrow is a slow
> constriction of the cell membrane (between the two sets of
> daughter chromosomes) which appears microscopically as a growing
> cleft (e.g., a groove or notch) that gradually separates the
> cell into two new cells. During the division process, there is a
> transient period (telophase) during which the cell structure is
> basically that of two sub-cells interconnected by a narrow
> "bridge" formed of the cell material. The division process is
> completed when the "bridge" between the two sub-cells is broken.
> The selective destruction of tumor cells using the present
> electronic apparatus utilizes this unique geometrical feature of
> dividing cells.   
>   
> [0023] When a cell or a group of cells are under natural
> conditions or environment, i.e., part of a living tissue, they
> are disposed surrounded by a conductive environment consisting
> mostly of an electrolytic inter-cellular fluid and other cells
> that are composed mostly of an electrolytic intra-cellular
> liquid. When an electric field is induced in the living tissue,
> by applying an electric potential across the tissue, an electric
> field is formed in the tissue and the specific distribution and
> configuration of the electric field lines defines the paths of
> electric currents in the tissue, if currents are in fact induced
> in the tissue. The distribution and configuration of the
> electric field is dependent on various parameters of the tissue,
> including the geometry and the electric properties of the
> different tissue components, and the relative conductivities,
> capacities and dielectric constants (that may be frequency
> dependent) of the tissue components.   
>   
> [0024] The electric current flow pattern for cells undergoing
> division is very different and unique as compared to
> non-dividing cells. Such cells including first and second
> sub-cells, namely an "original" cell and a newly formed cell,
> that are connected by a cytoplasm "bridge" or "neck". The
> currents penetrate the first sub-cell through part of the
> membrane ("the current source pole"); however, they do not exit
> the first sub-cell through a portion of its membrane closer to
> the opposite pole ("the current sink pole"). Instead, the lines
> of current flow converge at the neck or cytoplasm bridge,
> whereby the density of the current flow lines is greatly
> increased. A corresponding, "mirror image", process that takes
> place in the second sub-cell, whereby the current flow lines
> diverge to a lower density configuration as they depart from the
> bridge, and finally exit the second sub-cell from a part of its
> membrane closes to the current sink.   
>   
> [0025] When a polar or a polarizable object is placed in a
> non-uniform converging or diverging field, electric forces act
> on it and pull it towards the higher density electric field
> lines. In the case of dividing cell, electric forces are exerted
> in the direction of the cytoplasm bridge between the two cells.
> Since all intercellular organelles are polarizable, and most
> macromolecules are polar (have a dipole moment) they are all
> force towards the bridge between the two cells. The field
> polarity is irrelevant to the direction of the force and,
> therefore, an alternating electric having specific properties
> can be used to produce substantially the same effect. It will
> also be appreciated that the concentrated electric field present
> in or near the bridge or neck portion in itself exerts strong
> forces on charges and natural dipoles and can lead to the
> disruption of structures associated with these members.   
>   
> [0026] The movement of the cellular organelles towards the
> bridge disrupts the cell structure and results in increased
> pressure in the vicinity of the connecting bridge membrane. This
> pressure of the organelles on the bridge membrane is expected to
> break the bridge membrane and, thus, it is expected that the
> dividing cell will "explode" in response to this pressure. The
> ability to break the membrane and disrupt other cell structures
> can be enhanced by applying a pulsating alternating electric
> field that has a frequency from about 50 KHz to about 500 KHz.
> When this type of electric field is applied to the tissue, the
> forces exerted on the intercellular organelles have a
> "hammering" effect, whereby force pulses (or beats) are applied
> to the organelles numerous times per second, enhancing the
> movement of organelles of different sizes and masses towards the
> bridge (or neck) portion from both of the sub-cells, thereby
> increasing the probability of breaking the cell membrane at the
> bridge portion. The forces exerted on the intracellular
> organelles also affect the organelles themselves and may
> collapse or break the organelles.   
>   
> [0027] According to one exemplary embodiment, the apparatus for
> applying the electric field is an electronic apparatus that
> generates the desired electric signals in the shape of waveforms
> or trains of pulses. The electronic apparatus includes a
> generator that generates an alternating voltage waveform at
> frequencies in the range from about 50 KHz to about 500 KHz. The
> generator is operatively connected to conductive leads which are
> connected at their other ends to insulated conductors/electrodes
> (also referred to as isolects) that are activated by the
> generated waveforms. The insulated electrodes consist of a
> conductor in contact with a dielectric (insulating layer) that
> is in contact with the conductive tissue, thus forming a
> capacitor. The electric fields that are generated by the present
> apparatus can be applied in several different modes depending
> upon the precise treatment application.   
>   
> [0028] In one exemplary embodiment, the electric fields are
> applied by external insulated electrodes which are constructed
> so that the applied electric fields can be of a local type or of
> a widely distributed type. This embodiment is designed to treat
> skin tumors and lesions that are close to the skin surface.
> According to this embodiment, the insulated electrodes can be
> incorporated into a skin patch that is applied to a skin
> surface. The skin patch can be a self-adhesive flexible patch
> and can include one or more pairs of the insulated electrodes.   
>   
> [0029] According to another embodiment, the apparatus is used in
> an internal type application in that the insulated electrodes
> are in the form of plates, wires, etc., that are inserted
> subcutaneously or deeper within the body so as to generate an
> electric field having the above desired properties at a target
> area (e.g., a tumor).   
>   
> [0030] Thus, the present apparatus utilizes electric fields that
> fall into a special intermediate category relative to previous
> high and low frequency applications in that the present electric
> fields are bio-effective fields that have no meaningful
> stimulatory effects and no thermal effects. Advantageously, when
> non-dividing cells are subjected to these electric fields, there
> is no effect on the cells; however, the situation is much
> different when dividing cells are subjected to the present
> electric fields. Thus, the present electronic apparatus and the
> generated electric fields target dividing cells, such as tumors
> or the like, and do not target non-dividing cells that is found
> around in healthy tissue surrounding the target area.
> Furthermore, since the present apparatus utilizes insulated
> electrodes, the above mentioned negative effects, obtained when
> conductive electrodes are used, i.e., ion concentration changes
> in the cells and the formation of harmful agents by
> electrolysis, do not occur with the present apparatus. This is
> because, in general, no actual transfer of charges takes place
> between the electrodes and the medium, and there is no charge
> flow in the medium where the currents are capacitive.   
>   
> [0031] It should be appreciated that the present electronic
> apparatus can also be used in applications other than treatment
> of tumors in the living body. In fact, the selective destruction
> utilizing the present apparatus can be used in conjunction with
> any organism that proliferates division and multiplication, for
> example, tissue cultures, microorganisms, such as bacteria,
> mycoplasma, protozoa, fungi, algae, plant cells, etc. Such
> organisms divide by the formation of a groove or cleft as
> described above. As the groove or cleft deepens, a narrow bridge
> is formed between the two parts of the organism, similar to the
> bridge formed between the sub-cells of dividing animal cells.
> Since such organisms are covered by a membrane having a
> relatively low electric conductivity, similar to an animal cell
> membrane described above, the electric field lines in a dividing
> organism converge at the bridge connecting the two parts of the
> dividing organism. The converging field lines result in electric
> forces that displace polarizable elements within the dividing
> organism.   
>   
> [0032] The above, and other objects, features and advantages of
> the present apparatus will become apparent from the following
> description read in conjunction with the accompanying drawings,
> in which like reference numerals designate the same elements.   
>   
> BRIEF DESCRIPTION OF THE
> DRAWING FIGURES   
>   
>   
>   
> [0033] FIGS. 1A-1E are
> simplified, schematic, cross-sectional, illustrations of
> various stages of a cell division process;   
>   
> [0034] FIGS. 2A and 2B are
> schematic illustrations of a non-dividing cell being subjected
> to an electric field;   
>   
> [0035] FIGS. 3A, 3B and 3C are
> schematic illustrations of a dividing cell being subjected to
> an electric field according to one exemplary embodiment,
> resulting in destruction of the cell (FIG. 3C) in accordance
> with one exemplary embodiment;   
>   
> [0036] FIG. 4 is a schematic
> illustration of a dividing cell at one stage being subject to
> an electric field;   
>   
> [0037] FIG. 5 is a schematic
> diagram of an apparatus for applying an electric according to
> one exemplary embodiment for selectively destroying cells;   
>   
> [0038] FIG. 6 is a simplified
> schematic diagram of an equivalent electric circuit of
> insulated electrodes of the apparatus of FIG. 5;   
>   
> [0039] FIG. 7 is a schematic
> illustration of a skin patch incorporating the apparatus of
> FIG. 5 and for placement on a skin surface for treating a
> tumor or the like;  
>   
> [0040] FIG. 8 is a schematic
> illustration of the insulated electrodes implanted within the
> body for treating a tumor or the like;   
>   
> [0041] FIG. 9 is a schematic
> illustration of the insulated electrodes implanted within the
> body for treating a tumor or the like;   
>   
> [0042] FIGS. 10A-10D are
> schematic illustrations of various constructions of the
> insulated electrodes of the apparatus of FIG. 5;   
>   
> [0043] FIG. 11 is a schematic
> illustration of two insulated electrodes being arranged about
> a human torso for treatment of a tumor container within the
> body, e.g., a tumor associated with lung cancer;   
>   
> [0044] FIGS. 12A-12C are
> schematic illustrations of various insulated electrodes with
> and without protective members formed as a part of the
> construction thereof; and   
>   
> [0045] FIG. 13 is a schematic
> illustration of insulated electrodes that are arranged for
> focusing the electric field at a desired target while leaving
> other areas in low field density (i.e., protected areas).   
>   
> DETAILED DESCRIPTION OF
> PREFERRED EMBODIMENTS   
>   
> [0046] Reference is made to FIGS. 1A-1E which schematically
> illustrate various stages of a cell division process. FIG. 1A
> illustrates a cell 10 at its normal geometry, which can be
> generally spherical (as illustrated in the drawings),
> ellipsoidal, cylindrical, "pancake-like" or any other cell
> geometry, as is known in the art. FIGS. 1B-1D illustrate cell 10
> during different stages of its division process, which results
> in the formation of two new cells 18 and 20, shown in FIG. 1E.   
>   
> [0047] As shown in FIGS. 1B-1D, the division process of cell 10
> is characterized by a slowly growing cleft 12 which gradually
> separates cell 10 into two units, namely sub-cells 14 and 16,
> which eventually evolve into new cells 18 and 20 (FIG. 1E). A
> shown specifically in FIG. 1D, the division process is
> characterized by a transient period during which the structure
> of cell 10 is basically that of the two sub-cells 14 and 16
> interconnected by a narrow "bridge" 22 containing cell material
> (cytoplasm surrounded by cell membrane). [0048] Reference is now
> made to FIGS. 2A and 2B, which schematically illustrate
> non-dividing cell 10 being subjected to an electric field
> produced by applying an alternating electric potential, at a
> relatively low frequency and at a relatively high frequency,
> respectively. Cell 10 includes intracellular organelles, e.g., a
> nucleus 30. Alternating electric potential is applied across
> electrodes 28 and 32 that can be attached externally to a
> patient at a predetermined region, e.g., in the vicinity of the
> tumor being treated. When cell 10 is under natural conditions,
> i.e., part of a living tissue, it is disposed in a conductive
> environment (hereinafter referred to as a "volume conductor")
> consisting mostly of electrolytic inter-cellular liquid. When an
> electric potential is applied across electrodes 28 and 32, some
> of the field lines of the resultant electric field (or the
> current induced in the tissue in response to the electric field)
> penetrate the cell 10, while the rest of the field lines (or
> induced current) flow in the surrounding medium. The specific
> distribution of the electric field lines, which is substantially
> consistent with the direction of current flow in this instance,
> depends on the geometry and the electric properties of the
> system components, e.g., the relative conductivities and
> dielectric constants of the system components, that can be
> frequency dependent. For low frequencies, e.g., frequencies
> lower than 10 KHz, the conductance properties of the components
> completely dominate the current flow and the field distribution,
> and the field distribution is generally as depicted in FIG. 2A.
> At higher frequencies, e.g., at frequencies of between 10 KHz
> and 1 MHz, the dielectric properties of the components becomes
> more significant and eventually dominate the field distribution,
> resulting in field distribution lines as depicted generally in
> FIG. 2B.   
>   
> [0049] For constant (i.e., DC) electric fields or relatively low
> frequency alternating electric fields, for example, frequencies
> under 10 KHz, the dielectric properties of the various
> components are not significant in determining and computing the
> field distribution. Therefore, as a first approximation, with
> regard to the electric field distribution, the system can be
> reasonably represented by the relative impedances of its various
> components. Using this approximation, the intercellular (i.e.,
> extracellular) fluid and the intracellular fluid each has a
> relatively low impedance, while the cell membrane 11 has a
> relatively high impedance. Thus, under low frequency conditions,
> only a fraction of the electric field lines (or currents induced
> by the electric field) penetrate membrane 11 of the cell 10. At
> relatively high frequencies (e.g., 10 KHz-1 MHz), in contrast,
> the impedance of membrane 11 relative to the intercellular and
> intracellular fluids decreases, and thus, the fraction of
> currents penetrating the cells increases significantly. It
> should be noted that at very high frequencies, i.e., above 1
> MHz, the membrane capacitance can short the membrane resistance
> and, therefore, the total membrane resistance can become
> negligible.   
>   
> [0050] In any of the embodiments described above, the electric
> field lines (or induced currents) penetrate cell 10 from a
> portion of the membrane 11 closest to one of the electrodes
> generating the current, e.g., closest to positive electrode 28
> (also referred to herein as "source"). The current flow pattern
> across cell 10 is generally uniform because, under the above
> approximation, the field induced inside the cell is
> substantially homogeneous. The currents exit cell 10 through a
> portion of membrane 11 closest to the opposite electrode, e.g.,
> negative electrode 32 (also referred to herein as "sink").   
>   
> [0051] The distinction between field lines and current flow can
> depend on a number of factors, for example, on the frequency of
> the applied electric potential and on whether electrodes 28 and
> 32 are electrically insulated. For insulated electrodes applying
> a DC or low frequency alternating voltage, there is practically
> no current flow along the lines of the electric field. At higher
> frequencies, the displacement currents are induced in the tissue
> due to charging and discharging of the electrode insulation and
> the cell membranes (which act as capacitors to a certain
> extent), and such currents follow the lines of the electric
> field. Fields generated by non-insulated electrodes, in
> contrast, always generate some form of current flow,
> specifically, DC or low frequency alternating fields generate
> conductive current flow along the field lines, and high
> frequency alternating fields generate both conduction and
> displacement currents along the field lines. It should be
> appreciated, however, that movement of polarizable intracellular
> organelles according to the present invention (as described
> below) is not dependent on actual flow of current and,
> therefore, both insulated and non-insulated electrodes can be
> used efficiently. Several advantages of insulated electrodes are
> that they have lower power consumption and cause less heating of
> the treated regions.   
>   
> [0052] According to one exemplary embodiment of the present
> invention, the electric fields that are used are alternating
> fields having frequencies that are in the range from about 50
> KHz to about 500 KHz, and preferably from about 100 KHz to about
> 300 KHz. For ease of discussion, these type of electric fields
> are also referred to below as "TC fields", which is an
> abbreviation of "Tumor Curing electric fields", since these
> electric fields fall into an intermediate category (between high
> and low frequency ranges) that have bio-effective field
> properties while having no meaningful stimulatory and thermal
> effects. These frequencies are sufficiently low so that the
> system behavior is determined by the system's Ohmic (conductive)
> properties but sufficiently high enough not to have any
> stimulation effect on excitable tissues. Such a system consists
> of two types of elements, namely, the intercellular, or
> extracellular fluid, or medium and the individual cells. The
> intercellular fluid is mostly an electrolyte with a specific
> resistance of about 40-100 Ohm\*cm. As mentioned above, the cells
> are characterized by three elements, namely (1) a thin, highly
> electric resistive membrane that coats the cell; (2) internal
> cytoplasm that is mostly an electrolyte that contains numerous
> macromolecules and micro-organelles, including the nucleus; and
> (3) membranes, similar in their electric properties to the cell
> membrane, cover the micro-organelles.   
>   
> [0053] When this type of system is subjected to the present TC
> fields (e.g., alternating electric fields in the frequency range
> of 100 KHz-300 KHz) most of the lines of the electric field and
> currents tend away from the cells because of the high resistive
> cell membrane and therefore the lines remain in the
> extracellular conductive medium. In the above recited frequency
> range, the actual fraction of electric field or currents that
> penetrates the cells is a strong function of the frequency.   
>   
> [0054] FIG. 3 schematically depicts the resulting field
> distribution in the system. As illustrated, the lines of force,
> which also depict the lines of potential current flow across the
> cell volume mostly in parallel with the undistorted lines of
> force (the main direction of the electric field). In other
> words, the field inside the cells is mostly homogeneous. In
> practice, the fraction of the field or current that penetrates
> the cells is determined by the cell membrane impedance value
> relative to that of the extracellular fluid. Since the
> equivalent electric circuit of the cell membrane is that of a
> resistor and capacitor in parallel, the impedance is a function
> of the frequency. The higher the frequency, the lower the
> impedance, the larger the fraction of penetrating current and
> the smaller the field distortion.   
>   
> [0055] As previously mentioned, when cells are subjected to
> relatively weak electric fields and currents that alternate at
> high frequencies, such as the present TC fields having a
> frequency in the range of 50 KHz-500 KHz, they have no effect on
> the non-dividing cells. While the present TC fields have no
> detectable effect on such systems, the situation becomes
> different in the presence of dividing cells.   
>   
> [0056] Reference is now made to FIGS. 3A-3C which schematically
> illustrate the electric current flow pattern in cell 10 during
> its division process, under the influence of alternating fields
> (TC fields) in the frequency range from about 100 KHz to about
> 300 KHz in accordance with one exemplary embodiment. The field
> lines or induced currents penetrate cell 10 through a part of
> the membrane of sub-cell 16 closer to electrode 28. However,
> they do not exit through the cytoplasm bridge 22 that connects
> sub-cell 16 with the newly formed yet still attached sub-cell
> 14, or through a part of the membrane in the vicinity of the
> bridge 22. Instead, the electric field or current flow
> lines-that are relatively widely separated in sub-cell
> 16-converge as they approach bridge 22 (also referred to as
> "neck" 22) and, thus, the current/field line density within neck
> 22 is increased dramatically. A "mirror image" process takes
> place in sub-cell 14, whereby the converging field lines in
> bridge 22 diverge as they approach the exit region of sub-cell
> 14.   
>   
> [0057] It should be appreciated by persons skilled in the art
> that homogeneous electric fields do not exert a force on
> electrically neutral objects, i.e., objects having substantially
> zero net charge, although such objects can become polarized.
> However, under a non-uniform, converging electric field, as
> shown in FIGS. 3A-3C, electric forces are exerted on polarized
> objects, moving them in the direction of the higher density
> electric field lines. It will be appreciated that the
> concentrated electric field that is present in the neck or
> bridge area in itself exerts strong forces on charges and
> natural dipoles and can disrupt structures that are associated
> therewith.   
>   
> [0058] In the configuration of FIGS. 3A and 3B, the direction of
> movement of polarized objects is towards the higher density
> electric field lines, i.e., towards the cytoplasm bridge 22
> between sub-cells 14 and 16. It is known in the art that all
> intracellular organelles, for example, nuclei 24 and 26 of
> sub-cells 14 and 16, respectively, are polarizable and, thus,
> such intracellular organelles are electrically forced in the
> direction of the bridge 22. Since the movement is always from
> lower density currents to the higher density currents,
> regardless of the field polarity, the forces applied by the
> alternating electric field to organelles, such as nuclei 24 and
> 26, are always in the direction of bridge 22. A comprehensive
> description of such forces and the resulting movement of
> macromolecules of intracellular organelles, a phenomenon
> referred to as "dielectrophoresis" is described extensively in
> literature, e.g., in C. L. Asbury & G. van den Engh,
> Biophys. J. 74, 1024-1030, 1998, the disclosure of which is
> hereby incorporated by reference in its entirety.   
>   
> [0059] The movement of the organelles 24 and 26 towards the
> bridge 22 disrupts the structure of the dividing cell and,
> eventually, the pressure of the converging organelles on bridge
> membrane 22 results in the breakage of cell membrane 11 at the
> vicinity of the bridge 22, as shown schematically in FIG. 3C.
> The ability to break membrane 11 at bridge 22 and to otherwise
> disrupt the cell structure and organization can be enhanced by
> applying a pulsating AC electric field, rather than a steady AC
> field. When a pulsating field is applied, the forces acting on
> organelles 24 and 26 have a "hammering" effect, whereby pulsed
> forces beat on the intracellular organelles towards the neck 22
> from both sub-cells 14 and 16, thereby increasing the
> probability of breaking cell membrane 11 in the vicinity of neck
> 22.   
>   
> [0060] A very important element, which is very susceptible to
> the special fields that develop within the dividing cells is the
> microtubule spindle that plays a major role in the division
> process. In FIG. 4, a dividing cell 10 is illustrated, at an
> earlier stage as compared to FIGS. 3A and 3B, under the
> influence of external TC fields (e.g., alternating fields in the
> frequency range of about 100 KHz to about 300 KHz), generally
> indicated as lines 100, with a corresponding spindle mechanism
> generally indicated at 120. The lines 120 are microtubules that
> are known to have a very strong dipole moment. This strong
> polarization makes the tubules susceptible to electric fields.
> Their positive charges are located at the two centrioles while
> two sets of negative poles are at the center of the dividing
> cell and the other pair is at the points of attachment of the
> microtubules to the cell membrane, generally indicated at 130.
> This structure forms sets of double dipoles and therefore they
> are susceptible to fields of different directions. It will be
> understood that the effect of the TC fields on the dipoles does
> not depend on the formation of the bridge (neck) and thus, the
> dipoles are influenced by the TC fields prior to the formation
> of the bridge (neck).   
>   
> [0061] Since the present apparatus (as will be described in
> greater detail below) utilizes insulated electrodes, the
> above-mentioned negative effects obtained when conductive
> electrodes are used, i.e., ion concentration changes in the
> cells and the formation of harmful agents by electrolysis, do
> not occur when the present apparatus is used. This is because,
> in general, no actual transfer of charges takes place between
> the electrodes and the medium and there is no charge flow in the
> medium where the currents are capacitive, i.e., are expressed
> only as rotation of charges, etc.   
>   
> [0062] Turning now to FIG. 5, the TC fields described above that
> have been found to advantageously destroy tumor cells are
> generated by an electronic apparatus 200. FIG. 5 is a simple
> schematic diagram of the electronic apparatus 200 illustrating
> the major components thereof. The electronic apparatus 200
> generates the desired electric signals (TC signals) in the shape
> of waveforms or trains of pulses. The apparatus 200 includes a
> generator 210 and a pair of conductive leads 220 that are
> attached at one end thereof to the generator 210. The opposite
> ends of the leads 220 are connected to insulated conductors 230
> that are activated by the electric signals (e.g., waveforns).
> The insulated conductors 230 are also referred to hereinafter as
> isolects 230. Optionally and according to another exemplary
> embodiment, the apparatus 200 includes a temperature sensor 240
> and a control box 250 which are both added to control the
> amplitude of the electric field generated so as not to generate
> excessive heating in the area that is treated.  
>   
> [0063] The generator 210 generates an alternating voltage
> waveform at frequencies in the range from about 50 KHz to about
> 500 KHz (preferably from about 100 KHz to about 300 KHz) (i.e.,
> the TC fields). The required
> voltages are such that the electric field intensity in the
> tissue to be treated is in the range of about 0.1 V/cm to
> about 10 V/cm. To achieve this field, the actual
> potential difference between the two conductors in the isolects
> 230 is determined by the relative impedances of the system
> components, as described below.   
>   
> [0064] When the control box 250 is included, it controls the
> output of the generator 210 so that it will remain constant at
> the value preset by the user or the control box 250 sets the
> output at the maximal value that does not cause excessive
> heating, or the control box 250 issues a warning or the like
> when the temperature (sensed by temperature sensor 240) exceeds
> a preset limit.   
>   
> [0065] The leads 220 are standard isolated conductors with a
> flexible metal shield, preferably grounded so that it prevents
> the spread of the electric field generated by the leads 220. The
> isolects 230 have specific shapes and positioning so as to
> generate an electric field of the desired configuration,
> direction and intensity at the target volume and only there so
> as to focus the treatment.   
>   
> [0066] The specifications of the apparatus 200 as a whole and
> its individual components are largely influenced by the fact
> that at the frequency of the present TC fields (50 KHz-500 KHz),
> living systems behave according to their "Ohmic", rather than
> their dielectric properties. The only elements in the apparatus
> 200 that behave differently are the insulators of the isolects
> 230 (see FIGS. 7-9). The isolects 200 consist of a conductor in
> contact with a dielectric that is in contact with the conductive
> tissue thus forming a capacitor.   
>   
> [0067] The details of the construction of the isolects 230 is
> based on their electric behavior that can be understood from
> their simplified electric circuit when in contact with tissue as
> generally illustrated in FIG. 6. In the illustrated arrangement,
> the electric field distribution between the different components
> is determined by their relative electric impedance, i.e., the
> fraction of the field on each component is given by the value of
> its impedance divided by the total circuit impedance. For
> example, the potential drop on element [Delta]VA=A/(A+B+C+D+E).
> Thus, for DC or low frequency AC, practically all the potential
> drop is on the capacitor (that acts as an insulator). For
> relatively very high frequencies, the capacitor practically is a
> short and therefore, practically all the field is distributed in
> the tissues. At the frequencies of the present TC fields (e.g.,
> 50 KHz to 500 KHz), which are intermediate frequencies, the
> impedance of the capacitance of the capacitors is dominant and
> determines the field distribution. Therefore, in order to
> increase the effective voltage drop across the tissues (field
> intensity), the impedance of the capacitors is to be decreased
> (i.e., increase their capacitance). This can be achieved by
> increasing the effective area of the "plates" of the capacitor,
> decrease the thickness of the dielectric or use a dielectric
> with high dielectric constant. There a number of different
> materials that are suitable for use in the intended application
> and have high dielectric constants. For example, some materials
> include: lithium nibate (LiNbO3), which is a ferroelectric
> crystal and has a number of applications in optical,
> pyroelectric and piezoelectric devices; yittrium iron garnet
> (YIG) is a ferrimagnetic crystal and magneto-optical devices,
> e.g., optical isolator can be realized from this material;
> barium titanate (BaTiO3) is a ferromagnetic crystal with a large
> electro-optic effect; potassium tantalate (kTaO3) which is a
> dielectric crystal (ferroelectric at low temperature) and has
> very low microwave loss and tunability of dielectric constant at
> low temperature; and lithium tantalate (LiTaO3) which is a
> ferroelectric crystal with similar properties as lithium niobate
> and has utility in electro-optical, pyroelectric and
> piezoelectric devices. It will be understood that the
> aforementioned exemplary materials can be used in combination
> with the present device where it is desired to use a material
> having a high dielectric constant.   
>   
> [0068] In order to optimize the field distribution, the isolects
> 230 are configured differently depending upon the application in
> which the isolects 230 are to be used. There are two principle
> modes for applying the present electric fields (TC fields).
> First, the TC fields can be applied by external isolects and
> second, the TC fields can be applied by internal isolects.   
>   
> [0069] Electric fields (TC fields) that are applied by external
> isolects can be of a local type or widely distributed type. The
> first type includes, for example, the treatment of skin tumors
> and treatment of lesions close to the skin surface. FIG. 7
> illustrates an exemplary embodiment where the isolects 230 are
> incorporated in a skin patch 300. The skin patch 300 can be a
> self-adhesive flexible patch with one or more pairs of isolects
> 230. The patch 300 includes internal insulation 310 (formed of a
> dielectric material) and the external insulation 260 and is
> applied to skin surface 301 that contains a tumor 303 either on
> the skin surface 301 or slightly below the skin surface 301.
> Tissue is generally indicated at 305. To prevent the potential
> drop across the internal insulation 310 to dominate the system,
> the internal insulation 310 must have a relatively high
> capacity. This can be achieved by a large surface area; however,
> this may not be desired as it will result in the spread of the
> field over a large area (e.g., an area larger than required to
> treat the tumor). Alternatively, the internal insulation 310 can
> be made very thin and/or the internal insulation 310 can be of a
> high dielectric constant. As the skin resistance between the
> electrodes (labeled as A and E in FIG. 6) is normally
> significantly higher than that of the tissue (labeled as C in
> FIG. 6) underneath it (1-10 K[Omega] vs. 0.1-1 K[Omega]), most
> of the potential drop beyond the isolects occurs there. To
> accommodate for these impedances (Z), the characteristics of the
> internal insulation 310 (labeled as B and D in FIG. 6) should be
> such that they have impedance preferably under 100 K[Omega] at
> the frequencies of the present TC fields (e.g., 50 KHz to 500
> KHz). For example, if it is desired for the impedance to be
> about 10K Ohms, such that over 1% of the applied voltage falls
> on the tissues, for isolects with a surface area of 10
> mm<2>, at frequencies of 200 KHz, the capacity should be
> on the order of 10<-10 >F, which means that using standard
> insulations with a dielectric constant of 2-3, the thickness of
> the insulating layer 310 should be about 50-100 microns. An
> internal field 10 times stronger would be obtained with
> insulators with a dielectric constant of about 20-50. [0070]
> Since the insulating layer can be very vulnerable, etc., the
> insulation can be replaced by very high dielectric constant
> insulating materials, such as titanium dioxide (e.g., rutil),
> the dielectric constant can reach values of about 200. One must
> also consider another factor that effects the effective capacity
> of the isolects 230, namely the presence of air between the
> isolects 230 and the skin. Such presence, which is not easy to
> prevent, introduces a layer of an insulator with a dielectric
> constant of 1.0, a factor that significantly lowers the
> effective capacity of the isolects 230 and neutralizes the
> advantages of the titanium dioxide (routil), etc. To overcome
> this problem, the isolects 230 can be shaped so as to conform
> with the body structure and/or (2) an intervening filler 270 (as
> illustrated in FIG. 1C), such as a gel, that has high
> conductance and a dielectric constant, can be added to the
> structure. The shaping can be pre-structured (see FIG. 10A) or
> the system can be made sufficiently flexible so that shaping of
> the isolects 230 is readily achievable. The gel can be contained
> in place by having an elevated rim as depicted in FIG. 10C. The
> gel can be made of gelatins, agar, etc., and can have salts
> dissolved in it to increase its conductivity. FIGS. 10A-10C
> illustrate various exemplary configurations for the isolects
> 230. The exact thickness of the gel is not important so long as
> it is of sufficient thickness that the gel layer does not dry
> out during the treatment. In one exemplary embodiment, the
> thickness of the gel is about 0.5 mm to about 2 mm.   
>   
> [0071] In order to achieve the desirable features of the
> isolects 230, the dielectric coating of each should be very
> thin, for example from between 1-50 microns. Since the coating
> is so thin, the isolects 230 can easily be damaged mechanically.
> This problem can be overcome by adding a protective feature to
> the isolect's structure so as to provide desired protection from
> such damage. For example, the isolect 230 can be coated, for
> example, with a relatively loose net 340 that prevents access to
> the surface but has only a minor effect on the effective surface
> area of the isolect 230 (i.e., the capacity of the isolects 230
> (cross section presented in FIG. 12B). The loose net 340 does
> not effect the capacity and ensures good contact with the skin,
> etc. The loose net 340 can be formed of a number of different
> materials; however, in one exemplary embodiment, the net 340 is
> formed of nylon, polyester, cotton, etc. Alternatively, a very
> thin conductive coating 350 can be applied to the dielectric
> portion (insulating layer) of the isolect 230. One exemplary
> conductive coating is formed of a metal and more particularly of
> gold. The thickness of the coating 350 depends upon the
> particular application and also on the type of material used to
> form the coating 350; however, when gold is used, the coating
> has a thickness from about 0.1 micron to about 0.1 mm.
> Furthermore, the rim illustrated in FIG. 10 can also provide
> some mechanical protection.   
>   
> [0072] However, the capacity is not the only factor to be
> considered. The following two factors also influence how the
> isolects 230 are constructed. The dielectric strength of the
> internal insulating layer 310 and the dielectric losses that
> occur when it is subjected to the TC field, i.e., the amount of
> heat generated. The dielectric strength of the internal
> insulation 310 determines at what field intensity the insulation
> will be "shorted" and cease to act as an intact insulation.
> Typically, insulators, such as plastics, have dielectric
> strength values of about 100V per micron or more. As a high
> dielectric constant reduces the field within the internal
> insulator 310, a combination of a high dielectric constant and a
> high dielectric strength gives a significant advantage. This can
> be achieved by using a single material that has the desired
> properties or it can be achieved by a double layer with the
> correct parameters and thickness. In addition, to further
> decreasing the possibility that the insulating layer 310 will
> fail, all sharp edges of the insulating layer 310 should be
> eliminated as by rounding the corners, etc., as illustrated in
> FIG. 10D using conventional techniques.   
>   
> [0073] FIGS. 8 and 9 illustrate a second type of treatment using
> the isolects 230, namely electric field generation by internal
> isolects 230. A body to which the isolects 230 are implanted is
> generally indicated at 311 and includes a skin surface 313 and a
> tumor 315. In this embodiment, the isolects 230 can have the
> shape of plates, wires or other shapes that can be inserted
> subcutaneously or a deeper location within the body 311 so as to
> generate an appropriate field at the target area (tumor 315).  
>   
> [0074] It will also be appreciated that the mode of isolects
> application is not restricted to the above descriptions. In the
> case of tumors in internal organs, for example, liver, lung,
> etc., the distance between each member of the pair of isolects
> 230 can be large. The pairs can even by positioned opposite
> sides of a torso 410, as illustrated in FIG. 11. The arrangement
> of the isolects 230 in FIG. 11 is particularly useful for
> treating a tumor 415 associated with lung cancer. In this
> embodiment, the electric fields (TC fields) spread in a wide
> fraction of the body.   
>   
> [0075] In order to avoid overheating of the treated tissues, a
> selection of materials and field parameters is needed. The
> isolects insulating material should have minimal dielectric
> losses at the frequency ranges to be used during the treatment
> process. This factor can be taken into consideration when
> choosing the particular frequencies for the treatment. The
> direct heating of the tissues will most likely be dominated by
> the heating due to current flow (given by the I\*R product).   
>   
> [0076] The effectiveness of the treatment can be enhanced by an
> arrangement of isolects 230 that focuses the field at the
> desired target while leaving other sensitive areas in low field
> density (i.e., protected areas). The proper placement of the
> isolects 230 over the body can be maintained using any number of
> different techniques, including using a suitable piece of
> clothing that keeps the isolects at the appropriate positions.
> FIG. 13 illustrates such an arrangement in which an area labeled
> as "P" represents a protected area. The lines of field force do
> not penetrate this protected area and the field there is much
> smaller than near the isolects 230 where target areas can be
> located and treated well. In contrast, the field intensity near
> the four poles is very high.   
>   
> [0077] The following Example serves to illustrate an exemplary
> application of the present apparatus and application of TC
> fields; however, this Example is not limiting and does not limit
> the scope of the present invention in any way.   
>   
>  EXAMPLE   
>   
> [0078] To demonstrate the effectiveness of electric fields
> having the above described properties (e.g., frequencies between
> 50 KHz and 500 KHz) in destroying tumor cells, the electric
> fields were applied to treat mice with malignant melanoma
> tumors. Two pairs of isolects 230 were positioned over a
> corresponding pair of malignant melanomas. Only one pair was
> connected to the generator 210 and 200 KHz alternating electric
> fields (TC fields) were applied to the tumor for a period of 6
> days. One melanoma tumor was not treated so as to permit a
> comparison between the treated tumor and the non-treated tumor.
> After treatment for 6 days, the pigmented melanoma tumor
> remained clearly visible in the non-treated side of the mouse,
> while, in contrast, no tumor is seen on the treated side of the
> mouse. The only areas that were visible discernable on the skin
> were the marks that represented the points of insertion of the
> isolects 230. The fact that the tumor was eliminated at the
> treated side was further demonstrated by cutting and inversing
> the skin so that its inside face was exposed. Such a procedure
> indicated that the tumor has been substantially, if not
> completely, eliminated on the treated side of the mouse. The
> success of the treatment was also further verified by
> pathhistological examination.   
>   
> [0079] The present inventor has thus uncovered that electric
> fields having particular properties can be used to destroy
> dividing cells or tumors when the electric fields are applied to
> using an electronic device. More specifically, these electric
> fields fall into a special intermediate category, namely
> bio-effective fields that have no meaningful stimulatory and no
> thermal effects, and therefore overcome the disadvantages that
> were associated with the application of conventional electric
> fields to a body. It will also be appreciated that the present
> apparatus can further include a device for rotating the TC field
> relative to the living tissue. For example and according to one
> embodiment, the alternating electric potential applies to the
> tissue being treated is rotated relative to the tissue using
> conventional devices, such as a mechanical device that upon
> activation, rotates various components of the present system.   
>   
> [0080] While the invention has been particularly shown and
> described with reference to preferred embodiments thereof, it
> will be understood by those skilled in the art that various
> changes in form and details can be made without departing from
> the spirit and scope of the invention.  
>   
>
>
> ---
>
>   
>
> OPTIMIZING CHARACTERISTICS OF AN ELECTRIC FIELD TO
> INCREASE THE FIELD'S EFFECT ON PROLIFERATING CELLS   
> WO2007039799
>
>   
> CROSS REFERENCE TO RELATED
> APPLICATIONS  
>   
> [0001] This application claims the benefit of US provisional
> application No. 60/723,560, filed October 3, 2005, which is
> incorporated herein by reference.  
>   
>  [0004] BACKGROUND  
>   
>  [0002] US Patent Nos. 6,868,289 and 7,016,725, each of
> which is incorporated herein by reference, disclose methods and
> apparatuses for treating tumors using AC electric fields in the range of 1-lOV/cm, at
> frequencies between 50 kHz and 500 kHz, and that the
> effectiveness of those fields is increased when more than one
> field direction is used (e.g., when the field is switched
> between two or three directions that are oriented about
> 90[deg.] apart from each other). Those alternating electric
> fields are referred to herein as Tumor Treating Fields,
> or TTFields.  
>   
>  [0006] SUMMARY OF THE
> INVENTION   
>   
> [0003] The effectiveness of TTFields in stopping the
> proliferation of and destroying living cells that proliferate
> rapidly (e.g., cancer cells) can be enhanced by choosing the
> rate at which the field is switched between the various
> directions.   
>   
> [0008] BRIEF DESCRIPTION OF THE
> DRAWINGS  
>   
> [0004] FIG. 1 is a schematic
> representation of two pairs of insulated electrodes that
> alternately apply TTFields to target region.  
>   
> [0005] FIG. 2 shows examples of
> waveforms that are suitable for switching the fields that are
> applied between the electrodes on and off. [0011]   
>   
> [0006] FIG. 3 depicts the
> changes in growth rate of a glioma cell culture treated with
> alternating electric fields switched between two directions at
> different switching rates. [0012]  
>   
>  [0007] FIG. 4 is a graph
> of tumor volume vs. time for fields that were switched between
> two directions at different switching rates. [0013]  
>   
>  [0008] FIG. 5 is a block
> diagram of a system for generating the TTFields in different
> directions. [0014]  
>   
> [0009] FIG. 6 illustrates a
> preferred waveform for driving the electrodes.   
>   
> [0015] DETAILED DESCRIPTION OF
> THE PREFERRED EMBODIMENTS   
>   
> [0016] [0010] Since electric fields sum as vectors, two or more
> fields with different directions cannot be applied
> simultaneously at a given location. Instead, the different field
> directions must be applied sequentially, by applying a first
> field in one direction for a certain period of time tl, and then
> applying a second field in another direction for a period t2.
> During t2 the first field is not active and during tl the second
> field is inactive. When this cycle is repeated over and over,
> the result is that sequential field pulses of changing
> directions are applied in a cyclic manner. [0017]  
>   
>  [0011] The inventor has determined that that the
> effectiveness of TTFields for destroying proliferating cells in
> tissue culture as well as malignant tumors in experimental
> animals is dependent on the rate of switching between the
> various directions of which the fields are applied. In a set of
> experiments, TTFields were applied to the tissue cultures or
> experimental animals by means of two pairs 11, 12 of insulated
> electrodes that alternately apply TTFields 15, 16 normal to each
> other, shown schematically in FIG. 1. The waveforms applied were
> 100 - 200 kHz alternating fields modulated to stay On and Off
> for half cycle durations ranging from 10 ms to 1000 ms. [0018]  
>   
>  [0012] FIG. 2 shows two examples of waveforms that are
> suitable for modulating the AC signals that were applied between
> the electrodes: a first pair A of 50% duty cycle waveforms 21,
> 22 time shifted with respect to each other such that one is on
> when the other is off, and a second pair B of 50% duty cycle
> waveforms 23, 24 that is similar to the first set of waveforms,
> but switched at twice the frequency. Note that each set of
> waveforms consists of two 50% duty cycle square waves that are
> shifted in phase by one half cycle with respect to each other.
> [0019]  
>   
>  [0013] FIG. 3 depicts the results of one set of
> experiments by plotting the changes in growth rate of a glioma
> cell culture (F98) treated with 200 kHz alternating electric
> field waveforms switched between two directions at different
> switching rates. Experimental data was also obtained for the
> case where the field was applied continuously in one direction
> only. (Note that the control baseline of 100% is for the case
> when no field was applied.) The data shows that some switching
> frequencies are more effective than others for reducing the
> proliferation of glioma tumor cells in culture. The highest
> effectiveness was found when the half cycle duration was 50 ms
> (with a similar Off duration) waveform. However, the
> effectiveness differences in the range of 250 ms to 50 ms were
> small. Within this range, the cell proliferation rate is reduced
> to about half of what it is when either a continuous field was
> applied, or when a 1000 ms half cycle duration waveform is used.
>   
>   
> [0014] FIG. 4 is a graph of tumor volume vs. time for a set of
> experiment, and it shows the effect of 200 kHz TTFields on Vx2
> carcinoma growth in vivo, when the fields were applied in two
> different directions at different switching rates. In the
> experiment, tumors from the carcinoma line Vx2 were inoculated
> under the kidney capsule in rabbits. As expected, the tumor size
> increases with time during the 4 week follow up period in the
> control, non-treated, group of rabbits (curve 31). The growth
> rate was slower when the fields were applied in different
> directions with a switch in direction every 1000 ms (curve 32);
> and the growth rate was even slower when the field's direction
> was switched every 250 ms (curve 33) or every 50 ms (curve 34).
> Thus, we see that the effectiveness of the treatment is
> significantly higher for waveform having half duty cycle
> durations of between 50 and 250 ms, as compared with 1000 ms
> half cycles. [0020]  
>   
>  [0015] Based on the above, the following approach is
> recommended for tumor treatment with TTFields: Treatment should
> be carried out with at least two field directions, such that
> each pair of electrodes is activated for On periods of a
> duration that is preferably between 50 and 250 ms, interposed by
> Off periods of a similar duration. The TTFields basic
> alternation frequency (which corresponds to the carrier
> frequency in an amplitude modulation system) should preferably
> be in the range of 50 - 500 kHz, and more preferably in the
> range of 100- 200 kHz. The field intensity is preferably at
> least 1 V/cm, and more preferably between 1 and lO V/cm. [0021]
>   
>   
> [0016] FIG. 5 is a block diagram of a system for generating the
> TTFields in different directions by driving a first electrode
> pair 11 and a second electrode pair 12 that are positioned about
> a target. An AC signal generator 41 generates a sinusoid,
> preferably between 100 - 200 kHz, and a square wave generator 43
> generates a square wave that resembles the wave 21 shown in FIG.
> 2. Preferably the output of the square wave is high between 50
> and 250 ms and low for an equal amount of time in every cycle,
> although duty cycles that deviate from 50% may also be used. An
> inverter 44 inverts this square wave, thereby providing the
> second wave 22 shown in FIG 2. The amplifiers 42 amplify the
> sinusoid when their control input is in one state, and shut off
> when their control input is in the other state. Since the
> control input for the two amplifiers are out of phase, the
> amplifiers will alternately drive either the first electrode
> pair 11 or the second electrode pair 12 to generate either the
> first field 15 or the second field 16 in the target region. Of
> course, persons skilled in the relevant arts will recognize that
> a wide variety of other circuits may be used to alternately
> drive either the first or second pair of electrodes. For
> example, a suitable switching circuit may provided to route the
> output of a single amplifier to either the first or second pair
> of electrodes in an alternating manner, with the switching
> controlled by a single square wave. [0022]  
>   
>  [0017] As explained in patent 6,868,289, insulated
> electrodes are preferred for in vivo applications. Preferably,
> care should be taken to avoid overheating of the tissues by the
> capacitive currents and dielectric losses in the insulated
> electrodes. It is also preferable to avoid the generation of
> spikes during the switching process. This can be done, for
> example, by carrying out the switching itself while the AC
> signal is turned off and immediately afterwards turning the
> signal on. The rate of turning the field on t3 and off t4 should
> preferably be done at a rate that is slow relative to the
> reciprocal of the field frequency (i.e., the period t5), and
> fast relative to the half cycle duration tl, t2, as seen in FIG.
> 6 for waveform 61. An example of a suitable turn-on rate t3 and
> turn-on rate t4 is to reach 90% of the steady-state values
> within about 1 - 5 ms. Circuitry for implementing this slow turn
> on may be implemented using a variety of approaches that will be
> apparent to persons skilled in the relevant arts, such as using
> a slow-rising control signal to drive an accurate AM modulator,
> or by driving a gain control of the amplifier with a square wave
> and interposing a low pass filter in series with the gain
> control input. [0023]  
>   
>  [0018] While examples of the invention are described above
> in the context of F98 glioma and Vx2 carcinoma, the switching
> rate may be optimized for other cancers or other rapidly
> proliferating cells by running experiments to determine the best
> switching rate, and subsequently using that switching rate to
> treat the problem in future cases.  
>   
>
>
> ---
>
>   
>
> Treating a tumor or the like with electric fields
> at different orientations  
>  US2005209642
>
>   
>  REFERENCE TO RELATED
> APPLICATIONS  
>   
>  [0001] This application claims the benefit of U.S.
> provisional application 60/565,065, filed Apr. 23, 2004, which
> is hereby incorporated by reference in its entirety. This
> application is also a continuation-in-part of U.S. patent
> application Ser. No. 11/074,318, filed Mar. 7, 2005, which is a
> continuation-in-part of U.S. patent application Ser. No.
> 10/315,576, filed Dec. 10, 2002, which is a continuation-in-part
> of U.S. patent application Ser. No. 10/285,313, filed Oct. 31,
> 2002, which is a continuation-in-part application of U.S. patent
> application Ser. No. 10/263,329, filed Oct. 2, 2002, each of
> which is hereby incorporated by reference in its entirety. This
> application is also a continuation-in-part of U.S. patent
> application Ser. No. 10/402,327, filed Mar. 28, 2003, which is a
> continuation-in-part of U.S. patent application Ser. No.
> 10/204,334, filed Oct. 16, 2002, which is the U.S. national
> phase of PCT/IB01/00202, filed Feb. 16, 2001, which claims the
> benefit of U.S. provisional application 60/183,295, filed Feb.
> 17, 2000, each of which is hereby incorporated by reference in
> its entirety. This application is also a continuation-in-part of
> U.S. patent application Ser. No. 10/288,562, filed Nov. 5, 2002,
> which claims the benefit of U.S. provisional application
> 60/338,632, filed Nov. 6, 2001, each of which is hereby
> incorporated by reference in its entirety.  
>   
>  TECHNICAL FIELD [0002] This invention concerns selective
> destruction of rapidly dividing cells in a localized area, and
> more particularly, selectively destroying dividing cells without
> destroying nearby non-dividing cells by applying an electric
> field with specific characteristics to a target area in a living
> patient.   
>   
>  BACKGROUND  
>   
> 0003] All living organisms proliferate by cell division,
> including cell cultures, microorganisms (such as bacteria,
> mycoplasma, yeast, protozoa, and other single-celled organisms),
> fungi, algae, plant cells, etc. Dividing cells of organisms can
> be destroyed, or their proliferation controlled, by methods that
> are based on the sensitivity of the dividing cells of these
> organisms to certain agents. For example, certain antibiotics
> stop the multiplication process of bacteria.  
>   
>  [0004] The process of eukaryotic cell division is called
> "mitosis", which involves nice distinct phases (see Darnell et
> al., Molecular Cell Biology, New York: Scientific American
> Books, 1986, p. 149). During interphase, the cell replicates
> chromosomal DNA, which begins condensing in early prophase. At
> this point, centrioles (each cell contains 2) begin moving
> towards opposite poles of the cell. In middle prophase, each
> chromosome is composed of duplicate chromatids. Microtubular
> spindles radiate from regions adjacent to the centrioles, which
> are closer to their poles. By late prophase, the centrioles have
> reached the poles, and some spindle fibers extend to the center
> of the cell, while others extend from the poles to the
> chromatids. The cells then move into metaphase, when the
> chromosomes move toward the equator of the cell and align in the
> equatorial plane. Next is early anaphase, during which time
> daughter chromatids separate from each other at the equator by
> moving along the spindle fibers toward a centromere at opposite
> poles. The cell begins to elongate along the axis of the pole;
> the pole-to-pole spindles also elongate. Late anaphase occurs
> when the daughter chromosomes (as they are now called) each
> reach their respective opposite poles. At this point,
> cytokinesis begins as the cleavage furrow begins to form at the
> equator of the cell. In other words, late anaphase is the point
> at which pinching the cell membrane begins. During telophase,
> cytokinesis is nearly complete and spindles disappear. Only a
> relatively narrow membrane connection joins the two cytoplasms.
> Finally, the membranes separate fully, cytokinesis is complete
> and the cell returns to interphase.   
>   
> [0005] In meiosis, the cell undergoes a second division,
> involving separation of sister chromosomes to opposite poles of
> the cell along spindle fibers, followed by formation of a
> cleavage furrow and cell division. However, this division is not
> preceded by chromosome replication, yielding a haploid germ
> cell. Bacteria also divide by chromosome replication, followed
> by cell separation. However, since the daughter chromosomes
> separate by attachment to membrane components; there is no
> visible apparatus that contributes to cell division as in
> eukaryotic cells.  
>   
>  [0006] It is well known that tumors, particularly
> malignant or cancerous tumors, grow uncontrollably compared to
> normal tissue. Such expedited growth enables tumors to occupy an
> ever-increasing space and to damage or destroy tissue adjacent
> thereto. Furthermore, certain cancers are characterized by an
> ability to transmit cancerous "seeds", including single cells or
> small cell clusters (metastases), to new locations where the
> metastatic cancer cells grow into additional tumors.  
>   
>  [0007] The rapid growth of tumors, in general, and
> malignant tumors in particular, as described above, is the
> result of relatively frequent cell division or multiplication of
> these cells compared to normal tissue cells. The distinguishably
> frequent cell division of cancer cells is the basis for the
> effectiveness of existing cancer treatments, e.g., irradiation
> therapy and the use of various chemo-therapeutic agents. Such
> treatments are based on the fact that cells undergoing division
> are more sensitive to radiation and chemotherapeutic agents than
> non-dividing cells. Because tumors cells divide much more
> frequently than normal cells, it is possible, to a certain
> extent, to selectively damage or destroy tumor cells by
> radiation therapy and/or chemotherapy. The actual sensitivity of
> cells to radiation, therapeutic agents, etc., is also dependent
> on specific characteristics of different types of normal or
> malignant cell types. Thus, unfortunately, the sensitivity of
> tumor cells is not sufficiently higher than that many types of
> normal tissues. This diminishes the ability to distinguish
> between tumor cells and normal cells, and therefore, existing
> cancer treatments typically cause significant damage to normal
> tissues, thus limiting the therapeutic effectiveness of such
> treatments. Furthermore, the inevitable damage to other tissue
> renders treatments very traumatic to the patients and, often,
> patients are unable to recover from a seemingly successful
> treatment. Also, certain types of tumors are not sensitive at
> all to existing methods of treatment.  
>   
>  [0008] There are also other methods for destroying cells
> that do not rely on radiation therapy or chemotherapy alone. For
> example, ultrasonic and electrical methods for destroying tumor
> cells can be used in addition to or instead of conventional
> treatments. Electric fields and currents have been used for
> medical purposes for many years. The most common is the
> generation of electric currents in a human or animal body by
> application of an electric field by means of a pair of
> conductive electrodes between which a potential difference is
> maintained. These electric currents are used either to exert
> their specific effects, i.e., to stimulate excitable tissue, or
> to generate heat by flowing in the body since it acts as a
> resistor. Examples of the first type of application include the
> following: cardiac defibrillators, peripheral nerve and muscle
> stimulators, brain stimulators, etc. Currents are used for
> heating, for example, in devices for tumor ablation, ablation of
> malfunctioning cardiac or brain tissue, cauterization,
> relaxation of muscle rheumatic pain and other pain, etc.   
>   
> [0009] Another use of electric fields for medical purposes
> involves the utilization of high frequency oscillating fields
> transmitted from a source that emits an electric wave, such as
> an RF wave or a microwave source that is directed at the part of
> the body that is of interest (i.e., target). In these instances,
> there is no electric energy conduction between the source and
> the body; but rather, the energy is transmitted to the body by
> radiation or induction. More specifically, the electric energy
> generated by the source reaches the vicinity of the body via a
> conductor and is transmitted from it through air or some other
> electric insulating material to the human body.  
>   
>  [0010] In a conventional electrical method, electrical
> current is delivered to a region of the target tissue using
> electrodes that are placed in contact with the body of the
> patient. The applied electrical current destroys substantially
> all cells in the vicinity of the target tissue. Thus, this type
> of electrical method does not discriminate between different
> types of cells within the target tissue and results in the
> destruction of both tumor cells and normal cells.  
>   
> [0011] Electric fields that can be used in medical applications
> can thus be separated generally into two different modes. In the
> first mode, the electric fields are applied to the body or
> tissues by means of conducting electrodes. These electric fields
> can be separated into two types, namely (1) steady fields or
> fields that change at relatively slow rates, and alternating
> fields of low frequencies that induce corresponding electric
> currents in the body or tissues, and (2) high frequency
> alternating fields (above 1 MHz) applied to the body by means of
> the conducting electrodes. In the second mode, the electric
> fields are high frequency alternating fields applied to the body
> by means of insulated electrodes.  
>   
>  [0012] The first type of electric field is used, for
> example, to stimulate nerves and muscles, pace the heart, etc.
> In fact, such fields are used in nature to propagate signals in
> nerve and muscle fibers, central nervous system (CNS), heart,
> etc. The recording of such natural fields is the basis for the
> ECG, EEG, EMG, ERG, etc. The field strength in these
> applications, assuming a medium of homogenous electric
> properties, is simply the voltage applied to the
> stimulating/recording electrodes divided by the distance between
> them. These currents can be calculated by Ohm's law and can have
> dangerous stimulatory effects on the heart and CNS and can
> result in potentially harmful ion concentration changes. Also,
> if the currents are strong enough, they can cause excessive
> heating in the tissues. This heating can be calculated by the
> power dissipated in the tissue (the product of the voltage and
> the current).   
>   
> [0013] When such electric fields and currents are alternating,
> their stimulatory power, on nerve, muscle, etc., is an inverse
> function of the frequency. At frequencies above 1-10 KHz, the
> stimulation power of the fields approaches zero. This limitation
> is due to the fact that excitation induced by electric
> stimulation is normally mediated by membrane potential changes,
> the rate of which is limited by the RC properties (time
> constants on the order of 1 ms) of the membrane.  
>   
>  [0014] Regardless of the frequency, when such current
> inducing fields are applied, they are associated with harmful
> side effects caused by currents. For example, one negative
> effect is the changes in ionic concentration in the various
> "compartments" within the system, and the harmful products of
> the electrolysis taking place at the electrodes, or the medium
> in which the tissues are imbedded. The changes in ion
> concentrations occur whenever the system includes two or more
> compartments between which the organism maintains ion
> concentration differences. For example, for most tissues,
> [Ca<++> ] in the extracellular fluid is about 2\*10<-3
> > M, while in the cytoplasm of typical cells its
> concentration can be as low as 10<-7 > M. A current
> induced in such a system by a pair of electrodes, flows in part
> from the extracellular fluid into the cells and out again into
> the extracellular medium. About 2% of the current flowing into
> the cells is carried by the Ca<++> ions. In contrast,
> because the concentration of intracellular Ca<++> is much
> smaller, only a negligible fraction of the currents that exits
> the cells is carried by these ions. Thus, Ca<++> ions
> accumulate in the cells such that their concentrations in the
> cells increases, while the concentration in the extracellular
> compartment may decrease. These effects are observed for both DC
> and alternating currents (AC). The rate of accumulation of the
> ions depends on the current intensity ion mobilities, membrane
> ion conductance, etc. An increase in [Ca<++> ] is harmful
> to most cells and if sufficiently high will lead to the
> destruction of the cells. Similar considerations apply to other
> ions. In view of the above observations, long term current
> application to living organisms or tissues can result in
> significant damage. Another major problem that is associated
> with such electric fields, is due to the electrolysis process
> that takes place at the electrode surfaces. Here charges are
> transferred between the metal (electrons) and the electrolytic
> solution (ions) such that charged active radicals are formed.
> These can cause significant damage to organic molecules,
> especially macromolecules and thus damage the living cells and
> tissues.  
>   
>  [0015] In contrast, when high frequency electric fields,
> above 1 MHz and usually in practice in the range of GHz, are
> induced in tissues by means of insulated electrodes, the
> situation is quite different. These type of fields generate only
> capacitive or displacement currents, rather than the
> conventional charge conducting currents. Under the effect of
> this type of field, living tissues behave mostly according to
> their dielectric properties rather than their electric
> conductive properties. Therefore, the dominant field effect is
> that due to dielectric losses and heating. Thus, it is widely
> accepted that in practice, the meaningful effects of such fields
> on living organisms, are only those due to their heating
> effects, i.e., due to dielectric losses.  
>   
>  [0016] In U.S. Pat. No. 6,043,066 ('066) to Mangano, a
> method and device are presented which enable discrete objects
> having a conducting inner core, surrounded by a dielectric
> membrane to be selectively inactivated by electric fields via
> irreversible breakdown of their dielectric membrane. One
> potential application for this is in the selection and purging
> of certain biological cells in a suspension. According to the
> '066 patent, an electric field is applied for targeting selected
> cells to cause breakdown of the dielectric membranes of these
> tumor cells, while purportedly not adversely affecting other
> desired subpopulations of cells. The cells are selected on the
> basis of intrinsic or induced differences in a characteristic
> electroporation threshold. The differences in this threshold can
> depend upon a number of parameters, including the difference in
> cell size.  
>   
>  [0017] The method of the '066 patent is therefore based on
> the assumption that the electroporation threshold of tumor cells
> is sufficiently distinguishable from that of normal cells
> because of differences in cell size and differences in the
> dielectric properties of the cell membranes. Based upon this
> assumption, the larger size of many types of tumor cells makes
> these cells more susceptible to electroporation and thus, it may
> be possible to selectively damage only the larger tumor cell
> membranes by applying an appropriate electric field. One
> disadvantage of this method is that the ability to discriminate
> is highly dependent upon cell type, for example, the size
> difference between normal cells and tumor cells is significant
> only in certain types of cells. Another drawback of this method
> is that the voltages which are applied can damage some of the
> normal cells and may not damage all of the tumor cells because
> the differences in size and membrane dielectric properties are
> largely statistical and the actual cell geometries and
> dielectric properties can vary significantly.  
>   
>  [0018] What is needed in the art and has heretofore not
> been available is an apparatus for destroying dividing cells,
> wherein the apparatus better discriminates between dividing
> cells, including single-celled organisms, and non-dividing cells
> and is capable of selectively destroying the dividing cells or
> organisms with substantially no effect on the non-dividing cells
> or organisms.   
>   
> SUMMARY  
>   
>  [0019] While they are dividing, cells are vulnerable to
> damage by AC electric fields that have specific frequency and
> field strength characteristics. The selective destruction of
> rapidly dividing cells can therefore be accomplished by imposing
> an AC electric field in a target region for extended periods of
> time. Some of the cells that divide while the field is applied
> will be damaged, but the cells that do not divide will not be
> harmed. This selectively damages rapidly dividing cells like
> tumor cells, but does not harm normal cells that are not
> dividing. Since the vulnerability of the dividing cells is
> strongly related to the alignment between the long axis of the
> dividing cells and the lines of force of the electric field,
> improved results are obtained by sequentially imposing the field
> in different directions.   
>   
> [0020] A major use of the present apparatus is in the treatment
> of tumors by selective destruction of tumor cells with
> substantially no effect on normal tissue cells, and thus, the
> exemplary apparatus is described below in the context of
> selective destruction of tumor cells. It should be appreciated
> however, that for purpose of the following description, the term
> "cell" may also refer to a single-celled organism (eubacteria,
> bacteria, yeast, protozoa), multi-celled organisms (fungi,
> algae, mold), and plants as or parts thereof that are not
> normally classified as "cells". The exemplary apparatus enables
> selective destruction of cells undergoing division in a way that
> is more effective and more accurate (e.g., more adaptable to be
> aimed at specific targets) than existing methods. Further, the
> present apparatus causes minimal damage, if any, to normal
> tissue and, thus, reduces or eliminates many side-effects
> associated with existing selective destruction methods, such as
> radiation therapy and chemotherapy. The selective destruction of
> dividing cells using the present apparatus does not depend on
> the sensitivity of the cells to chemical agents or radiation.
> Instead, the selective destruction of dividing cells is based on
> distinguishable geometrical characteristics of cells undergoing
> division, in comparison to non-dividing cells, regardless of the
> cell geometry of the type of cells being treated.  
>   
>  [0021] According to one exemplary embodiment, cell
> geometry-dependent selective destruction of living tissue is
> performed by inducing a non-homogenous electric field in the
> cells using an electronic apparatus.  
>   
>  [0022] It has been observed by the present inventor that,
> while different cells in their non-dividing state may have
> different shapes, e.g., spherical, ellipsoidal, cylindrical,
> "pancake-like", etc., the division process of practically all
> cells is characterized by development of a "cleavage furrow" in
> late anaphase and telophase. This cleavage furrow is a slow
> constriction of the cell membrane (between the two sets of
> daughter chromosomes) which appears microscopically as a growing
> cleft (e.g., a groove or notch) that gradually separates the
> cell into two new cells. During the division process, there is a
> transient period (telophase) during which the cell structure is
> basically that of two sub-cells interconnected by a narrow
> "bridge" formed of the cell material. The division process is
> completed when the "bridge" between the two sub-cells is broken.
> The selective destruction of tumor cells using the present
> electronic apparatus utilizes this unique geometrical feature of
> dividing cells.  
>   
>  [0023] When a cell or a group of cells are under natural
> conditions or environment, i.e., part of a living tissue, they
> are disposed surrounded by a conductive environment consisting
> mostly of an electrolytic inter-cellular fluid and other cells
> that are composed mostly of an electrolytic intra-cellular
> liquid. When an electric field is induced in the living tissue,
> by applying an electric potential across the tissue, an electric
> field is formed in the tissue and the specific distribution and
> configuration of the electric field lines defines the direction
> of charge displacement, or paths of electric currents in the
> tissue, if currents are in fact induced in the tissue. The
> distribution and configuration of the electric field is
> dependent on various parameters of the tissue, including the
> geometry and the electric properties of the different tissue
> components, and the relative conductivities, capacities and
> dielectric constants (that may be frequency dependent) of the
> tissue components.  
>   
>  [0024] The electric current flow pattern for cells
> undergoing division is very different and unique as compared to
> non-dividing cells. Such cells including first and second
> sub-cells, namely an "original" cell and a newly formed cell,
> that are connected by a cytoplasm "bridge" or "neck". The
> currents penetrate the first sub-cell through part of the
> membrane ("the current source pole"); however, they do not exit
> the first sub-cell through a portion of its membrane closer to
> the opposite pole ("the current sink pole"). Instead, the lines
> of current flow converge at the neck or cytoplasm bridge,
> whereby the density of the current flow lines is greatly
> increased. A corresponding, "mirror image", process that takes
> place in the second sub-cell, whereby the current flow lines
> diverge to a lower density configuration as they depart from the
> bridge, and finally exit the second sub-cell from a part of its
> membrane closes to the current sink.  
>   
>  [0025] When a polarizable object is placed in a
> non-uniform converging or diverging field, electric forces act
> on it and pull it towards the higher density electric field
> lines. In the case of dividing cell, electric forces are exerted
> in the direction of the cytoplasm bridge between the two cells.
> Since all intercellular organelles and macromolecules are
> polarizable, they are all force towards the bridge between the
> two cells. The field polarity is irrelevant to the direction of
> the force and, therefore, an alternating electric having
> specific properties can be used to produce substantially the
> same effect. It will also be appreciated that the concentrated
> and inhomogeneous electric field present in or near the bridge
> or neck portion in itself exerts strong forces on charges and
> natural dipoles and can lead to the disruption of structures
> associated with these members.   
>   
> [0026] The movement of the cellular organelles towards the
> bridge disrupts the cell structure and results in increased
> pressure in the vicinity of the connecting bridge membrane. This
> pressure of the organelles on the bridge membrane is expected to
> break the bridge membrane and, thus, it is expected that the
> dividing cell will "explode" in response to this pressure. The
> ability to break the membrane and disrupt other cell structures
> can be enhanced by applying a pulsating alternating electric
> field that has a frequency from about 50 KHz to about 500 KHz.
> When this type of electric field is applied to the tissue, the
> forces exerted on the intercellular organelles have a
> "hammering" effect, whereby force pulses (or beats) are applied
> to the organelles numerous times per second, enhancing the
> movement of organelles of different sizes and masses towards the
> bridge (or neck) portion from both of the sub-cells, thereby
> increasing the probability of breaking the cell membrane at the
> bridge portion. The forces exerted on the intracellular
> organelles also affect the organelles themselves and may
> collapse or break the organelles.  
>   
>  [0027] According to one exemplary embodiment, the
> apparatus for applying the electric field is an electronic
> apparatus that generates the desired electric signals in the
> shape of waveforms or trains of pulses. The electronic apparatus
> includes a generator that generates an alternating voltage
> waveform at frequencies in the range from about 50 KHz to about
> 500 KHz. The generator is operatively connected to conductive
> leads which are connected at their other ends to insulated
> conductors/electrodes (also referred to as isolects) that are
> activated by the generated waveforms. The insulated electrodes
> consist of a conductor in contact with a dielectric (insulating
> layer) that is in contact with the conductive tissue, thus
> forming a capacitor. The electric fields that are generated by
> the present apparatus can be applied in several different modes
> depending upon the precise treatment application.  
>   
>  [0028] In one exemplary embodiment, the electric fields
> are applied by external insulated electrodes which are
> incorporated into an article of clothing and which are
> constructed so that the applied electric fields are of a local
> type that target a specific, localized area of tissue (e.g., a
> tumor). This embodiment is designed to treat tumors and lesions
> that are at or below the skin surface by wearing the article of
> clothing over the target tissue so that the electric fields
> generated by the insulated electrodes are directed at the tumors
> (lesions, etc.).   
>   
> [0029] According to another embodiment, the apparatus is used in
> an internal type application in that the insulated electrodes
> are in the form of a probe or catheter etc., that enter the body
> through natural pathways, such as the urethra or vagina, or are
> configured to penetrate living tissue, until the insulated
> electrodes are positioned near the internal target area (e.g.,
> an internal tumor).  
>   
>  [0030] Thus, the present apparatus utilizes electric
> fields that fall into a special intermediate category relative
> to previous high and low frequency applications in that the
> present electric fields are bio-effective fields that have no
> meaningful stimulatory effects and no thermal effects.
> Advantageously, when non-dividing cells are subjected to these
> electric fields, there is no effect on the cells; however, the
> situation is much different when dividing cells are subjected to
> the present electric fields. Thus, the present electronic
> apparatus and the generated electric fields target dividing
> cells, such as tumors or the like, and do not target
> non-dividing cells that is found around in healthy tissue
> surrounding the target area. Furthermore, since the present
> apparatus utilizes insulated electrodes, the above mentioned
> negative effects, obtained when conductive electrodes are used,
> i.e., ion concentration changes in the cells and the formation
> of harmful agents by electrolysis, do not occur with the present
> apparatus. This is because, in general, no actual transfer of
> charges takes place between the electrodes and the medium, and
> there is no charge flow in the medium where the currents are
> capacitive.  
>   
>  [0031] It should be appreciated that the present
> electronic apparatus can also be used in applications other than
> treatment of tumors in the living body. In fact, the selective
> destruction utilizing the present apparatus can be used in
> conjunction with any organism that proliferates by division, for
> example, tissue cultures, microorganisms, such as bacteria,
> mycoplasma, protozoa, fungi, algae, plant cells, etc. Such
> organisms divide by the formation of a groove or cleft as
> described above. As the groove or cleft deepens, a narrow bridge
> is formed between the two parts of the organism, similar to the
> bridge formed between the sub-cells of dividing animal cells.
> Since such organisms are covered by a membrane having a
> relatively low electric conductivity, similar to an animal cell
> membrane described above, the electric field lines in a dividing
> organism converge at the bridge connecting the two parts of the
> dividing organism. The converging field lines result in electric
> forces that displace polarizable elements and charges within the
> dividing organism.  
>   
>  [0032] The above, and other objects, features and
> advantages of the present apparatus will become apparent from
> the following description read in conjunction with the
> accompanying drawings, in which like reference numerals
> designate the same elements.  
>   
>  BRIEF DESCRIPTION OF THE
> DRAWINGS   
>   
>   
>   
> [0033] FIGS. 1A-1E are
> simplified, schematic, cross-sectional, illustrations of
> various stages of a cell division process;  
>   
>  [0034] FIGS. 2A and 2B are schematic illustrations of a
> non-dividing cell being subjected to an electric field;  
>   
>  [0035] FIGS. 3A, 3B and 3C are schematic illustrations
> of a dividing cell being subjected to an electric field
> according to one exemplary embodiment, resulting in
> destruction of the cell (FIG. 3C) in accordance with one
> exemplary embodiment;   
>   
> [0036] FIG. 4 is a schematic
> illustration of a dividing cell at one stage being subject to
> an electric field;  
>   
>  [0037] FIG. 5 is a
> schematic block diagram of an apparatus for applying an
> electric according to one exemplary embodiment for selectively
> destroying cells;  
>   
>  [0038] FIG. 6 is a
> simplified schematic diagram of an equivalent electric circuit
> of insulated electrodes of the apparatus of FIG. 5;   
>   
> [0039] FIG. 7 is a cross-sectional illustration of a skin
> patch incorporating the apparatus of FIG. 5 and for placement
> on a skin surface for treating a tumor or the like;  
>   
> [0040] FIG. 8 is a
> cross-sectional illustration of the insulated electrodes
> implanted within the body for treating a tumor or the like;  
>   
> [0041] FIG. 9 is a
> cross-sectional illustration of the insulated electrodes
> implanted within the body for treating a tumor or the like;  
>   
>  [0042] FIGS. 10A-10D are
> cross-sectional illustrations of various constructions of the
> insulated electrodes of the apparatus of FIG. 5;  
>   
>  [0043] FIG. 11 is a front
> elevational view in partial cross-section of two insulated
> electrodes being arranged about a human torso for treatment of
> a tumor container within the body, e.g., a tumor associated
> with lung cancer;  
>   
>  [0044] FIGS. 12A-12Care
> cross-sectional illustrations of various insulated electrodes
> with and without protective members formed as a part of the
> construction thereof;  
>   
>  [0045] FIG. 13 is a
> schematic diagram of insulated electrodes that are arranged
> for focusing the electric field at a desired target while
> leaving other areas in low field density (i.e., protected
> areas);  
>   
>  [0046] FIG. 14 is a
> cross-sectional view of insulated electrodes incorporated into
> a hat according to a first embodiment for placement on a head
> for treating an intra-cranial tumor or the like;  
>   
>  [0047] FIG. 15 is a
> partial section of a hat according to an exemplary embodiment
> having a recessed section for receiving one or more insulated
> electrodes;  
>   
>  [0048] FIG. 16 is a
> cross-sectional view of the hat of FIG. 15 placed on a head
> and illustrating a biasing mechanism for applying a force to
> the insulated electrode to ensure the insulated electrode
> remains in contact against the head;  
>   
>  [0049] FIG. 17 is a
> cross-sectional top view of an article of clothing having the
> insulated electrodes incorporated therein for treating a tumor
> or the like;  
>   
>  [0050] FIG. 18 is a
> cross-sectional view of a section of the article of clothing
> of FIG. 17 illustrating a biasing mechanism for biasing the
> insulated electrode in direction to ensure the insulated
> electrode is placed proximate to a skin surface where
> treatment is desired;  
>   
>  [0051] FIG. 19 is a
> cross-sectional view of a probe according to one embodiment
> for being disposed internally within the body for treating a
> tumor or the like;  
>   
>  [0052] FIG. 20 is an elevational view of an unwrapped
> collar according to one exemplary embodiment for placement
> around a neck for treating a tumor or the like in this area
> when the collar is wrapped around the neck;  
>   
>  [0053] FIG. 21 is a
> cross-sectional view of two insulated electrodes with
> conductive gel members being arranged about a body, with the
> electric field lines being shown;  
>   
>  [0054] FIG. 22 is a
> cross-sectional view of the arrangement of FIG. 21
> illustrating a point of insulation breakdown in one insulated
> electrode;   
>   
> [0055] FIG. 23 is a
> cross-sectional view of an arrangement of at least two
> insulated electrodes with conductive gel members being
> arranged about a body for treatment of a tumor or the like,
> wherein each conductive gel member has a feature for
> minimizing the effects of an insulation breakdown in the
> insulated electrode;  
>   
>  [0056] FIG. 24 is a
> cross-sectional view of another arrangement of at least two
> insulated electrodes with conductive gel members being
> arranged about a body for treatment of a tumor or the like,
> wherein a conductive member is disposed within the body near
> the tumor to create a region of increased field density;  
>   
>  [0057] FIG. 25 is a
> cross-sectional view of an arrangement of two insulated
> electrodes of varying sizes disposed relative to a body; and  
>   
>  [0058] FIG. 26 is a
> cross-sectional view of an arrangement of at least two
> insulated electrodes with conductive gel members being
> arranged about a body for treatment of a tumor or the like,
> wherein each conductive gel member has a feature for
> minimizing the effects of an insulation breakdown in the
> insulated electrode.  
>   
>  [0059] FIGS. 27A-C show a
> configuration of electrodes that facilitates the application
> of an electric field in different directions. [0060] FIG. 28
> shows a three-dimensional arrangement of electrodes about a
> body part that facilitates the application of an electric
> field in different directions.   
>   
> [0061] FIGS. 29A and 29B are
> graphs of the efficiency of the cell destruction process as a
> function of field strength for melanoma and glioma cells,
> respectively.   
>   
> [0062] FIGS. 30A and 30B are
> graphs that show how the cell destruction efficiency is a
> function of the frequency of the applied field for melanoma
> and glioma cells, respectively.  
>   
>  [0063] FIG. 31A is a
> graphical representation of the sequential application of a
> plurality of frequencies in a plurality of directions.   
>   
> [0064] FIG. 31B is a graphical
> representation of the sequential application of a sweeping
> frequency in a plurality of directions.   
>   
> DETAILED DESCRIPTION OF
> PREFERRED EMBODIMENTS  
>   
>  [0065] Reference is made to FIGS. 1A-1E which
> schematically illustrate various stages of a cell division
> process. FIG. 1A illustrates a cell 10 at its normal geometry,
> which can be generally spherical (as illustrated in the
> drawings), ellipsoidal, cylindrical, "pancake-like" or any other
> cell geometry, as is known in the art. FIGS. 1B-1D illustrate
> cell 10 during different stages of its division process, which
> results in the formation of two new cells 18 and 20, shown in
> FIG. 1E.  
>   
>  [0066] As shown in FIGS. 1B-1D, the division process of
> cell 10 is characterized by a slowly growing cleft 12 which
> gradually separates cell 10 into two units, namely sub-cells 14
> and 16, which eventually evolve into new cells 18 and 20 (FIG.
> 1E). A shown specifically in FIG. 1D, the division process is
> characterized by a transient period during which the structure
> of cell 10 is basically that of the two sub-cells 14 and 16
> interconnected by a narrow "bridge" 22 containing cell material
> (cytoplasm surrounded by cell membrane).  
>   
>  [0067] Reference is now made to FIGS. 2A and 2B, which
> schematically illustrate non-dividing cell 10 being subjected to
> an electric field produced by applying an alternating electric
> potential, at a relatively low frequency and at a relatively
> high frequency, respectively. Cell 10 includes intracellular
> organelles, e.g., a nucleus 30. Alternating electric potential
> is applied across electrodes 28 and 32 that can be attached
> externally to a patient at a predetermined region, e.g., in the
> vicinity of the tumor being treated. When cell 10 is under
> natural conditions, i.e., part of a living tissue, it is
> disposed in a conductive environment (hereinafter referred to as
> a "volume conductor") consisting mostly of electrolytic
> inter-cellular liquid. When an electric potential is applied
> across electrodes 28 and 32, some of the field lines of the
> resultant electric field (or the current induced in the tissue
> in response to the electric field) penetrate the cell 10, while
> the rest of the field lines (or induced current) flow in the
> surrounding medium. The specific distribution of the electric
> field lines, which is substantially consistent with the
> direction of current flow in this instance, depends on the
> geometry and the electric properties of the system components,
> e.g., the relative conductivities and dielectric constants of
> the system components, that can be frequency dependent. For low
> frequencies, e.g., frequencies lower than 10 KHz, the
> conductance properties of the components completely dominate the
> current flow and the field distribution, and the field
> distribution is generally as depicted in FIG. 2A. At higher
> frequencies, e.g., at frequencies of between 10 KHz and 1 MHz,
> the dielectric properties of the components becomes more
> significant and eventually dominate the field distribution,
> resulting in field distribution lines as depicted generally in
> FIG. 2B.  
>   
>  [0068] For constant (i.e., DC) electric fields or
> relatively low frequency alternating electric fields, for
> example, frequencies under 10 KHz, the dielectric properties of
> the various components are not significant in determining and
> computing the field distribution. Therefore, as a first
> approximation, with regard to the electric field distribution,
> the system can be reasonably represented by the relative
> impedances of its various components. Using this approximation,
> the intercellular (i.e., extracellular) fluid and the
> intracellular fluid each has a relatively low impedance, while
> the cell membrane 11 has a relatively high impedance. Thus,
> under low frequency conditions, only a fraction of the electric
> field lines (or currents induced by the electric field)
> penetrate membrane 11 of the cell 10. At relatively high
> frequencies (e.g., 10 KHz-1 MHz), in contrast, the impedance of
> membrane 11 relative to the intercellular and intracellular
> fluids decreases, and thus, the fraction of currents penetrating
> the cells increases significantly. It should be noted that at
> very high frequencies, i.e., above 1 MHz, the membrane
> capacitance can short the membrane resistance and, therefore,
> the total membrane resistance can become negligible.  
>   
>  [0069] In any of the embodiments described above, the
> electric field lines (or induced currents) penetrate cell 10
> from a portion of the membrane 11 closest to one of the
> electrodes generating the current, e.g., closest to positive
> electrode 28 (also referred to herein as "source"). The current
> flow pattern across cell 10 is generally uniform because, under
> the above approximation, the field induced inside the cell is
> substantially homogeneous. The currents exit cell 10 through a
> portion of membrane 11 closest to the opposite electrode, e.g.,
> negative electrode 32 (also referred to herein as "sink").   
>   
> [0070] The distinction between field lines and current flow can
> depend on a number of factors, for example, on the frequency of
> the applied electric potential and on whether electrodes 28 and
> 32 are electrically insulated. For insulated electrodes applying
> a DC or low frequency alternating voltage, there is practically
> no current flow along the lines of the electric field. At higher
> frequencies, the displacement currents are induced in the tissue
> due to charging and discharging of the electrode insulation and
> the cell membranes (which act as capacitors to a certain
> extent), and such currents follow the lines of the electric
> field. Fields generated by non-insulated electrodes, in
> contrast, always generate some form of current flow,
> specifically, DC or low frequency alternating fields generate
> conductive current flow along the field lines, and high
> frequency alternating fields generate both conduction and
> displacement currents along the field lines. It should be
> appreciated, however, that movement of polarizable intracellular
> organelles according to the present invention (as described
> below) is not dependent on actual flow of current and,
> therefore, both insulated and non-insulated electrodes can be
> used efficiently. Advantages of insulated electrodes include
> lower power consumption, less heating of the treated regions,
> and improved patient safety.   
>   
> [0071] According to one exemplary embodiment of the present
> invention, the electric fields that are used are alternating
> fields having frequencies that are in the range from about 50
> KHz to about 500 KHz, and preferably from about 100 KHz to about
> 300 KHz. For ease of discussion, these type of electric fields
> are also referred to below as "TC fields", which is an
> abbreviation of "Tumor Curing electric fields", since these
> electric fields fall into an intermediate category (between high
> and low frequency ranges) that have bio-effective field
> properties while having no meaningful stimulatory and thermal
> effects. These frequencies are sufficiently low so that the
> system behavior is determined by the system's Ohmic (conductive)
> properties but sufficiently high enough not to have any
> stimulation effect on excitable tissues. Such a system consists
> of two types of elements, namely, the intercellular, or
> extracellular fluid, or medium and the individual cells. The
> intercellular fluid is mostly an electrolyte with a specific
> resistance of about 40-100 Ohm\*cm. As mentioned above, the cells
> are characterized by three elements, namely (1) a thin, highly
> electric resistive membrane that coats the cell; (2) internal
> cytoplasm that is mostly an electrolyte that contains numerous
> macromolecules and micro-organelles, including the nucleus; and
> (3) membranes, similar in their electric properties to the cell
> membrane, cover the micro-organelles.   
>   
> [0072] When this type of system is subjected to the present TC
> fields (e.g., alternating electric fields in the frequency range
> of 100 KHz-300 KHz) most of the lines of the electric field and
> currents tend away from the cells because of the high resistive
> cell membrane and therefore the lines remain in the
> extracellular conductive medium. In the above recited frequency
> range, the actual fraction of electric field or currents that
> penetrates the cells is a strong function of the frequency.   
>   
> [0073] FIG. 2 schematically depicts the resulting field
> distribution in the system. As illustrated, the lines of force,
> which also depict the lines of potential current flow across the
> cell volume mostly in parallel with the undistorted lines of
> force (the main direction of the electric field). In other
> words, the field inside the cells is mostly homogeneous. In
> practice, the fraction of the field or current that penetrates
> the cells is determined by the cell membrane impedance value
> relative to that of the extracellular fluid. Since the
> equivalent electric circuit of the cell membrane is that of a
> resistor and capacitor in parallel, the impedance is a function
> of the frequency. The higher the frequency, the lower the
> impedance, the larger the fraction of penetrating current and
> the smaller the field distortion (Rotshenker S. & Y. Palti,
> Changes in fraction of current penetrating an axon as a function
> of duration of stimulating pulse, J. Theor. Biol. 41; 401-407
> (1973).  
>   
>  [0074] As previously mentioned, when cells are subjected
> to relatively weak electric fields and currents that alternate
> at high frequencies, such as the present TC fields having a
> frequency in the range of 50 KHz-500 KHz, they have no effect on
> the non-dividing cells. While the present TC fields have no
> detectable effect on such systems, the situation becomes
> different in the presence of dividing cells.  
>   
>  [0075] Reference is now made to FIGS. 3A-3C which
> schematically illustrate the electric current flow pattern in
> cell 10 during its division process, under the influence of
> alternating fields (TC fields) in the frequency range from about
> 100 KHz to about 300 KHz in accordance with one exemplary
> embodiment. The field lines or induced currents penetrate cell
> 10 through a part of the membrane of sub-cell 16 closer to
> electrode 28. However, they do not exit through the cytoplasm
> bridge 22 that connects sub-cell 16 with the newly formed yet
> still attached sub-cell 14, or through a part of the membrane in
> the vicinity of the bridge 22. Instead, the electric field or
> current flow lines-that are relatively widely separated in
> sub-cell 16-converge as they approach bridge 22 (also referred
> to as "neck" 22) and, thus, the current/field line density
> within neck 22 is increased dramatically. A "mirror image"
> process takes place in sub-cell 14, whereby the converging field
> lines in bridge 22 diverge as they approach the exit region of
> sub-cell 14.   
>   
> [0076] It should be appreciated by persons skilled in the art
> that homogeneous electric fields do not exert a force on
> electrically neutral objects, i.e., objects having substantially
> zero net charge, although such objects can become polarized.
> However, under a non-uniform, converging electric field, as
> shown in FIGS. 3A-3C, electric forces are exerted on polarized
> objects, moving them in the direction of the higher density
> electric field lines. It will be appreciated that the
> concentrated electric field that is present in the neck or
> bridge area in itself exerts strong forces on charges and
> natural dipoles and can disrupt structures that are associated
> therewith. One will understand that similar net forces act on
> charges in an alternating field, again in the direction of the
> field of higher intensity.  
>   
>  [0077] In the configuration of FIGS. 3A and 3B, the
> direction of movement of polarized and charged objects is
> towards the higher density electric field lines, i.e., towards
> the cytoplasm bridge 22 between sub-cells 14 and 16. It is known
> in the art that all intracellular organelles, for example,
> nuclei 24 and 26 of sub-cells 14 and 16, respectively, are
> polarizable and, thus, such intracellular organelles are
> electrically forced in the direction of the bridge 22. Since the
> movement is always from lower density currents to the higher
> density currents, regardless of the field polarity, the forces
> applied by the alternating electric field to organelles, such as
> nuclei 24 and 26, are always in the direction of bridge 22. A
> comprehensive description of such forces and the resulting
> movement of macromolecules of intracellular organelles, a
> phenomenon referred to as "dielectrophoresis" is described
> extensively in literature, e.g., in C. L. Asbury & G. van
> den Engh, Biophys. J. 74, 1024-1030, 1998, the disclosure of
> which is hereby incorporated by reference in its entirety.  
>   
>  [0078] The movement of the organelles 24 and 26 towards
> the bridge 22 disrupts the structure of the dividing cell,
> change the concentration of the various cell constituents and,
> eventually, the pressure of the converging organelles on bridge
> membrane 22 results in the breakage of cell membrane 11 at the
> vicinity of the bridge 22, as shown schematically in FIG. 3C.
> The ability to break membrane 11 at bridge 22 and to otherwise
> disrupt the cell structure and organization can be enhanced by
> applying a pulsating AC electric field, rather than a steady AC
> field. When a pulsating field is applied, the forces acting on
> organelles 24 and 26 have a "hammering" effect, whereby pulsed
> forces beat on the intracellular organelles towards the neck 22
> from both sub-cells 14 and 16, thereby increasing the
> probability of breaking cell membrane 11 in the vicinity of neck
> 22.  
>   
>  [0079] A very important element, which is very susceptible
> to the special fields that develop within the dividing cells is
> the microtubule spindle that plays a major role in the division
> process. In FIG. 4, a dividing cell 10 is illustrated, at an
> earlier stage as compared to FIGS. 3A and 3B, under the
> influence of external TC fields (e.g., alternating fields in the
> frequency range of about 100 KHz to about 300 KHz), generally
> indicated as lines 100, with a corresponding spindle mechanism
> generally indicated at 120. The lines 120 are microtubules that
> are known to have a very strong dipole moment. This strong
> polarization makes the tubules, as well as other polar
> macromolecules and especially those that have a specific
> orientation within the cells or its surrounding, susceptible to
> electric fields. Their positive charges are located at the two
> centrioles while two sets of negative poles are at the center of
> the dividing cell and the other pair is at the points of
> attachment of the microtubules to the cell membrane, generally
> indicated at 130. This structure forms sets of double dipoles
> and therefore they are susceptible to fields of different
> directions. It will be understood that the effect of the TC
> fields on the dipoles does not depend on the formation of the
> bridge (neck) and thus, the dipoles are influenced by the TC
> fields prior to the formation of the bridge (neck).  
>   
>  [0080] Since the present apparatus (as will be described
> in greater detail below) utilizes insulated electrodes, the
> above-mentioned negative effects obtained when conductive
> electrodes are used, i.e., ion concentration changes in the
> cells and the formation of harmful agents by electrolysis, do
> not occur when the present apparatus is used. This is because,
> in general, no actual transfer of charges takes place between
> the electrodes and the medium and there is no charge flow in the
> medium where the currents are capacitive, i.e., are expressed
> only as rotation of charges, etc.  
>   
>  [0081] Turning now to FIG. 5, the TC fields described
> above that have been found to advantageously destroy tumor cells
> are generated by an electronic apparatus 200. FIG. 5 is a simple
> schematic diagram of the electronic apparatus 200 illustrating
> the major components thereof. The electronic apparatus 200
> generates the desired electric signals (TC signals) in the shape
> of waveforms or trains of pulses. The apparatus 200 includes a
> generator 210 and a pair of conductive leads 220 that are
> attached at one end thereof to the generator 210. The opposite
> ends of the leads 220 are connected to insulated conductors 230
> that are activated by the electric signals (e.g., waveforms).
> The insulated conductors 230 are also referred to hereinafter as
> isolects 230. Optionally and according to another exemplary
> embodiment, the apparatus 200 includes a temperature sensor 240
> and a control box 250 which are both added to control the
> amplitude of the electric field generated so as not to generate
> excessive heating in the area that is treated.  
>   
>  [0082] The generator 210 generates an alternating voltage
> waveform at frequencies in the range from about 50 KHz to about
> 500 KHz (preferably from about 100 KHz to about 300 KHz) (i.e.,
> the TC fields). The required voltages are such that the electric
> field intensity in the tissue to be treated is in the range of
> about 0.1 V/cm to about 10 V/cm. To achieve this field, the
> actual potential difference between the two conductors in the
> isolects 230 is determined by the relative impedances of the
> system components, as described below.  
>   
> [0083] When the control box 250 is included, it controls the
> output of the generator 210 so that it will remain constant at
> the value preset by the user or the control box 250 sets the
> output at the maximal value that does not cause excessive
> heating, or the control box 250 issues a warning or the like
> when the temperature (sensed by temperature sensor 240) exceeds
> a preset limit.   
>   
> [0084] The leads 220 are standard isolated conductors with a
> flexible metal shield, preferably grounded so that it prevents
> the spread of the electric field generated by the leads 220. The
> isolects 230 have specific shapes and positioning so as to
> generate an electric field of the desired configuration,
> direction and intensity at the target volume and only there so
> as to focus the treatment.  
>   
>  [0085] The specifications of the apparatus 200 as a whole
> and its individual components are largely influenced by the fact
> that at the frequency of the present TC fields (50 KHz-500 KHz),
> living systems behave according to their "Ohmic", rather than
> their dielectric properties. The only elements in the apparatus
> 200 that behave differently are the insulators of the isolects
> 230 (see FIGS. 7-9). The isolects 200 consist of a conductor in
> contact with a dielectric that is in contact with the conductive
> tissue thus forming a capacitor.  
>   
>  [0086] The details of the construction of the isolects 230
> is based on their electric behavior that can be understood from
> their simplified electric circuit when in contact with tissue as
> generally illustrated in FIG. 6. In the illustrated arrangement,
> the potential drop or the electric field distribution between
> the different components is determined by their relative
> electric impedance, i.e., the fraction of the field on each
> component is given by the value of its impedance divided by the
> total circuit impedance. For example, the potential drop on
> element [Delta]VA=A/(A+B+C+D+E). Thus, for DC or low frequency
> AC, practically all the potential drop is on the capacitor (that
> acts as an insulator). For relatively very high frequencies, the
> capacitor practically is a short and therefore, practically all
> the field is distributed in the tissues. At the frequencies of
> the present TC fields (e.g., 50 KHz to 500 KHz), which are
> intermediate frequencies, the impedance of the capacitance of
> the capacitors is dominant and determines the field
> distribution. Therefore, in order to increase the effective
> voltage drop across the tissues (field intensity), the impedance
> of the capacitors is to be decreased (i.e., increase their
> capacitance). This can be achieved by increasing the effective
> area of the "plates" of the capacitor, decrease the thickness of
> the dielectric or use a dielectric with high dielectric
> constant.  
>   
>  [0087] In order to optimize the field distribution, the
> isolects 230 are configured differently depending upon the
> application in which the isolects 230 are to be used. There are
> two principle modes for applying the present electric fields (TC
> fields). First, the TC fields can be applied by external
> isolects and second, the TC fields can be applied by internal
> isolects.  
>   
>  [0088] Electric fields (TC fields) that are applied by
> external isolects can be of a local type or widely distributed
> type. The first type includes, for example, the treatment of
> skin tumors and treatment of lesions close to the skin surface.
> FIG. 7 illustrates an exemplary embodiment where the isolects
> 230 are incorporated in a skin patch 300. The skin patch 300 can
> be a self-adhesive flexible patch with one or more pairs of
> isolects 230. The patch 300 includes internal insulation 310
> (formed of a dielectric material) and the external insulation
> 260 and is applied to skin surface 301 that contains a tumor 303
> either on the skin surface 301 or slightly below the skin
> surface 301. Tissue is generally indicated at 305. To prevent
> the potential drop across the internal insulation 310 to
> dominate the system, the internal insulation 310 must have a
> relatively high capacity. This can be achieved by a large
> surface area; however, this may not be desired as it will result
> in the spread of the field over a large area (e.g., an area
> larger than required to treat the tumor). Alternatively, the
> internal insulation 310 can be made very thin and/or the
> internal insulation 310 can be of a high dielectric constant. As
> the skin resistance between the electrodes (labeled as A and E
> in FIG. 6) is normally significantly higher than that of the
> tissue (labeled as C in FIG. 6) underneath it (1-10 K[Omega] vs.
> 0.1-1 K[Omega]), most of the potential drop beyond the isolects
> occurs there. To accommodate for these impedances (Z), the
> characteristics of the internal insulation 310 (labeled as B and
> D in FIG. 6) should be such that they have impedance preferably
> under 100 K[Omega] at the frequencies of the present TC fields
> (e.g., 50 KHz to 500 KHz). For example, if it is desired for the
> impedance to be about 10 K Ohms or less, such that over 1% of
> the applied voltage falls on the tissues, for isolects with a
> surface area of 10 mm<2> , at frequencies of 200 KHz, the
> capacity should be on the order of 10<-10 > F., which
> means that using standard insulations with a dielectric constant
> of 2-3, the thickness of the insulating layer 310 should be
> about 50-100 microns. An internal field 10 times stronger would
> be obtained with insulators with a dielectric constant of about
> 20-50.  
>   
> [0089] Using an insulating material with a high dielectric
> constant increases the capacitance of the electrodes, which
> results in a reduction of the electrodes' impedance to the AC
> signal that is applied by the generator 1 (shown in FIG. 5).
> Because the electrodes A, E are wired in series with the target
> tissue C, as shown in FIG. 6, this reduction in impedance
> reduces the voltage drop in the electrodes, so that a larger
> portion of the applied AC voltage appears across the tissue C.
> Since a larger portion of the voltage appears across the tissue,
> the voltage that is being applied by the generator 1 can be
> advantageously lowered for a given field strength in the tissue.  
>   
>  [0090] The desired field strength in the tissue being
> treated is preferably between about 0.1 V/cm and about 10 V/cm,
> and more preferably between about 2 V/cm and 3 V/cm or between
> about 1 V/cm and about 5 V/cm. If the dielectric constant used
> in the electrode is sufficiently high, the impedance of the
> electrodes A, E drops down to the same order of magnitude as the
> series combination of the skin and tissue B, C, D. One example
> of a suitable material with an extremely high dielectric
> constant is CaCu3Ti4O12, which has a dielectric constant of
> about 11,000 (measured at 100 kHz). When the dielectric constant
> is this high, useful fields can be obtained using a generator
> voltage that is on the order of a few tens of Volts.  
>   
>  [0091] Since the thin insulating layer can be very
> vulnerable, etc., the insulation can be replaced by very high
> dielectric constant insulating materials, such as titanium
> dioxide (e.g., rutile), the dielectric constant can reach values
> of about 200. There a number of different materials that are
> suitable for use in the intended application and have high
> dielectric constants. For example, some materials include:
> lithium niobate (LiNbO3), which is a ferroelectric crystal and
> has a number of applications in optical, pyroelectric and
> piezoelectric devices; yttrium iron garnet (YIG) is a
> ferromagnetic crystal and magneto-optical devices, e.g., optical
> isolator can be realized from this material; barium titanate
> (BaTiO3) is a ferromagnetic crystal with a large electro-optic
> effect; potassium tantalate (KTaO3) which is a dielectric
> crystal (ferroelectric at low temperature) and has very low
> microwave loss and tunability of dielectric constant at low
> temperature; and lithium tantalate (LiTaO3) which is a
> ferroelectric crystal with similar properties as lithium niobate
> and has utility in electro-optical, pyroelectric and
> piezoelectric devices. Insulator ceramics with high dielectric
> constants may also be used, such as a ceramic made of a
> combination of Lead Magnesium Niobate and Lead Titanate. It will
> be understood that the aforementioned exemplary materials can be
> used in combination with the present device where it is desired
> to use a material having a high dielectric constant.  
>   
>  [0092] One must also consider another factor that affects
> the effective capacity of the isolects 230, namely the presence
> of air between the isolects 230 and the skin. Such presence,
> which is not easy to prevent, introduces a layer of an insulator
> with a dielectric constant of 1.0, a factor that significantly
> lowers the effective capacity of the isolects 230 and
> neutralizes the advantages of the titanium dioxide (rutile),
> etc. To overcome this problem, the isolects 230can be shaped so
> as to conform with the body structure and/or (2) an intervening
> filler 270 (as illustrated in FIG. 10C), such as a gel, that has
> high conductance and a high effective dielectric constant, can
> be added to the structure. The shaping can be pre-structured
> (see FIG. 10A) or the system can be made sufficiently flexible
> so that shaping of the isolects 230 is readily achievable. The
> gel can be contained in place by having an elevated rim as
> depicted in FIGS. 10C and 10C'. The gel can be made of
> hydrogels, gelatins, agar, etc., and can have salts dissolved in
> it to increase its conductivity. FIGS. 10A-10C' illustrate
> various exemplary configurations for the isolects 230. The exact
> thickness of the gel is not important so long as it is of
> sufficient thickness that the gel layer does not dry out during
> the treatment. In one exemplary embodiment, the thickness of the
> gel is about 0.5 mm to about 2 mm. Preferably, the gel has high
> conductivity, is tacky, and is biocompatible for extended
> periods of time. One suitable gel is AG603 Hydrogel, which is
> available from AmGel Technologies, 1667 S. Mission Road,
> Fallbrook, Calif. 92028-4115, USA. [0093] In order to achieve
> the desirable features of the isolects 230, the dielectric
> coating of each should be very thin, for example from between
> 1-50 microns. Since the coating is so thin, the isolects 230 can
> easily be damaged mechanically or undergo dielectric breakdown.
> This problem can be overcome by adding a protective feature to
> the isolect's structure so as to provide desired protection from
> such damage. For example, the isolect 230 can be coated, for
> example, with a relatively loose net 340 that prevents access to
> the surface but has only a minor effect on the effective surface
> area of the isolect 230 (i.e., the capacity of the isolects 230
> (cross section presented in FIG. 12B). The loose net 340 does
> not effect the capacity and ensures good contact with the skin,
> etc. The loose net 340 can be formed of a number of different
> materials; however, in one exemplary embodiment, the net 340 is
> formed of nylon, polyester, cotton, etc. Alternatively, a very
> thin conductive coating 350 can be applied to the dielectric
> portion (insulating layer) of the isolect 230. One exemplary
> conductive coating is formed of a metal and more particularly of
> gold. The thickness of the coating 350 depends upon the
> particular application and also on the type of material used to
> form the coating 350; however, when gold is used, the coating
> has a thickness from about 0.1 micron to about 0.1 mm.
> Furthermore, the rim illustrated in FIG. 10 can also provide
> some mechanical protection.  
>   
>  [0094] However, the capacity is not the only factor to be
> considered. The following two factors also influence how the
> isolects 230 are constructed. The dielectric strength of the
> internal insulating layer 310 and the dielectric losses that
> occur when it is subjected to the TC field, i.e., the amount of
> heat generated. The dielectric strength of the internal
> insulation 310 determines at what field intensity the insulation
> will be "shorted" and cease to act as an intact insulation.
> Typically, insulators, such as plastics, have dielectric
> strength values of about 100V per micron or more. As a high
> dielectric constant reduces the field within the internal
> insulator 310, a combination of a high dielectric constant and a
> high dielectric strength gives a significant advantage. This can
> be achieved by using a single material that has the desired
> properties or it can be achieved by a double layer with the
> correct parameters and thickness. In addition, to further
> decreasing the possibility that the insulating layer 310 will
> fail, all sharp edges of the insulating layer 310 should be
> eliminated as by rounding the corners, etc., as illustrated in
> FIG. 10D using conventional techniques.  
>   
> 0095] FIGS. 8 and 9 illustrate a second type of treatment using
> the isolects 230, namely electric field generation by internal
> isolects 230. A body to which the isolects 230 are implanted is
> generally indicated at 311 and includes a skin surface 313 and a
> tumor 315. In this embodiment, the isolects 230 can have the
> shape of plates, wires or other shapes that can be inserted
> subcutaneously or a deeper location within the body 311 so as to
> generate an appropriate field at the target area (tumor 315).  
>   
>  [0096] It will also be appreciated that the mode of
> isolects application is not restricted to the above
> descriptions. In the case of tumors in internal organs, for
> example, liver, lung, etc., the distance between each member of
> the pair of isolects 230 can be large. The pairs can even by
> positioned opposite sides of a torso 410, as illustrated in FIG.
> 11. The arrangement of the isolects 230 in FIG. 11 is
> particularly useful for treating a tumor 415 associated with
> lung cancer or gastro-intestinal tumors. In this embodiment, the
> electric fields (TC fields) spread in a wide fraction of the
> body.  
>   
>  [0097] In order to avoid overheating of the treated
> tissues, a selection of materials and field parameters is
> needed. The isolects insulating material should have minimal
> dielectric losses at the frequency ranges to be used during the
> treatment process. This factor can be taken into consideration
> when choosing the particular frequencies for the treatment. The
> direct heating of the tissues will most likely be dominated by
> the heating due to current flow (given by the I\*R product). In
> addition, the isolect (insulated electrode) 230 and its
> surroundings should be made of materials that facilitate heat
> losses and its general structure should also facilitate head
> losses, i.e., minimal structures that block heat dissipation to
> the surroundings (air) as well as high heat conductivity. Using
> larger electrodes also minimizes the local sensation of heating,
> since it spreads the energy that is being transferred into the
> patient over a larger surface area. Preferably, the heating is
> minimized to the point where the patient's skin temperature
> never exceeds about 39[deg.] C.   
>   
> [0098] Another way to reduce heating is to apply the field to
> the tissue being treated intermittently, by applying a field
> with a duty cycle between about 20% and about 50% instead of
> using a continuous field. For example, to achieve a duty cycle
> of 33%, the field would be repetitively switched on for one
> second, then switched off for two seconds. Preliminary
> experiments have shown that the efficacy of treatment using a
> field with a 33% duty cycle is roughly the same as for a field
> with a duty cycle of 100%. In alternative embodiments, the field
> could be switched on for one hour then switched off for one hour
> to achieve a duty cycle of 50%. Of course, switching at a rate
> of once per hour would not help minimize short-term heating. On
> the other hand, it could provide the patient with a welcome
> break from treatment.  
>   
>  [0099] The effectiveness of the treatment can be enhanced
> by an arrangement of isolects 230 that focuses the field at the
> desired target while leaving other sensitive areas in low field
> density (i.e., protected areas). The proper placement of the
> isolects 230 over the body can be maintained using any number of
> different techniques, including using a suitable piece of
> clothing that keeps the isolects at the appropriate positions.
> FIG. 13 illustrates such an arrangement in which an area labeled
> as "P" represents a protected area. The lines of field force do
> not penetrate this protected area and the field there is much
> smaller than near the isolects 230 where target areas can be
> located and treated well. In contrast, the field intensity near
> the four poles is very high.  
>   
>  [0100] The following Example serves to illustrate an
> exemplary application of the present apparatus and application
> of TC fields; however, this Example is not limiting and does not
> limit the scope of the present invention in any way.  
>   
>  EXAMPLE  
>   
>  [0101] To demonstrate the effectiveness of electric fields
> having the above described properties (e.g., frequencies between
> 50 KHz and 500 KHz) in destroying tumor cells, the electric
> fields were applied to treat mice with malignant melanoma
> tumors. Two pairs of isolects 230 were positioned over a
> corresponding pair of malignant melanomas. Only one pair was
> connected to the generator 210 and 200 KHz alternating electric
> fields (TC fields) were applied to the tumor for a period of 6
> days. One melanoma tumor was not treated so as to permit a
> comparison between the treated tumor and the non-treated tumor.
> After treatment for 6 days, the pigmented melanoma tumor
> remained clearly visible in the non-treated side of the mouse,
> while, in contrast, no tumor is seen on the treated side of the
> mouse. The only areas that were visible discernable on the skin
> were the marks that represented the points of insertion of the
> isolects 230. The fact that the tumor was eliminated at the
> treated side was further demonstrated by cutting and inversing
> the skin so that its inside face was exposed. Such a procedure
> indicated that the tumor has been substantially, if not
> completely, eliminated on the treated side of the mouse. The
> success of the treatment was also further verified by
> histopathological examination.  
>   
>  [0102] The present inventor has thus uncovered that
> electric fields having particular properties can be used to
> destroy dividing cells or tumors when the electric fields are
> applied to using an electronic device. More specifically, these
> electric fields fall into a special intermediate category,
> namely bio-effective fields that have no meaningful stimulatory
> and no thermal effects, and therefore overcome the disadvantages
> that were associated with the application of conventional
> electric fields to a body. It will also be appreciated that the
> present apparatus can further include a device for rotating the
> TC field relative to the living tissue. For example and
> according to one embodiment, the alternating electric potential
> applies to the tissue being treated is rotated relative to the
> tissue using conventional devices, such as a mechanical device
> that upon activation, rotates various components of the present
> system.  
>   
>  [0103] Moreover and according to yet another embodiment,
> the TC fields are applied to different pairs of the insulated
> electrodes 230 in a consecutive manner. In other words, the
> generator 210 and the control system thereof can be arranged so
> that signals are sent at periodic intervals to select pairs of
> insulated electrodes 230, thereby causing the generation of the
> TC fields of different directions by these insulated electrodes
> 230. Because the signals are sent at select times from the
> generator to the insulated electrodes 230, the TC fields of
> changing directions are generated consecutively by different
> insulated electrodes 230. This arrangement has a number of
> advantages and is provided in view of the fact that the TC
> fields have maximal effect when they are parallel to the axis of
> cell division. Since the orientation of cell division is in most
> cases random, only a fraction of the dividing cells are affected
> by any given field. Thus, using fields of two or more
> orientations increases the effectiveness since it increases the
> chances that more dividing cells are affected by a given TC
> field.  
>   
>  [0104] In vitro experiments have shown that the electric
> field has the maximum killing effect when the lines of force of
> the field are oriented generally parallel to the long axis of
> the hourglass-shaped cell during mitosis (as shown in FIGS.
> 3A-3C). In one experiment, a much higher proportion of the
> damaged cells had their axis of division oriented along the
> field: 56% of the cells oriented at or near 0[deg.] with respect
> to the field were damaged, versus an average of 15% of cells
> damaged for cells with their long axis oriented at more than
> 22[deg.] with respect to the field.  
>   
>  [0105] The inventor has recognized that applying the field
> in different directions sequentially will increase the overall
> killing power, because the field orientation that is most
> effectively in killing dividing cells will be applied to a
> larger population of the dividing cells. A number of examples
> for applying the field in different directions are discussed
> below.  
>   
>  [0106] FIGS. 27A, 27B, and 27C show a set of 6 electrodes
> E1-E6, and how the direction of the field through the target
> tissue 1510 can be changed by applying the AC signal from the
> generator 1 (shown in FIG. 1) across different pairs of
> electrodes. For example, if the AC signal is applied across
> electrodes E1 and E4, the field lines F would be vertical (as
> shown in FIG. 27A), and if the signal is applied across
> electrodes E2 and E5, or across electrodes E3 and E6, the field
> lines F would be diagonal (as shown in FIGS. 27B and 27C,
> respectively). Additional field directions can be obtained by
> applying the AC signal across other pairs of electrodes. For
> example, a roughly horizontal field could be obtained by
> applying the signal across electrodes E2 and E6.  
>   
>  [0107] In one embodiment, the AC signal is applied between
> the various pairs of electrodes sequentially. An example of this
> arrangement is to apply the AC signal across electrodes E1 and
> E4 for one second, then apply the AC signal across electrodes E2
> and E5 for one second, and then apply the AC signal across
> electrodes E3 and E6 for one second. This three-part sequence is
> then repeated for the desired period of treatment. Because the
> efficacy in cell-destruction is strongly dependant on the cell's
> orientation, cycling the field between the different directions
> increases the chance that the field will be oriented in a
> direction that favors cell destruction at least part of the
> time.  
>   
>  [0108] Of course, the 6 electrode configuration shown in
> FIGS. 27A-C is just one of many possible arrangement of multiple
> electrodes, and many other configurations of three or more
> electrodes could be used based on the same principles.  
>   
>  [0109] Application of the field in different directions
> sequentially is not limited to two dimensional embodiments, and
> FIG. 28 shows how the sequential application of signals across
> different sets of electrodes can be extended to three
> dimensions. A first array of electrodes A1-A9 is arranged around
> body part 1500, and a last array of electrodes N1-N9 is arranged
> around the body part 1500 a distance W away from the first
> array. Additional arrays of electrodes may optionally be added
> between the first array and the last array, but these additional
> arrays are not illustrated for clarity (so as not to obscure the
> electrodes A5-A9 and B5-B8 on the back of the body part 1500).
> [0110] As in the FIG. 27 embodiment, the direction of the field
> through the target tissue can be changed by applying the AC
> signal from the generator 1 (shown in FIG. 1) across different
> pairs of electrodes. For example, applying the AC signal between
> electrodes A2 and A7 would result in a field in a front-to-back
> direction between those two electrodes, and applying the AC
> signal between electrodes A5 and A9 would result in a roughly
> vertical field between those two electrodes. Similarly, applying
> the AC signal across electrodes A2 and N7 would generate
> diagonal field lines in one direction through the body part
> 1500, and applying the AC signal across electrodes A2 and B7
> would generate diagonal field lines in another direction through
> the body part.  
>   
>  [0111] Using a three-dimensional array of electrodes also
> makes it possible to energize multiple pairs of electrodes
> simultaneously to induce fields in the desired directions. For
> example, if suitable switching is provided so that electrodes A2
> through N2 are all connected to one terminal of the generator,
> and so that electrodes A7 through N7 are all connected to the
> other terminal of the generator, the resulting field would be a
> sheet that extends in a front-to-back direction for the entire
> width W. After the front-to-back field is maintained for a
> suitable duration (e.g., one second), the switching system (not
> shown) is reconfigured to connect electrodes A3 through N3 to
> one terminal of the generator, and electrodes A8 through N8 to
> the other terminal of the generator. This results in a
> sheet-shaped field that is rotated about the Z axis by about
> 40[deg.] with respect to the initial field direction. After the
> field is maintained in this direction for a suitable duration
> (e.g., one second), the next set of electrodes is activated to
> rotate the field an additional 40[deg.] to its next position.
> This continues until the field returns to its initial position,
> at which point the whole process is repeated.  
>   
>  [0112] Optionally, the rotating sheet-shaped field may be
> added (sequentially in time) to the diagonal fields described
> above, to better target cells that are oriented along those
> diagonal axes  
>   
>  [0113] Because the electric field is a vector, the signals
> may optionally be applied to combinations of electrodes
> simultaneously in order to form a desired resultant vector. For
> example, a field that is rotated about the X axis by 20[deg.]
> with respect to the initial position can be obtained by
> switching electrodes A2 through N2 and A3 through N3 all to one
> terminal of the generator, and switching electrodes A7 through
> N7 and A8 through N8 all to the other terminal of the generator.
> Applying the signals to other combinations of electrodes will
> result in fields in other directions, as will be appreciated by
> persons skilled in the relevant arts. If appropriate computer
> control of the voltages is implemented, the field's direction
> can even be swept through space in a continuous (i.e., smooth)
> manner, as opposed to the stepwise manner described above.  
>   
>  [0114] FIGS. 29A and 29B depict the results of in vitro
> experiments that show how the killing power of the applied field
> against dividing cells is a function of the field strength. In
> the FIG. 29A experiment, B16F1 melanoma cells were subjected to
> a 100 kHz AC field at different field strengths, for a period of
> 24 hours at each strength. In the FIG. 29B experiment, F-98
> glioma cells were subjected to a 200 kHz AC field at different
> field strengths, for a period of 24 hours at each strength. In
> both of these figures, the strength of the field (EF) is
> measured in Volts per cm. The magnitude of the killing effect is
> expressed in terms of TER, which is which is the ratio of the
> decrease in the growth rate of treated cells (GRT) compared with
> the growth rate of control cells (GRC). [mathematical formula -
> see original document] The experimental results show that the
> inhibitory effect of the applied field on proliferation
> increases with intensity in both the melanoma and the glioma
> cells. Complete proliferation arrest (TER=1) is seen at 1.35 and
> 2.25 V/cm in melanoma and glioma cells, respectively.  
>   
>  [0115] FIGS. 30A and 30B depict the results of in vitro
> experiments that show how the killing power of the applied field
> is a function of the frequency of the field. In the experiments,
> B16F1 melanoma cells (FIG. 30A) and F-98 glioma cells (FIG. 30B)
> were subjected to fields with different frequencies, for a
> period of 24 hours at each frequency. FIGS. 30A and 30B show the
> change in the growth rate, normalized to the field intensity
> (TER/EF). Data are shown as mean+SE. In FIG. 30A, a window
> effect is seen with maximal inhibition at 120 kHz in melanoma
> cells. In FIG. 30B, two peaks are seen at 170 and 250 kHz. Thus,
> if only one frequency is available during an entire course of
> treatment, a field with a frequency of about 120 kHz would be
> appropriate for destroying melanoma cells, and a field with a
> frequency on the order of 200 kHz would be appropriate for
> destroying glioma cells.  
>   
>  [0116] Not all the cells of any given type will have the
> exact same size. Instead, the cells will have a distribution of
> sizes, with some cells being smaller and some cells being
> larger. It is believed that the best frequency for damaging a
> particular cell is related to the physical characteristics
> (e.g., the size) of that particular cell. Thus, to best damage a
> population of cells with a distribution of sizes, it can be
> advantageous to apply a distribution of different frequencies to
> the population, where the selection of frequencies is optimized
> based on the expected size distribution of the target cells. For
> example, the data on FIG. 30B indicates that using two
> frequencies of 170 kHz and 250 kHz to destroy a population of
> glioma cells would be more effective than using a single
> frequency of 200 kHz.  
>   
>  [0117] Note that the optimal field strengths and
> frequencies discussed herein were obtained based on in vitro
> experiments, and that the corresponding parameters for in vivo
> applications may be obtained by performing similar experiments
> in vivo. It is possible that relevant characteristics of the
> cell itself (such as size and/or shape) or interactions with the
> cell's surroundings may result in a different set of optimal
> frequencies and/or field strengths for in vivo applications.
> [0118] When more than one frequency is used, the various
> frequencies may be applied sequentially in time. For example, in
> the case of glioma, field frequencies of 100, 150, 170, 200,
> 250, and 300 kHz may be applied during the first, second, third,
> fourth, fifth, and sixth minutes of treatment, respectively.
> That cycle of frequencies would then repeat during each
> successive six minutes of treatment. Alternatively, the
> frequency of the field may be swept in a stepless manner from
> 100 to 300 kHz.  
>   
>  [0119] Optionally, this frequency cycling may be combined
> with the directional cycling described above. FIG. 31A is an
> example of such a combination using three directions (D1, D2,
> and D3) and three frequencies (F1, F2, and F3). Of course, the
> same scheme can be extended to any other number of directions
> and/or frequencies. FIG. 31B is an example of such a combination
> using three directions (D1, D2, and D3), sweeping the frequency
> from 100 kHz to 300 kHz. Note that the break in the time axis
> between t1 and t2 provides the needed time for the sweeping
> frequency to rise to just under 300 kHz. The frequency sweeping
> (or stepping) may be synchronized with directional changes, as
> shown in FIG. 31A. Alternatively, the frequency sweeping (or
> stepping) may be asynchronous with respect to the directional
> changes, as shown in FIG. 31B. [0120] In an alternative
> embodiment, a signal that contains two or more frequencies
> components simultaneously (e.g., 170 kHz and 250 kHz) is applied
> to the electrodes to treat a populations of cells that have a
> distribution of sizes. The various signals will add by
> superposition to create a field that includes all of the applied
> frequency components.  
>   
>  [0121] Turning now to FIG. 14 in which an article of
> clothing 500 according to one exemplary embodiment is
> illustrated. More specifically, the article of clothing 500 is
> in the form of a hat or cap or other type of clothing designed
> for placement on a head of a person. For purposes of
> illustration, a head 502 is shown with the hat 500 being placed
> thereon and against a skin surface 504 of the head 502. An
> intra-cranial tumor or the like 510 is shown as being formed
> within the head 502 underneath the skin surface 504 thereof. The
> hat 500 is therefore intended for placement on the head 502 of a
> person who has a tumor 510 or the like.  
>   
>  [0122] Unlike the various embodiments illustrated in FIGS.
> 1-13 where the insulated electrodes 230 are arranged in a more
> or less planar arrangement since they are placed either on a
> skin surface or embedded within the body underneath it, the
> insulated electrodes 230 in this embodiment are specifically
> contoured and arranged for a specific application. The treatment
> of intra-cranial tumors or other lesions or the like typically
> requires a treatment that is of a relatively long duration,
> e.g., days to weeks, and therefore, it is desirable to provide
> as much comfort as possible to the patient. The hat 500 is
> specifically designed to provide comfort during the lengthy
> treatment process while not jeopardizing the effectiveness of
> the treatment.  
>   
>  [0123] According to one exemplary embodiment, the hat 500
> includes a predetermined number of insulated electrodes 230 that
> are preferably positioned so as to produce the optimal TC fields
> at the location of the tumor 510. The lines of force of the TC
> field are generally indicated at 520. As can be seen in FIG. 14,
> the tumor 510 is positioned within these lines of force 520. As
> will be described in greater detail hereinafter, the insulated
> electrodes 230 are positioned within the hat 500 such that a
> portion or surface thereof is free to contact the skin surface
> 504 of the head 502. In other words, when the patient wears the
> hat 500, the insulated electrodes 230 are placed in contact with
> the skin surface 504 of the head 502 in positions that are
> selected so that the TC fields generated thereby are focused at
> the tumor 510 while leaving surrounding areas in low density.
> Typically, hair on the head 502 is shaved in selected areas to
> permit better contact between the insulated electrodes 230 and
> the skin surface 504; however, this is not critical.  
>   
>  [0124] The hat 500 preferably includes a mechanism 530
> that applies a force to the insulated electrodes 230 so that
> they are pressed against the skin surface 502. For example, the
> mechanism 530 can be of a biasing type that applies a biasing
> force to the insulated electrodes 230 to cause the insulated
> electrodes 230 to be directed outwardly away from the hat 500.
> Thus, when the patient places the hat 500 on his/her head 502,
> the insulated electrodes 230 are pressed against the skin
> surface 504 by the mechanism 530. The mechanism 530 can slightly
> recoil to provide a comfortable fit between the insulated
> electrodes 230 and the head 502. In one exemplary embodiment,
> the mechanism 530 is a spring based device that is disposed
> within the hat 500 and has one section that is coupled to and
> applies a force against the insulated electrodes 230.  
>   
>  [0125] As with the prior embodiments, the insulated
> electrodes 230 are coupled to the generator 210 by means of
> conductors 220. The generator 210 can be either disposed within
> the hat 500 itself so as to provide a compact, self-sufficient,
> independent system or the generator 210 can be disposed external
> to the hat 500 with the conductors 220 exiting the hat 500
> through openings or the like and then running to the generator
> 210. When the generator 210 is disposed external to the hat 500,
> it will be appreciated that the generator 210 can be located in
> any number of different locations, some of which are in close
> proximity to the hat 500 itself, while others can be further
> away from the hat 500. For example, the generator 210 can be
> disposed within a carrying bag or the like (e.g., a bag that
> extends around the patient's waist) which is worn by the patient
> or it can be strapped to an extremity or around the torso of the
> patient. The generator 210 can also be disposed in a protective
> case that is secured to or carried by another article of
> clothing that is worn by the patient. For example, the
> protective case can be inserted into a pocket of a sweater, etc.
> FIG. 14 illustrates an embodiment where the generator 210 is
> incorporated directly into the hat 500.  
>   
>  [0126] Turning now to FIGS. 15 and 16, in one exemplary
> embodiment, a number of insulated electrodes 230 along with the
> mechanism 530 are preferably formed as an independent unit,
> generally indicated at 540, that can be inserted into the hat
> 500 and electrically connected to the generator (not shown) via
> the conductors (not shown). By providing these members in the
> form of an independent unit, the patient can easily insert
> and/or remove the units 540 from the hat 500 when they may need
> cleaning, servicing and/or replacement.  
>   
>  [0127] In this embodiment, the hat 500 is constructed to
> include select areas 550 that are formed in the hat 500 to
> receive and hold the units 540. For example and as illustrated
> in FIG. 15, each area 550 is in the form of an opening (pore)
> that is formed within the hat 500. The unit 540 has a body 542
> and includes the mechanism 530 and one or more insulated
> electrodes 230. The mechanism 530 is arranged within the unit
> 540 so that a portion thereof (e.g., one end thereof) is in
> contact with a face of each insulated electrode 230 such that
> the mechanism 530 applies a biasing force against the face of
> the insulated electrode 230. Once the unit 540 is received
> within the opening 550, it can be securely retained therein
> using any number of conventional techniques, including the use
> of an adhesive material or by using mechanical means. For
> example, the hat 500 can include pivotable clip members that
> pivot between an open position in which the opening 550 is free
> and a closed position in which the pivotable clip members engage
> portions (e.g., peripheral edges) of the insulated electrodes to
> retain and hold the insulated electrodes 230 in place. To remove
> the insulated electrodes 230, the pivotable clip members are
> moved to the open position. In the embodiment illustrated in
> FIG. 16, the insulated electrodes 230 are retained within the
> openings 550 by an adhesive element 560 which in one embodiment
> is a two sided self-adhesive rim member that extends around the
> periphery of the insulated electrode 230. In other words, a
> protective cover of one side of the adhesive rim 560 is removed
> and it is applied around the periphery of the exposed face of
> the insulated electrode 230, thereby securely attaching the
> adhesive rim 560 to the hat 500 and then the other side of the
> adhesive rim 560 is removed for application to the skin surface
> 504 in desired locations for positioning and securing the
> insulated electrode 230 to the head 502 with the tumor being
> positioned relative thereto for optimization of the TC fields.
> Since one side of the adhesive rim 560 is in contact with and
> secured to the skin surface 540, this is why it is desirable for
> the head 502 to be shaved so that the adhesive rim 560 can be
> placed flushly against the skin surface 540.  
>   
>  [0128] The adhesive rim 560 is designed to securely attach
> the unit 540 within the opening 550 in a manner that permits the
> unit 540 to be easily removed from the hat 500 when necessary
> and then replaced with another unit 540 or with the same unit
> 540. As previously mentioned, the unit 540 includes the biasing
> mechanism 530 for pressing the insulated electrode 230 against
> the skin surface 504 when the hat 500 is worn. The unit 540 can
> be constructed so that side opposite the insulated electrode 230
> is a support surface formed of a rigid material, such as
> plastic, so that the biasing mechanism 530 (e.g., a spring) can
> be compressed therewith under the application of force and when
> the spring 530 is in a relaxed state, the spring 530 remains in
> contact with the support surface and the applies a biasing force
> at its other end against the insulated electrode 230. The
> biasing mechanism 530 (e.g., spring) preferably has a contour
> corresponding to the skin surface 504 so that the insulated
> electrode 230 has a force applied thereto to permit the
> insulated electrode 230 to have a contour complementary to the
> skin surface 504, thereby permitting the two to seat flushly
> against one another. While the mechanism 530 can be a spring,
> there are a number of other embodiments that can be used instead
> of a spring. For example, the mechanism 530 can be in the form
> of an elastic material, such as a foam rubber, a foam plastic,
> or a layer containing air bubbles, etc.  
>   
>  [0129] The unit 540 has an electric connector 570 that can
> be hooked up to a corresponding electric connector, such as a
> conductor 220, that is disposed within the hat 500. The
> conductor 220 connects at one end to the unit 540 and at the
> other end is connected to the generator 210. The generator 210
> can be incorporated directly into the hat 500 or the generator
> 210 can be positioned separately (remotely) on the patient or on
> a bedside support, etc.  
>   
>  [0130] As previously discussed, a coupling agent, such as
> a conductive gel, is preferably used to ensure that an effective
> conductive environment is provided between the insulated
> electrode 230 and the skin surface 504. Suitable gel materials
> have been disclosed hereinbefore in the discussion of earlier
> embodiments. The coupling agent is disposed on the insulated
> electrode 230 and preferably, a uniform layer of the agent is
> provided along the surface of the electrode 230. One of the
> reasons that the units 540 need replacement at periodic times is
> that the coupling agent needs to be replaced and/or replenished.
> In other words, after a predetermined time period or after a
> number of uses, the patient removes the units 540 so that the
> coupling agent can be applied again to the electrode 230.  
>   
>  [0131] FIGS. 17 and 18 illustrate another article of
> clothing which has the insulated electrodes 230 incorporated as
> part thereof. More specifically, a bra or the like 700 is
> illustrated and includes a body that is formed of a traditional
> bra material, generally indicated at 705, to provide shape,
> support and comfort to the wearer. The bra 700 also includes a
> fabric support layer 710 on one side thereof. The support layer
> 710 is preferably formed of a suitable fabric material that is
> constructed to provide necessary and desired support to the bra
> 700.  
>   
>  [0132] Similar to the other embodiments, the bra 700
> includes one or more insulated electrodes 230 disposed within
> the bra material 705. The one or more insulated electrodes are
> disposed along an inner surface of the bra 700 opposite the
> support 710 and are intended to be placed proximate to a tumor
> or the like that is located within one breast or in the
> immediately surrounding area. As with the previous embodiment,
> the insulated electrodes 230 in this embodiment are specifically
> constructed and configured for application to a breast or the
> immediate area. Thus, the insulated electrodes 230 used in this
> application do not have a planar surface construction but rather
> have an arcuate shape that is complementary to the general
> curvature found in a typical breast.  
>   
>  [0133] A lining 720 is disposed across the insulated
> electrodes 230 so as to assist in retaining the insulated
> electrodes in their desired locations along the inner surface
> for placement against the breast itself. The lining 720 can be
> formed of any number of thin materials that are comfortable to
> wear against one's skin and in one exemplary embodiment, the
> lining 720 is formed of a fabric material.  
>   
>  [0134] The bra 700 also preferably includes a biasing
> mechanism 800 as in some of the earlier embodiments. The biasing
> mechanism 800 is disposed within the bra material 705 and
> extends from the support 710 to the insulated electrode 230 and
> applies a biasing force to the insulated electrode 230 so that
> the electrode 230 is pressed against the breast. This ensures
> that the insulated electrode 230 remains in contact with the
> skin surface as opposed to lifting away from the skin surface,
> thereby creating a gap that results in a less effective
> treatment since the gap diminishes the efficiency of the TC
> fields. The biasing mechanism 800 can be in the form of a spring
> arrangement or it can be an elastic material that applies the
> desired biasing force to the insulated electrodes 230 so as to
> press the insulated electrodes 230 into the breast. In the
> relaxed position, the biasing mechanism 800 applies a force
> against the insulated electrodes 230 and when the patient places
> the bra 700 on their body, the insulated electrodes 230 are
> placed against the breast which itself applies a force that
> counters the biasing force, thereby resulting in the insulated
> electrodes 230 being pressed against the patient's breast. In
> the exemplary embodiment that is illustrated, the biasing
> mechanism 800 is in the form of springs that are disposed within
> the bra material 705.  
>   
>  [0135] A conductive gel 810 can be provided on the
> insulated electrode 230 between the electrode and the lining
> 720. The conductive gel layer 810 is formed of materials that
> have been previously described herein for performing the
> functions described above.  
>   
>  [0136] An electric connector 820 is provided as part of
> the insulated electrode 230 and electrically connects to the
> conductor 220 at one end thereof, with the other end of the
> conductor 220 being electrically connected to the generator 210.
> In this embodiment, the conductor 220 runs within the bra
> material 705 to a location where an opening is formed in the bra
> 700. The conductor 220 extends through this opening and is
> routed to the generator 210, which in this embodiment is
> disposed in a location remote from the bra 700. It will also be
> appreciated that the generator 210 can be disposed within the
> bra 700 itself in another embodiment. For example, the bra 700
> can have a compartment formed therein which is configured to
> receive and hold the generator 210 in place as the patient wears
> the bra 700. In this arrangement, the compartment can be covered
> with a releasable strap that can open and close to permit the
> generator 210 to be inserted therein or removed therefrom. The
> strap can be formed of the same material that is used to
> construct the bra 700 or it can be formed of some other type of
> material. The strap can be releasably attached to the
> surrounding bra body by fastening means, such as a hook and loop
> material, thereby permitting the patient to easily open the
> compartment by separating the hook and loop elements to gain
> access to the compartment for either inserting or removing the
> generator 210.  
>   
>  [0137] The generator 210 also has a connector 211 for
> electrical connection to the conductor 220 and this permits the
> generator 210 to be electrically connected to the insulated
> electrodes 230.  
>   
>  [0138] As with the other embodiments, the insulated
> electrodes 230 are arranged in the bra 700 to focus the electric
> field (TC fields) on the desired target (e.g., a tumor). It will
> be appreciated that the location of the insulated electrodes 230
> within the bra 700 will vary depending upon the location of the
> tumor. In other words, after the tumor has been located, the
> physician will then devise an arrangement of insulated
> electrodes 230 and the bra 700 is constructed in view of this
> arrangement so as to optimize the effects of the TC fields on
> the target area (tumor). The number and position of the
> insulated electrodes 230 will therefore depend upon the precise
> location of the tumor or other target area that is being
> treated. Because the location of the insulated electrodes 230 on
> the bra 700 can vary depending upon the precise application, the
> exact size and shape of the insulated electrodes 230 can
> likewise vary. For example, if the insulated electrodes 230 are
> placed on the bottom section of the bra 700 as opposed to a more
> central location, the insulated electrodes 230 will have
> different shapes since the shape of the breast (as well as the
> bra) differs in these areas.  
>   
>  [0139] FIG. 19 illustrates yet another embodiment in which
> the insulated electrodes 230 are in the form of internal
> electrodes that are incorporated into in the form of a probe or
> catheter 600 that is configured to enter the body through a
> natural pathway, such as the urethra, vagina, etc. In this
> embodiment, the insulated electrodes 230 are disposed on an
> outer surface of the probe 600 and along a length thereof. The
> conductors 220 are electrically connected to the electrodes 230
> and run within the body of the probe 600 to the generator 210
> which can be disposed within the probe body or the generator 210
> can be disposed independent of the probe 600 in a remote
> location, such as on the patient or at some other location close
> to the patient.   
>   
> [0140] Alternatively, the probe 600 can be configured to
> penetrate the skin surface or other tissues to reach an internal
> target that lies within the body. For example, the probe 600 can
> penetrate the skin surface and then be positioned adjacent to or
> proximate to a tumor that is located within the body.   
>   
> [0141] In these embodiments, the probe 600 is inserted through
> the natural pathway and then is positioned in a desired location
> so that the insulated electrodes 230 are disposed near the
> target area (i.e., the tumor). The generator 210 is then
> activated to cause the insulated electrodes 230 to generate the
> TC fields which are applied to the tumor for a predetermined
> length of time. It will be appreciated that the illustrated
> probe 600 is merely exemplary in nature and that the probe 600
> can have other shapes and configurations so long as they can
> perform the intended function. Preferably, the conductors (e.g.,
> wires) leading from the insulated electrodes 230 to the
> generator 210 are twisted or shielded so as not to generate a
> field along the shaft.  
>   
>  [0142] It will further be appreciated that the probes can
> contain only one insulated electrode while the other can be
> positioned on the body surface. This external electrode should
> be larger or consist of numerous electrodes so as to result in
> low lines of force-current density so as not to affect the
> untreated areas. In fact, the placing of electrodes should be
> designed to minimize the field at potentially sensitive areas.
> Optionally, the external electrodes may be held against the skin
> surface by a vacuum force (e.g., suction).  
>   
>  [0143] FIG. 20 illustrates yet another embodiment in which
> a high standing collar member 900 (or necklace type structure)
> can be used to treat thyroid, parathyroid, laryngeal lesions,
> etc. FIG. 20 illustrates the collar member 900 in an unwrapped,
> substantially flat condition. In this embodiment, the insulated
> electrodes 230 are incorporated into a body 910 of the collar
> member 900 and are configured for placement against a neck area
> of the wearer. The insulated electrodes 230 are coupled to the
> generator 210 according to any of the manner described
> hereinbefore and it will be appreciated that the generator 210
> can be disposed within the body 910 or it can be disposed in a
> location external to the body 910. The collar body 910 can be
> formed of any number of materials that are traditionally used to
> form collars 900 that are disposed around a person's neck. As
> such, the collar 900 preferably includes a means 920 for
> adjusting the collar 900 relative to the neck. For example,
> complementary fasteners (hook and loop fasteners, buttons, etc.)
> can be disposed on ends of the collar 900 to permit adjustment
> of the collar diameter.  
>   
>  [0144] Thus, the construction of the present devices are
> particularly well suited for applications where the devices are
> incorporated into articles of clothing to permit the patient to
> easily wear a traditional article of clothing while at the same
> time the patient undergoes treatment. In other words, an extra
> level of comfort can be provided to the patient and the
> effectiveness of the treatment can be increased by incorporating
> some or all of the device components into the article of
> clothing. The precise article of clothing that the components
> are incorporated into will obviously vary depending upon the
> target area of the living tissue where tumor, lesion or the like
> exists. For example, if the target area is in the testicle area
> of a male patient, then an article of clothing in the form of a
> sock-like structure or wrap can be provided and is configured to
> be worn around the testicle area of the patient in such a manner
> that the insulated electrodes thereof are positioned relative to
> the tumor such that the TC fields are directed at the target
> tissue. The precise nature or form of the article of clothing
> can vary greatly since the device components can be incorporated
> into most types of articles of clothing and therefore, can be
> used to treat any number of different areas of the patient's
> body where a condition may be present.  
>   
>  [0145] Now turning to FIGS. 21-22 in which another aspect
> of the present device is shown. In FIG. 21, a body 1000, such as
> any number of parts of a human or animal body, is illustrated.
> As in the previous embodiments, two or more insulated electrodes
> 230 are disposed in proximity to the body 1000 for treatment of
> a tumor or the like (not shown) using TC fields, as has been
> previously described in great detail in the above discussion of
> other embodiments. The insulated electrode 230 has a conductive
> component and has external insulation 260 that surrounds the
> conductive component thereof. Each insulated electrode 230 is
> preferably connected to a generator (not shown) by the lead 220.
> Between each insulated electrode 220 and the body 1000, a
> conductive filler material (e.g., conductive gel member 270) is
> disposed. The insulated electrodes 230 are spaced apart from one
> another and when the generator is actuated, the insulated
> electrodes 230 generate the TC fields that have been previously
> described in great detail. The lines of the electric field (TC
> field) are generally illustrated at 1010. As shown, the electric
> field lines 1010 extend between the insulated electrodes 230 and
> through the conductive gel member 270.  
>   
>  [0146] Over time or as a result of some type of event, the
> external insulation 260 of the insulated electrode 230 can begin
> to breakdown at any given location thereof. For purpose of
> illustration only, FIG. 22 illustrates that the external
> insulation 260 of one of the insulated electrodes 230 has
> experienced a breakdown 1020 at a face thereof which is adjacent
> the conductive gel member 270. It will be appreciated that the
> breakdown 1020 of the external insulation 260 results in the
> formation of a strong current flow-current density at this point
> (i.e., at the breakdown 1020). The increased current density is
> depicted by the increased number of electric field lines 1010
> and the relative positioning and distance between adjacent
> electric field lines 1010. One of the side effects of the
> occurrence of breakdown 1020 is that current exists at this
> point which will generate heat and may burn the tissues/skin
> which have a resistance. In FIG. 22, an overheated area 1030 is
> illustrated and is a region or area of the tissues/skin where an
> increased current density exits due to the breakdown 1020 in the
> external insulation 260. A patient can experience discomfort and
> pain in this area 1030 due to the strong current that exists in
> the area and the increased heat and possible burning sensation
> that exist in area 1030.  
>   
> [0147] FIG. 23 illustrates yet another embodiment in which a
> further application of the insulated electrodes 230 is shown. In
> this embodiment, the conductive gel member 270 that is disposed
> between the insulated electrode 230 and the body 1000 includes a
> conductor 1100 that is floating in that the gel material forming
> the member 270 completely surrounds the conductor 1100. In one
> exemplary embodiment, the conductor 1100 is a thin metal sheet
> plate that is disposed within the conductor 1100. As will be
> appreciated, if a conductor, such as the plate 1100, is placed
> in a homogeneous electric field, normal to the lines of the
> electric field, the conductor 1100 practically has no effect on
> the field (except that the two opposing faces of the conductor
> 1100 are equipotential and the corresponding equipotentials are
> slightly shifted). Conversely, if the conductor 1100 is disposed
> parallel to the electric field, there is a significant
> distortion of the electric field. The area in the immediate
> proximity of the conductor 1100 is not equipotential, in
> contrast to the situation where there is no conductor 1100
> present. When the conductor 1100 is disposed within the gel
> member 270, the conductor 1100 will typically not effect the
> electric field (TC field) for the reasons discussed above,
> namely that the conductor 1100 is normal to the lines of the
> electric field.  
>   
> [0148] If there is a breakdown of the external insulation 260 of
> the insulated electrode 230, there is a strong current
> flow-current density at the point of breakdown as previously
> discussed; however, the presence of the conductor 1100 causes
> the current to spread throughout the conductor 1100 and then
> exit from the whole surface of the conductor 1100 so that the
> current reaches the body 1000 with a current density that is
> neither high nor low. Thus, the current that reaches the skin
> will not cause discomfort to the patient even when there has
> been a breakdown in the insulation 260 of the insulated
> electrode 230. It is important that the conductor 1100 is not
> grounded as this would cause it to abolish the electric field
> beyond it. Thus, the conductor 1100 is "floating" within the gel
> member 270.  
>   
> [0149] If the conductor 1100 is introduced into the body tissues
> 1000 and is not disposed parallel to the electric field, the
> conductor 1100 will cause distortion of the electric field. The
> distortion can cause spreading of the lines of force (low field
> density-intensity) or concentration of the lines of field
> (higher density) of the electric field, according to the
> particular geometries of the insert and its surroundings, and
> thus, the conductor 1100 can exhibit, for example, a screening
> effect. Thus, for example, if the conductor 1100 completely
> encircles an organ 1101, the electric field in the organ itself
> will be zero since this type of arrangement is a Faraday cage.
> However, because it is impractical for a conductor to be
> disposed completely around an organ, a conductive net or similar
> structure can be used to cover, completely or partially, the
> organ, thereby resulting in the electric field in the organ
> itself being zero or about zero. For example, a net can be made
> of a number of conductive wires that are arranged relative to
> one another to form the net or a set of wires can be arranged to
> substantially encircle or otherwise cover the organ 1101.
> Conversely, an organ 1103 to be treated (the target organ) is
> not covered with a member having a Faraday cage effect but
> rather is disposed in the electric field 1010 (TC fields).  
>   
> [0150] FIG. 24 illustrates an embodiment where the conductor
> 1100 is disposed within the body (i.e., under the skin) and it
> is located near a target (e.g., a target organ). By placing the
> conductor 1100 near the target, high field density (of the TC
> fields) is realized at the target. At the same time, another
> nearby organ can be protected by disposing the above described
> protective conductive net or the like around this nearby organ
> so as to protect this organ from the fields. By positioning the
> conductor 1100 in close proximity to the target, a high field
> density condition can be provided near or at the target. In
> other words, the conductor 1100 permits the TC fields to be
> focused at a particular area (i.e., a target).  
>   
> [0151] It will also be appreciated that in the embodiment of
> FIG. 24, the gel members 260 can each include a conductor as
> described with reference to FIG. 23. In such an arrangement, the
> conductor in the gel member 260 protects the skin surface
> (tissues) from any side effects that may be realized if a
> breakdown in the insulation of the insulated electrode 230
> occurs. At the same time, the conductor 1100 creates a high
> field density near the target.   
>   
> [0152] There are a number of different ways to tailor the field
> density of the electric field by constructing the electrodes
> differently and/or by strategically placing the electrodes
> relative to one another. For example, in FIG. 25, a first
> insulated electrode 1200 and a second insulated electrode 1210
> are provided and are disposed about a body 1300. Each insulated
> electrode includes a conductor that is preferably surrounded by
> an insulating material, thus the term "insulated electrode".
> Between each of the first and second electrodes 1200, 1210 and
> the body 1300, the conductive gel member 270 is provided.
> Electric field lines are generally indicated at 1220 for this
> type of arrangement. In this embodiment, the first insulated
> electrode 1200 has dimensions that are significantly greater
> than the dimensions of the second insulated electrode 1210 (the
> conductive gel member for the second insulated electrode 1210
> will likewise be smaller).  
>   
>  [0153] By varying the dimensions of the insulated
> electrodes, the pattern of the electric field lines 1220 is
> varied. More specifically, the electric field tapers inwardly
> toward the second insulated electrode 1210 due to the smaller
> dimensions of the second insulated electrode 1210. An area of
> high field density, generally indicated at 1230, forms near the
> interface between the gel member 270 associated with the second
> insulated electrode 1210 and the skin surface. The various
> components of the system are manipulated so that the tumor
> within the skin or on the skin is within this high field density
> so that the area to be treated (the target) is exposed to
> electric field lines of a higher field density.   
>   
> [0154] FIG. 26 also illustrates a tapering TC field when a
> conductor 1400 (e.g., a conductive plate) is disposed in each of
> the conductive gel members 270. In this embodiment, the size of
> the gel members 270 and the size of the conductors 1400 are the
> same or about the same despite the differences in the sizes of
> the insulated electrodes 1200, 1210. The conductors 1400 again
> can be characterized as "floating plates" since each conductor
> 1400 is surrounded by the material that forms the gel member
> 270. As shown in FIG. 26, the placement of one conductor 1400
> near the insulated electrode 1210 that is smaller than the other
> insulated electrode 1200 and is also smaller than the conductor
> 1400 itself and the other insulated electrode 1200 is disposed
> at a distance therefrom, the one conductor 1400 causes a
> decrease in the field density in the tissues disposed between
> the one conductor 1400 and the other insulated electrode 1200.
> The decrease in the field density is generally indicated at
> 1410. At the same time, a very inhomogeneous tapering field,
> generally indicated at 1420, changing from very low density to
> very high density is formed between the one conductor 1400 and
> the insulated electrode 1210. One benefit of this exemplary
> configuration is that it permits the size of the insulated
> electrode to be reduced without causing an increase in the
> nearby field density. This can be important since electrodes
> that having very high dielectric constant insulation can be very
> expensive. Some insulated electrodes, for example, can cost
> $500.00 or more; and further, the price is sensitive to the
> particular area of treatment. Thus, a reduction in the size of
> the insulated electrodes directly leads to a reduction in cost.  
>   
> [0155] As used herein, the term "tumor" refers to a malignant
> tissue comprising transformed cells that grow uncontrollably.
> Tumors include leukemias, lymphomas, myelomas, plasmacytomas,
> and the like; and solid tumors. Examples of solid tumors that
> can be treated according to the invention include sarcomas and
> carcinomas such as, but not limited to: fibrosarcoma,
> myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma,
> chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
> lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's
> tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma,
> pancreatic cancer, breast cancer, ovarian cancer, prostate
> cancer, squamous cell carcinoma, basal cell carcinoma,
> adenocarcinoma, sweat gland carcinoma, sebaceous gland
> carcinoma, papillary carcinoma, papillary adenocarcinomas,
> cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma,
> renal cell carcinoma, hepatoma, bile duct carcinoma,
> choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,
> cervical cancer, testicular tumor, lung carcinoma, small cell
> lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma,
> astrocytoma, medulloblastoma, craniopharyngioma, ependymoma,
> pinealoma, hemangioblastoma, acoustic neuroma,
> oligodendroglioma, meningioma, melanoma, neuroblastoma, and
> retinoblastoma. Because each of these tumors undergoes rapid
> growth, any one can be treated in accordance with the invention.
> The invention is particularly advantageous for treating brain
> tumors, which are difficult to treat with surgery and radiation,
> and often inaccessible to chemotherapy or gene therapies. In
> addition, the present invention is suitable for use in treating
> skin and breast tumors because of the ease of localized
> treatment provided by the present invention.  
>   
>  [0156] In addition, the present invention can control
> uncontrolled growth associated with non-malignant or
> pre-malignant conditions, and other disorders involving
> inappropriate cell or tissue growth by application of an
> electric field in accordance with the invention to the tissue
> undergoing inappropriate growth. For example, it is contemplated
> that the invention is useful for the treatment of arteriovenous
> (AV) malformations, particularly in intracranial sites. The
> invention may also be used to treat psoriasis, a dermatologic
> condition that is characterized by inflammation and vascular
> proliferation; and benign prostatic hypertrophy, a condition
> associated with inflammation and possibly vascular
> proliferation. Treatment of other hyperproliferative disorders
> is also contemplated.  
>   
> [0157] Furthermore, undesirable fibroblast and endothelial cell
> proliferation associated with wound healing, leading to scar and
> keloid formation after surgery or injury, and restenosis after
> angioplasty or placement of coronary stents can be inhibited by
> application of an electric field in accordance with the present
> invention. The non-invasive nature of this invention makes it
> particularly desirable for these types of conditions,
> particularly to prevent development of internal scars and
> adhesions, or to inhibit restenosis of coronary, carotid, and
> other important arteries.  
>   
> [0158] In addition to treating tumors that have already been
> detected, the above-described embodiments may also be used
> prophylactically to prevent tumors from ever reaching a
> detectable size in the first place. For example, the bra
> embodiment described above in connection with FIGS. 17 and 18
> may be worn by a woman for an 8 hour session every day for a
> week, with the week-long course of treatment being repeated
> every few months to kill any cells that have become cancerous
> and started to proliferate. This mode of usage is particularly
> appropriate for people who are at high risk for a particular
> type of cancer (e.g., women with a strong history of breast
> cancer in their families, or people who have survived a bout of
> cancer and are at risk of a relapse). The course of prophylactic
> treatment may be tailored based on the type of cancer being
> targeted and/or to suit the convenience of the patient. For
> example, undergoing a four 16 hour sessions during the week of
> treatment may be more convenient for some patients than seven 8
> hour session, and may be equally effective.  
>   
>  [0159] Thus, the present invention provides an effective,
> simple method of selectively destroying dividing cells, e.g.,
> tumor cells and parasitic organisms, while non-dividing cells or
> organisms are left affected by application of the method on
> living tissue containing both types of cells or organisms. Thus,
> unlike many of the conventional methods, the present invention
> does not damage the normal cells or organisms. In addition, the
> present invention does not discriminate based upon cell type
> (e.g., cells having differing sizes) and therefore may be used
> to treat any number of types of sizes having a wide spectrum of
> characteristics, including varying dimensions.  
>   
> [0160] While the invention has been particularly shown and
> described with reference to preferred embodiments thereof, it
> will be understood by those skilled in the art that various
> changes in form and details can be made without departing from
> the spirit and scope of the invention.  
>   
>
>
> ---
>
>   
>
> Apparatus and method for optimizing tumor treatment
> efficiency by electric fields  
> US2004176804
>
>   
> CROSS-REFERENCE TO RELATED
> APPLICATIONS   
>   
> [0001] This application is a continuation-in-part of U.S. patent
> application Ser. No. 10/204,334, filed Oct. 16, 2002, which
> claims the benefit of U.S. patent application Ser. No.
> 60/183,295, filed Feb. 17, 2000, both of which are hereby
> incorporated by reference in their entirety.   
>   
>  FIELD OF THE INVENTION  
>   
>  [0002] The present invention relates to the selective
> destruction of rapidly dividing cells in a localized area, and
> more particularly, to an apparatus and method for optimizing the
> selective destruction of dividing cells by calculating the
> spatial and temporal distribution of electric fields for optimal
> treatment of a specific patient with a specific tumor taking
> into account its location and characteristics.   
>   
>  BACKGROUND OF THE INVENTION   
>   
> [0003] All living organisms proliferate by cell division,
> including cell cultures, microorganisms (such as bacteria,
> mycoplasma, yeast, protozoa, and other single-celled organisms),
> fungi, algae, plant cells, etc. Dividing cells of organisms can
> be destroyed, or their proliferation controlled, by methods that
> are based on the sensitivity of the dividing cells of these
> organisms to certain agents. For example, certain antibiotics
> stop the multiplication process of bacteria.  
>   
> [0004] The process of eukaryotic cell division is called
> "mitosis", which involves a number of distinct phases. During
> interphase, the cell replicates chromosomal DNA, which begins
> condensing in early prophase. At this point, centrioles (each
> cell contains 2) being moving towards opposite poles of the
> cell. In middle prophase, each chromosome is composed of
> duplicate chromatids. Microtubular spindles radiate from regions
> adjacent to the centrioles, which are closer to their poles. By
> late prophase, the centrioles have reached the poles, and some
> spindle fibers extend to the center of the cell, while others
> extend from the poles to the chromatids. The cells then move
> into metaphase, when the chromosomes move toward the equator of
> the cell and align in the equatorial plane. Next is early
> anaphase, during which time daughter chromatids separate from
> each other at the equator by moving along the spindle fibers
> toward a centromere at opposite poles. The cell begins to
> elongate along the axis of the pole; the pole-to-pole spindles
> elongate. Late anaphase occurs when the daughter chromosomes (as
> they are now called) each reach their respective opposite poles.
> At this point, cytokinesis begins as the cleavage furrow begins
> to form at the equator of the cell. In other words, late
> anaphase is the point at which pinching the cell membrane
> begins. During telophase, cytokinesis is nearly complete and
> spindles disappear. Only a relatively narrow membrane connection
> joins the two cytoplasms. Finally, the membranes separate fully,
> cytokinesis is complete and the cell returns to interphase.   
>   
> [0005] In meiosis, the cell undergoes a second division,
> involving separation of sister chromosomes to opposite poles of
> the cell along spindle fibers, followed by formation of a
> cleavage furrow and cell division. However, this division is not
> preceded by chromosome replication, yielding a haploid germ
> cell.   
>   
> [0006] It is known in the art that tumors, particularly
> malignant or cancerous tumors, grow very uncontrollably compared
> to normal tissue. Such expedited growth enables tumors to occupy
> an ever-increasing space and to damage or destroy tissue
> adjacent thereto. Furthermore, certain cancers are characterized
> by an ability to transmit cancerous "seeds", including single
> cells or small cell clusters (metastasises), to new locations
> where the metastatic cancer cells grow into additional tumors.  
>   
> [0007] The rapid growth of tumors in general, and malignant
> tumors in particular, as described above, is the result of
> relatively frequent cell division or multiplication of these
> cells compared to normal tissue cells. The distinguishably
> frequent cell division of cancer cells is the basis for the
> effectiveness of existing cancer treatments, e.g., irradiation
> therapy and the use of various chemotherapeutic agents. Such
> treatments are based on the fact that cells undergoing division
> are more sensitive to radiation and chemo-therapeutic agents
> than non-dividing dells. Because tumor cells divide much more
> frequently than normal cells, it is possible, to a certain
> extent, to selectively damage or destroy tumor cells by
> radiation therapy and/or by chemotherapy. The actual sensitivity
> of cells to radiation, therapeutic agents, etc., is also
> dependent on specific characteristics of different types of
> normal or malignant cell type. Thus, unfortunately, the
> sensitivity of tumor cells is not sufficiently higher than that
> of many types of normal tissues. This diminishes the ability to
> distinguish between tumor cells and normal cells and, therefore,
> existing cancer treatments typically cause significant damage to
> normal tissues, thus limiting the therapeutic effectiveness of
> such treatments. Furthermore, the inevitable damage to other
> tissue renders treatments very traumatic to the patients and,
> often, patients are unable to recover from a seemingly
> successful treatment. Also, certain types of tumors are not
> sensitive at all to existing methods of treatment.   
>   
> [0008] There are also other methods for destroying cells that do
> not rely on radiation therapy or chemotherapy alone. For
> example, ultrasonic and electrical methods for destroying tumor
> cells can be used in addition to or instead of conventional
> treatments. Electric fields and currents have been used for
> medical purposes for many years. The most common is the
> generation of electric currents in a human or animal body by
> application of an electric field by means of a pair of
> conductive electrodes between which a potential difference is
> maintained. These electric currents are used either to exert
> their specific effects, i.e., to stimulate excitable tissue, or
> to generate heat by flowing in the body since it acts as a
> resistor. Examples of the first type of application include the
> following: cardiac defibrillators, peripheral nerve and muscle
> stimulators, brain stimulators, etc. Currents are used for
> heating, for example, in devices for tumor ablation, ablation of
> malfunctioning cardiac or brain tissue, cauterization,
> relaxation of muscle rheumatic pain and other pain, etc.   
>   
> [0009] Another use of electric fields for medical purposes
> involves the utilization of high frequency oscillating fields
> transmitted from a source that emits an electric wave, such as
> an RF wave or a microwave source that is directed at the part of
> the body that is of interest (i.e., target). In these instances,
> there is no electric energy conduction between the source and
> the body; but rather, the energy is transmitted to the body by
> radiation or induction. More specifically, the electric energy
> generated by the source reaches the vicinity of the body via a
> conductor and is transmitted from it through air or some other
> electric insulating material to the human body.  
>   
> [0010] In a conventional electrical method, electrical current
> is delivered to a region of the target tissue using electrodes
> that are placed in contact with the body of the patient. The
> applied electrical current destroys substantially all cells in
> the vicinity of the target tissue. Thus, this type of electrical
> method does not discriminate between different types of cells
> within the target tissue and results in the destruction of both
> tumor cells and normal cells.   
>   
> [0011] Electric fields that can be used in medical applications
> can thus be separated generally into two different modes. In the
> first mode, the electric fields are applied to the body or
> tissues by means of conducting electrodes. These electric fields
> can be separated into two types, namely (1) steady fields or
> fields that change at relatively slow rates, and alternating
> fields of low frequencies that induce corresponding electric
> currents in the body or tissues, and (2) high frequency
> alternating fields (above 1 MHz) applied to the body by means of
> the conducting electrodes. In the second mode, the electric
> fields are high frequency alternating fields applied to the body
> by means of insulated electrodes.  
>   
> [0012] The first type of electric field is used, for example, to
> stimulate nerves and muscles, pace the heart, etc. In fact, such
> fields are used in nature to propagate signals in nerve and
> muscle fibers, central nervous system (CNS), heart, etc. The
> recording of such natural fields is the basis for the ECG, EEG,
> EMG, ERG, etc. The field strength in these applications,
> assuming a medium of homogenous electric properties, is simply
> the voltage applied to the stimulating/recording electrodes
> divided by the distance between them. These currents can be
> calculated by Ohm's law and can have dangerous stimulatory
> effects on the heart and CNS and can result in potentially
> harmful ion concentration changes. Also, if the currents are
> strong enough, they can cause excessive heating in the tissues.
> This heating can be calculated by the power dissipated in the
> tissue (the product of the voltage and the current).   
>   
> [0013] When such electric fields and currents are alternating,
> their stimulatory power, on nerve, muscle, etc., is an inverse
> function of the frequency. At frequencies above 1-10 KHz, the
> stimulation power of the fields approaches zero. This limitation
> is due to the fact that excitation induced by electric
> stimulation is normally mediated by membrane potential changes,
> the rate of which is limited by the RC properties (time
> constants on the order of 1 ms) of the membrane.  
>   
> [0014] Regardless of the frequency, when such current inducing
> fields are applied, they are associated with harmful side
> effects caused by currents. For example, one negative effect is
> the changes in ionic concentration in the various "compartments"
> within the system, and the harmful products of the electrolysis
> taking place at the electrodes, or the medium in which the
> tissues are imbedded. The changes in ion concentrations occur
> whenever the system includes two or more compartments between
> which the organism maintains ion concentration differences. For
> example, for most tissues, [Ca<++> ] in the extracellular
> fluid is about 2\*10<-3 > M, while in the cytoplasm of
> typical cells its concentration can be as low as 10<-7 >
> M. A current induced in such a system by a pair of electrodes,
> flows in part from the extracellular fluid into the cells and
> out again into the extracellular medium. About 2% of the current
> flowing into the cells is carried by the Ca<++> ions. In
> contrast, because the concentration of intracellular
> Ca<++> is much smaller, only a negligible fraction of the
> currents that exits the cells is carried by these ions. Thus,
> Ca<++> ions accumulate in the cells such that their
> concentrations in the cells increases, while the concentration
> in the extracellular compartment may decrease. These effects are
> observed for both DC and alternating currents (AC). The rate of
> accumulation of the ions depends on the current intensity ion
> mobilities, membrane ion conductance, etc. An increase in
> [Ca<++> ] is harmful to most cells and if sufficiently
> high will lead to the destruction of the cells. Similar
> considerations apply to other ions. In view of the above
> observations, long term current application to living organisms
> or tissues can result in significant damage. Another major
> problem that is associated with such electric fields, is due to
> the electrolysis process that takes place at the electrode
> surfaces. Here charges are transferred between the metal
> (electrons) and the electrolytic solution (ions) such that
> charged active radicals are formed. These can cause significant
> damage to organic molecules, especially macromolecules and thus
> damage the living cells and tissues.  
>   
> [0015] In contrast, when high frequency electric fields, above 1
> MHz and usually in practice in the range of GHz, are induced in
> tissues by means of insulated electrodes, the situation is quite
> different. These type of fields generate only capacitive or
> displacement currents, rather than the conventional charge
> conducting currents. Under the effect of this type of field,
> living tissues behave mostly according to their dielectric
> properties rather than their electric conductive properties.
> Therefore, the dominant field effect is that due to dielectric
> losses and heating. Thus, it is widely accepted that in
> practice, the meaningful effects of such fields on living
> organisms, are only those due to their heating effects, i.e.,
> due to dielectric losses.   
>   
> [0016] In U.S. Pat. No. 6,043,066 ('066) to Mangano, a method
> and device are presented which enable discrete objects having a
> conducting inner core, surrounded by a dielectric membrane to be
> selectively inactivated by electric fields via irreversible
> breakdown of their dielectric membrane. One potential
> application for this is in the selection and purging of certain
> biological cells in a suspension. According to this patent, an
> electric field is applied for targeting selected cells to cause
> breakdown of the dielectric membranes of these tumor cells,
> while purportedly not adversely affecting other desired
> subpopulations of cells. The cells are selected on the basis of
> intrinsic or induced differences in a characteristic
> electroporation threshold. The differences in this threshold can
> depend upon a number of parameters, including the difference in
> cell size.   
>   
> [0017] The method of the '066 patent is therefore based on the
> assumption that the electroporation threshold of tumor cells is
> sufficiently distinguishable from that of normal cells because
> of differences in cell size and differences in the dielectric
> properties of the cell membranes. Based upon this assumption,
> the larger size of many types of tumor cells makes these cells
> more susceptible to electroporation and thus, it may be possible
> to selectively damage only the larger tumor cell membranes by
> applying an appropriate electric field. One disadvantage of this
> method is that the ability to discriminate is highly dependent
> upon on cell type, for example, the size difference between
> normal cells and tumor cells is significant only in certain
> types of cells. Another drawback of this method is that the
> voltages which are applied may damage some of the normal cells
> and may not damage all of the tumor cells because the
> differences in size and membrane dielectric properties are
> largely statistical and the actual cell geometries and
> dielectric properties may vary significantly. [  
>   
> 0018] What is needed in the art and has heretofore not been
> available is an apparatus for destroying dividing cells, wherein
> the apparatus better discriminates between dividing cells,
> including single-celled organisms, and non-dividing cells and is
> capable of selectively destroying the dividing cells or
> organisms with substantially no affect on the non-dividing cells
> or organisms and which can be configured to adopt its
> characteristics and spatial distribution within the patient's
> body so as to optimally destroy a specific tumor or tumors in a
> patient. The data regarding the specific tumor can be provided
> by conventional techniques, such as CT, MRI, etc., imaging of
> the tumor and its surroundings, as well as other means for
> characterization of the tumors.   
>   
> SUMMARY OF THE INVENTION
>   
>   
> [0019] An apparatus and related method for use in a number of
> different applications for optimization of the selective
> electric fields in destroying cells undergoing growth and
> division are provided. This includes cell (particularly tumor
> cells) in living tissues and organisms or other complex
> structures. The apparatus and method are designed to compute the
> optimal spatial and temporal characteristics for combating tumor
> growth within a body on the basis of cytological (as provided by
> biopsies, etc.) and anatomical data (as provided by CT, MRI,
> PET, etc.), as well as the electric properties of the different
> elements. On the basis of this computation, the apparatus
> applies the fields that have maximal effect on the tumor and
> minimal effect on all other tissues by adjusting both the field
> generator output characteristics and by optimal positioning of
> the insulated electrodes or isolects on the patient's body. For
> example and as will be described in greater detail hereinafter,
> the isolects are directly applied to the patient or by means of
> probes or pieces of clothing that are worn over the tumor area.
> In either case, the apparatus can activate the selected set of
> electrodes (isolects) to achieve optimal effect.   
>   
> [0020] A major use of the method and apparatus of the present
> invention is in treatment of tumors by selective destruction of
> tumor cells with substantially no affect on normal tissue cells
> and, thus, the invention is described below in the context of
> selective destruction of tumor cells. It should be appreciated
> however that, for the purpose of the description that follows,
> the term "cell" may also refer to single-celled organisms
> (eubacteria, bacteria, yeast, protozoa), multi-celled organisms
> (fungi, algae, mold), and plants as or parts thereof that are
> not normally classified as "cells". The method of the present
> invention enables selective destruction of tumor cells, or other
> organisms, by selective destruction of cells undergoing division
> in a way that is more effective and more accurate (e.g., more
> adaptable to be aimed at specific targets) than existing
> methods. Further, the method of the present invention causes
> minimal damage, if any, to normal tissue and, thus, reduces or
> eliminates many side-effects associated with existing selective
> destruction methods, such as radiation therapy and chemotherapy.
> The selective destruction of dividing cells in accordance with
> the method of the present invention does not depend on the
> sensitivity of the cells to chemical agents or radiation.
> Instead, the selective destruction of dividing cells is based on
> distinguishable geometrical characteristics of cells undergoing
> division, in comparison to non-dividing cells, regardless of the
> cell geometry of the type of cells being treated. As well as the
> electric properties of the special apparatus associated with
> cell division (microtubules, tubulin filaments, etc.).   
>   
> [0021] In an embodiment of the present invention, cell
> geometry-dependent selective destruction of living tissue is
> performed by inducing a non-homogenous electric field in the
> cells, as described below.   
>   
> [0022] It has been observed by the present inventor that, while
> different cells in their non-dividing state may have different
> shapes, e.g., spherical, ellipsoidal, cylindrical,
> "pancake-like", etc., the division process of practically all
> cells is characterized by development of a "cleavage furrow" in
> late anaphase and telophase. This cleavage furrow is a slow
> constriction of the cell membrane (between the two sets of
> daughter chromosomes) which appears microscopically as a growing
> cleft (e.g., a groove or notch) that gradually separates the
> cell into two new cells. During the division process, there is a
> transient period (telophase) during which the cell structure is
> basically that of two sub-cells interconnected by a narrow
> "bridge" formed of the cell material. The division process is
> completed when the "bridge" between the two sub-cells is broken.
> The selective destruction of tumor cells using the present
> electronic apparatus utilizes this unique geometrical feature of
> dividing cells.  
>   
>  [0023] When a cell or a group of cells are under natural
> conditions or environment, i.e., part of a living tissue, they
> are disposed surrounded by a conductive environment consisting
> mostly of an electrolytic inter-cellular fluid and other cells
> that are composed mostly of an electrolytic intra-cellular
> liquid. When an electric field is induced in the living tissue,
> by applying an electric potential across the tissue, an electric
> field is formed in the tissue and the specific distribution and
> configuration of the electric field lines defines the direction
> of charge displacement, or paths of electric currents in the
> tissue, if currents are in fact induced in the tissue. The
> distribution and configuration of the electric field is
> dependent on various parameters of the tissue, including the
> geometry and the electric properties of the different tissue
> components, and the relative conductivities, capacities and
> dielectric constants (that may be frequency dependent) of the
> tissue components.  
>   
>  [0024] The electric current flow pattern for cells
> undergoing division is very different and unique as compared to
> non-dividing cells. Such cells including first and second
> sub-cells, namely an "original" cell and a newly formed cell,
> that are connected by a cytoplasm "bridge" or "neck". The
> currents penetrate the first sub-cell through part of the
> membrane ("the current source pole"); however, they do not exit
> the first sub-cell through a portion of its membrane closer to
> the opposite pole ("the current sink pole"). Instead, the lines
> of current flow converge at the neck or cytoplasm bridge,
> whereby the density of the current flow lines is greatly
> increased. A corresponding, "mirror image", process that takes
> place in the second sub-cell, whereby the current flow lines
> diverge to a lower density configuration as they depart from the
> bridge, and finally exit the second sub-cell from a part of its
> membrane closes to the current sink.  
>   
> [0025] When a polarizable object is placed in a non-uniform
> converging or diverging field, electric forces act on it and
> pull it towards the higher density electric field lines. In the
> case of dividing cell, electric forces are exerted in the
> direction of the cytoplasm bridge between the two cells. Since
> all intercellular organelles and macromolecules are polarizable,
> they are all force towards the bridge between the two cells. The
> field polarity is irrelevant to the direction of the force and,
> therefore, an alternating electric having specific properties
> can be used to produce substantially the same effect. It will
> also be appreciated that the concentrated and inhomogeneous
> electric field present in or near the bridge or neck portion in
> itself exerts strong forces on charges and natural dipoles and
> can lead to the disruption of structures associated with these
> members.   
>   
> [0026] The movement of the cellular organelles towards the
> bridge disrupts the cell structure and results in increased
> pressure in the vicinity of the connecting bridge membrane. This
> pressure of the organelles on the bridge membrane is expected to
> break the bridge membrane and, thus, it is expected that the
> dividing cell will "explode" in response to this pressure. The
> ability to break the membrane and disrupt other cell structures
> can be enhanced by applying a pulsating alternating electric
> field that has a frequency from about 50 KHz to about 500 KHz.
> When this type of electric field is applied to the tissue, the
> forces exerted on the intercellular organelles have a
> "hammering" effect, whereby force pulses (or beats) are applied
> to the organelles numerous times per second, enhancing the
> movement of organelles of different sizes and masses towards the
> bridge (or neck) portion from both of the sub-cells, thereby
> increasing the probability of breaking the cell membrane at the
> bridge portion. The forces exerted on the intracellular
> organelles also affect the organelles themselves and may
> collapse or break the organelles.  
>   
>  [0027] According to one exemplary embodiment, the
> apparatus for applying the electric field is an electronic
> apparatus that generates the desired electric signals in the
> shape of waveforms or trains of pulses. The electronic apparatus
> includes a generator that generates an alternating voltage
> waveform at frequencies in the range from about 50 KHz to about
> 500 KHz. The generator is operatively connected to conductive
> leads which are connected at their other ends to insulated
> conductors/electrodes (also referred to as isolects) that are
> activated by the generated waveforms. The generator may provide
> each electrode with a specific selected waveform that is
> calculated for field distribution that gives optimal results.
> This can be represented in the form of an Optimal Map. The
> insulated electrodes consist of a conductor in contact with a
> dielectric (insulating layer) that is in contact with the
> conductive tissue, thus forming a capacitor. The electric fields
> that are generated by the present apparatus can be applied in
> several different modes depending upon the precise treatment
> application and physiological and anatomical characteristics of
> the patient's parts of the body undergoing treatment.   
>   
> BRIEF DESCRIPTION OF THE
> DRAWINGS   
>   
> ![](2004176804-1.jpg)  
>   
> ![](2004176804-4.jpg)  
> ![](2004176804-3.jpg)  
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>   
> [0028] FIG. 1A-1E are
> simplified, schematic, cross-sectional, illustrations of
> various stages of a cell division process;   
>   
> [0029] FIGS. 2A and 2B are
> schematic illustrations of a non-dividing cell being subjected
> to an electric field, in accordance with an embodiment of the
> present invention;   
>   
> [0030] FIGS. 3A, 3B and 3C are
> schematic illustrations of a dividing cell being subjected to
> an electric field, resulting in destruction of the cell (FIG.
> 3C), in accordance with an embodiment of the present
> invention;   
>   
> [0031] FIG. 4 is a schematic
> illustration of a dividing cell at one stage being subjected
> to an electric field;   
>   
> [0032] FIG. 5 is a schematic
> block diagram of an apparatus for applying an electric field
> according to one exemplary embodiment for selectively
> destroying cells;   
>   
> [0033] FIG. 6 is a simplified
> schematic diagram of an equivalent electric circuit of
> insulated electrodes of the apparatus of FIG. 5;   
>   
> [0034] FIG. 7 is diagrammatic
> flow chart for computing an optimal electric field;   
>   
> [0035] FIG. 8 is a front
> elevation view of an undershirt incorporating the present
> apparatus being worn over a human body;   
>   
> [0036] FIG. 9 is a
> cross-sectional taken along the line 9-9;   
>   
> [0037] FIG. 10 is schematic
> view of a target area on which the electric field is to be
> focused;   
>   
> [0038] FIG. 11 is a
> photographic image of the optimal position of electrodes
> around the target area (tissue mass) of FIG. 10;   
>   
> [0039] FIG. 12 is a schematic
> illustration of a geometric model for positioning electrodes
> around a spine of a human patient where the electrodes are
> arranged symmetrically;   
>   
> [0040] FIG. 13 is an enlarged
> schematic illustration of one electrode of the arrangement of
> FIG. 12;   
>   
> [0041] FIG. 14 is a
> photographic image of a resulting electric field generated
> when the electrodes are arranged symmetrically as illustrated
> in FIG. 12;   
>   
> [0042] FIG. 15 is a schematic
> illustration representing the electric field of FIG. 14 by
> arrows;   
>   
> [0043] FIG. 16 is a schematic
> illustration of a geometric model for positioning electrodes
> around the spine in an asymmetric manner so that the electric
> field in the area of the spine is zero;   
>   
> [0044] FIG. 17 is a
> photographic image of a resulting electric field generated
> when the electrodes are arranged asymmetrically as illustrated
> in FIG. 16;   
>   
> [0045] FIG. 18 is a schematic
> illustration representing the electric field of FIG. 17 by
> arrows;   
>   
> [0046] FIG. 19 is a
> cross-sectional illustration of a skin patch incorporating the
> apparatus of FIG. 5 and for placement on a skin surface for
> treating a tumor or the like;   
>   
> [0047] FIG. 20 is a
> cross-sectional illustration of the insulated electrodes
> implanted within the body for treating a tumor or the like;   
>   
> [0048] FIG. 21 is a
> cross-sectional illustration of the insulated electrodes
> implanted within the body for treating a tumor or the like;   
>   
> [0049] FIGS. 22A-22D are
> cross-sectional illustrations of various constructions of the
> insulated electrodes of FIG. 5;   
>   
> [0050] FIG. 23 is a front
> elevation view in partial cross-section of two insulated
> electrodes being arranged about a human torso for treatment of
> a tumor contained within the body, e.g., a tumor associated
> with lung cancer;   
>   
> [0051] FIGS. 24A-24C are
> cross-sectional illustrations of various insulated electrodes
> with and without protective members formed as a part of the
> construction thereof;   
>   
> [0052] FIG. 25 is a schematic
> diagram of insulated electrodes that are arranged for focusing
> the electric field at a desired target while leaving other
> areas in low field density (i.e., protected areas);   
>   
> [0053] FIG. 26 is a
> cross-sectional view of insulated electrodes incorporated into
> a hat according to a first embodiment for placement on a head
> for treating an intra-cranial tumor or the like;   
>   
> [0054] FIG. 27 is a partial
> section of a hat according to an exemplary embodiment having a
> recessed section for receiving one or more insulated
> electrodes;   
>   
> [0055] FIG. 28 is a
> cross-sectional view of the hat of FIG. 27 placed on a head
> and illustrating a biasing mechanism for applying a force to
> the insulated electrode to ensure the insulated electrode
> remains in contact against the head;   
>   
> [0056] FIG. 29 is a
> cross-sectional top view of an article of clothing having the
> insulated electrodes incorporated therein for treating a tumor
> or the like;   
>   
> [0057] FIG. 30 is a
> cross-sectional view of a section of the article of clothing
> of FIG. 29 illustrating a biasing mechanism for biasing the
> insulated electrode in a direction to ensure the insulated
> electrode is placed proximate to a skin surface where
> treatment is desired;   
>   
> [0058] FIG. 31 is a
> cross-sectional view of a probe according to one embodiment
> for being disposed internally within the body for treating a
> tumor or the like;  
>   
> [0059] FIG. 32 is an elevation
> view of an unwrapped collar according to one exemplary
> embodiment for placement around a neck for treating a tumor or
> the like in the area where the collar is wrapped around the
> neck;   
>   
> [0060] FIG. 33is a side
> elevation view of the present apparatus being used to prevent
> restenosis of arteries after angioplasty; and  
>   
> [0061] FIG. 34 is an enlarged
> view of a stent used in the arrangement of FIG. 33.   
>   
> DETAILED DESCRIPTION OF
> PREFERRED EMBODIMENTS THE INVENTION   
>   
> [0062] Reference is made to FIGS. 1A-1E which schematically
> illustrate various stages of a cell division process. FIG. 1A
> shows a cell 10 at its normal geometry, which may be generally
> spherical (as shown in the drawings), ellipsoidal, cylindrical,
> "pancake" like, or any other cell geometry, as is known in the
> art. FIGS. 1B-1D show cell 10 during different stages of its
> division process, which results in the formation of two new
> cells 18 and 20, shown in FIG. 1E.  
>   
> [0063] As shown in FIGS. 1B-1D, the division process of cell 10
> is characterized by a slowly growing cleft 12 which gradually
> separates cell 10 into two units, namely, sub-cells 14 and 16,
> which eventually evolve into new cells 18 and 20 (FIG. 1E). As
> shown specifically in FIG. 1D, the division process is
> characterized by a transient period during which the structure
> of cell 10 is basically that of the two sub-cells 14 and 16
> interconnected by a narrow "bridge" 22 containing cell material
> (cytoplasm surrounded by cell membrane).  
>   
>  [0064] Reference is now made to FIGS. 2A and 2B, which
> schematically illustrate non-dividing cell 10 being subjected to
> an electric field produced by applying an alternating electric
> potential, at a relatively low frequency and at a relatively
> high frequency, respectively. Cell 10 includes intracellular
> organelles, e.g., a nucleus 30. Alternating electrical potential
> is applied across electrodes 28 and 32 that may be attached
> externally to a patient at a predetermined region, e.g., in the
> vicinity of a tumor being treated. When cell 10 is under natural
> conditions, i.e., part of a living tissue, it is disposed in a
> conductive environment (hereinafter referred to as a "volume
> conductor") consisting mostly of electrolytic inter-cellular
> liquid. When an electric potential is applied across electrode
> 28 and 32, some of the field lines of the resultant electric
> field (or the current induced in the tissue in response to the
> electric field) penetrate cell 10, while the rest of the field
> lines (or induced current) flow in the surrounding medium. The
> specific distribution of the electric field lines, which is
> substantially consistent with the direction of current flow in
> this case, depends on the geometry and the electric properties
> of the system components, e.g., the relative conductivities and
> dielectric constants of the system components, that may be
> frequency dependent. For low frequencies, e.g., frequencies
> considerably lower than 10 kHz, the conductance properties of
> the components dominate the current flow, and the field
> distribution is generally as depicted in FIG. 2A. At higher
> frequencies, e.g., at frequencies of between 10 kHz and 1 MHz,
> the dielectric properties of the components become more
> significant and eventually dominate the field distribution,
> resulting in field distribution lines as depicted generally in
> FIG. 2B.   
>   
> [0065] For constant (i.e., DC) electric fields or relatively low
> frequency alternating electric fields, for example, frequencies
> under 10 kHz, the dielectric properties of the various
> components are not significant in determining and computing the
> field distribution. Therefore, as a first approximation, with
> regard to the electric field distribution, the system can be
> reasonably represented by the relative impedances of its various
> components. Under this approximation, the intercellular (i.e.,
> extracellular) fluid and the intracellular fluid have a
> relatively low impedance, while the cell membrane 11 has a
> relatively high impedance. Thus, under low frequency conditions,
> only a fraction of the electric field lines (or currents induced
> by the electric field) penetrate membrane 11 of cell 10. At
> relatively high frequencies (e.g., 10 kHz-1 MHz), in contrast,
> the impedance of membrane 11 relative to the intercellular and
> intracellular fluids decreases and, thus, the fraction of
> currents penetrating the cells increases significantly. It
> should be noted that at very high frequencies, i.e., above 1
> MHz, the membrane capacitance may short the membrane resistance
> and, therefore, the total membrane resistance may become
> negligible.   
>   
> [0066] In any of the embodiments described above, the electric
> field lines (or induced currents) penetrate cell 10 from a
> portion of membrane 11 closest to one of the electrodes
> generating the current, e.g., closest to positive electrode 28
> (also referred to herein as "source"). The current flow pattern
> across cell 10 is generally uniform because, under the above
> approximation, the field induced inside the cell is
> substantially homogenous. The currents exit cell 10 through a
> portion of membrane 11 closest to the opposite electrode, e.g.,
> negative electrode 32 (also referred to herein as "sink").   
>   
> [0067] The distinction between field lines and current flow may
> depend on a number of factors, for example, on the frequency of
> the applied electric potential and on whether electrodes 28 and
> 32 are electrically insulated. For insulated electrodes applying
> a DC or low frequency alternating voltage, there is practically
> no current flow along the lines of the electric field. At higher
> frequencies, displacement currents are induced in the tissue due
> to charging and discharging of the cell membranes (which act as
> capacitors to a certain extent), and such currents follow the
> lines of the electric field. Fields generated by non-insulated
> electrodes, in contrast, always generate some form of current
> flow, specifically, DC or low frequency alternating fields
> generate conductive current flow along the field lines, and high
> frequency alternating fields generate both conduction and
> displacement currents along the field lines. It should be
> appreciated, however, that movement of polarizable intracellular
> organelles according to the present invention (as described
> below) is not dependent on actual flow of current and,
> therefore, both insulated and non-insulated electrodes may be
> used efficiently in conjunction with the present invention.
> Nevertheless, insulated electrodes have the advantage of lower
> power consumption and causing less heating of the treated
> regions.   
>   
> [0068] According to one exemplary embodiment, the electric
> fields that are used in the present apparatus are alternating
> fields having frequencies that in the range from about 50 KHz to
> about 500 KHz, and preferably from about 100 KHz to about 300
> KHz. For ease of discussion, these type of electric fields are
> also referred to hereinafter as "TC fields", which is an
> abbreviation of "Tumor Curing electric fields", since these
> electric fields fall into an intermediate category (between high
> and low frequency ranges) that have bio-effective field
> properties, while having no meaningful stimulatory and thermal
> effects. These frequencies are sufficiently low so that the
> system behavior is determined by the system's "Ohmic"
> (conductive) properties but sufficiently high enough not to have
> any stimulation effect on excitable tissues. Such a system
> consists of two types of elements, namely, the intercellular, or
> extracellular fluid, or medium and the individual cells. The
> intercellular fluid is mostly an electrolyte with a specific
> resistance of about 40-100 ohm\*cm. As mentioned above, the cells
> are characterized by three elements, namely (1) a thin, highly
> electric resistive membrane that coats the cell; (2) internal
> cytoplasm that is mostly an electrolyte that contains numerous
> macromolecules and micro-organelles, including the nucleus; and
> (3) membranes, similar in their electric properties to the cell
> membranes, cover the micro-organelles.   
>   
> [0069] When this type of system is subjected to the present TC
> fields (e.g., alternating electric fields in the frequency range
> of 100 KHz-300 KHz), most of the lines of the electric field and
> currents tend away from the cells because of the high resistive
> cell membrane and therefore, the lines remain in the
> extracellular conductive medium. In the above recited frequency
> range, the actual fraction of electric field or currents that
> penetrate the cells is a strong function of the frequency.  
>   
>  [0070] FIG. 2 schematically depicts the resulting field
> distribution in the system. As illustrated, the lines of force,
> which also depict the lines of potential current flow across the
> cell volume mostly in parallel with the undistorted lines of
> force (the main direction of the electric field). In other
> words, the field inside the cells is mostly homogeneous. In
> practice, the fraction of the field or current that penetrates
> the cells is determined by the cell membrane impedance value
> relative to that of the extracellular fluid. Since the
> equivalent electric circuit of the cell membrane is that of a
> resistor and capacitor in parallel, the impedance is function of
> the frequency. The higher the frequency, the lower the
> impedance, the larger the fraction of penetrating current and
> the smaller the field distortion. [0071] As previously
> mentioned, when cells are subjected to relatively weak electric
> fields and currents that alternate at high frequencies, such as
> the present TC fields having a frequency in the range of 50 KHz
> to 500 KHz, they have no effect on the non-dividing cells. While
> the present TC fields have no detectable effect on such systems,
> the situation becomes different in the presence of dividing
> cells.  
>   
>  [0072] Reference is now made to FIGS. 3A-3C which
> schematically illustrate the electric current flow pattern in
> cell 10 during its division process, under the influence of high
> frequency alternating electric field in accordance with an
> embodiment of the invention. The field lines or induced currents
> penetrate cell 10 through a part of the membrane of sub-cell 16
> closer to electrode 28. However, they do not exit through the
> cytoplasm bridge 22 that connects sub-cell 16 with the newly
> formed yet still attached sub-cell 14, or through a part of the
> membrane in the vicinity of bridge 22. Instead, the electric
> field or current flow lines-that are relatively widely separated
> in sub-cell 16-converge as they approach bridge 22 (also
> referred to as "neck" 22) and, thus, the current/field line
> density within neck 22 is increased dramatically. A "mirror
> image" process takes place in sub-cell 14, whereby the
> converging field lines in bridge 22 diverge as they approach the
> exit region of sub-cell 14.  
>   
> [0073] It should be appreciated by persons skilled in the art
> that homogenous electric fields do not exert a force on
> electrically neutral objects, i.e., objects having substantially
> zero net charge, although such objects may become polarized.
> However, under a non-uniform, converging electric field, as
> shown in FIGS. 3A-3C, electric forces are exerted on polarized
> objects, moving them in the direction of the higher density
> electric field lines. It will be appreciated that the
> concentrated electric field that is present in the neck or
> bridge area in itself exerts strong forces on charges and
> natural dipoles and can disrupt structures that are associated
> therewith. One will understand that similar net forces act on
> charges in an alternating field, again in the direction of the
> field of higher intensity.   
>   
> [0074] In the configuration of FIGS. 3A and 3B, the direction of
> movement of polarized objects is towards the higher density
> electric filed lines, i.e., towards the cytoplasm bridge 22
> between sub-cells 14 and 16. It is known in the art that all
> intracellular organelles, for example, nuclei 24 and 26 of
> sub-cells 14 and 16, respectively, are polarizable and, thus,
> such intracellular organelles will be electrically forced in the
> direction of bridge 22. Since the movement is always from the
> lower density currents to the higher density currents,
> regardless of the field polarity, the forces applied by the
> alternating electric field to organelles such as nuclei 24 and
> 26 are always in the direction of bridge 22. A comprehensive
> description of such forces and the resulting movement of
> macromolecules or intracellular organelles, a phenomenon
> referred to as dielectrophoresis, is described extensively in
> the literature, for example, in C. L. Asbury & G. van den
> Engh, Biophys. J. 74, 1024-1030, 1998, the disclosure of which
> is incorporated herein by reference.  
>   
> [0075] The movement of organelles 24 and 26 towards bridge 22
> disrupts the structure of the dividing cell and, eventually, the
> pressure of the converging organelles on bridge membrane 22
> results in breakage of cell membrane 11 at the vicinity of
> bridge 22, as shown schematically in FIG. 3C. The ability to
> break membrane 11 at bridge 22 and to otherwise disrupt the cell
> structure and organization may be enhanced by applying a
> pulsating AC electric field, rather than a steady AC field. When
> a pulsating field is applied, the forces acting on organelles 24
> and 26 may have a "hammering" effect, whereby pulsed forces beat
> on the intracellular organelles at a desired rhythm, e.g., a
> pre-selected number of times per second. Such "hammering" is
> expected to enhance the movement of intracellular organelles
> towards neck 22 from both sub cells 14 and 16), thereby
> increasing the probability of breaking cell membrane 11 in the
> vicinity of neck 22. [0076] A very important element, which is
> very susceptible to the special fields that develop within the
> dividing cells is the microtubule spindle that plays a major
> role in the division process. In FIG. 4, a dividing cell 10 is
> illustrated, at an earlier stage as compared to FIGS. 3A and 3B,
> under the influence of external TC fields (e.g., alternating
> fields in the frequency range of about 100 KHz to about 300
> KHz), generally indicated as lines 100, with a corresponding
> spindle mechanism generally indicated at 120. The lines 120 are
> microtubules that are known to have a very strong dipole moment.
> This strong polarization makes the tubules susceptible to
> electric fields. Their positive charges are located at two
> centrioles while two sets of negative poles are at the center of
> the dividing cells and the other pair is at the points of
> attachment of the microtubules to the cell membrane, generally
> indicated at 130. This structure forms sets of double dipoles
> and therefore, they are susceptible to fields of different
> directions. It will be understood that the effects of the TC
> fields on the dipoles does not depend on the formation of the
> bridge (neck) and thus, the dipoles are influenced by the TC
> fields prior to the formation of the bridge (neck).   
>   
> [0077] Since the present apparatus, as described in greater
> detail hereinafter, utilizes insulated electrodes, the
> above-mentioned negative effects obtained when conductive
> electrodes are used, i.e., ion concentration changes in the
> cells and the formation of harmful agents by electrolysis, do
> not occur when the present apparatus is used. This is because,
> in general, no actual transfer of charges takes place between
> the electrodes and the medium and there is no charge flow in the
> medium where the currents are capacitive, i.e., are expressed
> only as rotation of charges, etc.   
>   
> [0078] Turning now to FIG. 5, the TC fields described above that
> have been found to advantageously destroy tumor cells are
> generated by an electronic apparatus 200. FIG. 5 is a simple
> schematic diagram of the electronic apparatus 200 illustrating
> the major components thereof. The electronic apparatus 200
> generates the desired electric field signals (TC signals) in the
> shape of waveforms or trains of pulses. The apparatus 200
> includes a generator 210 and a set of pairs of conductive leads
> 220 that are attached at one end thereof to the generator 210.
> The opposite ends of the leads 220 are connected to the
> insulated conductors 230 that are activated by the electric
> signals (e.g., waveforms). The insulated conductors 230 are also
> referred to hereinafter as "isolects" 230. Optionally and
> according to one exemplary embodiment, the apparatus 200
> includes a temperature sensor 240 or sensors and a control box
> 250 which are added to control the amplitude of the electric
> field generated so not to generate excessive heating in the area
> that is treated.   
>   
> [0079] The generator 210 generates multiple alternating voltage
> waveforms at frequencies in the range from about 50 KHz to about
> 500 KHz (preferably from about 100 KHz to about 300 KHz)(i.e.,
> the TC fields) as instructed by a controller 300. Preferably,
> the controller 300 is a programmable unit, such as a personal
> computer or the like, that permits the user to input certain
> parameters and the controller 300 will then make the necessary
> computations. The controller 300 also distributes to each
> electrode 230 the designated potential wave. The required
> voltages are such the electric field intensity in the tissue to
> be treated is in the range of about 0.1V/cm, according to one
> exemplary embodiment, to about 10V/cm while in the other areas
> it is significantly lower.  
>   
> [0080] When the control box 250 is included, it controls the
> outputs of the generator 210 so that they will remain constant
> at the values preset by the user or the control box 250. The
> controller 300 issues a warning or the like when the temperature
> (sensed by temperature sensor 240) exceeds a preset limit.  
>   
>  [0081] The details of the construction of the isolects 230
> is based on their electric behavior that can be understood from
> their simplified electric circuit when in contact with tissue as
> generally illustrated in FIG. 6. In the illustrated arrangement,
> the potential drop or the electric field distribution between
> the different components is determined by their relative
> electric impedance, i.e., the fraction of the field on each
> component is given by the value of its impedance divided by the
> total circuit impedance. For example, the potential drop on
> element [Delta]VA=A/(A+B+C+D+E). Thus, for DC or low frequency
> AC, practically all the potential drop is on the capacitor (that
> acts as an insulator). For relatively very high frequencies, the
> capacitor practically is a short and therefore, practically all
> the field is distributed in the tissues. At the frequencies of
> the present TC fields (e.g., 50 KHz to 500 KHz), which are
> intermediate frequencies, the impedance of the capacitance of
> the capacitors is dominant and determines the field
> distribution. Therefore, in order to increase the effective
> voltage drop across the tissues (field intensity), the impedance
> of the capacitors is to be decreased (i.e., increase their
> capacitance). This can be achieved by increasing the effective
> area of the "plates" of the capacitor, decrease the thickness of
> the dielectric or use a dielectric with high dielectric
> constant.  
>   
> [0082] In order to optimize the field distribution, the isolects
> 230 are configured differently depending upon the application in
> which the isolects 230 are to be used. There are two principle
> modes for applying the present electric fields (TC fields).
> First, the TC fields can be applied by external isolects and
> second, the TC fields can be applied by internal isolects.   
>   
> [0083] Since the thin insulating layer can be very vulnerable,
> etc., the insulation can be replaced by very high dielectric
> constant insulating materials, such as titanium dioxide (e.g.,
> rutil), the dielectric constant can reach values of about 200.
> There a number of different materials that are suitable for use
> in the intended application and have high dielectric constants.
> For example, some materials include: lithium nibate (LiNbO3),
> which is a ferroelectric crystal and has a number of
> applications in optical, pyroelectric and piezoelectric devices;
> yittrium iron garnet (YIG) is a ferrimagnetic crystal and
> magneto-optical devices, e.g., optical isolator can be realized
> from this material; barium titanate (BaTiO3) is a ferromagnetic
> crystal with a large electro-optic effect; potassium tantalate
> (KTaO3) which is a dielectric crystal (ferroelectric at low
> temperature) and has very low microwave loss and tunability of
> dielectric constant at low temperature; and lithium tantalate
> (LiTaO3) which is a ferroelectric crystal with similar
> properties as lithium niobate and has utility in
> electro-optical, pyroelectric and piezoelectric devices. It will
> be understood that the aforementioned exemplary materials can be
> used in combination with the present device where it is desired
> to use a material having a high dielectric constant.  
>   
>  [0084] One must also consider another factor that effects
> the effective capacity of the isolects 230, namely the presence
> of air between the isolects 230 and the skin. Such presence,
> which is not easy to prevent, introduces a layer of an insulator
> with a dielectric constant of 1.0, a factor that significantly
> lowers the effective capacity of the isolects 230 and
> neutralizes the advantages of the titanium dioxide (routil),
> etc. To overcome this problem, the isolects 230 can be shaped so
> as to conform with the body structure and/or (2) an intervening
> filler 270 (as illustrated in FIG. 22C), such as a gel, that has
> high conductance and a high effective dielectric constant, can
> be added to the structure. The shaping can be pre-structured
> (see FIG. 22A) or the system can be made sufficiently flexible
> so that shaping of the isolects 230 is readily achievable. The
> gel can be made of hydrogels, gelatins, agar, etc., and can have
> salts dissolved in it to increase its conductivity. The exact
> thickness of the gel is not important so long as it is of
> sufficient thickness that the gel layer does not dry out during
> the treatment. In one exemplary embodiment, the thickness of the
> gel is about 0.5 mm to about 2 mm.  
>   
>  [0085] In order to avoid overheating of the treated
> tissues, a selection of materials and field parameters is
> needed. The isolects insulating material should have minimal
> dielectric losses at the frequency ranges to be used during the
> treatment process. This factor can be taken into consideration
> when choosing the particular frequencies for the treatment. The
> direct heating of the tissues will most likely be dominated by
> the heating due to current flow (given by the I\*R product).
> However, dielectric losses can also contribute and in addition,
> the isolect (insulated electrode) 230 and its surroundings
> should be made of materials that facilitate heat losses and its
> general structure should also facilitate head losses, i.e.,
> minimal structures that block heat dissipation to the
> surroundings (air) as well as high heat conductivity.   
>   
> [0086] As previously mentioned, a coupling agent, such as a
> conductive gel, is preferably used to ensure that an effective
> conductive environment is provided between the insulated
> electrode 230 and the skin surface 231. The coupling agent is
> disposed on the insulated electrode 230 and preferably, a
> uniform layer of the agent is provided along the surface of the
> electrode 230. One of the reasons that the units 540 need
> replacement at periodic times is that the coupling agent needs
> to be replaced and/or replenished. In other words, after a
> predetermined time period or after a number of uses, the patient
> removes the units 540 so that the coupling agent can be applied
> again to the electrode 230.   
>   
> [0087] The leads 220 are standard isolated conductors with a
> flexible metal shield, preferably grounded so that it prevents
> the spread of the electric field generated by the leads 220. The
> isolects 230 have specific shapes and positioning so as to
> generate an electric field of the desired configuration,
> direction and intensity at the target volume and only there so
> as to focus the treatment. The generation of electric field
> distribution of the desired characteristics is achieved by
> placement of numerous isolects on the body surface, and when
> necessary also inside the body. The number of electrodes 230 can
> typically be about 20-100, placed about 4-12 cm apart. The
> electrodes 230 can be positioned individually on the skin, etc.,
> (as by an adhesive), or be part of an article of clothing, such
> as elastic undershirt, as illustrated in FIGS. 8-9, that holds
> the electrodes in place. Each isolect 230 (electrode) is
> connected to the controller 300 and is provided with a voltage
> signal the amplitude and shape of which was calculated
> specifically for the particular electrode. One will also
> appreciate that the calculation for the voltage signal
> (amplitude and shape) can be made for groups of isolects as well
> instead of for individual isolects.   
>   
> [0088] According to one aspect, a method for optimizing the
> selective destruction of dividing cells is provided and the
> method includes the general steps of calculating the spatial and
> temporal distribution of electric fields for optimal treatment
> of a specific patient that has a tumor of specific
> characteristics. This calculation takes into consideration the
> location and the specific characteristics of the tumor. [0089]
> One exemplary process for computing and applying an optimal
> electric field is described with reference to the flow chart of
> FIG. 7. FIG. 7 thus gives a general overview of the present
> optimization process. In steps 400, 410, 420, the user inputs
> different types of information that is used to compute the
> optimal electric field. For example, at step 400, the user
> inputs characteristics of the tissue cells in the area to be
> treated; at step 410, the user inputs characteristics of the
> tumor cells to be treated; and at step 420, the user inputs the
> anatomy of the area to be treated, including the tumor and its
> relevant surroundings. At step 430, this inputted information is
> used to compute the necessary field intensity in the tumor. The
> relative sensitivities of the non-tumor tissues to the electric
> fields is computed in step 440. At step 450, the maximal allowed
> field intensity at the various areas is determined and then
> based on the information inputted in steps 400 through 450, an
> optimal field map is computed at step 460. At step 470, the
> selected isolects (those present in the optimal field map) are
> computed as well as their position and waveform and the voltage
> that is to be delivered to each isolect. In order to further
> minimize the field map, the number of isolects is preferably
> reduced in step 480 to produce a modified field map and then the
> deviation of the modified map from the optimum is calculated.
> The calculated deviation is then compared to an inputted
> threshold value and if the calculated deviation is below the
> inputted threshold, the process of reducing the number of
> isolects is continued until the inputted threshold is obtained.
> Once the inputted threshold is obtained, a signal is delivered
> to the controller to activate the reduced number of isolects. At
> step 490, a signal is generated and delivered to the function
> generating system (e.g., the generator that produces the
> waveforms mentioned in step 470, such as an analog wave
> generator or a digital one, e.g., a waveform generated by a PC
> and outputted through a digital to analog converter) or the
> system is otherwise instructed to provide the selected waveform
> and voltage to the isolects. The field that results from
> activation of the isolects is monitored at step 510 and any
> errors are corrected. If any errors or abnormalities are
> detected, the field is modified as necessary according to the
> treatment protocol at step 520. The various algorithms that are
> used for the necessary computations are described hereinafter.  
>   
> [0090] Since the signal that is delivered to each electrode
> (isolect) is a voltage signal that has been specifically created
> for the specific electrode or for a specific group of
> electrodes, the calculation of this voltage signal is an
> important aspect of the present invention.  
>   
>  [0091] The voltages for the isolects are calculated as
> follows. Following the anatomical definition of the areas to be
> treated, taking into consideration the specific sensitivity of
> the different tissues to the TC fields and the target area, the
> desired field distribution map is constructed, as described in
> the flow chart of FIG. 7. The processor, which was fed the
> coordinates of all available isolects, now computes the vector
> sum of the fields generated by each isolect at each point in
> time. The computation can be made significantly faster in cases
> where an analytical expression for the electric field
> originating from arbitrary placed electrodes is available. Such
> a computation can be performed, for example, for the simple
> case; an isolect placed on a muscle, or similar tissue, for
> which an analytical expression for the electric field is:
> [mathematical formula - see original document]  
>   
>  [0092] Where R1 is the radius of the metallic part of the
> isolect, R2 is the isolect radius including coating [element
> of]coat and [element of]muscle are the dielectric constants of
> the isolect coating and muscle, respectively and r is the
> distance between the electrodes to the point where one wants to
> calculate the field. The fields generated in more complex
> systems are usually computed by finite element methods, as
> described below.  
>   
> [0093] Using this analytical expression, a series of iterations
> is initiated and the controller 300, more specifically the CPU
> thereof, calculates the TC field, using optimization methods, to
> optimize the voltage and the position of each electrode so that
> one gets the desired spatial arrangement of the electric field.
> The computation begins with a set of isolect locations and
> initial conditions, chosen arbitrary, or based on a set of
> assumptions or previous experience. The field maps thus
> generated are compared with the reference optimal map that was
> generated, as described in the flow chart illustrated in FIG. 7.
> In the subsequent iterations, the voltage and the position of
> the different isolects are changed and an optimal fit with the
> optimal map is sought. In other words, one optimizes the
> correlation between the calculated electric field (TC field) and
> the desired electric field (TC field). In the above optimization
> method one can use, for example, the robust numeric optimization
> method, known as the Nelder-Mead simplex method, as described in
> Neider and Mead, Computer Journal Vol. 7, p. 308 (1965);
> Lagarias, J. C., J. A. Reeds, M. H. Wright and P. E. Wright
> "Convergence Properties of the Neider-Mead Simplex Method in Low
> Dimensions", SIAM Journal of Optimization, Vol. 9, Number 1, pp.
> 112-147, 1986, all of which are hereby incorporated by reference
> in their entirety. In addition, the calculations of the
> optimization method include the method "Sequential Quadratic
> Programming", and this method is intended for checking that the
> first one went fine. The references include Fletcher, R. and M.
> J. D. Powell, "A Rapid Convergent Descent Method for
> Minimization," Computer Journal, Vol. 6, pp. 163-168; and
> Goldfarb, D., "A Family of Variable Metric Updates Derived by
> Variational Means:," Mathematics of Computing, Vol. 24, pp.
> 23-26, 1970, all of which are hereby incorporated by reference
> in their entirety. [0094] Now referring to FIGS. 8-9 in which an
> article of clothing 600 in the form of an undershirt is shown.
> Depending upon the precise location of the tumor (target
> tissue), the undershirt 600 can be of an oversized type in that,
> as illustrated, the undershirt 600 extends below the waist of
> the patient and in fact, it protrudes around a portion of the
> user's upper legs (thighs); however, it will be appreciated that
> the undershirt 600 can be of a more conventional type that lies
> above the waist. The undershirt 600 has a predetermined number
> of electrodes 230 (e.g., 20-100 in number) that are arranged
> either in an orderly manner as shown (rows and columns) or they
> can be arranged in a irregular pattern depending upon where the
> optimal positioning of the electrodes 230 is determined to be.
> The electrodes 230 are held in place by the undershirt
> construction, e.g., by adhesives or by stitching, etc. As shown
> in FIG. 9, the electrodes 230 completely extend radially around
> the body of the patient.  
>   
>  [0095] In FIG. 10, this type of procedure was carried out
> with the aim to effectively focus the field at the selected
> area, which in this Figure is denoted by the circle 610. In this
> example, random initialization of the electrode voltage and
> positions were used.  
>   
>  [0096] In FIG. 11, the calculated optimal position of the
> electrodes, depicted by circles 620, is illustrated around the
> tissue mass 630 where the electric field (TC field) intensity is
> minimal, as denoted by 640, while the intensity of the electric
> field increases in the vicinity of the target (tissue mass) 630.  
>   
>  [0097] In yet another example of the procedure of
> calculating the isolect placement that would give high field
> intensity at a number of skin locations, for treatment of
> malignant melanoma's while having minimal field at the spine is
> illustrated and described with reference to FIGS. 12-18. In this
> example, one will appreciate how the anatomy, the isolect
> structure and the tissue electric characteristics are
> incorporated into the calculations. One of the advantages of
> using an electric field to repress the prosperity of cells is
> that areas inside a human being can be left outside of the
> electric field influence. According to this one example, a model
> is constructed for a human having four electrodes around the mid
> body portion and the electrodes are specifically arranged so
> that the electric field around the human's spine is zero. The
> calculations are based on finite element mesh (FEM) and the
> geometric model is described and illustrated with reference to
> FIG. 12. In FIG. 12, the axis units are in millimeters and the
> body is 0.5 m width with a 0.35 thickness. FIG. 12 shows the
> location of the spine 650 relative to four electrodes 660 that
> are spaced therearound. A skin boundary or layer of the patient
> is generally shown at 670 with muscle 680 being shown as
> occupying the area within the skin boundary 670 and around the
> spine 650.   
>   
> [0098] FIG. 13 is also a geometric model illustrating an
> enlargement of the area around one electrode 670 of FIG. 12
> showing the interaction between the electrode 670 and the skin
> layer 670. The axis units in FIG. 13 are in millimeters and in
> this exemplary embodiment, the electrode 660 includes a coating
> 662 that is formed of PVC or potassium tantalate. In this
> example, the electrode 660 has a diameter of about 10 mm and the
> coating 662 that is disposed around an outer surface 661 thereof
> has a thickness of about 0.1 mm. The skin layer 670 has a
> thickness of about 1 mm. Table 1 sets forth the parameters for
> the materials that are used in the calculations that are used
> with the geometric models of FIGS. 12 and 13. TABLE 1 Material
> Data Dielectric Dielectric medium Constant Conductivity (S/m)
> Air 1 0 PVC Coating 2.6 0 Muscle 8089 0.36 Skin 1119 0.00045
> Spine 227 0.0208   
>   
> [0099] In all of the calculations for this example, the voltage
> between the electrodes 660 was 1V and the frequency of the sine
> voltage was 100 KHz.   
>   
> [0100] In this example, the electrodes 660 are placed in a
> symmetric formation such that the electric field in the middle
> of the body is zero. FIG. 14 is photographic image of the
> electrodes 660 around the spine 650 illustrating the electric
> field representation in the symmetric formation of the
> electrodes. FIG. 15 is another representation of the electric
> field; however, this representation of the electric field is by
> arrows. As will be appreciated, only the electric field inside
> the body is shown. As can be seen from both FIGS. 14 and 15, the
> electric field is zero in the middle of the body and is very
> high in the area of the spine 650. This is unwanted since the
> presence of the electric field near the spine 650 can be
> potentially harmful. In FIG. 16, the electrodes 660 have been
> rearranged so that the electric field is zero in the spine area
> 650 and not zero in the middle of the body. FIG. 16 is a
> schematic illustration of the arrangement of the electrodes 660
> that causes a zero electric field in the area of the spine 650.
> FIG. 17 is a photographic image of the electric field in an
> asymmetric formation of the electrodes and FIG. 18 is another
> representation of the electric field, similar to FIG. 15, in
> which the electric field is represented by arrows and only the
> electric field inside the body is drawn. As can be seen from
> FIGS. 17 and 18, the asymmetric arrangement of the electrodes
> causes a zero electric field in the area of the spine 650, while
> the field outside the spine 650 is not zero.   
>   
> [0101] Based on the above calculations, one will appreciate that
> a proper arrangement of the electrodes can shape the electric
> field so that it becomes zero at areas we choose, such as the
> spine area 650, in this example. In application, the procedure
> can entail using a CT image to position the internal organs,
> calculate on-line the electric field using the present
> methodology and automatically position the electrodes on the
> patient's body so that an area that we do not want to harm will
> not suffer from the presence of an electric field.   
>   
> [0102] The specifications of the apparatus 200 as a whole and
> its individual components are largely influenced by the fact
> that at the frequency of the present TC fields (50 KHz-500 KHz),
> living systems behave according to their "Ohmic", rather than
> their dielectric properties. The only elements in the apparatus
> 200 that behave differently are the insulators of the isolects
> 230 (see FIGS. 19-21). The isolects 200 consist of a conductor
> in contact with a dielectric that is in contact with the
> conductive tissue thus forming a capacitor.   
>   
> [0103] There are any number of different types of applications
> in which the apparatus 200 or one of the others disclosed herein
> can be used. The following applications are merely exemplary and
> not limiting of the number of different types of applications
> which can be used. FIG. 19 illustrates an exemplary embodiment
> where the isolects 230 are incorporated in a skin patch 700. The
> skin patch 700 can be a self-adhesive flexible patch with one or
> more pairs of isolects 230. The patch 700 includes internal
> insulation 710 (formed of a dielectric material) and the
> external insulation 260 and is applied to skin surface 701 that
> contains a tumor 703 either on the skin surface 701 or slightly
> below the skin surface 701. Tissue is generally indicated at
> 705. To prevent the potential drop across the internal
> insulation 710 to dominate the system, the internal insulation
> 710 must have a relatively high capacity. This can be achieved
> by a large surface area; however, this may not be desired as it
> will result in the spread of the field over a large area (e.g.,
> an area larger than required to treat the tumor). Alternatively,
> the internal insulation 710 can be made very thin and/or the
> internal insulation 710 can be of a high dielectric constant. As
> the skin resistance between the electrodes (labeled as A and E
> in FIG. 6) is normally significantly higher than that of the
> tissue (labeled as C in FIG. 6) underneath it (1-10 K[Omega] vs.
> 0.1-1 K[Omega]), most of the potential drop beyond the isolects
> occurs there. To accommodate for these impedances (Z), the
> characteristics of the internal insulation 710 (labeled as B and
> D in FIG. 6) should be such that they have impedance preferably
> under 100 K[Omega] at the frequencies of the present TC fields
> (e.g., 50 KHz to 500 KHz). For example, if it is desired for the
> impedance to be about 10 K Ohms or less, such that over 1% of
> the applied voltage falls on the tissues, for isolects with a
> surface area of 10 mm<2> , at frequencies of 200 KHz, the
> capacity should be on the order of 10<-10 > F, which means
> that using standard insulations with a dielectric constant of
> 2-3, the thickness of the insulating layer 710 should be about
> 50-100 microns. An internal field 10 times stronger would be
> obtained with insulators with a dielectric constant of about
> 20-50.  
>   
>  [0104] FIGS. 20 and 21 illustrate a second type of
> treatment using the isolects 230, namely electric field
> generation by internal isolects 230. A body to which the
> isolects 230 are implanted is generally indicated at 711 and
> includes a skin surface 713 and a tumor 715. In this embodiment,
> the isolects 230 can have the shape of plates, wires or other
> shapes that can be inserted subcutaneously or a deeper location
> within the body 711 so as to generate an appropriate field at
> the target area (tumor 715). FIG. 22 illustrates the various
> constructions of the isolects 230, including the use of internal
> insulation 710, a filler or gel 270 and external insulation 260.  
>   
>  [0105] It will also be appreciated that the mode of
> isolects application is not restricted to the above
> descriptions. In the case of tumors in internal organs, for
> example, liver, lung, etc., the distance between each member of
> the pair of isolects 230 can be large. The pairs can even by
> positioned opposite sides of a torso 720, as illustrated in FIG.
> 23. The arrangement of the isolects 230 in FIG. 23 is
> particularly useful for treating a tumor 730 associated with
> lung cancer or gastrointestinal tumors. In this embodiment, the
> electric fields (TC fields) spread in a wide fraction of the
> body. [0106] In order to achieve the desirable features of the
> isolects 230, the dielectric coating of each should be very
> thin, for example from between 1-50 microns. Since the coating
> is so thin, the isolects 230 can easily be damaged mechanically.
> This problem can be overcome by adding a protective feature to
> the isolect's structure so as to provide desired protection from
> such damage. For example, the isolect 230 can be coated, for
> example, with a relatively loose net 340 that prevents access to
> the surface but has only a minor effect on the effective surface
> area of the isolect 230 (i.e., the capacity of the isolects 230
> (cross section presented in FIG. 24B). The loose net 340 does
> not effect the capacity and ensures good contact with the skin,
> etc. The loose net 340 can be formed of a number of different
> materials; however, in one exemplary embodiment, the net 340 is
> formed of nylon, polyester, cotton, etc. Alternatively, a very
> thin conductive coating 350 can be applied to the dielectric
> portion (insulating layer) of the isolect 230. One exemplary
> conductive coating is formed of a metal and more particularly of
> gold. The thickness of the coating 350 depends upon the
> particular application and also on the type of material used to
> form the coating 350; however, when gold is used, the coating
> has a thickness from about 0.1 micron to about 0.1 mm.   
>   
> [0107] In order to avoid overheating of the treated tissues, a
> selection of materials and field parameters is needed. The
> isolects insulating material should have minimal dielectric
> losses at the frequency ranges to be used during the treatment
> process. This factor can be taken into consideration when
> choosing the particular frequencies for the treatment. The
> direct heating of the tissues will most likely be dominated by
> the heating due to current flow (given by the I\*R product). In
> addition, the isolect (insulated electrode) 230 and its
> surroundings should be made of materials that facilitate heat
> losses and its general structure should also facilitate head
> losses, i.e., minimal structures that block heat dissipation to
> the surroundings (air) as well as high heat conductivity.   
>   
> [0108] The effectiveness of the treatment can be enhanced by an
> arrangement of isolects 230 that focuses the field at the
> desired target while leaving other sensitive areas in low field
> density (i.e., protected areas). The proper placement of the
> isolects 230 over the body can be maintained using any number of
> different techniques, including using a suitable piece of
> clothing that keeps the isolects at the appropriate positions.
> FIG. 25 illustrates such an arrangement in which an area labeled
> as "P" represents a protected area. The lines of field force do
> not penetrate this protected area and the field there is much
> smaller than near the isolects 230 where target areas can be
> located and treated well. In contrast, the field intensity near
> the four poles is very high.   
>   
> [0109] The present inventor has thus uncovered that electric
> fields having particular properties can be used to destroy
> dividing cells or tumors when the electric fields are applied to
> using an electronic device. More specifically, these electric
> fields fall into a special intermediate category, namely
> bio-effective fields that have no meaningful stimulatory and no
> thermal effects, and therefore overcome the disadvantages that
> were associated with the application of conventional electric
> fields to a body. It will also be appreciated that the present
> apparatus can further include a device for rotating the TC field
> relative to the living tissue. For example and according to one
> embodiment, the alternating electric potential applies to the
> tissue being treated is rotated relative to the tissue using
> conventional devices, such as a mechanical device that upon
> activation, rotates various components of the present system.   
>   
> [0110] Moreover and according to yet another embodiment, the TC
> fields are applied to different pairs of the insulated
> electrodes 230 in a consecutive manner. In other words, the
> generator 210 and the control system thereof can be arranged so
> that signals are sent at periodic intervals to select pairs of
> insulated electrodes 230, thereby causing the generation of the
> TC fields of different directions by these insulated electrodes
> 230. Because the signals are sent at select times from the
> generator to the insulated electrodes 230, the TC fields of
> changing directions are generated consecutively by different
> insulated electrodes 230. This arrangement has a number of
> advantages and is provided in view of the fact that the TC
> fields have maximal effect when they are parallel to the axis of
> cell division. Since the orientation of cell division is in most
> cases random, only a fraction of the dividing cells are affected
> by any given field. Thus, using fields of two or more
> orientations increases the effectiveness since it increases the
> chances that more dividing cells are affected by a given TC
> field.   
>   
> [0111] Turning now to FIG. 26 in which an article of clothing
> 800 according to one exemplary embodiment is illustrated. More
> specifically, the article of clothing 800 is in the form of a
> hat or cap or other type of clothing designed for placement on a
> head of a person. For purposes of illustration, a head 802 is
> shown with the hat 800 being placed thereon and against a skin
> surface 804 of the head 802. An intra-cranial tumor or the like
> 810 is shown as being formed within the head 802 underneath the
> skin surface 804 thereof. The hat 800 is therefore intended for
> placement on the head 802 of a person who has a tumor 810 or the
> like.   
>   
> [0112] Unlike the various embodiments illustrated in the other
> Figures where the insulated electrodes 230 are arranged in a
> more or less planar arrangement since they are placed either on
> a skin surface or embedded within the body underneath it, the
> insulated electrodes 230 in this embodiment are specifically
> contoured and arranged for a specific application. The treatment
> of intra-cranial tumors or other lesions or the like typically
> requires a treatment that is of a relatively long duration,
> e.g., days to weeks, and therefore, it is desirable to provide
> as much comfort as possible to the patient. The hat 800 is
> specifically designed to provide comfort during the lengthy
> treatment process while not jeopardizing the effectiveness of
> the treatment.   
>   
> [0113] According to one exemplary embodiment, the hat 800
> includes a predetermined number of insulated electrodes 230 that
> are preferably positioned so as to produce the optimal TC fields
> at the location of the tumor 810. The lines of force of the TC
> field are generally indicated at 820. As can be seen in FIG. 26,
> the tumor 810 is positioned within these lines of force 820. As
> will be described in greater detail hereinafter, the insulated
> electrodes 230 are positioned within the hat 800 such that a
> portion or surface thereof is free to contact the skin surface
> 804 of the head 802. In other words, when the patient wears the
> hat 800, the insulated electrodes 230 are placed in contact with
> the skin surface 804 of the head 802 in positions that are
> selected so that the TC fields generated thereby are focused at
> the tumor 810 while leaving surrounding areas in low density.
> Typically, hair on the head 802 is shaved in selected areas to
> permit better contact between the insulated electrodes 230 and
> the skin surface 804; however, this is not critical.   
>   
> [0114] The hat 800 preferably includes a mechanism 830 that
> applies or force to the insulated electrodes 230 so that they
> are pressed against the skin surface 802. For example, the
> mechanism 830 can be of a biasing type that applies a biasing
> force to the insulated electrodes 230 to cause the insulated
> electrodes 230 to be directed outwardly away from the hat 800.
> Thus, when the patient places the hat 800 on his/her head 802,
> the insulated electrodes 230 are pressed against the skin
> surface 804 by the mechanism 830. The mechanism 830 can slightly
> recoil to provide a comfortable fit between the insulated
> electrodes 230 and the head 802. In one exemplary embodiment,
> the mechanism 830 is a spring based device that is disposed
> within the hat 800 and has one section that is coupled to and
> applies a force against the insulated electrodes 230, as
> described below with reference to FIGS. 27 and 28. [0115] As
> with the prior embodiments, the insulated electrodes 230 are
> coupled to the generator 210 by means of conductors 220. The
> generator 210 can be either disposed within the hat 800 itself
> so as to provide a compact, self-sufficient, independent system
> or the generator 210 can be disposed external to the hat 800
> with the conductors 220 exiting the hat 800 through openings or
> the like and then running to the generator 210. When the
> generator 210 is disposed external to the hat 800, it will be
> appreciated that the generator 210 can be located in any number
> of different locations, some of which are in close proximity to
> the hat 800 itself, while others can be further away from the
> hat 800. For example, the generator 210 can be disposed within a
> carrying bag or the like (e.g., a bag that extends around the
> patient's waist) which is worn by the patient or it can be
> strapped to an extremity or around the torso of the patient. The
> generator 210 can also be disposed in a protective case that is
> secured to or carried by another article of clothing that is
> worn by the patient. For example, the protective case can be
> inserted into a pocket of a sweater, etc. FIG. 26 illustrates an
> embodiment where the generator 210 is incorporated directly into
> the hat 800.  
>   
>  [0116] Turning now to FIGS. 27 and 28, in one exemplary
> embodiment, a number of insulated electrodes 230 along with the
> mechanism 830 are preferably formed as an independent unit,
> generally indicated at 840, that can be inserted into the hat
> 800 and electrically connected to the generator (not shown) via
> the conductors (not shown). By providing these members in the
> form of an independent unit, the patient can easily insert
> and/or remove the units 840 from the hat 800 when they may need
> cleaning, servicing and/or replacement.  
>   
>  [0117] In this embodiment, the hat 800 is constructed to
> include select areas 850 that are formed in the hat 800 to
> receive and hold the units 840. For example and as illustrated
> in FIG. 27, each area 850 is in the form of an opening (pore)
> that is formed within the hat 800. The unit 840 has a body 842
> and includes the mechanism 830 and one or more insulated
> electrodes 230. The mechanism 830 is arranged within the unit
> 840 so that a portion thereof (e.g., one end thereof) is in
> contact with a face of each insulated electrode 230 such that
> the mechanism 830 applies a biasing force against the face of
> the insulated electrode 230. Once the unit 840 is received
> within the opening 850, it can be securely retained therein
> using any number of conventional techniques, including the use
> of an adhesive material or by using mechanical means. For
> example, the hat 800 can include pivotable clip members that
> pivot between an open position in which the opening 850 is free
> and a closed position in which the pivotable clip members engage
> portions (e.g., peripheral edges) of the insulated electrodes to
> retain and hold the insulated electrodes 230 in place. To remove
> the insulated electrodes 230, the pivotable clip members are
> moved to the open position. In the embodiment illustrated in
> FIG. 28, the insulated electrodes 230 are retained within the
> openings 850 by an adhesive element 860 which in one embodiment
> is a two sided self-adhesive rim member that extends around the
> periphery of the insulated electrode 230. In other words, a
> protective cover of one side of the adhesive rim 860 is removed
> and it is applied around the periphery of the exposed face of
> the insulated electrode 230, thereby securely attaching the
> adhesive rim 860 to the hat 800 and then the other side of the
> adhesive rim 860 is removed for application to the skin surface
> 804 in desired locations for positioning and securing the
> insulated electrode 230 to the head 802 with the tumor being
> positioned relative thereto for optimization of the TC fields.
> Since one side of the adhesive rim 860 is in contact with and
> secured to the skin surface 840, this is why it is desirable for
> the head 802 to be shaved so that the adhesive rim 860 can be
> placed flushly against the skin surface 840.  
>   
>  [0118] The adhesive rim 860 is designed to securely attach
> the unit 840 within the opening 850 in a manner that permits the
> unit 840 to be easily removed from the hat 800 when necessary
> and then replaced with another unit 840 or with the same unit
> 840. As previously mentioned, the unit 840 includes the biasing
> mechanism 830 for pressing the insulated electrode 230 against
> the skin surface 804 when the hat 800 is worn. The unit 840 can
> be constructed so that side opposite the insulated electrode 230
> is a support surface formed of a rigid material, such as
> plastic, so that the biasing mechanism 830 (e.g., a spring) can
> be compressed therewith under the application of force and when
> the spring 830 is in a relaxed state, the spring 830 remains in
> contact with the support surface and the applies a biasing force
> at its other end against the insulated electrode 230. The
> biasing mechanism 830 (e.g., spring) preferably has a contour
> corresponding to the skin surface 804 so that the insulated
> electrode 230 has a force applied thereto to permit the
> insulated electrode 230 to have a contour complementary to the
> skin surface 804, thereby permitting the two to seat flushly
> against one another. While the mechanism 830 can be a spring,
> there are a number of other embodiments that can be used instead
> of a spring. For example, the mechanism 830 can be in the form
> of an elastic material, such as a foam rubber, a foam plastic,
> or a layer containing air bubbles, etc. [0119] The unit 840 has
> an electric connector 870 that can be hooked up to a
> corresponding electric connector, such as a conductor 220, that
> is disposed within the hat 800. The conductor 220 connects at
> one end to the unit 840 and at the other end is connected to the
> generator 210. The generator 210 can be incorporated directly
> into the hat 800 or the generator 210 can be positioned
> separately (remotely) on the patient or on a bedside support,
> etc. [0120] As previously discussed, a coupling agent, such as a
> conductive gel, is preferably used to ensure that an effective
> conductive environment is provided between the insulated
> electrode 230 and the skin surface 804. Suitable gel materials
> have been disclosed hereinbefore in the discussion of earlier
> embodiments. The coupling agent is disposed on the insulated
> electrode 230 and preferably, a uniform layer of the agent is
> provided along the surface of the electrode 230. One of the
> reasons that the units 840 need replacement at periodic times is
> that the coupling agent needs to be replaced and/or replenished.
> In other words, after a predetermined time period or after a
> number of uses, the patient removes the units 840 so that the
> coupling agent can be applied again to the electrode 230.  
>   
> [0121] FIGS. 29 and 30 illustrate another article of clothing
> which has the insulated electrodes 230 incorporated as part
> thereof. More specifically, a bra or the like 900 is illustrated
> and includes a body that is formed of a traditional bra
> material, generally indicated at 905, to provide shape, support
> and comfort to the wearer. The bra 900 also includes a fabric
> support layer 910 on one side thereof. The support layer 910 is
> preferably formed of a suitable fabric material that is
> constructed to provide necessary and desired support to the bra
> 900.  
>   
>  [0122] Similar to the other embodiments, the bra 900
> includes one or more insulated electrodes 230 disposed within
> the bra material 905. The one or more insulated electrodes are
> disposed along an inner surface of the bra 900 opposite the
> support 910 and are intended to be placed proximate to a tumor
> or the like that is located within one breast or in the
> immediately surrounding area. As with the previous embodiment,
> the insulated electrodes 230 in this embodiment are specifically
> constructed and configured for application to a breast or the
> immediate area. Thus, the insulated electrodes 230 used in this
> application do not have a planar surface construction but rather
> have an arcuate shape that is complementary to the general
> curvature found in a typical breast.  
>   
>  [0123] A lining 920 is disposed across the insulated
> electrodes 230 so as to assist in retaining the insulated
> electrodes in their desired locations along the inner surface
> for placement against the breast itself. The lining 920 can be
> formed of any number of thin materials that are comfortable to
> wear against one's skin and in one exemplary embodiment, the
> lining 920 is formed of a fabric material.  
>   
>  [0124] The bra 900 also preferably includes a biasing
> mechanism 1000 as in some of the earlier embodiments. The
> biasing mechanism 1000 is disposed within the bra material 905
> and extends from the support 910 to the insulated electrode 230
> and applies a biasing force to the insulated electrode 230 so
> that the electrode 230 is pressed against the breast. This
> ensures that the insulated electrode 230 remains in contact with
> the skin surface as opposed to lifting away from the skin
> surface, thereby creating a gap that results in a less effective
> treatment since the gap diminishes the efficiency of the TC
> fields. The biasing mechanism 1000 can be in the form of a
> spring arrangement or it can be an elastic material that applies
> the desired biasing force to the insulated electrodes 230 so as
> to press the insulated electrodes 230 into the breast. In the
> relaxed position, the biasing mechanism 1000 applies a force
> against the insulated electrodes 230 and when the patient places
> the bra 900 on their body, the insulated electrodes 230 are
> placed against the breast which itself applies a force that
> counters the biasing force, thereby resulting in the insulated
> electrodes 230 being pressed against the patient's breast. In
> the exemplary embodiment that is illustrated, the biasing
> mechanism 1000 is in the form of springs that are disposed
> within the bra material 905.  
>   
>  [0125] A conductive gel 1010 can be provided on the
> insulated electrode 230 between the electrode and the lining
> 920. The conductive gel layer 1010 is formed of materials that
> have been previously described herein for performing the
> functions described above.  
>   
>  [0126] An electric connector 1020 is provided as part of
> the insulated electrode 230 and electrically connects to the
> conductor 220 at one end thereof, with the other end of the
> conductor 220 being electrically connected to the generator 210.
> In this embodiment, the conductor 220 runs within the bra
> material 905 to a location where an opening is formed in the bra
> 900. The conductor 220 extends through this opening and is
> routed to the generator 210, which in this embodiment is
> disposed in a location remote from the bra 900. It will also be
> appreciated that the generator 210 can be disposed within the
> bra 900 itself in another embodiment. For example, the bra 900
> can have a compartment formed therein which is configured to
> receive and hold the generator 210 in place as the patient wears
> the bra 900. In this arrangement, the compartment can be covered
> with a releasable strap that can open and close to permit the
> generator 210 to be inserted therein or removed therefrom. The
> strap can be formed of the same material that is used to
> construct the bra 900 or it can be formed of some other type of
> material. The strap can be releasably attached to the
> surrounding bra body by fastening means, such as a hook and loop
> material, thereby permitting the patient to easily open the
> compartment by separating the hook and loop elements to gain
> access to the compartment for either inserting or removing the
> generator 210.   
>   
> [0127] The generator 210 also has a connector 211 for electrical
> connection to the conductor 220 and this permits the generator
> 210 to be electrically connected to the insulated electrodes
> 230.  
>   
> [0128] As with the other embodiments, the insulated electrodes
> 230 are arranged in the bra 900 to focus the electric field (TC
> fields) on the desired target (e.g., a tumor). It will be
> appreciated that the location of the insulated electrodes 230
> within the bra 900 will vary depending upon the location of the
> tumor. In other words, after the tumor has been located, the
> physician will then devise an arrangement of insulated
> electrodes 230 and the bra 900 is constructed in view of this
> arrangement so as to optimize the effects of the TC fields on
> the target area (tumor). The number and position of the
> insulated electrodes 230 will therefore depend upon the precise
> location of the tumor or other target area that is being
> treated. Because the location of the insulated electrodes 230 on
> the bra 900 can vary depending upon the precise application, the
> exact size and shape of the insulated electrodes 230 can
> likewise vary. For example, if the insulated electrodes 230 are
> placed on the bottom section of the bra 900 as opposed to a more
> central location, the insulated electrodes 230 will have
> different shapes since the shape of the breast (as well as the
> bra) differs in these areas.   
>   
> [0129] FIG. 31 illustrates yet another embodiment in which the
> insulated electrodes 230 are in the form of internal electrodes
> that are incorporated into in the form of a probe or catheter
> 1100 that is configured to enter the body through a natural
> pathway, such as the urethra, vagina, etc. In this embodiment,
> the insulated electrodes 230 are disposed on an outer surface of
> the probe 1100 and along a length thereof. The conductors 220
> are electrically connected to the electrodes 230 and run within
> the body of the probe 1100 to the generator 210 which can be
> disposed within the probe body or the generator 210 can be
> disposed independent of the probe 1100 in a remote location,
> such as on the patient or at some other location close to the
> patient.  
>   
>  [0130] Alternatively, the probe 1100 can be configured to
> penetrate the skin surface or other tissue to reach an internal
> target that lies within the body. For example, the probe 1100
> can penetrate the skin surface and then be positioned adjacent
> to or proximate to a tumor that is located within the body.   
>   
> [0131] In these embodiments, the probe 1100 is inserted through
> the natural pathway and then is positioned in a desired location
> so that the insulated electrodes 230 are disposed near the
> target area (i.e., the tumor). The generator 210 is then
> activated to cause the insulated electrodes 230 to generate the
> TC fields which are applied to the tumor for a predetermined
> length of time. It will be appreciated that the illustrated
> probe 1100 is merely exemplary in nature and that the probe 1100
> can have other shapes and configurations so long as they can
> perform the intended function. Preferably, the conductors (e.g.,
> wires) leading from the insulated electrodes 230 to the
> generator 210 are twisted or shielded so as not to generate a
> field along the shaft.  
>   
>  [0132] It will further be appreciated that the probes can
> contain only one insulated electrode while the other can be
> positioned on the body surface. This external electrode should
> be larger or consist of numerous electrodes so as to result in
> low lines of force-current density so as not to affect the
> untreated areas. In fact, the placing of electrodes should be
> designed to minimize the field at potentially sensitive areas.  
>   
>  [0133] FIG. 32 illustrates yet another embodiment in which
> a high standing collar member 1200 (or necklace type structure)
> can be used to treat thyroid, parathyroid, laryngeal lesions,
> etc. FIG. 32 illustrates the collar member 1200 in an unwrapped,
> substantially flat condition. In this embodiment, the insulated
> electrodes 230 are incorporated into a body 1210 of the collar
> member 1200 and are configured for placement against a neck area
> of the wearer. The insulated electrodes 230 are coupled to the
> generator 210 according to any of the manner described
> hereinbefore and it will be appreciated that the generator 210
> can be disposed within the body 1210 or it can be disposed in a
> location external to the body 1210. The collar body 1210 can be
> formed of any number of materials that are traditionally used to
> form collars 1200 that are disposed around a person's neck. As
> such, the collar 1200 preferably includes a means 1220 for
> adjusting the collar 1200 relative to the neck. For example,
> complementary fasteners (hook and loop fasteners, buttons, etc.)
> can be disposed on ends of the collar 1200 to permit adjustment
> of the collar diameter. It will be appreciated that one can
> extend this exemplary structure to accommodate any tubular part
> of the body, e.g., a limb, etc.  
>   
>  [0134] FIGS. 33 and 34 illustrate yet another embodiment
> of the present device. In FIG. 33, a pair of electrodes 230 are
> arranged about a torso 1300. The electrodes 230 are operated in
> the same manner as was previously described and in this
> embodiment, the electrodes 230 are arranged so that the electric
> field passes through the heart and its surrounding area.  
>   
>  [0135] The present inventor has thus appreciated that the
> above described TC fields that stop cell proliferation can be
> used to prevent restenosis of arteries after angioplasty, with
> or without introduction of stents. This also applies for other
> body tubing, such as urethra. The coronary restenosis which
> follows 20-30% of stenting, etc., is a major problem. The
> restenosis is due to the cellular reaction of the arterial wall
> and the resulting cell proliferation. This proliferation grows
> into the artery from its ends and on top of it, there is
> sedimentation, etc., that occludes the artery. The conditions
> for the effect of the TC fields are good as the stent is usually
> a bare metal conductor (but not necessarily) that will result in
> field intensification exactly where it is needed. The TC fields
> should be applied for 3-8 weeks to prevent the stenosis.   
>   
> [0136] As shown in FIGS. 33 and 34, the electrodes 230 are
> arranged about the torso 1300 so that the TC fields, indicated
> by field lines 1310, passes through the heart region 1320. A
> coronary artery 1330 is illustrated within the heart region 1320
> and within the TC fields. One or more stents 1340 are disposed
> within the coronary artery 1330 as part of the surgical
> procedure. One of the results of the angioplasty and mainly due
> to the presence of the stents 1340 is a proliferation of a mass
> of cells 1350 that is located along the artery wall. Since the
> stent 1340 acts as a conductor, the area around the stent 1340
> is an area of high density electric field due to the presence of
> the stent 1340. The stent 1340 does not necessarily have to be a
> bare metal conductor and the present method of treatment can be
> used without stents 1340 so long as the mass of proliferating
> cells 1350 is disposed within the area of the high density
> electric field.  
>   
>  [0137] Thus, the construction of the present devices are
> particularly well suited for applications where the devices are
> incorporated into articles of clothing to permit the patient to
> easily wear a traditional article of clothing while at the same
> time the patient undergoes treatment. In other words, an extra
> level of comfort can be provided to the patient and the
> effectiveness of the treatment can be increased by incorporating
> some or all of the device components into the article of
> clothing. The precise article of clothing that the components
> are incorporated into will obviously vary depending upon the
> target area of the living tissue where tumor, lesion or the like
> exists. For example, if the target area is in the testicle area
> of a male patient, then an article of clothing in the form of a
> sock-like structure or wrap can be provided and is configured to
> be worn around the testicle area of the patient in such a manner
> that the insulated electrodes thereof are positioned relative to
> the tumor such that the TC fields are directed at the target
> tissue. The precise nature or form of the article of clothing
> can vary greatly since the device components can be incorporated
> into most types of articles of clothing and therefore, can be
> used to treat any number of different areas of the patient's
> body where a condition may be present.   
>   
> [0138] The present invention is thus for an apparatus and method
> for optimizing the selective destruction of dividing cells by
> calculating the spatial and temporal distribution of the
> electric fields for optimal treatment of a specific patient with
> a specific tumor, taking into account its location and
> characteristics of all components of the system. An optimal
> field map is generated by calculating and computing an electric
> field in terms of its strength and other characteristics for a
> given arrangement of electrodes and based on other inputted
> information, such as tumor type. This calculation can be done by
> a controller or other device, such as an integrated personal
> computer, and additional calculations are conducted for
> different arrangement of electrodes relative to the target area
> (tumor) and/or different voltages for the electrodes. Standard
> optimization methods are used to determine the optimal minimal
> field map. It is therefore desirable that the optimum field map
> not only includes a maximum electric field at the target area
> (tumor) but also that there be a maximal field strength
> difference between the electric field at the target tissue and
> the surrounding tissue that is to be protected. It will
> therefore be appreciated that the optimal field may not
> necessarily be one that has the highest electric field strength
> focused at the targeted area but it may be one where the
> electric field strength is less but the difference in field
> strength between the target area and the surrounding areas is at
> a maximum. In other words, the present method optimizes the
> correlation between the calculated electric field and the
> desired electric field (the previously calculated optimal field
> map). For optimization, standard techniques can be used, such as
> the Nelder-Mead simplex method.  
>   
>  [0139] As used herein, the term "tumor" refers to a
> malignant tissue comprising transformed cells that grow
> uncontrollably. Tumors include leukemias, lymphomas, myelomas,
> plasmacytomas, and the like; and solid tumors. Examples of solid
> tumors that can be treated according to the invention include
> sarcomas and carcinomas such as, but not limited to:
> fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma,
> osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma,
> lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma,
> mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma,
> colon carcinoma, pancreatic cancer, breast cancer, ovarian
> cancer, prostate cancer, squamous cell carcinoma, basal cell
> carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous
> gland carcinoma, papillary carcinoma, papillary adenocarcinomas,
> cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma,
> renal cell carcinoma, hepatoma, bile duct carcinoma,
> choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,
> cervical cancer, testicular tumor, lung carcinoma, small cell
> lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma,
> astrocytoma, medulloblastoma, craniopharyngioma, ependymoma,
> pinealoma, hemangioblastoma, acoustic neuroma,
> oligodendroglioma, meningioma, melanoma, neuroblastoma, and
> retinoblastoma. Because each of these tumors undergoes rapid
> growth, any one can be treated in accordance with the invention.
> The invention is particularly advantageous for treating brain
> tumors, which are difficult to treat with surgery and radiation,
> and often inaccessible to chemotherapy or gene therapies. In
> addition, the present invention is suitable for use in treating
> skin and breast tumors because of the ease of localized
> treatment provided by the present invention.  
>   
>  [0140] In addition, the present invention can control
> uncontrolled growth associated with non-malignant or
> pre-malignant conditions, and other disorders involving
> inappropriate cell or tissue growth by application of an
> electric field in accordance with the invention to the tissue
> undergoing inappropriate growth. For example, it is contemplated
> that the invention is useful for the treatment of arteriovenous
> (AV) malformations, particularly in intracranial sites. The
> invention may also be used to treat psoriasis, a dermatologic
> condition that is characterized by inflammation and vascular
> proliferation; and benign prostatic hypertrophy, a condition
> associated with inflammation and possibly vascular
> proliferation. Treatment of other hyperproliferative disorders
> is also contemplated.  
>   
>  [0141] Furthermore, undesirable fibroblast and endothelial
> cell proliferation associated with wound healing, leading to
> scar and keloid formation after surgery or injury, and
> restenosis after angioplasty or placement of coronary stents can
> be inhibited by application of an electric field in accordance
> with the present invention. The non-invasive nature of this
> invention makes it particularly desirable for these types of
> conditions, particularly to prevent development of internal
> scars and adhesions, or to inhibit restenosis of coronary,
> carotid, and other important arteries.   
>   
> [0142] Thus, the present invention provides an effective, simple
> method of selectively destroying dividing cells, e.g., tumor
> cells and parasitic organisms, while non-dividing cells or
> organisms are left affected by application of the method on
> living tissue containing both types of cells or organisms. Thus,
> unlike many of the conventional methods, the present invention
> does not damage the normal cells or organisms. In addition, the
> present invention does not discriminate based upon cell type
> (e.g., cells having differing sizes) and therefore may be used
> to treat any number of types of sizes having a wide spectrum of
> characteristics, including varying dimensions.  
>   
>  [0143] It will be appreciated by persons skilled in the
> art that the present invention is not limited to the embodiments
> described thus far with reference to the accompanying drawing.
> Rather the present invention is limited only by the following
> claims. ==  
>   
>
>
> ---
>
>   
>
> TREATING CANCER WITH ELECTRIC FIELDS THAT ARE GUIDED
> TO DESIRED LOCATIONS WITHIN A BODY  
> US2006282122
>
>   
> CROSS REFERENCE TO RELATED
> APPLICATIONS   
>   
> [0001] This application claims priority to U.S. provisional
> application No. 60/688,998, filed Jun. 8, 2005.   
>   
> BACKGROUND   
>   
> [0002] U.S. Pat. No. 6,868,289,
> which is incorporated herein by reference, discloses methods and
> apparatuses for treating tumors using an electric field with
> particular characteristics. It also discloses various ways to
> modifying the electric field intensity at desired locations
> (see, e.g., FIGS. 21-26). [0003] This application discloses
> additional ways for modifying the field so as to significantly
> increase or decrease it at desired locations in a patient's
> body. These modifications can improve the quality and
> selectivity of treatment of lesions and tumors and improve
> selective tissue ablation or destruction.   
>   
> [0004] FIG. 1A shows an arrangement where two electrodes 11, 11'
> are placed on the patient's skin 15 above the underlying tissue
> 10 (e.g., muscle) in an environment of air 16. FIG. 1B depicts
> the results of a finite element simulation of the electric field
> generated in the air and in the muscle tissue, when the
> insulated electrodes 11, 11' are positioned on the skin 15 as
> shown in FIG. 1A, and a 100 kHz AC signal is applied to the
> electrodes. Preferably, the insulated electrodes have a
> conductive core and an insulating layer with a high dielectric
> constant as described in U.S. Pat. No. 6,868,289, and they are
> configured to contact the surface of the body with the
> insulating layer disposed between the conductive core and the
> surface of the body.   
>   
> [0005] FIG. 1B, (like all the other field intensity maps
> included herein) shows the field intensity in mV/cm when 1 Volt
> AC (measured zero-to-peak) is induced between the proximal side
> of the tissue just beneath the first electrode and the proximal
> side of the tissue just beneath the second electrode (by
> applying a sufficiently large voltage between the electrodes'
> terminals). The numbers along the x and y axes in the main
> section of FIG. 1B (and in the other field intensity maps
> included herein) represent distance measured in cm. Each contour
> line represents a constant step size down from the 1 V peak, and
> the units are given in mV/cm. Note, however, that because the
> voltage changes so rapidly at the higher values, the contour
> lines run together to form what appears to be a solid black
> region.   
>   
> [0006] It is seen in FIG. 1B that, both in the air above the
> skin 15 and the tissue below the skin 15, the field intensity is
> maximal in regions that are close to the edges of the electrodes
> 11, 11' and that the field intensity is attenuated rapidly with
> distance. As a result, if a tumor lies relatively deep below the
> skin 15, it may be difficult to deliver the desired field
> strength that is needed for effective treatment to that tumor to
> the target region.   
>   
> [0007] A similar situation exists in the human head. FIG. 2 is a
> schematic representation of a human head 5 in which all tissue
> components are given their corresponding electric properties.
> The head includes skin 1, bone 2, gray matter 3 and white matter
> 4. FIG. 3A is a schematic representation of the positioning of
> the electrodes 11, 11' on the skin surface on the same side of
> the head, and FIG. 3A shows the electric field that is generated
> under those conditions when a 100 kHz AC field is applied
> between the electrodes. (The field calculation was done by a
> finite element simulation based on the schematic representation
> of the head shown in FIG. 2.) The field intensity is highest in
> the vicinity of the electrodes in the skin and the superficial
> areas of the brain and drops rapidly. Notably, the field
> strength near the middle of the head is very weak (i.e., less
> than 20 mV/cm).   
>   
> [0008] FIG. 4A is a schematic representation of the positioning
> of the electrodes 11, 11' on opposite sides of a human head, and
> FIG. 4B shows the electric field that is generated under those
> conditions when a 100 kHz AC field is applied between the
> electrodes. Once again, the field calculation was done by a
> finite element simulation, and once again, the field strength
> near the middle of the head is very weak (i.e., less than 24
> mV/cm). The field intensity is highest in the vicinity of the
> electrodes in the skin and the superficial areas of the brain
> and drops rapidly, so that the field intensity is relatively low
> at the center of the head. Thus, the treatment efficacy of the
> field for any tumor or lesion at a distance from the surface or
> electrodes would be correspondingly diminished. \  
>   
> SUMMARY   
>   
> [0009] A biocompatible field guide is positioned between the
> surface of the body and the target region beneath the surface.
> Electrodes are positioned on either side of the field guide, and
> an AC voltage with an appropriate frequency and amplitude is
> applied between the electrodes so that the field guide routes
> the electric field to the target region. In an alternative
> embodiment, one of the electrodes is positioned directly on top
> of the field guide.   
>   
> BRIEF DESCRIPTION OF THE
> DRAWINGS   
>   
> ![](us200628-1.jpg)  
>   
> ![](us200628-2.jpg)  
> ![](us200628-3.jpg)  
>   
> ![](us200628-4.jpg)  
>   
> ![](us200628-5.jpg)  
> ![](us200628-6.jpg)  
> ![](us200628-7.jpg)  
> ![](us200628-8.jpg)  
>   
> ![](us200628-9.jpg)  
>   
>   
> ![](us200628-9c.jpg)  
>   
> ![](us200628-10.jpg)  
>   
> ![](us200628-11.jpg)  
> ![](us200628-12.jpg)  
>   
> ![](us200628-13.jpg)  
>   
> ![](us200628-15.jpg)  
>   
> ![](us200628-16.jpg)  
>   
> [0010] FIG. 1A is a schematic
> representation of two electrodes placed on a patient's skin
> above a target region.  
>   
> [0011] FIG. 1B shows the
> electric field that results from the FIG. 1A arrangement.   
>   
> [0012] FIG. 2 is a schematic
> representation of a human head.  
>   
> [0013] FIG. 3A is a schematic
> representation two electrodes positioned on the same side of
> the head.  
>   
> [0014] FIG. 3B shows the
> electric field that results from the FIG. 3A arrangement.   
>   
> [0015] FIG. 4A is a schematic
> representation two electrodes positioned on opposite sides of
> the head.  
>   
> [0016] FIG. 4B shows the
> electric field that results from the FIG. 4A arrangement.  
>   
> [0017] FIGS. 5A and 5B are
> section and plan views, respectively, of a first embodiment of
> the invention using a solid insulated rod.   
>   
> [0018] FIG. 6A shows the
> electric field that results from the FIG. 5 arrangement.  
>   
> [0019] FIG. 6B is a magnified
> view of the center of FIG. 6A.   
>   
> [0020] FIG. 7A shows the
> electric field for a second embodiment using a hollow
> insulated rod.   
>   
> [0021] FIG. 7B is a magnified
> view of the center of FIG. 7A.   
>   
> [0022] FIG. 8A shows the
> electric field for the third embodiment when a conductive gel
> is added.   
>   
> [0023] FIG. 8B is a magnified
> view of the center of FIG. 8A. [0024] FIG. 9A shows the
> electric field for a third embodiment using a hollow
> conducting rod. [0025] FIG. 9B is a magnified view of the
> center of FIG. 9A.   
>   
> [0026] FIG. 9C depicts a set of
> field strength plots for six hollow metal tube field guides.   
>   
> [0027] FIG. 10A shows the
> electric field that results from using a solid conducting rod.
>   
>   
> [0028] FIG. 10B is a magnified
> view of the center of FIG. 10A.   
>   
> [0029] FIGS. 11A and 11B are
> section and plan views, respectively, of a fourth embodiment
> of the invention using a solid insulated bead.  
>   
> [0030] FIG. 12A shows the
> electric field that results from the FIG. 11 arrangement.  
>   
> [0031] FIG. 12B is a magnified
> view of the center of FIG. 12A.  
>   
> [0032] FIG. 13A shows the
> electric field for a fifth embodiment using a hollow
> conducting bead.  
>   
> [0033] FIG. 13B is a magnified
> view of the center of FIG. 13A.  
>   
> [0034] FIG. 14 shows the
> electric field for a sixth embodiment in which a conductive
> gel is placed on the surface of the skin between the
> electrodes.  
>   
> [0035] FIG. 15 shows the
> electric field for an alternative arrangement in which a
> rod-shaped field guide is placed directly beneath one of the
> electrodes.  
>   
> [0036] FIG. 16 shows a curved
> field guide that guides the field to a target area without
> passing through a vital organ.   
>   
> DESCRIPTION OF THE PREFERRED
> EMBODIMENTS   
>   
> [0037] The inventor has recognized that the field can be guided
> to the desired location in the patient's body using appropriate
> field guides.  
>   
>  [0038] In some embodiments of the invention, an insulating
> member is introduced into the medium or tissue in a position
> that enables the member to act as a Field Guide (FG) in the
> given medium. While elongated shapes such as rods, tubes, bars,
> or threads are preferred, other shapes (e.g., sheets or plates)
> may also be used. In these embodiments, the electric impedance
> of the FG, ZFG is significantly higher than that of the medium
> ZFG (ZFG>>ZM). For example, the FG may be made of a
> dielectric insulating material such as plastic (e.g.
> polystyrene, PVC, Teflon), silicone, rubber, etc., while the
> medium is tissue (e.g., muscle). Insulators with a very high
> dielectric constant (see the electrode insulations of the '289
> patent) may be preferable to those with low dielectric
> properties. For use in medical application, the FG should
> preferably be made of a biocompatible material. Optionally, the
> FG may be made of a biodegradable material, as long as the
> electrical properties remain as described herein.  
>   
> [0039] FIGS. 5A and 5B are section and plan views of a first
> embodiment in which an insulated rod 12 is inserted into tissue
> 10 between a pair of insulated electrodes 11, 11'. The upper end
> of the FG rod 12 is positioned just under the skin 15. The
> preferred diameter for the rod is between about 0.5 mm and about
> 10 mm, but diameters outside of that range may also be used.  
>   
>  [0040] FIG. 6A shows a finite element simulation of the
> electric field that is generated in the tissue when a 5 cm long,
> 3 mm diameter, insulated FG rod 12a made of solid plastic with
> an impedance between 4-6 orders of magnitude higher than the
> impedance of the tissue and a dielectric constant of about 2-3
> is inserted into the tissue 10 between the pair of insulated
> electrodes 11, 11'. The upper (proximal) ends of the electrodes
> are located on the skin surface, and a 100 kHz AC voltage is
> applied between the electrodes. FIG. 6B is a magnified portion
> of the center of FIG. 6A, to show the field in greater detail.
> As seen in FIGS. 6A and 6B, the strength of the field is much
> higher just below the rod 12a. Thus, by inserting the FG so that
> it sits right above the desired target location, the field is
> directed to the desired location, along with the corresponding
> beneficial effects of that field (as described in the '289
> patent).  
>   
> [0041] The second embodiment is similar to the first embodiment,
> except that a hollow insulated rod 12b is used in place of the
> solid insulated rod 12a of the first embodiment. The rod in this
> example has an outer diameter of 3 mm and an inner diameter of
> 2.5 mm, and is also 5 cm long. FIG. 7A shows a finite element
> simulation of the electric field for this second embodiment, and
> FIG. 7B shows a magnified view of the center of FIG. 7A. Here
> again, the strength of the field is much higher just below the
> rod. We therefore see that a hollow insulating FG can also be
> used to direct the field to a desired location.  
>   
> [0042] Optionally, conductive gel may be placed on the surface
> of the skin in the region between the insulated electrodes. FIG.
> 8A shows a finite element simulation of the electric field for
> the second embodiment (using the hollow insulated rod 12b) when
> conductive gel 42 is spread on the skin between the electrodes
> 11, 11', and FIG. 8B shows a magnified view of the center of
> FIG. 8A. Here again, the strength of the field is much higher
> just below the rod. In addition, the field is also stronger in
> the region between the electrodes just below the surface of the
> skin 15 beneath the gel 42. Note that the conductive gel
> described in connection with this embodiment may also be used in
> the other embodiments described herein, with similar results.
> [0043] In a third embodiment, a hollow conducting rod is used
> instead of the hollow insulating rod of the second embodiment.
> In this third embodiment, the electric impedance of the FG, ZFG
> is significantly lower than that of the medium ZM (ZFG<3 mm) Metastases
> Treated 19 +- 14 72 +- 66 Control 41 +- 68 143 +- 134   
>   
> [0021] In patients, in the present invention the preventive
> treatment is achieved by means of at least one set (pair) of
> electrodes, preferably two or more sets. The electrodes are
> connected to a waveform generator and amplifier so as to
> generate TTFields in the patient. Electrodes specifically
> designed for long term application without eliciting severe
> side effects and without causing patient discomfort and having
> minimal interference with the normal everyday activities of
> the patient are preferred. The placement of the electrodes is
> made so as to generate the desired field at the location or
> locations where the chances for tumor appearance are
> statistically high. In the case that a primary tumor is also
> present, the placement is preferably made so as to cover all
> tumors. Alternatively, for the presence, or projected presence
> of more than one tumor, additional sets of electrodes can be
> activated simultaneously. In such a case, it is preferable
> that the different sets of electrodes be connected to
> different generators which are isolated from one another.
> Isolation can be achieved by separate voltage sources
> (batteries) or, for example, by using isolation transformers.  
>   
>  [0022] FIG. 1 is a timeline of an alternative approach,
> in which the different sets of electrodes are positioned to
> treat different parts of the patient and are energized
> sequentially in a time-multiplexed manner. In the illustrated
> timeline, the primary tumor is treated in the first time slot
> 12 and the remote sites where metastases are likely to appear
> (e.g., the liver and lungs) are treated in the second and
> third time slots 14, 16, respectively. After all relevant
> regions have been treated, the three-part cycle is repeated.
> For example, the field could be applied to the primary tumor
> for one second, then to the liver for one second, then to
> lungs for one second, after which the three-part cycle is
> repeated for the desired period of treatment. Optionally,
> breaks may be included in the cycles of treatment. For
> example, the field could be applied to the primary tumor for
> 1-3 days, then to the liver for 1-3 days, then to the lungs
> for 1-3 days, then removed for 1-3 days, after which the
> four-part cycle is repeated for the desired period of
> treatment.  
>   
>  [0023] Since the various regions are treated
> sequentially when this approach is used, a single field
> generator can be used for all the sets of electrodes, and
> isolation transformers are not required. Optionally, the field
> may be applied in each time slot with a plurality of
> orientations and/or a plurality of frequencies, as described
> in U.S. patent application Ser. No. 11/111,439, filed Apr. 21,
> 2005, which is incorporated herein by reference.  
>   
>  [0024] One example of a suitable electrode designed for
> comfortable long term use is shown in FIGS. 2a and 2b, with
> FIG. 2a being an plan view of a flexible electrode patch 20
> and FIG. 2b being a detailed crossed section view the flexible
> electrode patch 20 along lines B-B. In this embodiment, the
> flexible electrode patch 20 is actually a composite of many
> small electrodes 40 that are mounted on a flexible substrate
> 22. The flexibility of the substrate 22 and the use of
> relatively small electrodes 40 helps provide flexibility,
> which allows the patch 20 to fit the relevant body curvature.
> Optionally, perforations 26 may be provided in the substrate
> to permit the skin beneath the substrate 22 to "breathe". In
> some embodiments, the material of the substrate 22 is selected
> so that it can be cut to a desired shape to fit the skin area
> to which the flexible patch 20 will be applied.   
>   
> [0025] Depending on the location within the body that is being
> treated, one or more of the flexible electrode patches 20
> would be used. For example, to treat a shallow melanoma, a
> single patch can be used, with the field being induced by
> applying an appropriate voltage between different electrodes
> 40 within the single patch 20. For deeper sites in the body,
> two or more patches 20 would preferably be placed on opposing
> sides of the site, and all the electrodes on any given patch
> would be wired together in parallel. An appropriate driving
> signal would then be applied between the various patches 20.  
>   
>  [0026] FIG. 2b shows a detailed cross-section of the
> flexible electrode patch 20 in which all the electrodes 40 on
> the patch are wired in parallel, depicted in cross-section. In
> this embodiment, the substrate is made of a preferably
> conductive flexible layer 32 mounted beneath a flexible
> insulating layer 30. Suitable materials for the conductive
> layer 32 include conductive rubber, graphite, thin flexible
> metal sheets such as copper or aluminum, etc.; and suitable
> materials for the flexible insulating layer 30 include rubber,
> silicon, Teflon and polyethylene vinyl. A lead 38 is wired in
> electrical contact with the conductive flexible layer 32 to
> facilitate application of the appropriate AC signals to each
> patch 20.  
>   
>  [0027] The cross-section view of FIG. 2b depicts
> electrodes 40 separated by insulators 34, which are preferably
> made of a flexible insulating material such as silicon rubber,
> vinyl, polyurethane, etc. In the illustrated embodiment, each
> electrode 40 includes conductive core 42 made of, for example,
> metal or conductive rubber, and a thin dielectric layer 46.
> Preferably, the dielectric layer is very thin (e.g., 0.1 mm)
> and has a very high dielectric constant (e.g., greater than
> 1000, or more preferably greater than 5000). Preferably, one
> layer of conductive adhesive 44 is provided between the core
> 42 and the conductive layer 32, and another layer of
> conductive adhesive 45 is provided between the core 42 and the
> dielectric layer 46.  
>   
>  [0028] Optionally, the portions of the insulator 34 that
> contact the patient's body may be coated with a biocompatible
> adhesive 36 to help the patch 20 adhere to the patient's body.
> A conductive layer 48 is preferably provided between the
> dielectric 46 and the patient's body to improve the electrical
> contact with the patient's body. Examples of suitable
> materials for this conductive layer 48 include conductive gels
> and carbon (graphite) powders, which maybe imbedded in a
> suitable cream (e.g. a cosmetic base with an electrolyte).
> Graphite has the advantage in that it has a much higher
> electric conductance, as compared with gels, and that it is
> inert and has extremely high biocompatibility. Optionally, a
> suitable adhesive may be included in the conductive layer 48
> to help the patch 20 adhere to the patient's body. A number of
> alternative electrode configurations are described in U.S.
> patent application Ser. No. 11/294,780, filed Dec. 5, 2005,
> which is incorporated herein by reference.  
>   
>  [0029] The TTFields generated in the target regions are
> preferably in the order of 1-10 V/cm and the field frequency
> is preferably 100-300 kHz for certain types of cancers (e.g.,
> certain gliomas and melanomas) and may be outside that range
> for other types of cancer, as described in the applications
> referenced above. The electrodes can be incorporated into
> articles of clothing so as to provide maximal comfort to the
> patient, as described in U.S. Pat. No. 6,868,289, which is
> also incorporated herein by reference.  
>   
>  [0030] FIG. 3 is a flow chart of a process for using the
> above-described approaches to treat patients. The process
> begins in step 60, where information about the patient is
> obtained. This information should preferably include racial
> information and a family history that is sufficient to
> evaluate genetic risk of developing cancer, as well as
> personal history indicating whether the patient has or is
> suspected to have a tumor that may generate metastases.  
>   
>  [0031] In step 62, the process flow diverges depending
> on whether the patient is known to have a metastatic tumor. If
> the patient has a metastatic tumor, process flow continues at
> step 64, where the location or locations where metastases are
> expected to develop and the time frame when such metastasis
> may develop are determined. For example, metastases commonly
> develop in the lungs from certain types of melanomas, and in
> the liver, brain, or bone for certain other types of cancers.
> The process flow then continues in step 66, where the way to
> get the desired beneficial electrical fields to the locations
> identified in step 64 is computed (or, in alternative
> embodiments, estimated). This may be accomplished by running
> computer simulations to identify the type, size, and shape of
> the electrodes that should be used, the positions to place
> those electrodes, and the voltages that should be applied to
> those electrodes in order to induce the desired fields at the
> identified locations. The process flow then continues in step
> 68, where suitable electrodes for generating the desired
> fields are constructed. Finally, in step 70, the electrodes
> are applied to the patient's body and stimulated with
> appropriate voltages in order to generate the desired fields
> in the locations identified previously in step 64.   
>   
> [0032] If, back in step 62, it turns out that the patient
> being evaluated does not have metastatic tumor, the process
> flow continues at step 80 where, based on the patient data
> that was entered in step 60, a determination is made as to
> whether the patient is at a high risk for developing cancer.
> If the patient's risk of developing cancer is not too high,
> the process stops (and the patient is not treated). If, on the
> other hand, it is determined that that patient's risk of
> developing cancer is sufficiently high, process flow continues
> at step 82, where the location or locations where cancer is
> likely to develop are determined. For example, patients with a
> strong family history of breast cancer or a genetic marker
> that is correlated with breast cancer, the determined location
> would be the breasts. The process then proceeds to step 66,
> and continues from there as described above.  
>   
>  [0033] Note that the above-described treatment may be
> advantageously combined with other cancer treatments such as
> surgery, chemotherapy, radiation therapy, etc. It may also be
> convenient to implement the above-described treatment using
> electrodes that are integrated into articles of clothing
> (e.g., a bra or a hat) as described in U.S. Pat. No.
> 6,868,289, which is incorporated herein by reference. ==  
>   
>
>
> ---
>
>   
>  CA2563817   
>   
> CROSS-REFERENCE
> TO RELATED APPLICATIONS   
>   
> [0001] This application claims the benefit of U. S.
> provisional application 60/565,065, filed April 23,2004,
> which is hereby incorporated by reference in its entirety.  
>   
>  TECHNICAL FIELD  
>   
>  [0002] This invention concerns selective destruction
> of rapidly dividing cells in a localized area, and more
> particularly, selectively destroying dividing cells without
> destroying nearby non-dividing cells by applying an electric
> field with specific characteristics to a target area in a
> living patient.   
>   
> BACKGROUND   
>   
> [0003] All living organisms proliferate by cell division,
> including cell cultures, microorganisms (such as bacteria,
> mycoplasma, yeast, protozoa, and other single-celled
> organisms), fungi, algae, plant cells, etc. Dividing cells
> of organisms can be destroyed, or their proliferation
> controlled, by methods that are based on the sensitivity of
> the dividing cells of these organisms to certain agents. For
> example, certain antibiotics stop the multiplication process
> of bacteria.  
>   
>  [0004] The process of eukaryotic cell division is
> called "mitosis", which involves nice distinct phases (see
> Darnell et al. , Molecular Cell Biology, New York:
> Scientific American Books, 1986, p. 149). During interphase,
> the cell replicates chromosomal DNA, which begins condensing
> in early prophase. At this point, centrioles (each cell
> contains 2) begin moving towards opposite poles of the cell.
> In middle prophase, each chromosome is composed of duplicate
> chromatids. Microtubular spindles radiate from regions
> adjacent to the centrioles, which are closer to their poles.
> By late prophase, the centrioles have reached the poles, and
> some spindle fibers extend to the center of the cell, while
> others extend from the poles to the  chromatids. The cells then move into
> metaphase, when the chromosomes move toward the equator of
> the cell and align in the equatorial plane. Next is early
> anaphase, during which time daughter chromatids separate
> from each other at the equator by moving along the spindle
> fibers toward a centromere at opposite poles. The cell
> begins to elongate along the axis of the pole; the
> pole-to-pole spindles also elongate. Late anaphase occurs
> when the daughter chromosomes (as they are now called)
> each reach their respective opposite poles. At this point,
> cytokinesis begins as the cleavage furrow begins to form
> at the equator of the cell. In other words, late anaphase
> is the point at which pinching the cell membrane begins.
> During telophase, cytokinesis is nearly complete and
> spindles disappear. Only a relatively narrow membrane
> connection joins the two cytoplasms. Finally, the
> membranes separate fully, cytokinesis is complete and the
> cell returns to interphase.  
>   
>  [0005] In meiosis, the cell undergoes a second
> division, involving separation of sister chromosomes to
> opposite poles of the cell along spindle fibers, followed
> by formation of a cleavage furrow and cell division.
> However, this division is not preceded by chromosome
> replication, yielding a haploid germ cell. Bacteria also
> divide by chromosome replication, followed by cell
> separation. However, since the daughter chromosomes
> separate by attachment to membrane components; there is no
> visible apparatus that contributes to cell division as in
> eukaryotic cells.  
>   
>  [0006] It is well known that tumors, particularly
> malignant or cancerous tumors, grow uncontrollably
> compared to normal tissue. Such expedited growth enables
> tumors to occupy an ever-increasing space and to damage or
> destroy tissue adjacent thereto. Furthermore, certain
> cancers are characterized by an ability to transmit
> cancerous "seeds", including single cells or small cell
> clusters (metastases), to new locations where the
> metastatic cancer cells grow into additional tumors.  
>   
>  [0007] The rapid growth of tumors, in general, and
> malignant tumors in particular, as described above, is the
> result of relatively frequent cell division or
> multiplication of these cells compared to normal tissue
> cells. The distinguishably frequent cell division of
> cancer cells is the basis for the effectiveness of
> existing cancer treatments, e. g., irradiation therapy and
> the use of various chemo-therapeutic agents. Such
> treatments are based on the fact that cells undergoing
> division are more sensitive to radiation and
> chemo-therapeutic agents than non-dividing cells. Because
> tumors cells divide much more frequently than normal
> cells, it is possible, to a certain extent, to selectively
> damage or destroy tumor cells by radiation therapy  and/or chemotherapy. The
> actual sensitivity of cells to radiation, therapeutic
> agents, etc. , is also dependent on specific
> characteristics of different types of normal or
> malignant cell types. Thus, unfortunately, the
> sensitivity of tumor cells is not sufficiently higher
> than that many types of normal tissues. This diminishes
> the ability to distinguish between tumor cells and
> normal cells, and therefore, existing cancer treatments
> typically cause significant damage to normal tissues,
> thus limiting the therapeutic effectiveness of such
> treatments. Furthermore, the inevitable damage to other
> tissue renders treatments very traumatic to the patients
> and, often, patients are unable to recover from a
> seemingly successful treatment. Also, certain types of
> tumors are not sensitive at all to existing methods of
> treatment.  
>   
>  [0008] There are also other methods for destroying
> cells that do not rely on radiation therapy or
> chemotherapy alone. For example, ultrasonic and
> electrical methods for destroying tumor cells can be
> used in addition to or instead of conventional
> treatments. Electric fields and currents have been used
> for medical purposes for many years. The most common is
> the generation of electric currents in a human or animal
> body by application of an electric field by means of a
> pair of conductive electrodes between which a potential
> difference is maintained. These electric currents are
> used either to exert their specific effects, i. e., to
> stimulate excitable tissue, or to generate heat by
> flowing in the body since it acts as a resistor.
> Examples of the first type of application include the
> following: cardiac defibrillators, peripheral nerve and
> muscle stimulators, brain stimulators, etc. Currents are
> used for heating, for example, in devices for tumor
> ablation, ablation of malfunctioning cardiac or brain
> tissue, cauterization, relaxation of muscle rheumatic
> pain and other pain, etc.   
>   
> [0009] Another use of electric fields for medical
> purposes involves the utilization of high frequency
> oscillating fields transmitted from a source that emits
> an electric wave, such as an RF wave or a microwave
> source that is directed at the part of the body that is
> of interest (i. e., target). In these instances, there
> is no electric energy conduction between the source and
> the body; but rather, the energy is transmitted to the
> body by radiation or induction. More specifically, the
> electric energy generated by the source reaches the
> vicinity of the body via a conductor and is transmitted
> from it through air or some other electric insulating
> material to the human body.  
>   
>  [0010] In a conventional electrical method,
> electrical current is delivered to a region of the
> target tissue using electrodes that are placed in
> contact with the body of the patient. The applied
> electrical current destroys substantially all cells in
> the vicinity of the target  tissue. Thus, this type of electrical
> method does not discriminate between different types
> of cells within the target tissue and results in the
> destruction of both tumor cells and normal cells.  
>   
>  [0011] Electric fields that can be used in
> medical applications can thus be separated generally
> into two different modes. In the first mode, the
> electric fields are applied to the body or tissues by
> means of conducting electrodes. These electric fields
> can be separated into two types, namely (1) steady
> fields or fields that change at relatively slow rates,
> and alternating fields of low frequencies that induce
> corresponding electric currents in the body or
> tissues, and (2) high frequency alternating fields
> (above 1 MHz) applied to the body by means of the
> conducting electrodes. In the second mode, the
> electric fields are high frequency alternating fields
> applied to the body by means of insulated electrodes.  
>   
>  [0012] The first type of electric field is used,
> for example, to stimulate nerves and muscles, pace the
> heart, etc. In fact, such fields are used in nature to
> propagate signals in nerve and muscle fibers, central
> nervous system (CNS), heart, etc. The recording of
> such natural fields is the basis for the ECG, EEG,
> EMG, ERG, etc. The field strength in these
> applications, assuming a medium of homogenous electric
> properties, is simply the voltage applied to the
> stimulating/recording electrodes divided by the
> distance between them. These currents can be
> calculated by Ohm's law and can have dangerous
> stimulatory effects on the heart and CNS and can
> result in potentially harmful ion concentration
> changes. Also, if the currents are strong enough, they
> can cause excessive heating in the tissues. This
> heating can be calculated by the power dissipated in
> the tissue (the product of the voltage and the
> current).   
>   
> [0013] When such electric fields and currents are
> alternating, their stimulatory power, on nerve,
> muscle, etc. , is an inverse function of the
> frequency. At frequencies above 1-10 KHz, the
> stimulation power of the fields approaches zero. This
> limitation is due to the fact that excitation induced
> by electric stimulation is normally mediated by
> membrane potential changes, the rate of which is
> limited by the RC properties (time constants on the
> order of 1 ms) of the membrane.  
>   
>  [0014] Regardless of the frequency, when such
> current inducing fields are applied, they are
> associated with harmful side effects caused by
> currents. For example, one negative effect is the
> changes in ionic concentration in the various
> "compartments" within the system, and the harmful
> products of the electrolysis taking place at the
> electrodes, or the medium in  which the tissues are imbedded. The
> changes in ion concentrations occur whenever the
> system includes two or more compartments between
> which the organism maintains ion concentration
> differences. For example, for most tissues, [Ca@] in
> the extracellular fluid is about 2#10-3 M, while in
> the cytoplasm of typical cells its concentration can
> be as low as 10-7 M. A current induced in such a
> system by a pair of electrodes, flows in part from
> the extracellular fluid into the cells and out again
> into the extracellular medium. About 2% of the
> current flowing into the cells is carried by the Ca@
> ions. In contrast, because the concentration of
> intracellular Ca@ is much smaller, only a negligible
> fraction of the currents that exits the cells is
> carried by these ions. Thus, Ca++ ions accumulate in
> the cells such that their concentrations in the
> cells increases, while the concentration in the
> extracellular compartment may decrease. These
> effects are observed for both DC and alternating
> currents (AC). The rate of accumulation of the ions
> depends on the current intensity ion mobilities,
> membrane ion conductance, etc. An increase in [Ca++]
> is harmful to most cells and if sufficiently high
> will lead to the destruction of the cells. Similar
> considerations apply to other ions. In view of the
> above observations, long term current application to
> living organisms or tissues can result in
> significant damage. Another major problem that is
> associated with such electric fields, is due to the
> electrolysis process that takes place at the
> electrode surfaces. Here charges are transferred
> between the metal (electrons) and the electrolytic
> solution (ions) such that charged active radicals
> are formed. These can cause significant damage to
> organic molecules, especially macromolecules and
> thus damage the living cells and tissues.  
>   
>  [0015] In contrast, when high frequency
> electric fields, above 1 MHz and usually in practice
> in the range of GHz, are induced in tissues by means
> of insulated electrodes, the situation is quite
> different. These type of fields generate only
> capacitive or displacement currents, rather than the
> conventional charge conducting currents. Under the
> effect of this type of field, living tissues behave
> mostly according to their dielectric properties
> rather than their electric conductive properties.
> Therefore, the dominant field effect is that due to
> dielectric losses and heating. Thus, it is widely
> accepted that in practice, the meaningful effects of
> such fields on living organisms, are only those due
> to their heating effects, i. e., due to dielectric
> losses.  
>   
>  [0016] In U. S. Pat. No. 6,043,066 ('066) to
> Mangano, a method and device are presented which
> enable discrete objects having a conducting inner
> core, surrounded by a dielectric membrane to be
> selectively inactivated by electric fields via
> irreversible breakdown of their dielectric membrane.
> One potential application for this is in the
> selection and purging  of certain biological cells in a
> suspension. According to the '066 patent, an
> electric field is applied for targeting selected
> cells to cause breakdown of the dielectric
> membranes of these tumor cells, while purportedly
> not adversely affecting other desired
> subpopulations of cells. The cells are selected on
> the basis of intrinsic or induced differences in a
> characteristic electroporation threshold. The
> differences in this threshold can depend upon a
> number of parameters, including the difference in
> cell size.  
>   
>  [0017] The method of the '066 patent is
> therefore based on the assumption that the
> electroporation threshold of tumor cells is
> sufficiently distinguishable from that of normal
> cells because of differences in cell size and
> differences in the dielectric properties of the
> cell membranes. Based upon this assumption, the
> larger size of many types of tumor cells makes
> these cells more susceptible to electroporation
> and thus, it may be possible to selectively damage
> only the larger tumor cell membranes by applying
> an appropriate electric field. One disadvantage of
> this method is that the ability to discriminate is
> highly dependent upon cell type, for example, the
> size difference between normal cells and tumor
> cells is significant only in certain types of
> cells. Another drawback of this method is that the
> voltages which are applied can damage some of the
> normal cells and may not damage all of the tumor
> cells because the differences in size and membrane
> dielectric properties are largely statistical and
> the actual cell geometries and dielectric
> properties can vary significantly.  
>   
>  [0018] What is needed in the art and has
> heretofore not been available is an apparatus for
> destroying dividing cells, wherein the apparatus
> better discriminates between dividing cells,
> including single-celled organisms, and
> non-dividing cells and is capable of selectively
> destroying the dividing cells or organisms with
> substantially no effect on the non-dividing cells
> or organisms.  
>   
>  SUMMARY  
>   
>  [0019] While they are dividing, cells are
> vulnerable to damage by AC electric fields that
> have specific frequency and field strength
> characteristics. The selective destruction of
> rapidly dividing cells can therefore be
> accomplished by imposing an AC electric field in a
> target region for extended periods of time. Some
> of the cells that divide while the field is
> applied will be damaged, but the cells that do not
> divide will not be harmed. This selectively
> damages rapidly dividing cells like tumor cells,
> but does not harm normal cells that are not
> dividing. Improved results may be achieved by
> using a field with two or more frequencies.  
>   
>  [0020]
> A major use of the present apparatus is in the
> treatment of tumors by selective destruction of
> tumor cells with substantially no effect on
> normal tissue cells, and thus, the exemplary
> apparatus is described below in the context of
> selective destruction of tumor cells. It should
> be appreciated however, that for purpose of the
> following description, the term "cell" may also
> refer to a single-celled organism (eubacteria,
> bacteria, yeast, protozoa), multi- celled
> organisms (fungi, algae, mold), and plants as or
> parts thereof that are not normally classified
> as "cells". The exemplary apparatus enables
> selective destruction of cells undergoing
> division in a way that is more effective and
> more accurate (e. g., more adaptable to be aimed
> at specific targets) than existing methods.
> Further, the present apparatus causes minimal
> damage, if any, to normal tissue and, thus,
> reduces or eliminates many side-effects
> associated with existing selective destruction
> methods, such as radiation therapy and
> chemotherapy. The selective destruction of
> dividing cells using the present apparatus does
> not depend on the sensitivity of the cells to
> chemical agents or radiation. Instead, the
> selective destruction of dividing cells is based
> on distinguishable geometrical characteristics
> of cells undergoing division, in comparison to
> non-dividing cells, regardless of the cell
> geometry of the type of cells being treated.  
>   
> [0021] According to one exemplary embodiment,
> cell geometry-dependent selective destruction of
> living tissue is performed by inducing a
> non-homogenous electric field in the cells using
> an electronic apparatus.  
>   
>  [0022] It has been observed by the present
> inventor that, while different cells in their
> non-dividing state may have different shapes, e.
> g., spherical, ellipsoidal, cylindrical,
> "pancake-like", etc. , the division process of
> practically all cells is characterized by
> development of a "cleavage furrow" in late
> anaphase and telophase. This cleavage furrow is
> a slow constriction of the cell membrane
> (between the two sets of daughter chromosomes)
> which appears microscopically as a growing cleft
> (e. g., a groove or notch) that gradually
> separates the cell into two new cells. During
> the division process, there is a transient
> period (telophase) during which the cell
> structure is basically that of two sub-cells
> interconnected by a narrow "bridge" formed of
> the cell material. The division process is
> completed when the "bridge" between the two
> sub-cells is broken. The selective destruction
> of tumor cells using the present electronic
> apparatus utilizes this unique geometrical
> feature of dividing cells.  
>   
>  [0023] When a cell or a group of cells are
> under natural conditions or environment, i. e.,
> part of a living tissue, they are disposed
> surrounded by a conductive environment  consisting
> mostly of an electrolytic inter-cellular fluid
> and other cells that are composed mostly of an
> electrolytic intra-cellular liquid. When an
> electric field is induced in the living
> tissue, by applying an electric potential
> across the tissue, an electric field is formed
> in the tissue and the specific distribution
> and configuration of the electric field lines
> defines the direction of charge displacement,
> or paths of electric currents in the tissue,
> if currents are in fact induced in the tissue.
> The distribution and configuration of the
> electric field is dependent on various
> parameters of the tissue, including the
> geometry and the electric properties of the
> different tissue components, and the relative
> conductivities, capacities and dielectric
> constants (that may be frequency dependent) of
> the tissue components.  
>   
>  [0024] The electric current flow pattern
> for cells undergoing division is very
> different and unique as compared to
> non-dividing cells. Such cells including first
> and second sub-cells, namely an "original"
> cell and a newly formed cell, that are
> connected by a cytoplasm "bridge" or "neck".
> The currents penetrate the first sub-cell
> through part of the membrane ("the current
> source pole") ; however, they do not exit the
> first sub-cell through a portion of its
> membrane closer to the opposite pole ("the
> current sink pole"). Instead, the lines of
> current flow converge at the neck or cytoplasm
> bridge, whereby the density of the current
> flow lines is greatly increased. A
> corresponding, "mirror image", process that
> takes place in the second sub-cell, whereby
> the current flow lines diverge to a lower
> density configuration as they depart from the
> bridge, and finally exit the second sub-cell
> from a part of its membrane closes to the
> current sink.  
>   
>  [0025] When a polarizable object is
> placed in a non-uniform converging or
> diverging field, electric forces act on it and
> pull it towards the higher density electric
> field lines. In the case of dividing cell,
> electric forces are exerted in the direction
> of the cytoplasm bridge between the two cells.
> Since all intercellular organelles and
> macromolecules are polarizable, they are all
> force towards the bridge between the two
> cells. The field polarity is irrelevant to the
> direction of the force and, therefore, an
> alternating electric having specific
> properties can be used to produce
> substantially the same effect. It will also be
> appreciated that the concentrated and
> inhomogeneous electric field present in or
> near the bridge or neck portion in itself
> exerts strong forces on charges and natural
> dipoles and can lead to the disruption of
> structures associated with these members.  
>   
>  [0026] The movement of the cellular
> organelles towards the bridge disrupts the
> cell structure and results in increased
> pressure in the vicinity of the connecting
> bridge membrane.  This pressure of the
> organelles on the bridge membrane is
> expected to break the bridge membrane and,
> thus, it is expected that the dividing cell
> will "explode" in response to this pressure.
> The ability to break the membrane and
> disrupt other cell structures can be
> enhanced by applying a pulsating alternating
> electric field that has a frequency from
> about 50 KHz to about 500 KHz. When this
> type of electric field is applied to the
> tissue, the forces exerted on the
> intercellular organelles have a "hammering"
> effect, whereby force pulses (or beats) are
> applied to the organelles numerous times per
> second, enhancing the movement of organelles
> of different sizes and masses towards the
> bridge (or neck) portion from both of the
> sub-cells, thereby increasing the
> probability of breaking the cell membrane at
> the bridge portion. The forces exerted on
> the intracellular organelles also affect the
> organelles themselves and may collapse or
> break the organelles.  
>   
>  [0027] According to one exemplary
> embodiment, the apparatus for applying the
> electric field is an electronic apparatus
> that generates the desired electric signals
> in the shape of waveforms or trains of
> pulses. The electronic apparatus includes a
> generator that generates an alternating
> voltage waveform at frequencies in the range
> from about 50 KHz to about 500 KHz. The
> generator is operatively connected to
> conductive leads which are connected at
> their other ends to insulated
> conductors/electrodes (also referred to as
> isolects) that are activated by the
> generated waveforms. The insulated
> electrodes consist of a conductor in contact
> with a dielectric (insulating layer) that is
> in contact with the conductive tissue, thus
> forming a capacitor. The electric fields
> that are generated by the present apparatus
> can be applied in several different modes
> depending upon the precise treatment
> application.   
>   
> [0028] In one exemplary embodiment, the
> electric fields are applied by external
> insulated electrodes which are incorporated
> into an article of clothing and which are
> constructed so that the applied electric
> fields are of a local type that target a
> specific, localized area of tissue (e. g., a
> tumor). This embodiment is designed to treat
> tumors and lesions that are at or below the
> skin surface by wearing the article of
> clothing over the target tissue so that the
> electric fields generated by the insulated
> electrodes are directed at the tumors
> (lesions, etc.).  
>   
>  [0029] According to another
> embodiment, the apparatus is used in an
> internal type application in that the
> insulated electrodes are in the form of a
> probe or catheter etc. , that enter the body
> through natural pathways, such as the
> urethra or vagina, or are configured to  penetrate
> living tissue; until the insulated
> electrodes are positioned near the
> internal target area (e.g., an internal
> tumor).   
>   
> [0030] Thus, the present apparatus
> utilizes electric fields that fall into a
> special intermediate category relative to
> previous high and low frequency
> applications in that the present electric
> fields are bio-effective fields that have
> no meaningful stimulatory effects and no
> thermal effects. Advantageously, when
> non-dividing cells are subjected to these
> electric fields, there is no effect on the
> cells; however, the situation is much
> different when dividing cells are
> subjected to the present electric fields.
> Thus, the present electronic apparatus and
> the generated electric fields target
> dividing cells, such as tumors or the
> like, and do not target non-dividing cells
> that is found around in healthy tissue
> surrounding the target area. Furthermore,
> since the present apparatus utilizes
> insulated electrodes, the above mentioned
> negative effects, obtained when conductive
> electrodes are used, i. e., ion
> concentration changes in the cells and the
> formation of harmful agents by
> electrolysis, do not occur with the
> present apparatus. This is because, in
> general, no actual transfer of charges
> takes place between the electrodes and the
> medium, and there is no charge flow in the
> medium where the currents are capacitive.
>   
>   
> [0031] It should be appreciated that the
> present electronic apparatus can also be
> used in applications other than treatment
> of tumors in the living body. In fact, the
> selective destruction utilizing the
> present apparatus can be used in
> conjunction with any organism that
> proliferates by division, for example,
> tissue cultures, microorganisms, such as
> bacteria, mycoplasma, protozoa, fungi,
> algae, plant cells, etc. Such organisms
> divide by the formation of a groove or
> cleft as described above. As the groove or
> cleft deepens, a narrow bridge is formed
> between the two parts of the organism,
> similar to the bridge formed between the
> sub- cells of dividing animal cells. Since
> such organisms are covered by a membrane
> having a relatively low electric
> conductivity, similar to an animal cell
> membrane described above, the electric
> field lines in a dividing organism
> converge at the bridge connecting the two
> parts of the dividing organism. The
> converging field lines result in electric
> forces that displace polarizable elements
> and charges within the dividing organism.  
>   
>  [0032] The above, and other objects,
> features and advantages of the present
> apparatus will become apparent from the
> following description read in conjunction
> with the accompanying drawings, in which
> like reference numerals designate the same
> elements.    
>   
> BRIEF
> DESCRIPTION OF THE DRAWINGS   
>   
> [0033]
> FIGS. 1A-1E are simplified, schematic,
> cross-sectional, illustrations of
> various stages of a cell division
> process;  
>   
>  [0034]
> FIGS. 2A and 2B are schematic
> illustrations of a non-dividing cell
> being subjected to an electric field;  
>   
>  [0035]
> FIGS. 3A, 3B and 3C are schematic
> illustrations of a dividing cell being
> subjected to an electric field
> according to one exemplary embodiment,
> resulting in destruction of the cell
> (FIG. 3C) in accordance with one
> exemplary embodiment; [0036] FIG. 4 is
> a schematic illustration of a dividing
> cell at one stage being subject to an
> electric field; [0037] FIG. 5 is a
> schematic block diagram of an
> apparatus for applying an electric
> according to one exemplary embodiment
> for selectively destroying cells;
> [0038] FIG. 6 is a simplified
> schematic diagram of an equivalent
> electric circuit of insulated
> electrodes of the apparatus of FIG. 5;  
>   
>  [0039]
> FIG. 7 is a cross-sectional
> illustration of a skin patch
> incorporating the apparatus of FIG. 5
> and for placement on a skin surface
> for treating a tumor or the like;
> [0040] FIG. 8 is a cross-sectional
> illustration of the insulated
> electrodes implanted within the body
> for treating a tumor or the like;  
>   
>  [0041]
> FIG. 9 is a cross-sectional
> illustration of the insulated
> electrodes implanted within the body
> for treating a tumor or the like;
> [0042] FIGS. 10A-10D are
> cross-sectional illustrations of
> various constructions of the insulated
> electrodes of the apparatus of FIG. 5;
>   
>   
> [0043]
> FIG. 11 is a front elevational view in
> partial cross-section of two insulated
> electrodes being arranged about a
> human torso for treatment of a tumor
> container within the body, e. g., a
> tumor associated with lung cancer;  
>   
>  [0044]
> FIGS. 12A-12C are cross-sectional
> illustrations of various insulated
> electrodes with and without protective
> members formed as a part of the
> construction thereof;  
>   
>  [0045]
> FIG. 13 is a schematic diagram of
> insulated electrodes that are
> arranged for focusing the electric
> field at a desired target while
> leaving other areas in low field
> density (i. e., protected areas);  
>   
>  [0046]
> FIG. 14 is a cross-sectional view of
> insulated electrodes incorporated
> into a hat according to a first
> embodiment for placement on a head
> for treating an intra-cranial tumor
> or the like;  
>   
>  [0047]
> FIG. 15 is a partial section of a
> hat according to an exemplary
> embodiment having a recessed section
> for receiving one or more insulated
> electrodes;  
>   
>  [0048]
> FIG. 16 is a cross-sectional view of
> the hat of FIG. 15 placed on a head
> and illustrating a biasing mechanism
> for applying a force to the
> insulated electrode to ensure the
> insulated electrode remains in
> contact against the head;   
>   
> [0049]
> FIG. 17 is a cross-sectional top
> view of an article of clothing
> having the insulated electrodes
> incorporated therein for treating a
> tumor or the like;  
>   
>  [0050]
> FIG. 18 is a cross-sectional view of
> a section of the article of clothing
> of FIG. 17 illustrating a biasing
> mechanism for biasing the insulated
> electrode in direction to ensure the
> insulated electrode is placed
> proximate to a skin surface where
> treatment is desired;  
>   
>  [0051]
> FIG. 19 is a cross-sectional view of
> a probe according to one embodiment
> for being disposed internally within
> the body for treating a tumor or the
> like;  
>   
>  [0052]
> FIG. 20 is an elevational view of an
> unwrapped collar according to one
> exemplary embodiment for placement
> around a neck for treating a tumor
> or the like in this area when the
> collar is wrapped around the neck;
> [0053] FIG. 21 is a cross-sectional
> view of two insulated electrodes
> with conductive gel members being
> arranged about a body, with the
> electric field lines being shown;  
>   
>  [0054]
> FIG. 22 is a cross-sectional view of
> the arrangement of FIG. 21
> illustrating a point of insulation
> breakdown in one insulated
> electrode;  
>   
>  [0055]
> FIG. 23 is a cross-sectional view of
> an arrangement of at least two
> insulated electrodes with conductive
> gel members being arranged about a
> body for treatment of a tumor or the
> like, wherein each conductive gel
> member has a feature for minimizing
> the effects of an insulation
> breakdown in the insulated
> electrode;  
>   
>  [0056]
> FIG. 24 is a cross-sectional view
> of another arrangement of at least
> two insulated electrodes with
> conductive gel members being
> arranged about a body for
> treatment of a tumor or the like,
> wherein a conductive member is
> disposed within the body near the
> tumor to create a region of
> increased field density;  
>   
>  [0057]
> FIG. 25 is a cross-sectional view
> of an arrangement of two insulated
> electrodes of varying sizes
> disposed relative to a body; and  
>   
>  [0058]
> FIG. 26 is a cross-sectional view
> of an arrangement of at least two
> insulated electrodes with
> conductive gel members being
> arranged about a body for
> treatment of a tumor or the like,
> wherein each conductive gel member
> has a feature for minimizing the
> effects of an insulation breakdown
> in the insulated electrode.  
>   
>  [0059]
> FIGS. 27A-C show a configuration
> of electrodes that facilitates the
> application of an electric field
> in different directions.  
>   
>  [0060]
> FIG. 28 shows a three-dimensional
> arrangement of electrodes about a
> body part that facilitates the
> application of an electric field
> in different directions.  
>   
>  [0061]
> FIGS. 29A and 29B are graphs of
> the efficiency of the cell
> destruction process as a function
> of field strength for melanoma and
> glioma cells, respectively. [0062]
> FIGS. 30A and 30B are graphs that
> show how the cell destruction
> efficiency is a function of the
> frequency of the applied field for
> melanoma and glioma cells,
> respectively.  
>   
> [0063]
> FIG. 31A is a graphical
> representation of the sequential
> application of a plurality of
> frequencies in a plurality of
> directions.  
>   
>  [0064]
> FIG. 31B is a graphical
> representation of the sequential
> application of a sweeping
> frequency in a plurality of
> directions.   
>   
> DETAILED
> DESCRIPTION OF PREFERRED
> EMBODIMENTS   
>   
> [0065] Reference is made to FIGS.
> 1A-1E which schematically illustrate
> various stages of a cell division
> process. FIG. 1A illustrates a cell
> 10 at its normal geometry, which can
> be generally spherical (as
> illustrated in the drawings),
> ellipsoidal, cylindrical, "pancake-
> like" or any other cell geometry, as
> is known in the art. FIGS. 1B-1D
> illustrate cell 10 during different
> stages of its division process,
> which results in the formation of
> two new cells 18 and 20, shown in
> FIG. 1E.  
>   
>  [0066] As shown in
> FIGS. 1B-1D, the division process
> of cell 10 is characterized by a
> slowly growing cleft 12 which
> gradually separates cell 10 into
> two units, namely sub-cells 14 and
> 16, which eventually evolve into
> new cells 18 and 20 (FIG. 1E). A
> shown specifically in FIG. 1D, the
> division process is characterized
> by a transient period during which
> the structure of cell 10 is
> basically that of the two
> sub-cells 14 and 16 interconnected
> by a narrow "bridge" 22 containing
> cell material (cytoplasm
> surrounded by cell membrane).  
>   
>  [0067] Reference is now made
> to FIGS. 2A and 2B, which
> schematically illustrate
> non-dividing cell 10 being
> subjected to an electric field
> produced by applying an
> alternating electric potential, at
> a relatively low frequency and at
> a relatively high frequency,
> respectively. Cell 10 includes
> intracellular organelles, e. g., a
> nucleus 30. Alternating electric
> potential is applied across
> electrodes 28 and 32 that can be
> attached externally to a patient
> at a predetermined region, e. g.,
> in the vicinity of the tumor being
> treated. When cell 10 is under
> natural conditions, i. e., part of
> a living tissue, it is disposed in
> a conductive environment
> (hereinafter referred to as a
> "volume conductor") consisting
> mostly of electrolytic inter-
> cellular liquid. When an electric
> potential is applied across
> electrodes 28 and 32, some of the
> field lines of the resultant
> electric field (or the current
> induced in the tissue in response
> to the electric field) penetrate
> the cell 10, while the rest of the
> field lines (or induced current)
> flow in the surrounding medium.
> The specific distribution of the
> electric field lines, which is
> substantially consistent with the
> direction of current flow in this
> instance, depends on the geometry
> and the electric properties of the
> system components, e. g., the
> relative conductivities and
> dielectric constants of the system
> components, that can be frequency
> dependent. For low frequencies, e.
> g., frequencies lower than 10 KHz,
> the conductance properties of the
> components completely dominate the
> current flow and the field
> distribution, and the field
> distribution is generally as
> depicted in FIG. 2A. At higher
> frequencies, e. g., at frequencies
> of between 10 KHz and 1 MHz, the
> dielectric properties of the
> components becomes more
> significant and eventually
> dominate the field distribution,
> resulting in field distribution
> lines as depicted generally in
> FIG. 2B.  
>   
>  [0068] For constant (i. e.,
> DC) electric fields or relatively
> low frequency alternating electric
> fields, for example, frequencies
> under 10 KHz, the dielectric
> properties of the various
> components are not significant in
> determining and computing the
> field distribution. Therefore, as
> a first approximation, with regard
> to the electric field
> distribution, the system can be
> reasonably represented by the
> relative impedances of its various
> components. Using this
> approximation, the intercellular
> (i. e., extracellular) fluid and
> the intracellular fluid each 
> has a relatively low impedance,
> while the cell membrane 11 has a
> relatively high impedance. Thus,
> under low frequency conditions,
> only a fraction of the electric
> field lines (or currents induced
> by the electric field) penetrate
> membrane 11 of the cell 10. At
> relatively high frequencies (e.
> g., 10 KHz-1 MHz), in contrast,
> the impedance of membrane 11
> relative to the intercellular
> and intracellular fluids
> decreases, and thus, the
> fraction of currents penetrating
> the cells increases
> significantly. It should be
> noted that at very high
> frequencies, i. e., above 1 MHz,
> the membrane capacitance can
> short the membrane resistance
> and, therefore, the total
> membrane resistance can become
> negligible. [0069] In any of the
> embodiments described above, the
> electric field lines (or induced
> currents) penetrate cell 10 from
> a portion of the membrane 11
> closest to one of the electrodes
> generating the current, e. g.,
> closest to positive electrode 28
> (also referred to herein as
> "source"). The current flow
> pattern across cell 10 is
> generally uniform because, under
> the above approximation, the
> field induced inside the cell is
> substantially homogeneous. The
> currents exit cell 10 through a
> portion of membrane 11 closest
> to the opposite electrode, e.g.,
> negative electrode 32 (also
> referred to herein as "sink").  
>   
>  [0070] The distinction
> between field lines and current
> flow can depend on a number of
> factors, for example, on the
> frequency of the applied
> electric potential and on
> whether electrodes 28 and 32 are
> electrically insulated. For
> insulated electrodes applying a
> DC or low frequency alternating
> voltage, there is practically no
> current flow along the lines of
> the electric field. At higher
> frequencies, the displacement
> currents are induced in the
> tissue due to charging and
> discharging of the electrode
> insulation and the cell
> membranes (which act as
> capacitors to a certain extent),
> and such currents follow the
> lines of the electric field.
> Fields generated by
> non-insulated electrodes, in
> contrast, always generate some
> form of current flow,
> specifically, DC or low
> frequency alternating fields
> generate conductive current flow
> along the field lines, and high
> frequency alternating fields
> generate both conduction and
> displacement currents along the
> field lines. It should be
> appreciated, however, that
> movement of polarizable
> intracellular organelles
> according to the present
> invention (as described below)
> is not dependent on actual flow
> of current and, therefore, both
> insulated and non-insulated
> electrodes can be used
> efficiently. Advantages of
> insulated electrodes include
> lower power consumption, less
> heating of the treated regions,
> and improved patient safety.  
>   
>  [0071] According to one
> exemplary embodiment of the
> present invention, the electric
> fields that are used are
> alternating fields having
> frequencies that are in the
> range from about  50
> KHz to about 500 KHz, and
> preferably from about 100 KHz
> to about 300 KHz. For ease of
> discussion, these type of
> electric fields are also
> referred to below as "TC
> fields", which is an
> abbreviation of "Tumor Curing
> electric fields", since these
> electric fields fall into an
> intermediate category (between
> high and low frequency ranges)
> that have bio-effective field
> properties while having no
> meaningful stimulatory and
> thermal effects. These
> frequencies are sufficiently
> low so that the system
> behavior is determined by the
> system's Ohmic (conductive)
> properties but sufficiently
> high enough not to have any
> stimulation effect on
> excitable tissues. Such a
> system consists of two types
> of elements, namely, the
> intercellular, or
> extracellular fluid, or medium
> and the individual cells. The
> intercellular fluid is mostly
> an electrolyte with a specific
> resistance of about 40-100
> Ohm\*cm. As mentioned above,
> the cells are characterized by
> three elements, namely (1) a
> thin, highly electric
> resistive membrane that coats
> the cell; (2) internal
> cytoplasm that is mostly an
> electrolyte that contains
> numerous macromolecules and
> micro-organelles, including
> the nucleus; and (3)
> membranes, similar in their
> electric properties to the
> cell membrane, cover the
> micro-organelles.  
>   
>  [0072] When this type of
> system is subjected to the
> present TC fields (e. g.,
> alternating electric fields in
> the frequency range of 100
> KHz-300 KHz) most of the lines
> of the electric field and
> currents tend away from the
> cells because of the high
> resistive cell membrane and
> therefore the lines remain in
> the extracellular conductive
> medium. In the above recited
> frequency range, the actual
> fraction of electric field or
> currents that penetrates the
> cells is a strong function of
> the frequency.  
>   
>  [0073] FIG. 2
> schematically depicts the
> resulting field distribution
> in the system. As illustrated,
> the lines of force, which also
> depict the lines of potential
> current flow across the cell
> volume mostly in parallel with
> the undistorted lines of force
> (the main direction of the
> electric field). In other
> words, the field inside the
> cells is mostly homogeneous.
> In practice, the fraction of
> the field or current that
> penetrates the cells is
> determined by the cell
> membrane impedance value
> relative to that of the
> extracellular fluid. Since the
> equivalent electric circuit of
> the cell membrane is that of a
> resistor and capacitor in
> parallel, the impedance is a
> function of the frequency. The
> higher the frequency, the
> lower the impedance, the
> larger the fraction of
> penetrating current and the
> smaller the field distortion
> (Rotshenker S. & Y. Palti,
> Changes infraction of current
> penetrating an axon as a
> function of duration of
> stimulating pulse, J. Theor.
> Biol. 41; 401-407 (1973).  
>   
>  [0074] As
> previously mentioned, when
> cells are subjected to
> relatively weak electric
> fields and currents that
> alternate at high
> frequencies, such as the
> present TC fields having a
> frequency in the range of 50
> KHz-500 KHz, they have no
> effect on the non-dividing
> cells. While the present TC
> fields have no detectable
> effect on such systems, the
> situation becomes different
> in the presence of dividing
> cells.  
>   
>  [0075] Reference is
> now made to FIGS. 3A-3C
> which schematically
> illustrate the electric
> current flow pattern in cell
> 10 during its division
> process, under the influence
> of alternating fields (TC
> fields) in the frequency
> range from about 100 KHz to
> about 300 KHz in accordance
> with one exemplary
> embodiment. The field lines
> or induced currents
> penetrate cell 10 through a
> part of the membrane of
> sub-cell 16 closer to
> electrode 28. However, they
> do not exit through the
> cytoplasm bridge 22 that
> connects sub-cell 16 with
> the newly formed yet still
> attached sub-cell 14, or
> through a part of the
> membrane in the vicinity of
> the bridge 22. Instead, the
> electric field or current
> flow lines--that are
> relatively widely separated
> in sub- cell 16--converge as
> they approach bridge 22
> (also referred to as "neck"
> 22) and, thus, the
> current/field line density
> within neck 22 is increased
> dramatically. A "mirror
> image" process takes place
> in sub-cell 14, whereby the
> converging field lines in
> bridge 22 diverge as they
> approach the exit region of
> sub-cell 14.   
>   
> [0076] It should be
> appreciated by persons
> skilled in the art that
> homogeneous electric fields
> do not exert a force on
> electrically neutral
> objects, i. e., objects
> having substantially zero
> net charge, although such
> objects can become
> polarized. However, under a
> non-uniform, converging
> electric field, as shown in
> FIGS. 3A-3C, electric forces
> are exerted on polarized
> objects, moving them in the
> direction of the higher
> density electric field
> lines. It will be
> appreciated that the
> concentrated electric field
> that is present in the neck
> or bridge area in itself
> exerts strong forces on
> charges and natural dipoles
> and can disrupt structures
> that are associated
> therewith. One will
> understand that similar net
> forces act on charges in an
> alternating field, again in
> the direction of the field
> of higher intensity.  
>   
>  [0077] In the
> configuration of FIGS. 3A
> and 3B, the direction of
> movement of polarized and
> charged objects is towards
> the higher density electric
> field lines, i. e., towards
> the cytoplasm bridge 22
> between sub-cells 14 and 16.
> It is known in the art that
> all intracellular
> organelles, for example,
> nuclei 24 and 26 of
> sub-cells 14 and 16,
> respectively, are
> polarizable and, thus, such
> intracellular organelles are
> electrically forced in the
> direction of the bridge 22.
> Since the movement is always
> from lower density currents
> to the higher 
> density currents,
> regardless of the field
> polarity, the forces
> applied by the alternating
> electric field to
> organelles, such as nuclei
> 24 and 26, are always in
> the direction of bridge
> 22. A comprehensive
> description of such forces
> and the resulting movement
> of macromolecules of
> intracellular organelles,
> a phenomenon referred to
> as "dielectrophoresis" is
> described extensively in
> literature, e. g., in C.
> L. Asbury & G. van den
> Engh, Biophys. J. 74,
> 1024-1030, 1998, the
> disclosure of which is
> hereby incorporated by
> reference in its entirety.  
>   
>  [0078] The movement
> of the organelles 24 and
> 26 towards the bridge 22
> disrupts the structure of
> the dividing cell, change
> the concentration of the
> various cell constituents
> and, eventually, the
> pressure of the converging
> organelles on bridge
> membrane 22 results in the
> breakage of cell membrane
> 11 at the vicinity of the
> bridge 22, as shown
> schematically in FIG. 3C.
> The ability to break
> membrane 11 at bridge 22
> and to otherwise disrupt
> the cell structure and
> organization can be
> enhanced by applying a
> pulsating AC electric
> field, rather than a
> steady AC field. When a
> pulsating field is
> applied, the forces acting
> on organelles 24 and 26
> have a "hammering" effect,
> whereby pulsed forces beat
> on the intracellular
> organelles towards the
> neck 22 from both
> sub-cells 14 and 16,
> thereby increasing the
> probability of breaking
> cell membrane 11 in the
> vicinity of neck 22.  
>   
>  [0079] A very
> important element, which
> is very susceptible to the
> special fields that
> develop within the
> dividing cells is the
> microtubule spindle that
> plays a major role in the
> division process. In FIG.
> 4, a dividing cell 10 is
> illustrated, at an earlier
> stage as compared to FIGS.
> 3A and 3B, under the
> influence of external TC
> fields (e. g., alternating
> fields in the frequency
> range of about 100 KHz to
> about 300 KHz), generally
> indicated as lines 100,
> with a corresponding
> spindle mechanism
> generally indicated at
> 120. The lines 120 are
> microtubules that are
> known to have a very
> strong dipole moment. This
> strong polarization makes
> the tubules, as well as
> other polar macromolecules
> and especially those that
> have a specific
> orientation within the
> cells or its surrounding,
> susceptible to electric
> fields. Their positive
> charges are located at the
> two centrioles while two
> sets of negative poles are
> at the center of the
> dividing cell and the
> other pair is at the
> points of attachment of
> the microtubules to the
> cell membrane, generally
> indicated at 130. This
> structure forms sets of
> double dipoles and
> therefore they are
> susceptible to fields of
> different directions. It
> will be understood that
> the effect of the TC
> fields on the dipoles does
> not depend on the
> formation of the bridge
> (neck) and thus, the
> dipoles are influenced by
> the TC fields prior to the
> formation of the bridge
> (neck).  
>   
>  [0080]
> Since the present
> apparatus (as will be
> described in greater
> detail below) utilizes
> insulated electrodes,
> the above-mentioned
> negative effects
> obtained when conductive
> electrodes are used, i.
> e., ion concentration
> changes in the cells and
> the formation of harmful
> agents by electrolysis,
> do not occur when the
> present apparatus is
> used. This is because,
> in general, no actual
> transfer of charges
> takes place between the
> electrodes and the
> medium and there is no
> charge flow in the
> medium where the
> currents are capacitive,
> i. e., are expressed
> only as rotation of
> charges, etc.  
>   
>  [0081] Turning now
> to FIG. 5, the TC fields
> described above that
> have been found to
> advantageously destroy
> tumor cells are
> generated by an
> electronic apparatus
> 200. FIG. 5 is a simple
> schematic diagram of the
> electronic apparatus 200
> illustrating the major
> components thereof. The
> electronic apparatus 200
> generates the desired
> electric signals (TC
> signals) in the shape of
> waveforms or trains of
> pulses. The apparatus
> 200 includes a generator
> 210 and a pair of
> conductive leads 220
> that are attached at one
> end thereof to the
> generator 210. The
> opposite ends of the
> leads 220 are connected
> to insulated conductors
> 230 that are activated
> by the electric signals
> (e. g., waveforms). The
> insulated conductors 230
> are also referred to
> hereinafter as isolects
> 230. Optionally and
> according to another
> exemplary embodiment,
> the apparatus 200
> includes a temperature
> sensor 240 and a control
> box 250 which are both
> added to control the
> amplitude of the
> electric field generated
> so as not to generate
> excessive heating in the
> area that is treated.  
>   
>  [0082] The
> generator 210 generates
> an alternating voltage
> waveform at frequencies
> in the range from about
> 50 KHz to about 500 KHz
> (preferably from about
> 100 KHz to about 300
> KHz) (i. e., the TC
> fields). The required
> voltages are such that
> the electric field
> intensity in the tissue
> to be treated is in the
> range of about 0.1 V/cm
> to about 10 V/cm. To
> achieve this field, the
> actual potential
> difference between the
> two conductors in the
> isolects 230 is
> determined by the
> relative impedances of
> the system components,
> as described below.  
>   
>  [0083] When the
> control box 250 is
> included, it controls
> the output of the
> generator 210 so that it
> will remain constant at
> the value preset by the
> user or the control box
> 250 sets the output at
> the maximal value that
> does not cause excessive
> heating, or the control
> box 250 issues a warning
> or the like when the
> temperature (sensed by
> temperature sensor 240)
> exceeds a preset limit.  
>   
>  [0084] The leads
> 220 are standard
> isolated conductors with
> a flexible metal shield,
> preferably grounded so
> that it prevents the
> spread of the electric
> field generated by the
> leads  220. The
> isolects 230 have
> specific shapes and
> positioning so as to
> generate an electric
> field of the desired
> configuration,
> direction and
> intensity at the
> target volume and only
> there so as to focus
> the treatment.  
>   
>  [0085] The
> specifications of the
> apparatus 200 as a
> whole and its
> individual components
> are largely influenced
> by the fact that at
> the frequency of the
> present TC fields (50
> KHz-500 KHz), living
> systems behave
> according to their
> "Ohmic", rather than
> their dielectric
> properties. The only
> elements in the
> apparatus 200 that
> behave differently are
> the insulators of the
> isolects 230 (see
> FIGS. 7-9). The
> isolects 200 consist
> of a conductor in
> contact with a
> dielectric that is in
> contact with the
> conductive tissue thus
> forming a capacitor.  
>   
>  [0086] The
> details of the
> construction of the
> isolects 230 is based
> on their electric
> behavior that can be
> understood from their
> simplified electric
> circuit when in
> contact with tissue as
> generally illustrated
> in FIG. 6. In the
> illustrated
> arrangement, the
> potential drop or the
> electric field
> distribution between
> the different
> components is
> determined by their
> relative electric
> impedance, i. e., the
> fraction of the field
> on each component is
> given by the value of
> its impedance divided
> by the total circuit
> impedance. For
> example, the potential
> drop on element A
> VA=A/(A+B+C+D+E).
> Thus, for DC or low
> frequency AC,
> practically all the
> potential drop is on
> the capacitor (that
> acts as an insulator).
> For relatively very
> high frequencies, the
> capacitor practically
> is a short and
> therefore, practically
> all the field is
> distributed in the
> tissues. At the
> frequencies of the
> present TC fields (e.
> g., 50 KHz to 500
> KHz), which are
> intermediate
> frequencies, the
> impedance of the
> capacitance of the
> capacitors is dominant
> and determines the
> field distribution.
> Therefore, in order to
> increase the effective
> voltage drop across
> the tissues (field
> intensity), the
> impedance of the
> capacitors is to be
> decreased (i. e.,
> increase their
> capacitance). This can
> be achieved by
> increasing the
> effective area of the
> "plates" of the
> capacitor, decrease
> the thickness of the
> dielectric or use a
> dielectric with high
> dielectric constant.   
>   
> [0087] In order to
> optimize the field
> distribution, the
> isolects 230 are
> configured differently
> depending upon the
> application in which
> the isolects 230 are
> to be used. There are
> two principle modes
> for applying the
> present electric
> fields (TC fields).
> First, the TC fields
> can be applied by
> external isolects and
> second, the TC fields
> can be applied by
> internal isolects.  
>   
>  [0088]
> Electric fields (TC
> fields) that are
> applied by external
> isolects can be of a
> local type or widely
> distributed type.
> The first type
> includes, for
> example, the
> treatment of skin
> tumors and treatment
> of lesions close to
> the skin surface.
> FIG. 7 illustrates
> an exemplary
> embodiment where the
> isolects 230 are
> incorporated in a
> skin patch 300. The
> skin patch 300 can
> be a self-adhesive
> flexible patch with
> one or more pairs of
> isolects 230. The
> patch 300 includes
> internal insulation
> 310 (formed of a
> dielectric material)
> and the external
> insulation 260 and
> is applied to skin
> surface 301 that
> contains a tumor 303
> either on the skin
> surface 301 or
> slightly below the
> skin surface 301.
> Tissue is generally
> indicated at 305. To
> prevent the
> potential drop
> across the internal
> insulation 310 to
> dominate the system,
> the internal
> insulation 310 must
> have a relatively
> high capacity. This
> can be achieved by a
> large surface area;
> however, this may
> not be desired as it
> will result in the
> spread of the field
> over a large area
> (e. g., an area
> larger than required
> to treat the tumor).
> Alternatively, the
> internal insulation
> 310 can be made very
> thin and/or the
> internal insulation
> 310 can be of a high
> dielectric constant.
> As the skin
> resistance between
> the electrodes
> (labeled as A and E
> in FIG. 6) is
> normally
> significantly higher
> than that of the
> tissue (labeled as C
> in FIG. 6)
> underneath it (1-10
> K# vs. 0.1-1 K#),
> most of the
> potential drop
> beyond the isolects
> occurs there. To
> accommodate for
> these impedances
> (Z), the
> characteristics of
> the internal
> insulation 310
> (labeled as B and D
> in FIG. 6) should be
> such that they have
> impedance preferably
> under 100 K# at the
> frequencies of the
> present TC fields
> (e. g., 50 KHz to
> 500 KHz). For
> example, if it is
> desired for the
> impedance to be
> about 10 K Ohms or
> less, such that over
> 1% of the applied
> voltage falls on the
> tissues, for
> isolects with a
> surface area of 10
> mm, at frequencies
> of 200 KHz, the
> capacity should be
> on the order of
> 10-10 F. , which
> means that using
> standard insulations
> with a dielectric
> constant of 2-3, the
> thickness of the
> insulating layer 310
> should be about
> 50-100 microns. An
> internal field 10
> times stronger would
> be obtained with
> insulators with a
> dielectric constant
> of about 20-50.  
>   
>  [0089] Using
> an insulating
> material with a high
> dielectric constant
> increases the
> capacitance of the
> electrodes, which
> results in a
> reduction of the
> electrodes'
> impedance to the AC
> signal that is
> applied by the
> generator 1 (shown
> in FIG. 5). Because
> the electrodes A, E
> are wired in series
> with the target
> tissue C, as shown
> in FIG. 6, this
> reduction in
> impedance reduces
> the voltage drop in
> the electrodes, so
> that a larger
> portion of the
> applied AC voltage
> appears across the
> tissue C. Since a
> larger portion of
> the voltage appears
> across the tissue,
> the voltage that is
> being applied by the
> generator 1 can be
> advantageously
> lowered for a given
> field strength in
> the tissue.  
>   
>  [0090] The
> desired field
> strength in the
> tissue being
> treated is
> preferably between
> about 0.1 V/cm and
> about 10 V/cm, and
> more preferably
> between about 2
> V/cm and 3 V/cm or
> between about 1
> V/cm and about 5
> V/cm. If the
> dielectric
> constant used in
> the electrode is
> sufficiently high,
> the impedance of
> the electrodes A,
> E drops down to
> the same order of
> magnitude as the
> series combination
> of the skin and
> tissue B, C, D.
> One example of a
> suitable material
> with an extremely
> high dielectric
> constant is
> CaCu3Ti4O12, which
> has a dielectric
> constant of about
> 11,000 (measured
> at 100 kHz). When
> the dielectric
> constant is this
> high, useful
> fields can be
> obtained using a
> generator voltage
> that is on the
> order of a few
> tens of Volts.  
>   
>  [0091] Since
> the thin
> insulating layer
> can be very
> vulnerable, etc. ,
> the insulation can
> be replaced by
> very high
> dielectric
> constant
> insulating
> materials, such as
> titanium dioxide
> (e. g., rutile),
> the dielectric
> constant can reach
> values of about
> 200. There a
> number of
> different
> materials that are
> suitable for use
> in the intended
> application and
> have high
> dielectric
> constants. For
> example, some
> materials include:
> lithium niobate
> (LiNb03), which is
> a ferroelectric
> crystal and has a
> number of
> applications in
> optical,
> pyroelectric and
> piezoelectric
> devices; yttrium
> iron garnet (YIG)
> is a ferromagnetic
> crystal and
> magneto- optical
> devices, e. g.,
> optical isolator
> can be realized
> from this
> material; barium
> titanate (BaTi03)
> is a ferromagnetic
> crystal with a
> large
> electro-optic
> effect; potassium
> tantalate (KTa03)
> which is a
> dielectric crystal
> (ferroelectric at
> low temperature)
> and has very low
> microwave loss and
> tunability of
> dielectric
> constant at low
> temperature; and
> lithium tantalate
> (LiTa03) which is
> a ferroelectric
> crystal with
> similar properties
> as lithium niobate
> and has utility in
> electro-optical,
> pyroelectric and
> piezoelectric
> devices. Insulator
> ceramics with high
> dielectric
> constants may also
> be used, such as a
> ceramic made of a
> combination of
> Lead Magnesium
> Niobate and Lead
> Titanate. It will
> be understood that
> the aforementioned
> exemplary
> materials can be
> used in
> combination with
> the present device
> where it is
> desired to use a
> material having a
> high dielectric
> constant.  
>   
>  [0092] One
> must also consider
> another factor
> that affects the
> effective capacity
> of the isolects
> 230, namely the
> presence of air
> between the
> isolects 230 and
> the skin. Such
> presence, which is
> not easy to
> prevent,
> introduces a layer
> of an insulator
> with a dielectric
> constant of 1.0, a
> factor that
> significantly
> lowers the
> effective capacity
> of the isolects
> 230 and
> neutralizes the
> advantages of the
> titanium dioxide
> (rutile), etc. To
> overcome this
> problem, the
> isolects 230 can
> be shaped so as to
> conform with the
> body structure
> and/or (2) an
> intervening filler
> 270 (as
> illustrated in
> FIG. 10C), such as
> a gel, that has
> high conductance
> and a high
> effective 
> dielectric
> constant, can be
> added to the
> structure. The
> shaping can be
> pre-structured
> (see FIG. 10A)
> or the system
> can be made
> sufficiently
> flexible so that
> shaping of the
> isolects 230 is
> readily
> achievable. The
> gel can be
> contained in
> place by having
> an elevated rim
> as depicted in
> FIGS. 10C and
> 10C'. The gel
> can be made of
> hydrogels,
> gelatins, agar,
> etc. , and can
> have salts
> dissolved in it
> to increase its
> conductivity.
> FIGS. 10A-10C'
> illustrate
> various
> exemplary
> configurations
> for the isolects
> 230. The exact
> thickness of the
> gel is not
> important so
> long as it is of
> sufficient
> thickness that
> the gel layer
> does not dry out
> during the
> treatment. In
> one exemplary
> embodiment, the
> thickness of the
> gel is about 0.5
> mm to about 2
> mm. Preferably,
> the gel has high
> conductivity, is
> tacky, and is
> biocompatible
> for extended
> periods of time.
> One suitable gel
> is AG603
> Hydrogel, which
> is available
> from AmGel
> Technologies,
> 1667 S. Mission
> Road, Fallbrook,
> CA 92028-4115,
> USA.  
>   
>  [0093] In
> order to achieve
> the desirable
> features of the
> isolects 230,
> the dielectric
> coating of each
> should be very
> thin, for
> example from
> between 1-50
> microns. Since
> the coating is
> so thin, the
> isolects 230 can
> easily be
> damaged
> mechanically or
> undergo
> dielectric
> breakdown. This
> problem can be
> overcome by
> adding a
> protective
> feature to the
> isolect's
> structure so as
> to provide
> desired
> protection from
> such damage. For
> example, the
> isolect 230 can
> be coated, for
> example, with a
> relatively loose
> net 340 that
> prevents access
> to the surface
> but has only a
> minor effect on
> the effective
> surface area of
> the isolect 230
> (i. e., the
> capacity of the
> isolects 230
> (cross section
> presented in
> FIG. 12B). The
> loose net 340
> does not effect
> the capacity and
> ensures good
> contact with the
> skin, etc. The
> loose net 340
> can be formed of
> a number of
> different
> materials;
> however, in one
> exemplary
> embodiment, the
> net 340 is
> formed of nylon,
> polyester,
> cotton, etc.
> Alternatively, a
> very thin
> conductive
> coating 350 can
> be applied to
> the dielectric
> portion
> (insulating
> layer) of the
> isolect 230. One
> exemplary
> conductive
> coating is
> formed of a
> metal and more
> particularly of
> gold. The
> thickness of the
> coating 350
> depends upon the
> particular
> application and
> also on the type
> of material used
> to form the
> coating 350;
> however, when
> gold is used,
> the coating has
> a thickness from
> about 0.1 micron
> to about 0.1 mm.
> Furthermore, the
> rim illustrated
> in FIG. 10 can
> also provide
> some mechanical
> protection.  
>   
> [0094] However,
> the capacity is
> not the only
> factor to be
> considered. The
> following two
> factors also
> influence how
> the isolects 230
> are constructed.
> The dielectric
> strength of the
> internal
> insulating layer
> 310 and the
> dielectric
> losses that
> occur when it is
> subjected to the
> TC field, i. e.,
> the amount of
> heat generated.
> The dielectric
> strength of the
> internal
> insulation 310
> determines at
> what field
> intensity the
> insulation will
> be "shorted" and
> cease to act as
> an intact 
> insulation.
> Typically,
> insulators,
> such as
> plastics, have
> dielectric
> strength
> values of
> about 100V per
> micron or
> more. As a
> high
> dielectric
> constant
> reduces the
> field within
> the internal
> insulator 310,
> a combination
> of a high
> dielectric
> constant and a
> high
> dielectric
> strength gives
> a significant
> advantage.
> This can be
> achieved by
> using a single
> material that
> has the
> desired
> properties or
> it can be
> achieved by a
> double layer
> with the
> correct
> parameters and
> thickness. In
> addition, to
> further
> decreasing the
> possibility
> that the
> insulating
> layer 310 will
> fail, all
> sharp edges of
> the insulating
> layer 310
> should be
> eliminated as
> by rounding
> the comers,
> etc., as
> illustrated in
> FIG. 10D using
> conventional
> techniques.  
>   
>  [0095]
> FIGS. 8 and 9
> illustrate a
> second type of
> treatment
> using the
> isolects 230,
> namely
> electric field
> generation by
> internal
> isolects 230.
> A body to
> which the
> isolects 230
> are implanted
> is generally
> indicated at
> 311 and
> includes a
> skin surface
> 313 and a
> tumor 315. In
> this
> embodiment,
> the isolects
> 230 can have
> the shape of
> plates, wires
> or other
> shapes that
> can be
> inserted
> subcutaneously
> or a deeper
> location
> within the
> body 311 so as
> to generate an
> appropriate
> field at the
> target area
> (tumor 315).  
>   
>  [0096]
> It will also
> be appreciated
> that the mode
> of isolects
> application is
> not restricted
> to the above
> descriptions.
> In the case of
> tumors in
> internal
> organs, for
> example,
> liver, lung,
> etc. , the
> distance
> between each
> member of the
> pair of
> isolects 230
> can be large.
> The pairs can
> even by
> positioned
> opposite sides
> of a torso
> 410, as
> illustrated in
> FIG. 11. The
> arrangement of
> the isolects
> 230 in FIG. 11
> is
> particularly
> useful for
> treating a
> tumor 415
> associated
> with lung
> cancer or
> gastro-intestinal
> tumors. In
> this
> embodiment,
> the electric
> fields (TC
> fields) spread
> in a wide
> fraction of
> the body.  
>   
>  [0097]
> In order to
> avoid
> overheating of
> the treated
> tissues, a
> selection of
> materials and
> field
> parameters is
> needed. The
> isolects
> insulating
> material
> should have
> minimal
> dielectric
> losses at the
> frequency
> ranges to be
> used during
> the treatment
> process. This
> factor can be
> taken into
> consideration
> when choosing
> the particular
> frequencies
> for the
> treatment. The
> direct heating
> of the tissues
> will most
> likely be
> dominated by
> the heating
> due to current
> flow (given by
> the I\*R
> product). In
> addition, the
> isolect
> (insulated
> electrode) 230
> and its
> surroundings
> should be made
> of materials
> that
> facilitate
> heat losses
> and its
> general
> structure
> should also
> facilitate
> head losses,
> i. e., minimal
> structures
> that block
> heat
> dissipation to
> the
> surroundings
> (air) as well
> as high heat
> conductivity.
> Using larger
> electrodes
> also minimizes
> the local
> sensation of
> heating, since
> it spreads the
> energy that is
> being
> transferred
> into the  patient
> over a larger
> surface area.
> Preferably,
> the heating is
> minimized to
> the point
> where the
> patient's skin
> temperature
> never exceeds
> about 39 C.
> [0098] Another
> way to reduce
> heating is to
> apply the
> field to the
> tissue being
> treated
> intermittently,
> by applying a
> field with a
> duty cycle
> between about
> 20% and about
> 50% instead of
> using a
> continuous
> field. For
> example, to
> achieve a duty
> cycle of 33%,
> the field
> would be
> repetitively
> switched on
> for one
> second, then
> switched off
> for two
> seconds.
> Preliminary
> experiments
> have shown
> that the
> efficacy of
> treatment
> using a field
> with a 33%
> duty cycle is
> roughly the
> same as for a
> field with a
> duty cycle of
> 100%. In
> alternative
> embodiments,
> the field
> could be
> switched on
> for one hour
> then switched
> off for one
> hour to
> achieve a duty
> cycle of 50%.
> Of course,
> switching at a
> rate of once
> per hour would
> not help
> minimize
> short-term
> heating. On
> the other
> hand, it could
> provide the
> patient with a
> welcome break
> from
> treatment.  
>   
>  [0099]
> The
> effectiveness
> of the
> treatment can
> be enhanced by
> an arrangement
> of isolects
> 230 that
> focuses the
> field at the
> desired target
> while leaving
> other
> sensitive
> areas in low
> field density
> (i. e.,
> protected
> areas). The
> proper
> placement of
> the isolects
> 230 over the
> body can be
> maintained
> using any
> number of
> different
> techniques,
> including
> using a
> suitable piece
> of clothing
> that keeps the
> isolects at
> the
> appropriate
> positions.
> FIG. 13
> illustrates
> such an
> arrangement in
> which an area
> labeled as "P"
> represents a
> protected
> area. The
> lines of field
> force do not
> penetrate this
> protected area
> and the field
> there is much
> smaller than
> near the
> isolects 230
> where target
> areas can be
> located and
> treated well.
> In contrast,
> the field
> intensity near
> the four poles
> is very high.  
>   
>  [00100]
> The following
> Example serves
> to illustrate
> an exemplary
> application of
> the present
> apparatus and
> application of
> TC fields;
> however, this
> Example is not
> limiting and
> does not limit
> the scope of
> the present
> invention in
> any way.
> EXAMPLE
> [00101] To
> demonstrate
> the
> effectiveness
> of electric
> fields having
> the above
> described
> properties (e.
> g.,
> frequencies
> between 50 KHz
> and 500 KHz)
> in destroying
> tumor cells,
> the electric
> fields were
> applied to
> treat mice
> with malignant
> melanoma
> tumors. Two
> pairs of
> isolects 230
> were
> positioned
> over a
> corresponding
> pair of
> malignant
> melanomas.
> Only one pair
> was connected
> to the
> generator 210
> and 200 KHz
> alternating
> electric
> fields (TC
> fields)  were
> applied to the
> tumor for a
> period of 6
> days. One
> melanoma tumor
> was not
> treated so as
> to permit a
> comparison
> between the
> treated tumor
> and the
> non-treated
> tumor. After
> treatment for
> 6 days, the
> pigmented
> melanoma tumor
> remained
> clearly
> visible in the
> non-treated
> side of the
> mouse, while,
> in contrast,
> no tumor is
> seen on the
> treated side
> of the mouse.
> The only areas
> that were
> visible
> discemable on
> the skin were
> the marks that
> represented
> the points of
> insertion of
> the isolects
> 230. The fact
> that the tumor
> was eliminated
> at the treated
> side was
> further
> demonstrated
> by cutting and
> inversing the
> skin so that
> its inside
> face was
> exposed. Such
> a procedure
> indicated that
> the tumor has
> been
> substantially,
> if not
> completely,
> eliminated on
> the treated
> side of the
> mouse. The
> success of the
> treatment was
> also further
> verified by
> histopathological
> examination.  
>   
>  [00102]
> The present
> inventor has
> thus uncovered
> that electric
> fields having
> particular
> properties can
> be used to
> destroy
> dividing cells
> or tumors when
> the electric
> fields are
> applied to
> using an
> electronic
> device. More
> specifically,
> these electric
> fields fall
> into a special
> intermediate
> category,
> namely
> bio-effective
> fields that
> have no
> meaningful
> stimulatory
> and no thermal
> effects, and
> therefore
> overcome the
> disadvantages
> that were
> associated
> with the
> application of
> conventional
> electric
> fields to a
> body. It will
> also be
> appreciated
> that the
> present
> apparatus can
> further
> include a
> device for
> rotating the
> TC field
> relative to
> the living
> tissue. For
> example and
> according to
> one
> embodiment,
> the
> alternating
> electric
> potential
> applies to the
> tissue being
> treated is
> rotated
> relative to
> the tissue
> using
> conventional
> devices, such
> as a
> mechanical
> device that
> upon
> activation,
> rotates
> various
> components of
> the present
> system.   
>   
> [00103]
> Moreover and
> according to
> yet another
> embodiment,
> the TC fields
> are applied to
> different
> pairs of the
> insulated
> electrodes 230
> in a
> consecutive
> manner. In
> other words,
> the generator
> 210 and the
> control system
> thereof can be
> arranged so
> that signals
> are sent at
> periodic
> intervals to
> select pairs
> of insulated
> electrodes
> 230, thereby
> causing the
> generation of
> the TC fields
> of different
> directions by
> these
> insulated
> electrodes
> 230. Because
> the signals
> are sent at
> select times
> from the
> generator to
> the insulated
> electrodes
> 230, the TC
> fields of
> changing
> directions are
> generated
> consecutively
> by different
> insulated
> electrodes
> 230. This
> arrangement
> has a number
> of advantages
> and is
> provided in
> view of the
> fact that the
> TC fields have
> maximal effect
> when they are
> parallel to
> the axis of
> cell division.
> Since the
> orientation of
> cell division
> is in most
> cases random,
> only a
> fraction of
> the dividing
> cells are
> affected by
> any given
> field. Thus,
> using fields
> of two or more
> orientations
> increases the
> effectiveness
> since it
> increases the
> chances that
> more dividing
> cells are
> affected by a
> given TC
> field.  
>   
>  [00104]
> In vitro
> experiments
> have shown
> that the
> electric field
> has the
> maximum
> killing effect
> when the lines
> of force of
> the field are
> oriented
> generally
> parallel to
> the long axis
> of the
> hourglass-shaped
> cell during
> mitosis (as
> shown in FIGS.
> 3A-3C). In one
> experiment, a
> much higher
> proportion of
> the damaged
> cells had
> their axis of
> division
> oriented along
> the field: 56%
> of the cells
> oriented at or
> near 0 with
> respect to the
> field were
> damaged,
> versus an
> average of 15%
> of cells
> damaged for
> cells with
> their long
> axis oriented
> at more than
> 22 with
> respect to the
> field.  
>   
>  [00105]
> The inventor
> has recognized
> that applying
> the field in
> different
> directions
> sequentially
> will increase
> the overall
> killing power,
> because the
> field
> orientation
> that is most
> effectively in
> killing
> dividing cells
> will be
> applied to a
> larger
> population of
> the dividing
> cells. A
> number of
> examples for
> applying the
> field in
> different
> directions are
> discussed
> below.  
>   
>  [00106]
> FIGS. 27A,
> 27B, and 27C
> show a set of
> 6 electrodes
> E1-E6, and how
> the direction
> of the field
> through the
> target tissue
> 1510 can be
> changed by
> applying the
> AC signal from
> the generator
> 1 (shown in
> FIG. 1) across
> different
> pairs of
> electrodes.
> For example,
> if the AC
> signal is
> applied across
> electrodes El
> and E4, the
> field lines F
> would be
> vertical (as
> shown in FIG.
> 27A), and if
> the signal is
> applied across
> electrodes E2
> and E5, or
> across
> electrodes E3
> and E6, the
> field lines F
> would be
> diagonal (as
> shown in FIGS.
> 27B and 27C,
> respectively).
> Additional
> field
> directions can
> be obtained by
> applying the
> AC signal
> across other
> pairs of
> electrodes.
> For example, a
> roughly
> horizontal
> field could be
> obtained by
> applying the
> signal across
> electrodes E2
> and E6.  
>   
>  [00107]
> In one
> embodiment,
> the AC signal
> is applied
> between the
> various pairs
> of electrodes
> sequentially.
> An example of
> this
> arrangement is
> to apply the
> AC signal
> across
> electrodes E1
> and E4 for one
> second, then
> apply the AC
> signal across
> electrodes E2
> and E5 for one
> second, and
> then apply the
> AC signal
> across
> electrodes E3
> and E6 for one
> second. This
> three-part
> sequence is
> then repeated
> for the
> desired period
> of treatment.
> Because the
> efficacy in
> cell-destruction
> is strongly
> dependant on
> the cell's
> orientation,
> cycling the
> field between
> the different
> directions
> increases the
> chance that
> the field will
> be oriented in
> a direction
> that favors
> cell
> destruction at
> least part of
> the time.   
>   
> [00108] Of
> course, the 6
> electrode
> configuration
> shown in FIGS.
> 27A-C is just
> one of many
> possible
> arrangement of
> multiple
> electrodes,
> and many other
> configurations
> of three or
> more
> electrodes
> could be used
> based on the
> same
> principles.  
>   
>  [00109]
> Application of
> the field in
> different
> directions
> sequentially
> is not limited
> to two
> dimensional
> embodiments,
> and FIG. 28
> shows how the
> sequential
> application of
> signals across
> different sets
> of electrodes
> can be
> extended to
> three
> dimensions. A
> first array of
> electrodes
> Al-A9 is
> arranged
> around body
> part 1500, and
> a last array
> of electrodes
> N1-N9 is
> arranged
> around the
> body part 1500
> a distance W
> away from the
> first array.
> Additional
> arrays of
> electrodes may
> optionally be
> added between
> the first
> array and the
> last array,
> but these
> additional
> arrays are not
> illustrated
> for clarity
> (so as not to
> obscure the
> electrodes A5-
> A9 and B5-B8
> on the back of
> the body part
> 1500).  
>   
>  [00110]
> As in the FIG.
> 27 embodiment,
> the direction
> of the field
> through the
> target tissue
> can be changed
> by applying
> the AC signal
> from the
> generator 1
> (shown in FIG.
> 1) across
> different
> pairs of
> electrodes.
> For example,
> applying the
> AC signal
> between
> electrodes A2
> and A7 would
> result in a
> field in a
> front-to-back
> direction
> between those
> two
> electrodes,
> and applying
> the AC signal
> between
> electrodes A5
> and A9 would
> result in a
> roughly
> vertical field
> between those
> two
> electrodes.
> Similarly,
> applying the
> AC signal
> across
> electrodes A2
> and N7 would
> generate
> diagonal field
> lines in one
> direction
> through the
> body part
> 1500, and
> applying the
> AC signal
> across
> electrodes A2
> and B7 would
> generate
> diagonal field
> lines in
> another
> direction
> through the
> body part.  
>   
>  [00111]
> Using a
> three-dimensional
> array of
> electrodes
> also makes it
> possible to
> energize
> multiple pairs
> of electrodes
> simultaneously
> to induce
> fields in the
> desired
> directions.
> For example,
> if suitable
> switching is
> provided so
> that
> electrodes A2
> through N2 are
> all connected
> to one
> terminal of
> the generator,
> and so that
> electrodes A7
> through N7 are
> all connected
> to the other
> terminal of
> the generator,
> the resulting
> field would be
> a sheet that
> extends in a
> front-to-back
> direction for
> the entire
> width W. After
> the
> front-to-back
> field is
> maintained for
> a suitable
> duration (e.
> g., one
> second), the
> switching
> system (not
> shown) is
> reconfigured
> to connect
> electrodes A3
> through N3 to
> one terminal
> of the
> generator, and
> electrodes A8
> through N8 to
> the other
> terminal of
> the generator.
> This results
> in a sheet-
> shaped field
> that is
> rotated about
> the Z axis by
> about 40 with
> respect to the
> initial field
> direction.
> After the
> field is
> maintained in
> this direction
> for a suitable
> duration (e.
> g., one
> second), the
> next set of
> electrodes is
> activated to
> rotate the
> field an
> additional 40
> to its next
> position. This
> continues
> until the
> field returns
> to its initial
> position, at
> which point
> the whole
> process is
> repeated.  
>   
>  [00112]
> Optionally,
> the rotating
> sheet-shaped
> field may be
> added
> (sequentially
> in time) to
> the diagonal
> fields
> described
> above, to
> better target
> cells that are
> oriented along
> those diagonal
> axes.  
>   
>  [00113]
> Because the
> electric field
> is a vector,
> the signals
> may optionally
> be applied to
> combinations
> of electrodes
> simultaneously
> in order to
> form a desired
> resultant
> vector. For
> example, a
> field that is
> rotated about
> the X axis by
> 20 with
> respect to the
> initial
> position can
> be obtained by
> switching
> electrodes A2
> through N2 and
> A3 through N3
> all to one
> terminal of
> the generator,
> and switching
> electrodes A7
> through N7 and
> A8 through N8
> all to the
> other terminal
> of the
> generator.
> Applying the
> signals to
> other
> combinations
> of electrodes
> will result in
> fields in
> other
> directions, as
> will be
> appreciated by
> persons
> skilled in the
> relevant arts.
> If appropriate
> computer
> control of the
> voltages is
> implemented,
> the field's
> direction can
> even be swept
> through space
> in a
> continuous (i.
> e., smooth)
> manner, as
> opposed to the
> stepwise
> manner
> described
> above.  
>   
>  [00114]
> FIGS. 29A and
> 29B depict the
> results of in
> vitro
> experiments
> that show how
> the killing
> power of the
> applied field
> against
> dividing cells
> is a function
> of the field
> strength. In
> the FIG. 29A
> experiment,
> B16F1 melanoma
> cells were
> subjected to a
> 100 kHz AC
> field at
> different
> field
> strengths, for
> a period of 24
> hours at each
> strength. In
> the FIG. 29B
> experiment,
> F-98 glioma
> cells were
> subjected to a
> 200 kHz AC
> field at
> different
> field
> strengths, for
> a period of 24
> hours at each
> strength. In
> both of these
> figures, the
> strength of
> the field (EF)
> is measured in
> Volts per cm.
> The magnitude
> of the killing
> effect is
> expressed in
> terms of TER,
> which is which
> is the ratio
> of the
> decrease in
> the growth
> rate of
> treated cells
> (GRT) compared
> with the
> growth rate of
> control cells
> (GRc). EMI29.1
> The
> experimental
> results show
> that the
> inhibitory
> effect of the
> applied field
> on
> proliferation
> increases with
> intensity in
> both the
> melanoma and
> the glioma
> cells.
> Complete
> proliferation
> arrest (TER =
> 1) is seen at
> 1.35 and 2.25
> V/cm in
> melanoma and
> glioma cells,
> respectively.  
>   
>  [00115]
> FIGS. 30A and
> 30B depict the
> results of in
> vitro
> experiments
> that show how
> the killing
> power of the
> applied field
> is a function
> of the
> frequency of
> the field. In
> the 
> experiments,
> B16F1 melanoma
> cells (FIG.
> 30A) and F-98
> glioma cells
> (FIG. 30B)
> were subjected
> to fields with
> different
> frequencies,
> for a period
> of 24 hours at
> each
> frequency.
> FIGS. 30A and
> 30B show the
> change in the
> growth rate,
> normalized to
> the field
> intensity
> (TER/EF). Data
> are shown as
> mean + SE. In
> FIG. 30A, a
> window effect
> is seen with
> maximal
> inhibition at
> 120 kHz in
> melanoma
> cells. In FIG.
> 30B, two peaks
> are seen at
> 170 and 250
> kHz. Thus, if
> only one
> frequency is
> available
> during an
> entire course
> of treatment,
> a field with a
> frequency of
> about 120 kHz
> would be
> appropriate
> for destroying
> melanoma
> cells, and a
> field with a
> frequency on
> the order of
> 200 kHz would
> be appropriate
> for destroying
> glioma cells.  
>   
>  [00116]
> Not all the
> cells of any
> given type
> will have the
> exact same
> size. Instead,
> the cells will
> have a
> distribution
> of sizes, with
> some cells
> being smaller
> and some cells
> being larger.
> It is believed
> that the best
> frequency for
> damaging a
> particular
> cell is
> related to the
> physical
> characteristics
> (e. g., the
> size) of that
> particular
> cell. Thus, to
> best damage a
> population of
> cells with a
> distribution
> of sizes, it
> can be
> advantageous
> to apply a
> distribution
> of different
> frequencies to
> the
> population,
> where the
> selection of
> frequencies is
> optimized
> based on the
> expected size
> distribution
> of the target
> cells. For
> example, the
> data on FIG.
> 30B indicates
> that using two
> frequencies of
> 170 kHz and
> 250 kHz to
> destroy a
> population of
> glioma cells
> would be more
> effective than
> using a single
> frequency of
> 200 kHz.  
>   
>  [00117]
> Note that the
> optimal field
> strengths and
> frequencies
> discussed
> herein were
> obtained based
> on in vitro
> experiments,
> and that the
> corresponding
> parameters for
> in vivo
> applications
> may be
> obtained by
> performing
> similar
> experiments in
> vivo. It is
> possible that
> relevant
> characteristics
> of the cell
> itself (such
> as size and/or
> shape) or
> interactions
> with the
> cell's
> surroundings
> may result in
> a different
> set of optimal
> frequencies
> and/or field
> strengths for
> in vivo
> applications.  
>   
>  [00118]
> When more than
> one frequency
> is used, the
> various
> frequencies
> may be applied
> sequentially
> in time. For
> example, in
> the case of
> glioma, field
> frequencies of
> 100, 150,170,
> 200,250, and
> 300 kHz may be
> applied during
> the first,
> second, third,
> fourth, fifth,
> and sixth
> minutes of
> treatment,
> respectively.
> That cycle of
> frequencies
> would then
> repeat during
> each
> successive six
> minutes of
> treatment.
> Alternatively,
> the frequency
> of the field
> may be swept
> in a stepless
> manner from
> 100 to 300
> kHz.  
>   
>  [00119]
> Optionally,
> this frequency
> cycling may be
> combined with
> the
> directional
> cycling
> described
> above. FIG.
> 31A is an
> example of
> such a
> combination
> using three 
> directions
> (D1, D2, and
> D3) and three
> frequencies
> (F1, F2, and
> F3). Of
> course, the
> same scheme
> can be
> extended to
> any other
> number of
> directions
> and/or
> frequencies.
> FIG. 31B is an
> example of
> such a
> combination
> using three
> directions
> (D1, D2, and
> D3), sweeping
> the frequency
> from 100 kHz
> to 300 kHz.
> Note that the
> break in the
> time axis
> between tl and
> t2 provides
> the needed
> time for the
> sweeping
> frequency to
> rise to just
> under 300 kHz.
> The frequency
> sweeping (or
> stepping) may
> be
> synchronized
> with
> directional
> changes, as
> shown in FIG.
> 31A.
> Alternatively,
> the frequency
> sweeping (or
> stepping) may
> be
> asynchronous
> with respect
> to the
> directional
> changes, as
> shown in FIG.
> 31B.   
>   
> [00120] In an
> alternative
> embodiment, a
> signal that
> contains two
> or more
> frequencies
> components
> simultaneously
> (e. g., 170
> kHz and 250
> kHz) is
> applied to the
> electrodes to
> treat a
> populations of
> cells that
> have a
> distribution
> of sizes. The
> various
> signals will
> add by
> superposition
> to create a
> field that
> includes all
> of the applied
> frequency
> components.  
>   
>  [00121]
> Turning now to
> FIG. 14 in
> which an
> article of
> clothing 500
> according to
> one exemplary
> embodiment is
> illustrated.
> More
> specifically,
> the article of
> clothing 500
> is in the form
> of a hat or
> cap or other
> type of
> clothing
> designed for
> placement on a
> head of a
> person. For
> purposes of
> illustration,
> a head 502 is
> shown with the
> hat 500 being
> placed thereon
> and against a
> skin surface
> 504 of the
> head 502. An
> intra-cranial
> tumor or the
> like 510 is
> shown as being
> formed within
> the head 502
> underneath the
> skin surface
> 504 thereof.
> The hat 500 is
> therefore
> intended for
> placement on
> the head 502
> of a person
> who has a
> tumor 510 or
> the like.  
>   
>  [00122]
> Unlike the
> various
> embodiments
> illustrated in
> FIGS. 1-13
> where the
> insulated
> electrodes 230
> are arranged
> in a more or
> less planar
> arrangement
> since they are
> placed either
> on a skin
> surface or
> embedded
> within the
> body
> underneath it,
> the insulated
> electrodes 230
> in this
> embodiment are
> specifically
> contoured and
> arranged for a
> specific
> application.
> The treatment
> of
> intra-cranial
> tumors or
> other lesions
> or the like
> typically
> requires a
> treatment that
> is of a
> relatively
> long duration,
> e. g., days to
> weeks, and
> therefore, it
> is desirable
> to provide as
> much comfort
> as possible to
> the patient.
> The hat 500 is
> specifically
> designed to
> provide
> comfort during
> the lengthy
> treatment
> process while
> not
> jeopardizing
> the
> effectiveness
> of the
> treatment.   
>   
> [00123]
> According to
> one exemplary
> embodiment,
> the hat 500
> includes a
> predetermined
> number of
> insulated
> electrodes 230
> that are
> preferably
> positioned so
> as to produce
> the optimal TC
> fields at the
> location of
> the tumor 510.
> The lines of
> force of the
> TC field are
> generally
> indicated at
> 520. As can be
> seen in FIG.
> 14, the tumor
> 510 is
> positioned  within
> these lines of
> force 520. As
> will be
> described in
> greater detail
> hereinafter,
> the insulated
> electrodes 230
> are positioned
> within the hat
> 500 such that
> a portion or
> surface
> thereof is
> free to
> contact the
> skin surface
> 504 of the
> head 502. In
> other words,
> when the
> patient wears
> the hat 500,
> the insulated
> electrodes 230
> are placed in
> contact with
> the skin
> surface 504 of
> the head 502
> in positions
> that are
> selected so
> that the TC
> fields
> generated
> thereby are
> focused at the
> tumor 510
> while leaving
> surrounding
> areas in low
> density.
> Typically,
> hair on the
> head 502 is
> shaved in
> selected areas
> to permit
> better contact
> between the
> insulated
> electrodes 230
> and the skin
> surface 504;
> however, this
> is not
> critical.  
>   
>  [00124]
> The hat 500
> preferably
> includes a
> mechanism 530
> that applies a
> force to the
> insulated
> electrodes 230
> so that they
> are pressed
> against the
> skin surface
> 502. For
> example, the
> mechanism 530
> can be of a
> biasing type
> that applies a
> biasing force
> to the
> insulated
> electrodes 230
> to cause the
> insulated
> electrodes 230
> to be directed
> outwardly away
> from the hat
> 500. Thus,
> when the
> patient places
> the hat 500 on
> his/her head
> 502, the
> insulated
> electrodes 230
> are pressed
> against the
> skin surface
> 504 by the
> mechanism 530.
> The mechanism
> 530 can
> slightly
> recoil to
> provide a
> comfortable
> fit between
> the insulated
> electrodes 230
> and the head
> 502. In one
> exemplary
> embodiment,
> the mechanism
> 530 is a
> spring based
> device that is
> disposed
> within the hat
> 500 and has
> one section
> that is
> coupled to and
> applies a
> force against
> the insulated
> electrodes
> 230.  
>   
>  [00125]
> As with the
> prior
> embodiments,
> the insulated
> electrodes 230
> are coupled to
> the generator
> 210 by means
> of conductors
> 220. The
> generator 210
> can be either
> disposed
> within the hat
> 500 itself so
> as to provide
> a compact,
> self-sufficient,
> independent
> system or the
> generator 210
> can be
> disposed
> external to
> the hat 500
> with the
> conductors 220
> exiting the
> hat 500
> through
> openings or
> the like and
> then running
> to the
> generator 210.
> When the
> generator 210
> is disposed
> external to
> the hat 500,
> it will be
> appreciated
> that the
> generator 210
> can be located
> in any number
> of different
> locations,
> some of which
> are in close
> proximity to
> the hat 500
> itself, while
> others can be
> further away
> from the hat
> 500. For
> example, the
> generator 210
> can be
> disposed
> within a
> carrying bag
> or the like
> (e. g., a bag
> that extends
> around the
> patient's
> waist) which
> is worn by the
> patient or it
> can be
> strapped to an
> extremity or
> around the
> torso of the
> patient. The
> generator 210
> can also be
> disposed in a
> protective
> case that is
> secured to or
> carried by
> another
> article of
> clothing that
> is worn by the
> patient. For
> example, the
> protective
> case can be
> inserted into
> a pocket of a
> sweater, etc.
> FIG. 14
> illustrates an
> embodiment
> where the
> generator 210
> is
> incorporated
> directly into
> the hat 500.  
>   
>   
>  [00126]
> Turning now to
> FIGS. 15 and
> 16, in one
> exemplary
> embodiment, a
> number of
> insulated
> electrodes 230
> along with the
> mechanism 530
> are preferably
> formed as an
> independent
> unit,
> generally
> indicated at
> 540, that can
> be inserted
> into the hat
> 500 and
> electrically
> connected to
> the generator
> (not shown)
> via the
> conductors
> (not shown).
> By providing
> these members
> in the form of
> an independent
> unit, the
> patient can
> easily insert
> and/or remove
> the units 540
> from the hat
> 500 when they
> may need
> cleaning,
> servicing
> and/or
> replacement.  
>   
>  [00127]
> In this
> embodiment,
> the hat 500 is
> constructed to
> include select
> areas 550 that
> are formed in
> the hat 500 to
> receive and
> hold the units
> 540. For
> example and as
> illustrated in
> FIG. 15, each
> area 550 is in
> the form of an
> opening (pore)
> that is formed
> within the hat
> 500. The unit
> 540 has a body
> 542 and
> includes the
> mechanism 530
> and one or
> more insulated
> electrodes
> 230. The
> mechanism 530
> is arranged
> within the
> unit 540 so
> that a portion
> thereof (e.
> g., one end
> thereof) is in
> contact with a
> face of each
> insulated
> electrode 230
> such that the
> mechanism 530
> applies a
> biasing force
> against the
> face of the
> insulated
> electrode 230.
> Once the unit
> 540 is
> received
> within the
> opening 550,
> it can be
> securely
> retained
> therein using
> any number of
> conventional
> techniques,
> including the
> use of an
> adhesive
> material or by
> using
> mechanical
> means. For
> example, the
> hat 500 can
> include
> pivotable clip
> members that
> pivot between
> an open
> position in
> which the
> opening 550 is
> free and a
> closed
> position in
> which the
> pivotable clip
> members engage
> portions (e.
> g., peripheral
> edges) of the
> insulated
> electrodes to
> retain and
> hold the
> insulated
> electrodes 230
> in place. To
> remove the
> insulated
> electrodes
> 230, the
> pivotable clip
> members are
> moved to the
> open position.
> In the
> embodiment
> illustrated in
> FIG. 16, the
> insulated
> electrodes 230
> are retained
> within the
> openings 550
> by an adhesive
> element 560
> which in one
> embodiment is
> a two sided
> self-adhesive
> rim member
> that extends
> around the
> periphery of
> the insulated
> electrode 230.
> In other
> words, a
> protective
> cover of one
> side of the
> adhesive rim
> 560 is removed
> and it is
> applied around
> the periphery
> of the exposed
> face of the
> insulated
> electrode 230,
> thereby
> securely
> attaching the
> adhesive rim
> 560 to the hat
> 500 and then
> the other side
> of the
> adhesive rim
> 560 is removed
> for
> application to
> the skin
> surface 504 in
> desired
> locations for
> positioning
> and securing
> the insulated
> electrode 230
> to the head
> 502 with the
> tumor being
> positioned
> relative
> thereto for
> optimization
> of the TC
> fields. Since
> one side of
> the adhesive
> rim 560 is in
> contact with
> and secured to
> the skin
> surface 540,
> this is why it
> is desirable
> for the head
> 502 to be
> shaved so that
> the adhesive
> rim 560 can be
> placed flushly
> against the
> skin surface
> 540.  
>   
>  [00128]
> The adhesive
> rim 560 is
> designed to
> securely
> attach the
> unit 540
> within the
> opening 550 in
> a manner that
> permits the
> unit 540 to be
> easily removed
> from the hat
> 500 when
> necessary and
> then replaced
> with another
> unit 540 or
> with the same
> unit 540. As
> previously
> mentioned, the
> unit 540
> includes the
> biasing
> mechanism 530
> for pressing
> the insulated
> electrode 230
> against the
> skin surface
> 504 when the
> hat 500 is
> worn. The unit
> 540 can be
> constructed so
> that side
> opposite the
> insulated
> electrode 230
> is a support
> surface formed
> of a rigid
> material, such
> as plastic, so
> that the
> biasing
> mechanism 530
> (e. g., a
> spring) can be
> compressed
> therewith
> under the
> application of
> force and when
> the spring 530
> is in a
> relaxed state,
> the spring 530
> remains in
> contact with
> the support
> surface and
> the applies a
> biasing force
> at its other
> end against
> the insulated
> electrode 230.
> The biasing
> mechanism 530
> (e. g.,
> spring)
> preferably has
> a contour
> corresponding
> to the skin
> surface 504 so
> that the
> insulated
> electrode 230
> has a force
> applied
> thereto to
> permit the
> insulated
> electrode 230
> to have a
> contour
> complementary
> to the skin
> surface 504,
> thereby
> permitting the
> two to seat
> flushly
> against one
> another. While
> the mechanism
> 530 can be a
> spring, there
> are a number
> of other
> embodiments
> that can be
> used instead
> of a spring.
> For example,
> the mechanism
> 530 can be in
> the form of an
> elastic
> material, such
> as a foam
> rubber, a foam
> plastic, or a
> layer
> containing air
> bubbles, etc.  
>   
>  [00129]
> The unit 540
> has an
> electric
> connector 570
> that can be
> hooked up to a
> corresponding
> electric
> connector,
> such as a
> conductor 220,
> that is
> disposed
> within the hat
> 500. The
> conductor 220
> connects at
> one end to the
> unit 540 and
> at the other
> end is
> connected to
> the generator
> 210. The
> generator 210
> can be
> incorporated
> directly into
> the hat 500 or
> the generator
> 210 can be
> positioned
> separately
> (remotely) on
> the patient or
> on a bedside
> support, etc.
>   
>   
> [00130] As
> previously
> discussed, a
> coupling
> agent, such as
> a conductive
> gel, is
> preferably
> used to ensure
> that an
> effective
> conductive
> environment is
> provided
> between the
> insulated
> electrode 230
> and the skin
> surface 504.
> Suitable gel
> materials have
> been disclosed
> hereinbefore
> in the
> discussion of
> earlier
> embodiments.
> The coupling
> agent is
> disposed on
> the insulated
> electrode 230
> and
> preferably, a
> uniform layer
> of the agent
> is provided
> along the
> surface of the
> electrode 230.
> One of the
> reasons that
> the units 540
> need
> replacement at
> periodic times
> is that the
> coupling agent
> needs to be
> replaced
> and/or
> replenished.
> In other
> words, after a
> predetermined
> time period or
> after a number
> of uses, the
> patient
> removes the
> units 540 so
> that the
> coupling agent
> can be applied
> again to the
> electrode 230.  
>   
>  [00131]
> FIGS. 17 and
> 18 illustrate
> another
> article of
> clothing which
> has the
> insulated
> electrodes 230
> incorporated
> as part
> thereof. More
> specifically,
> a bra or the
> like 700 is
> illustrated
> and includes a
> body that is
> formed of a
> traditional
> bra material,
> generally
> indicated at
> 705, to
> provide shape,
> support and
> comfort to the
> wearer. The
> bra 700 also
> includes a
> fabric support
> layer 710 on
> one side
> thereof. The
> support layer
> 710 is
> preferably
> formed of a
> suitable
> fabric
> material that
> is constructed
> to provide
> necessary and
> desired
> support to the
> bra 700.  
>   
>  [00132]
> Similar to the
> other
> embodiments,
> the bra 700
> includes one
> or more
> insulated
> electrodes 230
> disposed
> within the bra
> material 705.
> The one or
> more insulated
> electrodes are
> disposed along
> an inner
> surface of the
> bra 700
> opposite the
> support 710
> and are
> intended to be
> placed
> proximate to a
> tumor or the
> like that is
> located within
> one breast or
> in the
> immediately
> surrounding
> area. As with
> the previous
> embodiment,
> the insulated
> electrodes 230
> in this
> embodiment are
> specifically
> constructed
> and configured
> for
> application to
> a breast or
> the immediate
> area. Thus,
> the insulated
> electrodes 230
> used in this
> application do
> not have a
> planar surface
> construction
> but rather
> have an
> arcuate shape
> that is
> complementary
> to the general
> curvature
> found in a
> typical
> breast.
> [00133] A
> lining 720 is
> disposed
> across the
> insulated
> electrodes 230
> so as to
> assist in
> retaining the
> insulated
> electrodes in
> their desired
> locations
> along the
> inner surface
> for placement
> against the
> breast itself.
> The lining 720
> can be formed
> of any number
> of thin
> materials that
> are
> comfortable to
> wear against
> one's skin and
> in one
> exemplary
> embodiment,
> the lining 720
> is formed of a
> fabric
> material.  
>   
>  [00134]
> The bra 700
> also
> preferably
> includes a
> biasing
> mechanism 800
> as in some of
> the earlier
> embodiments.
> The biasing
> mechanism 800
> is disposed
> within the bra
> material 705
> and extends
> from the
> support 710 to
> the insulated
> electrode 230
> and applies a
> biasing force
> to the
> insulated
> electrode 230
> so that the
> electrode 230
> is pressed
> against the
> breast. This
> ensures that
> the insulated
> electrode 230
> remains in
> contact with
> the skin
> surface as
> opposed to
> lifting away
> from the skin
> surface,
> thereby
> creating a gap
> that results
> in a less
> effective
> treatment
> since the gap
> diminishes the
> efficiency of
> the TC fields.
> The biasing
> mechanism 800
> can be in the
> form of a
> spring
> arrangement or
> it can be an
> elastic
> material that
> applies the
> desired
> biasing force
> to the
> insulated
> electrodes 230
> so as to press
> the insulated
> electrodes 230
> into the
> breast. In the
> relaxed
> position, the
> biasing
> mechanism 800
> applies a
> force against
> the insulated
> electrodes 230
> and when the
> patient places
> the bra 700 on
> their body,
> the 
> insulated
> electrodes 230
> are placed
> against the
> breast which
> itself applies
> a force that
> counters the
> biasing force,
> thereby
> resulting in
> the insulated
> electrodes 230
> being pressed
> against the
> patient's
> breast. In the
> exemplary
> embodiment
> that is
> illustrated,
> the biasing
> mechanism 800
> is in the form
> of springs
> that are
> disposed
> within the bra
> material 705.  
>   
>  [00135]
> A conductive
> gel 810 can be
> provided on
> the insulated
> electrode 230
> between the
> electrode and
> the lining
> 720. The
> conductive gel
> layer 810 is
> formed of
> materials that
> have been
> previously
> described
> herein for
> performing the
> functions
> described
> above.   
>   
> [00136] An
> electric
> connector 820
> is provided as
> part of the
> insulated
> electrode 230
> and
> electrically
> connects to
> the conductor
> 220 at one end
> thereof, with
> the other end
> of the
> conductor 220
> being
> electrically
> connected to
> the generator
> 210. In this
> embodiment,
> the conductor
> 220 runs
> within the bra
> material 705
> to a location
> where an
> opening is
> formed in the
> bra 700. The
> conductor 220
> extends
> through this
> opening and is
> routed to the
> generator 210,
> which in this
> embodiment is
> disposed in a
> location
> remote from
> the bra 700.
> It will also
> be appreciated
> that the
> generator 210
> can be
> disposed
> within the bra
> 700 itself in
> another
> embodiment.
> For example,
> the bra 700
> can have a
> compartment
> formed therein
> which is
> configured to
> receive and
> hold the
> generator 210
> in place as
> the patient
> wears the bra
> 700. In this
> arrangement,
> the
> compartment
> can be covered
> with a
> releasable
> strap that can
> open and close
> to permit the
> generator 210
> to be inserted
> therein or
> removed
> therefrom. The
> strap can be
> formed of the
> same material
> that is used
> to construct
> the bra 700 or
> it can be
> formed of some
> other type of
> material. The
> strap can be
> releasably
> attached to
> the
> surrounding
> bra body by
> fastening
> means, such as
> a hook and
> loop material,
> thereby
> permitting the
> patient to
> easily open
> the
> compartment by
> separating the
> hook and loop
> elements to
> gain access to
> the
> compartment
> for either
> inserting or
> removing the
> generator 210.  
>   
>  [00137]
> The generator
> 210 also has a
> connector 211
> for electrical
> connection to
> the conductor
> 220 and this
> permits the
> generator 210
> to be
> electrically
> connected to
> the insulated
> electrodes
> 230.  
>   
>  [00138]
> As with the
> other
> embodiments,
> the insulated
> electrodes 230
> are arranged
> in the bra 700
> to focus the
> electric field
> (TC fields) on
> the desired
> target (e. g.,
> a tumor). It
> will be
> appreciated
> that the
> location of
> the insulated
> electrodes 230
> within the bra
> 700 will vary
> depending upon
> the location
> of the tumor.
> In other
> words, after
> the tumor has
> been located,
> the physician
> will then
> devise an
> arrangement of
> insulated
> electrodes 230
> and the bra
> 700 is
> constructed in
> view of this
> arrangement so
> as to optimize
> the effects of
> the TC fields
> on the  target
> area (tumor).
> The number and
> position of
> the insulated
> electrodes 230
> will therefore
> depend upon
> the precise
> location of
> the tumor or
> other target
> area that is
> being treated.
> Because the
> location of
> the insulated
> electrodes 230
> on the bra 700
> can vary
> depending upon
> the precise
> application,
> the exact size
> and shape of
> the insulated
> electrodes 230
> can likewise
> vary. For
> example, if
> the insulated
> electrodes 230
> are placed on
> the bottom
> section of the
> bra 700 as
> opposed to a
> more central
> location, the
> insulated
> electrodes 230
> will have
> different
> shapes since
> the shape of
> the breast (as
> well as the
> bra) differs
> in these
> areas.  
>   
>  [00139]
> FIG. 19
> illustrates
> yet another
> embodiment in
> which the
> insulated
> electrodes 230
> are in the
> form of
> internal
> electrodes
> that are
> incorporated
> into in the
> form of a
> probe or
> catheter 600
> that is
> configured to
> enter the body
> through a
> natural
> pathway, such
> as the
> urethra,
> vagina, etc.
> In this
> embodiment,
> the insulated
> electrodes 230
> are disposed
> on an outer
> surface of the
> probe 600 and
> along a length
> thereof. The
> conductors 220
> are
> electrically
> connected to
> the electrodes
> 230 and run
> within the
> body of the
> probe 600 to
> the generator
> 210 which can
> be disposed
> within the
> probe body or
> the generator
> 210 can be
> disposed
> independent of
> the probe 600
> in a remote
> location, such
> as on the
> patient or at
> some other
> location close
> to the
> patient.  
>   
>  [00140]
> Alternatively,
> the probe 600
> can be
> configured to
> penetrate the
> skin surface
> or other
> tissues to
> reach an
> internal
> target that
> lies within
> the body. For
> example, the
> probe 600 can
> penetrate the
> skin surface
> and then be
> positioned
> adjacent to or
> proximate to a
> tumor that is
> located within
> the body.  
>   
>  [00141]
> In these
> embodiments,
> the probe 600
> is inserted
> through the
> natural
> pathway and
> then is
> positioned in
> a desired
> location so
> that the
> insulated
> electrodes 230
> are disposed
> near the
> target area
> (i. e., the
> tumor). The
> generator 210
> is then
> activated to
> cause the
> insulated
> electrodes 230
> to generate
> the TC fields
> which are
> applied to the
> tumor for a
> predetermined
> length of
> time. It will
> be appreciated
> that the
> illustrated
> probe 600 is
> merely
> exemplary in
> nature and
> that the probe
> 600 can have
> other shapes
> and
> configurations
> so long as
> they can
> perform the
> intended
> function.
> Preferably,
> the conductors
> (e. g., wires)
> leading from
> the insulated
> electrodes 230
> to the
> generator 210
> are twisted or
> shielded so as
> not to
> generate a
> field along
> the shaft.  
>   
>  [00142]
> It will
> further be
> appreciated
> that the
> probes can
> contain only
> one insulated
> electrode
> while the
> other can be
> positioned on
> the body
> surface. This
> external
> electrode
> should be
> larger or
> consist of
> numerous
> electrodes so
> as to result
> in low lines
> of
> force-current
>  density
> so as not to
> affect the
> untreated
> areas. In
> fact, the
> placing of
> electrodes
> should be
> designed to
> minimize the
> field at
> potentially
> sensitive
> areas.
> Optionally,
> the external
> electrodes may
> be held
> against the
> skin surface
> by a vacuum
> force (e.g.,
> suction).  
>   
>  [00143]
> FIG. 20
> illustrates
> yet another
> embodiment in
> which a high
> standing
> collar member
> 900 (or
> necklace type
> structure) can
> be used to
> treat thyroid,
> parathyroid,
> laryngeal
> lesions, etc.
> FIG. 20
> illustrates
> the collar
> member 900 in
> an unwrapped,
> substantially
> flat
> condition. In
> this
> embodiment,
> the insulated
> electrodes 230
> are
> incorporated
> into a body
> 910 of the
> collar member
> 900 and are
> configured for
> placement
> against a neck
> area of the
> wearer. The
> insulated
> electrodes 230
> are coupled to
> the generator
> 210 according
> to any of the
> manner
> described
> hereinbefore
> and it will be
> appreciated
> that the
> generator 210
> can be
> disposed
> within the
> body 910 or it
> can be
> disposed in a
> location
> external to
> the body 910.
> The collar
> body 910 can
> be formed of
> any number of
> materials that
> are
> traditionally
> used to form
> collars 900
> that are
> disposed
> around a
> person's neck.
> As such, the
> collar 900
> preferably
> includes a
> means 920 for
> adjusting the
> collar 900
> relative to
> the neck. For
> example,
> complementary
> fasteners
> (hook and loop
> fasteners,
> buttons, etc.
> ) can be
> disposed on
> ends of the
> collar 900 to
> permit
> adjustment of
> the collar
> diameter.  
>   
>  [00144]
> Thus, the
> construction
> of the present
> devices are
> particularly
> well suited
> for
> applications
> where the
> devices are
> incorporated
> into articles
> of clothing to
> permit the
> patient to
> easily wear a
> traditional
> article of
> clothing while
> at the same
> time the
> patient
> undergoes
> treatment. In
> other words,
> an extra level
> of comfort can
> be provided to
> the patient
> and the
> effectiveness
> of the
> treatment can
> be increased
> by
> incorporating
> some or all of
> the device
> components
> into the
> article of
> clothing. The
> precise
> article of
> clothing that
> the components
> are
> incorporated
> into will
> obviously vary
> depending upon
> the target
> area of the
> living tissue
> where tumor,
> lesion or the
> like exists.
> For example,
> if the target
> area is in the
> testicle area
> of a male
> patient, then
> an article of
> clothing in
> the form of a
> sock-like
> structure or
> wrap can be
> provided and
> is configured
> to be worn
> around the
> testicle area
> of the patient
> in such a
> manner that
> the insulated
> electrodes
> thereof are
> positioned
> relative to
> the tumor such
> that the TC
> fields are
> directed at
> the target
> tissue. The
> precise nature
> or form of the
> article of
> clothing can
> vary greatly
> since the
> device
> components can
> be
> incorporated
> into most
> types of
> articles of
> clothing and
> therefore, can
> be used to
> treat any
> number of
> different
> areas of the
> patient's body
> where a
> condition may
> be present.  
>   
>  [00145]
> Now turning to
> FIGS. 21-22 in
> which another
> aspect of the
> present device
> is shown. In
> FIG. 21, a
> body 1000,
> such as any
> number of
> parts of a
> human or
> animal body,
> is
> illustrated.
> As in the
> previous
> embodiments,
> two or more
> insulated
> electrodes 230
> are disposed
> in proximity
> to the body
> 1000 for
> treatment of a
> tumor or the
> like (not
> shown) using
> TC fields, as
> has been
> previously
> described in
> great detail
> in the above
> discussion of
> other
> embodiments.
> The insulated
> electrode 230
> has a
> conductive
> component and
> has external
> insulation 260
> that surrounds
> the conductive
> component
> thereof. Each
> insulated
> electrode 230
> is preferably
> connected to a
> generator (not
> shown) by the
> lead 220.
> Between each
> insulated
> electrode 220
> and the body
> 1000, a
> conductive
> filler
> material (e.
> g., conductive
> gel member
> 270) is
> disposed. The
> insulated
> electrodes 230
> are spaced
> apart from one
> another and
> when the
> generator is
> actuated, the
> insulated
> electrodes 230
> generate the
> TC fields that
> have been
> previously
> described in
> great detail.
> The lines of
> the electric
> field (TC
> field) are
> generally
> illustrated at
> 1010. As
> shown, the
> electric field
> lines 1010
> extend between
> the insulated
> electrodes 230
> and through
> the conductive
> gel member
> 270.   
>   
> [00146] Over
> time or as a
> result of some
> type of event,
> the external
> insulation 260
> of the
> insulated
> electrode 230
> can begin to
> breakdown at
> any given
> location
> thereof. For
> purpose of
> illustration
> only, FIG. 22
> illustrates
> that the
> external
> insulation 260
> of one of the
> insulated
> electrodes 230
> has
> experienced a
> breakdown 1020
> at a face
> thereof which
> is adjacent
> the conductive
> gel member
> 270. It will
> be appreciated
> that the
> breakdown 1020
> of the
> external
> insulation 260
> results in the
> formation of a
> strong current
> flow-current
> density at
> this point (i.
> e., at the
> breakdown
> 1020). The
> increased
> current
> density is
> depicted by
> the increased
> number of
> electric field
> lines 1010 and
> the relative
> positioning
> and distance
> between
> adjacent
> electric field
> lines 1010.
> One of the
> side effects
> of the
> occurrence of
> breakdown 1020
> is that
> current exists
> at this point
> which will
> generate heat
> and may burn
> the
> tissues/skin
> which have a
> resistance. In
> FIG. 22, an
> overheated
> area 1030 is
> illustrated
> and is a
> region or area
> of the
> tissues/skin
> where an
> increased
> current
> density exits
> due to the
> breakdown 1020
> in the
> external
> insulation
> 260. A patient
> can experience
> discomfort and
> pain in this
> area 1030 due
> to the strong
> current that
> exists in the
> area and the
> increased heat
> and possible
> burning
> sensation that
> exist in area
> 1030.  
>   
>  [00147]
> FIG. 23
> illustrates
> yet another
> embodiment in
> which a
> further
> application of
> the insulated
> electrodes 230
> is shown. In
> this
> embodiment,
> the conductive
> gel member 270
> that is
> disposed
> between the
> insulated
> electrode 230
> and the body
> 1000 includes
> a conductor
> 1100 that is
> floating in
> that the gel
> material
> forming the
> member 270
> completely
> surrounds  the
> conductor
> 1100. In one
> exemplary
> embodiment,
> the conductor
> 1100 is a thin
> metal sheet
> plate that is
> disposed
> within the
> conductor
> 1100. As will
> be
> appreciated,,if
> a conductor,
> such as the
> plate 1100, is
> placed in a
> homogeneous
> electric
> field, normal
> to the lines
> of the
> electric
> field, the
> conductor 1100
> practically
> has no effect
> on the field
> (except that
> the two
> opposing faces
> of the
> conductor 1100
> are
> equipotential
> and the
> corresponding
> equipotentials
> are slightly
> shifted).
> Conversely, if
> the conductor
> 1100 is
> disposed
> parallel to
> the electric
> field, there
> is a
> significant
> distortion of
> the electric
> field. The
> area in the
> immediate
> proximity of
> the conductor
> 1100 is not
> equipotential,
> in contrast to
> the situation
> where there is
> no conductor
> 1100 present.
> When the
> conductor 1100
> is disposed
> within the gel
> member 270,
> the conductor
> 1100 will
> typically not
> effect the
> electric field
> (TC field) for
> the reasons
> discussed
> above, namely
> that the
> conductor 1100
> is normal to
> the lines of
> the electric
> field.  
>   
>  [00148]
> If there is a
> breakdown of
> the external
> insulation 260
> of the
> insulated
> electrode 230,
> there is a
> strong current
> flow-current
> density at the
> point of
> breakdown as
> previously
> discussed;
> however, the
> presence of
> the conductor
> 1100 causes
> the current to
> spread
> throughout the
> conductor 1100
> and then exit
> from the whole
> surface of the
> conductor 1100
> so that the
> current
> reaches the
> body 1000 with
> a current
> density that
> is neither
> high nor low.
> Thus, the
> current that
> reaches the
> skin will not
> cause
> discomfort to
> the patient
> even when
> there has been
> a breakdown in
> the insulation
> 260 of the
> insulated
> electrode 230.
> It is
> important that
> the conductor
> 1100 is not
> grounded as
> this would
> cause it to
> abolish the
> electric field
> beyond it.
> Thus, the
> conductor 1100
> is "floating"
> within the gel
> member 270.  
>   
>  [00149]
> If the
> conductor 1100
> is introduced
> into the body
> tissues 1000
> and is not
> disposed
> parallel to
> the electric
> field, the
> conductor 1100
> will cause
> distortion of
> the electric
> field. The
> distortion can
> cause
> spreading of
> the lines of
> force (low
> field
> density-intensity)
> or
> concentration
> of the lines
> of field
> (higher
> density) of
> the electric
> field,
> according to
> the particular
> geometries of
> the insert and
> its
> surroundings,
> and thus, the
> conductor 1100
> can exhibit,
> for example, a
> screening
> effect. Thus,
> for example,
> if the
> conductor 1100
> completely
> encircles an
> organ 1101,
> the electric
> field in the
> organ itself
> will be zero
> since this
> type of
> arrangement is
> a Faraday
> cage. However,
> because it is
> impractical
> for a
> conductor to
> be disposed
> completely
> around an
> organ, a
> conductive net
> or similar
> structure can
> be used to
> cover,
> completely or
> partially, the
> organ, thereby
> resulting in
> the electric
> field in the
> organ itself
> being zero or
> about zero.
> For example, a
> net can be
> made of a
> number of
> conductive
> wires that are
> arranged
> relative to
> one another to
> form the net
> or a set of
> wires can be
> arranged to
> substantially
> encircle or
> otherwise
> cover the
> organ 1101.
> Conversely, an
> organ  1103 to
> be treated
> (the target
> organ) is not
> covered with a
> member having
> a Faraday cage
> effect but
> rather is
> disposed in
> the electric
> field 1010 (TC
> fields).   
>   
> [00150] FIG.
> 24 illustrates
> an embodiment
> where the
> conductor 1100
> is disposed
> within the
> body (i. e.,
> under the
> skin) and it
> is located
> near a target
> (e. g., a
> target organ).
> By placing the
> conductor 1100
> near the
> target, high
> field density
> (of the TC
> fields) is
> realized at
> the target. At
> the same time,
> another nearby
> organ can be
> protected by
> disposing the
> above
> described
> protective
> conductive net
> or the like
> around this
> nearby organ
> so as to
> protect this
> organ from the
> fields. By
> positioning
> the conductor
> 1100 in close
> proximity to
> the target, a
> high field
> density
> condition can
> be provided
> near or at the
> target. In
> other words,
> the conductor
> 1100 permits
> the TC fields
> to be focused
> at a
> particular
> area (i. e., a
> target).
> [00151] It
> will also be
> appreciated
> that in the
> embodiment of
> FIG. 24, the
> gel members
> 260 can each
> include a
> conductor as
> described with
> reference to
> FIG. 23. In
> such an
> arrangement,
> the conductor
> in the gel
> member 260
> protects the
> skin surface
> (tissues) from
> any side
> effects that
> may be
> realized if a
> breakdown in
> the insulation
> of the
> insulated
> electrode 230
> occurs. At the
> same time, the
> conductor 1100
> creates a high
> field density
> near the
> target.  
>   
>  [00152]
> There are a
> number of
> different ways
> to tailor the
> field density
> of the
> electric field
> by
> constructing
> the electrodes
> differently
> and/or by
> strategically
> placing the
> electrodes
> relative to
> one another.
> For example,
> in FIG. 25, a
> first
> insulated
> electrode 1200
> and a second
> insulated
> electrode 1210
> are provided
> and are
> disposed about
> a body 1300.
> Each insulated
> electrode
> includes a
> conductor that
> is preferably
> surrounded by
> an insulating
> material, thus
> the term
> "insulated
> electrode".
> Between each
> of the first
> and second
> electrodes
> 1200, 1210 and
> the body 1300,
> the conductive
> gel member 270
> is provided.
> Electric field
> lines are
> generally
> indicated at
> 1220 for this
> type of
> arrangement.
> In this
> embodiment,
> the first
> insulated
> electrode 1200
> has dimensions
> that are
> significantly
> greater than
> the dimensions
> of the second
> insulated
> electrode 1210
> (the
> conductive gel
> member for the
> second
> insulated
> electrode 1210
> will likewise
> be smaller).  
>   
>  [00153]
> By varying the
> dimensions of
> the insulated
> electrodes,
> the pattern of
> the electric
> field lines
> 1220 is
> varied. More
> specifically,
> the electric
> field tapers
> inwardly
> toward the
> second
> insulated
> electrode 1210
> due to the
> smaller
> dimensions of
> the second
> insulated
> electrode
> 1210. An area
> of high field
> density,
> generally
> indicated at
> 1230, forms
> near the
> interface
> between the
> gel member 270
> associated
> with the
> second
> insulated
> electrode 1210
>  and the
> skin surface.
> The various
> components of
> the system are
> manipulated so
> that the tumor
> within the
> skin or on the
> skin is within
> this high
> field density
> so that the
> area to be
> treated (the
> target) is
> exposed to
> electric field
> lines of a
> higher field
> density.  
>   
>  [00154]
> FIG. 26 also
> illustrates a
> tapering TC
> field when a
> conductor 1400
> (e.g., a
> conductive
> plate) is
> disposed in
> each of the
> conductive gel
> members 270.
> In this
> embodiment,
> the size of
> the gel
> members 270
> and the size
> of the
> conductors
> 1400 are the
> same or about
> the same
> despite the
> differences in
> the sizes of
> the insulated
> electrodes
> 1200, 1210.
> The conductors
> 1400 again can
> be
> characterized
> as "floating
> plates" since
> each conductor
> 1400 is
> surrounded by
> the material
> that forms the
> gel member
> 270. As shown
> in FIG. 26,
> the placement
> of one
> conductor 1400
> near the
> insulated
> electrode 1210
> that is
> smaller than
> the other
> insulated
> electrode 1200
> and is also
> smaller than
> the conductor
> 1400 itself
> and the other
> insulated
> electrode 1200
> is disposed at
> a distance
> therefrom, the
> one conductor
> 1400 causes a
> decrease in
> the field
> density in the
> tissues
> disposed
> between the
> one conductor
> 1400 and the
> other
> insulated
> electrode
> 1200. The
> decrease in
> the field
> density is
> generally
> indicated at
> 1410. At the
> same time, a
> very
> inhomogeneous
> tapering
> field,
> generally
> indicated at
> 1420, changing
> from very low
> density to
> very high
> density is
> formed between
> the one
> conductor 1400
> and the
> insulated
> electrode
> 1210. One
> benefit of
> this exemplary
> configuration
> is that it
> permits the
> size of the
> insulated
> electrode to
> be reduced
> without
> causing an
> increase in
> the nearby
> field density.
> This can be
> important
> since
> electrodes
> that having
> very high
> dielectric
> constant
> insulation can
> be very
> expensive.
> Some insulated
> electrodes,
> for example,
> can cost
> $500.00 or
> more; and
> further, the
> price is
> sensitive to
> the particular
> area of
> treatment.
> Thus, a
> reduction in
> the size of
> the insulated
> electrodes
> directly leads
> to a reduction
> in cost.  
>   
>  [00155]
> As used
> herein, the
> term "tumor"
> refers to a
> malignant
> tissue
> comprising
> transformed
> cells that
> grow
> uncontrollably.
> Tumors include
> leukemias,
> lymphomas,
> myelomas,
> plasmacytomas,
> and the like;
> and solid
> tumors.
> Examples of
> solid tumors
> that can be
> treated
> according to
> the invention
> include
> sarcomas and
> carcinomas
> such as, but
> not limited
> to:
> fibrosarcoma,
> myxosarcoma,
> liposarcoma,
> chondrosarcoma,
> osteogenic
> sarcoma,
> chordoma,
> angiosarcoma,
> endotheliosarcoma,
> lymphangiosarcoma,
> lymphangioendotheliosarcoma,
> synovioma,
> mesothelioma,
> Ewing's tumor,
> leiomyosarcoma,
> rhabdomyosarcoma,
> colon
> carcinoma,
> pancreatic
> cancer, breast
> cancer,
> ovarian
> cancer,
> prostate
> cancer,
> squamous cell
> carcinoma,
> basal cell
> carcinoma,
> adenocarcinoma,
> sweat gland
> carcinoma,
> sebaceous
> gland
> carcinoma,
> papillary
> carcinoma,
> papillary
> adenocarcinomas,
> cystadenocarcinoma,
> medullary
> carcinoma,
> bronchogenic
> carcinoma,
> renal cell
> carcinoma, 
> hepatoma, bile
> duct
> carcinoma,
> choriocarcinoma,
> seminoma,
> embryonal
> carcinoma,
> Wilms' tumor,
> cervical
> cancer,
> testicular
> tumor, lung
> carcinoma,
> small cell
> lung
> carcinoma,
> bladder
> carcinoma,
> epithelial
> carcinoma,
> glioma,
> astrocytoma,
> medulloblastoma,
> craniopharyngioma,
> ependymoma,
> pinealoma,
> hemangioblastoma,
> acoustic
> neuroma,
> oligodendroglioma,
> meningioma,
> melanoma,
> neuroblastoma,
> and
> retinoblastoma.
> Because each
> of these
> tumors
> undergoes
> rapid growth,
> any one can be
> treated in
> accordance
> with the
> invention. The
> invention is
> particularly
> advantageous
> for treating
> brain tumors,
> which are
> difficult to
> treat with
> surgery and
> radiation, and
> often
> inaccessible
> to
> chemotherapy
> or gene
> therapies. In
> addition, the
> present
> invention is
> suitable for
> use in
> treating skin
> and breast
> tumors because
> of the ease of
> localized
> treatment
> provided by
> the present
> invention.  
>   
>  [00156]
> In addition,
> the present
> invention can
> control
> uncontrolled
> growth
> associated
> with
> non-malignant
> or
> pre-malignant
> conditions,
> and other
> disorders
> involving
> inappropriate
> cell or tissue
> growth by
> application of
> an electric
> field in
> accordance
> with the
> invention to
> the tissue
> undergoing
> inappropriate
> growth. For
> example, it is
> contemplated
> that the
> invention is
> useful for the
> treatment of
> arteriovenous
> (AV)
> malformations,
> particularly
> in
> intracranial
> sites. The
> invention may
> also be used
> to treat
> psoriasis, a
> dermatologic
> condition that
> is
> characterized
> by
> inflammation
> and vascular
> proliferation;
> and benign
> prostatic
> hypertrophy, a
> condition
> associated
> with
> inflammation
> and possibly
> vascular
> proliferation.
> Treatment of
> other
> hyperproliferative
> disorders is
> also
> contemplated.  
>   
>  [00157]
> Furthermore,
> undesirable
> fibroblast and
> endothelial
> cell
> proliferation
> associated
> with wound
> healing,
> leading to
> scar and
> keloid
> formation
> after surgery
> or injury, and
> restenosis
> after
> angioplasty or
> placement of
> coronary
> stents can be
> inhibited by
> application of
> an electric
> field in
> accordance
> with the
> present
> invention. The
> non-invasive
> nature of this
> invention
> makes it
> particularly
> desirable for
> these types of
> conditions,
> particularly
> to prevent
> development of
> internal scars
> and adhesions,
> or to inhibit
> restenosis of
> coronary,
> carotid, and
> other
> important
> arteries.  
>   
>  [00158]
> In addition to
> treating
> tumors that
> have already
> been detected,
> the above-
> described
> embodiments
> may also be
> used
> prophylactically
> to prevent
> tumors from
> ever reaching
> a detectable
> size in the
> first place.
> For example,
> the bra
> embodiment
> described
> above in
> connection
> with FIGS. 17
> and 18 may be
> worn by a
> woman for an 8
> hour session
> every day for
> a week, with
> the week-long
> course of
> treatment
> being repeated
> every few
> months to kill
> any cells that
> have become
> cancerous and
> started to
> proliferate.
> This mode of  usage
> is
> particularly
> appropriate
> for people who
> are at high
> risk for a
> particular
> type of cancer
> (e. g., women
> with a strong
> history of
> breast cancer
> in their
> families, or
> people who
> have survived
> a bout of
> cancer and are
> at risk of a
> relapse). The
> course of
> prophylactic
> treatment may
> be tailored
> based on the
> type of cancer
> being targeted
> and/or to suit
> the
> convenience of
> the patient.
> For example,
> undergoing a
> four 16 hour
> sessions
> during the
> week of
> treatment may
> be more
> convenient for
> some patients
> than seven 8
> hour session,
> and may be
> equally
> effective.  
>   
>  [00159]
> Thus, the
> present
> invention
> provides an
> effective,
> simple method
> of selectively
> destroying
> dividing
> cells, e. g.,
> tumor cells
> and parasitic
> organisms,
> while
> non-dividing
> cells or
> organisms are
> left affected
> by application
> of the method
> on living
> tissue
> containing
> both types of
> cells or
> organisms.
> Thus, unlike
> many of the
> conventional
> methods, the
> present
> invention does
> not damage the
> normal cells
> or organisms.
> In addition,
> the present
> invention does
> not
> discriminate
> based upon
> cell type (e.
> g., cells
> having
> differing
> sizes) and
> therefore may
> be used to
> treat any
> number of
> types of sizes
> having a wide
> spectrum of
> characteristics,
> including
> varying
> dimensions.  
>   
>  [00160]
> While the
> invention has
> been
> particularly
> shown and
> described with
> reference to
> preferred
> embodiments
> thereof, it
> will be
> understood by
> those skilled
> in the art
> that various
> changes in
> form and
> details can be
> made without
> departing from
> the spirit and
> scope of the
> invention.  
>   
>
>
> ---
>
>
>
> **Foreign Patents**
>
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> CELLS   
> WO2007039799   
> 2007-04-12
>
> TREATING A TUMOR OR THE LIKE WITH
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> CA2563817   
> 2005-12-08
>
> APPARATUS AND METHOD FOR
> PREVENTING THE SPREAD OF CANCEROUS METASTASES AND FOR
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> WO2006131816   
> 2006-12-14
>
> PARALLEL REACTOR   
> DE112004002246T   
> 2006-10-05
>
> TREATING A TUMOR OR THE LIKE WITH
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> WO2006085150   
> 2006-08-17
>
> ELECTRODES FOR APPLYING AN
> ELECTRIC FIELD IN-VIVO OVER AN EXTENDED PERIOD OF TIME   
> WO2006061688   
> 2006-06-15
>
> METHOD AND APPARATUS FOR DETECTING
> ARTERIAL STENOSIS   
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> 2006-08-03
>
> APPARATUS AND METHOD FOR
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> WO2004084747   
> 2004-10-07
>
> APPARATUS FOR TREATING A
> TUMOR OR THE LIKE AND ARTICLES INCORPORATING THE APPARATUS
> FOR TREATMENT OF THE TUMOR   
>  WO2004030760   
>  2004-04-15
>
> ---