Apparatus for treating a tumor by an electric field

This application claims priority to US Patent Application Serial No. 10 / 315,576, filed December 10, 2002. The application itself is a partial continuation of US Patent Application Serial No. 10 / 285,313, filed October 31, 2002. The application itself is a partial continuation of US Patent Application Serial No. 10 / 263,329, filed October 2, 2002. The contents of these documents are incorporated herein by reference.

The present invention relates to the selective destruction of rapidly dividing cells within a local region. More specifically, such dividing cells are selected by applying an electric field with certain predetermined properties using a device configured to be complementary to a particular part of the body. It relates to devices and methods that can be destroyed.

All living organisms include cell division, including cell culture, microorganisms (eg, bacteria, mycoplasmas, yeasts, protozoans, and other unicellular organisms), fungi, algae, plant cells, etc. Proliferate by etc. The cell division of organisms can be disrupted or their proliferation can be controlled by techniques based on the sensitivity of the organisms to cell division to certain agents. For example, certain antibiotics stop the bacterial growth process.

The process of eukaryotic cell division is called "mitosis." Mitosis has subtle individual phases (Molecular Cell Biology, New York: Scientific by Darnell et al.) American Books, 1986, p. 149, see). In the interphase phase, cells replicate chromosomal DNA. Chromosomal DNA begins to aggregate early in the early phase. At this point, the centriole (each cell has two) begins to move towards the poles at both ends of the cell. In the middle of the early phase, each chromosome is composed of replica chromatids. Microtubule spindles are radiated from the closest region adjacent to the centriole. By late in the early phase, the centriole has already reached the pole. Also, some spindle fibers extend to the center of the cell. On the other hand, other spindle fibers extend from the poles to the chromatids. The cell then transitions to the metaphase phase of cell division. In this metaphase, chromosomes migrate toward the cell's equator and align in the equator plane. Next is the early phase of the late phase of mitosis. In this early stage, the daughter chromatids are separated from each other on the equator and move along the spindle fiber towards the centriole located at both poles. The cells begin to grow along the axis of the pole. The pole-to-pole spindle also extends. In the late phase of the late phase, each of the daughter chromosomes (when they are not so named) reaches their respective poles. At this point, cytokinesis begins as the cleavage furrows begin to form at the equator of the cell. In other words, in the late phase of the late phase of mitosis, cell membrane pinching begins. In the telophase phase, cytokinesis is almost complete and the spindle disappears. A relatively narrow cell membrane connection connects the two cytoplasms. Finally, the cell membrane is completely separated, cytokinesis is complete, and the cell returns to the interphase phase.

In meiosis, cells undergo a second division. In the second division, sister chromatids separate from each other along the spindle fiber toward both poles of the cell, and then cleavage furrows are formed, resulting in cell division. However, this division does not occur after chromosomal replication, resulting in haploid germ cells.

Bacteria also divide by chromosomal replication, followed by cell segregation. However, as in the case of eukaryotic cells, there is no visual device for cell division because the daughter chromosomes separate by attachment to cell membrane members.

It is well known that tumors, especially malignant or cancerous tumors, grow in an uncontrolled manner as compared to normal tissue. With such accelerated growth, the tumor can occupy an ever-increasing space and can damage or destroy adjacent tissue. In addition, some types of cancer can transfer the "seed" (or seed) of the cancer, including single cells or small cell clusters, to a new location (metastasis), and the metastasized cancer cells It is characterized by growing as a further tumor.

The rapid growth of tumors is generally the result of the rapid growth of malignant tumors as described above, which results in more frequent cell division or proliferation of these cells as compared to normal histiocytes. The apparently frequent cell division of cancer cells is the basis for the effectiveness of existing cancer treatments, such as radiation therapy and the use of various chemical agents. Such treatments are based on the fact that dividing cells are more sensitive to radiation and chemical treatments than non-dividing cells. By dividing cancer cells much more frequently than normal cells, radiation therapy and / or chemotherapy can, to some extent, selectively damage or destroy tumor cells. .. The actual sensitivity of cells to radiation therapy, chemicals, etc. also depends on the specific properties of different types of normal cells or different types of malignant cells. So, unfortunately, the sensitivity of tumor cells is not high enough compared to many types of normal cells. This reduces the ability to discriminate between tumor cells and normal cells. Therefore, existing cancer treatments typically result in serious damage to normal tissue. Therefore, the therapeutic effect of such treatment is limited. In addition, unavoidable damage to other tissues makes the treatment highly damaging to the patient. In many cases, patients are unable to recover from what appears to be successful treatment. Moreover, certain types of tumors are completely insensitive to existing treatment methods.

There are also other methods for destroying cells without relying solely on radiation therapy or chemotherapy. For example, ultrasonic and electrical techniques can be used additionally or alternatively to destroy tumor cells. For many years, electric and current have been used for medical applications. The most common is to generate an electric current in the human or animal body by applying an electric field using a pair of conductive electrodes that maintain a potential difference. The use of these currents can have specific consequences, i.e. can stimulate sensitive tissues, or generate heat by passing an electric current through the body by acting as an electrical resistance in the tissues. can do. Examples of first-type applications include: That is, there are vibration defibrillators, peripheral nerve and muscle stimulating means, brain simulators, and the like. The current is used for heating, for example, in a tumor evaporator, in an evaporator of dysfunctional tissue of the heart or brain, in a cautery device, and to relieve muscle and other pain caused by rheumatism. Used in.

Other uses of electric fields for medical purposes include directing high-frequency electric fields emitted from sources of electromagnetic waves, such as RF waves and microwaves, toward a targeted portion of the body (ie, a target). Is to use. In these examples, there is no electrical energy conduction between the source and the body. Instead, energy is transmitted to the body by radiation or induction. More specifically, the electrical energy generated by the emission source reaches the vicinity of the body through conductors and is transmitted to the human body via air or some other electrical insulating material.

In conventional electrical methods, current is delivered to an area of target tissue using electrodes placed in contact with the patient's body. The applied current destroys virtually all cells located in the vicinity of the target tissue. Therefore, this type of electrical method cannot distinguish between different types of cells in the target tissue and destroys both tumor cells and normal cells.

Thus, the electric fields that can be used in medical applications can generally be classified into two different modes. In the first mode, an electric field is applied to the body or tissue by using conductive electrodes. These electric fields can be classified into two types. That is, (1) a stable electric field, that is, an electric field that changes at a relatively slow speed, and a low-frequency alternating electric field that can induce a corresponding current in the body or tissue, and (2) a conductive electrode. It can be classified into a high-frequency alternating electric field (1 MHz or more) applied to the body. In the second mode, the electric field is a high frequency alternating electric field applied to the body by an insulated electrode.

The first type of electric field is used, for example, to stimulate nerves and muscles, and as a pacemaker for the heart. In fact, by using such a natural electric field, signals can be propagated in nerves and muscle fibers, in the central nervous system (CNS), in the heart and the like. The recording of such a natural electric field is the basis for ECG, EEG, EMG, ERG, and so on. The strength of the electric field in these applications is simply the voltage applied to the stimulating / recording electrodes located apart from each other, assuming that the electrical properties of the medium are uniform. is there. These currents, which can be calculated by Ohm's law, can have dangerous stimulating effects on the heart and CNS, and can cause potentially harmful ion concentration changes. Also, if the currents are large enough, they can cause excessive heating within the tissue. This heating can be calculated by the power consumed in the tissue (the product of voltage and current).

When such electric and current are alternating current, the stimulating force of these on nerves, muscles, etc. is the inverse function of frequency. At frequencies above 1-10 kHz, the stimulating force of the electric field approaches zero. This limitation is due to the fact that the excitation caused by electrical stimulation is usually mediated by potential changes in the cell membrane. The rate of change in the potential of the cell membrane is limited by the RC characteristics of the cell membrane (time constant of about 1 ms).

Regardless of the frequency, when such an electric field induced by an electric current is applied, the electric field is associated with the harmful side effects caused by the electric current. For example, one negative effect is the change in ion concentration into various "partitions" within the system, and the harmful effects of electrolysis that occur at the electrodes or in media intervening in the tissue. Product. Whenever the system has two or more septa that maintain the ion concentration difference, a change in ion concentration occurs. For example, in most tissues, [Ca] in extracellular fluid⁺⁺] Is about 2 × 10^-3It is M. On the other hand, in the cytoplasm of a typical cell, its concentration is 10^-7It can be as small as M. The current induced in such a system by the pair of electrodes flows, in part, from the extracellular fluid into the cell and then back into the extracellular fluid. Approximately 2% of the current flowing into the cell is Ca⁺⁺It is carried by Aeon. On the other hand, intracellular Ca⁺⁺Due to the much lower concentration of, these ions carry only a negligible amount of current out of the cell. Therefore, Ca⁺⁺Ions can accumulate intracellularly and increase their concentration within the cell, while the concentration of those ions within the extracellular septum can decrease. Such results are observed both in the case of direct current and in the case of alternating current (AC) current. The ion accumulation rate depends on the current intensity, the mobility of the ions, the ionic conductivity of the cell membrane, and the like. [Ca⁺⁺] Is detrimental to most cells. And if it becomes large enough, it will lead to the destruction of cells. Similar considerations apply to other ions. Considering the above observations, applying an electric current to a living organism or tissue over a long period of time will cause serious damage. Another significant problem associated with such electric fields is due to the electrolysis process that occurs on the electrode surface. Here, the charge is transferred between the metal (electrons) and the electrolyte solution (ions). At that time, charged active radicals are formed. These active radicals cause significant damage to organic molecules, especially to macromolecules, and thus damage living cells and tissues.

In contrast, the situation is quite different when a high frequency electric field, usually above 1 MHz and practically in the GHz range, is induced in the tissue by the insulated electrodes. These types of electric fields generate merely capacitive or displacement currents rather than traditional charge conduction currents. Under the influence of this type of electric field, living tissue behaves on the basis of dielectric properties, not on electrical conduction properties. Therefore, the dominant field effect is based on dielectric loss and heating. Therefore, it is practically widely acceptable and the meaningful effect of such an electric field on living organisms is solely due to the heating effect, i.e. due to dielectric loss only.

In Mangano's US Pat. No. 6,043,066 (hereinafter referred to as the "'066 patent"), an individual object surrounded by a dielectric cell membrane and having a conductive internal core is referred to as an irreversible dielectric cell membrane. Methods and devices have been disclosed that can be selectively inactivated by an electric field via breakdown. One potential application in this regard is to selectively purge certain suspended biological cells. In the '066 patent, an electric field is applied to selected cells of interest. This causes dielectric breakdown of the dielectric cell membrane of these tumor cells. On the other hand, the claims of this document have no adverse effect on other desired cell subpopulations. Cells are selected based on intrinsic or induced differences with respect to the inherent electroporation threshold. Differences regarding this threshold can depend on many parameters, including differences in cell size.

Therefore, the '066 patented method allows the electroporation threshold of tumor cells to be well discernible compared to the electroporation threshold of normal cells based on differences in cell size and cell membrane dielectric properties. It is based on the precondition that it is. Based on this precondition, many types of large tumor cells are more susceptible to electroporation and therefore, by applying an appropriate electric field, only the cell membranes of larger size tumor cells are selectively selected. Can be damaged. One drawback of this method is that the ability to discriminate is highly dependent on cell type. For example, the size difference between normal cells and tumor cells is only large for certain types of cells. Another drawback of this method is that the applied voltage can damage some normal cells, not all tumor cells. This is because the difference in size and the difference in the dielectric properties of cell membranes are fairly statistical, and the actual cell shape and dielectric properties vary significantly.

What is required in the art and is not currently available is a device for destroying dividing cells, in which case dividing cells, including single-cell organisms, and non-dividing cells. It can better distinguish between dividing cells and can selectively destroy dividing cells, i.e., it has a substantial effect on non-dividing cells or organisms. It is a device that does not reach, and is configured to be applicable to specific parts of the body, such as the end, and thus can be incorporated into clothing products.<patcit num="1"><text>U.S. Patent Application Serial Number 10 / 315,576</text></patcit><patcit num="2"><text>U.S. Patent Application Serial Number 10 / 285,313</text></patcit><patcit num="3"><text>U.S. Patent Application Serial Number 10 / 263,329</text></patcit><patcit num="4"><text>U.S. Pat. No. 6,043,066</text></patcit><nplcit num="1"><text>Molecular Cell Biology, New York: Scientific American Books, 1986, p. 149 by Darnell et al.</text></nplcit>

<p> The present invention provides devices that can be used in a variety of applications so that cells undergoing growth and division can be selectively destroyed. The subject is a cell in a living tissue, particularly a tumor cell, and a single cell organism. The device according to the invention can be incorporated into various configurations that are effective for a particular body part. This allows the device to clearly target local areas so that the growth of such living tissue or organisms can be removed or controlled. For example, as described in detail below, the device can be incorporated, in particular, within a garment product that can be worn over the tumor area. One of the configurations of the device is in the form of a hat, a cap, or another type of structure that can be worn on a person's head. This allows treatment of intracranial tumors, external scalp injuries, or other injuries. In other configurations, the device is in the form of a modified brassiere or the like so that it can be worn over the breast. This allows treatment of breast cancer or other types of tumor conditions. In addition, the device can be incorporated into garment products that can be worn on other parts of the body, such as the testicles and hands, legs, arms and neck. This allows local tumors to be treated at these locations (body parts). For example, large upright collar members or necklace-type structures can be used to treat injuries to the thyroid gland, epithelial bodies, larynx, and the like. In this embodiment, the device (all or part) is placed within a garment product worn around the neck to treat these situations. From another point of view, topical treatment can be performed by taking the form of an internal member (eg, a probe or catheter) that is inserted into the body through a natural passage such as the urethra or vaginal cavity. Alternatively, the member can reach the internal target by penetrating the skin or other tissue.</p><p> The main use of the device according to the invention is the treatment of tumors, in which case tumor cells are selectively destroyed without substantial effect on normal histiocytes. Therefore, an exemplary device will be described below with respect to the selective destruction of tumor cells. However, for the purposes of the present invention, the term "cell" also refers to single-celled organisms (eubacteria, bacteria, yeast, protozoa) and multicellular organisms (fungi, algae, molds). It will be understood that it can be a plant or part of it that is not normally classified as a "cell". The exemplary device selectively selects dividing cells in a more effective and more accurate manner (eg, more preferably targeted at a particular target) as compared to prior art methods. Can be destroyed. In addition, the device according to the invention causes minimal damage to normal tissue, if any, thereby causing many side effects associated with existing selective destruction methods such as radiation therapy and chemotherapy. To reduce or eliminate. The selective destruction of dividing cells when using the apparatus according to the invention does not depend on the sensitivity of the cells to chemicals or radiation. Instead, the selective destruction of dividing cells is based on differences in the geometric shape of dividing cells relative to non-dividing cells, regardless of the shape of the cells being treated.</p><p> In one exemplary embodiment, the selective destruction of living tissue, such as shape-dependent, is performed by using an electronic device to create a non-uniform electric field in the cell.</p><p> We present that non-dividing cells can take on various shapes, such as spherical, oval, columnar, or "pancake-like", but the actual division process of all cells is anaphase late. Or in the final phase, it was observed to be characterized by the development of "cleavage furrows". This cleavage furrow is a slow compression of the cell membrane (between two pairs of daughter chromosomes) that microscopically divides the cell into two new cells (eg, a rift). Observed as growth of grooves or notches). During the division process, there is a transition period (telophase). During this transition period, the cell structure is basically a structure in which two small cells are interconnected by narrow "bridges" formed from the cellular material. The division process is complete when the "bridge" between the two small cells breaks. The selective destruction of tumor cells when using the electronic devices according to the invention takes advantage of this unique geometry of dividing cells.</p><p> When a cell or a group of cells is under natural conditions or environment, that is, when they are present as part of living tissue, the cells are electrolyzed with an electrolytic intracellular fluid. It is surrounded and arranged by other cells, which are mostly composed of intracellular fluid, and by a conductive environment, which is mostly composed of. When an electric field is created in a living tissue by applying a voltage across the tissue, an electric field is formed in the tissue and the distribution and arrangement of lines of electric force defines the direction of charge displacement, or When an electric current is actually induced in the cell, it defines the direction of the electric current path in the tissue. The distribution and arrangement of the electric field includes the shape and electrical properties of various tissue components, the relative conductivity, capacitance and dielectric constant of the tissue components (which can be frequency dependent). Depends on various parameters of.</p><p> The current flow pattern in dividing cells is very different and unique compared to non-dividing cells. Such dividing cells include first and second small cells, i.e., "original" cells and newly formed cells, which are cytoplasmic "bridges" or "bridges" or " It is connected by a "neck". The electric current penetrates into the first small cell through a part of the cell membrane (the "pole that forms the source of the electric current"). However, the current is not derived from the first small cell through the cell membrane portion near the opposite pole (the "pole that drains the current"). Instead, the current flow lines are concentrated at the neck or cytoplasmic bridge. This significantly increases the density of the current flow line. A corresponding "mirror image" process is triggered within the second small cell, which causes the current flow line to disperse into a low density state as it moves away from the bridge, eventually from the cell membrane portion near the current drain. , Exit the second small cell.</p><p> When a polarizable object is placed in a non-uniform convergent or divergent electric field, an electrical force acts on the object, causing the object to have a high density of lines of electric force. Pull towards a certain place. In the case of dividing cells, an electrical force acts in the direction of the cytoplasmic bridge between the two cells. The ability of all intracellular granules and macromolecules to be polarized drives them all towards the bridge between the two cells. The electric field polarity is independent of the direction of force. Therefore, by using an alternating electric field having specific characteristics, substantially the same effect can be caused. Also, a concentrated, non-uniform electric field, such as that present in or near the bridge or neck, exerts a strong force on the charge and the natural dipole, these members. It will be understood that it can cause structural destruction associated with.</p><p> The movement of intracellular granules towards the bridge divides the cell structure and results in increased pressure in the vicinity of the connecting bridge membrane. This pressure of the intracellular granules on the bridge membrane is expected to break the bridge membrane, and thus the dividing cells are expected to "explode" in response to this pressure. The ability to disrupt cell membranes and the ability to disrupt other cell structures can be enhanced by the application of a pulsed AC electric field with frequencies of about 50 KHz to about 500 KHz. When this type of electric field is applied to the tissue, the force exerted on the intracellular granules has a "hammer" effect. This causes a pulsed force (or beat) to be applied to the intracellular granules several times per second, with varying sizes from both small cells towards the bridge (or neck). And enhances the movement of intracellular granules of mass, thereby increasing the likelihood of cell membrane disruption at the bridge moiety. The force exerted on the intracellular granules can also affect the intracellular granules themselves and destroy the intracellular granules.</p><p> According to one exemplary embodiment, the device for applying the electric field is an electronic device that produces the desired electrical signal in the form of a corrugated or sequence of pulses. Electronic devices are equipped with a power supply that generates AC voltage waveforms at frequencies in the range of about 50 KHz to 500 KHz. The power supply is operably connected to the conductive leads. Conductive leads are connected to insulating conductors / electrodes (also referred to as isolects) at the other end. The generated AC waveform is applied to the insulated electrode / electrode. The insulated electrode is composed of a conductor and a dielectric (insulating layer) in contact with the conductor and with respect to the conductive tissue, thereby forming a capacitor. The electric field generated by the apparatus according to the present invention can be applied in various modes depending on the specific therapeutic application.</p><p> In one exemplary embodiment, the electric field is applied by an external insulating electrode incorporated within the garment product. The insulated electrode can be configured such that the applied electric field is of a local type targeting a particular local tissue area (eg, a tumor). This embodiment can be configured to treat tumors and injuries located on or just below the skin surface by wearing a garment product on the target tissue. In this case, the electric field generated by the insulating electrode is directed at the tumor (such as an injury).</p><p> In other embodiments, the device is used in buried type applications. In this case, the insulating electrode is in the form of a probe, catheter, etc., and is configured to be inserted into the body through a natural passage such as the urethra or vaginal cavity, or to be inserted through living tissue. To. Ultimately, the insulating electrode is placed near a target area in the body (eg, an internal tumor).</p><p> Therefore, the apparatus according to the present invention utilizes an electric field that falls into a special intermediate category, unlike the high frequency and low frequency applications in the prior art. The electric field according to the present invention is a bioeffective electric field and has no stimulating effect or thermal effect. Advantageously, if the non-dividing cells are subjected to such an electric field, the non-dividing cells are unaffected. However, the situation is very different when cell division is subjected to an electric field according to the present invention. Therefore, the electronic device and the generated electric field according to the present invention target dividing cells such as tumors, not non-dividing cells in healthy tissues located around the target region. Furthermore, since the device according to the present invention uses an insulating electrode, the above-mentioned negative effects when a conductive electrode is used, that is, changes in ion concentration in cells and generation of harmful substances by electrolysis, etc. Such a negative effect does not occur when the device according to the invention is used. This is because, in general, no actual transfer of charge occurs between the electrode and the medium, and because the current is capacitive and no charge flows through the medium.</p><p> It will be appreciated that the electronic devices according to the invention can also be used in applications other than the treatment of tumors in vivo. In fact, selective disruption using the apparatus according to the invention can be used in connection with all organisms that multiply by division. For example, it can be used in relation to tissue culture, microorganisms such as bacteria, and organisms such as mycoplasma, protozoans, fungi, algae, and plant cells. Such organisms divide by the formation of grooves or crevices, as described above. As the groove or rift deepens, a narrow bridge is formed between the two organisms, similar to the bridge formed between small cells during animal cell division. As in the case of the cell membrane of animal cells as described above, such an organism is covered with a cell membrane having a relatively small conductivity, so that the lines of electric force in the organism during division Concentrates at the bridge connecting the two parts of the fission organism. Concentrated lines of electric force provide electrical forces that displace the polarizable elements and charges inside the splitting organism.</p>

The above or other objectives, features and advantages of the device according to the invention will become clear by reading the following description with reference to the accompanying drawings. In the attached drawings, the same reference numerals are given to the same members.

Figures 1A-1E schematically show the various stages of the cell division process. FIG. 1A shows the cell (10) in its normal shape. The cells (10) are generally spherical, elliptical, cylindrical, "pancake-shaped", or any other various shapes, as is known in the art. Can be. Figures 1B-1D illustrate cells (10) at various stages of the division process. Division forms two new cells (18,20), as shown in Figure 1E.

As shown in FIGS. 1B-1D, the division process of cell (10) is characterized by the slow growth of cleavage furrows (12). Cleavage furrow (12) gradually separates cells (10) into two units, i.e. small cells (14,16), and finally new cells (18,20) (figure). 1 E) is generated. The division process is characterized by a transitional period, especially as shown in Figure 1D. During this transitional period, the structure of the cell (10) is essentially two small cells (14,) interconnected by a thin "bridge" (22) containing the cellular material (cytoplasm surrounded by the cell membrane). 16).

Now, in FIGS. 2A and 2B, the non-dividing cell (10) is schematically illustrated, and the non-dividing cell (10) is subjected to an electric field formed by applying an AC potential. In FIG. 2A, the AC potential has a relatively low frequency, and in FIG. 2B, the AC potential has a relatively high frequency. The cell (10) comprises intracellular granules such as the nucleus (30). The alternating potential is applied between electrodes (28,32) that can be externally attached to the patient at a predetermined region, such as in the vicinity of the tumor to be treated. When cells (10) are in a normal state, i.e., when they are part of living tissue, cells (10) are in a conductive environment consisting mostly of electrolytic intercellular fluids. It is placed under (hereinafter referred to as "volumetric conductor"). When an electric potential is applied between the electrodes (28,32), some of the lines of electric force of the combined electric field (or the current induced in the tissue in response to the electric field) are cells (10). Invade inside. On the other hand, the rest of the lines of electric force (or induced current) flow in the surrounding medium. In this example, the particular distribution of lines of electric force, such that it substantially coincides with the direction of current flow, depends on the shape of the system components and also the relative conductivity of the system components, eg, relative conductivity. It also depends on electrical properties, such as the permittivity of system components, which can be frequency dependent. At low frequencies, such as frequencies below 10 KHz, the conductive properties of the components completely dominate the current flow and electric field distribution. The electric field distribution is generally as shown in FIG. 2A. There is. At higher frequencies, such as frequencies between 10KHz and 1MHz, the dielectric properties of the components become more important and ultimately dominate the electric field distribution. As a result, the distribution of lines of electric force is generally as shown in FIG. 2B.

In the case of a constant (ie, DC) electric field, and in the case of relatively low frequency AC electric fields, such as frequencies below 10 KHz, the dielectric properties of the various components determine the electric field distribution and It is not important in the calculation. Therefore, as a first approximation, with respect to the electric field distribution, the system can be adequately represented by the relative impedances of the various components. Using this approximation, the intercellular (ie, extracellular) fluid and the intracellular fluid each have relatively small impedances, while the cell membrane (11) is relatively large. It has impedance. Therefore, under the condition of low frequency, only a part of the lines of electric force (or the electric current induced by the electric field) penetrates into the cell membrane (11) of the cell (10). In contrast, at relatively high frequencies (eg 10KHz-1MHz), the impedance of the cell membrane (11) to the intercellular and intracellular fluids is reduced, thus allowing the current to enter the cell. The proportion of is increased considerably. At very high frequencies, i.e. above 1 MHz, the capacitance of the cell membrane can short-circuit the resistance of the cell membrane, so that the total cell membrane resistance can be negligible. Please be careful.

In any of the embodiments described above, the lines of electric force (or induced current) are, for example, positive electrodes (28) (the present specification) with respect to one of the electrodes for current generation in the cell membrane (11). Inside, it invades the cell (10) from the part closest to the "source"). The pattern of current flow across the cell (10) is generally uniform. This is because, under the above approximation, the electric field induced in the cell is substantially uniform. The current is applied to the cell from the portion of the cell membrane (11) that is closest to the counter electrode, eg, the negative electrode (32) (also referred to herein as the "drain"). (10) Derived to the outside.

The difference between electric lines of force and current flow depends on many factors. For example, it depends on the frequency of the applied potential, or which electrode (28,32) is electrically isolated. For insulated electrodes for applying DC voltage or low frequency AC voltage, there is no actual current flow along the lines of electric force. At higher frequencies, displacement currents are induced in the tissue by charging and discharging the insulating material of the electrodes and the cell membranes, which, to some extent, act as capacitors. Also, such currents follow the lines of electric force. In contrast, the electric field generated by the uninsulated electrodes always produces the same form of electric current. In particular, a DC electric field or a low-frequency AC electric field generates a conductive current along the lines of electric force, and a high-frequency AC electric field generates both a conductive current and a displacement current along the lines of electric force. However, in the present invention (discussed below), the movement of the polarizable intracellular granules is independent of the actual current, and thus both insulated and uninsulated electrodes can be effectively used. Please understand that. Some advantages of insulated electrodes are low power consumption and low heat generation in the therapeutic area.

According to an exemplary embodiment of the invention, the electric field used has a frequency in the range of about 100 KHz to about 300 KHz, preferably having a frequency in the range of about 50 KHz to about 500 KHz. It is an AC electric field as if it were. For the sake of brevity, this type of electric field is also referred to herein as the "TC electric field". This is "Tumor Curing Abbreviation for "electric field". These electric fields fall into the medium category (between the high and low frequency ranges), have biologically effective properties, and are substantially stimulating. It has neither a target effect nor a heating effect. These frequencies are small enough that the behavior of the system can be determined by the ohm-like (conductive) properties of the system, yet have no stimulating effect on the excitable tissue. It's big enough. Such a system consists of two types of components. That is, it is composed of an intercellular fluid or an extracellular fluid or a medium, and individual cells. Interstitial fluids are often electrolytes with an intrinsic resistance of about 40 to about 100 Ωcm. As mentioned above, cells are characterized by three components. That is, (1) a cell membrane that coats cells and has a thin and large electrical resistance value; (2) an electrolyte that often has a large number of macromolecules and microgranule including nuclei. Characterized by the internal cytoplasm, such as; (3) membranes, which have electrical properties similar to cell membranes and coat microgranule.

When this type of system is subjected to the TC electric field according to the present invention (for example, an AC electric field in the frequency range of 100 KHz to 300 KHz), most of the lines of electric force and the current have a large resistance value of the cell membrane. Therefore, it tends to separate from the cell. Therefore, the lines of electric force are maintained in the extracellular conductive medium. In the frequency range exemplified above, the actual percentage of lines of electric force or current that penetrates into the cell is highly frequency dependent.

2A and 2B schematically show the electric field distribution that occurs in the system. As shown, the lines of electric force represent potential current flow lines that can flow across the cell volume and are mostly undistorted, parallel lines of electric force (main of the electric field). Parallel to the direction). In other words, the electric field inside the cell is almost uniform. In practice, the rate of electric or current entering the cell is determined by the impedance value of the cell membrane compared to the impedance value of the extracellular fluid. Impedance is a function of frequency because the electrical equivalent circuit of the cell membrane is a parallel circuit of a resistor and a capacitor. The higher the frequency, the smaller the impedance value, the higher the percentage of incoming current, and the smaller the distortion of the electric field (Rotshenker S. &amp; 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)).

As mentioned above, when a cell is subjected to a relatively weak electric and current of high frequency alternating current, such as the TC electric field according to the invention having frequencies in the range of 50 KHz to 500 KHz, the non-dividing cell will receive There is no effect. Although the TC electric field according to the invention has no detectable effect in such a system, the situation is different in the presence of dividing cells.

Now, FIGS. 3A to 3C show cells (10) in the process of division under the influence of an alternating electric field (TC electric field) in the frequency range of about 100 KHz to about 300 KHz, based on an exemplary embodiment. The current flow pattern is shown schematically. Lines of electric force or induced currents penetrate into the cell (10) through a portion of the cell membrane of the small cell (16) near the electrode (28). The invading lines of electric force or induced currents also pass through the bridge (22) connecting the newly formed and still attached small cells (14) to the small cells (16) and within the cell membrane. , It is not derived through the part located near the bridge (22). Instead, the relatively widely dispersed lines of electric force or current paths within the small cell (16) converge as they approach the bridge (22) (also referred to as the "neck" (22)). This dramatically increases the current density / line of force density within the neck (22). The "mirror image" process is also triggered within the small cell (14). Therefore, the lines of electric force concentrated in the bridge (22) diverge as they approach the exit region towards the small cells (14).

Those skilled in the art will not exert a force on an electrically neutral object, i.e., an object whose net charge is substantially zero. That will be understood. However, such objects will be polarized. However, under non-uniform and concentrated electric fields, as shown in FIGS. 3A-C, electrical forces act on polarized objects, which have high lines of electric force. Move towards where the density is. It is understood that the concentrated electric field that is substantially present in the area of the neck or bridge can exert a large force on the charge and the natural dipoles and destroy the structures associated with them. Will be. It will be appreciated that a similar net force acts on the charge in the AC electric field, again in the direction of the higher density of the electric field.

In the configurations of FIGS. 3A and 3B, the moving direction of the polarized and charged object is in the direction of high density of electric lines of force. That is, it goes to the cytoplasmic bridge (22) between the small cells (14, 16). It is known in the art that all intracellular granules, such as the nuclei (24,26) of small cells (14,16), are polarizable. Therefore, such intracellular granules are electrically urged and migrate towards the bridge (22). Its movement is always alternating current to intracellular granules, such as the nucleus (24,26), by moving from a lower current density to a higher current density, regardless of the polarity of the field. The force applied by the electric field is always directed towards the bridge (22). A comprehensive description of such forces and the migration caused by the macromolecules of intracellular granules, a phenomenon called "dielectric electrophoresis", eg, CL Asbury &amp; G. van den Engh, Biophys. J. It is described in the literature 74, 1024-1030, 1998. The contents of this document are incorporated herein by reference in their entirety for reference.

The migration of intracellular granules (24,26) towards the bridge (22) disrupts the structure of dividing cells, altering the concentration of various cell components and eventually to the bridge membrane (22). Concentrated intracellular granule pressure causes the cell membrane (11) to rupture near the bridge (22), as schematically shown in Figure 3C. The ability to disrupt the cell membrane (11) at the bridge (22), or otherwise disrupt the cell structure and tissue, is further enhanced by the application of a pulsed AC electric field rather than a stable AC electric field. be able to. When a pulsed electric field is applied, the force acting on the intracellular granules (24,26) has a "hammer" effect. This causes a pulsatile force to impact the intracellular granules from both small cells (14,16) towards the neck (22), thereby destroying the cell membrane (11) in the vicinity of the neck (22). Increase the potential.

A very important component, which is highly sensitive to the special electric field passing through the dividing cell, is the microtubule spindle, which plays a major role in the division process. In FIG. 4, the dividing cells (10) are shown as being in an earlier stage than in FIGS. 3A and 3B, and are affected by an external TC electric field (eg, an alternating electric field in the frequency range of 100 KHz to 300 KHz). Is receiving. Lines of electric force are indicated by reference numeral (100) and the corresponding spindle mechanism is indicated by reference numeral (120). Line (120) is a microtubule known to have a very strong dipole moment. This strong polarization causes microtubules and other polarizable macromolecules to, in particular, microtubules and polarizable macromolecules that have specific orientations in and around the cell, with respect to the electric field. Be susceptible. Two positive charges are located at the two centrioles, while two pairs of negative electrodes are located at the center of the dividing cell, indicated overall by sign (130). Another pair, such as the one above, is located at the location of microtubule attachment to the cell membrane. This structure forms a pair of double dipoles. Therefore, they are susceptible to electric fields that are oriented differently from each other. It will be understood that the effect of the TC electric field on the dipole does not depend on the formation of the bridge (neck). Therefore, the dipole is affected by the TC electric field before the formation of the bridge (neck).

In the apparatus according to the invention, by using an insulated electrode (as described in detail later), the above-mentioned negative effect that occurs when a conductive electrode is used, that is, an ion in a cell. The problem of concentration change and the problem of generation of harmful substances by electrolysis do not occur when the apparatus according to the present invention is used. This is because, in general, the actual transfer of electric charge does not occur between the electrode and the medium, and the current does not flow in the medium such that the current is capacitive, that is, the rotation of the electric charge, etc. This is because no current flows in the medium as expressed only as.

Now, in FIG. 5, the TC electric field found to be effective in destroying tumor cells is generated by an electronic device (200). FIG. 5 is a simplified and schematic view of the electronic device (200), showing the main components. The electronic device (200) generates a desired electrical signal (TC signal) in the form of a waveform or in the form of a plurality of pulses forming a series. The device (200) comprises a power supply (210) and a pair of conductive leads (220) connected to the corresponding terminals of the power supply (210). The opposite end of the lead (220) is connected to an insulated conductor (230) that is activated by an electrical signal (eg, a waveform). The insulated conductor (230) is also referred to herein as an insulated conductor (or isolect) (230). Additionally, in another exemplary embodiment, the device (200) comprises a temperature sensor (240) and a control box (250). These members are provided to control the amplitude of the generated electric field so as not to generate excessive heating in the therapeutic area.

The power supply (210) produces an AC voltage waveform (ie, a TC electric field) with frequencies in the range of about 50 KHz to about 500 KHz (preferably about 100 KHz to about 300 KHz). The required voltage is such that the electric field strength in the tissue to be treated is in the range of about 0.1 V / cm to about 10 V / cm. To form this electric field, the actual potential difference between the two conductors of the insulating conductor (230) is determined by the relative impedance of the system components, as described below.

If a control box (250) is provided, the control box (250) controls the output of the power supply (210). As a result, the power output is kept constant at a value preset by the user. Alternatively, the control box (250) sets a maximum power value that does not cause excessive heating. Alternatively, the control box (250) issues a warning or the like when the temperature (detected by the temperature sensor (240)) exceeds a preset limit value.

The lead (220) is a standard insulated conductor with a flexible metal shield. Preferably, it is grounded so as to prevent the diffusion of the electric field generated by the lead wire (220). The insulating conductor (230) has a particular shape and arrangement so that it can generate an electric field with the desired distribution, direction and strength at the target volume and can only be treated at the target volume. have.

Regarding the whole and individual components, the specification of the device (200) is that at the frequency of the TC electric field (50KHz to 500KHz) according to the present invention, the living system has "omic characteristics" instead of dielectric characteristics. It is greatly influenced by the fact that it behaves on the basis of it. The only component in a device (200) that behaves differently is the insulator of the insulating conductor (230) (see FIGS. 7-9). The insulating conductor (230) is composed of a conductor that is in contact with the dielectric that is in contact with the conductive structure and thus forms a capacitor.

The details of the configuration of the insulating conductor (230) are based on electrical behavior as can be understood from a simplified electrical circuit when in contact with the tissue, as is commonly shown in FIG. ing. In the illustrated configuration, the voltage drop or electric field distribution between the different components is determined by their relative electrical impedance, that is, the proportion of the electric field for each component is the impedance value of that component. It is given by dividing by the sum of the circuit impedance values. For example, with respect to the voltage drop for component (A), ΔV_A = A / (A + B + C + D + E). Therefore, in the case of DC or low frequency AC, all actual voltage drops are related to the capacitor (the capacitor acts as an insulator). At relatively high frequencies, the capacitors are actually short-circuited. Therefore, in fact, all electric fields are distributed in the tissue. At the frequency in the TC electric field according to the present invention (for example, 50KHz to 500KHz), since it is an intermediate frequency, the impedance value of the capacitance of the capacitor becomes dominant and determines the electric field distribution. Therefore, in order to increase the effective voltage drop across the structure (electric field strength), the impedance values of the capacitors should be reduced (ie, their capacitance should be increased). This can be achieved by increasing the effective area of the "plate" that forms the capacitor, by reducing the thickness of the dielectric, or by using a dielectric with a large permittivity. Can be done.

In order to optimize the electric field distribution, the insulating conductor (230) is variously configured depending on the application in which the insulating conductor (230) should be used. There are two main modes for applying an electric field (TC electric field) according to the present invention. First, the TC electric field can be applied by an external (or external) insulating conductor. Second, the TC electric field can be applied by an internal (or internal) insulating conductor.

The electric field (TC electric field) applied by the external insulating conductor can be of a local type or of a widely dispersed type. The first type includes, for example, the treatment of skin tumors and the treatment of injuries close to the surface of the skin. FIG. 7 shows an exemplary embodiment in which the insulating conductor (230) is incorporated into the skin patch (300). The skin patch (300) can be a self-adhesive flexible patch and can include a pair or more of insulating conductors (230). Does the skin patch (300) have an inner insulator (310) (formed from a dielectric material) and an outer insulator (260) and have a tumor (303) on the skin? Alternatively, it is applied to a skin surface (301) that has a tumor (303) slightly below the skin. Tissues are generally indicated by the code (305). The inner insulator (310) must have a relatively large capacitance to prevent a voltage drop across the inner insulator (310) that governs the system. This can be obtained with a large surface area. However, in that case, it is not desirable because it results in the distribution of the electric field over a large area (eg, a larger area than was needed to treat the tumor). Alternatively, the inner insulator (310) can be formed as very thin and / or the inner insulator (310) can have a large dielectric constant. The resistance of the skin between the electrodes (indicated as symbol (A, E) in FIG. 6) is usually the tissue located just below the skin (indicated as symbol (C) in FIG. 6). Most of the voltage drop beyond the insulating conductor occurs in the skin because it is significantly greater than the resistance of (1-10 KΩ, pair, 0.1-1 KΩ). In order to accommodate such impedance (Z), the inner insulator (310) (in FIG. 6, reference numeral (B,) The property (shown as D)) should be such that it has an impedance of preferably 100 KΩ or less at frequencies of TC electric fields (eg, 50 KHz to 500 KHz) according to the present invention. For example, 10mm² In the case of an insulated conductor with a surface area of about 10 KΩ, at a frequency of 200 KHz, 1% or more of the applied voltage can be applied to the tissue. When pedance is desired, the capacitance is about 10^-10Should be a degree of F. This means that a standard insulator having a dielectric constant of 2 to 3 and a thickness of the insulating layer (310) of about 50 to 100 μm is used. A 10-fold stronger internal electric field could be obtained by using an insulator with a dielectric constant of about 20-50.

The insulator can be replaced with an insulating material having a very high dielectric constant, such as titanium dioxide (eg, rutile), such as because the thin insulating layer can be very fragile. In that case, the permittivity can reach a value of about 200. There are many different materials that are suitable for use in their intended application and that have a large dielectric constant. For example, such materials include: That is, lithium niobate (LiNbO), which is a ferroelectric crystal and has many applications in optical devices, pyroelectric devices, and piezoelectric devices.₃ ) And; Yttrium iron garnet (YIG), which is a ferrimagnetic crystal and can form a magneto-optical device such as an optical insulator, and; is a ferromagnetic crystal and has a large electro-optical effect. Barium titanate (BaTiO₃ ) And; Potassium tantalate (KTaO), which is a dielectric crystal (ferroelectric at low temperatures), has a very small microwave loss, and has an adjustable permittivity at low temperatures.₃ ) And; Lithium tantalate (LiTaO), which is a ferroelectric crystal having the same characteristics as lithium niobate and is used in electro-optical devices, pyroelectric devices, and piezoelectric devices.₃ ); It will be appreciated that the materials exemplified above can be used in combination with the present invention if it is desired to use a material with a large dielectric constant.

Other factors that affect the effective capacitance of the insulating conductor (230) must be considered. In particular, other factors that affect the effective capacitance of the insulating conductor (230) in the presence of air between the insulating conductor (230) and the skin must be considered. The presence of such air is not easily preventable and provides a dielectric constant of 1.0 in the insulating layer. This significantly reduces the effective capacitance of the insulating conductor (230) and negates the advantages of titanium dioxide (eg routil) and the like. To overcome this problem, the insulating conductor (230) can be shaped to fit the body structure. Intervening fillers (270) (shown in FIG. 10C'), such as gels, which have high conductivity and high effective dielectric constant, can be added to the structure. Molding can be preformed (see Figure 10A). Alternatively, the system can be kept sufficiently flexible so that the insulating conductor (230) can be easily molded. The gel can be housed in place by a rim with a high edge, as shown in FIGS. 10C and 10C'. The gel can be formed from hydrogel, gelatin, Amakusa, etc., and salts can be dissolved inside to increase the conductivity. 10A to 10C'show various configuration examples of the insulating conductor (230). The exact thickness of the gel is not important as long as it is thick enough to prevent the gel layer from drying out during treatment. In one exemplary embodiment, the gel thickness is from about 0.5 mm to about 2 mm.

In order to achieve the desired characteristics of the insulating conductor (230), each dielectric coating should be very thin. For example, it should be 1-50 μm. Due to the very thin coating, the insulating conductor (230) can easily be mechanically damaged. This problem can be overcome by adding protective measures to the structure forming the insulating conductor. This can provide the desired protection against such damage. For example, the insulating conductor (230) can be coated with a relatively sparse net (340). The net (340) prevents access to the surface, but has little effect on the effective surface area of the insulating conductor (230) (ie, as shown in the cross section of FIG. 12B). It has little effect on the capacitance of 230). The sparse net (340) guarantees good contact with the skin etc. without affecting the capacitance. The sparse net (340) ) Can be formed from many different materials, however, in one exemplary embodiment, the net (340) is formed from nylon, polyester, cotton, etc. Instead. , A very thin conductive coating (350) can be added to the dielectric portion (insulating layer) of the insulating conductor (230). The conductive coating as an example is made of metal, especially gold. The thickness of the coating (350) depends on the particular application and also on the type of material used to form the coating (350), however, gold. When used, the coating has a thickness of about 0.1 μm to about 0.1 mm. In addition, rims such as those shown in FIG. 10 can provide some kind of mechanical protection. it can.

However, capacitance is not the only factor to consider. The following two factors also influence how the insulating conductor (230) is constructed. That is, the dielectric strength of the inner insulating layer (310) and the dielectric loss that occurs when a TC electric field is applied, that is, when heat is generated. The dielectric strength of the inner insulator (310) is determined by at what electric field strength the insulation "shorts" and loses its insulating function. Typically, an insulator such as plastic has a dielectric strength of about 100 V or more per μm. As the large dielectric constant reduces the electric field in the inner insulator (310), the combination of the large dielectric constant and the large dielectric strength brings great advantages. This can be obtained by using a single material with the desired properties, or by a double layer with the appropriate parameters and thickness. In addition, to further reduce the likelihood of failure of the insulating layer (310), using conventional techniques, rounding the corners, as shown in FIG. 10D, thereby the insulating layer (310). All sharp edges should be removed.

8 and 9 show a second type of treatment using an insulating conductor (230), in particular an electric field is generated by the internal insulating conductor (230). The body in which the insulating conductor (230) is embedded is generally indicated by the symbol (311) and has a skin surface (313) and a tumor (315). In this embodiment, the insulating conductor (230) has a plate shape, wire shape, or other shape that can be inserted subcutaneously, i.e. deeper within the body (311). Can have. This makes it possible to generate an appropriate electric field in the target region (tumor 315).

It will be appreciated that the mode of application of the insulating conductor is not limited to the above description. In the case of tumors in internal organs such as the liver and lungs, the distance between each member of the pair of insulating conductors (230) can be made larger. Paired electrodes can even be placed on both sides of the fuselage (410), as shown in FIG. The arrangement of the insulating conductor (230) in FIG. 11 is particularly effective in treating a tumor (415) associated with lung cancer or gastric cancer or intestinal cancer. In this embodiment, the electric field (TC electric field) extends over a wide area of the body.

Selection of materials and selection of electric field parameters is necessary to avoid overheating of the tissue to be treated. The insulating material of the insulating conductor should have the least dielectric loss in the frequency range used during the therapeutic process. This factor can be taken into account when selecting a particular frequency for treatment. Direct heating of the tissue will most likely be dominated by heating based on the current flow (given by the product I × R). In addition, the insulating conductor (insulated electrode) (230) and its surroundings should be made of a material that can facilitate heat dissipation, and the overall structure of the insulating conductor is heat dissipation. It should be the smallest structure that can prevent heat release to the surrounding environment (air) and has a large thermal conductivity. is there.

The effectiveness of treatment is enhanced by the placement of insulating conductors (230) so that the electric field can be concentrated at the desired target and other sensitive areas (ie, protected areas) can be maintained at a low electric field density. Can be done. Proper placement of the insulating conductor (230) over the body can be maintained using any variety of techniques, including the use of suitable clothing that can keep the insulating conductor in the proper position. .. FIG. 13 shows such an arrangement such that the region indicated by the symbol P is a protected region. The electric field lines do not penetrate into this protected area, and the electric field in the protected area is much smaller than in the vicinity of the insulating conductor (230) where the target area can be placed and treated. In contrast, the electric field strength near the four electrodes is very large.

The following examples exemplify an application example of the device according to the present invention and an application example of the TC electric field. However, the following examples do not limit the scope of the present invention in any way.

"Example" To demonstrate that an electric field with the above characteristics (eg, a frequency of 50 KHz to 500 KHz) is effective in destroying tumor cells, an electric field was applied to treat mice with malignant black tumors. .. Two pairs of insulating conductors (230) were placed on the corresponding pair of malignant melanomas. Only a pair of electrodes were connected to the power source (210) and an alternating electric field (TC electric field) of 200 KHz was applied to the tumor for 6 days. One black tumor has not been treated. This allows comparisons between treated and untreated tumors. After 6 days of treatment, colored black tumors remained clearly visible for the untreated tumors of the mice. On the other hand, in contrast, no tumors could be visually recognized in the treated tumors of the mice. The only area recognizable and visible on the skin was the trace of the insertion point of the insulating conductor (230). The fact that the treated tumor was removed was further confirmed by cutting the skin and flipping it over so that the inner surface of the skin could be exposed. This showed that for the treated tumor of the mice, the tumor was substantially removed, although it may not be complete. Successful treatment was also confirmed by pathological examination.

Thus, the inventor has found that by using an electric field with exceptional properties, dividing cells or tumors can be destroyed when an electric field is applied using an electronic device. More specifically, such electric fields fall into a special intermediate category. That is, it is classified as a biologically effective electric field. Such an electric field has neither a stimulating effect nor a heating effect. Therefore, it is possible to overcome the drawbacks of applying an electric field to the body by the prior art. It will be appreciated that the device according to the invention may further comprise a device for rotating the TC electric field with respect to living tissue. For example, in one embodiment, the AC potential applied to the tissue to be treated may be a device according to the prior art, such as a mechanical device capable of rotating various components in the system according to the present invention at startup. Used to rotate against tissue.

Furthermore, in other embodiments, the TC electric field is applied to the various pairs of insulating electrodes (230) in a continuous manner. In other words, the power supply (210) and its control system are configured so that signals can be sent at periodic intervals to select electrode (230) pairs. As a result, a plurality of pairs of insulating electrodes (230) form TC electric fields in various directions. By transmitting a signal from the power supply to the insulating electrode (230) at a selected timing, a TC electric field that changes direction is continuously generated by the various insulating electrodes (230). This configuration has many advantages and is based on the view that the TC electric field is most effective when it is parallel to the axis of cell division. Due to the fact that the orientation of cell division is random in most cases, only some of the large number of dividing cells are affected by the applied electric field. Therefore, the use of multiple electric fields with more than one orientation increases effectiveness by increasing the chances that a given TC electric field will affect more dividing cells.

Now, FIG. 14 shows a garment product (500) as an exemplary embodiment. More specifically, a garment product (500) is in the form of a hat, cap, or other type of garment product configured to be worn on a person's head. For illustrative purposes, the head (502) wears a hat (500). The hat (500) is placed relative to the head and is placed relative to the skin surface (504) of the head (502). Intracranial tumors (510) and the like are shown as being formed inside the head (502), just below the skin surface (504). Therefore, the cap (500) is intended to be placed on the head (502) of a person who has a tumor (510) or the like.

What are the various embodiments shown in FIGS. 1 to 13 such that the insulating electrodes (230) are more or less planarized because they are placed on the skin surface or embedded in vivo? Unlike, the insulating electrode (230) in this embodiment has a special configuration and is used in a specific application. Treatment of intracranial tumors or other injuries typically requires relatively long-term treatment, for example days to weeks. Therefore, it is desirable to provide the patient with as much comfort as possible. The hat (500) is specifically configured to be able to provide comfort during long treatment periods without interfering with the effectiveness of the treatment.

According to one exemplary embodiment, the cap (500) comprises a predetermined number of insulating electrodes (230). These insulated electrodes (230) are preferably arranged so that an optimal TC electric field can be generated at the tumor (510). The lines of electric force of the TC electric field are generally indicated by the code (520). As can be seen from FIG. 14, the tumor (510) is located inside these lines of electric force (520). As will be described in detail later, the insulating electrode (230) allows a part or surface of the insulating electrode (230) to freely contact the skin surface (504) of the head (502) in the hat (500). Is placed in. In other words, when the patient wears a hat (500), the insulating electrodes (230) are arranged so that they can contact the skin surface (504) of the head (502) at the selected position. .. As a result, the TC electric field generated by the insulating electrode (230) can be concentrated on the tumor (510), and the electric field can be maintained at a low density in the peripheral region. Typically, the hair on the head (502) is shaved in selected areas to allow better contact between the insulating electrodes (230) and the skin surface (504). However, this is not important.

The cap (500) preferably comprises a mechanism (530) for applying a urging force to the insulating electrode (230) so that the insulating electrode (230) can be pressed against the skin surface (504). ing. For example, the mechanism (530) can be of a bias type such that a bias force is applied to the insulating electrode (230). As a result, the insulating electrode (230) is pressed in a direction away from the hat (500). Therefore, when the patient wears a hat (500) on the head (502), the insulating electrode (230) is pressed against the skin surface (504) by the mechanism (530). The mechanism (530) can be slightly contracted to provide a comfortable fit between the insulating electrode (230) and the head (502). In one exemplary embodiment, the mechanism (530) is a spring-based device located within the cap (500) and is coupled so that a pressing force can be applied to the insulating electrode (230). Has a part of it.

As in the previous embodiment, the insulating electrode (230) is connected to the power supply (210) by a conductor (220). The power supply (210) can be placed within the cap (500) to provide a compact, self-supporting and stand-alone system. Alternatively, the power supply (210) can be externally attached to the hat (500). In this case, the power supply (210) is connected by using the conductor (220) derived from the hat (500) through an opening or the like. It will be appreciated that the power supply (210) can be located in any position by being located outside the hat (500). Such a position is close to the hat (500). Alternatively, there is a position away from the hat (500). For example, the power supply (210) can be placed inside a carrying bag used by the patient (eg, a bag placed around the patient's waist). Alternatively, the power supply (210) can be tied around the patient's torso. Alternatively, the power supply (210) can be placed in a protective case attached to other clothing products worn by the patient. For example, the protective case can be inserted into a pocket such as a sweater. FIG. 14 illustrates an embodiment in which the power supply (210) is incorporated directly into the hat (500).

Now, as shown in FIGS. 15 and 16, in one exemplary embodiment, the plurality of insulating electrodes (230) to which the mechanism (530) is attached are preferably formed as independent units. It is indicated by the symbol (540) as a whole. This unit can be inserted into a cap (500) and is electrically connected to a power source (not shown) via a conductor (not shown). By providing these components in the form of independent units, the patient can easily remove the unit (540) from the hat (500) or into the hat (500) when cleaning, repair or replacement is required. On the other hand, the unit (540) can be easily inserted or inserted.

In this embodiment, the cap (500) is configured with a selection region (550) formed within the cap (500) so that the unit (540) can be received and held. For example, as shown in FIG. 15, each region (550) is in the form of an opening (pore) formed within the hat (500). The unit (540) is composed of a body (542) and includes a mechanism (530) and one or more insulating electrodes (230). In the mechanism (530), a part of the mechanism (for example, one end of the mechanism) is in contact with the surface of each insulating electrode (230) inside the unit (540), whereby the mechanism (530) is insulated. It is arranged so that a bias force can be applied to the surface of the electrode (230). After the unit (540) is received inside the opening (550), the unit (540) uses any variety of conventional techniques, including the use of adhesive materials and the use of mechanical means. Therefore, it can be fixedly held in the opening. For example, the hat (500) can include a rotatable clip member. This clip member is in an open state where the opening (550) is free, and the clip member engages with a part of the insulating electrode (for example, the peripheral edge), thereby holding the insulating electrode (230) in a predetermined position. It is made rotatable between the closed state and the closed state. When removing the insulating electrode (230), the rotatable clip member is moved to the open state. In the embodiment shown in FIG. 16, the insulating electrode (230) is held in the opening (550) by the adhesive member (560). In one embodiment, the adhesive member (560) is a double-sided adhesive rim member and extends around the peripheral edge of the insulating electrode (230). In other words, by removing the protective cover located on one side of the adhesive rim (560), the adhesive rim is applied around the exposed surface of the insulating electrode (230). This allows the adhesive rim (560) to be fixedly attached to the hat (500). Then the adhesive rim (5 Remove the protective cover located on the opposite surface of 60) and secure the insulating electrode (230) to the head (502) in a position positioned relative to the tumor for optimal application of the TC electric field. It is applied to the skin surface (504) in a desired position where it can be placed. One side of the adhesive rim (560) is the skin surface ( It is desirable to shave the head (502) by being in contact with the 540). This allows the adhesive rim (560) to be flush with the skin surface (540).

The adhesive rim (560) allows the unit (540) to be easily attached to and detached from the hat (500) if necessary, and the unit (540) is fixedly mounted within the opening (550). Configured to get. In that case, the unit can be replaced with another unit (540) or the same unit (540). As mentioned above, the unit (540) is provided with a bias mechanism (530) so that the insulating electrode (230) can be pressed against the skin surface (504) when wearing the hat (500). There is. The unit (540) can be configured such that the surface facing the insulating electrode (230) forms a supporting surface made of a rigid material such as plastic. This allows the bias mechanism (530) (eg, spring) to be compressed when a force is applied. Further, when the spring (530) is in a loosened state, the spring (530) is kept in contact with the support surface, and a bias force is applied to the insulating electrode (230) at the other end. The bias mechanism (530) (eg, spring) preferably has a contour corresponding to the skin surface (504), whereby the insulating electrode (for example) when a force is applied to the insulating electrode (230). 230) can have contours corresponding to the skin surface (504). As a result, the insulating electrode (230) and the skin surface (504) can be maintained in a flush state with each other. Although the mechanism (530) can be formed from a spring, there are many other embodiments in which it can be used in place of the spring. For example, the mechanism (530) can be in the form of an elastic material such as sponge rubber, foamed plastic, or an air bubble containing layer.

The unit (540) is equipped with an electrical connector (570). The electrical connector (570) can be connected to a corresponding electrical connector, such as a conductor (220), such as located within a cap (500). One end of the conductor (220) is connected to the unit (540) and the other end is connected to the power supply (210). The power supply (210) can be incorporated directly into the hat (500). Alternatively, the power supply (210) can be placed at a distance (far away) on the patient or at a support or the like near the bed.

As mentioned above, a connecting material, such as a conductive gel, is preferably used, which can ensure an effective conductive environment between the insulating electrode (230) and the skin surface (504). it can. Suitable gel materials can be as described above for the earlier embodiments. The connecting material is arranged on the insulating electrode (230), preferably a uniform layered binder is provided along the surface of the electrode (230). One reason the unit (540) needs to be replaced on a regular basis is that the connecting material needs to be replaced and / or replenished. In other words, after a predetermined period of time, or after a predetermined number of uses, the patient can remove the unit (540) and reapply the connector to the electrode (230).

17 and 18 show other examples of garment products, such as those incorporating an insulating electrode (230) as part. More specifically, a brassiere (700) and the like are shown. The brassiere (700) has a body formed from conventional brassiere material. The body is generally indicated by the symbol (705). The body (705) provides the wearer with shape, support and comfort. The brassiere (700) further comprises a woven support layer (710) on one side. The support layer (710) is preferably formed from a suitable woven material configured to provide the desired support performance required for the brassiere (700).

Like other embodiments, the brassiere (700) comprises one or more insulating electrodes (230) disposed within the brassiere material (705). One or more insulating electrodes are arranged along the inner surface of the brassiere (700) on the surface opposite the support layer (710). The insulating electrode is intended to be placed in the vicinity of a tumor or the like existing in the breast or in a peripheral region thereof. Similar to the previous embodiment, the insulating electrode (230) in this embodiment is specifically configured for application to the breast or nearby regions. Therefore, the insulating electrode (230) used in this application does not have a planar configuration and has an arc shape that is complementary to the general degree of curvature typically found in breasts. doing.

A lining (720) is located across the insulating electrode (230). This assists in holding the insulating electrode in a desired position along the inner surface so that it can be placed relative to the breast itself. The lining (720) can be formed from any number of thin materials that are comfortable to wear against the skin. Also, in one exemplary embodiment, the lining (720) is formed from a woven material.

The brassiere (700) further preferably comprises a bias mechanism (800), as in some previous embodiments. The bias mechanism (800) is located within the brassiere material (705) and extends from the support layer (710) to the insulating electrode (230). The bias mechanism (800) applies a bias force to the insulating electrode (230). As a result, the insulating electrode (230) is pressed against the breast. This means that the insulating electrode (230) does not float from the skin surface to form a gap, which reduces the efficiency of the TC electric field and reduces the therapeutic effect on the skin surface. Guarantee contact. The bias mechanism (800) can be in the form of a spring configuration. Alternatively, the bias mechanism (800) can be an elastic material that applies a desired bias force to the insulating electrode (230) so that the insulating electrode (230) can be pressed against the breast. In the relaxed state, the bias mechanism (800) applies force to the insulating electrode (230), and when the patient wears a brassiere (700) on the body, the insulating electrode (230) points toward the breast. The electrodes apply a force that opposes the bias force. As a result, the insulating electrode (230) is pressed toward the patient's breast. In the illustrated exemplary embodiment, the bias mechanism (800) is in the form of a spring disposed within the brassiere material (705).

The conductive gel (810) can be applied on the insulating electrode (230) between the electrode and the lining (720). The conductive gel layer (810) is formed from the above-mentioned materials so as to be able to perform the above-mentioned functions.

The electrical connector (820) is provided as part of the insulating electrode (230) and is connected to one end of the conductor (220). The other end of the conductor (220) is electrically connected to the power supply (210). In this embodiment, the conductor (220) extends through the brassiere material (705) to the opening formed in the brassiere (700). The conductor (220) extends through the opening and extends to the power supply (210). In this embodiment, the power supply (210) is located away from the brassiere (700). It will be appreciated that in other embodiments, the power supply (210) can be located inside the brassiere (700). For example, the brassiere (700) can have a partition wall formed inside. The partition is configured to receive and hold the power supply (210) in place when the patient wears the brassiere (700). In this configuration, the bulkhead can be covered with removable straps. The strap is openable and closable, allowing the power supply (210) to be housed inside or the power supply (210) to be taken out from the inside. The strap can be made from the same material used to form the brassiere (700). Alternatively, the strap can be formed from some other type of material. The strap can be detachably attached to the perimeter of the brassiere body by a fixing means, such as a material consisting of a hook and a loop. This allows the patient to easily open the septum by separating the material consisting of the hook and the loop. As a result, access to the partition wall can be performed, and the power supply (210) can be taken in and out.

The power supply (210) also has a connector (211) for electrical connection to the conductor (220). As a result, the power supply (210) can be electrically connected to the insulating electrode (230).

As with other embodiments, an insulating electrode (230) is located within the brassiere (700) so that the electric field (TC electric field) can be concentrated on the desired target (eg, tumor). It will be appreciated that the position of the insulating electrode (230) within the brassiere (700) can be changed depending on the position of the tumor. In other words, after the tumor has been positioned, the surgeon decides on the placement of the insulating electrodes (230) and the brassiere (700) is constructed based on this decision. This makes it possible to optimize the effect of the TC electric field on the target region (tumor). Therefore, the number and location of insulated electrodes (230) will depend on the exact location of the tumor or other target area to be treated. Since the position of the insulating electrode (230) on the brassiere (700) can be changed according to a specific application, the exact size and shape of the insulating electrode (230) can be changed as well. is there. For example, if the insulating electrode (230) is located at the bottom of the brassiere (700), unlike the more central position, the insulating electrode (230) will be on the breast (and brassiere) depending on the area of interest. Due to the difference in shape, the shape becomes different.

FIG. 19 shows yet another embodiment. In this embodiment, the insulating electrode (230) is referred to as an internal electrode incorporated in the form of a probe or catheter (600) configured to allow entry into the body through a natural passage such as the urethra or vaginal cavity. It is said to be an aspect. In this embodiment, the insulating electrode (230) is located on the outer surface of the probe (600) along the longitudinal direction of the probe (600). The conductor (220) is electrically connected to the electrode (230) and extends inside the body of the probe (600) up to the power supply (210). The power supply (210) can be located inside the probe body. Alternatively, the power supply (210) can be located at a remote location, separate from the probe (600). For example, it can be placed on the patient or at another location near the patient.

Alternatively, the probe (600) can be configured to penetrate the skin surface or other tissues so that it can reach internal targets located within the body. For example, the probe (600) can invade the surface of the skin and can then be placed adjacent to or near the tumor placed in the body.

In such an embodiment, the probe (600) may be inserted through a natural passage and then placed in the desired position, such as the insulating electrode (230) located near the target region (ie, tumor). it can. Then, by activating the power supply (210), the insulated electrodes (230), against the tumor for a predetermined length of time it can generate a TC field applied to. It is understood that the probe (600) shown is merely an example of the properties and that the probe (600) can be in other shapes and arrangements as long as it can perform its intended function. Will be. Preferably, the conductor (eg, wire) extending from the insulating electrode (230) to the power source (210) is twisted or shielded so as not to generate an electric field along the axial direction.

It will also be appreciated that the probe can include only one insulating electrode, yet the other electrode can be placed on the living body surface. This external electrode should be larger or should consist of a large number of electrodes. As a result, the density and current density of the electric field lines in the non-treatment area can be made small so as not to affect those non-treatment areas. In fact, the electrode placement should be configured so that the electric field in potentially sensitive regions can be minimized.

Figure 20 shows yet other practices, such as using a large collar member (900) (or necklace-type structure) in the stretched state to treat injuries such as the thyroid gland, epithelial bodies, and larynx. Shows morphology. In FIG. 20, the collar member (900) is shown in an open, substantially flat state. In this embodiment, the insulating electrode (230) is built into the body (910) of the collar member (900) and is configured so that it can be placed relative to the area of the wearer's neck. The insulating electrode (230) is connected to the power supply (210) by any of the methods described above. It will also be appreciated that the power supply (210) can be located inside the body (910), or the power supply (210) can be located outside the body (910). The color body (910) can be formed from any material conventionally used to form a collar (900) that is placed around a person's neck. Therefore, the collar (900) preferably comprises means (920) for adjusting the collar (900) with respect to the neck. For example, complementary fasteners (hook and loop fasteners, buttons, etc.) can be placed at the ends of the collar (900) so that the diameter of the collar can be adjusted.

Therefore, the configuration of the device according to the present invention is particularly suitable for applications in which the device can be incorporated into a garment product so that the patient can easily wear the conventional garment product and at the same time receive treatment. Is. In other words, it can provide greater comfort to the patient and increase the effectiveness of the treatment by incorporating some or all of the components of the device into the garment product. It is clear that the type of garment product into which the component will be incorporated can vary depending on the target area of the living tissue in which the tumor, injury, etc. are present. For example, if the target area is within the testicular area of a male patient, a garment product in the form of a sock-like structure or a wrap-like structure can be provided and worn around the testicular area of the patient. Can be configured to obtain. In that case, the insulating electrode is positioned relative to the tumor so that the TC electric field is directed towards the target tissue. The exact nature and morphology of the garment product can vary greatly due to the ability to incorporate the components of the device within most types of garment products, and therefore the patient's body in which conditions may exist. It can be used to treat various areas of the body.

By the way, FIGS. 21 to 22 show other viewpoints in the apparatus according to the present invention. In FIG. 21, a body (1000), such as a human body or any part of an animal body, is illustrated. Similar to the previous embodiment, as described in detail above, two or more insulated electrodes (230) are used in the body (1000) for the treatment of tumors (not shown) and the like using a TC electric field. It is located in the vicinity of. The insulating electrode (230) includes a conductive component and an outer insulator (260) surrounding the conductive component. Each insulating electrode (230) is preferably connected to a power source (not shown) by a lead wire (220). A conductive filler material (eg, conductive gel member 270) is arranged between each insulating electrode (230) and the body (1000). The insulating electrodes (230) are arranged apart from each other, and when the power supply is started, the insulating electrodes (230) generate a TC electric field as described in detail above. The lines of electric force of the electric field (TC electric field) are generally indicated by the code (1010). As shown, the lines of electric force (1010) extend through the conductive gel member (270) between the insulating electrodes (230).

Over time or as a result of certain events, the outer insulator (260) of the insulating electrode (230) can cause dielectric breakdown at any location. By way of example, FIG. 22 shows dielectric breakdown (1020) where the outer insulator (260) of one insulating electrode (230) is adjacent to the conductive gel member (270). It will be understood that the breakdown (1020) of the outer insulator (260) results in a large current density at this location (ie, where the breakdown (1020) occurred). The increase in current density is illustrated by the increase in the number of lines of electric force (1010), the distribution of the lines of electric force (1010), and the spacing between adjacent lines of force (1010). Has been done. One of the side effects of the occurrence of dielectric breakdown (1020) is that the presence of an electric current causes heating at the breakdown site. Therefore, the tissue / skin having the resistance value may burn. In FIG. 22, the superheated region (1030) is shown. This overheated region (1030) is the tissue / skin region where there is an increased current due to breakdown (1020) within the outer insulator (260). The patient feels discomfort and distress in this area (1030) due to the large current present in this area, due to overheating, and due to the burning sensation in this area (1030).

FIG. 23 shows yet another embodiment to which the additional insulating electrode (230) has been applied. In this embodiment, the conductive gel member (270) disposed between the insulating electrode (230) and the body (1000) comprises a conductor (1100). The conductor (1100) is suspended in the gel material forming the member (270). The gel material completely surrounds the conductor (1100). In one exemplary embodiment, the conductor (1100) is a thin metal sheet plate disposed within the conductor (1100). As will be appreciated, if a conductor, such as a plate (1100), is placed in a uniform electric field in a manner perpendicular to the lines of electric force, then the conductor (1100) is actually , Has no effect on the electric field (however, if the two opposing surfaces of the conductor (1100) are equipotential, the corresponding equipotential shifts slightly). On the contrary, when the conductor (1100) is arranged parallel to the electric field, there is considerable distortion in the electric field. The region near the conductor (1100) is not equipotential. This situation is in contrast to the situation where the conductor (1100) is absent. When the conductor (1100) is placed within the gel member (270), the conductor (1100) is typically the conductor (1100) perpendicular to the lines of electric force for the reasons mentioned above. For that reason, it has no effect on the electric field (TC electric field).

When the outer insulator (260) of the insulating electrode (230) undergoes dielectric breakdown, a large current density is generated at the dielectric breakdown point as described above. However, the presence of the conductor (1100) disperses the current throughout the conductor (1100) and then derives the current from the entire surface of the conductor (1100). This causes the current to reach the body (1000) with a current density that is neither large nor small. Therefore, the current reaching the skin does not cause discomfort to the patient, even if dielectric breakdown occurs in the outer insulator (260) of the insulating electrode (230). It is important that the conductor (1100) is not grounded. This is because if grounded, the electric field cannot extend beyond the conductor (1100). Therefore, the conductor (1100) is in a "floating state" inside the gel member (270).

If the conductor (1100) is introduced into the body tissue (1000) and placed parallel to the electric field, the conductor (1100) causes distortion of the electric field. Distortion may disperse the lines of electric force of the electric field (reduce the electric field density) or concentrate the lines of electric force of the electric field (increase the electric field density) depending on the introduction situation and its surroundings. be able to. Therefore, the conductor (1100) can exhibit a screening effect, for example. So, for example, if the conductor (1100) completely surrounds the organ (1101), the electric field within the organ itself will be zero because this type of arrangement is a Faraday cage. However, since it is impractical to place the conductor completely around the organ, the organ can be completely or partially covered by using a conductive net or similar structure. .. As a result, the electric field in the organ itself becomes zero or almost zero. For example, the net can be formed from various conductive wires woven together to form the net. Alternatively, a pair of wires can be arranged to substantially surround or cover the organ (1101). Conversely, the organ to be treated (1103) (target organ) is located within the electric field (1010) (TC electric field), although it is not covered by a member with a Faraday cage effect.

FIG. 24 is an embodiment in which the conductor (1100) is placed within the body (ie, under the skin) and the conductor (1100) is located near a target (eg, a target organ). Is shown. By placing the conductor (1100) near the target, a large electric field density (of the TC electric field) is achieved at the target. At the same time, other organs in the vicinity can be protected from the surroundings by arranging the above-mentioned protective conductive net or the like. This allows other organs in the vicinity to be protected from the electric field. By placing the conductor (1100) near the target, large field density conditions can be formed near the target. In other words, the conductor (1100) can concentrate the TC electric field at a particular region (ie, the target).

It will be appreciated that in the embodiment of FIG. 24, each of the gel members (270) can be provided with a conductor as described with respect to FIG. In such a configuration, the conductor in the gel member (270) protects the skin surface (tissue) from all possible side effects, even if dielectric breakdown occurs in the insulator of the insulating electrode (230). At the same time, the conductor (1100) forms a large electric field density near the target.

There are many different ways in adjusting the electric field density of an electric field, by configuring the electrodes in various ways and / or by intentionally arranging the electrodes relative to each other. For example, in FIG. 25, a first insulating electrode (1200) and a second insulating electrode (1210) are provided and are arranged around the body (1300). Each insulating electrode comprises a conductor such that it is preferably surrounded by an insulating material. In this sense, the term "insulated electrode" is used. A conductive gel member (270) is provided between each of the first and second electrodes (1200, 1210) and the body (1300). Lines of electric force are generally indicated by the code (1220) in this type of configuration. In this embodiment, the first insulated electrode (1200) has significantly larger dimensions than the second insulated electrode (1210) (also the conductive gel member for the second insulated electrode (1210)). , Equally small).

By changing the dimensions of the insulating electrode, the pattern of the electric lines of force (1220) can be changed. More specifically, the electric field is tapered inward toward the second insulated electrode (1210) due to the smaller dimensions of the second insulated electrode (1210). A region of high electric field density, as indicated by the overall sign (1230), is formed near the boundary between the gel member (270) associated with the second insulating electrode (1210) and the skin surface. ing. The various components of the system are manipulated so that tumors in or on the skin are within this large field density. As a result, the area (target) to be treated can be exposed to electric lines of force having a higher electric field density.

FIG. 26 shows a tapered TC electric field when a conductor (1400) (eg, a conductive plate) is placed inside each of the conductive gel members (270). In this embodiment, the size of the gel member (270) and the size of the conductor (1400) are the same or about the same, despite the differences between the insulating electrodes (1200,1210). There is. Again, the conductor (1400) can be characterized by being a "floating plate". This is because each conductor (1400) is surrounded by the material that forms the gel member (270). As shown in FIG. 26, one conductor (1400) is located near the insulating electrode (1210), which is smaller than the other insulating electrode (1200) and smaller than the conductor (1400) itself. Have been placed. The other insulating electrode (1200) is located away from the conductor. One conductor (1400) causes a decrease in electric field density in the tissue placed between one conductor (1400) and the other electrode (1200). The decrease in electric field density is indicated by the sign (1410) as a whole. At the same time, a very non-uniform tapered electric field, as indicated by the sign (1420) overall, varies from very low density to very high density, one conductor (1400). It is formed between the insulating electrode (1210) and the insulating electrode (1210). One advantage of this exemplary configuration is that the size of the insulating electrode can be reduced without causing an increase in the electric field density in the vicinity. This is important because electrodes with insulators with very high dielectric constants are very expensive. For example, one insulated electrode can cost more than $ 500.00. Also, the price is sensitive to a particular therapeutic area. Therefore, reducing the size of the insulating electrode directly leads to cost reduction.

Although the invention has been specifically described and illustrated with respect to preferred embodiments thereof, it will be appreciated by those skilled in the art that various modifications can be made in form and detail without departing from the spirit and scope of the invention. There will be.

<figref num="1A">It is a schematic cross-sectional view which shows each stage of a cell division process.</figref><figref num="1B">It is a schematic cross-sectional view which shows each stage of a cell division process.</figref><figref num="1C">It is a schematic cross-sectional view which shows each stage of a cell division process.</figref><figref num="1D">It is a schematic cross-sectional view which shows each stage of a cell division process.</figref><figref num="1E">It is a schematic cross-sectional view which shows each stage of a cell division process.</figref><figref num="2A">It is a schematic diagram which shows the non-dividing cell to which an electric field was applied.</figref><figref num="2B">It is a schematic diagram which shows the non-dividing cell to which an electric field was applied.</figref><figref num="3A">FIG. 5 is a schematic diagram showing a dividing cell to which an electric field is applied in one embodiment as an example.</figref><figref num="3B">FIG. 5 is a schematic diagram showing a dividing cell to which an electric field is applied in one embodiment as an example.</figref><figref num="3C">In one exemplary embodiment, it is a schematic diagram showing cells destroyed by the application of an electric field.</figref><figref num="4">It is a schematic diagram which shows the dividing cell in one stage of electric field application.</figref><figref num="5">FIG. 6 is a schematic block diagram showing a device for applying an electric field based on an exemplary embodiment that can selectively destroy cells.</figref><figref num="6">It is a schematic diagram which shows the electrical equivalent circuit about the insulated electrode in the apparatus of FIG.</figref><figref num="7">It is sectional drawing which shows the skin patch equipped with the apparatus of FIG.</figref><figref num="8">It is sectional drawing which shows the insulated electrode embedded in the body for the treatment of a tumor and the like.</figref><figref num="9">It is sectional drawing which shows the insulated electrode embedded in the body for the treatment of a tumor and the like.</figref><figref num="10">It is sectional drawing which shows various structural examples about the insulated electrode in the apparatus of FIG.</figref><figref num="11">It is a front view including a partial cross section showing two insulated electrodes arranged around a person's torso for the treatment of tumor-affected sites, for example for the treatment of tumors associated with lung cancer.</figref><figref num="12">FIG. 5 is a cross-sectional view showing various insulated electrodes with or without a protective member formed as a structural member.</figref><figref num="13">FIG. 5 is a schematic diagram showing an insulated electrode configured such that the electric field can be concentrated in a desired target region and the electric field density can be reduced for other regions (ie, protected regions).</figref><figref num="14">FIG. 5 is a cross-sectional view showing an insulated electrode as if incorporated into a cap that can be placed relative to the head, based on the first embodiment for the treatment of intracranial tumors and the like.</figref><figref num="15">FIG. 6 is a cross-sectional view showing a portion of a hat according to an exemplary embodiment, comprising a recess for receiving one or more insulated electrodes.</figref><figref num="16">FIG. 15 is a cross-sectional view showing a cap of FIG. 15 placed relative to the head, showing an urging mechanism for applying force to an insulated electrode, which is provided by the urging mechanism. , It is supposed that it can surely contact the head.</figref><figref num="17">FIG. 5 is a plan view including a partial cross section showing a garment product in which an insulated electrode is incorporated for treatment of a tumor or the like.</figref><figref num="18">FIG. 17 is a cross-sectional view showing a garment product of FIG. 17 for urging the insulated electrodes in an orientation that ensures that the insulated electrodes are located in the vicinity of the skin surface where treatment is requested. The urging mechanism of.</figref><figref num="19">FIG. 5 is a cross-sectional view showing a probe according to an embodiment that can be placed inside a body for treatment of a tumor or the like.</figref><figref num="20">It is a figure which shows the collar by one Embodiment in the unwrapped state which was made possible to arrange around the neck by wrapping around the neck for the treatment of a tumor or the like in the area of a neck.</figref><figref num="21">It is a cross-sectional view showing two insulated electrodes, in which a conductive gel member is arranged with respect to the body, and electric lines of force are shown.</figref><figref num="22">FIG. 21 is a cross-sectional view showing the configuration of FIG. 21, where dielectric breakdown points are illustrated for one insulated electrode.</figref><figref num="23">FIG. 6 is a cross-sectional view showing a configuration consisting of at least two insulated electrodes arranged with respect to a body using a conductive gel member for the treatment of a tumor or the like, and each conductive gel member is insulated. It has the property of being able to minimize the effect of dielectric breakdown on the electrode.</figref><figref num="24">A cross-sectional view showing another configuration consisting of at least two insulated electrodes placed relative to the body using a conductive gel member for the treatment of tumors, etc., wherein one conductive member , Which is located in the body in the vicinity of the tumor, forming a region with increased electric field density.</figref><figref num="25">FIG. 5 is a cross-sectional view showing a configuration consisting of two insulated electrodes arranged with respect to the body and having different sizes.</figref><figref num="26">FIG. 6 is a cross-sectional view showing a configuration consisting of at least two insulated electrodes arranged with respect to a body using a conductive gel member for the treatment of a tumor or the like, and each conductive gel member is insulated. It has the property of being able to minimize the effect of dielectric breakdown on the electrode.</figref>

Code description

10 cells 12 Cleavage furrow 18 cells 20 cells 22 Bridge (intracellular membrane) 28 electrodes 32 electrodes 200 electronics 210 power supply 220 Conductive lead wire 230 Insulated conductor 270 Intervening filler, conductive gel member 300 skin patch 340 sparse net 350 thin conductive coating 500 clothing products, hats 530 Bias mechanism 540 units 550 opening 560 Adhesive member 600 probe 700 bra 800 bias mechanism 900 color parts 1100 conductor (third conductor) 1200 1st insulation electrode 1210 Second insulating electrode 1400 conductor (third conductor)