Delivery of Tumor Treating Fields (TTFields) using embedded graphite sheets

Abstract

An AC electric field (Tumor Treatment Field, also known as TT Field) can be applied to a target area within a subject's body via a graphite sheet implanted within the subject's body. One or more ports configured for fastening to the subject's body include or are connected to one or more mating electrical connectors. Electrical conductors are arranged to route electrical signals between the electrical connector(s) and the graphite sheet. An AC electric field is applied to the target area by applying (via the ports) an AC voltage between two arranged graphite sheets on opposite sides of the target area.

Description

[Background technology]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Application No. 63 / 325,650, filed March 31, 2022, which is incorporated by reference herein in its entirety.

[0002] TT field (Tumor Treating Field) therapy is a proven approach to treat tumors using alternating electric fields at frequencies between 50 kHz and 1 MHz, such as 100 kHz and 500 kHz. In a conventional Optune® system for delivering TT fields, the TT field is delivered to the patient via four transducer arrays placed on the patient's skin near the tumor. The transducer arrays are arranged in two sets. One of these sets is placed on the left and right of the target area (e.g., glioblastoma), and the other is placed in front and back of the target area. Each transducer array is connected to an AC voltage generator via a cable. The AC voltage generator (a) delivers an AC current to one set of arrays during a first period, then (b) delivers an AC current to the other set of arrays during a second period, and then repeats steps (a) and (b) for the duration of the treatment period. Summary of the Invention

[0003] One aspect of the present application relates to a first device for applying an alternating electric field to a target region within a subject's body. The first device includes a graphite sheet, a port, and an electrical conductor. The graphite sheet has a front surface and a back surface. The port is configured to be secured to a body of a living subject, the port having an exterior surface that includes or connects to a mating electrical connector. The electrical conductor is positioned to route electrical signals between the electrical connector and the graphite sheet.

[0004] In some embodiments of the first device, the graphite sheet is placed subcutaneously or implanted within the subject's body such that a front surface of the graphite sheet faces the target area. The mating electrical connector is located at a location accessible from outside the subject's body. In some embodiments of the first device, the graphite sheet further includes an AC signal generator configured to provide an AC voltage. In some embodiments of the first device, the graphite sheet is a mesh sheet.

[0005] Some embodiments of the first device further include a layer of a biocompatible insulating polymeric material disposed on at least one surface of the graphite sheet, the insulating polymeric material having a dielectric constant of at least 10.

[0006] In some embodiments of the first device, the sheet of biocompatible material configured to support the back surface of the graphite sheet is or may include a graphite mesh sheet. In some embodiments of the first device, the sheet of biocompatible material configured to support the back surface of the graphite sheet is or may include a graphite mesh sheet.

[0007] In some embodiments of the first apparatus, the graphite sheet comprises pyrolytic graphite made from compressed high purity exfoliated mineral graphite, a graphitized polymer film, or a graphite foil, or at least partially oxidized forms thereof. In some embodiments of the first apparatus, the electrical conductor comprises a graphite wire. In some embodiments of the first apparatus, the graphite sheet comprises synthetic graphite.

[0008] Another aspect of the present application relates to a second device for applying an alternating electric field to a target region within a subject's body. The second device includes a graphite sheet having a front surface and a rear surface, and a layer of a biocompatible insulating polymeric material disposed on at least one surface of the graphite sheet. The graphite sheet is configured for implantation within a living body. The insulating polymeric material has a dielectric constant of at least 10.

[0009] In some embodiments of the second device, the graphite sheet is placed subcutaneously or implanted within the subject's body such that a front surface of the graphite sheet faces the target area. In some embodiments of the second device, the graphite sheet is a mesh sheet.

[0010] Some embodiments of the second device further include a sheet of biocompatible material configured to support the rear surface of the graphite sheet. In some embodiments, the sheet of biocompatible material configured to support the rear surface of the graphite sheet is or can include a graphite mesh sheet. Some embodiments of the second device further include a biocompatible graphite mesh sheet configured to support the rear surface of the graphite sheet.

[0011] In some embodiments of the second device, the wire is made of graphite.

[0012] In some embodiments of the second apparatus, the graphite sheet comprises pyrolytic graphite made from compressed high purity exfoliated mineral graphite, a graphitized polymer film, or a graphite foil, or at least partially oxidized forms thereof. In some embodiments of the second apparatus, the graphite sheet comprises synthetic graphite.

[0013] Another aspect of the present application relates to a first method of applying an AC electric field to a target area within a subject's body, the first method including applying an AC voltage between a first graphite sheet pre-implanted within the subject's body and a second graphite sheet pre-implanted within the subject's body, the first graphite sheet and the second graphite sheet being positioned on opposite sides of the target area.

[0014] Some examples of the first method further include embedding a first graphite sheet within the subject's body prior to the application, and embedding a second graphite sheet within the subject's body prior to the application.

[0015] In some examples of the first method, a layer of a biocompatible insulating polymeric material having a dielectric constant of at least 10 is disposed on at least one surface of a first graphite sheet, and a layer of a biocompatible insulating polymeric material having a dielectric constant of at least 10 is disposed on at least one surface of a second graphite sheet.

[0016] In some examples of the first method, the first graphite sheet is supported by a first sheet of biocompatible material and the second graphite sheet is supported by a second sheet of biocompatible material, hi some embodiments, the first sheet of biocompatible material is a graphite mesh sheet.

[0017] In some examples of the first method, the first graphite sheet comprises pyrolytic graphite made from compressed high purity exfoliated mineral graphite, a graphitized polymer film, or a graphite foil, or at least partially oxidized forms thereof. In some examples of the first method, the first graphite sheet comprises synthetic graphite; [Brief description of the drawings]

[0018] [Figure 1A] Shows two graphite sheets implanted into a subject on opposite sides of a target area. [Figure 1B] 1B illustrates a variation of the embodiment of FIG. 1A, in which an additional layer of material is included. [Diagram 2] FIG. 1 is a plan view of an apparatus for applying an alternating electric field to a target area within a subject's body. [Diagram 3] FIG. 3 is a side view of the device of FIG. 2. [Figure 4] 2 and 3, showing a variation of the embodiment of FIG. [Diagram 5] 2-3, depicting another variation of the embodiment of FIGS. 2-3, in which an additional layer of material is added. [Figure 6] 1A and 1B are plan and side views of another apparatus for applying an alternating electric field to a target area within a subject's body. [Figure 7] 1A and 1B are plan and side views of another apparatus for applying an alternating electric field to a target area within a subject's body. [Figure 8] 1 is a side view of another apparatus for applying an alternating electric field to a target site within a subject; [Figure 9] 1 is a side view of another apparatus for applying an alternating electric field to a target site within a subject; [Figure 10] FIG. 2 is a side view of another apparatus for applying an alternating electric field to a target site within a subject. [Figure 11] 1B illustrates a variation of the embodiment of FIG. 1A utilizing a single multi-conductor port. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Various embodiments will now be described in detail with reference to the accompanying drawings, in which like reference numbers represent like elements and in which: Instead of using a transducer array placed on the patient's skin to deliver the TT field, the embodiments described herein use electrodes implanted within the patient's body to deliver the TT field. Implanting the electrodes provides several potential advantages. These potential advantages include: (1) the array can be hidden from people with whom the patient interacts; (2) improved patient comfort (by avoiding skin irritation, heating sensation, and / or movement restrictions caused by an array placed on the patient's skin); (3) improved electrical contact between the electrodes and the patient's body; (4) elimination of the need to shave the area where the array is placed (as hair growth may interfere with the delivery of the TT field); (5) avoiding the risk of the electrodes becoming dislodged and interrupting the delivery of the TT field; (6) significantly reducing the power required to deliver the TT field (e.g., by reducing the physical distance between the electrode and the tumor and bypassing highly resistive anatomical structures such as the skull); (7) significantly reducing the weight of the device that the patient must carry (e.g., by using smaller batteries to take advantage of the reduced power requirements); and (8) avoiding skin irritation that may occur when the transducer array is placed on the patient's skin. and (9) allowing the delivery of TT fields to anatomical structures that cannot be treated with transducer arrays placed on the patient's skin (e.g., the spinal cord is surrounded by highly conductive cerebrospinal fluid, which is surrounded by the bony structures of the spine, both of which prevent penetration of the TT field into the spinal cord itself).

[0020] There is a need for improvements to conventional implantable medical devices for delivering alternating electric fields to target regions within a subject's body. Such devices are bulky due to the number of electrodes required in the array and the size of the electrode elements within the array. Furthermore, the operating current is low (usually less than 1 A) due to the need to avoid hot spots that could damage tissue within the body, limiting their effectiveness. The present application addresses these and other important issues.

[0021] Preferably, each electrode implanted in the patient's body is formed using a graphite sheet. The use of a graphite sheet provides significant advantages over other materials, since the graphite sheet spreads the current arriving from the AC signal generator in a direction parallel to the front surface of the sheet, and also spreads heat in a direction parallel to the front surface of the sheet. These two advantages are more pronounced when the graphite sheet is a high-purity exfoliated mineral graphite sheet. And these two advantages are even more pronounced when the graphite sheet is a synthetic graphite sheet, such as a pyrolytic graphite sheet, or a graphitized polymer film (e.g., graphitized polyimide). In these embodiments, hot spots are eliminated (or at least minimized) because both the current and the heat are distributed over a larger area in front of each electrode. Thus, the surface area of ​​the electrodes can be reduced (with respect to embodiments that do not include a graphite sheet) and / or the current can be increased without generating excessive heat or hot spots that would require operation at a lower current. This increase in current advantageously increases the effectiveness of the TT field treatment. In addition, graphite is biocompatible.

[0022] FIG. 1A shows two graphite sheets 10 implanted on opposite sides of a target region in a subject's body. Each graphite sheet has a corresponding port 40, where a wire 30 or another electrical conductor routes electrical signals between each port 40 and the respective graphite sheet 10. The ports 40 are designed to allow the distal ends of cables 45 to be safely attached and detached from outside the body. This can be accomplished, for example, by incorporating a connector at each port 40, as described below in connection with FIG. 2. The proximal ends of both cables 45 terminate in an AC signal generator 50. As a result, when the AC signal generator 50 applies an AC signal between the two cables 45, a corresponding voltage is generated between the two embedded graphite sheets 10.

[0023] FIG. 1A shows a graphite sheet implanted subcutaneously adjacent to the skin of a subject. However, in other embodiments, the graphite sheet may be further implanted within the subject's body. For example, the graphite sheet may be positioned adjacent to or on either side of a target (e.g., a tumor) within a target region or location, or adjacent to or wrapped around a body organ in which the target is located (e.g., as shown in FIG. 1B). The graphite sheet may be supported on a substrate or by a backing layer. FIG. 1B shows a graphite sheet further implanted within the subject's body incorporating a biocompatible material sheet 15 positioned behind the back surface of the graphite sheet 10, the sheet 15 being configured to support the back surface of the graphite sheet 10. Suitable materials for the sheet 15 include, for example, biocompatible polymers, ceramics, composites, metals, and the like (e.g., acrylic polymers, titanium metal). Alternatively, the biocompatible material sheet 15 may be a graphite mesh sheet.

[0024] Optionally, additional graphite sheets (not shown) may be implanted within the subject's body. For example, in addition to the pair of graphite sheets 10 implanted on the right and left sides of the subject's abdomen shown in FIG. 1, an additional pair of graphite sheets may be implanted on the front and back of the subject's abdomen. If additional graphite sheets are provided, signals from AC signal generator 50 are supplied to those graphite sheets at appropriate times. Optionally, a third pair of graphite sheets may be implanted in a similar manner. The additional embedded graphite sheets may be implanted subcutaneously adjacent to the subject's skin or may be implanted further within the subject's body.

[0025] In further embodiments, one or more electrodes may be implanted in the body and one or more electrodes may be placed outside the body. For example, one pair (or pairs) of electrodes may be implanted in the body and another pair (or pairs) of electrodes may be placed outside the body. Alternatively, one of the pair of electrodes may be implanted in the body and the other electrode may be placed outside the body. It should be understood that throughout this disclosure, these options are included even if not specifically mentioned. That is, a reference to two electrodes or two graphite sheets implanted in the subject's body or placed subcutaneously in the subject's body also refers to at least one electrode or graphite sheet implanted in the subject's body or placed subcutaneously in the subject's body, and one or more electrodes or graphite sheets placed externally on the subject's body or clothing. In either case, the graphite sheets are positioned such that the front surface of each graphite sheet faces the target site in the subject's body.

[0026] The location of the graphite sheet 10 depends on the location of the tumor to be treated. Examples of suitable locations include subcutaneous locations, such as just below the surface of the subject's skin, between the subject's skin and the skull, or just below the subject's skull. Other suitable locations include placing one or more graphite sheets 10 deeper within the subject's brain (e.g., within a resection cavity created during surgery), or placing one or more graphite sheets within the subject's torso, for example, within the abdomen (e.g., on either side of an organ such as the pancreas).

[0027] The graphite sheet 10 can be made from pyrolytic graphite, graphitized polymer film, graphite foil made from compressed high purity exfoliated mineral graphite, or other forms of graphite. Graphite sheets are anisotropic with respect to both electrical and thermal conductivity, the sheet dispersing both heat and electrical current evenly over a larger surface area.

[0028] Anisotropic thermal properties include directional thermal properties. Specifically, the sheet has a first thermal conductivity in a direction perpendicular to its front surface. Also, the thermal conductivity in a direction parallel to the front surface of the sheet is at least twice as high as the first thermal conductivity. In some preferred embodiments, the thermal conductivity in the parallel direction is at least 10 times higher than the first thermal conductivity. For example, the thermal conductivity in a direction parallel to the front surface of the sheet may be 1.5 times, 2 times, 3 times, 5 times, 10 times, 20 times, 100 times, 200 times, or 1,000 times higher than the first thermal conductivity.

[0029] Anisotropic electrical properties include directional electrical properties. Specifically, the sheet has a first resistance in a direction perpendicular to its front surface, and a resistance in a direction parallel to the front surface of the sheet is less than the first resistance. In some preferred embodiments, the resistance in the parallel direction is less than half the first resistance, or less than 10% of the first resistance. For example, the resistance in a direction parallel to the front surface of the sheet 70 may be less than 75%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.5%, or 0.1% of the first resistance.

[0030] For example, the thermal conductivity of a pyrolytic graphite sheet in the xy plane is 10 to 20 times higher than in the perpendicular z direction, and the electrical resistivity of a pyrolytic graphite sheet in the xy plane is about three orders of magnitude (1,000 times) lower than in the perpendicular z direction.

[0031] Examples of suitable forms of graphite include synthetic graphite, such as pyrolytic graphite (including but not limited to pyrolytic graphite sheet (PGS) available from Panasonic Industrial Co., Ltd., Kadoma, Osaka, Japan), or graphitized polymer films (e.g., graphitized polyimide films) (including but not limited to those supplied by Kaneka Corporation, Moka, Ibaraki, Japan). Graphite foils made from compressed high-purity exfoliated mineral graphite may also be suitable (such as, but not limited to, those provided by MinGraph® 2010A Flexible Graphite available from Mineral Seal, Tucson, Arizona, USA). In alternative embodiments, electrically conductive anisotropic materials other than graphite may be used in place of graphite.

[0032] FIG. 2 illustrates an apparatus for applying an alternating electric field to a target area within a subject's body. The apparatus includes a graphite sheet 10 having a front surface and a rear surface. The graphite sheet 10 may be, for example, a non-porous continuous sheet with no openings or pores therethrough, or may be a continuous sheet with openings or pores therethrough. The graphite sheet 10 may be flexible to facilitate implantation and may be implanted within the subject's body using techniques similar to those for implanting a hernia mesh within the subject's body, including, but not limited to, laparoscopic techniques. When a flexible graphite sheet is used, it may be inserted into the subject's body in a folded or rolled state through a small incision. The graphite sheet 10 may then be folded or rolled at the desired location within the subject's body to provide a larger surface area. The flexibility of the graphite sheet allows the size of the surgical incision and procedure to be minimized.

[0033] The port 40 is configured to be secured to the body of a living subject. The port(s) may be located directly adjacent to the embedded graphite sheet, in close proximity to the embedded graphite sheet, or across the skin at a distance from the embedded graphite sheet. The port includes a mating electrical connector 42 or has an exterior surface that is connected to a mating electrical connector 42. Securing the port 40 to the subject's body may be accomplished by implanting the port such that the connector 42 is externally accessible. The connector 42 is configured to receive a cable 45 (shown in FIGS. 1A and 1B). Preferably, the connector 42 is configured to allow the cable 45 to be disconnected, for example, if the subject does not want to be disturbed by the cable.

[0034] One or more electrical conductors are disposed to route electrical signals between the electrical connector 42 and the graphite sheet. In the embodiment shown in FIG. 2, these conductors are implemented using the graphite sheet 10, the wires 30, and terminals 20 (e.g., conductive metal) attached to portions of the ports 40. A side view of a portion of this embodiment is shown in FIG. 3. The wires 30 in these embodiments may be, for example, biocompatible metal wires or graphite wires. The terminals 20 in these embodiments may be connected to the graphite sheet 10, for example, using a conductive adhesive. In another embodiment, the wires 30 may be omitted, in which case the ports 40 are connected directly to the graphite sheet 10, for example, using a suitable conductive adhesive. In these latter examples, the conductive portions of the ports 40 and the conductive adhesive act as electrical conductors.

[0035] 1A-3, the graphite sheet 10 is placed subcutaneously or implanted in the subject's body with the front surface of the graphite sheet facing the target area. The mating electrical connector 42 is located in a position accessible from outside the subject's body. When the cable 45 is connected to the port 40 via the electrical connector 42, each graphite sheet 10 can be powered by the AC signal generator 50 via the respective cable 45, port 40, and wire / conductor 30. When an AC voltage is applied between the two graphite sheets 10, an electric field is conductively coupled to the area between the two graphite sheets (including the target area in the subject's body).

[0036] In some embodiments, a layer of biocompatible insulating polymeric material 15F may be disposed on the front surface of the graphite sheet 10, as shown in Figure 4. The insulating polymeric material has a dielectric constant of at least 10 (or, in some embodiments, at least 20).

[0037] Suitable materials for use as insulating polymer material 15F include poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) and / or poly(vinylidene fluoride-trifluoroethylene-1-chlorofluoroethylene). These two polymers are abbreviated herein as "poly(VDF-TrFE-CtFE)" and "poly(VDF-TrFE-CFE)", respectively. Optionally, ceramic nanoparticles may be mixed into poly(VDF-TrFE-CtFE) and / or poly(VDF-TrFE-CFE) to form a "nanocomposite". Optionally, these ceramic nanoparticles may include ferroelectric metal oxides (e.g., barium titanate and / or barium strontium titanate). In alternative embodiments, different polymers may be used that provide a high dielectric constant (e.g., at least 10 or at least 20). Examples of alternative polymeric materials that can be used in place of poly(VDF-TrFE-CtFE) and / or poly(VDF-TrFE-CFE) include: (1) ceramic nanoparticles mixed with at least one of poly(VDF-TrFE), P(VDF-HFP), PVDF, or other polymers (HFP is hexafluoropropylene), and (2) barium titanate and / or barium strontium titanate ceramic nanoparticles mixed with at least one of poly(VDF-TrFE), P(VDF-HFP), PVDF. In other embodiments, insulating polymeric material 15F is formed by mixing ceramic nanoparticles with at least one other polymer.

[0038] In some embodiments, including the embodiment shown in FIG. 4, a sheet of biocompatible material 15 is disposed behind the back surface of graphite sheet 10, with sheet 15 configured to support the back surface of graphite sheet 10. Suitable materials for sheet 15 include, for example, biocompatible polymers, ceramics, composites, metals, and the like (e.g., acrylic polymers, titanium metal). Alternatively, the sheet of biocompatible material 15 may be a graphite mesh sheet. Optionally, a sheet of biocompatible material may be included in other embodiments herein, such as, for example, the embodiment configured to support the back surface of a graphite sheet as shown in FIG. 3.

[0039] 5, a biocompatible insulating polymer material 15F is disposed on both sides of the graphite sheet 10. The insulating polymer material has a dielectric constant of at least 10 (or, in some embodiments, at least 20) and may be made from the same materials as layer 15F described above with reference to FIG.

[0040] To use the embodiment described above with reference to Figures 4-5, two graphite sheets 10 are placed subcutaneously or implanted within a subject's body with the front side of each graphite sheet facing the target area. When an AC voltage is applied between the two graphite sheets 10, an electric field is capacitively coupled (by polymer layer 15F) to the area between the two graphite sheets (which includes the target area of ​​the subject's body).

[0041] 6 and 7 are plan and side views of another device for applying an alternating electric field to a target area within a subject's body. This device is similar to the embodiment described above with reference to FIGS. 2 and 3, except that instead of the graphite sheet described above with reference to FIGS. 2 and 3, the graphite sheet is a sheet of graphite mesh 110. The graphite mesh sheet 110 may be flexible to facilitate implantation (e.g., as described above with reference to FIG. 2), and may be implanted within the subject's body using techniques similar to those for implanting a hernia mesh within the subject's body. The sheet of graphite mesh 110 may be made from pyrolytic graphite, graphitized polymer film, graphite foil made from compressed high purity exfoliated mineral graphite, or other forms of graphite.

[0042] To use the embodiment of Figures 6-7, two graphite meshes 110 are placed subcutaneously or implanted in the subject's body with the front side of each graphite sheet facing the target area. When an AC voltage is applied between the two graphite meshes 110, an electric field is conductively coupled to the area between the two graphite meshes (including the target area of ​​the subject's body). Variations of the embodiments of Figures 4 and 5 may be applied to the embodiments of Figures 6 and 7.

[0043] FIG. 8 is a side view of another device for applying an AC electric field to a target area in a subject's body. This device is similar to the embodiment described above with reference to FIGS. 2 and 3, except that an additional layer of material 60 having a high dielectric constant (e.g., at least 10 or at least 20) is disposed between the terminal 20 and the graphite sheet 10. When this embodiment is used for implantation in a subject's body and an AC voltage is applied between two graphite 10 sheets implanted in the body, an electric field is capacitively coupled to the area located between the two graphite 10 sheets, including the target area in the subject's body. The layer of material 60 may be formed from a high dielectric constant ceramic material or may be formed from the same high dielectric constant polymer material as layer 15F described above with reference to FIG. 4. Keeping the layer of high dielectric constant material 60 thin (e.g., less than 20 μm, less than 10 μm, or less than 5 μm) is preferred to improve capacitive coupling. Variations of the embodiments of FIGS. 4 and 5 or FIGS. 6 and 7 may be applied to the embodiment of FIG. 8.

[0044] FIG. 9 is a side view of another apparatus for applying an AC electric field to a target area of ​​a subject's body. This apparatus is similar to the embodiment described above with reference to FIGS. 2 and 3, except that it includes two additional layers. More specifically, a layer of graphite mesh 110 is placed behind the graphite sheet 10, and a layer of additional material 160 having a high dielectric constant (e.g., at least 10 or at least 20) is placed between the layer of graphite mesh 110 and the graphite sheet 10. When this embodiment is placed subcutaneously or implanted in the subject's body and an AC voltage is applied between the two graphite 10 sheets implanted in the body, an electric field is capacitively coupled to the area between the two graphite 10 sheets, including the target area in the subject's body. The layer of material 160 can be formed from a high dielectric constant ceramic material or the same high dielectric constant polymer material as layer 15F described above with reference to FIG. 4, and layer 160 is preferably thin (e.g., less than 20 μm, less than 10 μm, or less than 5 μm).

[0045] 9 may be reversed and the resulting device may operate similarly. In other embodiments, the graphite mesh layer 110 may be replaced with a second graphite sheet 10 and a layer 160 of material having a high dielectric constant (e.g., at least 10 or at least 20) may be placed between the two graphite sheets 10 and the resulting device may operate similarly.

[0046] Figure 10 is a side view of another apparatus for applying an alternating electric field to a target area within a subject's body. This apparatus is similar to the embodiment described above with reference to Figures 2 and 3, except that instead of connecting the graphite sheet 10 to a port (e.g., port 40 in Figures 1A, 1B, 2, and 6) via wires 30, the graphite sheet 10 and port 40A are combined into an integrated unit and implanted within the subject's body beneath the subject's skin. Electrical connections to the graphite sheet 10 are made through this port 40A.

[0047] 10, a support layer made of graphite mesh 110 is positioned behind the graphite sheet 10. However, in alternative embodiments, this support layer may be made from a different material (e.g., an acrylic polymer) or omitted entirely.

[0048] In the embodiment shown in Figure 10, a layer 60 of material having a high dielectric constant (e.g., at least 10 or at least 20) is interposed between the electrical terminal 20 and the graphite sheet 10. When an AC voltage is applied (e.g., via two ports 40A) between the two embedded graphite 10 sheets, this layer of material 60 is included and an electric field is capacitively coupled to the area between the two graphite 10 sheets, including the target area within the subject's body. The layer of material 60 can be formed from a high dielectric constant ceramic material or the same high dielectric constant polymer material as layer 15F described above with reference to Figure 4, and layer 60 is preferably thin (e.g., less than 20 μm, less than 10 μm, or less than 5 μm).

[0049] In alternative embodiments, the layer of material 60 may be omitted, in which case the terminals 20 of the port 40A are in electrical contact with the graphite sheet 10, either directly or through the optional support layer 110A. In these alternative embodiments, when an AC voltage is applied between the two graphite sheets 10 (e.g., through the two ports 40A), an electric field is conductively coupled to the area between the two graphite sheets 10, including the target area of ​​the subject's body. Optionally, a connecting layer of conductive adhesive may be used to enhance the electrical contact between the terminals 20 of the port 40A and the graphite sheet 10 or the support layer 110A.

[0050] Figure 10 shows one electrode assembly positioned immediately adjacent to port 40A. However, other layered configurations of electrode assemblies described herein may also be used in this manner, and indeed in embodiments incorporating high dielectric material layers (e.g., 15F in Figures 4 and 5, 60 in Figure 8, and 160 in Figure 9), it may be preferable to position the electrode assembly immediately adjacent to port 40A.

[0051] FIG. 11 illustrates another approach for connecting embedded graphite sheets. This approach is similar to that shown in the embodiment of FIGS. 1A and 1B, but instead of providing separate ports 40 for connection to each sheet of graphite, this FIG. 11 approach uses a single multi-conductor port 40B that accepts a multi-conductor cable 45B from an AC signal generator 50. Individual wires 30 or other electrical conductors run through the subject's body to route one of the electrical signals arriving via the multi-conductor cable 45B between the single port 40B and one of the graphite sheets 10. And a second wire 30 (or other electrical conductor) runs through the subject's body to route the other electrical signal arriving via the multi-conductor cable 45B between the single port 40B and the other graphite sheet 10. In this FIG. 11 embodiment, the structure of the graphite sheet 10 and the connections thereto (e.g., the use of wires 30) may be as described above with reference to FIGS. 2-9. If more than one graphite sheet is implanted in the subject's body, a single port 40B can send signals to all of the implanted sheets 10 (e.g., using individual wires 30 for each embedded graphite sheet).

[0052] The hardware described above with reference to Figures 1-11 may be used to practice the following method of applying an AC electric field to a target area on a subject's body. The method includes applying an AC voltage between a first graphite sheet 10 pre-implanted in the subject's body and a second graphite sheet 10 pre-implanted in the subject's body, the first and second graphite sheets being positioned on opposite sides of the target area. In some embodiments, the frequency of the AC voltage is between 50 kHz and 1 MHz, or between 100 kHz and 500 kHz.

[0053] At some point prior to application, the first and second graphite sheets 10 are implanted within the subject's body.

[0054] Optionally, a layer of biocompatible insulating polymeric material 15F having a dielectric constant of at least 10 is disposed on at least one side of the first graphite sheet 10, and a layer of biocompatible insulating polymeric material 15F having a dielectric constant of at least 10 is disposed on at least one side of the second graphite sheet 10.

[0055] Optionally, the first graphite sheet 10 is supported by a first sheet of biocompatible material 15 and the second graphite sheet is supported by a second sheet of biocompatible material 15. In either case, the biocompatible support may be a graphite mesh sheet.

[0056] The graphite sheet 10 may be made from synthetic graphite. The graphite sheet 10 may be made from pyrolytic graphite, graphitized polymer film, or graphite foil made from compressed high purity exfoliated mineral graphite. In some embodiments, the graphite sheet 10 may be an oxidized (or partially oxidized) graphite sheet, or the sheet may be composed of oxidized (or partially oxidized) graphite that may be used to improve adhesion to the graphite sheet. As described above with reference to Figures 6-7, the first graphite sheet may be a mesh sheet 110.

[0057] In any of the embodiments and methods described herein, a sensor (such as a thermistor) for measuring temperature can be placed on or near the graphite sheet 10 so that the temperature of the tissue can be controlled and thermal damage to the tissue can be avoided.

[0058] In any of the embodiments and methods described herein, adhesion between components or layers of the electrode assembly, or between the electrode assembly and the surrounding tissue, may be achieved using a conductive adhesive.

[0059] In any of the embodiments and methods described herein, it is preferred to connect the internal wiring / circuitry to external wiring / circuitry outside the body via one or more ports placed on or across the subject's skin, as shown in Figures 1A, 1B, and 11. However, in alternative embodiments, the port or ports are not present, and a separate connection is utilized outside the body (e.g., one or more connectors). The use of ports has the advantage that the subject can disconnect the external wiring at the connectors of the ports, thereby allowing the subject to be undisturbed by the external wiring at a time of their choosing.

[0060] In any of the embodiments and methods described herein, it is preferred to place the electric field generator and / or the AC signal generator outside the body, as shown in Figures 1A, 1B, and 11. These figures also show wired connections to components inside the body. However, in alternative embodiments, the external device may communicate wirelessly with components inside the body. It is desirable to minimize the number of percutaneous wires. For example, a small electronic package may be implanted inside the body and connected to an external unit and electronics by a single wire (e.g., the same wire that provides the electric field). The implanted electronic package may include circuitry and switches that can be wirelessly controlled from outside the body.

[0061] The embedded electrodes of the embodiments described herein have the advantage that they can be significantly smaller in size than conventional embedded electrodes. In some embodiments, the surface area of ​​the graphite sheet (and the front surface of the electrode assembly) is less than about 1 cm. 2 ~40cm 2 or more, and the thickness of the electrode assembly may be less than 1 mm or greater than 1 mm.

[0062] Optionally, in addition to implanting two graphite sheets on opposite sides of the target area as described above and then applying an AC voltage between the two graphite sheets to induce an AC electric field in the target area, two more graphite sheets can be implanted in the subject's body on opposite sides of the target area. For example, if the original two graphite sheets are implanted on the left and right sides of the target area, two additional graphite sheets must be implanted before and after the target area. Once the two additional graphite sheets are implanted, applying an AC voltage between the original two graphite sheets applies an AC electric field in a first direction to the target area, and applying an AC voltage between the additional two graphite sheets applies an AC electric field in a second direction to the target area. Details of the structure of the additional graphite sheets, and the structures supporting them, are as described above with reference to Figures 2-10.

[0063] In alternative embodiments, instead of embedding two graphite sheets on opposite sides of the target area and applying an AC voltage between the two graphite sheets to induce an AC electric field in the target area (as described above), only one graphite sheet can be embedded on one side of the target area. In these embodiments, a second electrode (which may or may not be constructed of graphite) is placed outside the subject's body on the opposite side of the target area, and an AC voltage is applied between the embedded graphite sheet and the second electrode (i.e., the external electrode).

[0064] In these embodiments, an AC electric field is applied to a target area of ​​the subject's body by applying an AC voltage between a graphite sheet that has been previously embedded in the subject's body and a second electrode that is positioned outside the subject's body. Details of the structure of the embedded graphite sheet (and the structure supporting the graphite sheet) are as described above with reference to Figures 2 to 10. The graphite sheet and the second electrode are positioned on opposite sides of the target area. Prior to applying the AC voltage, a first graphite sheet is embedded in the subject's body and the second electrode is positioned in contact with the subject's body.

[0065] Any embodiment described under any heading or in any part of this disclosure may be combined with embodiments described under the same heading or in another part of this disclosure, unless otherwise stated herein or clearly contradicted by context.

[0066] Although the present invention has been disclosed with reference to specific embodiments, numerous modifications, changes, and variations are possible to the described embodiments without departing from the scope and spirit of the present invention, as defined in the appended claims. It is therefore intended that the present invention not be limited to the described embodiments, but rather have its full scope defined by the following claims and equivalents thereof.

Claims

1. 1. An apparatus for applying an alternating electric field to a target area within a subject, comprising: a graphite sheet having a front surface and a rear surface; a port configured to be secured to a living body, the port including or having an exterior surface that connects to a mating electrical connector; and an electrical conductor disposed to route electrical signals between the electrical connector and the graphite sheet.

2. the graphite sheet is placed subcutaneously or implanted within the subject's body such that the front surface of the graphite sheet faces the target area; The apparatus of claim 1 , wherein the mating electrical connector is disposed in a location accessible from outside the subject's body.

3. The apparatus of claim 1 , wherein the graphite sheet is a mesh sheet.

4. 10. The device of claim 1, further comprising a layer of a biocompatible insulating polymeric material disposed on at least one surface of said graphite sheet, said insulating polymeric material having a dielectric constant of at least 10.

5. 10. The device of claim 1, further comprising a biocompatible graphite mesh sheet configured to support a back surface of the graphite sheet.

6. 10. The apparatus of claim 1, wherein the graphite sheet comprises pyrolytic graphite, a graphitized polymer film, or a graphite foil made from compressed high purity exfoliated mineral graphite, or at least partially oxidized forms thereof.

7. 1. An apparatus for applying an alternating electric field to a target area within a subject, comprising: a graphite sheet having a front surface and a back surface, the graphite sheet being configured to be implanted within the living subject; a layer of biocompatible insulating polymeric material disposed on at least one surface of said graphite sheet, said insulating polymeric material having a dielectric constant of at least 10.

8. 8. The device of claim 7, wherein the graphite sheet is placed subcutaneously or implanted within the subject's body such that the front side of the graphite sheet faces the target area.

9. The apparatus of claim 7 , wherein the graphite sheet is a mesh sheet.

10. 8. The device of claim 7, further comprising a biocompatible graphite mesh sheet configured to support a back surface of the graphite sheet.

11. 8. The apparatus of claim 7, wherein the graphite sheet comprises pyrolytic graphite, a graphitized polymer film, or a graphite foil made from compressed high purity exfoliated mineral graphite, or at least partially oxidized forms thereof.

12. 1. A method of applying an alternating electric field to a target area within a subject, comprising: applying an AC voltage between a first graphite sheet pre-embedded in the subject's body and a second graphite sheet pre-embedded in the subject's body; The first graphite sheet and the second graphite sheet are positioned on opposite sides of the target area.

13. the layer of biocompatible insulating polymeric material having a dielectric constant of at least 10 is disposed on at least one surface of the first graphite sheet; 13. The method of claim 12, wherein the layer of biocompatible insulating polymeric material having a dielectric constant of at least 10 is disposed on at least one side of the second graphite sheet.

14. the first graphite sheet is supported by the first sheet of biocompatible material; The method of claim 12 , wherein the second graphite sheet is supported by the second sheet of biocompatible material.

15. The method of claim 12 , wherein the first graphite sheet is a mesh sheet.

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