Electrode assembly for applying tumor therapeutic electric fields (TTFields) with graphite sheets

Abstract

Alternating electric fields (e.g., TTFields) can be applied to the body of a subject using one or more electrode assemblies including a sheet of graphite, at least one layer of conductive material disposed on a front surface of the sheet of graphite, and an electrode element disposed behind the sheet of graphite. The electrode element has a front surface disposed in electrical contact with a rear surface of the sheet of graphite. The sheet of graphite spreads both heat and current in a direction parallel to the front surface of the sheet, eliminating or at least minimizing hot spots on the electrode assembly. This in turn allows for increased current flow without exceeding a temperature safety threshold (e.g., 41°C).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 230438, filed on August 6, 2021, U.S. Provisional Application No. 63 / 275841, filed on November 4, 2021, and U.S. Provisional Application No. 63 / 275843, filed on November 4, 2021, which are hereby incorporated by reference in their entirety.

Background Art

[0002] Tumor Treating Fields (TTFields) therapy is a proven approach for treating tumors using an alternating current electric field with a frequency between 50 kHz and 1 MHz, such as 100 - 500 kHz. The alternating current electric field is induced by an electrode assembly (an array of capacitive electrodes, also called a transducer array for example) placed on opposite sides of the subject's body. When an AC voltage is applied between the opposing electrode assemblies, an AC current is coupled through the electrode assemblies into the subject's body. And a higher current is strongly correlated with a higher treatment effect.

[0003] FIG. 1A is a schematic view of a prior - art electrode assembly 40 including nine prior - art electrode elements labeled X1 - X9. FIG. 1B is a cross - sectional schematic view of electrode elements X7 - X9 of electrode assembly 40 taken along the dashed line of FIG. 1A.

[0004] As shown in FIG. 1B, the electrode element X7 (taken as an example) includes a metal layer (shown by diagonal hatching) and a ceramic (dielectric material) layer. Layers of conductive hydrogel are provided between each ceramic layer and the subject's skin to ensure good electrical contact of the electrode element with the body. An AC voltage from an AC voltage generator (not shown) is applied to the metal layer of the electrode elements of the opposing electrode assemblies to generate TTFields in the subject's body.

[0005] During use, the skin beneath the hydrogel and electrode elements gradually heats up, so for safety reasons, it is necessary to keep the skin temperature below a safety threshold (e.g., 41°C). Since most of the heat appears directly beneath electrode elements X1-X9 (as shown in Figure 1C), conventional electrode assemblies have hot spots directly beneath the electrode elements, and cold regions located between the electrode elements. These hot spots then limit the amount of current that can be supplied through conventional electrode assemblies. [Overview of the project] [Means for solving the problem]

[0006] One aspect of the present invention is directed to a first apparatus for applying an alternating electric field to the body of a subject. The first apparatus comprises a graphite sheet having a front and a rear surface, at least one conductive material layer disposed on the front surface of the sheet, the at least one conductive material layer having a biocompatible front surface, and a first electrode element positioned behind the sheet. The first electrode element has a first front surface disposed to be in electrical contact with the rear surface of the sheet.

[0007] In some embodiments of the first apparatus, the first electrode element comprises (i) a first dielectric material layer having a front and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. In these embodiments, the front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer (rear layer) positioned between the first front surface of the first electrode element and the rear surface of the sheet. The first conductive material rear layer facilitates electrical contact between the first front surface of the first electrode element and the rear surface of the sheet.

[0008] Some embodiments of the first apparatus further include a second electrode element positioned behind the sheet. The second electrode element has a second front surface disposed to be in electrical contact with the rear surface of the sheet. In these embodiments, the second electrode element comprises (i) a second dielectric material layer having a front and a rear surface, and (ii) a second metal layer disposed on the rear surface of the second dielectric material layer. The front surface of the second dielectric material layer is the second front surface of the second electrode element. The first conductive material rear layer is positioned between the second front surface of the second electrode element and the rear surface of the sheet. The first conductive material rear layer facilitates electrical contact between the second front surface of the second electrode element and the rear surface of the sheet.

[0009] Some embodiments of the first apparatus further include a second electrode element positioned behind the sheet. The second electrode element has a second front surface disposed to be in electrical contact with the rear surface of the sheet. The second electrode element comprises (i) a second dielectric material layer having a front and a rear surface, and (ii) a second metal layer disposed on the rear surface of the second dielectric material layer. The front surface of the second dielectric material layer is the second front surface of the second electrode element. In these embodiments, the apparatus further includes a second conductive material rear layer positioned between the second front surface of the second electrode element and the rear surface of the sheet. The second conductive material rear layer facilitates electrical contact between the second front surface of the second electrode element and the rear surface of the sheet.

[0010] In some embodiments of the first apparatus, the first conductive material rear layer comprises a conductive hydrogel. In some embodiments of the first apparatus, the first conductive material rear layer comprises a conductive adhesive. In some embodiments of the first apparatus, the first conductive material layer comprises a conductive adhesive comprising an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes. In some embodiments of the first apparatus, the first conductive material layer comprises a conductive adhesive having a thickness between 10 and 2000 μm.

[0011] In some embodiments of the first apparatus, the first electrode element includes a metal piece having a front surface, the front surface of the metal piece being the first front surface of the first electrode element.

[0012] In some embodiments of the first apparatus, the first electrode element includes a metal piece having a front surface, the front surface of the metal piece being the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet. The first conductive material rear layer facilitates electrical contact between the first front surface of the first electrode element and the rear surface of the sheet.

[0013] In some embodiments of the first apparatus, the first electrode element includes a metal piece having a front surface, the front surface of the metal piece being the first front surface of the first electrode element. In these embodiments, the first front surface of the first electrode element is positioned in direct contact with the rear surface of the sheet.

[0014] In some embodiments of the first apparatus, the graphite sheet is a sheet of pyrolytic graphite. In some embodiments of the first apparatus, the graphite sheet is a sheet of graphite foil or graphitized polymer film made of high-purity compression-exfoliated mineral graphite.

[0015] In some embodiments of the first apparatus, at least one conductive material layer comprises a hydrogel. In some embodiments of the first apparatus, at least one conductive material layer comprises a layer of hydrogel having a thickness between 50 and 2000 μm. In some embodiments of the first apparatus, at least one conductive material layer comprises a conductive adhesive. In some embodiments of the first apparatus, a prelayer of the biocompatible conductive material comprises a conductive adhesive, the conductive adhesive comprising an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes. In some embodiments of the first apparatus, a prelayer of the biocompatible conductive material comprises a conductive adhesive having a thickness between 10 and 2000 μm.

[0016] Some embodiments of the first apparatus further include a sheet, a first electrode element, and a flexible self-adhesive backing configured to support at least one conductive material layer, thereby allowing the front surface of the at least one conductive material layer to contact and position against the skin of a subject. Some embodiments of the first apparatus further include leads electrically connected to the first electrode element.

[0017] Another aspect of the present invention is directed to a first method for applying an alternating electric field to a target region inside a subject's body. The first method includes positioning a first electrode assembly at a first location on or inside the subject's body. The first electrode assembly includes a first sheet of graphite having a first front and a first rear surface, and the first electrode assembly is positioned so that the first front surface of the first sheet faces the target region. The first method also includes positioning a second electrode assembly at a second location on or inside the subject's body. The second electrode assembly includes a second sheet of graphite having a second front and a second rear surface, and the second electrode assembly is positioned so that the second front surface of the second sheet faces the target region. The first method also includes applying an alternating voltage between the first electrode assembly and the second electrode assembly. This application is performed after the first electrode assembly and the second electrode assembly have been positioned.

[0018] In some examples of the first method, the application is carried out by applying an alternating voltage between (i) a first electrode element disposed in electrical contact with a first rear surface and (ii) a second electrode element disposed in electrical contact with a second rear surface. Optionally, these examples may further include measuring a first temperature of the first electrode element, measuring a second temperature of the second electrode element, and controlling the application based on the first and second temperatures.

[0019] In some examples of the first method, the first electrode assembly further includes a first conductive adhesive layer disposed on a first front surface, and the second electrode assembly further includes a second conductive adhesive layer disposed on a second front surface.

[0020] In some cases of the first method, each of the first and second sheets of graphite is a sheet of pyrolytic graphite. In some cases of the first method, each of the first and second sheets of graphite is a sheet of graphite foil made of high purity compressed exfoliated mineral graphite, or a graphitized polymer film.

Brief Description of the Drawings

[0021] [Figure 1A] It is a schematic diagram of a prior art electrode assembly. [Figure 1B] It is a cross-sectional view of an electrode element of a prior art electrode assembly taken along the dashed line in FIG. 1A. [Figure 1C] It is a cross-sectional view showing the heat generation characteristics of a prior art electrode element. [Figure 1D] It is a cross-sectional view showing the heat generation characteristics of an element with a hypothetical modification added to the electrode element in FIG. 1B. [Figure 2] It is a plan schematic view of an electrode assembly including an electrode element used to apply TTFields to the body of a subject. [Figure 3A] It is a cross-sectional view of the first embodiment including electrode elements E1 and E2 taken along the dashed line in FIG. 2. [Figure 3B] It is a cross-sectional view showing the heat generation characteristics of the embodiment in FIG. 3A. [Figure 4A] It is a thermal image of a prior art electrode assembly. [Figure 4B] It is a thermal image of an electrode assembly corresponding to the embodiment in FIG. 3A. [Figure 4C] It is a graph comparing the thermal characteristics of a prior art electrode assembly with the embodiment in FIG. 3A. [Figure 4D] It is a diagram showing a thermal camera image of a simulated electrode array constructed using a metal (aluminum) sheet. [Figure 4E] It is a diagram showing a thermal camera image of a simulated electrode array constructed using a sheet of pyrolytic graphite. [Figure 4F]This figure shows the experimental results when electrode arrays with and without graphite sheets were used to apply TTFields to the torso of a rat. [Figure 5] Figure 2 is a cross-sectional view of a second embodiment including electrode elements E1 and E2, taken along the dashed line. [Figure 6] This is a cross-sectional view of a third embodiment including a single electrode element E1. [Figure 7] This is a cross-sectional view of a fourth embodiment including a single electrode element E1. [Figure 8] This is a cross-sectional view of a fifth embodiment including a single electrode element E1. [Figure 9] This is a block diagram of a system incorporating two electrode assemblies used to apply TTFields to the subject's body. [Modes for carrying out the invention]

[0022] Various embodiments are described in detail below with reference to the attached drawings, and similar reference numbers represent similar elements.

[0023] This application describes an exemplary electrode assembly that may be used, for example, to deliver TTFields to the body of a subject and treat one or more cancers or tumors located within the body of the subject.

[0024] When TTFields are applied to a subject's body, the subject's body temperature may rise in proportion to the induced electric field. Regulation limits the amount of current that can be driven through the transducer array to an amount that keeps the measured temperature at the placement on the subject's body below a temperature threshold. As practiced in the art, the temperature at the placement of the transducer array on the subject's body is controlled to remain below the temperature threshold by reducing the operating current driven by the transducer array, thereby weakening the resulting TTFields intensity. This then becomes a critical limit on the intensity of TTFields that may be used to treat tumors. Therefore, it is necessary in the art to be able to safely access higher TTFields intensities without exceeding the temperature threshold at the subject's skin.

[0025] In a transducer array with multiple electrode elements, the portion of the transducer array positioned directly beneath the electrode elements becomes hotter than the portion positioned between the electrode elements. Furthermore, in a transducer array with multiple electrode elements, a larger current flows through the electrode elements positioned along the edges of the array compared to the electrode elements positioned in the center of the array. Moreover, electrode elements positioned at the corners or similar sharp bends of the array's edges have a larger current than other electrode elements along the edges and near the center. This tendency of transducer arrays to conduct higher currents through electrode elements positioned along the edges, particularly at corners, is referred to herein as the “edge effect.”

[0026] Non-uniform current distribution through a transducer array, either due to electrode element distribution or edge effects, can create higher temperature zones (or "hot spots"), for example, at the corners or edges of the transducer array. These hot spots are the first to reach a threshold temperature and therefore control the requirement to reduce the current. As such, the occurrence of hot spots limits the maximum operating current that can be driven by the transducer array, and the resulting intensity of TTFields.

[0027] The inventors now recognize the need for transducer arrays that reduce or minimize the non-uniform distribution of current, thereby enabling the application of larger operating currents. Transducer arrays operating at high currents can induce stronger TTFields within the subject's body, potentially leading to better patient outcomes. The electrode assemblies disclosed herein allow current and heat to be uniformly diffused across the array, thereby minimizing or eliminating hot spots.

[0028] The embodiments described herein incorporate a sheet of graphite within the electrode assembly, as described below. This lowers the temperature of the hot spot and raises the temperature of the colder areas (compared to the prior art configuration described above) when a given AC voltage is applied to the electrode assembly. Thus, the current can be increased without exceeding a safe temperature threshold at any point on the subject's skin (thereby enhancing the therapeutic effect).

[0029] In some preferred embodiments, the graphite sheet is a sheet of pyrolytic graphite. In particular, since graphite is a nonmetal, this is advantageous as it prevents the movement of ions into the body of the subject.

[0030] The present invention may be more readily understood by referring to the following detailed description, examples, drawings, and claims, as well as the preceding and following descriptions thereof. However, it should be understood that the present invention is not limited to any particular apparatus, device, system, and / or method disclosed unless otherwise specified, and may, of course, be modified as such.

[0031] The headings are provided for convenience and should not be construed as limiting the invention in any way. Embodiments illustrated in any heading or portion of this disclosure may be combined with embodiments illustrated under the same heading or other headings or portions of this disclosure.

[0032] Any combination of the elements described herein and all possible variations thereof are incorporated into the present invention unless otherwise indicated herein or unless clearly contradicted by the context.

[0033] As used herein and in the accompanying claims, the singular forms indicated by “one” and “it” (corresponding to the articles “a,” “an,” and “the” in the original English text) include the plural form unless the context clearly indicates otherwise.

[0034] Figure 2 is a schematic diagram of an electrode assembly 50 of one embodiment, comprising electrode elements used to apply TTFields to the body of a subject. In Figure 2, only two electrode elements labeled E1 and E2 are shown, but additional electrode elements may be included in the electrode assembly 50. In an alternative embodiment, the electrode assembly 50 includes only a single electrode element. In particular, Figure 2 is a general depiction of the electrode assembly 50, and those electrode assemblies E1 and E2 may have different configurations (as described below, for example, in relation to Figures 3A to 8).

[0035] Figure 3A is a cross-sectional view of a first embodiment of the electrode assembly 50a, including electrode elements E1 and E2, taken along the dashed line in Figure 2.

[0036] In the embodiment shown in Figure 3A, the electrode assembly 50a includes a sheet 70 of pyrolytic graphite having a front surface (facing the subject's skin in Figure 3A) and a rear surface. Examples of preferred forms of graphite include synthetic graphite such as pyrolytic graphite (including, but not limited to, pyrolytic graphite sheets (PGS) available from Panasonic Industries Ltd., Kadoma City, Osaka Prefecture), other forms of synthetic graphite, but not limited to, graphite foil made of high-purity compression-exfoliated mineral graphite (including, but not limited to, those supplied by MinGraph® 2010A Flexible Graphite available from Mineral Seal Corp., Tucson, Arizona, USA), or synthetic graphite such as graphitized polymer films, such as graphitized polyimide films (including, but not limited to, those supplied by Tochigi Kaneka Corporation, Mooka City, Tochigi Prefecture).

[0037] The electrode assembly 50a further includes at least one conductive material layer 60 disposed on the front surface of the sheet 70, the at least one conductive material layer 60 having a biocompatible front surface. Note that in the embodiment shown in Figure 3, there is only a single conductive material layer 60, and that single layer is biocompatible. However, in alternative embodiments (not shown), there may be multiple layers, in which case only the front layer must be biocompatible. At least one material layer 60 is configured to ensure good electrical contact between the device and the body. In some embodiments, at least one material layer 60 should cover the entire front surface of the sheet 70 of pyrolytic graphite. At least one material layer 60 may be the same size as or larger than the sheet 70 of pyrolytic graphite. In some embodiments (and as shown in Figure 3A), at least one conductive material layer 60 includes a single layer of hydrogel. In these embodiments, the hydrogel may have a thickness between 50 and 2000 μm, such as 100 to 1000 μm, or even 300 to 500 μm. In some embodiments, at least one conductive material layer 60 is a single layer of non-hydrogel biocompatible conductive adhesive. In some embodiments, at least one conductive material layer 60 is a single layer of non-hydrogel biocompatible conductive adhesive such as product FLX068983 - FLEXcon® OMNI-WAVE® TT 200 BLACK H-502 150 POLY H-9 44PP-8 developed by FLEXcon, Inc., located in Spencer, Massachusetts, USA, or other such OMNI-WAVE products from FLEXcon, Inc., or ARcare® 8006 conductive adhesive composition manufactured and sold by Adhesives Research, Inc., located in Glenrock, Pennsylvania, USA. Non-hydrogel conductive adhesives may contain anhydrous polymers having adhesive properties, and carbon particles, powders, fibers, flakes, or nanotubes. The adhesive polymer may be, for example, an acrylic polymer, a silicone polymer, or a combination thereof, which may be available as acrylic or silicone-based carbon-filled adhesive tapes.The adhesive may also contain one or more conductive polymers (for example, polyaniline (PANI), poly(3,4-ethylenedioxythiophene (PEDOT), or others known in the art). The conductive filler in at least one conductive material layer 60 should be nonmetallic. In these embodiments, the biocompatible conductive adhesive may have a thickness between 10 and 2000 μm, such as 20 to 1000 μm, or even 30 to 400 μm.

[0038] The electrode assembly 50a further includes a first electrode element E1 positioned behind the sheet 70. The first electrode element E1 has a first front surface disposed to be in electrical contact with the rear surface of the sheet 70. In the embodiment of Figure 3A, the first electrode element E1 comprises a first dielectric (e.g., ceramic) material layer 310 having a front and a rear surface, and a first metal layer 320 disposed on the rear surface of the first dielectric material layer 310. The front surface of the first dielectric material layer 310 is the first front surface of the first electrode element E1. Although the figure (e.g., Figure 3A) depicts the dielectric material 310 as "ceramic," it should be noted that a variety of other suitable dielectric materials may be used instead of the ceramic material. Examples include a polymer layer having a dielectric constant of at least 10, or another material having a dielectric constant of at least 10.

[0039] In some embodiments, the dielectric material layer 310 may have a dielectric constant (relative permittivity) in the range of 10 to 50,000. In some embodiments, the dielectric material layer 310 comprises a highly dielectric polymer material such as 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. These embodiments are particularly advantageous because the dielectric constants of these materials are on the order of 40. In some embodiments, the polymer layer may be poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) or "poly(VDF-TrFE-CTFE-CFE)."

[0040] In some embodiments, the dielectric material layer 310 comprises a terpolymer containing polymerization units of monomers such as VDF, TrFE, CFE, and / or CTFE in any preferred molar ratio. Preferred terpolymers include, for example, those having 30 to 80 mol% VDF, 5 to 60 mol% TrFE, and CFE and / or CTFE constituting the remaining mol% of the terpolymer.

[0041] In some embodiments, the sheet 70 has a center of gravity, and the center of gravity of the first front surface of the first electrode element E1 is positioned less than 3 cm away from the center of gravity of the sheet 70. In some embodiments, the sheet 70 has a center of gravity and a dimension (e.g., length or width) parallel to the rear surface of the sheet 70, and the center of gravity of the first front surface of the first electrode element E1 is positioned less than 30% or less than 10% of this dimension away from the center of gravity of the sheet 70.

[0042] The electrode assembly 50a further includes a first conductive material rear layer 80 positioned between the first front surface of the first electrode element E1 (i.e., the front surface of the first dielectric material layer 310) and the rear surface of the sheet 70. The first conductive material rear layer 80 facilitates electrical contact between the first front surface of the first electrode element E1 and the rear surface of the sheet 70. In some embodiments, the conductive material rear layer 80 is a layer of hydrogel. However, in alternative embodiments, different conductive materials (e.g., conductive grease, conductive adhesive, conductive tape, conductive composite material, etc.) may be used. In some embodiments, the conductive material 80 may be a non-hydrogel conductive adhesive as described above.

[0043] The electrode assembly 50a may optionally include one or more additional electrode elements. In the embodiment illustrated, the electrode assembly 50a includes a second electrode element E2 positioned behind the sheet 70. The second electrode element E2 has a second front surface disposed to be in electrical contact with the rear surface of the sheet 70. The two electrode elements E1 and E2 in Figure 3A have the same structure. Thus, the second electrode element E2 comprises a second dielectric (e.g., ceramic) material layer 310 having a front and a rear surface, and a second metal layer 320 disposed on the rear surface of the second dielectric material layer 310. The front surface of the second dielectric material layer 310 is the second front surface of the second electrode element E2. In some embodiments, the combined area of ​​all electrode elements is less than the area of ​​the sheet 70, less than half the area of ​​the sheet 70, less than one-quarter of the area of ​​the sheet 70, or less than one-tenth of the area of ​​the sheet 70.

[0044] The first conductive material rear layer 80 is positioned between the second front surface of the second electrode element E2 (i.e., the front surface of the second dielectric material layer 310) and the rear surface of the sheet 70. The first conductive material rear layer 80 facilitates electrical contact between the second front surface of the second electrode element E2 and the rear surface of the sheet 70. As described for E1 and as shown in Figure 3A, the conductive material 80 may be a layer of hydrogel, but in alternative embodiments, different conductive materials may also be used (e.g., conductive grease, conductive adhesives including the non-hydrogel conductive adhesive described above, conductive tape, conductive composite material, etc.).

[0045] The metal layers 320 of all electrode elements (i.e., E1 and E2 in the illustrated embodiment) can be wired together to leads 90 (e.g., using wires, traces on a flexible circuit, etc.). The leads 90 supply AC voltage from an AC voltage generator (not shown) to the electrode elements to generate TTFields when the electrode assembly 50a is attached to the subject's body for treatment.

[0046] Optionally, the electrode assembly 50a includes a sheet 70, a first electrode element E1 (and other electrode elements present in the electrode assembly), and a flexible self-adhesive backing 55 configured to support at least one conductive material layer 60, such that at least one conductive material layer 60 can be positioned relative to the skin of the subject.

[0047] As described above, Figure 2 is a schematic plan view of the electrode assembly 50 including electrode elements E1 and E2. This diagram in Figure 2 (not to scale) also shows that the area of ​​sheet 70 is larger than the combined area of ​​electrode elements E1 and E2 (for example, at least twice as large, at least four times as large, or at least ten times as large). When an AC voltage is applied to electrode elements E1 and E2, the heat is diffused throughout sheet 70, minimizing or eliminating hot spots.

[0048] This reduction in hot spots (compared to the conventional technology) becomes more apparent when comparing Figure 1C and Figure 3B. More specifically, Figure 1C shows the current distribution and heat generation for conventional electrode elements, each positioned on a conductive hydrogel layer covering approximately the same area as the electrode element. As shown in Figure 1C, all current passes through the hydrogel layer directly beneath the electrode element, resulting in a hot spot directly beneath the electrode element.

[0049] One might initially think that this problem could be solved by increasing the area of ​​the hydrogel to cover all regions between the electrode elements (i.e., by covering a significantly larger area in the xy-plane compared to the area of ​​the electrode elements). However, this is not the case. More specifically, Figure 1D shows the current distribution and heat generation for this hypothetical electrode assembly. As shown in Figure 1D, all the current passes straight through the hydrogel layer directly beneath the electrode elements, resulting in a hot spot directly beneath the electrode elements.

[0050] In contrast, Figure 3B shows the current distribution for the embodiment in Figure 3A. As shown in Figure 3B, the current is still distributed only in the region beneath the electrode element within the post-conductive material layer (e.g., 80 in Figure 3B). However, the pyrolytic graphite sheet 70 has high horizontal thermal conductivity, so it diffuses heat throughout its entire region. In addition to diffusing heat, the low electrical resistance of the sheet 70 in the horizontal direction diffuses the current outward across the sheet 70, and this diffused current distribution continues within the conductive material layer 60, from there to the skin of the subject. In this embodiment, both current and heat are diffused over a wider area of ​​the conductive material layer 60, so that hot spots are eliminated (or at least minimized). This means that for a given applied AC voltage, the hottest point beneath the electrode assembly in the embodiment in Figure 3A / B has a lower temperature than the hottest point beneath the electrode assembly in the prior art example in Figure 1. Thus, the current can be increased (with respect to the prior art current) without exceeding the safe temperature threshold at any point beneath the electrode assembly in the embodiment in Figure 3A. Furthermore, this increase in current advantageously enhances the effectiveness of TTFields treatment. Similar results can also be achieved when hydrogels are replaced with conductive adhesive composite materials.

[0051] The superior performance of the embodiment shown in Figure 3A is demonstrated in Figures 4A, 4B, and 4C. Figure 4A is a thermal image of a prior art electrode assembly including two electrode elements and a layer of hydrogel disposed in front of the electrode elements. There is no graphite sheet between the front of the electrode elements and the rear of the hydrogel layer. During use, the front of the hydrogel layer is positioned on the skin of the subject. Figure 4A shows a hot spot generated within the region corresponding to the electrode element.

[0052] Figure 4B is a thermal image of an electrode assembly corresponding to the embodiment of Figure 3A, in which pyrolytic graphite 70 is positioned between the front surfaces of electrode elements E1 and E2 and the rear surface of the conductive layer 60, and the conductive layer 60 is made of hydrogel. Figure 4B shows that hot spots, which occurred in the conventional electrode assembly, are minimized, and the maximum temperature is reduced. Figure 4C is a graph showing a comparison of the thermal performance of the embodiment of Figure 3A (using pyrolytic graphite) and the conventional technology (without graphite) for the same applied current (500 mA). In particular, the hottest part of the conventional electrode assembly was 41°C. However, when the same current of 500 mA was applied in the embodiment of Figure 3A, the hottest part of the electrode assembly was only 32°C. Similar experiments were performed using graphite foil made of high-purity compression-exfoliated mineral graphite, and similar results were obtained.

[0053] In the relevant experiments, the optimized conventional array (without graphite sheets) rose to an average temperature of up to 40°C with an applied current of 2A, but this was limited. The same type of array with added pyrolytic graphite sheets (as in the embodiment shown in Figure 3A) was able to operate at increased power levels (applied current of 3A) and operated at an average temperature of 38°C, 2–3°C below the temperature threshold limit. These results suggest that the apparatus and methods of the present invention described herein may achieve more beneficial therapeutic outcomes by operating with higher applied currents.

[0054] In experimental simulations of electrodes for therapeutic target placement within the body, the heat distribution obtained using graphite sheets was compared with that obtained using metal sheets. In half of the experiment, a phantom gel was implanted sandwiched between two sheets of metal (aluminum), and a voltage was applied between the two metal sheets (directly to the center of the sheets). In the other half of the experiment, the phantom gel was implanted sandwiched between two sheets of pyrolytic graphite, and a voltage was applied between the two pyrolytic graphite sheets (directly to the center of the sheets). When the voltage was applied between a pair of metal sheets (aluminum), the current density was high at the edges of the sheets, resulting in uneven heating of different regions. In contrast, applying the voltage between two graphite sheets resulted in a more uniform current density at the center and edges of the sheets, and a more uniform temperature profile of the sheets.

[0055] Figures 4D and 4E show thermal camera images of simulated electrode arrays using metal (aluminum) sheets and pyrolytic graphite sheets, respectively. The aluminum sheets result in a non-uniform thermal distribution, which controls the requirements by causing the outer edges to reach the threshold temperature first and thus reduce the current. In contrast, the pyrolytic graphite sheets result in a very uniform thermal distribution across the entire sheet.

[0056] Figure 4F shows experimental results when electrode arrays with and without graphite sheets were used to apply TTFields to the torso of rats (using small animal arrays). The two lower traces show the measured currents for two rats when the conventional electrode arrays depicted in Figure 1A / 1B were used, and the two upper traces show the measured currents for two rats when the electrode elements depicted in Figure 3A (using graphite sheets) were used. The temperature setpoint was the same for all implementations. In particular, when the graphite sheet was included, the resistance was 20% lower and the current was 50% higher at the same temperature setpoint, resulting from improved heat and current distribution attributable to the graphite. And since the higher current is associated with improved results, these experiments indicate that incorporating a layer of graphite into the electrode array can lead to improved results.

[0057] Figure 5 is a cross-sectional view of a second embodiment of electrode assembly 50b, including electrode elements E1 and E2, taken along the dashed line in Figure 2. The embodiment in Figure 5 is similar to the embodiment in Figure 3A in all respects except for the following: The embodiment in Figure 3A includes a broad rear layer 80 of conductive material (e.g., hydrogel) positioned between the sheet 70 and the front surfaces of both the first and second electrode elements E1 and E2. In contrast, the embodiment in Figure 5 includes separate regions 380 of conductive material for each individual electrode element. Thus, the embodiment in Figure 5 includes a first conductive material rear layer 380 positioned between the first front surface of the first electrode element E1 and the rear surface of the sheet 70, and also includes a second conductive material rear layer 380 positioned between the second front surface of the second electrode element E2 and the rear surface of the sheet 70. The first and second rear layers 380 of conductive material facilitate electrical contact between the front surfaces of the respective electrodes and the rear surface of the sheet 70. In some embodiments, the rear layer 380 of the conductive material is a layer of hydrogel. However, in alternative embodiments, different conductive materials (e.g., conductive grease, conductive adhesives including the non-hydrogel conductive adhesives described above, conductive tapes, conductive composite materials, etc.) may be used. In some embodiments, the combined area of ​​all electrode elements is less than the area of ​​sheet 70, less than half the area of ​​sheet 70, less than one-quarter the area of ​​sheet 70, or less than one-tenth the area of ​​sheet 70.

[0058] Similar to the embodiment in Figure 3A, the current in the embodiment in Figure 5 is still concentrated in the rear layer 380 of the conductive material only in the region beneath the electrode element. The sheet 70 of pyrolytic graphite diffuses heat and current as described above in relation to the embodiment in Figure 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest point under the electrode assembly in the embodiment in Figure 5 is at a lower temperature than the hottest point under the electrode assembly in the prior art example in Figure 1. Thus, the current can be increased (with respect to the current in the prior art) without exceeding the safe temperature threshold at any point under the electrode assembly in the embodiment in Figure 5. And this increase in current is advantageous in that it enhances the effectiveness of the TTFields treatment.

[0059] Figure 6 is a cross-sectional view of a third embodiment of an electrode assembly 50c including a single electrode element E1. The embodiment in Figure 6 is similar to the embodiment in Figure 3A, except that the embodiment in Figure 6 does not include a layer of dielectric material. In the embodiment in Figure 6, the electrode assembly 50c includes a sheet 70 of pyrolytic graphite having a front surface (facing the skin of the subject in Figure 6) and a rear surface. This sheet 70 is similar to the sheet 70 described above in relation to Figure 3A.

[0060] The electrode assembly 50c further includes at least one conductive material layer 60 disposed on the front surface of the sheet 70, the at least one conductive material layer 60 having a biocompatible front surface. Note that in the embodiment shown in Figure 6, there is only a single layer 60 of conductive material, and that single layer is biocompatible. However, in alternative embodiments (not shown), there may be multiple layers, in which case only the front layer must be biocompatible. The at least one conductive material layer 60 is configured to ensure good electrical contact between the device and the body. In a preferred embodiment, the at least one conductive material layer 60 should cover the entire front surface of the sheet 70 of pyrolytic graphite. The at least one conductive material layer 60 may be the same size as the sheet 70 of pyrolytic graphite or larger (i.e., covering the same or a larger area). In some embodiments, the at least one conductive material layer 60 includes a single layer of hydrogel. In these embodiments, the hydrogel may have a thickness between 50 and 2000 μm, such as 100 to 1000 μm, or even 300 to 500 μm. In some embodiments, at least one conductive material layer 60 is a single layer of a non-hydrogel biocompatible conductive adhesive, such as FLEXcon's OMNI-WAVE product or Adhesives Research, Inc.'s ARcare® product, as described above. The non-hydrogel conductive adhesive may comprise an anhydrous polymer having adhesive properties (e.g., an acrylic polymer, a silicone polymer, or a combination thereof) and a conductive filler. The conductive filler in at least one conductive material layer 60 should be nonmetallic. In these embodiments, the biocompatible conductive adhesive may have a thickness between 10 and 2000 μm, such as 20 to 1000 μm, or even 30 to 400 μm.

[0061] The electrode assembly 50c further includes a first electrode element E1 positioned behind the sheet 70. The first electrode element E1 includes a metal piece 500 having a front surface disposed to electrically contact the rear surface of the sheet 70. In the embodiment of Figure 6, the front surface of the metal piece 500 is the first front surface of the first electrode element E1. Thus, the embodiment of Figure 6 differs from the embodiments of Figure 3A or Figure 5 in that it lacks a layer of dielectric material. The positional relationship between the first electrode element E1 and the sheet 70 in this embodiment of Figure 6 may be as described above in relation to Figure 3A.

[0062] The electrode assembly 50c further includes a first conductive material rear layer 80 positioned between the first front surface of the first electrode element E1 (i.e., the front surface of the metal piece 500) and the rear surface of the sheet 70. The first conductive material rear layer 80 facilitates electrical contact between the first front surface of the first electrode element E1 and the rear surface of the sheet 70. In some embodiments, the conductive material rear layer 80 is a layer of hydrogel. However, in alternative embodiments, different conductive materials (e.g., conductive grease, conductive adhesives including the non-hydrogel conductive adhesives described above, conductive tapes, conductive composite materials, etc.) may be used.

[0063] The metal piece 500 of the electrode element E1 is wired to a lead 90 (for example, using a wire, trace on a flexible circuit, etc.), which supplies an AC voltage to the electrode element from an AC voltage generator (not shown) to generate TTFields when the electrode assembly 50c is attached to the subject's body for treatment.

[0064] The electrode assembly 50c may optionally include one or more additional electrode elements (not shown) that have the same structure and function as electrode element E1 and are positioned to have the same function. In such a case, the metal pieces 500 of all electrode elements may be wired together to the lead 90 (for example, using wires, traces on a flexible circuit, etc.).

[0065] In some embodiments including only a single electrode element E1, the area of ​​the sheet 70 is larger than the area of ​​the electrode element E1 (for example, at least twice as large, at least four times as large, or at least ten times as large). In some embodiments including multiple electrode elements (not shown), the area of ​​the sheet 70 is larger than the combined area of ​​all the electrode elements (for example, at least two, four, or ten times as large). When an AC voltage is applied to the electrode elements, heat is diffused throughout the sheet 70, minimizing or eliminating hot spots.

[0066] Similar to the embodiment in Figure 3A, the pyrolytic graphite sheet 70 in the embodiment in Figure 6 diffuses heat and current as described above in relation to the embodiment in Figure 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest point under the electrode assembly in the embodiment in Figure 6 has a lower temperature than the hottest point under the electrode assembly in the prior art example in Figure 1. Thus, the current can be increased (with respect to the current in the prior art) without exceeding the safe temperature threshold at any point under the electrode assembly in the embodiment in Figure 6. And this increase in current is advantageous in that it enhances the effectiveness of TTFields treatment.

[0067] Figure 7 is a cross-sectional view of a fourth embodiment of an electrode assembly 50d including a single electrode element E1. The embodiment in Figure 7 is similar to the embodiment in Figure 6, except that the first front surface of the first electrode element E1 (i.e., the front surface of the metal piece 600) is positioned in direct contact with the rear surface of the sheet 70 (instead of being electrically connected via an intervening layer of conductive material).

[0068] Similar to the embodiment in Figure 6, the pyrolytic graphite sheet 70 in the embodiment in Figure 7 diffuses heat and current, as described above in relation to the embodiment in Figure 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest point under the electrode assembly in the embodiment in Figure 7 has a lower temperature than the hottest point under the electrode assembly in the prior art example in Figure 1. Thus, the current can be increased (with respect to the current in the prior art) without exceeding the safe temperature threshold at any point under the electrode assembly in the embodiment in Figure 7. And this increase in current is advantageous in that it enhances the effectiveness of TTFields treatment.

[0069] Figure 8 is a cross-sectional view of a fifth embodiment of the electrode assembly 50e, which includes a single electrode element E1. The embodiment in Figure 8 is similar to the embodiment in Figure 7, except that a capacitor 700 is added in series with the metal piece 600, after which it is connected. A similar addition of a capacitor 700 connected after the metal piece 600, in series with the metal piece 600, could also be considered for the embodiment in Figure 6.

[0070] Figure 9 shows how the pair of electrode assemblies 50a shown in Figure 3A are used to apply an alternating electric field to a target area within the body of a subject. The subject may be a human or other mammal, including but not limited to rats and mice. (Note that any of the electrode assemblies described above in relation to Figures 5-8 may be used instead of the electrode assemblies 50a shown in Figure 3A.)

[0071] This method involves positioning the first electrode assembly 50a at a first location on or inside the body of a subject. (In the example shown in Figure 9, the first electrode assembly 50a is positioned on the skin of the subject on the right side of the subject's head facing a target area, for example, a tumor). The first electrode assembly 50a may be configured as described above herein. In the embodiment of Figure 9, the first electrode assembly 50a includes a first sheet 70 of pyrolytic graphite 70 having a first front surface and a first rear surface. When in use, the first electrode assembly 50a is positioned so that the first front surface of the first sheet 70 faces the target area.

[0072] This method also includes positioning the second electrode assembly 50a at a second location inside or on the body of the subject. (In the example shown in Figure 9, the second electrode assembly 50a is positioned on the skin of the subject on the left side of the subject's head, facing the target area.) The second electrode assembly 50a may be configured as described above herein. In the embodiment of Figure 9, the second electrode assembly 50a includes a second sheet 70 of pyrolytic graphite 70 having a second front surface and a second rear surface. When in use, the second electrode assembly 50a is positioned so that the second front surface of the second sheet 70 faces the target area.

[0073] The method further includes applying an alternating current voltage between the first electrode assembly 50a and the second electrode assembly 50a. This application is performed after the first electrode assembly 50a and the second electrode assembly 50a have been positioned. This application can be carried out by applying an alternating current voltage between (i) a first electrode element disposed in electrical contact with the first rear surface of the first sheet 70 and (ii) a second electrode element disposed in electrical contact with the second rear surface of the second sheet 70.

[0074] In some embodiments, the first electrode assembly 50a further includes a first layer of biocompatible conductive material 60 disposed on the first front surface of the first sheet 70. Correspondingly, the second electrode assembly further includes a second layer of biocompatible conductive material 60 disposed on the second front surface of the second sheet 70. As described above, the biocompatible conductive material 60 may be a hydrogel, or it may be a conductive grease, a conductive adhesive including the non-hydrogel conductive adhesive described above, a conductive tape, a conductive composite material, etc.

[0075] In some embodiments, the first electrode assembly 50a further includes a first conductive material rear layer 80 (as described above) positioned between the first front surface of the first electrode element of the first electrode assembly 50a and the first rear surface of the first sheet 70. Correspondingly, the second electrode assembly further includes a second conductive material rear layer 80 (as described above) positioned between the second front surface of the second electrode element of the second electrode assembly and the second rear surface of the second sheet 70.

[0076] An AC voltage between the first electrode assembly and the second electrode assembly can be applied by an AC voltage generator 820. In some embodiments, the frequency of the AC voltage is between 50 kHz and 1 MHz, or between 100 kHz and 500 kHz. In the illustrated example, the AC voltage generator is controlled by a controller 822. The controller 822 may control the amplitude of the current supplied through the first and second electrode assemblies 50a using temperature measurements to maintain the temperature below a safety threshold (e.g., 41°C). This can be achieved, for example, by measuring a first temperature of the first electrode element, measuring a second temperature of the second electrode element, and controlling the application of the AC voltage based on the first and second temperatures, as described below.

[0077] Figure 9 shows an example of hardware suitable for this purpose. More specifically, a temperature sensor 800 (e.g., a thermistor) is positioned to make thermal contact with each electrode element 310 / 320 in each of the electrode assemblies 50a. The temperature sensor 800 measures the respective first and second temperatures (e.g., in the first and second electrode elements in the first and second electrode assemblies, respectively), and the controller 822 controls the output of the AC voltage generator 820 based on these temperatures.

[0078] Similar embodiments and methods are conceivable that utilize any of the electrode assemblies 50a-e, or a combination thereof, instead of either or both of the first electrode assembly 50a and the second electrode assembly 50a.

[0079] In the embodiments described above in relation to Figures 2 to 9, the sheet 70 is made of pyrolytic graphite. However, in alternative embodiments, the sheet 70 may be made of other types of graphite, including, but not limited to, graphite foil made of high-purity compression-exfoliated mineral graphite (including, but not limited to, MinGraph® 2010A Flexible Graphite available from Mineral Seal Corp. in Tucson, Arizona, USA), or other synthetic graphites such as isotropic graphite (including, but not limited to, isotropic graphite grade G330 available from Tokai Carbon Europe in Oldbury, UK, and double-sided carbon tape for scanning electron microscopes available from Thermo Fisher Scientific in Hampton, New Hampshire, USA).

[0080] While the present invention is disclosed with reference to several embodiments, numerous modifications, alterations, and changes are possible to the embodiments described without departing from the scope and realm of the invention, as defined in the supplementary claims. Therefore, the present invention should not be limited to the embodiments described, but is intended to have the entire scope defined by the wording of the following claims and their equivalents. [Explanation of Symbols]

[0081] 50 electrode assemblies 50a Electrode assembly, first electrode assembly, second electrode assembly 50b Electrode Assembly 50c electrode assembly 50d electrode assembly 50e Electrode Assembly 60 layers, conductive layer 70 sheets, pyrolytic graphite, first sheet, second sheet 80 First conductive material rear layer 310 First dielectric material layer 320 First metal layer 380 Different areas of conductive materials 500 metal pieces 600 metal pieces 700 Capacitor 800 Temperature Sensor 820 AC voltage generator 822 Controller

Claims

1. A device for applying an alternating electric field to the body of a test subject, A sheet consisting solely of graphite, having a front and a back, At least one conductive material layer disposed on the front surface of the sheet, the at least one conductive material layer having a biocompatible front surface, A first electrode element positioned behind the sheet, the first electrode element having a first front surface disposed to electrically contact the rear surface of the sheet, The first electrode assembly comprises a temperature sensor positioned to be in thermal contact with the first electrode element, The temperature sensor measures the first temperature of the first electrode element in the first electrode assembly. The first temperature is used to control the amplitude of the current supplied through the first electrode assembly and to keep the skin temperature of the subject below a safety threshold. The first electrode element comprises a metal piece having a front surface and a capacitor connected in series with the metal piece after the metal piece, and does not include a dielectric material layer. The apparatus wherein the front surface of the metal piece is the first front surface of the first electrode element.

2. The apparatus according to claim 1, wherein the first front surface of the first electrode element is positioned in direct contact with the rear surface of the sheet.

3. The apparatus according to claim 1, wherein the graphite sheet is a sheet of pyrolytic graphite.

4. The apparatus according to claim 1, wherein the graphite sheet is a graphite foil made of high-purity compression-exfoliated mineral graphite, or a sheet of graphitized polymer film.

5. The apparatus according to claim 1, wherein the at least one conductive material layer comprises a hydrogel.

6. The apparatus according to claim 1, wherein the at least one conductive material layer includes a hydrogel layer having a thickness between 50 and 2000 μm.

7. The apparatus according to claim 1, wherein the at least one conductive material layer includes a conductive adhesive.

8. The apparatus according to claim 7, wherein the conductive adhesive comprises an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes.

9. The apparatus according to claim 7, wherein the conductive adhesive has a thickness between 10 and 2000 μm.

10. The apparatus according to claim 1, further comprising the sheet, the first electrode element, and a flexible self-adhesive backing configured to support the at least one conductive material layer, wherein the front surface of the at least one conductive material layer is in contact with the skin of the subject by the flexible self-adhesive backing.

11. The apparatus according to claim 1, further comprising a lead electrically connected to the first electrode element.

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