Electrode assembly for applying tumor treatment fields, including a graphite sheet

Abstract

Alternating electric fields (e.g., TTFields) can be applied to a subject's body using one or more electrode arrays comprising a graphite sheet, at least one layer of conductive material on the front face of the graphite sheet, and an electrode element located behind the graphite sheet. The electrode element has a front face in electrical contact with the back face of the graphite sheet. The graphite sheet distributes both heat and current in directions parallel to its front face, eliminating or minimizing hot spots in the electrode array. This, in turn, allows the current to be increased without exceeding a safe temperature threshold (e.g., 41 °C).

Description

Electrode assembly for the application of tumor treatment fields including a graphite sheet Background Tumor Treatment Fields (TTFields) is a proven approach to treating tumors using alternating electric fields at frequencies between 50 kHz and 1 MHz, such as 100–500 kHz. These alternating electric fields are induced by electrode arrays (e.g., capacitively coupled electrode arrays, also called transducer arrays) positioned on opposite sides of a subject's body. When an AC voltage is applied between the opposing electrode arrays, an AC current is coupled through the electrode arrays and into the subject's body. Higher currents are strongly correlated with greater treatment efficacy. FIG. 1A is a schematic representation of a prior art electrode assembly 40 comprising nine prior art electrode elements, labeled X1-X9. FIG. 1B is a schematic cross-sectional view of electrode elements X7-X9 of the electrode assembly 40, taken along the dashed line in FIG. 1A. As shown in FIG. 1B, electrode element X7 (taken as an example) includes a metallic layer (shown with diagonal shading) and a ceramic (dielectric) layer. Between each ceramic layer and the subject's skin is a layer of electrically conductive hydrogel to ensure good electrical contact between the electrode elements and the body. An AC voltage from an AC voltage generator (not shown) is applied to the metallic layers of the electrode elements in opposing electrode arrays to generate the TTFields in the subject's body. During use, the hydrogel and the skin beneath the electrode elements heat up, and safety considerations require that the skin temperature be kept below a safety threshold (e.g., 41°C). Since most of the heat occurs immediately beneath electrode elements X1–X9 (as shown in Figure 1C), the prior art electrode assembly has hot spots immediately beneath the electrode elements and cooler regions between them. These hot spots limit the amount of current that can be delivered through the prior art electrode assemblies. US patent A-2006 / 0276858 discloses the provision of a conductive layer between a dielectric and a patient's body to improve electrical contact. Examples of suitable materials for the conductive layer include conductive gels and carbon (graphite) powders, which can be incorporated into a suitable cream (e.g., a cosmetic base with an electrolyte). Compendium of the invention One aspect of the invention relates to an apparatus for applying an alternating electric field to the body of a subject according to claim 1. The embodiments of the invention are disclosed in the dependent claims. Brief description of the drawings FIG.1A is a schematic representation of an electrode array of the previous technique. FIG. 1B is a cross-sectional view of the electrode elements of the electrode assembly of the prior art, taken along the dashed line of FIG. 1A. FIG. 1C is a cross-sectional view showing the heat generation properties of a prior art electrode element. FIG.1D is a cross-sectional view showing the heat generation properties of a hypothetical modification of the electrode element in FIG.1B. FIG.2 is a schematic plan view of an electrode array that includes electrode elements used to apply TTFields to a subject's body. FIG. 3A is a cross-sectional representation of a first embodiment including electrode elements E1, E2, taken along the dashed line of FIG. 2. FIG. 3B is a cross-sectional view showing the heat generation properties of the embodiment of FIG. 3A. FIG.4A is a thermal image of an electrode array of the above technique. FIG.4B is a thermal image of an electrode array corresponding to the implementation of FIG.3A. FIG. 4C is a graph comparing the thermal properties of the electrode array of the previous technique with the embodiment of FIG. 3A. FIG.4D shows a thermographic camera image of simulated electrode arrays constructed using metal sheets (aluminum). FIG.4E shows a thermographic camera image of simulated electrode arrays constructed using pyrolytic graphite sheets. FIG.4F shows experimental results when electrode arrays with and without a graphite sheet were used to apply TTFields to the torso of rats. FIG. 5 is a cross-sectional representation of a second embodiment including electrode elements E1, E2, taken along the dashed line of FIG. 2. FIG. 6 is a cross-sectional representation of a third embodiment that includes a single electrode element E1. FIG.7 is a cross-sectional representation of a fourth embodiment that includes a single electrode element E1. FIG. 8 is a cross-sectional representation of a fifth embodiment that includes a single electrode element E1. FIG.9 is a block diagram of a system incorporating two sets of electrodes used to apply TTFields to a subject's body. Several embodiments are described in detail below with reference to the accompanying drawings, where similar reference numbers represent similar elements. Description of preferred embodiments This application describes exemplary electrode arrays that can be used, for example, to deliver TTFields to a subject's body and treat one or more cancers or tumors located in the body. subject. When TTFields are applied to a subject's body, their body temperature can increase proportionally to the induced electric field. Regulations limit the amount of current that can be conducted through a transducer array to a quantity that keeps the measured temperature at locations on the subject's body below a temperature threshold. According to standard practice, the temperature at the transducer array locations on the subject's body is controlled to remain below the temperature threshold by reducing the operating current driven by the transducer arrays and thus reducing the strength of the resulting TTFields. This, in turn, becomes a primary limitation on the power of the TTFields that can be used to treat the tumor.Consequently, there is a need in the technique to safely access higher TTField intensities without exceeding the temperature threshold in the subject's skin. In transducer arrays comprising multiple electrode elements, the portions of the array positioned directly beneath the electrode elements heat up more than the portions positioned between the electrode elements. Furthermore, in transducer arrays comprising multiple electrode elements, higher currents flow through the electrode elements located along the edge of the array compared to those located toward the center. Additionally, an electrode element located at a corner or similar sharp bend on the edge of the array will have a higher current than other electrode elements along the edge and near the center of the array.The tendency of a transducer array to conduct higher currents through the electrode elements located along the edge of the array, and particularly at the corners, is referred to here as the "edge effect". Uneven current distribution across the transducer array, due to the electrode element arrangement or edge effects, can lead to areas of higher temperature (or "hot spots"), for example, at the corners or edges of the transducer array. These hot spots are the locations that reach the threshold temperature first and thus dictate the need to reduce the current. As such, the generation of hot spots limits the maximum operating current that can be driven by a transducer array and the strength of the resulting TTFields. The inventors have now recognized a need for transducer arrays that reduce or minimize uneven current distribution, thereby enabling the application of higher operating currents. Transducer arrays operating at higher currents can induce more intense TTFields in the subject's body, ultimately resulting in improved patient outcomes. The electrode arrays disclosed here allow current and heat to be distributed evenly across the array, thereby minimizing or eliminating hot spots. The embodiments described herein incorporate a graphite sheet in the electrode array, as described below. This reduces the temperature of hot spots and increases the temperature of cooler regions when a specific AC voltage is applied to the electrode array (compared to the configuration of the prior art described above). Consequently, the current can be increased (thus enhancing the therapeutic effect) without exceeding the safe temperature threshold at any point on the subject's skin. In some preferred embodiments, the graphite sheet is a pyrolytic graphite sheet. In particular, because graphite is nonmetallic, it advantageously prevents the transfer of ions to the subject's body. The present invention can be more easily understood by reference to the following detailed description, examples, drawings, and claims, as well as to its preceding and following descriptions. However, it should be understood that this invention is not limited to the specific apparatus, devices, systems, and / or methods disclosed unless otherwise specified, and as such, it may, of course, vary. The headings are provided for convenience only and should not be construed as a limitation of the invention. The embodiments illustrated under any heading or in any part of the disclosure may be combined with embodiments illustrated under the same or any other heading or in any other part of the disclosure. Any combination of the elements described herein and all possible variations thereof are included in the invention, unless otherwise stated herein or clearly contradicted by the context. As used in the descriptive memorandum and accompanying claims, the singular terms "a", "an", "the" and "the" include plural terms unless the context clearly indicates otherwise. Figure 2 is a schematic representation of an electrode array 50 of an embodiment that includes electrode elements used to apply TTFields to a subject's body. In Figure 2, only two electrode elements, labeled E1 and E2, are shown, but additional electrode elements may be included in the electrode array 50. In alternative embodiments, the electrode array 50 includes only a single electrode element. In particular, Figure 2 represents an electrode array 50 generically, and these electrode arrays E1 and E2 may have different configurations (e.g., as described below in relation to Figures 3A-8). FIG. 3A is a cross-sectional representation of a first embodiment of an electrode assembly 50a that includes electrode elements E1, E2, taken along the dashed line of FIG. 2. In the realization of FIG.3A, the electrode assembly 50a includes a pyrolytic graphite sheet 70 having a front face (oriented towards the subject's skin in FIG. 3A) and a back face. 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 Industr y, Kadoma, Osaka, Japan), other forms of synthetic graphite, including, but not limited to, graphite sheet manufactured from high-purity compressed exfoliated mineral graphite (including, but not limited to, that supplied as MinGraph® 2010A flexible graphite, available from Mineral Seal Corp, Tucson, Arizona, USA), or graphitized polymer sheet, for example, graphitized polyimide sheet (including, but not limited to, that supplied by Kaneka Corp., Moka, Tochigi, Japan). The electrode assembly 50a further comprises at least one layer of conductive material 60 disposed on the front face of the sheet 70, and said at least one layer of conductive material 60 has a biocompatible front surface. Note that, in the embodiment illustrated in FIG. 3, there is only a single layer of conductive material 60, and that single layer is biocompatible. But in alternative embodiments (not shown) there could be more than one layer, in which case only the front layer needs to be biocompatible. The at least one layer of material 60 is configured to ensure good electrical contact between the device and the body. In some embodiments, the at least one layer of material 60 should cover the entire front face of the pyrolytic graphite sheet 70. The at least one layer of material 60 can be the same size as, or larger than, the pyrolytic graphite sheet 70. In some embodiments (and as shown in FIG. 3), the layer of material 60 should cover the entire front face of the pyrolytic graphite sheet 70. 3A), the at least one layer of conductive material 60 comprises a single layer of hydrogel. In these embodiments, the hydrogel may have a thickness of between 50 and 2000 µm, such as 100 to 1000 µm, or even 300 to 500 µm. In some embodiments, the at least one layer of conductive material 60 is a single layer of biocompatible conductive adhesive that is not hydrogel. In some embodiments, at least one front layer of conductive material 60 is a single layer of biocompatible, non-hydrogel conductive adhesive, such as the development product FLX06898.- FLEXcon® OMNI-WAVE™ TT 200 BLACK H-502150 POLY H-944PP-8 from FLEXcon, Spencer, MA, USA, or other such OMNI-WAVE products from FLEXcon; or the electrically conductive adhesive composition ARcare® 8006 manufactured and marketed by Adhesives Research, Inc. (Glen Rock, PA, USA). The non-hydrogel conductive adhesives may comprise an aqua-free polymer with adhesive properties and carbon particles, powder, fibers, flakes, or nanotubes. The adhesive polymer may be, for example, an acrylic polymer or a silicone polymer, or a combination thereof, which may be available as acrylic- or silicone-based carbon-filled adhesive tapes.The adhesive may additionally include one or more conductive polymers (such as, for example, polyaniline (PANI) or poly(3,4-ethylenedioxythiophene (PEDOT)), or others known in the art). The conductive filler in at least one layer of conductive material 60 should be non-metallic. In these embodiments, the biocompatible conductive adhesive may have a thickness of between 10 and 2,000 µm, for example, from 20 to 1,000 µm or even from 30 to 400 µm. 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 face arranged in electrical contact with the rear face of the sheet 70. In the embodiment of FIG. 3A, the first electrode element E1 includes a first layer of dielectric material (e.g., ceramic) 310 having a front and a rear face, and a first metal layer 320 disposed on the rear face of the first layer of dielectric material 310. The front face of the first layer of dielectric material 310 is the first front face of the first electrode element E1. Note that, although the figures (e.g., FIG. 3A) represent the dielectric material 310 as "ceramic," a variety of other suitable dielectric materials may be used instead of ceramic materials.Examples include a polymer layer that has a dielectric constant of at least 10, or other material that has a dielectric constant of at least 10. In some embodiments, the dielectric material 310 layer may have a dielectric constant ranging from 10 to 50,000. In some embodiments, the dielectric material 310 layer comprises a high dielectric constant 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 constant of these materials is on the order of 40. In some embodiments, the polymer layer may be poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene-chlorofluoroethylene) or "Poly(VDF-TrFE-CTFE-CFE)". In some embodiments, the dielectric material 310 layer comprises a terpolymer comprising polymerized units of monomers such as VDF, TrFE, CFE, and / or CTFE in any suitable molar ratio. Suitable terpolymers include, for example, those having 30 to 80 mol% VDF, 5 to 60 mol% TrFE, with CFE and / or CTFE constituting the remaining mol% of the terpolymer. In some embodiments, sheet 70 has a centroid, and the centroid of the first front face of the first electrode element E1 is located less than 3 cm from the centroid of sheet 70. In some embodiments, sheet 70 has a centroid and a dimension parallel to the back face of sheet 70 (e.g., a length or a width), and the centroid of the first front face of the first electrode element E1 is positioned less than 30% or less than 10% of the dimension of the centroid of sheet 70. The electrode assembly 50a further includes a first back layer of conductive material 80 located between the first front face of the first electrode element E1 (i.e., the front face of the first dielectric material layer 310) and the back face of the foil 70. The first back layer of conductive material 80 facilitates electrical contact between the first front face of the first electrode element E1 and the back face of the foil 70. In some embodiments, the back layer of conductive material 80 is a hydrogel layer. However, in alternative embodiments, a different conductive material could be used (e.g., conductive grease, conductive adhesive, conductive tape, conductive compound, etc.). In some embodiments, the conductive material 80 may be a conductive adhesive other than a hydrogel, as described above. The electrode assembly 50a may optionally include one or more additional electrode elements. In the illustrated embodiment, the electrode assembly 50a includes a second electrode element E2 positioned behind the foil 70. The second electrode element E2 has a second front face arranged in electrical contact with the rear face of the foil 70. The two electrode elements E1 and E2 of FIG. 3A have identical structures. Thus, the second electrode element E2 includes a second layer of dielectric material (e.g., ceramic) 310 having a front and a rear face, and a second metal layer 320 disposed on the rear face of the second layer of dielectric material 310. The front face of the second layer of dielectric material 310 is the second front face of the second electrode element E2.In some embodiments, the collective area of ​​all the electrode elements is less than the area of ​​sheet 70, less than half the area of ​​sheet 70, less than a quarter of the area of ​​sheet 70, or less than one tenth of the area of ​​sheet 70. The first back layer of conductive material 80 is positioned between the second front face of the second electrode element E2 (i.e., the front face of the second layer of dielectric material 310) and the back face of the foil 70. The first back layer of conductive material 80 facilitates electrical contact between the second front face of the second electrode element E2 and the back face of the foil 70. As described for E1, and as shown in FIG. 3A, the conductive material 80 can be a hydrogel layer, but in alternative embodiments, a different conductive material can be used (e.g., conductive grease, conductive adhesive including the non-hydrogel conductive adhesive described above, conductive tape, conductive compound, etc.). The 320 metal layers of all electrode elements (i.e., E1 and E2 in the illustrated embodiment) can be connected to each other (e.g., by cables, traces in a flexible circuit, etc.) to a cable 90. The cable 90 supplies an AC voltage from an AC voltage generator (not shown) to the electrode elements to generate the TTFields when the 50a electrode assembly is attached to the subject's body for treatment. Optionally, the electrode assembly 50a includes a flexible self-adhesive support 55 configured to support the foil 70, the first electrode element E1 (and any other electrode elements present in the electrode assembly) and the at least one layer of conductive material 60 so that the at least one layer of conductive material 60 can be positioned against the subject's skin. As noted above, FIG. 2 is a schematic plan view of an electrode assembly 50, including electrode elements E1 and E2. This view in FIG. 2 (not to scale) also demonstrates that the area of ​​sheet 70 is larger (e.g., at least 2 times larger, at least 4 times larger, or at least 10 times larger) than the combined areas of electrode elements E1 and E2. When an AC voltage is applied to electrode elements E1 and E2, the heat is distributed throughout the sheet 70, minimizing or eliminating hot spots. This reduction in hot spots (compared to the prior art) becomes evident when comparing FIG. 1C with FIG. 3B. More specifically, FIG. 1C shows the current distribution and heat generation for electrode elements of the prior art, each of which is positioned on a conductive hydrogel layer covering approximately the same area as the electrode element. As shown in FIG. 1C, all the current passes through the hydrogel layer directly beneath the electrode elements, generating hot spots directly under them. Initially, one might think that this problem could be solved by increasing the hydrogel area to cover all the regions between the electrode elements (i.e., covering a significantly larger area in the xy plane than the electrode elements themselves). However, this is not the case. More specifically, Figure 1D shows the current distribution and heat generation for this hypothetical electrode array. As shown in Figure 1D, all the current still passes through the hydrogel layer directly beneath the electrode elements, resulting in hot spots directly under them. In contrast, FIG. 3B shows the current distribution for the embodiment of FIG. 3A. As shown in FIG. 3B, the current is still distributed in the back conductive material layer (e.g., 80 in FIG. 3B) only in the area beneath the electrode element. However, the pyrolytic graphite sheet 70 distributes heat over its entire area because of its high thermal conductivity in the horizontal directions. In addition to distributing heat, the low electrical resistance of sheet 70 in the horizontal direction distributes the current outward across the entire sheet 70, and this distributed current continues into the conductive material layer 60, and from there to the subject's skin. Because in this embodiment both the current and the heat are distributed over a larger area of ​​the conductive material layer 60, hot spots are eliminated (or at least minimized).This means that for a given applied AC voltage, the hottest spot under the electrode array in the embodiment of FIG. 3A / B will have a lower temperature than the hottest spot under the electrode array in the example of FIG. 1 of the prior art. Consequently, the current can be increased (compared to the current of the prior art) without exceeding the safe temperature threshold at any point below the electrode array in the embodiment of FIG. 3A. This increase in current will advantageously enhance the effectiveness of the TTFields treatment. Similar results can be achieved when the hydrogel is replaced by a conductive adhesive compound. The superior performance of the embodiment of FIG. 3A is shown in FIGS. 4A, 4B, and 4C. FIG. 4A is a thermal image of a prior art electrode assembly comprising two electrode elements and a hydrogel layer disposed on the front faces of the electrode elements. There is no graphite sheet between the front faces of the electrode elements and the back face of the hydrogel layer. During use, the front face of the hydrogel layer is placed against the subject's skin. FIG. 4A shows hot spots generated in the areas corresponding to the electrode elements. Figure 4B is a thermal image of an electrode assembly corresponding to the embodiment of Figure 3A, where pyrolytic graphite 70 is positioned between the front faces of electrode elements E1 and E2 and the back face of the conductive layer 60, and the conductive layer 60 is made of hydrogel. Figure 4B shows that hot spots, such as those generated in the electrode assembly of the prior art, have been minimized, and the maximum temperature has also been reduced. Figure 4C is a graph comparing the thermal performance of the embodiment of Figure 3A (with pyrolytic graphite) with the prior art (without graphite) for the same applied current (500 mA). It is noteworthy that the highest temperature of the electrode assembly of the prior art was 41 °C. However, when applying the same 500 mA current to the implementation of FIG.3A, the highest temperature of the electrode assembly was only 32 °C.Similar experiments were performed using a graphite sheet made from compressed high-purity exfoliated mineral graphite, with similar results. In a related experiment, conventional optimized arrays (without a graphite sheet), operating with an applied current of 2 A, reached a maximum average temperature of 40 °C and were therefore limited. The same type of array with an added pyrolytic graphite sheet (as in the embodiment of FIG. 3A) was able to operate at a higher power level (with an applied current of 3 A) and functioned at an average temperature of 38 °C, 2–3 °C below the threshold temperature limit. This result suggests that the apparatus and inventive methods described herein should be able to achieve more beneficial treatment results when operating with higher applied currents. An experimental simulation of electrodes for treating a target location on a body compared the heat distribution obtained using graphite sheets with that obtained using metal sheets. In one half of the experiment, a phantom gel was placed between two metal (aluminum) sheets, and a voltage (directly at the center of the sheet) was applied between them. In the other half of the experiment, a phantom gel was placed between two pyrolytic graphite sheets, and a voltage (directly at the center of the sheet) was applied between them. When a voltage is applied between a pair of metal (aluminum) sheets, a higher current density at the edges of the sheet results in uneven heating of different areas.Conversely, applying voltage between two graphite sheets produces much more uniform current densities in the center and edges of the sheet and results in a more uniform temperature profile of the sheet. Figures 4D and 4E show thermal imaging camera images of simulated electrode arrays constructed using metal (aluminum) sheets and simulated electrode arrays constructed using pyrolytic graphite sheets, respectively. The aluminum sheet results in an uneven heat distribution map, causing the outer edges to reach the threshold temperature first and thus controlling the current reduction requirement. In contrast, the pyrolytic graphite sheet produces a more even heat distribution. very uniform across the entire sheet. Figure 4F shows experimental results when electrode arrays with and without a graphite sheet were used to apply TTFields to the torsos of rats (using small animal arrays). The two lower traces show the measured current for two rats when the electrode arrays of the prior art depicted in Figure 1A / 1B were used, while the two upper traces show the measured current for two rats when the electrode elements depicted in Figure 3A were used (using graphite sheets). The thermal set point was identical for all runs. In particular, when the graphite sheet was included, the improved heat distribution and current attributable to the graphite resulted in 20% lower resistances and 50% higher currents for the same thermal set point.And because higher currents are associated with better results, these experiments show that incorporating a graphite layer into the electrode arrays can provide better results. Figure 5 is a cross-sectional representation of a second embodiment of an electrode assembly 50b comprising 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 (including figure labeling) except for the following. The embodiment in Figure 3A includes a large back layer of conductive material 80 (e.g., hydrogel) positioned between the foil 70 and the front faces of the first and second electrode elements E1 and E2. In contrast, the embodiment in Figure 5 includes a separate region of conductive material 380 for each individual electrode element. Thus, the embodiment in Figure 5...5 includes a first back layer of conductive material 380 positioned between the first front face of the first electrode element E1 and the back face of the foil 70, and also includes a second back layer of conductive material 380 positioned between the second front face of the second electrode element E2 and the back face of the foil 70. The first and second back layers of conductive material 380 facilitate electrical contact between the respective front faces of the electrodes and the back face of the foil 70. In some embodiments, the back layers of conductive material 380 are hydrogel layers. However, in alternative embodiments, different conductive materials could be used (e.g., conductive grease, conductive adhesive, including the non-hydrogel conductive adhesives described above, conductive tape, conductive compound, etc.).In some embodiments, the collective area of ​​all the electrode elements is less than the area of ​​sheet 70, less than half the area of ​​sheet 70, less than a quarter of the area of ​​sheet 70, or less than one tenth of the area of ​​sheet 70. As in the embodiment of FIG. 3A, the current in the embodiment of FIG. 5 remains concentrated in the back layers of the conductive material 380 only in the areas located below the electrode elements. The pyrolytic graphite sheet 70 distributes the heat and current as described above in relation to the embodiment of FIG. 3A, thereby eliminating or at least minimizing hot spots. This means that for a given applied AC voltage, the hottest spot under the electrode assembly in the embodiment of FIG. 5 will be at a lower temperature than the hottest spot located under the electrode assembly in the example of FIG. 1 of the prior art. Consequently, the current can be increased (relative to the current of the prior art) without exceeding the safety temperature threshold at any point below the electrode assembly in the embodiment of FIG. 5.And this increase in current will advantageously increase the effectiveness of the TTFields treatment. Figure 6 is a cross-sectional representation of a third embodiment of an electrode assembly 50c that includes 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 the dielectric layer. In the embodiment of Figure 6, the electrode assembly 50c includes a pyrolytic graphite sheet 70 having a front face (facing the subject's skin in Figure 6) and a back face. This sheet 70 is similar to the sheet 70 described above in relation to Figure 3A. The electrode assembly 50a further comprises at least one layer of conductive material 60 disposed on the front face of the sheet 70, and said at least one layer of conductive material 60 has a biocompatible front surface. Note that, in the embodiment illustrated in FIG. 6, there is only a single layer of conductive material 60, and that single layer is biocompatible. However, in alternative embodiments (not shown), there could be more than one layer, in which case only the front layer needs to be biocompatible. The at least one layer of conductive material 60 is configured to ensure good electrical contact between the device and the body. In a preferred embodiment, the at least one layer of conductive material 60 must cover the entire front face of the pyrolytic graphite sheet 70. The at least one layer of conductive material 60 can be the same size as, or larger than (i.e., cover the same area as, or larger than), the pyrolytic graphite sheet 70.In some embodiments, the at least one conductive material layer 60 comprises a single hydrogel layer. In these embodiments, the hydrogel may have a thickness ranging from 50 to 2000 µm, such as 100 to 1000 µm, or even 300 to 500 µm. In some embodiments, the at least one conductive material layer 60 is a single layer of biocompatible conductive adhesive that is not a hydrogel, as described above. In some embodiments, the at least one conductive material layer 60 is a single layer of biocompatible conductive adhesive that is not a hydrogel, such as FLEXcon's OMNI-WAVE products or Adhesives Research, Inc.'s ARcare® products, described above. The non-hydrogel conductive adhesives may comprise an aqua-free polymer with adhesive properties (e.g., an acrylic polymer or a silicone polymer, or a combination of both) and a conductive filler.The conductive filler in at least one layer of conductive material 60 should be non-metallic. In these embodiments, the biocompatible conductive adhesive can have a thickness of between 10 and 2,000 µm, for example, from 20 to 1,000 µm or even from 30 to 400 µm. The electrode assembly 50c further includes a first electrode element E1 located behind the sheet 70. The first electrode element E1 includes a metal piece 500 having a front face arranged in electrical contact with the rear face of the sheet 70. In the embodiment of FIG. 6, the front face of the metal piece 500 is the first front face of the first electrode element E1. Consequently, the embodiment of FIG. 6 differs from the embodiments of FIG. 3A or FIG. 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 FIG. 6 can be as described above in relation to FIG. 3A. The electrode assembly 50c further includes a first back layer of conductive material 80 positioned between the first front face of the first electrode element E1 (i.e., the front face of the metal piece 500) and the back face of the foil 70. The first back layer of conductive material 80 facilitates electrical contact between the first front face of the first electrode element E1 and the back face of the foil 70. In some embodiments, the back layer of conductive material 80 is a hydrogel layer. However, in alternative embodiments, a different conductive material could be used (e.g., conductive grease, conductive adhesive including the non-hydrogel conductive adhesive described above, conductive tape, conductive compound, etc.). The metal piece 500 of electrode element E1 is connected (e.g., by wires, tracks in a flexible circuit, etc.) to a cable 90, which supplies an AC voltage from an AC voltage generator (not shown) to the electrode element to generate the TTFields when the electrode assembly 50c is attached to the subject's body for treatment. The electrode assembly 50c may optionally include one or more additional electrode elements (not shown) with an identical structure to electrode element E1 and positioned to have the same functionality. In such a case, the metal parts 500 of all electrode elements can be connected to each other (e.g., via wires, traces on a flexible circuit, etc.) to wire 90. In some embodiments that include a single electrode element E1, the area of ​​sheet 70 is larger (for example, at least 2 times, at least 4 times, or at least 10 times larger) than the area of ​​electrode element E1. In some embodiments that include a plurality of electrode elements (not shown), the area of ​​sheet 70 is larger (for example, at least 2, 4, or 10 times larger) than the collective area of ​​all the electrode elements. When an alternating voltage is applied to the electrode elements, the heat is distributed throughout the sheet 70, minimizing or eliminating hot spots. Similar to the embodiment of FIG. 3A, the pyrolytic graphite sheet 70 in the embodiment of FIG. 6 distributes heat and current as described above in relation to the embodiment of FIG. 3A, eliminating or at least minimizing hot spots. This means that for a given applied AC voltage, the hottest spot under the electrode array in the embodiment of FIG. 6 will have a lower temperature than the hottest spot under the electrode array in the example of FIG. 1 of the prior art. Consequently, the current can be increased (relative to the current of the prior art) without exceeding the safety temperature threshold at any point below the electrode array in the embodiment of FIG. 6. This increased current will advantageously enhance the effectiveness of the TTFields treatment. FIG. 7 is a cross-sectional representation of a fourth embodiment of an electrode assembly 50d that includes a single electrode element E1. The embodiment of FIG. 7 is similar to the embodiment of FIG. 6, except that the first front face of the first electrode element E1 (i.e., the front face of the metal piece 600) is positioned in direct contact with the back face of the sheet 70 (rather than being electrically connected through an intermediate layer of conductive material). Similar to the embodiment in FIG. 6, the pyrolytic graphite sheet 70 in the embodiment of FIG. 7 distributes heat and current as described above in relation to the embodiment in FIG. 3A, thereby eliminating or at least minimizing hot spots. This means that for a given applied AC voltage, the hottest spot under the electrode array in the embodiment of FIG. 7 will have a lower temperature than the hottest spot under the electrode array in the example in FIG. 1 of the prior art. Consequently, the current can be increased (relative to the current of the prior art) without exceeding the safety temperature threshold at any point below the electrode array in the embodiment of FIG. 7. This increased current will advantageously enhance the effectiveness of the TTFields treatment. Figure 8 is a cross-sectional representation of a fifth embodiment of an electrode assembly 50e that includes a single electrode element E1. The embodiment in Figure 8 is similar to the embodiment in Figure 7, but adds a capacitor 700 connected in series with and behind the metal piece 600. A similar addition of a capacitor 700 connected in series with and behind the metal piece 600 could also be provided for the embodiment in Figure 6. Figure 9 shows how a pair of electrode assemblies 50a of Figure 3A can be used to apply an alternating electric field to a target region of the subject's body. The subject could be a human or another 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 of Figure 3A shown here.)The method includes placing a first electrode array 50a in a first position on or within the subject's body. (In the example illustrated in FIG. 9, the first electrode array 50a is placed on the subject's skin to the right of the subject's head, facing a target region, e.g., a tumor.) The first electrode array 50a can be constructed as described earlier in this document. In the embodiment of FIG. 9, the first electrode array 50a includes a first sheet 70 of pyrolytic graphite 70 having a first front face and a first back face. During use, the first electrode array 50a is positioned so that the first front face of the first sheet 70 is oriented toward the target region. The method also includes placing a second electrode set 50a in a second position on or over the subject's body. (In the example in FIG. 9, the second electrode set 50a is placed on the subject's skin to the left of the subject's head, facing the target region.) The second electrode set 50a can be constructed as described earlier in this document. In the embodiment of FIG. 9, the second electrode set 50a includes a second sheet 70 of pyrolytic graphite 70 having a second front face and a second back face. During use, the second electrode set 50a is positioned so that the second front face of the second sheet 70 faces the target region. The method further includes applying an alternating voltage between the first set of electrodes 50a and the second set of electrodes 50a. The application is performed after positioning the first set of electrodes 50a and the second set of electrodes 50a. The application can be carried out by applying the alternating voltage between (i) a first electrode element arranged in electrical contact with the first back face of the first sheet 70 and (ii) a second electrode element arranged in electrical contact with the second back face of the second sheet 70. In some embodiments, the first electrode assembly 50a further includes a first layer of biocompatible conductive material 60 disposed on the first front face 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 face of the second sheet 70. As described above, the biocompatible conductive material 60 may be a hydrogel or may be a conductive grease, conductive adhesive including the non-hydrogel conductive adhesives described above, conductive tape, conductive compound, etc. In some embodiments, the first electrode set 50a further includes a first back layer of conductive material 80 (as described above) positioned between the first front face of the first electrode element of the first electrode set 50a and the first back face of the first sheet 70. Correspondingly, the second electrode set further includes a second back layer of conductive material 80 (as described above) positioned between the second front face of the second electrode element of the second electrode set and the second back face of the second sheet 70. The alternating voltage between the first and second electrode sets 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 can use temperature measurements to control the amplitude of the current supplied through the first and second electrode sets 50a in order to maintain the temperatures 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. Figure 9 shows an example of suitable hardware for this purpose. More specifically, the temperature sensors 800 (e.g., thermistors) are placed in thermal contact with the respective electrode elements 310 / 320 within each of the electrode assemblies 50a. The temperature sensors 800 measure the respective first and second temperatures (e.g., at the first and second electrode element of the first and second electrode assemblies, respectively), and the controller 822 controls the output of the AC voltage generator 820 based on these temperatures. Similar embodiments and methods are foreseen using any of the 50a-e electrode assemblies, or combinations thereof, instead of one or both of the first 50a electrode assembly and the second 50a electrode assembly. In the embodiments described above in relation to FIGS. 2-9, sheet 70 is made of pyrolytic graphite. But in alternative embodiments, sheet 70 may be made of other types of graphite, including, but not limited to, other synthetic graphite, such as a graphite sheet made of compressed high-purity exfoliated mineral graphite (including, but not limited to, MinGraph® 2010A Flexible Graphite, available from Mineral Seal Corp., Tucson, Arizona, USA); isotropic graphite (including but not limited to G330 grade isotropic graphite available from Tokai Carbon Europe, Oldbury, UK; or double-sided carbon tape for scanning electron microscopy, available from Fisher Scientific, a unit of Thermo Fisher Scientific, Hampton, NH, USA). Although the present invention has been disclosed with reference to certain embodiments, numerous modifications, alterations, and changes to the described embodiments are possible without departing from the scope of the present invention, as defined in the appended claims. Accordingly, it is intended that the present invention is not limited to the described embodiments but has the full scope defined by the language of the following claims.

Claims

1. An apparatus for applying an alternating electric field to a subject's body, the apparatus comprising: a graphite sheet (70) having a front face and a back face, wherein the graphite sheet (70) has high thermal conductivity in a horizontal direction parallel to its front face, such that the graphite sheet (70) is configured to distribute heat across the entire area of ​​the graphite sheet (70); at least one layer of conductive material (60) arranged in electrical contact with the front face of the graphite sheet (70), wherein the at least one layer of conductive material (60) has a biocompatible front surface; and at least one electrode element (E1, E2) positioned behind the graphite sheet (70), wherein the at least one electrode element (E1, E2) has a front face arranged in electrical contact with the back face of the graphite sheet (70). 2.The apparatus of claim 1, wherein the at least one electrode element (E1, E2) comprises a layer of dielectric material (310) having a front face and a back face and a metal layer (320) disposed on the back face of the dielectric material layer (310), the front face of the dielectric material layer (310) being the front face of the at least one electrode element (E1, E2); and further comprising: a back layer of conductive material (80) positioned between the front face of the at least one electrode element (E1, E2) and the back face of the graphite sheet (70), wherein the back layer of conductive material (80) is configured to facilitate electrical contact between the front face of the at least one electrode element (E1, E2) and the back face of the graphite sheet (70). 3.The apparatus of claim 1, wherein the at least one electrode element (E1, E2) comprises a layer of dielectric material (310) having a front face and a back face, a metal layer (320) disposed on the back face of the dielectric material layer (310), the front face of the dielectric material layer (310) being the front face of the at least one electrode element (E1, E2), and a back layer of conductive material (380) positioned between the front face of the at least one electrode element (E1, E2) and the back face of the graphite sheet (70), wherein the back layer of conductive material (380) is configured to facilitate electrical contact between the front face of the at least one electrode element (E1, E2) and the back face of the graphite sheet (70).

4. The apparatus of claim 2 or 3, wherein the back layer of conductive material (80; 380) comprises conductive hydrogel. 5.The apparatus of claim 2 or 3, wherein the back layer of conductive material (80; 380) comprises a conductive adhesive, optionally comprising an adhesive polymer and powder, particles, fibers, flakes, or carbon nanotubes.

6. The apparatus of claim 4, wherein the conductive adhesive has a thickness of between 10 and 2,000 µm.

7. The apparatus of claim 1, wherein the at least one electrode element (E1, E2) comprises a metal piece (500; 600) having a front face, the front face of the metal piece (500; 600) being the front face of the at least one electrode element (E1, E2), optionally the front face of the at least one electrode element (E1, E2) is positioned in direct contact with the back face of the graphite sheet (70). 8.The apparatus of claim 7 further comprising: a back layer of conductive material (80; 380) positioned between the front face of the at least one electrode element (E1, E2) and the back face of the graphite sheet (70), wherein the back layer of conductive material (80; 380) is configured to facilitate electrical contact between the front face of the at least one electrode element (E1, E2) and the back face of the graphite sheet (70).

9. The apparatus of claim 1, wherein the graphite sheet (70) is a pyrolytic graphite sheet.

10. The apparatus of claim 1, wherein the graphite sheet (70) is a sheet of compressed, high-purity exfoliated mineral graphite or a graphitized polymer film.

11. The apparatus of claim 1, wherein the at least one layer of conductive material (60) comprises hydrogel. 12.The apparatus of claim 1, wherein the at least one layer of conductive material (60) comprises a hydrogel layer with a thickness between 50 and 2000 µm.

13. The apparatus of claim 1, wherein the at least one layer of conductive material (60) comprises a conductive adhesive, optionally comprising an adhesive polymer and powder, particles, fibers, flakes, or carbon nanotubes.

14. The apparatus of claim 1, wherein the at least one layer of conductive material (60) comprises a conductive compound, optionally comprising an acrylic or silicone polymer and powder, particles, fibers, flakes, or carbon nanotubes. 15.The apparatus of claim 1, further comprising: a flexible self-adhesive backing (55) configured to support the graphite sheet (70), the at least one electrode element (E1, E2), and the at least one layer of conductive material (60) such that the front surface of the at least one layer of conductive material (60) can be positioned against the skin of a subject.

16. The apparatus of claim 1, comprising a plurality of electrode elements (E1, E2).

17. The apparatus of claim 1, wherein the at least one layer of conductive material (60) is the same size as or larger than the graphite sheet (70).

18. The apparatus of claim 1, wherein the graphite sheet (70) has low electrical resistance in the horizontal direction, such that the graphite sheet (70) is configured to distribute the current outward along the graphite sheet (70).

Images