CN117642208A - Electrode assembly for applying a Tumor Treatment Field (TTFIELD) comprising graphite flakes - Google Patents

Abstract

An alternating electric field (e.g., TTField) may be applied to the body of the subject using one or more electrode assemblies that include a graphite sheet, at least one layer of conductive material disposed on the front face of the graphite sheet, and an electrode element positioned behind the graphite sheet. The electrode element has a front surface arranged in electrical contact with the back surface of the graphite sheet. The graphite sheet spreads both the heat and the current in a direction parallel to the front face of the sheet, which eliminates or at least minimizes hot spots on the electrode assembly. This in turn makes it possible to increase the current without exceeding a temperature safety threshold (e.g. 41 ℃).

Description

Electrode assembly for applying a Tumor Treatment Field (TTFIELD) comprising graphite flakes

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application 63/230,438 (filed 8/6/2021), 63/275,841 (filed 11/4/2021), and 63/275,843 (filed 11/4/2021), each of which is incorporated herein by reference in its entirety.

Background

Tumor treatment field (TTField) therapy is a proven method for treating tumors using alternating electric fields at frequencies between 50kHz and 1MHz, such as, for example, 100-500 kHz. The alternating electric field is induced by an electrode assembly (e.g., an array of capacitively coupled electrodes, also referred to as a transducer array) 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 into the body of the subject through the electrode assemblies. And higher current correlates strongly with higher efficacy of the treatment.

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 cross-sectional schematic view of electrode elements X7-X9 of electrode assembly 40 taken along the dashed line in fig. 1A.

As shown in fig. 1B, the electrode element X7 (which is exemplified by it) includes a metal layer (shown in diagonal hatching) and a ceramic (dielectric) layer. A respective conductive hydrogel layer is provided between each ceramic layer and the skin of the subject to ensure good electrical contact of the electrode elements with the body. An AC voltage from an AC voltage generator (not shown) is applied to the metal layers of the electrode elements in the counter electrode assembly to create ttfields within the subject's body.

During use, the skin under the hydrogel and electrode elements heats up (heatup), and safety considerations require that the skin temperature remain below a safe threshold (e.g., 41 ℃). Because most of the heat occurs directly under the electrode elements X1-X9 (as shown in fig. 1C), the prior art electrode assemblies have hot spots located directly under the electrode elements, and cooler regions located between the electrode elements. And those hot spots limit the amount of current that can be delivered through the prior art electrode assembly.

Disclosure of Invention

One aspect of the invention relates to a first device for applying an alternating electric field to a body of a subject. The first device comprises a graphite sheet having a front side and a back side; at least one layer of conductive material disposed on the front side of the sheet, the at least one layer of conductive material having a biocompatible front surface; and a first electrode element positioned behind the sheet. The first electrode element has a first front surface arranged in electrical contact with the back surface of the sheet.

In some embodiments of the first device, the first electrode element comprises: (i) A first layer of dielectric material having a front side and a back side, and (ii) a first metal layer disposed on the back side of the first layer of dielectric material. 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 back layer of a first conductive material positioned between the first front side of the first electrode element and the back side of the sheet. The first conductive material back layer facilitates electrical contact between the first front surface of the first electrode element and the back surface of the sheet.

Some embodiments of the first device further comprise a second electrode element positioned behind the sheet. The second electrode element has a second front surface arranged in electrical contact with the back surface of the sheet. In these embodiments, the second electrode element comprises: (i) A second layer of dielectric material having a front side and a back side, and (ii) a second layer of metal disposed on the back side of the second layer of dielectric material. The front side of the second dielectric material layer is the second front side of the second electrode element. The first conductive material back layer is positioned between the second front surface of the second electrode element and the back surface of the sheet. And the first conductive material back layer facilitates electrical contact between the second front surface of the second electrode element and the back surface of the sheet.

Some embodiments of the first device further comprise a second electrode element positioned behind the sheet. The second electrode element has a second front surface arranged in electrical contact with the back surface of the sheet. The second electrode element includes: (i) A second layer of dielectric material having a front side and a back side, and (ii) a second layer of metal disposed on the back side of the second layer of dielectric material. The front side of the second dielectric material layer is the second front side of the second electrode element. In these embodiments, the device further comprises a second back layer of conductive material positioned between the second front side of the second electrode element and the back side of the sheet. The second conductive material back layer facilitates electrical contact between the second front surface of the second electrode element and the back surface of the sheet.

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

In some embodiments of the first device, the first electrode element comprises a metal sheet having a front face, and the front face of the metal sheet is the first front face of the first electrode element.

In some embodiments of the first device, the first electrode element comprises a metal sheet having a front face, and the front face of the metal sheet is the first front face of the first electrode element. These embodiments further include a back layer of a first conductive material positioned between the first front side of the first electrode element and the back side of the sheet. The first conductive material back layer facilitates electrical contact between the first front surface of the first electrode element and the back surface of the sheet.

In some embodiments of the first device, the first electrode element comprises a metal sheet having a front face, and the front face of the metal sheet is the first front face of the first electrode element. In these embodiments, the first front face of the first electrode element is positioned in direct contact with the back face of the sheet.

In some embodiments of the first device, the graphite sheet is a pyrolytic graphite sheet. In some embodiments of the first apparatus, the graphite sheet is a graphite foil made of compressed high purity exfoliated mineral graphite or graphitized polymer film.

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

Some embodiments of the first device further comprise a flexible self-adhesive backing configured to support the sheet, the first electrode element and the at least one layer of conductive material such that a front surface of the at least one layer of conductive material can be positioned against the skin of the subject. Some embodiments of the first device further comprise a lead electrically connected to the first electrode element.

Another aspect of the invention relates to a first method of applying an alternating electric field to a target region within a body of a subject. The first method includes positioning a first electrode assembly at a first location on or within a body of a subject. The first electrode assembly includes a first graphite sheet having a first front face and a first back face, and the first electrode assembly is positioned such that the first front face of the first sheet faces the target area. The first method further includes positioning the second electrode assembly at a second location on or within the body of the subject. The second electrode assembly includes a second graphite sheet having a second front face and a second back face, and the second electrode assembly is positioned such that the second front face of the second sheet faces the target area. The first method further includes applying an alternating voltage between the first electrode assembly and the second electrode assembly. The application is performed after positioning the first electrode assembly and the second electrode assembly.

In some examples of the first method, the applying is achieved by applying an alternating voltage between (i) a first electrode element arranged in electrical contact with the first back side and (ii) a second electrode element arranged in electrical contact with the second back side. Optionally, the 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 applying based on the first temperature and the second temperature.

In some examples of the first method, the first electrode assembly further comprises a first conductive adhesive layer disposed on the first front side, and the second electrode assembly further comprises a second conductive adhesive layer disposed on the second front side.

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

Drawings

Fig. 1A is a schematic representation of a prior art electrode assembly.

Fig. 1B is a cross-sectional view of an electrode element of the prior art electrode assembly taken along the dashed line in fig. 1A.

Fig. 1C is a cross-sectional view showing the heat generating properties of a prior art electrode element.

Fig. 1D is a cross-sectional view showing a hypothetical modified heat generating property of the electrode element of fig. 1B.

Fig. 2 is a schematic plan representation of an electrode assembly including electrode elements for applying TTField to the body of a subject.

Fig. 3A is a cross-sectional representation of a first embodiment comprising electrode elements E1, E2, taken along the dashed line in fig. 2.

Fig. 3B is a cross-sectional view showing the heat generating properties of the embodiment of fig. 3A.

Fig. 4A is a thermal image of a prior art electrode assembly.

Fig. 4B is a thermal image of an electrode assembly corresponding to the embodiment of fig. 3A.

Fig. 4C is a graph comparing the thermal properties of a prior art electrode assembly with the embodiment of fig. 3A.

Fig. 4D shows a thermal camera image of a simulated electrode array constructed using metal (aluminum) sheets.

Fig. 4E shows a thermal camera image of a simulated electrode array constructed using pyrolytic graphite sheets.

Fig. 4F depicts experimental results when TTField was applied to the trunk of a rat using an electrode array with and without graphite sheets.

Fig. 5 is a cross-sectional representation of a second embodiment comprising electrode elements E1, E2, taken along the dashed line in fig. 2.

Fig. 6 is a cross-sectional representation of a third embodiment comprising a single electrode element E1.

Fig. 7 is a cross-sectional representation of a fourth embodiment comprising a single electrode element E1.

Fig. 8 is a cross-sectional representation of a fifth embodiment comprising a single electrode element E1.

FIG. 9 is a block diagram of a system including two electrode assemblies for applying TTField to a subject's body.

Various embodiments are described in detail below with reference to the drawings, wherein like reference numerals represent like elements.

Detailed Description

The present application describes exemplary electrode assemblies that may be used, for example, to deliver TTField to a subject's body and treat one or more cancers or tumors located within the subject's body.

When TTField is applied to the body of a subject, the temperature at the body of the subject may increase in proportion to the induced electric field. Regulations limit the amount of current that can be driven through a transducer array to an amount that maintains a measured temperature at a location on the body of a subject below a temperature threshold. As implemented in the art, the temperature at the location of the transducer array on the body of the subject is controlled to be below a temperature threshold by reducing the operating current driven by the transducer array and reducing the strength of the resulting TTField. This in turn becomes the primary limitation of TTField strength (over-riding limitation) that can be used to treat tumors. Accordingly, there is a need in the art to safely obtain (access) higher TTField intensities without exceeding a temperature threshold at the skin of the subject.

On a transducer array comprising a plurality of electrode elements, the portion of the transducer array positioned directly below the electrode elements becomes hotter than the portion of the transducer array positioned between the electrode elements. Furthermore, on a transducer array comprising a plurality of electrode elements, a higher current flows through the electrode elements located along the edges of the array than the electrode elements located towards the middle of the array. Still further, electrode elements positioned at corners or similar sharp bends in the edges of the array will have higher currents than other electrode elements along the edges of the array and near the center of the array. The tendency of a transducer array to drive higher currents through electrode elements positioned along the edges (and particularly at corners) of the array is referred to herein as the "edge effect".

Uneven distribution of current through the transducer array due to the distribution or edge effect of the electrode elements may result in higher temperature regions (or "hot spots") at, for example, corners or edges of the transducer array. These hot spots are the locations where the threshold temperature is first reached, and thus the control requirements to reduce the current. Thus, the creation of hot spots limits the maximum operating current that can be driven by the transducer array and the resulting strength of the TTField.

The inventors have now recognized that there is a need for a transducer array that reduces or minimizes the uneven distribution of current and thereby allows for the application of higher operating currents. Transducer arrays operating with increased current may produce stronger ttfields within the body of the subject, ultimately resulting in better patient results. The electrode assemblies disclosed herein allow for uniform diffusion of current and heat across the array, thereby minimizing or eliminating hot spots.

The embodiments described herein incorporate graphite sheets into an electrode assembly, as described below. This reduces the temperature of the hot spot and increases the temperature of the colder region when a given AC voltage is applied to the electrode assembly (as compared to the prior art arrangements described above). Thus, the current (and thus the therapeutic effect) may be increased without exceeding a safe temperature threshold at any point on the subject's skin.

In some preferred embodiments, the graphite sheets are pyrolytic graphite sheets. Notably, because graphite is nonmetallic, it facilitates preventing ion transfer into the body of the subject.

The invention may be understood more readily by reference to the following detailed description, examples, drawings and claims, and their previous and following description. However, it is to be understood that this invention is not limited to the specific devices, apparatus, systems and/or methods disclosed unless otherwise specified, and, therefore, may, of course, vary.

Headings are provided for convenience only and are not to be construed as limiting the invention in any way. The embodiments illustrated under any heading or in any portion of the disclosure may be combined with the embodiments illustrated under the same or any other heading or other portion of the disclosure.

Any combination of the elements described herein and all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Fig. 2 is a schematic representation of an electrode assembly 50 including an embodiment of an electrode element for applying TTField to a subject's body. In fig. 2, only two electrode elements labeled E1 and E2 are shown, but additional electrode elements may be included in the electrode assembly 50. In alternative embodiments, the electrode assembly 50 includes only a single electrode element. Notably, fig. 2 generally depicts electrode assemblies 50, and those electrode assemblies E1 and E2 may have different configurations (e.g., as described below in connection with fig. 3A-8).

Fig. 3A is a cross-sectional representation of a first embodiment of an electrode assembly 50a comprising electrode elements E1, E2, taken along the dashed lines in fig. 2.

In the fig. 3A embodiment, electrode assembly 50a includes pyrolytic graphite sheet 70 having a front side (facing the subject's skin in fig. 3A) and a back side. Examples of suitable forms of graphite include synthetic graphite such as pyrolytic graphite (including but not limited to pyrolytic graphite flake (PGS) available from Panasonic Industry of kaadoma, osaka, japan), other forms of synthetic graphite including but not limited to graphite foil made of compressed high purity exfoliated Mineral graphite (including but not limited to graphite foil available from Mineral Seal corporation of atlasen, arizona, usa)2010A flexible graphite supplied graphite foil), or a graphitized polymer film, such as a graphitized polyimide film (including but not limited to films supplied by Kaneka corporation of singa, japan .

The electrode assembly 50a further includes at least one layer of conductive material 60 disposed on the front face of the sheet 70, and the at least one layer of conductive material 60 has a biocompatible front surface. Note that the embodiment illustrated in fig. 3 only has a single layer 60 of conductive material and that the single layer is biocompatible. In alternative embodiments (not shown) there may be more than one layer, in which case only the anterior layer must be biocompatible. The 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 layer of material 60 should cover the entire front surface of pyrolytic graphite sheet 70.At least one material layer 60 may be the same size as pyrolytic graphite sheet 70 or larger than pyrolytic graphite sheet 70. In some embodiments (and as shown in fig. 3A), at least one layer of conductive material 60 comprises a single hydrogel layer. In these embodiments, the hydrogel may have a thickness of between 50 and 2000 μm (such as from 100 to 1000 μm, or even 300 to 500 μm). In some embodiments, at least one layer of conductive material 60 is a single layer of non-hydrogel biocompatible conductive adhesive. In some embodiments, at least one layer of conductive material 60 is a single non-hydrogel biocompatible conductive adhesive layer, such as FLX068983, a development product of FLEXcon from Sibinse, mass., U.S.A.)OMNI-WAVE ^TM TT 200BLACK H-502150POLY H-944PP-8, or other such OMNI-WAVE product from FLEXcon; or manufactured and sold by Adhesives Research company (Geranolog, pa., U.S.A.)>8006 conductive adhesive composition. The non-hydrogel conductive adhesive may include an anhydrous polymer having adhesive properties and carbon particles, powders, 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 obtained as an acrylic or silicone based carbon filled tape. The adhesive may additionally comprise one or more conductive polymers such as, for example, polyaniline (PANI) or poly (3, 4-ethylenedioxythiophene (PEDOT), or other polymers known in the art.) the conductive filler in the at least one conductive material layer 60 should be non-metallic in these embodiments, the biocompatible conductive adhesive may have a thickness of between 10 μm and 2000 μm, such as from 20 μm to 1000 μm, or even 30 μm 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 surface arranged in electrical contact with the back surface of the sheet 70. In the fig. 3A embodiment, the first electrode element E1 includes a first dielectric (e.g., ceramic) material layer 310 having a front side and a back side, and a first metal layer 320 disposed on the back side 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. Note that while the figures (e.g., fig. 3A) depict dielectric material 310 as "ceramic," various other suitable dielectric materials may be used in place 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.

In some embodiments, the dielectric material layer 310 may have a dielectric constant ranging from 10 to 50000. In some embodiments, the dielectric material layer 310 includes a high dielectric polymer material, such as poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) and/or poly (vinylidene fluoride-trifluoroethylene-1-chlorotrifluoroethylene). Those two polymers are abbreviated herein as "poly (VDF-TrFE-CTFE)" and "poly (VDF-TrFE-CFE)", respectively. These embodiments are particularly advantageous because these materials have a dielectric constant of about 40. In some embodiments, the polymer layer may be poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) or "poly (VDF-TrFE-CTFE-CFE)".

In some embodiments, the dielectric material layer 310 includes a terpolymer including 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 mole% VDF, 5 to 60 mole% TrFE, where CFE and/or CTFE comprise the balance of mole% of the terpolymer.

In some embodiments, the patch 70 has a centroid and the centroid of the first face of the first electrode element E1 is positioned less than 3cm from the centroid of the patch 70. In some embodiments, the patch 70 has a centroid and a dimension (e.g., length or width) parallel to the back side of the patch 70, and the centroid of the first front side of the first electrode element E1 is positioned less than 30% of the dimension, or less than 10% of the dimension, from the centroid of the patch 70.

The electrode assembly 50a further includes a back layer 80 of a first conductive material positioned between the first front side of the first electrode element E1 (i.e., the front side of the first dielectric material layer 310) and the back side of the sheet 70. The first conductive material back layer 80 facilitates electrical contact between the first front side of the first electrode element E1 and the back side of the sheet 70. In some embodiments, the conductive material back layer 80 is a hydrogel layer. In alternative embodiments, however, different conductive materials (e.g., conductive grease, conductive adhesive, conductive tape, conductive composite, etc.) may be used. In some embodiments, the conductive material 80 may be a non-hydrogel conductive adhesive, such 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 sheet 70. The second electrode element E2 has a second front surface arranged in electrical contact with the back surface of the sheet 70. The two electrode elements E1, E2 in fig. 3A have the same structure. Accordingly, the second electrode element E2 includes a second dielectric (e.g., ceramic) material layer 310 having a front surface and a back surface, and a second metal layer 320 disposed on the back 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 total area of all 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 a tenth of the area of sheet 70.

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

The metal layers 320 of all electrode elements (i.e., E1 and E2 in the illustrated embodiment) may be wired together (e.g., using wires, traces on a flexible circuit, etc.) to the leads 90. When electrode assembly 50a is secured to the body of a subject for treatment, lead 90 supplies an AC voltage from an AC voltage generator (not shown) to the electrode elements to produce TTField.

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

As described above, fig. 2 is a schematic plan representation of an electrode assembly 50 comprising electrode elements E1, E2. This view of fig. 2 (not to scale) also shows that the area of the sheet 70 is larger (e.g., at least 2 times, at least 4 times, or at least 10 times) than the combined area of the electrode elements E1, E2. When an AC voltage is applied to the electrode elements E1, E2, heat diffuses across the entire sheet 70, which minimizes or eliminates hot spots.

By comparing fig. 1C with fig. 3B, this reduction in hot spots (as compared to the prior art) becomes apparent. More specifically, fig. 1C shows the current distribution and heating of prior art electrode elements, each of which is positioned on a conductive hydrogel layer covering approximately the same area as the electrode elements. As shown in fig. 1C, all of the current passes through the hydrogel layer directly under the electrode element, which results in a hot spot directly under the electrode element.

It was originally thought that this problem could be solved by increasing the area of the hydrogel to cover all areas between the electrode elements (i.e. by covering an area in the x-y plane that is significantly larger than the area of the electrode elements). But this is not the case. More specifically, fig. 1D shows the current distribution and heat generation of this hypothetical electrode assembly. As shown in fig. 1D, all current still passes through the hydrogel layer directly under the electrode element, which results in a hot spot directly under the electrode element.

In contrast, fig. 3B shows the current distribution of the embodiment of fig. 3A. As shown in fig. 3B, the current is still distributed only in the rear conductive material layer (e.g., 80 in fig. 3B) in the region below the electrode elements. However, the pyrolytic graphite sheet 70 spreads heat across its entire area because of high thermal conductivity in the horizontal direction. In addition to spreading the heat, the low resistance of the sheet 70 in the horizontal direction spreads the current outward through the sheet 70, and this spread current distribution continues in the conductive material layer 60 and thus reaches the skin of the subject. Because both current and heat in this embodiment are spread 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 assembly in the fig. 3A/B embodiment will have a lower temperature than the hottest spot under the electrode assembly in the prior art example of fig. 1. Thus, the current (relative to prior art currents) may be increased without exceeding a safe temperature threshold at any point below the electrode assembly in the fig. 3A embodiment. And this increase in current will advantageously increase the efficacy of TTField therapy. Similar results can be obtained when the hydrogel is replaced with a conductive adhesive composite.

The advantageous performance of the embodiment of fig. 3A is shown in fig. 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 side of the electrode elements. There is no graphite sheet between the front side of the electrode element and the back side of the hydrogel layer. In use, the front side of the hydrogel layer is positioned on the skin of a subject. Fig. 4A shows hot spots generated in the region corresponding to the electrode elements.

Fig. 4B is a thermal image of an electrode assembly corresponding to the embodiment of fig. 3A, wherein pyrolytic graphite 70 is positioned between the front faces of electrode elements E1, E2 and the back face of conductive layer 60, and conductive layer 60 is made of hydrogel. Fig. 4B shows that hot spots such as those generated in prior art electrode assemblies have been minimized, and also shows that the maximum temperature has been reduced. Fig. 4C is a graph comparing the thermal performance of the embodiment of fig. 3A (with pyrolytic graphite) with the prior art (without graphite) for the same applied current (500 mA). Notably, the hottest portion of the prior art electrode assembly is 41 ℃. But the hottest portion of the electrode assembly is only 32 c when the same 500mA current is applied to the fig. 3A embodiment. Similar experiments were performed with similar results using graphite foils made of compressed high purity exfoliated mineral graphite.

In the relevant experiments, the optimized conventional array (without graphite flakes) was run with 2A applied current up to a maximum average temperature of 40 ℃ and was thus limited. The same type of array with added pyrolytic graphite sheets (by way of example in fig. 3A) can be operated at increased power levels (with 3A applied current) and at an average temperature of 38 ℃ (2-3 ℃ below the temperature threshold limit). This result demonstrates that the inventive devices and methods described herein should be able to achieve more beneficial therapeutic results by operating at higher applied currents.

Experimental simulations of electrodes for treating a target site in the body compare the thermal profile obtained using graphite sheets with the thermal profile obtained using metal sheets. In half of the experiment, a model gel (phastomgel) was sandwiched between two metal (aluminum) sheets and a voltage was applied between the two metal sheets (directly to the center of the sheet). In the other half of the experiment, the model gel was placed sandwiched between two pyrolytic graphite sheets and a voltage was applied between the two pyrolytic graphite sheets (directly to the center of the sheets). When a voltage is applied between a pair of metal sheets (aluminum), the higher current density at the edges of the sheets results in uneven heating of the different areas. In contrast, applying a voltage between two graphite sheets advantageously results in a much more uniform current density at the center and edges of the sheets, and in a more uniform temperature distribution of the sheets.

Fig. 4D and 4E show thermal camera images of a simulated electrode array constructed using metal (aluminum) sheets and a simulated electrode array constructed using pyrolytic graphite sheets, respectively. The aluminum sheet causes a non-uniform thermal profile, which causes the outer edge to reach the threshold temperature first, and thus controls the requirements to reduce the current. In contrast, pyrolytic graphite sheets produce a very uniform heat distribution across the entire sheet.

Fig. 4F depicts experimental results when TTField was applied to the trunk of a rat (using a small animal array) using an electrode array with and without graphite flakes. The two lower traces show the measured currents for two rats when using the prior art electrode array depicted in fig. 1A/1B, while the two upper traces show the measured currents for two rats when using the electrode element depicted in fig. 3A (using graphite sheets). The heat set point for all runs is the same. Notably, when graphite flakes are included, the improved heat and current distribution due to the graphite results in a 20% decrease in resistance and a 50% increase in current for the same heat set point. And because higher currents are associated with improved results, these experiments demonstrate that incorporating graphite layers into an electrode array can provide improved results.

Fig. 5 is a cross-sectional representation of a second embodiment of an electrode assembly 50b comprising electrode elements E1, E2, taken along the dashed lines in fig. 2. The fig. 5 embodiment is similar to the fig. 3A embodiment in all respects, including reference numerals, except for the following. The fig. 3A embodiment includes a large back layer 80 of conductive material (e.g., hydrogel) positioned between the sheet 70 and the front faces of both the first and second electrode elements E1 and E2. In contrast, the fig. 5 embodiment includes separate regions 380 of conductive material for each individual electrode element. Thus, the fig. 5 embodiment includes a back layer 380 of a first conductive material positioned between the first front side of the first electrode element E1 and the back side of the sheet 70, and further includes a back layer 380 of a second conductive material positioned between the second front side of the second electrode element E2 and the back side of the sheet 70. The first and second back layers 380 of conductive material facilitate electrical contact between the respective electrode frontside and the backside of the sheet 70. In some embodiments, the conductive material back layer 380 is a hydrogel layer. In alternative embodiments, however, different conductive materials (e.g., conductive grease, conductive adhesive including the non-hydrogel conductive adhesives discussed above, conductive tape, conductive composite, etc.) may be used. In some embodiments, the total area of all 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 a tenth of the area of sheet 70.

As in the fig. 3A embodiment, the current in the fig. 5 embodiment is still concentrated only in the conductive material back layer 380 in the region below the electrode elements. As described above in connection with the fig. 3A embodiment, pyrolytic graphite sheet 70 spreads heat and current, which eliminates or at least minimizes 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 under the electrode assembly in the prior art example of fig. 1. Thus, the current (relative to prior art currents) may be increased without exceeding the safe temperature threshold at any point below the electrode assembly in the fig. 5 embodiment. And this increase in current will advantageously increase the efficacy of TTField therapy.

Fig. 6 is a cross-sectional representation of a third embodiment of an electrode assembly 50c comprising a single electrode element E1. The embodiment of fig. 6 is similar to the embodiment of fig. 3A except that the embodiment of fig. 6 does not include a layer of dielectric material. In the fig. 6 embodiment, electrode assembly 50c includes pyrolytic graphite sheet 70 having a front side (facing the subject's skin in fig. 6) and a back side. The sheet 70 is similar to the sheet 70 described above in connection with fig. 3A.

The electrode assembly 50c further includes at least one layer of conductive material 60 disposed on the front face of the sheet 70, and the at least one layer of conductive material 60 has a biocompatible front surface. Note that the embodiment illustrated in fig. 6 only has a single layer 60 of conductive material and that the single layer is biocompatible. In alternative embodiments (not shown) there may be more than one layer, in which case only the anterior layer must be biocompatible. The at least one layer 60 of conductive material 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 should cover the entire front surface of the pyrolytic graphite sheet 70. The at least one layer of conductive material 60 may be the same size as the pyrolytic graphite sheet 70 or larger (i.e., cover the same area or larger) than the pyrolytic graphite sheet 70. In some embodiments, at least one layer of conductive material 60 comprises a single hydrogel layer. In these embodiments, the hydrogel may have a thickness of between 50 and 2000 μm (such as from 100 to 1000 μm, or even 300 to 500 μm). In some embodiments, at least one layer of conductive material 60 is a single non-hydrogel biocompatible conductive adhesive layer as discussed above. In some embodiments, at least one layer of conductive material 60 is a single non-conductive material Hydrogel biocompatible conductive adhesive layers, such as the OMNI-WAVE products from FLEXcon discussed above, or from Adhesives Research companyAnd (5) a product. The non-hydrogel conductive adhesive may include an anhydrous polymer (e.g., an acrylic polymer or a silicone polymer, or a combination thereof) having adhesive properties and a conductive filler. The conductive filler in the 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 μm and 2000 μm (such as from 20 μm to 1000 μm, or even 30 μm to 400 μm).

The electrode assembly 50c further includes a first electrode element E1 positioned behind the sheet 70. The first electrode element E1 comprises a metal sheet 500 having a front side arranged in electrical contact with the back side of the sheet 70. In the embodiment of fig. 6, the front surface of the metal sheet 500 is the first front surface of the first electrode element E1. Thus, the embodiment of fig. 6 differs from the embodiment of fig. 3A or 5 in the absence of a layer of dielectric material. The positional relationship between the first electrode element E1 and the sheet 70 in this fig. 6 embodiment may be as described above in connection with fig. 3A.

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

The sheet metal 500 of electrode element E1 is wired (e.g., using wires, traces on a flexible circuit, etc.) to lead 90, and lead 90 supplies an AC voltage from an AC voltage generator (not shown) to the electrode element to create TTField when electrode assembly 50c is secured to the subject's body for treatment.

The electrode assembly 50c may optionally include one or more additional electrode elements (not shown) having the same structure and positioned to have the same function as the electrode element E1. In such a case, the metal sheets 500 of all electrode elements may be wired together (e.g., using wires, traces on a flexible circuit, etc.) to the leads 90.

In some embodiments that include only a single electrode element E1, the area of the sheet 70 is greater (e.g., at least 2 times, at least 4 times, or at least 10 times) than the area of the electrode element E1. In some embodiments including a plurality of electrode elements (not shown), the area of sheet 70 is greater (e.g., at least 2, 4, or 10 times) than the total area of all of the electrode elements. When an AC voltage is applied to the electrode elements, heat diffuses across the entire sheet 70, which minimizes or eliminates hot spots.

Similar to the embodiment of fig. 3A, the pyrolytic graphite sheet 70 in the embodiment of fig. 6 spreads heat and current, as described above in connection with the embodiment of fig. 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest spot under the electrode assembly in the embodiment of fig. 6 will have a lower temperature than the hottest spot under the electrode assembly in the prior art example of fig. 1. Thus, the current (relative to prior art currents) may be increased without exceeding the safe temperature threshold at any point below the electrode assembly in the fig. 6 embodiment. And this increase in current will advantageously increase the efficacy of TTField therapy.

Fig. 7 is a cross-sectional representation of a fourth embodiment of an electrode assembly 50d comprising a single electrode element E1. The fig. 7 embodiment is similar to the fig. 6 embodiment except that the first front side of the first electrode element E1 (i.e., the front side of the metal sheet 600) is positioned in direct contact with the back side of the sheet 70 (rather than making electrical connection via an intervening conductive material layer).

Similar to the embodiment of fig. 6, the pyrolytic graphite sheet 70 in the embodiment of fig. 7 spreads heat and current, as described above in connection with the embodiment of fig. 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest spot under the electrode assembly in the embodiment of fig. 7 will have a lower temperature than the hottest spot under the electrode assembly in the prior art example of fig. 1. Thus, the current (relative to prior art currents) may be increased without exceeding the safe temperature threshold at any point below the electrode assembly in the fig. 7 embodiment. And this increase in current will advantageously increase the efficacy of TTField therapy.

Fig. 8 is a cross-sectional representation of a fifth embodiment of an electrode assembly 50E comprising a single electrode element E1. The embodiment of fig. 8 is similar to the embodiment of fig. 7, but adds a capacitor 700 connected in series with the metal sheet 600 and located behind the metal sheet 600. It is also conceivable for the fig. 6 embodiment to add a capacitor 700 connected in series with the metal sheet 600 and located behind the metal sheet 600.

Fig. 9 shows how a pair of the electrode assemblies 50a of fig. 3A may be used to apply an alternating electric field to a target region in the body of a subject. The subject may be a human or another mammal, including but not limited to rats and mice. (Note that any of the electrode assemblies described above in connection with FIGS. 5-8 may be used in place of the electrode assembly 50a of FIG. 3A shown herein).

The method includes positioning the first electrode assembly 50a at a first location on or within the body of the subject. (in the example depicted in fig. 9, the first electrode assembly 50a is positioned on the skin of a subject at the right side of the subject's head facing a target area (e.g., tumor)) the first electrode assembly 50a may be configured as described earlier herein. In the fig. 9 embodiment, first electrode assembly 50a includes a first sheet 70 of pyrolytic graphite 70 having a first front side and a first back side. During use, the first electrode assembly 50a is positioned such that the first front face of the first sheet 70 faces the target area.

The method further includes positioning the second electrode assembly 50a at a second location within or on the body of the subject. (in the example depicted in fig. 9, the second electrode assembly 50a is positioned on the skin of the subject at the left side of the subject's head facing the target area.) the second electrode assembly 50a may be configured as described earlier herein. In the fig. 9 embodiment, second electrode assembly 50a includes a second sheet 70 of pyrolytic graphite 70 having a second front side and a second back side. During use, the second electrode assembly 50a is positioned such that the second front face of the second sheet 70 faces the target area.

The method further includes applying an alternating voltage between the first electrode assembly 50a and the second electrode assembly 50 a. The application is performed after positioning the first electrode assembly 50a and the second electrode assembly 50 a. This application may be accomplished by applying an alternating voltage between (i) a first electrode element disposed in electrical contact with the first back side of the first sheet 70 and (ii) a second electrode element disposed in electrical contact with the second back side of the second sheet 70.

In some embodiments, the first electrode assembly 50a further comprises a first biocompatible conductive material layer 60 disposed on the first front side of the first sheet 70. Accordingly, the second electrode assembly further comprises a second biocompatible conductive material layer 60 disposed on the second front side of the second sheet 70. As described above, the biocompatible conductive material 60 may be a hydrogel or may be a conductive grease, a conductive adhesive including the non-hydrogel conductive adhesives discussed above, a conductive tape, a conductive composite, or the like.

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

An alternating voltage may be applied between the first electrode assembly and the second electrode assembly by an AC voltage generator 820. In some embodiments, the frequency of the alternating voltage is between 50kHz and 1MHz, or between 100kHz and 500 kHz. In the illustrated example, the AC voltage generator is controlled by a controller 822. The controller 822 can use the temperature measurements to control the magnitude of the current to be delivered via the first and second electrode assemblies 50a in order to maintain the temperature below a safe threshold (e.g., 41 ℃). This may 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 alternating voltage based on the first temperature and the second temperature, as described below.

Fig. 9 depicts one example of hardware suitable for this purpose. More specifically, temperature sensors 800 (e.g., thermistors) are positioned in thermal contact with respective electrode elements 310/320 within each of the electrode assemblies 50 a. The temperature sensor 800 measures respective first and second temperatures (e.g., at 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.

Similar embodiments and methods are contemplated that utilize any one or a combination of electrode assemblies 50a-e in place of any one or both of first electrode assembly 50a and second electrode assembly 50 a.

In the embodiment discussed above in connection with fig. 2-9, sheet 70 is made of pyrolytic graphite. In alternative embodiments, however, sheet 70 may be made of other types of graphite, including but not limited to other synthetic graphites, such as graphite foil made of compressed high purity exfoliated Mineral graphite (including but not limited to that available from Mineral Seal, inc. of atlasen, arizona, usa)2010A flexible graphite); isotropic graphite (including but not limited to isotropic graphite grade G330 available from Tokai CarbonEurope of aldebrile, england; or double-sided carbon tape for scanning electron microscopy available from Fisher Scientific under the flag of hampston Thermo Fisher Scientific, new hampshire, usa).

Although the present invention has been disclosed with reference to certain embodiments, many modifications, alterations and changes to the described embodiments are possible without departing from the sphere and scope of the present invention, as defined in the appended claims. Accordingly, it is intended that the invention not be limited to the described embodiments, but that it have the full scope defined by the language of the following claims and equivalents thereof.

Claims (26)

1. A device for applying an alternating electric field to a body of a subject, the device comprising:

a graphite sheet having a front side and a back side;

at least one layer of conductive material disposed on the front side of the sheet, wherein the at least one layer of conductive material has a biocompatible front surface; and

a first electrode element positioned behind the sheet, the first electrode element having a first front surface arranged in electrical contact with the back surface of the sheet.

2. The device according to claim 1,

wherein the first electrode element comprises: (i) A first layer of dielectric material having a front side and a back side, and (ii) a first layer of metal disposed on the back side of the first layer of dielectric material,

wherein the front side of the first dielectric material layer is the first front side of the first electrode element, and

wherein the device further comprises a back layer of a first conductive material positioned between the first front side of the first electrode element and the back side of the sheet, and wherein the back layer of the first conductive material facilitates electrical contact between the first front side of the first electrode element and the back side of the sheet.

3. The device of claim 2, further comprising a second electrode element positioned behind the sheet, the second electrode element having a second front surface disposed in electrical contact with the back surface of the sheet,

Wherein the second electrode element comprises: (i) A second layer of dielectric material having a front side and a back side and (ii) a second layer of metal disposed on the back side of the second layer of dielectric material,

wherein the front side of the second dielectric material layer is the second front side of the second electrode element, and

wherein the first conductive material back layer is positioned between the second front side of the second electrode element and the back side of the sheet, and wherein the first conductive material back layer facilitates electrical contact between the second front side of the second electrode element and the back side of the sheet.

4. The device of claim 2, further comprising a second electrode element positioned behind the sheet, the second electrode element having a second front surface disposed in electrical contact with the back surface of the sheet,

wherein the second electrode element comprises: (i) A second layer of dielectric material having a front side and a back side and (ii) a second layer of metal disposed on the back side of the second layer of dielectric material,

wherein the front side of the second dielectric material layer is the second front side of the second electrode element, and

wherein the device further comprises a second back layer of conductive material positioned between the second front side of the second electrode element and the back side of the sheet, and wherein the second back layer of conductive material facilitates electrical contact between the second front side of the second electrode element and the back side of the sheet.

5. The device of claim 2, wherein the first conductive material back layer comprises a conductive hydrogel.

6. The apparatus of claim 2, wherein the first back layer of conductive material comprises a conductive adhesive.

7. The device of claim 6, wherein the conductive adhesive comprises an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes.

8. The device of claim 6, wherein the conductive adhesive has a thickness between 10 and 2000 μm.

9. The device according to claim 1,

wherein the first electrode element comprises a metal sheet having a front face, and

wherein the front side of the metal sheet is the first front side of the first electrode element.

10. The device of claim 9, further comprising a back layer of a first conductive material positioned between the first front side of the first electrode element and the back side of the sheet,

wherein the back layer of the first conductive material facilitates electrical contact between the first front side of the first electrode element and the back side of the sheet.

11. The device of claim 9, wherein the first front face of the first electrode element is positioned in direct contact with the back face of the sheet.

12. The apparatus of claim 1, wherein the graphite sheet is a pyrolytic graphite sheet.

13. The device of claim 1, wherein the graphite sheet is a graphite foil made of compressed high purity exfoliated mineral graphite or graphitized polymer film.

14. The device of claim 1, wherein the at least one layer of conductive material comprises a hydrogel.

15. The device of claim 1, wherein the at least one layer of conductive material comprises a hydrogel layer having a thickness between 50 μιη and 2000 μιη.

16. The device of claim 1, wherein the at least one layer of conductive material comprises a conductive adhesive.

17. The device of claim 16, wherein the conductive adhesive comprises an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes.

18. The device of claim 16, wherein the conductive adhesive has a thickness between 10 μιη and 2000 μιη.

19. The device of claim 1, further comprising a flexible self-adhesive backing configured to support the sheet, the first electrode element, and the at least one layer of conductive material such that a front surface of the at least one layer of conductive material can be positioned against the skin of the subject.

20. The device of claim 1, further comprising a lead electrically connected to the first electrode element.

21. A method of applying an alternating electric field to a target region within a subject's body, the method comprising positioning a first electrode assembly at a first location on or within the subject's body, wherein the first electrode assembly comprises a first graphite sheet having a first front face and a first back face, and wherein the first electrode assembly is positioned such that the first front face of the first sheet faces the target region;

positioning a second electrode assembly at a second location on or within the body of the subject, wherein the second electrode assembly comprises a second graphite sheet having a second front face and a second back face, and wherein the second electrode assembly is positioned such that the second front face of the second sheet faces the target area; and is also provided with

An alternating voltage is applied between the first electrode assembly and the second electrode assembly,

wherein the applying is performed after positioning the first electrode assembly and the second electrode assembly.

22. The method of claim 21, wherein the applying is accomplished by applying an alternating voltage between (i) a first electrode element arranged in electrical contact with the first back side and (ii) a second electrode element arranged in electrical contact with the second back side.

23. The method of claim 22, further comprising:

measuring a first temperature of the first electrode element; measuring a second temperature of the second electrode element; and

the application is controlled based on the first temperature and the second temperature.

24. The method of claim 21, wherein the first electrode assembly further comprises a first conductive adhesive layer disposed on the first front side, and

wherein the second electrode assembly further comprises a second conductive adhesive layer disposed on the second front side.

25. The method of claim 21, wherein each of the first and second graphite sheets is pyrolytic graphite sheet.

26. The method of claim 21, wherein each of the first and second graphite sheets is a graphite foil made of compressed high purity exfoliated mineral graphite or graphitized polymer film.