Flexible transducer array with polymer insulating layer for applying tumor treatment electric field (TT field)

Abstract

To provide a device for applying an alternating electric field.SOLUTION: Described herein are devices for applying an alternating electric field to a living subject or an in vitro medium at a frequency between 100 kHz and 500 kHz. Also described herein are methods of using the described devices for applying an AC electric field to a target region comprising rapidly dividing cells, e.g., cells associated with a variety of disorders or conditions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Application No. 63 / 046337, filed on June 30, 2020; U.S. Application No. 63 / 083557, filed on September 25, 2020; and U.S. Application No. 63 / 146516, filed on February 5, 2021, the contents of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Tumor treating field (TT field) therapy is a proven method for treating tumors, and the Optune® system is a device used to deliver the TT field. The Optune® uses four transducer arrays placed on the patient's skin near the tumor (e.g., in front of, behind, to the left, and to the right of the tumor) to deliver an alternating electric field to the tumor. These transducer arrays are driven by an AC (alternating current) signal generator operating, for example, at 100 - 500 kHz.

[0003] Patent Document 1 describes the design of a transducer array using a plurality of ceramic disks. One side of each ceramic disk is placed on the patient's skin, and the other side of each disk has a conductive backing. An electrical signal is applied to the conductive backing, and the signal is capacitively coupled to the patient's body through the ceramic disk. In some embodiments, the capacitance of each disk is at least 2 nF. In some embodiments, the capacitance of each disk is at least 20 nF. [[ID=Z19]]

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

[0005] While the transducer array described in Patent Document 1 is effective, it is relatively hard because it is made of a solid ceramic disc with a diameter of about 2 cm and a thickness of about 1 mm. This hardness can make it difficult to position the transducer array in the desired location and / or may cause mild discomfort to the patient. Until now, using ceramic transducer arrays (with very high relative permittivity (dielectric constant)) has been the only way to obtain the sufficiently high level of capacitance necessary to effectively capacitively couple AC signals to the patient's body. More specifically, because the relative permittivity of all polymers was too low to provide sufficient capacitive coupling, it has not been possible to construct a transducer array using a polymer insulating layer to capacitively couple AC signals to the human body until now. [Means for solving the problem]

[0006] Embodiments of the present disclosure feature polymer compositions having significantly higher dielectric constants than conventional polymers. More specifically, the dielectric constants of the polymer compositions of the present disclosure are, for the first time, high enough to construct transducer arrays (or simple electrodes) capable of effectively capacitively coupling AC signals to the human body via a polymer insulating layer.

[0007] One aspect of the present invention relates to a first apparatus for applying an alternating electric field to a living organism or an in vitro medium at a frequency between 100 kHz and 500 kHz. The first apparatus comprises a layer of a conductive material having a front surface of a certain region (area), a flexible polymer layer (the polymer layer has a front surface) located in front of the conductive material and covering at least a portion (e.g., the entire region) of the region, and a conductor located in electrical contact with the layer of conductive material. The polymer layer comprises at least one of poly(VDF-TrFE-CTFE), poly(VDF-TrFE-CFE), and poly(VDF-TrFE-CFE-CTFE).

[0008] In some embodiments, the first apparatus further comprises a flexible third layer located behind the layer of conductive material, the flexible third layer having a front surface. At least a portion of the front surface of the third layer is covered with an adhesive. A first region of the adhesive is located directly behind the layer of conductive material and supports the layer of conductive material. A second region of the adhesive is located outside the first region and is configured to (a) adhere to the skin when pressed against a region of skin, support the polymer layer in close proximity to the skin, and (b) be easily removed from the skin. Optionally, such embodiments may further comprise a layer of conductive hydrogel positioned in front of the polymer layer. The conductive hydrogel layer is positioned to contact the skin when the polymer layer is held in close proximity to the skin by the second region of the adhesive.

[0009] In the first apparatus of some embodiments, the polymer layer has a thickness of 20 μm or less, for example, 1 μm to 20 μm. In the first apparatus of some embodiments, the polymer layer has a thickness of 10 μm or less, for example, 1 μm to 10 μm. In the first apparatus of further embodiments, the polymer layer has a thickness of 5 μm or less, for example, 1 μm to 5 μm. In the first apparatus of yet another embodiment, the polymer layer has a thickness of 3 μm or less, for example, 1 μm to 3 μm or 2 μm to 3 μm.

[0010] Another aspect of the present invention relates to a second apparatus for applying an alternating electric field to a living organism or in vitro medium at a frequency between 100 kHz and 500 kHz. The second apparatus comprises a layer of conductive material having a front surface having a certain region (area), a flexible polymer layer (the polymer layer has a front surface) located in front of the conductive material and covering at least a portion of the region, and a conductor located in electrical contact with the layer of conductive material. At at least one frequency between 100 kHz and 500 kHz, the polymer layer has a relative permittivity of at least 20.

[0011] In the second apparatus of one embodiment, the polymer layer has a thickness of 20 μm or less in the direction perpendicular to the front surface of the polymer layer, for example, a thickness of 1 μm to 20 μm. In the second apparatus of a further embodiment, the polymer layer has a thickness of 10 μm or less in the direction perpendicular to the front surface of the polymer layer, for example, a thickness of 1 μm to 10 μm. In the second apparatus of another embodiment, the polymer layer has a thickness of 5 μm or less in the direction perpendicular to the front surface of the polymer layer, for example, a thickness of 1 μm to 5 μm. In the second apparatus of a further embodiment, the polymer layer has a thickness of 3 μm or less in the direction perpendicular to the front surface of the polymer layer, for example, a thickness of 1 μm to 3 μm.

[0012] In the second apparatus of a certain embodiment, the polymer layer has a dielectric constant of at least 20 at 200 kHz. In the second apparatus of a certain embodiment, the conductive material layer comprises at least one metal, is flexible, and has a thickness of less than 0.1 mm in a direction perpendicular to the front surface of the conductive material layer.

[0013] In some embodiments, the second apparatus further comprises a flexible third layer located behind the layer of conductive material. The flexible third layer has a front surface. At least a portion of the front surface of the third layer is covered with an adhesive. A first region of the adhesive is located directly behind the layer of conductive material and supports the layer of conductive material. A second region of the adhesive is located outside the first region and is configured to (i) adhere to the skin when pressed against a region of skin, support the polymer layer in close proximity to the skin, and (ii) be easily removed from the skin. These embodiments further comprise a layer of conductive hydrogel positioned in front of the polymer layer. The hydrogel is positioned to contact the skin when the polymer layer is held in close proximity to the skin by the second region of the adhesive.

[0014] A second apparatus of a certain embodiment further comprises a flexible third layer configured to support a layer of conductive material. The flexible third layer has a front surface. A first portion of the front surface of the flexible third layer is covered with an adhesive that adheres to human skin and is easily removable from the skin. The first portion is located outside both the conductive material layer and the polymer layer, so that when the first portion is pressed against an area of ​​skin, the adhesive on the first portion adheres to the skin, holding the polymer layer in close proximity to the skin. Such embodiments further comprise a layer of conductive hydrogel positioned in front of the polymer layer. The hydrogel is positioned to be in contact with the skin when the polymer layer is held in close proximity to the skin by the adhesive.

[0015] In the second apparatus of a certain embodiment, the polymer layer comprises at least one of poly(VDF-TrFE-CTFE), poly(VDF-TrFE-CFE), and poly(VDF-TrFE-CFE-CTFE). In the second apparatus of a certain embodiment, the polymer layer comprises ceramic nanoparticles mixed with at least one of poly(VDF-TrFE-CTFE) and poly(VDF-TrFE-CFE). In the second apparatus of a certain embodiment, the polymer layer comprises barium titanate ceramic nanoparticles and / or barium strontium titanate ceramic nanoparticles mixed with at least one of poly(VDF-TrFE-CTFE) and poly(VDF-TrFE-CFE). In the second apparatus of a certain embodiment, the polymer layer comprises ceramic nanoparticles mixed with at least one of poly(VDF-TrFE), P(VDF-HFP), and PVDF. In the second apparatus of some embodiments, the polymer layer comprises barium titanate ceramic nanoparticles and / or barium strontium titanate ceramic nanoparticles mixed with at least one of poly(VDF-TrFE), P(VDF-HFP), and PVDF. In the second apparatus of some embodiments, the ceramic nanoparticles are mixed into the polymer layer.

[0016] Another aspect of the present invention relates to a third apparatus for applying an alternating electric field to a living organism or in vitro medium at a frequency between 100 kHz and 500 kHz. The flexible circuit of the third apparatus includes (a) a plurality of conductive pads located on the front of the flexible circuit (each conductive pad having a certain region (area)), and (b) at least one conductive trace positioned in electrical contact with the plurality of conductive pads. The at least one conductive trace is positioned so that each conductive pad can be driven by an electrical signal. The third apparatus also comprises a plurality of flexible polymer regions, each region having a front surface, and positioned on the front of the flexible circuit, in front of each corresponding conductive pad. At at least one frequency between 100 kHz and 500 kHz, each polymer region has a relative permittivity of at least 20. Each polymer region has a thickness of 20 μm or less in the direction perpendicular to its front surface.

[0017] In a third device of one embodiment, each polymer region independently has a thickness of 20 μm or less, for example, a thickness of 1 μm to 20 μm, in a direction perpendicular to its front surface. In a third device of a further embodiment, each polymer region independently has a thickness of 10 μm or less, for example, a thickness of 1 μm to 10 μm, in a direction perpendicular to its front surface. In a third device of another embodiment, each polymer region independently has a thickness of 5 μm or less, for example, a thickness of 1 μm to 5 μm, in a direction perpendicular to its front surface. In a third device of a further embodiment, each polymer region independently has a thickness of 3 μm or less, for example, a thickness of 1 μm to 3 μm, in a direction perpendicular to its front surface.

[0018] In a third device of one embodiment, the plurality of polymer regions are directly printed, sprayed or molded (cast) onto the plurality of conductive pads. In a third device of one embodiment, each polymer region has a thickness of 5 μm or less, for example, a thickness of 1 μm to 5 μm. In a third device of one embodiment, the total area of the plurality of conductive pads reaches at least 25 cm 2 and reaches.

[0019] A third device of one embodiment further includes a plurality of thermistors located on the back surface of the flexible circuit. Each thermistor is in thermal contact with a corresponding one of the conductive pads. The flexible circuit further includes a plurality of conductive traces for accessing the plurality of thermistors.

[0020] In some embodiments, the third apparatus further comprises a flexible third layer located behind the flex circuit. The flexible third layer has a front surface. At least a portion of the front surface of the third layer is covered with an adhesive. A first region of the adhesive is located directly behind the flex circuit and supports the flex circuit. A second region of the adhesive is located outside the first region and is configured to (i) adhere to the skin when pressed against a region of skin, thereby holding a plurality of polymer regions in close proximity to the skin, and (ii) be easily removed from the skin. These embodiments further comprise a layer of conductive hydrogel positioned in front of each polymer region. The hydrogel is positioned to contact the skin when each polymer region is held in close proximity to the skin by the second region of the adhesive.

[0021] In some embodiments, the third apparatus further comprises a flexible third layer configured to support the flex circuit. The flexible third layer has a front surface. A first portion of the front surface of the flexible third layer is covered with an adhesive that adheres to human skin but is easily removable from the skin. The first portion is located outside the flex circuit, and when the first portion is pressed against an area of ​​skin, the adhesive on the first portion adheres to the skin, holding multiple polymer regions in close proximity to the skin. These embodiments further comprise a layer of conductive hydrogel positioned in front of each polymer region. The hydrogel is positioned to be in contact with the skin when each polymer region is held in close proximity to the skin by the adhesive.

[0022] Another aspect of the present invention is directed to a fourth device for applying an alternating electric field to a living body or an in vitro medium at a frequency between 100 kHz and 500 kHz. The flexible circuit included in the fourth device includes (a) a plurality of conductive pads located on the front surface of the flexible circuit, and (b) at least one conductive trace disposed in electrical contact with the plurality of conductive pads. The at least one conductive trace is arranged and configured to drive each conductive pad by an electrical signal. The fourth device also includes a plurality of metal foil pieces located in front of the flexible circuit, each piece having a front surface with a certain area. Each piece is electrically connected to a corresponding one of the conductive pads. The fourth device further includes a plurality of flexible polymer regions, each region having a front surface and being disposed above a corresponding one of the plurality of metal foil pieces. At at least one frequency between 100 kHz and 500 kHz, each polymer region has a relative permittivity of at least 20. Each polymer region has a thickness of 20 μm or less in a direction perpendicular to its front surface.

[0023] In the fourth device of some embodiments, each polymer region independently has a thickness of 20 μm or less, for example, a thickness of 1 μm to 20 μm, in a direction perpendicular to its front surface. In the fourth device of further embodiments, each polymer region independently has a thickness of 10 μm or less, for example, a thickness of 1 μm to 10 μm, in a direction perpendicular to its front surface. In the fourth device of other embodiments, each polymer region independently has a thickness of 5 μm or less, for example, a thickness of 1 μm to 5 μm, in a direction perpendicular to its front surface. In the fourth device of further embodiments, each polymer region independently has a thickness of 3 μm or less, for example, a thickness of 1 μm to 3 μm, in a direction perpendicular to its front surface.

[0024] In the fourth device of some embodiments, each polymer region has a thickness of less than 5 μm. In the fourth device of some embodiments, the total area of the plurality of metal flakes reaches at least 25 cm 2 or more.

[0025] In some embodiments, the fourth apparatus further comprises a plurality of thermistors located on the back of the flex circuit. Each thermistor is in thermal contact with a corresponding metal flap among a plurality of metal flaps. In such embodiments, the flex circuit further includes a plurality of conductive traces for accessing the plurality of thermistors.

[0026] A fourth apparatus in some embodiments further comprises a flexible third layer located behind the flex circuit, the flexible third layer having a front surface. At least a portion of the front surface of the third layer is covered with an adhesive. A first region of the adhesive is located directly behind the flex circuit and supports the flex circuit. A second region of the adhesive is located outside the first region and is configured to (i) adhere to the skin when pressed against a region of skin, thereby holding a plurality of polymer regions in close proximity to the skin, and (ii) be easily removed from the skin. Such embodiments further comprise a layer of conductive hydrogel positioned in front of each polymer region. The hydrogel is positioned to contact the skin when each polymer region is held in close proximity to the skin by the adhesive.

[0027] A fourth apparatus in some embodiments further comprises a flexible third layer configured to support a flex circuit, the flexible third layer having a front surface. A first portion of the front surface of the flexible third layer is covered with an adhesive that adheres to human skin and is easily removable from the skin. The first portion is located outside the flex circuit, and when the first portion is pressed against an area of ​​skin, the adhesive on the first portion adheres to the skin, holding multiple polymer layers in close proximity to the skin. Such embodiments further comprise a layer of conductive hydrogel positioned in front of each polymer region. The hydrogel is positioned to contact the skin when each polymer region is held in close proximity to the skin by the second region of adhesive.

[0028] In the second, third, or fourth embodiment, each polymer region may comprise at least one of poly(VDF-TrFE-CTFE), poly(VDF-TrFE-CFE), and poly(VDF-TrFE-CFE-CTFE). In the second, third, or fourth embodiment, each polymer region may comprise ceramic nanoparticles mixed with at least one of poly(VDF-TrFE-CTFE) and poly(VDF-TrFE-CFE). In the second, third, or fourth embodiment, each polymer region may comprise ceramic nanoparticles mixed with at least one of poly(VDF-TrFE-CTFE) and poly(VDF-TrFE-CFE), and the ceramic nanoparticles comprise at least one of barium titanate and barium strontium titanate. In the second, third, or fourth embodiment, each polymer region may comprise ceramic nanoparticles mixed with at least one of poly(VDF-TrFE), P(VDF-HFP), and PVDF. In the second, third, or fourth embodiment, each polymer region may comprise ceramic nanoparticles mixed with at least one of poly(VDF-TrFE), P(VDF-HFP), and PVDF, wherein the ceramic nanoparticles comprise at least one of barium titanate and barium strontium titanate. In the second, third, or fourth embodiment, the ceramic nanoparticles may be mixed into each polymer region.

[0029] Other aspects of the present disclosure relate to a method for selectively destroying or inhibiting the growth of rapidly dividing cells located within a target region of a subject or in vitro medium. The method includes placing a first apparatus of the present disclosure at a first position near the target region, placing a second apparatus of the present disclosure at a second position near the target region (the second position being opposite the first position), and applying an AC electric field to the target region by applying an AC voltage between the first and second apparatuses, wherein the frequency range of the AC electric field is 100 kHz to 500 kHz, and when the AC electric field is applied to the target region for a certain duration, the AC electric field selectively destroys or inhibits the growth of rapidly dividing cells within the target region. The first and second apparatuses may be the same or different in terms of structure and components.

[0030] A further aspect of the present disclosure relates to a method for selectively destroying or inhibiting the growth of rapidly dividing cells in a target region, the method comprising: providing a first apparatus of the present disclosure for placement at a first position near the target region; and providing a second apparatus of the present disclosure for placement at a second position near the target region (the second position being opposite the first position), wherein when an AC voltage is applied between the first and second apparatuses, an AC electric field having a frequency in the range of 100 kHz to 500 kHz is applied to the target region, and when the AC electric field is applied to the target region for an effective duration, the AC electric field selectively destroys or inhibits the growth of rapidly dividing cells in the target region.

[0031] Further aspects of the present disclosure relate to the apparatus of the present disclosure for placement in or near a living organism or an in vitro medium for selectively destroying or inhibiting the growth of rapidly dividing cells in a target region of the living organism or an in vitro medium. Also disclosed is a method of using the apparatus of the present disclosure for selectively destroying or inhibiting the growth of rapidly dividing cells. Furthermore disclosed is a kit comprising the apparatus of the present disclosure together with one or more therapeutic agents useful for treating conditions involving rapidly dividing cells. [Brief explanation of the drawing]

[0032] [Figure 1] Figures 1A and 1B are a front view and a side view of a first embodiment of an electrode used to apply a TT field to the human body. [Figure 2] Figures 2A and 2B show the front and side views of a transducer array implemented using a flexible circuit. [Figure 3] Figures 3A, 3B, and 3C show the front, side, and exploded views of other transducer arrays implemented using flex circuits. [Figure 4] Figures 4A and 4B show front and side views of other transducer arrays implemented using flex circuits. [Modes for carrying out the invention]

[0033] Various embodiments will be described below with reference to the attached drawings, where similar reference numbers in the drawings represent similar elements.

[0034] Figures 1A and 1B show a simple embodiment, front view, and side view of electrode 10 used to apply a TT field to a human body. In all embodiments of this disclosure, the front (FRONT) of the electrode or transducer array is the side facing the human body, and the rear (REAR) of the electrode or transducer array is the opposite side.

[0035] Each electrode 10 has a layer of conductive material 20, which is preferably made of a thin (for example, less than 0.3 mm thick, and less than 0.1 mm thick in some embodiments) flexible metal foil (for example, copper, stainless steel, etc.). In some embodiments, the thickness of the layer of conductive material 20 is uniform. In alternative embodiments, the thickness may be non-uniform. The conductive material 20 has a front surface, which has a region (area) A. A conductor 70 is positioned in electrical contact with the layer of conductive material 20, and the conductor 70 exits from the back surface of the electrode 10.

[0036] Furthermore, each electrode 10 has a flexible polymer layer 30 positioned in front of the conductive material 20 so as to cover region A. Optionally, as shown in Figure 1B, the flexible polymer layer 30 may also cover the side edges of the conductive material 20 (if the polymer layer 30 does not cover the side edges of the conductive material 20, it is preferable to cover the side edges with a suitable insulator such as medical-grade silicone to prevent non-capacitive bonding between the conductive material 20 and the patient's body). The polymer layer 30 is an insulator and has a front surface. In some preferred embodiments, the polymer layer 30 comprises poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) and / or poly(vinylidene fluoride-trifluoroethylene-1-chlorofluoroethylene). These two types of polymers are abbreviated in this application as "poly(VDF-TrFE-CTFE)" and "poly(VDF-TrFE-CFE)," respectively. Since the relative dielectric constant of these materials is about 40, these embodiments are particularly advantageous. In some embodiments, the polymer used in the insulating layer may be poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene-chlorofluoroethylene), or "poly(VDF-TrFE-CTFE-CFE)."

[0037] In some embodiments, the terpolymer used in the insulating polymer layer may comprise VDF, TrFE, CFE, and / or CTFE in any suitable molar ratio. Suitable terpolymers include, for example, those comprising 30-80 mol% VDF, 5-60 mol% TrFE, and CFE and / or CTFE making up the remaining mol% of the terpolymer. In further embodiments, the terpolymer comprises 40-70 mol% VDF, 20-50 mol% TrFE, and CFE and / or CTFE making up the remaining mol% of the terpolymer. In other further embodiments, VDF and TrFE constitute 80-97 mol% of the terpolymer, and CFE and / or CTFE constitute the remaining portion, i.e., 3-20 mol%. In other embodiments, VDF and TrFE constitute 90-95 mol% of the terpolymer, and CFE and / or CTFE constitute the remaining portion, i.e., 5-10 mol%. For example, the terpolymer may comprise 61.8 mol% VDF, 29.8 mol% TrFE, and 8.5 mol% CFE and / or CTFE.

[0038] In further embodiments, a terpolymer suitable for use in an insulating polymer layer may comprise, for example, 30-80 mol% VDF, 5-60 mol% TrFE, and CTFE making up the remaining mol% of the terpolymer. In some embodiments, the terpolymer comprises 40-70 mol% VDF, 20-50 mol% TrFE, and CTFE making up the remaining mol% of the terpolymer. In other further embodiments, VDF and TrFE constitute 80-97 mol% of the terpolymer, with CTFE making up the remaining portion, i.e., 3-20 mol%. In other embodiments, VDF and TrFE constitute 90-95 mol% of the terpolymer, with CTFE making up the remaining portion, i.e., 5-10 mol%. For example, the terpolymer may comprise 61.8 mol% VDF, 29.8 mol% TrFE, and 8.5 mol% CTFE.

[0039] According to various embodiments, the terpolymer may have an average molecular weight exceeding 400,000 g / mol as measured by viscosity measurement. For example, the terpolymer may have an average molecular weight of approximately 413,000 g / mol as measured by viscosity measurement at 20°C using methyl ethyl ketone as a solvent. In some embodiments, the terpolymer may be in powder form and without an outer layer or skin before the polymer is formed into an insulating layer.

[0040] Polymers comprising VDF, TrFE, CFE, and / or CTFE can be produced by methods known in the art. In some embodiments, such polymers can be prepared according to the following process: An initial mixture of VDF and TrFE (without CFT and CTFE) can be supplied to a pressurized autoclave or other suitable reactor. An initiator mixed with water can be injected into the autoclave to form a suspension of VDF and TrFE monomers by bringing it to a suitable pressure, e.g., at least 80 bar. A secondary mixture comprising VDF, TrFE, CFE, and / or CTFE can then be injected into the autoclave. In some embodiments, once the polymerization reaction has started, the secondary mixture can be continuously reinjected into the autoclave to maintain a constant pressure of at least 80 bar.

[0041] In some embodiments, the initial mixture supplied to the autoclave may comprise 25–95 wt% VDF (e.g., 55–80 wt% VDF) and 5–75 wt% TrFE (e.g., 20–45 wt% TrFE). The secondary mixture may comprise 20–80 wt% VDF (e.g., 35–70 wt% VDF), 3–60 wt% TrFE (e.g., 14–40 wt% TrFE), and 4–67 wt% CFE and / or CTFE (e.g., 7–34 wt% CFE and / or CTFE). In some embodiments, the weight ratio of the initial mixture to the secondary mixture is in the range of approximately 0.4 to approximately 2.

[0042] In some embodiments, the pressure inside the autoclave or reactor may be between approximately 80 bar and approximately 110 bar. The reaction temperature may be maintained between 40°C and 60°C. In some embodiments, the secondary mixture of VDF, TrFE, and CFE and / or CTFE may be continuously reinjected into the autoclave or reactor, for example, through a gate with a backflow prevention valve. In some embodiments, the secondary mixture may be compressed using two compressors in series before being reinjected into the autoclave. As is known, the secondary mixture may be injected into the autoclave at a pressure higher than the pressure circulating within the autoclave, i.e., a pressure greater than 80 bar.

[0043] Other polymers comprising VDF, TrFE, CFE, and / or CTFE are also intended for use in insulating polymer layers. For example, polymers with 50-80 mol% VDF, 15-40 mol% TrFE, and 2-20 mol% CFE and / or CFTE are available. Such polymers may have number-average moles greater than approximately 10,000 g / mol, for example, greater than 30,000 g / mol. Polymers of such compositions are described in Patent Document 2, which is incorporated in whole into this application as a reference to teach VDF, TrFE, and CFE / CTFE-containing polymers and methods for preparing them.

[0044] Referring again to Figure 1, the TT field is capacitively coupled via the electrode 10, and the capacitance is inversely proportional to the thickness of the dielectric layer, so it is preferable that the polymer layer 30 be thin (for example, 20 μm or less in some embodiments, 10 μm or less in other embodiments, and 5 μm or less in yet other embodiments). Generally, as the thickness of the polymer layer 30 increases, the voltage applied to the test subject through the apparatus becomes wasted.

[0045] On the other hand, it is desirable that the polymer layer 30 not be too thin, as this would impair manufacturability, compromise the structural integrity of the layer, and pose a risk of dielectric breakdown when an AC signal is applied. In some embodiments, the polymer layer 30 has a thickness of at least 1 μm. In some embodiments, the polymer layer 30 is 1 to 3 μm thick (e.g., approximately 2 μm), providing a balance between the above-mentioned parameters. The thickness of the polymer layer 30 can be uniform. In alternative embodiments, its thickness can be non-uniform.

[0046] In the embodiments shown in Figures 1A / B, the electrode 10 is attached to the skin of a human body using a flexible third layer 40 located behind the layer of conductive material 20. The flexible third layer 40 has a front surface, and at least a portion of the front surface of the third layer is covered with an adhesive 42. A first region of the adhesive 42 is located directly behind the layer of conductive material 20, and this region of the adhesive 42 supports the layer of conductive material 20. It should be noted that direct contact between the first region of the adhesive 42 and the layer of conductive material 20 is not required, and additional components or layers (illustrated) may be placed between these two components 20 and 42. A second region of the adhesive 42 is located outside the first region and is configured to (a) adhere to the skin when pressed against an area of ​​skin, holding the polymer layer close to the skin, and (b) be easily removed from the skin. Thus, the flexible third layer 40 in these embodiments is like a bandage.

[0047] Optionally, embodiments including the flexible third layer 40 also have a thin layer (not shown) of conductive hydrogel positioned in front of the polymer layer 30. This conductive hydrogel layer is positioned to contact the skin when the polymer layer 30 is held in close proximity to the skin by the second region of the adhesive 42.

[0048] Typically, during use, the first electrode 10 is positioned on the human skin on one side of the tumor, and the second electrode 10 is positioned on the human skin on the opposite side of the tumor. For example, in the case of a brain tumor located in the center of the human head, the first electrode 10 may be positioned on the right side of the human head, and the second electrode 10 may be positioned on the left side of the human head. For both electrodes 10, the front surfaces of the electrodes 10 face the human skin, that is, the polymer layer 30 faces the human skin. The second region of the adhesive 42, when pressed against the skin, adheres to the skin and holds the polymer layer in close proximity to the skin. If a layer of conductive hydrogel is provided, the hydrogel is positioned between the polymer layer 30 and the human skin. If the conductive hydrogel is omitted (which is less preferable), the polymer layer 30 is directly on the human skin.

[0049] When the pair of electrodes 10 are attached to human skin, an AC voltage is applied between these two electrodes 10. The layer of conductive material 20 acts as the plate of the capacitor, and the polymer layer 30 acts as the insulating layer of the capacitor, and the AC electric field is capacitively coupled to the human body through the pair of electrodes 10.

[0050] Optionally, ceramic nanoparticles may be mixed with poly(VDF-TrFE-CTFE), poly(VDF-TrFE-CFE), and / or poly(VDF-TrFE-CFE-CTFE) to form "nanocomposites." Optionally, the ceramic nanoparticles may comprise a ferroelectric metal oxide (e.g., at least one of barium titanate and barium strontium titanate).

[0051] In alternative embodiments, instead of forming the polymer layer 30 from poly(VDF-TrFE-CTFE) and / or poly(VDF-TrFE-CFE), another polymer that provides a high level of capacitance may be used. In some embodiments, the other polymer may have the following properties: (1) the polymer layer has a relative permittivity of at least 20 at at least one frequency between 100 kHz and 500 kHz; (2) the polymer layer has a thickness of 20 μm or less in the direction perpendicular to the front surface of the polymer layer. In some embodiments, the value obtained by multiplying the thickness of the polymer layer by its dielectric strength (dielectric strength) is at least 50 V, and in other embodiments, the value is at least 200 V. Examples of alternative polymers that can be used instead of poly(VDF-TrFE-CTFE) and / or poly(VDF-TrFE-CFE) include: (1) a mixture of ceramic nanoparticles with at least one of poly(VDF-TrFE), P(VDF-HFP), PVDF, or other polymers; and (2) a mixture of ceramic nanoparticles of barium titanate and / or barium strontium titanate with at least one of poly(VDF-TrFE), P(VDF-HFP), or PVDF. In other embodiments, the polymer layer 30 is formed by mixing ceramic nanoparticles with at least one other polymer (i.e., polymers not listed in this paragraph).

[0052] In some embodiments, the thickness of the polymer layer is 10 μm or less, for example, 1 μm to 10 μm, and in some embodiments, the thickness of the polymer layer is 5 μm or less, for example, 1 μm to 5 μm. In some embodiments, the value obtained by multiplying the thickness of the polymer layer by its dielectric strength is at least 400 V, and in some embodiments, the polymer layer has a relative permittivity of at least 20 when measured at 200 kHz. The relative permittivity and dielectric breakdown voltage values ​​specified in this application are specified within a temperature range of 30 to 42°C, for example, 35 to 42°C or 38 to 41°C, and the values ​​of parameters outside that temperature range are not of much concern.

[0053] In some embodiments, the conductive material layer comprises at least one metal (stainless steel, gold, and / or copper), is flexible, and has a thickness of less than 0.3 mm in a direction perpendicular to the front surface of the conductive material layer. In some embodiments, the thickness of the conductive material is less than 0.1 mm.

[0054] These embodiments can be attached to human skin using a flexible third layer, such as an adhesive bandage. One method of attaching the electrode 10 to human skin using a flexible third layer is to position the flexible third layer 40 behind the layer of conductive material. The flexible third layer 40 has a front surface, and at least a portion of the front surface of the third layer is covered with an adhesive 42. A first region of the adhesive 42 is located directly behind the layer of conductive material 20 and supports the layer of conductive material (direct contact is not required, and interposed components may be placed between them). A second region of the adhesive 42 is located outside the first region and is configured to (i) adhere to the skin and hold the polymer layer in close proximity to the skin when pressed against an area of ​​skin, and (ii) be easily removed from the skin. A layer of conductive hydrogel (not shown) is placed in front of the polymer layer 30, and the hydrogel is positioned to contact the skin when the polymer layer 30 is held in close proximity to the skin by the second region of the adhesive 42.

[0055] Another technique for attaching the electrode 10 to human skin using a flexible third layer is to configure the flexible third layer 40 to support a layer of conductive material 20. In such embodiments, the flexible third layer 40 has a front surface. The first portion of the front surface of the flexible third layer 40 is coated with an adhesive 42 that adheres to human skin but is easily removable from the skin. The first portion is located outside both the layer of conductive material 20 and the polymer layer 30, and when the first portion is pressed against an area of ​​skin, the adhesive 42 on the first portion adheres to the skin, holding the polymer layer 30 in close proximity to the skin. A layer of conductive hydrogel (not shown) is placed in front of the polymer layer 30. The hydrogel is positioned to contact the skin when the polymer layer 30 is held in close proximity to the skin by the adhesive 42.

[0056] Figures 2A and 2B show front and side views of another embodiment in which a transducer array is implemented using a flexible circuit. This embodiment is used to apply an alternating electric field to a living or in vitro medium at a frequency between 100 kHz and 500 kHz. The embodiment in Figure 2 has a flexible circuit, with a plurality of conductive pads 20 located in front of the flexible circuit 25. Each conductive pad 20 has a certain region (area). At least one conductive trace (not shown) is arranged in electrical contact with the plurality of conductive pads 20. At least one conductive trace is arranged and configured so that each conductive pad 20 can be driven by an electrical signal.

[0057] Furthermore, this embodiment also has a plurality of flexible polymer regions 30. These flexible polymer regions 30 can be multiple regions within a single continuous sheet of polymer material, as shown in Figure 2A. Alternatively, these regions 30 can be discrete regions of flexible polymer separated by gaps. Each flexible polymer region 30 has a front surface and is positioned in front of each of the conductive pads 20 on the front surface of the flex circuit 25.

[0058] The polymer region 30 of this embodiment may have the following properties: (1) Each polymer region 30 has a relative permittivity of at least 20 at at least one frequency between 100 kHz and 500 kHz; (2) Each polymer region 30 has a thickness of 20 μm or less in the direction perpendicular to its front surface. In some embodiments, the value obtained by multiplying the thickness of each polymer region 30 by its dielectric strength (dielectric strength) is at least 50 V, and in other embodiments, this value is at least 200 V. The polymer region 30 of the embodiment in Figure 2 can be implemented using any of the polymer materials described above with respect to the embodiment in Figure 1.

[0059] In some embodiments of Figure 2, each polymer region independently has a thickness of 20 μm or less in the direction perpendicular to its front surface, for example, a thickness between 1 μm and 20 μm. In further embodiments of Figure 2, each polymer region independently has a thickness of 10 μm or less in the direction perpendicular to its front surface, for example, a thickness between 1 μm and 10 μm. In other embodiments of Figure 2, each polymer region independently has a thickness of 5 μm or less in the direction perpendicular to its front surface, for example, a thickness between 1 μm and 5 μm. In further embodiments of Figure 2, each polymer region independently has a thickness of 3 μm or less in the direction perpendicular to its front surface, for example, a thickness between 1 μm and 3 μm.

[0060] In the embodiment shown in Figure 2, the multiple polymer regions 30 can be directly printed, sprayed, or molded (cast) onto the multiple conductive pads 20, making it much easier to obtain a thin polymer layer. In some embodiments (for example, embodiments in which the polymer regions 30 are directly printed, sprayed, or molded onto the conductive pads 20), the polymer regions have a thickness of 5 μm or less, for example, 1 μm to 5 μm.

[0061] As the total area covered by the conductive pads 20 increases, the capacitance of the entire device increases. In some embodiments, the total area of ​​the multiple conductive pads 20 is at least 25 cm². 2 It reaches.

[0062] The embodiment in Figure 2 can be attached to human skin using a flexible third layer, such as an adhesive bandage. In this embodiment, the flexible third layer 40 is located behind the flex circuit 25. The flexible third layer 40 has a front surface. At least a portion of the front surface of the third layer 40 is covered with an adhesive. A first region of the adhesive is located directly behind the flex circuit 25, supporting the flex circuit 25, while a second region of the adhesive is located outside the first region (this is the portion not covered by the flex circuit in Figure 2A). This second region is configured to adhere to the skin when pressed against a region of skin, holding a plurality of polymer regions 30 in close proximity to the skin. It is desirable that the adhesive used in the second region be easily removable from the skin. Although the flexible third layer 40 holds a plurality of polymer regions 30 in close proximity to the skin, a layer of conductive hydrogel 50 may be interposed between the polymer regions 30 and the skin. However, even then, the relationship between the polymer regions 30 and the skin is considered "proximity" (this applies not only to the embodiment in Figure 2 but also to other embodiments of this disclosure). In this situation, a layer of hydrogel 50 is positioned in front of each polymer region 30. The hydrogel 50 is positioned to contact the skin when each polymer region 30 is held in close proximity to the skin by the second region of adhesive.

[0063] In a modified embodiment of Figure 2, a different method is used to hold the polymer regions close to the skin using a flexible third layer. In such embodiments, the flexible third layer is configured to support the flex circuit. The flexible third layer has a front surface and may optionally include a plurality of cutout open regions corresponding to the positions of the conductive pads 20. The first portion of the front surface of the flexible third layer is covered with an adhesive that adheres to human skin but is easily removable from the skin. This first portion is located outside the flex circuit 25, and when the first portion is pressed against a region of skin, the adhesive on the first portion adheres to the skin, holding the plurality of polymer regions 30 close to the skin. Similar to the embodiments described above, a layer of conductive hydrogel 50 may be placed in front of each polymer region 30. The hydrogel 50 is positioned to contact the skin when each polymer region 30 is held close to the skin by the adhesive.

[0064] In the embodiment shown in Figure 2, multiple thermistors may be incorporated. One method to achieve this is to position multiple thermistors 60 on the back of the flex circuit 25 (i.e., between the flex circuit 25 and the flexible third layer 40) so that each thermistor 60 is in thermal contact with one of the multiple conductive pads 20. In such embodiments, the flex circuit 25 further includes multiple conductive traces for accessing the multiple thermistors 60. In alternative embodiments (not shown), the thermistors 60 may be positioned between the conductive pads 20. However, in this case, it is desirable to provide additional insulation in front of the thermistors.

[0065] Figures 3A, 3B, and 3C show front, side, and exploded views of other embodiments of implementing a transducer array using a flex circuit. These embodiments are also used to apply an alternating electric field to a biological or in vitro medium at frequencies between 100 kHz and 500 kHz. However, instead of using conductive pads integrated within the flex circuit (as in the embodiment of Figure 2 described above), the embodiment of Figure 3 has multiple metal foil pieces positioned in front of the flex circuit and electrically connected to each pad of the flex circuit.

[0066] The flex circuit 145 in the embodiment shown in Figure 3 includes (a) a plurality of conductive pads 140 located on the front of the flex circuit 145, and (b) at least one conductive trace (not shown) arranged in electrical contact with the plurality of conductive pads 140. The at least one conductive trace is arranged and configured so that each conductive pad 140 can be driven by an electrical signal. A plurality of metal foil pieces 120 are located in front of the flex circuit 145, and each piece 120 has a front surface having a certain area. Each piece 120 is electrically connected to one conductive pad 140.

[0067] The electrical connection between each piece 120 and each conductive pad 140 can be achieved by placing an insulating layer 130 between each piece 120 and each corresponding conductive pad 140, as shown in Figure 3B. The insulating layer 130 in the embodiment of Figure 3B has an opening behind each metal foil piece 120, through which a conductive path (e.g., metal, solder, etc.) is provided.

[0068] Furthermore, all modifications of the embodiment in Figure 3 also have a plurality of flexible polymer regions 30, each region having a front surface and positioned on the front surface of each of the plurality of metal foil pieces 120. The polymer regions 30 of this embodiment may have the following properties: (1) at at least one frequency between 100 kHz and 500 kHz, each polymer region 30 has a relative permittivity of at least 20; (2) each polymer region 30 has a thickness of 20 μm or less in the direction perpendicular to its front surface. In some embodiments, the value obtained by multiplying the thickness of each polymer region 30 by its dielectric strength is at least 50 V, and in other embodiments, the value is at least 200 V. The polymer regions 30 of the embodiment in Figure 3 can be carried out using any of the polymer materials described above with respect to the embodiment in Figure 1.

[0069] In some embodiments of Figure 3, each polymer region independently has a thickness of 20 μm or less in the direction perpendicular to its front surface, for example, a thickness of 1 μm to 20 μm. In further embodiments of Figure 3, each polymer region independently has a thickness of 10 μm or less in the direction perpendicular to its front surface, for example, a thickness of 1 μm to 10 μm. In other embodiments of Figure 3, each polymer region independently has a thickness of 5 μm or less in the direction perpendicular to its front surface, for example, a thickness of 1 μm to 5 μm. In further embodiments of Figure 3, each polymer region independently has a thickness of 3 μm or less in the direction perpendicular to its front surface, for example, a thickness of 1 μm to 3 μm.

[0070] In the embodiment shown in Figure 3, multiple polymer regions 30 can be directly printed, sprayed, or molded (cast) onto the metal foil piece 120, making it much easier to obtain an ultrathin polymer layer. In some embodiments (for example, embodiments in which the polymer regions 30 are directly printed, sprayed, or molded onto the metal foil piece 120), the polymer regions have a thickness of less than 5 μm.

[0071] As the total area covered by the metal foil pieces 120 increases, the capacitance of the entire device increases. In some embodiments, the combined area of ​​the multiple metal foil pieces is at least 25 cm². 2 It reaches.

[0072] The embodiment in Figure 3 can be attached to human skin using a flexible third layer 40, and its appearance is similar to that of the flexible third layer described above with respect to Figure 2. Additionally, as described above with respect to the embodiment in Figure 2, a layer of conductive hydrogel 50 may be placed in front of each polymer region.

[0073] Furthermore, as described above with respect to the embodiment in Figure 2, multiple thermistors can also be incorporated into the embodiment in Figure 3.

[0074] Figures 4A and 4B are similar to the embodiment in Figure 3 described above, but differ in that they use an alternative method to establish the electrical connection between each piece 120 and each corresponding conductive pad 140. Similar to the method in Figure 3, an insulating layer 130 is located between each piece 120 and the corresponding conductive pad 140. However, the insulating layer 130 in the embodiment of Figure 4 does not have an opening behind each metal foil piece 120. Instead, the insulating layer 130 in the embodiment of Figure 4 is continuous. The electrical connection between each metal foil piece 120 and the conductive pad 140 of the flex circuit is provided using a side-end electrical connection portion 160 between the conductive pad 140 and the metal foil piece 120.

[0075] The embodiments of this disclosure can advantageously provide large-area coverage. Furthermore, because heat is dissipated over a large area of ​​skin, these embodiments can deliver more energy to the patient's body without exceeding safety requirements at a given location on human skin. Also, the embodiments of this disclosure are thinner, lighter, and more flexible than the conventional ceramic disc-type embodiments. This makes the transducer array more comfortable, improves compliance, and makes it easier for the patient to use the device for most of the day. Additionally, because the embodiments described above are thin and light, low-strength adhesives can be used, reducing skin irritation.

[0076] Embodiments of the present disclosure are particularly useful for selectively destroying or inhibiting the growth of rapidly dividing cells located within a target region of a subject or an in vitro medium (e.g., an in vitro medium containing stem cells for later transplantation into the subject). As described above, the therapeutic method may comprise placing a first device of the present disclosure at a first position near the target region (e.g., on the skin of a subject near the target region, or near the target region of an in vitro medium). A second device of the present disclosure (which may be the same as or different from the first device) may then be placed at a second position near the target region. The second position is opposite or substantially opposite the first position and is configured to apply an electric field with an appropriate orientation to the target region.

[0077] An AC (alternating current) electric field can be applied to a target region by applying an AC voltage between the first and second devices. The frequency range of the AC electric field can be 100 kHz to 500 kHz. When the AC electric field is applied to the target region for a certain duration, the AC electric field selectively destroys or inhibits the growth of rapidly dividing cells in the target region of the subject or in vitro medium.

[0078] The term "subject" includes vertebrates, such as mammals, fish, birds, reptiles, and amphibians. Therefore, a subject could be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cattle, a cattle, a guinea pig, or a rodent. This term does not indicate a specific age or sex. In one embodiment, the subject is a mammal. In some embodiments, the subject is a living human subject. In some embodiments, the subject has been diagnosed prior to the treatment for a condition involving rapid cell growth. In further embodiments, the treatment further includes a step to confirm the subject's need for treatment.

[0079] The duration for which an AC electric field is applied to the target region varies depending on the condition being treated. In some embodiments, the duration may be determined based on the time it takes for the therapeutic majority of rapidly dividing cells to die. For example, the duration may range from a few hours to several days, e.g., 1 to 48 hours or longer, e.g., 2 to 14 days.

[0080] In some embodiments, rapidly dividing cells may be present in tumors located within the target region. The term “tumor” refers to malignant tissue containing uncontrolledly growing transformed cells. Examples of tumors include leukemia, lymphoma, myeloma, plasmacytoma, and solid tumors. Examples of solid tumors treatable by the methods disclosed herein include non-epithelial malignancies (sarcomas) and epithelial malignancies (carcinomas), such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, endolymphatic sarcoma, synoviomas, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, and sebaceous gland cancer. This method can treat a wide range of tumors, including, but is not limited to, cancer, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, cervical cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma. Since each of these tumors grows rapidly, all can be treated using this method. This method is particularly advantageous for treating brain tumors that are difficult to treat with surgery or radiation and are often inaccessible with chemotherapy or gene therapy. Furthermore, because this method allows for easy localized treatment, it is suitable for treating skin tumors and breast tumors.

[0081] In some embodiments, this method can be used to treat a variety of cancers present in the target region, including, but not limited to, glioblastoma (including recurrent and newly diagnosed glioblastoma), mesothelioma, brain metastases, non-small cell lung cancer, pancreatic cancer, ovarian cancer, liver cancer, breast cancer, cervical cancer, colorectal cancer, ependymoma, gastric adenocarcinoma, gliosarcoma, malignant melanoma, medulloblastoma, meningioma, renal adenocarcinoma, small cell lung cancer, urinary tract transitional cell carcinoma, and teratomas, which may be present in living organisms or in in vitro media such as media containing stem cells for later transplantation into subjects.

[0082] Furthermore, the therapeutic methods disclosed herein can control uncontrolled growth associated with non-malignant diseases and precancerous conditions, as well as other diseases involving inappropriate cell and tissue growth, by applying an electric field to improperly growing tissue. For example, this method may be useful in treating arteriovenous (AV) malformations, particularly AV malformations located in the intracranial region. This method can also be used to treat psoriasis, skin diseases characterized by inflammation and angiogenesis, benign prostatic hyperplasia, and diseases with the potential for inflammation and defective growth. Treatment of other hyperproliferative diseases is also envisioned.

[0083] Furthermore, by applying an electric field according to the method of this disclosure, it is possible to suppress the undesirable proliferation of fibroblasts and endothelial cells associated with wound healing that leads to the formation of scars and keloids after surgery or injury, as well as restenosis after angiogenesis or coronary artery stent placement. The non-invasive nature of this method is particularly desirable for these types of conditions, as it prevents the development of internal scars and adhesions and suppresses restenosis of the coronary arteries, carotid arteries, and other important arteries.

[0084] In addition to treating tumors that have already been detected, embodiments of the present disclosure can also be used to prevent tumors from reaching a detectable size. This use may be beneficial for individuals at high risk of certain types of cancer (e.g., women with a family history of breast cancer, or individuals who have survived cancer but are at high risk of recurrence). Preventive therapy can be tailored based on the type of cancer targeted and / or to the patient's needs.

[0085] Further details of the treatment method are described in Patent Documents 3 and 4, which are incorporated in their entirety into this application as references to teach the treatment and prevention of tumors and other conditions involving rapidly dividing cells using TT fields.

[0086] In a further embodiment, embodiments of the present disclosure are useful for selectively disrupting or inhibiting the growth of rapidly dividing cells located within a target region of an in vitro medium. For example, stem cells being cultured for later transplantation into a subject may develop teratomas during development. Since rapidly dividing cells are involved in such teratomas, the methods of the present disclosure may be useful for reducing, eliminating, or preventing the development of teratomas in an in vitro stem cell medium that can later be transplanted into a living organism.

[0087] In further embodiments, embodiments of the present disclosure are useful for selectively destroying or inhibiting the growth of rapidly dividing viral or bacterial cells within a target region of a subject or in vitro medium. Embodiments of the present disclosure can be used to treat viral or bacterial infections in a subject or in vitro medium, as described in Patent Document 5, which is incorporated entirely into this application as a reference to teach the application of an AC electric field for antiviral purposes. For example, in some embodiments, embodiments of the present disclosure can be used in antiviral or antimicrobial methods in which an AC electric field is applied to a target region in combination with an effective amount of an antiviral or antibacterial agent. In further embodiments, by applying an AC electric field to a target region characterized by rapidly dividing bacterial cells or viruses, the AC electric field may enable an effective therapeutic amount of the antiviral or antibacterial agent to reach the target region and exert its therapeutically effective function.

[0088] Similarly, in some embodiments, applying an AC electric field to a target region characterized by rapidly dividing bacterial cells or viruses can prevent damage caused by new cell infection (changes in cellular function, cell death, cell transformation), halt the proliferation and spread of viruses and bacteria, and avoid unintended consequences for the health of infected individuals. Likewise, AC electric field therapy can be useful in protecting uninfected, healthy subjects from threatening infection, such as healthcare workers who come into close contact with infected individuals (especially in the acute phase of viral diseases where infectious particles are found in the blood, skin lesions, saliva, etc., and are transmitted through direct or indirect contact, such as droplets or aerosols). Furthermore, AC electric field therapy using embodiments of this disclosure can also be used by individuals with suppressed immune systems who lack the body's robust natural defenses (e.g., those with congenital immunodeficiency, organ transplants, or cancer).

[0089] Furthermore, suppressing viral infection can be extremely important for the progression of ongoing viral diseases. Human immunodeficiency virus (HIV) is an example of a virus that remains clinically dormant in the human body, particularly in the lymph nodes, for extended periods, but survives and replicates during this time. Over time, the number of susceptible immune cells decreases, leading to infection and the development of AIDS (acquired immune deficiency syndrome). By pausing the continuous viral infection cycle, its spread can be suppressed, and disease progression can be prevented.

[0090] In further embodiments, embodiments of the present disclosure may be useful for treating a variety of autoimmune diseases, for example, as described in Patent Document 6, which is incorporated in whole by reference into this application for teaching AC electric field therapy for treating or preventing the progression of autoimmune diseases.

[0091] In further embodiments, embodiments of the present disclosure may be useful for treating a variety of central nervous system disorders. These disorders are often characterized by the growth of rapidly dividing cells and the accumulation of certain charged proteins and platelets, which can be inhibited by AC field therapy using embodiments of the present disclosure. Non-limiting examples of such disorders include, in particular, Alzheimer's disease, multiple sclerosis, neurofibromatosis, and Parkinson's disease. As described above, AC field therapy can be used in combination with drugs known for treating these central nervous system disorders. In some embodiments, AC field therapy using embodiments of the present disclosure may be useful in ensuring that a therapeutically effective amount of drug reaches the therapeutic target region; for example, AC field therapy may ensure that a therapeutically effective amount of drug crosses the blood-brain barrier and enters the target region.

[0092] Disclosed herein are devices placed on or near a living organism or in vitro medium to selectively destroy or inhibit the growth of rapidly dividing cells within a target region of a subject or in vitro medium. Further disclosed herein are methods of using the device of the disclosure for selectively destroying or inhibiting the growth of rapidly dividing cells. Furthermore disclosed herein are kits comprising the device of the disclosure together with one or more therapeutic agents useful for treating conditions involving rapidly dividing cells, such as anticancer agents, antiviral agents, antibacterial agents, or drugs for treating central nervous system disorders or other diseases involving rapidly dividing cells.

[0093] While the present invention is disclosed with reference to specific embodiments, numerous modifications, substitutions, and changes are possible to the disclosed embodiments without departing from the spirit and scope of the invention as defined in the claims. Accordingly, the present invention is not limited to the disclosed embodiments and has the full scope as defined by the appended claims and their equivalents.

Claims

1. An apparatus for applying an alternating electric field at a frequency between 100 kHz and 500 kHz to a target area of ​​a living organism or an in vitro medium, A layer of conductive material having a front surface having a region, A flexible polymer layer having a front surface, located on the front surface of the conductive material and covering at least a portion of the region, The system comprises a conductive wire positioned in electrical contact with the layer of the conductive material, An apparatus wherein the flexible polymer layer has a relative permittivity of at least 20 at at least one frequency between 100 kHz and 500 kHz.

2. The following further comprises a flexible third layer located behind the conductive material layer and having a front surface: At least a portion of the front surface of the flexible third layer is covered with an adhesive, The first region of the adhesive is located directly behind the layer of the conductive material, supporting the layer of the conductive material. The apparatus according to claim 1, wherein the second region of the adhesive is located outside the first region and is configured to adhere to the skin when pressed against a region of skin, to hold the flexible polymer layer in close proximity to the skin, and to be easily removed from the skin.

3. The flexible polymer layer further comprises a layer of conductive hydrogel located in front of the flexible polymer layer, The apparatus according to claim 2, wherein the conductive hydrogel layer is positioned to contact the skin when the flexible polymer layer is held in close proximity to the skin by the second region of the adhesive.

4. The apparatus according to claim 1, wherein the flexible polymer layer has a thickness of 20 μm or less.

5. The apparatus according to claim 1, wherein ceramic nanoparticles are mixed in the flexible polymer layer.

6. The apparatus according to claim 5, wherein the ceramic nanoparticles comprise at least one of barium titanate and barium strontium titanate.

7. The apparatus according to claim 5, wherein the ceramic nanoparticles are mixed with at least one of poly(VDF-TrFE), poly(VDF-HFP), and PVDF.

8. The apparatus according to claim 7, wherein the ceramic nanoparticles comprise at least one of barium titanate and barium strontium titanate.

9. The apparatus according to claim 8, wherein the flexible polymer layer has a thickness of 20 μm or less.

10. The apparatus according to claim 1, wherein the flexible polymer layer comprises at least one of poly(VDF-TrFE-CTFE), poly(VDF-TrFE-CFE), and poly(VDF-TrFE-CFE-CTFE).

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