Two-phase injection possible electrode

Abstract

The present disclosure generally relates to a biphasic injectable electrode having a plurality of solid particles and a transporter phase, both of which have poly(3,4-ethylenedioxythiophene) polystyrene sulfonate. A biphasic injectable electrode for use in a brain surgical resection cavity includes inserting a biphasic injectable electrode (3) into a brain surgical resection cavity having a tumor resection margin (4). A probe (1) is inserted into the electrode, and four counter electrodes (2) are embedded in the surrounding brain tissue. A charge supply (6) supplies charge to the probe via wires (5).

Description

Technical Field

[0001] The present invention relates to a biphasic injectable electrode. More specifically, the present invention relates to a biphasic injectable electrode having a plurality of solid particles and a transporter phase, both the solid particles and the transporter phase having poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, and its use in electrotherapy treatment of diseases.

Background Art

[0002] According to the National Cancer Institute, a solid tumor is "an abnormal mass of tissue that results from cells dividing more than they should or not dying when they should." It can occur in various locations such as bone, muscle, and organs, and can be either benign or malignant. Various types of solid tumors are named according to the type of cells that form them, such as sarcoma, carcinoma, lymphoma, etc., and treatment generally involves a combination of multiple types of treatments including surgery, chemotherapy, and radiotherapy.

[0003] Surgical resection of a tumor is a procedure performed to remove the tumor and, if necessary, the surrounding normal tissue. Surgical partial resection of a tumor, sometimes called debulking, is a derivative form of this surgery. By partially removing a surgically incurable tumor, subsequent chemotherapy, radiotherapy, and other adjuvant treatments can be made more effective and the survival period can be prolonged. Surgical partial resection is clinically performed for several cancers including testicular and ovarian cancers, lymphomas, sarcomas, renal cell cancers, endocrine-related tumors such as adrenal gland tumors, cancers of the central nervous system (e.g., glioblastoma multiforme), and other solid tumors.

[0004] The goal of surgical resection of a tumor is to remove the maximum amount of tumor that can be safely removed. A cavity remains, but its size, shape, and location vary from patient to patient. Distinguishing between cancer and healthy tissue during surgery is extremely difficult, and it is unavoidable that cancer cells will remain in the surrounding tissue; this is called the tumor resection margin (TRM). This is a particular problem in grade IV gliomas and glioblastoma multiforme (GBM).

[0005] Electrotherapy has proven to be an effective treatment for GBM. In a Phase III multicenter clinical trial, electrotherapy, when used in addition to surgery, chemotherapy, and radiotherapy, was shown to extend patients' overall survival to 21 months (Stupp et al; JAMA; 2017; 318(23): 2306-16; doi: 10.1001 / jama.2017.18718). This is achieved by alternately supplying a sinusoidal electric field to the head at specific frequencies (50–300 kHz). At these frequencies, the electric field has been shown to inhibit mitosis of cancer cells, thereby slowing the growth of recurrent tumors and extending patient survival (Kirson et al.; PNAS; 2007; 104(24): 10152-7; doi: 10.1073 / PNAS.0702916104).

[0006] Currently, there is only one electrotherapy device clinically used for cancer treatment. In this device, a therapeutic electric field is delivered to the patient's head via a transducer array attached to the scalp. These transducers are connected to an external battery and stimulator pack that the patient must carry with them, and the recommended treatment time is 18 hours per day. However, this external stimulation approach has several problems. First, the electric field generated in the center of the brain (where the tumor resection margin is located) is exponentially weaker than the electric field on the skin surface where the field is generated, thus limiting the therapeutic effect. Considering this, a large, heavy battery is used to ensure that an electric field of effective strength is generated at the treatment site, resulting in a very cumbersome device that affects the patient's autonomy and mobility. Furthermore, the transducers attached to the scalp are very noticeable, taking about 50 minutes to attach to the head each morning, and the patient's head needs to be shaved every two days. This significantly impacts the patient's quality of life, and the prolonged presence of the transducers on the scalp can cause serious skin irritation, potentially resulting in pain as a result of the large currents crossing the skin. The impact on patients' quality of life in this regard is that only a small percentage of patients adhere to the recommended daily dosing schedule (Toms et al.; Journal of Neuro-Oncology; 2019; 141(2): 467-473; doi: 10.1007 / sll060-018-03057-z). There is a clear correlation between the amount of time GBM patients receive electrotherapy daily and their overall survival, and the data strongly suggest that continuous dosing (24 hours / day) leads to the best overall survival, indicating that patient compliance issues directly limit the effectiveness of treatment.

[0007] To make electrotherapy after tumor resection more effective, several challenges must be overcome. First, the presence of a cavity (created by surgery) acts as a resistance barrier, reducing the effective electric field strength in the TRM. Second, residual cancer cells are present three-dimensionally in all directions from the center of the resection cavity. Third, although estimations can be made with preoperative scans, the exact size and shape of the cavity cannot be determined until during surgery. Fourth, since any surgery carries some degree of risk to the patient and is expensive, ideally, the electrotherapy device should be implanted during existing tumor resection surgery. Fifth, many patients receive radiation therapy after resection surgery. Immediately after radiation therapy, tissue often swells temporarily, and the dimensions of the tumor resection cavity shrink. The introduction of rigid implanted electrodes, or anything that restricts the cavity's ability to contract, can lead to fatal consequences for organs such as the brain as a result of increased intracranial pressure. Finally, since the implanted electrodes are expected to remain in place for the remainder of the patient's life (which may be several years), the materials must be biocompatible and not cause adverse reactions. Biocompatibility requirements apply to both the implanted material and its changes over time, including degradation products. All products must be non-toxic and non-pyrogenic and must not release ionic species into the tissue as a result of corrosive reactions with tissue fluid. These reactions can be aggravated by the electric field that provides the activation energy required for many corrosive reactions, and the resulting released ionic species may be cytotoxic and pro-inflammatory. Biocompatibility requirements also include the mechanical properties of the electrode itself. For example, brain tissue is very soft, on the order of less than 2 kPa, and introducing a mechanically mismatched, rigid material can cause localized scarring and other harmful biological reactions. Therefore, it is desirable that the material used is as hard as, or softer than, the host tissue.

[0008] A further problem that needs to be addressed with the proposed electrotherapy device is that there are two types of charge transfer mechanisms that can deliver electrical stimulation from electrodes to the treatment site: Faraday charge transfer and capacitive charge transfer. The Faraday charge transfer mechanism causes localized changes in the chemical composition of the electrolyte, leading to tissue damage and electrode degradation (SF Cogan; Neural Stimulation and recording electrodes; Annual Review of Biomedical Engineering; 2008). Therefore, in order to ensure good performance, biocompatibility, and long-term functionality of implanted electrotherapy devices, electrodes capable of supplying a large amount of charge under a capacitive charge injection system within the body must be employed. Capacitive charge injection does not result in the release of chemical species into tissue and is therefore far less likely to cause harm, but the current supplied to surrounding tissue is typically about 10 times lower compared to Faraday charge injection at the same applied voltage. This can be counteracted by applying a higher voltage for the capacitive charge injection system.

[0009] WO2018 / 227165 describes electrodes manufactured by curing in the body, as well as related methods and apparatus, and WO2018 / 111949 describes electrodes that are curable and can be molded to the contour of a target in body tissue, as well as methods for manufacturing and deploying the same, and dispensers. Neither application discloses a two-phase injectable electrode comprising both phases of poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0010] This specification discloses a two-phase injectable electrode that overcomes these challenges and the shortcomings of current electrotherapy. The two-phase injectable electrode of this disclosure can take on the shape and volume of the cavity in which it exists, directly interface with the TRM, and enable three-dimensional generation of the electric field. Furthermore, these electrodes can dynamically respond to changes in the size of the tumor cavity and maintain constant direct contact with the TRM wall. By supplying an electric field from within the tumor resection cavity, the intensity of the electric field in the TRM is increased, which should improve patient outcomes. In addition, this approach eliminates the problem of painful skin irritation experienced with the existing devices described above (e.g., there is no sensation from within the brain tissue). Finally, the technology of injectable electrodes has the potential to enable continuous electrotherapy treatment and significantly improve patient outcomes.

[0011] The characteristics of the two-phase injectable electrodes described herein also offer advantages to the accompanying equipment required to supply the charge. Because the electric field is applied at a reduced intensity, the voltage required to generate the same electric field strength is exponentially lower than with existing devices. Using lower voltage allows for the use of smaller (longer-lasting) batteries, enabling miniaturization and implantation of the device. Complete implantation of the device overcomes several problems: nothing is visible outside the body, it is not cumbersome to carry, and (for brain tumors) there is no need to shave the head. [Overview of the Initiative]

[0012] This specification partially discloses a two-phase injectable electrode comprising a plurality of solid particles and a transporter phase, both of which comprise poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0013] This specification partially discloses a two-phase injectable electrode comprising multiple solid particles and a transporter phase, both of which contain poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid for therapeutic use.

[0014] This specification partially discloses a two-phase injectable electrode comprising a plurality of solid particles and a transporter phase, both of which contain poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid for use in electrotherapy.

[0015] This specification discloses a therapeutic method in a warm-blooded animal, such as a human, which involves administering electrotherapy to an animal having a two-phase injectable electrode comprising a plurality of solid particles and a transporter phase, both of which comprise poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0016] This specification partially discloses an apparatus for use in electrotherapy, the apparatus comprising a two-phase injectable electrode comprising a plurality of solid particles and a transporter phase, wherein both the solid particles and the transporter phase comprise poly(3,4-ethylenedioxythiophene)polystyrenesulfonic acid, a counter electrode, a probe, and a charge supply device.

[0017] This specification is in part, a) A two-phase implantable electrode comprising a plurality of solid particles and a transporter phase, wherein both the solid particles and the transporter phase contain poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid, b) Opposite poles, c) Probe and, d) A kit including a charge supply device is disclosed.

[0018] [Detailed description of the present invention] Many embodiments of the present invention are described in detail throughout this specification and will be apparent to those skilled in the art. The present invention is not construed to be limited to any of the embodiments cited.

[0019] "One" means "at least one." In any embodiment in which "one" is used to indicate a material or element, "one" may mean one.

[0020] "Having" means that a material or element may include other materials or elements. In any embodiment where "having" is mentioned, a material or element may be formed of at least 10% w / w, at least 20% w / w, at least 30% w / w, or at least 40% w / w of that material or element. In any embodiment where "having" is mentioned, "having" may mean "consisting of" or "essentially consisting of" a material or element.

[0021] "Composed of" means that a material or element is formed only of that material or element. In any embodiment where "composed of" is mentioned, a material or element may be formed of 100% w / w of that material or element.

[0022] "Essentially composed of" means that a material or element is composed almost entirely of that material or element. In any embodiment where "essentially composed of" is mentioned, a material or element may be formed of at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w, or at least 99% w / w of that material or element.

[0023] In any embodiment where "is" or "may be" is used to define a material or element, "is" or "may be" may mean that the material or element is "composed" or "essentially composed" of that material or element.

[0024] Claims indicate embodiments.

[0025] Embodiments may be combined.

[0026] [Injectable] This specification describes the two-phase injectable electrodes described herein that form an interface with tissue, particularly human tissue, and can fill surgical cavities of unknown shape. The two-phase injectable electrodes described herein may be introduced by injection.

[0027] In certain embodiments, the two-phase injectable electrodes described herein may be suitable for introduction into a cavity under pressure.

[0028] In certain embodiments, the two-phase injectable electrodes described herein may be suitable for introduction into a surgically created cavity under pressure.

[0029] In certain embodiments, the two-phase injectable electrodes described herein may be suitable for introduction into a cavity by injection.

[0030] In certain embodiments, the two-phase injectable electrodes described herein may be suitable for introduction into a surgically created cavity by injection.

[0031] In certain embodiments, the two-phase injectable electrodes described herein may be suitable for introduction into a cavity by a syringe.

[0032] In certain embodiments, the two-phase injectable electrodes described herein may be suitable for introduction into a surgically created cavity by a syringe.

[0033] [Electrode] An electrode is a conductor that conducts and receives an electric current from one medium to another. The electrode may be used for the purpose of passing an electric current between a charge supply device and the human body.

[0034] [Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate] Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) is a conductive polymer mixture of sodium polystyrene sulfonate and poly(3,4-ethylenedioxythiophene) (PEDOT).

[0035] [Biphasic] The two-phase injectable electrode described herein comprises at least two phases: a solid phase having a plurality of solid particles and a transporter phase.

[0036] In one embodiment, the two-phase injectable electrode has two phases.

[0037] In one embodiment, the two-phase injectable electrode has three or more phases.

[0038] [Solid particles] The two-phase injectable electrode described herein comprises a plurality of solid particles having poly(3,4-ethylenedioxythiophene)polystyrenesulfonic acid. The solid particles are solid in that they maintain their shape and do not flow in a steady state or in response to shear forces during injection. The solid particles are injectable because their size and shape are small enough to be injected with a syringe. The solid particles are distributed within the transporter phase. The solid particles have excellent conductivity due to the dense network of poly(3,4-ethylenedioxythiophene)polystyrenesulfonic acid chains, but their ability to form an easily injectable electrode depends on the fluidity of the transporter phase.

[0039] In one embodiment, the solid particles have a gel. A gel is a non-fluid colloidal network of particles, polymers, or other molecules that expands to its entire volume by a fluid but does not flow.

[0040] In one embodiment, the solid particles are composed of a gel.

[0041] In one embodiment, solid particles are essentially composed of a gel.

[0042] In one embodiment, the solid particles have a non-shearing gel.

[0043] In one embodiment, the solid particles are composed of a non-shearing gel.

[0044] In one embodiment, solid particles are essentially composed of a non-shearing gel.

[0045] In one embodiment, the solid particles have a plurality of solid particles that are small enough to be injected by a syringe.

[0046] In one embodiment, the solid particles consist of a plurality of solid particles, each having a maximum dimension of 4 mm.

[0047] In one embodiment, the solid particles consist of a plurality of solid particles having a maximum dimension of 1.5 mm.

[0048] In one embodiment, the solid particles consist of a plurality of solid particles having a minimum dimension of 0.1 mm.

[0049] In one embodiment, the solid particles consist of a plurality of solid particles having dimensions of 0.1–1.5 mm.

[0050] In one embodiment, the solid particles consist of a plurality of solid particles having dimensions of 0.1–4 mm.

[0051] In one embodiment, the solid particles consist of a plurality of solid particles having dimensions of 1-4 mm.

[0052] In one embodiment, the solid particles consist of a plurality of solid particles having dimensions of approximately 1-4 mm.

[0053] In one embodiment, the solid particles consist of a plurality of solid particles, each having a dimension of approximately 1 mm.

[0054] In one embodiment, solid particles account for 40-85% v / v of the injectable electrode.

[0055] In one embodiment, solid particles account for 60-85% v / v of the injectable electrode.

[0056] In one embodiment, solid particles account for 40% v / v of the injectable electrode.

[0057] In one embodiment, solid particles account for 50% v / v of the injectable electrode.

[0058] In one embodiment, solid particles account for 60% v / v of the injectable electrode.

[0059] In one embodiment, solid particles account for 70% v / v of the injectable electrode.

[0060] In one embodiment, solid particles account for 75% v / v of the injectable electrode.

[0061] In one embodiment, solid particles account for 80% v / v of the injectable electrode.

[0062] In one embodiment, solid particles account for 85% v / v of the injectable electrode.

[0063] In one embodiment, solid particles account for approximately 40-50% v / v of the injectable electrode.

[0064] In one embodiment, solid particles account for approximately 50-60% v / v of the injectable electrode.

[0065] In one embodiment, solid particles account for approximately 60-70% v / v of the injectable electrode.

[0066] In one embodiment, solid particles account for approximately 70-80% v / v of the injectable electrode.

[0067] In one embodiment, solid particles account for approximately 75-85% v / v of the injectable electrode.

[0068] In one embodiment, solid particles account for approximately 80-90% v / v of the injectable electrode.

[0069] In one embodiment, solid particles account for approximately 85-95% v / v of the injectable electrode.

[0070] In one embodiment, the solid particles have at least 90% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0071] In one embodiment, the solid particles have at least 95% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0072] In one embodiment, the solid particles have poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0073] In one embodiment, the solid particles are essentially composed of poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0074] In one embodiment, the solid particles are composed of poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0075] [Transporter phase] The two-phase injectable electrode described herein has a transporter phase containing poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid. The transporter phase of the two-phase injectable electrode can fill the cavity to its precise volume in seconds (regardless of patient differences). As a result, the electrical contact with the resection wall is tight and the injection speed is fast, so the surgical time is not significantly prolonged (important for patient safety). The transporter phase of the two-phase injectable electrode contains a substance that can flow under steady state or in response to the shear force applied during injection, such as a shear-thinning gel or a highly viscous fluid, but should not diffuse significantly into the surrounding tissue. Diffusion into the surrounding tissue can potentially lead to biocompatibility issues and / or destabilization of the transporter phase. "Shear-thinning" describes the non-Newtonian behavior of a fluid in which viscosity decreases due to shear strain. The poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid in the transporter phase is solubilized. The less dense molecular network of poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid in the transporter phase imparts some conductivity, but relatively less than that of solid particles. A key function of the transporter phase is to facilitate fluidity and create an easily implantable electrode.

[0076] In one embodiment, the transporter phase must be poorly soluble.

[0077] In one embodiment, the transporter phase has a viscous liquid.

[0078] In one embodiment, the transporter phase is composed of a viscous liquid.

[0079] In one embodiment, the transporter phase is essentially composed of a viscous liquid.

[0080] In one embodiment, the transporter phase has a shea-thinning gel.

[0081] In one embodiment, the transporter phase is composed of a shea-thinning gel.

[0082] In one embodiment, the transporter phase is essentially composed of a shea-thinning gel.

[0083] In one embodiment, the transporter phase accounts for 15-60% v / v of the injectable electrode.

[0084] In one embodiment, the transporter phase accounts for 15-40% v / v of the injectable electrode.

[0085] In one embodiment, the transporter phase accounts for 60% v / v of the injectable electrode.

[0086] In one embodiment, the transporter phase accounts for 50% v / v of the injectable electrode.

[0087] In one embodiment, the transporter phase accounts for 40% v / v of the injectable electrode.

[0088] In one embodiment, the transporter phase accounts for 30% v / v of the injectable electrode.

[0089] In one embodiment, the transporter phase accounts for 25% v / v of the injectable electrode.

[0090] In one embodiment, the transporter phase accounts for 20% v / v of the injectable electrode.

[0091] In one embodiment, the transporter phase accounts for 15% v / v of the injectable electrode.

[0092] In one embodiment, the transporter phase accounts for 60-70% v / v of the injectable electrode.

[0093] In one embodiment, the transporter phase accounts for 50-60% v / v of the injectable electrode.

[0094] In one embodiment, the transporter phase accounts for 40-50% v / v of the injectable electrode.

[0095] In one embodiment, the transporter phase accounts for 30-40% v / v of the injectable electrode.

[0096] In one embodiment, the transporter phase accounts for 20-30% v / v of the injectable electrode.

[0097] In one embodiment, the transporter phase accounts for 15-25% v / v of the injectable electrode.

[0098] In one embodiment, the transporter phase accounts for 10-20% v / v of the injectable electrode.

[0099] In one embodiment, the transporter phase accounts for 5-15% v / v of the injectable electrode.

[0100] In one embodiment, the transporter phase has <5% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0101] In one embodiment, the transporter phase contains 0.05-0.25% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0102] In one embodiment, the transporter phase has approximately 0.15% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0103] In one embodiment, the transporter phase has 0.15% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0104] In one embodiment, the transporter phase has a polymer that can undergo partial crosslinking after injection. This may be via UV crosslinking, temperature-dependent crosslinking (e.g., crosslinking occurring at body temperature), and / or salt-dependent crosslinking. Partial crosslinking after injection may help stabilize the transporter phase.

[0105] [Additional configuration] The transporter phase and solid particles of the two-phase injectable electrode described herein may consist of poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid alone, or as a mixture or composite with other materials such as clay, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polydimethylsiloxane (PDMS), xanthan gum, (3-glycidyloxypropyl)trimethoxysilane, ethylene glycol, dodecylbenzenesulfonic acid, cyclodextrin and / or polyvinylamine, or clay, polyethylene glycol (PEG), poly(ethyleneglycyl) It may also be present as a mixture or complex with other materials such as poly(ethylene glycol) diacrylate, polyvinyl alcohol (PVA), polydimethylsiloxane (PDMS), xanthan gum, (3-glycidyloxypropyl)trimethoxysilane, ethylene glycol, dodecylbenzenesulfonic acid, methylcellulose, hydroxymethylcellulose, guar gum, Pluronic® F-127, poly(N-isopropylacrylamide) (PNIPAAM), kappa-carrageenan, cyclodextrin, phosphate-buffered saline (PBS), and / or polyvinylamine.

[0106] A mixture is a material made from two or more materials, in which the constituent materials are completely distributed throughout. The distribution is random, and there is no fixed structure.

[0107] A composite material is a material made from two or more materials with significantly different physical or chemical properties. When combined, it creates a material with properties different from those of the individual components. These constituent materials may have a fixed structure and texture throughout the whole. The distribution of these fixed structures throughout the composite material can impart properties to the composite material that would not be present in a random mixture of the two materials.

[0108] Clay is a material formed from layered silicates and may be compounded with metals or metal oxides, including species formed from aluminum, iron, magnesium, and sodium. In embodiments where clay is mentioned, clay may refer to hectorite, which has the chemical formula "Na". 0.3 (Mg,Li)3Si4O 10 It is a soft, oily white clay mineral represented as (OH)2. In embodiments where clay is mentioned, clay may refer to clay nanoparticles. In any embodiment where clay is mentioned, clay may refer to smectite clay, in particular smectite clay nanoparticles having magnesium oxide and silica, such as Laponite®. Laponite® is a synthetic smectite clay with a structure and composition very similar to the natural clay mineral hectorite. It is a layered hydrated magnesium silicate belonging to the (2:1) phyllosilicate group, with a structure in which a sheet of octahedral-coordinated magnesium oxide is sandwiched between two parallel sheets of tetrahedral-coordinated silica.

[0109] Polyethylene glycol (PEG) is a synthetic polymer produced by polymerizing ethylene glycol.

[0110] Poly(ethylene glycol) methacrylate is a diester formed by the condensation of methacrylic acid and ethylene glycol.

[0111] Polyethylene glycol diacrylate is a long-chain hydrophilic crosslinked monomer.

[0112] Polyvinyl alcohol (PVA) is a water-soluble synthetic polymer prepared by the hydrolysis of polyvinyl acetate.

[0113] Polydimethylsiloxane (PDMS) is a non-toxic dimethylsilicone-based organic polymer belonging to the group of high-molecular-weight organosilicon compounds known as silicones.

[0114] Xanthan gum is a substance produced by bacterial fermentation or synthesis and used in food as a gelling agent and thickener. Xanthan gum is a polysaccharide composed of glucose, mannose, and glucuronic acid.

[0115] Methylcellulose and hydroxymethylcellulose are cellulose esters obtained from cellulosic raw materials such as natural wood and cotton linters. They are commonly used as thickeners and emulsifiers in various foods and cosmetics. Water-soluble methylcellulose is obtained by treatment with sodium hydroxide, methyl chloride, and / or propylene oxide.

[0116] Guar gum is extracted from guar beans and is a thickening and stabilizing agent commonly used in the food industry.

[0117] Pluronic F-127 is a nonionic copolymer surfactant composed of ethylene oxide and polypropylene oxide, which are amphiphilic copolymers.

[0118] Kappa-carrageenan is a naturally occurring linear sulfated polysaccharide, part of the carrageenan family, extracted from certain red algae. Kappa-carrageenan is commonly used as a stabilizer, thickener, and gelling agent.

[0119] Cyclodextrins are a group of cyclic oligosaccharides. A cyclodextrin is a macrocyclic ring in which glucose subunits are linked by α-1,4 glycosidic bonds. Cyclodextrins may also be produced from starch by enzymatic conversion. Like amylose (a fragment of starch), a cyclodextrin consists of five or more α-D-glucopyranoside units linked in a 1->4 chain.

[0120] Polyvinylamines are polymers typically produced by the polymerization of N-vinylformamide. Polyvinylamines have repeating vinylamine monomers.

[0121] In some embodiments, the two-phase injectable electrode described herein may further comprise clay, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polydimethylsiloxane (PDMS), xanthan gum, (3-glycidyloxypropyl)trimethoxysilane, ethylene glycol, dodecylbenzenesulfonic acid, cyclodextrin, and / or polyvinylamine.

[0122] In one embodiment, the two-phase injectable electrode described herein may additionally include clay.

[0123] In one embodiment, the two-phase injectable electrode described herein may further include polyethylene glycol (PEG).

[0124] In one embodiment, the two-phase injectable electrode described herein may further comprise poly(ethylene glycol) methacrylate.

[0125] In some embodiments, the two-phase injectable electrode described herein may further comprise polyethylene glycol diacrylate.

[0126] In one embodiment, the two-phase injectable electrode described herein may further include polyvinyl alcohol (PVA).

[0127] In one embodiment, the two-phase injectable electrode described herein may further comprise polydimethylsiloxane (PDMS).

[0128] In some embodiments, the two-phase injectable electrode described herein may further include xanthan gum.

[0129] In one embodiment, the two-phase injectable electrode described herein may further comprise (3-glycidyloxypropyl)trimethoxysilane.

[0130] In some embodiments, the two-phase injectable electrode described herein may additionally include ethylene glycol.

[0131] In some embodiments, the two-phase implantable electrode described herein may additionally include dodecylbenzenesulfonic acid.

[0132] In some embodiments, the two-phase injectable electrode described herein may additionally include methylcellulose.

[0133] In one embodiment, the two-phase injectable electrode described herein may further comprise hydroxymethylcellulose.

[0134] In one embodiment, the two-phase injectable electrode described herein may further comprise methylcellulose and hydroxymethylcellulose.

[0135] In one embodiment, the two-phase injectable electrode described herein may further include guar gum.

[0136] In one embodiment, the two-phase injectable electrode described herein may additionally include a Pluronic F-127.

[0137] In some embodiments, the two-phase injectable electrode described herein may additionally include phosphate-buffered saline.

[0138] In some embodiments, the two-phase injectable electrode described herein may further comprise kappa-carrageenan.

[0139] In one embodiment, the two-phase injectable electrode described herein may further include cyclodextrin.

[0140] In one embodiment, the two-phase injectable electrode described herein may further comprise a polyvinylamine.

[0141] In one embodiment, the solid particles have poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid and polyvinyl alcohol (PVA), (3-glycidyloxypropyl)trimethoxysilane and / or ethylene glycol.

[0142] In one embodiment, the transporter phase further comprises clay, polyethylene glycol (PEG), poly(ethylene glycol) methacrylate, poly(ethylene glycol) diacrylate, polyvinyl alcohol (PVA), polydimethylsiloxane (PDMS), xanthan gum, (3-glycidyloxypropyl)trimethoxysilane, ethylene glycol, dodecylbenzenesulfonic acid, methylcellulose, hydroxymethylcellulose, guar gum, Pluronic F-127, poly(N-isopropylacrylamide) (PNIPAAM), kappa-carrageenan, cyclodextrin, phosphate-buffered saline (PBS), and / or polyvinylamine.

[0143] In one embodiment, the transporter phase comprises poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid and clay, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polydimethylsiloxane (PDMS), xanthan gum, (3-glycidyloxypropyl)trimethoxysilane and / or ethylene glycol.

[0144] In one embodiment, the transporter phase comprises poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid and polyvinyl alcohol (PVA), (3-glycidyloxypropyl)trimethoxysilane and / or ethylene glycol.

[0145] In some embodiments, the transporter phase described herein may further include clay, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polydimethylsiloxane (PDMS), xanthan gum, (3-glycidyloxypropyl)trimethoxysilane, ethylene glycol, dodecylbenzenesulfonic acid, cyclodextrin, and / or polyvinylamine.

[0146] In some embodiments, the transporter phase described herein may additionally include clay.

[0147] In some embodiments, the transporter phase described herein may additionally include polyethylene glycol (PEG).

[0148] In some embodiments, the transporter phase described herein may additionally include poly(ethylene glycol) methacrylate.

[0149] In some embodiments, the transporter phase described herein may additionally include polyethylene glycol diacrylate.

[0150] In some embodiments, the transporter phase described herein may additionally include polyvinyl alcohol (PVA).

[0151] In some embodiments, the transporter phase described herein may additionally include polydimethylsiloxane (PDMS).

[0152] In some embodiments, the transporter phase described herein may additionally include xanthan gum.

[0153] In some embodiments, the transporter phase described herein may additionally include (3-glycidyloxypropyl)trimethoxysilane.

[0154] In some embodiments, the transporter phase described herein may additionally include ethylene glycol.

[0155] In some embodiments, the transporter phase described herein may additionally include dodecylbenzenesulfonic acid.

[0156] In some embodiments, the transporter phase described herein may additionally include methylcellulose.

[0157] In some embodiments, the transporter phase described herein may additionally contain 5-10% w / v methylcellulose.

[0158] In some embodiments, the transporter phase described herein may additionally contain 7-9% w / v methylcellulose.

[0159] In one embodiment, the transporter phase described herein may additionally contain about 8% w / v methylcellulose.

[0160] In some embodiments, the transporter phase described herein may additionally contain 8% w / v methylcellulose.

[0161] In some embodiments, the transporter phase described herein may additionally include hydroxymethylcellulose.

[0162] In some embodiments, the transporter phase described herein may further include methylcellulose and hydroxymethylcellulose.

[0163] In some embodiments, the transporter phase described herein may additionally include guar gum.

[0164] In some embodiments, the transporter phase described herein may additionally include a Pluronic F-127.

[0165] In some embodiments, the transporter phase described herein may additionally include phosphate-buffered saline.

[0166] In some embodiments, the transporter phase described herein may additionally include 0.5-5% v / v phosphate-buffered saline.

[0167] In some embodiments, the transporter phase described herein may additionally include 0.5-3% v / v phosphate-buffered saline.

[0168] In some embodiments, the transporter phase described herein may additionally include about 1% v / v phosphate-buffered saline.

[0169] In some embodiments, the transporter phase described herein may additionally include 1% v / v phosphate-buffered saline.

[0170] In some embodiments, the transporter phase described herein may additionally include kappa-carrageenan.

[0171] In some embodiments, the transporter phase described herein may additionally include cyclodextrin.

[0172] In some embodiments, the transporter phase described herein may additionally include a polyvinylamine.

[0173] In one embodiment, the transporter phase described herein comprises methylcellulose, poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid, phosphate-buffered saline, and water.

[0174] In one embodiment, the transporter phase described herein essentially consists of methylcellulose, poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid, phosphate-buffered saline, and water.

[0175] In one embodiment, the transporter phase described herein comprises methylcellulose, poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid, phosphate-buffered saline, and water.

[0176] In one embodiment, the transporter phase described herein is 65-85% v / v, 10% w / v methylcellulose, 10-20% v / v, 1% w / v poly(3,4-ethylenedioxythiophene) polystyrene sulfonic acid, and It contains 5-15% v / v, 10x phosphate-buffered saline.

[0177] "65-85% v / v, 10% w / v methylcellulose" means that the transporter phase contains 65-85% v / v of a 10% w / v aqueous solution of methylcellulose. "10-20% v / v, 1% w / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid" means that the transporter phase contains 10-20% v / v of a 1% w / v aqueous solution of poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid. 10x phosphate-buffered saline is a standard isotonic solution having, for example, 1.37 M NaCl, 27 mM KCl, 100 mM Na2HPO4, and 18 mM KH2PO4.

[0178] In one embodiment, the transporter phase described herein is Approximately 75% v / v, 10% w / v methylcellulose, Approximately 15% v / v, 1% w / v poly(3,4-ethylenedioxythiophene) polystyrene sulfonic acid, and It contains approximately 10% v / v, 10x phosphate-buffered saline.

[0179] In one embodiment, the transporter phase described herein is 75% v / v, 10% w / v methylcellulose, 15% v / v, 1% w / v poly(3,4-ethylenedioxythiophene) polystyrene sulfonic acid, and It contains 10% v / v, 10x phosphate-buffered saline.

[0180] [soft] In some embodiments, the two-phase injectable electrode described herein may be a soft two-phase injectable electrode. In some embodiments, when the two-phase injectable electrode described herein is used in the brain, it may be soft and have an elastic modulus similar to that of brain tissue. Ensuring that the two-phase injectable electrode does not have significantly higher rigidity than brain tissue, as described herein, improves its ability to dynamically respond to tissue expansion (maintain contact with the cavity wall).

[0181] In one embodiment, the storage modulus of the two-phase injectable electrode described herein is <5 kPa at a vibrational strain of 0.1% when evaluated by vibrational rheometry at a temperature of 37°C and a frequency of 1 Hz.

[0182] In one embodiment, the storage modulus of the two-phase injectable electrode described herein is <4 kPa at a vibrational strain of 0.1% when evaluated by vibrational rheometry at a temperature of 37°C and a frequency of 1 Hz.

[0183] In one embodiment, the storage modulus of the two-phase injectable electrode described herein is <3 kPa at a vibrational strain of 0.1% when evaluated by vibrational rheometry at a temperature of 37°C and a frequency of 1 Hz.

[0184] In one embodiment, the storage modulus of the two-phase injectable electrode described herein is <2 kPa at a vibrational strain of 0.1% when evaluated by vibrational rheometry at a temperature of 37°C and a frequency of 1 Hz.

[0185] In one embodiment, the storage modulus of the two-phase injectable electrode described herein is 0.1–2 kPa at a vibrational strain of 0.1%, when the vibrational rheometry is evaluated at a temperature of 37°C and a frequency of 1 Hz.

[0186] [High-level charge injection] In one embodiment, the two-phase implantable electrode described herein has a material that can supply a high level of capacitive charge injection without inducing a Faraday reaction.

[0187] Capacitive charge injection occurs under an applied voltage at all material-electrolyte interfaces, but to prevent the Faraday reaction, it is necessary to ensure that the applied voltage is below the activation voltage of the most reactive Faraday process in the system. Hydrolysis of water to hydrogen and oxygen occurs at an applied potential of approximately ±1.1V, and since all biological tissues are water-based, this represents the maximum potential that can be applied under the capacitive charge injection method used in implantable medical devices. Therefore, electrotherapy implants need to be able to safely apply the highest possible voltage under the capacitive charge injection method.

[0188] In one embodiment, the two-phase injectable electrode described herein can supply ±1V to human tissue under a capacitive charge transfer method without inducing a Faraday reaction.

[0189] [Low electrical impedance] In one embodiment, the two-phase injectable electrode described herein has a material with low electrical impedance. This ensures efficient charge transfer from the two-phase injectable electrode to the tissue without causing excessive heating (which can damage the tissue).

[0190] In one embodiment, the two-phase injectable electrode described herein has an interfacial electrical impedance of less than 200 Ω when measured by electrochemical impedance spectroscopy at 1000 Hz.

[0191] In one embodiment, the two-phase implantable electrode described herein has an interfacial electrical impedance of less than 250 Ω when measured by electrochemical impedance spectroscopy at 1000 Hz.

[0192] In one embodiment, the two-phase implantable electrode described herein has an interfacial electrical impedance of less than 300 Ω when measured by electrochemical impedance spectroscopy at 1000 Hz.

[0193] In one embodiment, the two-phase implantable electrode described herein has an interfacial electrical impedance of less than 350 Ω when measured by electrochemical impedance spectroscopy at 1000 Hz.

[0194] In one embodiment, the two-phase implantable electrode described herein has an interfacial electrical impedance of approximately 350 Ω when measured by electrochemical impedance spectroscopy at 1000 Hz.

[0195] [Biocompatibility] In some embodiments, the two-phase injectable electrode described herein comprises a biocompatible material. The biocompatible material is important to avoid adverse biological reactions at acute or chronic stages after implantation.

[0196] [Use in electrotherapy] In some embodiments, the charge supplied to the two-phase injectable electrode described herein is supplied from a charge supply device, which may be a stimulator / battery pack. In some embodiments, the charge supply device may be surgically implanted. In some embodiments, the charge supply device may be surgically implanted in a thoracic cavity. Suitable charge supply devices include, for example, implantable pulse generators (IPGs) used in deep brain stimulation for tremor relief in Parkinson's disease.

[0197] In one embodiment, a probe is inserted in situ into the center of the two-phase injectable electrode described herein to facilitate connection with the remaining electronic equipment and to complete the circuit. The probe supplies charge to the two-phase injectable electrode under DC conditions. Under AC conditions, the probe performs both charge supply and charge reception from the two-phase injectable electrode. The probe may consist of an insulating rod having an exposed conductive area that may contact the two-phase injectable electrode described herein. The exposed conductive area may be made from platinum, platinum alloy, platinum wire, iridium oxide, platinum-iridium alloy, carbon, graphene, conductive polymer, and / or conductive composite material. The probe may be connected to the charge supply device by an electrical cable. In one embodiment, the electrical cable may be embedded subcutaneously.

[0198] In some embodiments, one or more counter electrodes may be implanted in the tissue surrounding the tumor resection cavity. These complete an electrical circuit and collect the current injected from the two-phase injectable electrode under DC conditions. Under AC conditions, the counter electrodes receive charge from the two-phase injectable electrode and supply charge to the two-phase injectable electrode. The two-phase injectable electrode and the counter electrodes work together. In some embodiments, there may be one counter electrode. In some embodiments, there may be two counter electrodes. In some embodiments, there may be three counter electrodes. In some embodiments, there may be four counter electrodes. In some embodiments, the counter electrodes may be platinum, platinum alloy, platinum wire, iridium oxide, platinum-iridium alloy, carbon, graphene, conductive polymer and / or conductive composite material. In some embodiments, the counter electrode may be platinum. In some embodiments, the counter electrode may be a platinum alloy. In some embodiments, the counter electrode may be a platinum wire. In some embodiments, the counter electrode may be iridium oxide. In some embodiments, the counter electrode may be a platinum-iridium alloy. In some embodiments, the counter electrode may be carbon. In some embodiments, the counter electrode may be graphene. In one embodiment, the counter electrode may have a conductive polymer. In another embodiment, the counter electrode may have a conductive composite material.

[0199] In one embodiment, a device for use in electrotherapy is provided, having a two-phase injectable electrode, counter electrode, probe, and charge supply device as described herein. Figure 1 shows one possible configuration for use in the brain.

[0200] A possible surgical protocol utilizing a biphasic injectable electrode in the treatment of brain tumors after surgical resection may consist of the following steps: 1. Make an incision in the scalp and fold over the skin flap. 2. Open the skull window. 3. The dura mater is incised and the tumor is removed. 4. Inject the two-phase injectable electrode described herein to fill the excised cavity. 5. Suture the dura mater to close it. 6. Fit an appropriate prosthesis to cover the cranial window. 7. Insert the center probe into the two-phase injection electrode. 8. Embed the opposite pole. 9. Connect the probe and the counter electrode to the main lead. 10. Return the skin flap to its original position and suture it closed.

[0201] [process] Solid particles for two-phase injectable electrodes may be produced by mixing PEDOT:PSS with DMSO and optionally adding synthetic polymers (e.g., PVA, PEG, xanthan gum, and / or laponite) and / or stabilizers (e.g., ethylene glycol, DBSA, and / or GOPS). The PEDOT:PSS / DMSO / polymer mixture may be cured in a cylindrical mold under heating to form a solid sheet of PEDOT:PSS / DMSO / polymer. Excess DMSO can be removed by a series of washes (distilled water, phosphate-buffered saline (PBS), and ethanol), after which the sheet is punched out using a spherical punch to form particles of the desired size.

[0202] The transporter gel phase of a two-phase injectable electrode may be prepared by mixing PEDOT:PSS with DMSO and optionally adding synthetic polymers (PVA, PEG, xanthan gum, laponite) and / or stabilizers (e.g., ethylene glycol, DBSA, GOPS). Alternatively, the transporter phase may be prepared by mixing a solution of PEDOT:PSS with a solution of additional components such as methylcellulose and / or phosphate-buffered saline. This solution may be heated with periodic stirring until a gel-like consistency / viscosity is achieved. Any excess DMSO may be removed from the gel by dialysis using a dialysis membrane with a series of washes with distilled water, PBS, and ethanol. After dialysis, synthetic polymers may be added to the gel with heating to improve gel stability and viscosity.

[0203] The solid particles and the transporter phase are mixed to form a two-phase injection electrode.

[0204] [use] In one embodiment, a two-phase injectable electrode for use in electrotherapy is provided, as described herein. Electrotherapy is the use of electrical energy as a therapeutic agent.

[0205] In one embodiment, a two-phase injectable electrode is provided for therapeutic use, having a plurality of solid particles and a transporter phase. Both the solid particles and the transporter phase have poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0206] In one embodiment, a two-phase injectable electrode for use in electrotherapy is provided, having a plurality of solid particles and a transporter phase. Both the solid particles and the transporter phase have poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0207] In one embodiment, a biphase injectable electrode is provided, as described herein, for use in the treatment of solid tumors, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, retinal implants for vision restoration, regeneration of nerve tissue including the brain, spinal cord, and peripheral nerves, brain / spinal cord / peripheral nerve interfacing, wound healing, treatment of infections (antibacterial / antiviral / antifungal), or augmentation of drug delivery / gene therapy.

[0208] In one embodiment, a two-phase injectable electrode is provided for use in the following electrotherapy treatments, as described herein. Brain tumors (grade I, II, III or IV glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, oligodendroglioma, oligodendroglioma NOS, anaplastic astrocytoma, undifferentiated oligodendroglioma) tumor, anaplastic oligodendroglioma NOS, glioblastoma, giant cell glioblastoma, glioblastoma multiforme, subependymal giant cell astrocytoma, pyromyxoid astrocytoma, pleomorphic xanthoastrocytoma, glioma, oligoastrocytoma, meningioma (gray This includes I, II, or III meningiomas and other neoplasms associated with the meninges (e.g., perivascular cell tumors), pediatric brain tumors (including ependymoma, medulloblastoma, atypical teratomas / rhabdoid tumors (AT / RT), choroid plexus papillomas, choroid plexus carcinomas, intracranial teratomas, and embryonic tumors (ETMRs) with multilayer rosettes), pineal gland tumors (e.g., pineoblastomas), and pituitary gland tumors (e.g., pituitary adenomas, craniopharyngiomas, and chordomas). • Metastases originating from any type of cancer (e.g., brain metastases including those from lung cancer, breast cancer, genitourinary cancer, osteosarcoma, and melanoma) • Lung cancer (including mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, and small cell lung cancer) • Pancreatic cancer (e.g., locally advanced pancreatic adenocarcinoma) • Ovarian cancer (e.g., ovarian cancer resistant to chemotherapy) • Liver cancer (e.g., advanced hepatocellular carcinoma) • Breast cancer • Cervical cancer • Colorectal cancer • Stomach cancer (including gastric adenocarcinoma) • Spinal nerve sheath tumors (including schwannomas, neurofibromas, and gangliomas) Malignant melanoma • Renal adenocarcinoma, and • Transitional cell carcinoma of the urinary tract

[0209] In one embodiment, a two-phase injectable electrode is provided for use in the following electrotherapy treatments, as described herein. • Brain metastases, and • Diffuse median glioma

[0210] In one embodiment, a two-phase injectable electrode for use in electrotherapy treatment of solid tumors is provided, as described herein.

[0211] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade I, II, III, or IV gliomas, as described herein.

[0212] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade I glioma, as described herein.

[0213] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of pilocytic astrocytoma, as described herein.

[0214] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade II glioma, as described herein.

[0215] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of diffuse astrocytoma or oligodendroglioma, as described herein.

[0216] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade III glioma, as described herein.

[0217] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of undifferentiated astrocytoma or undifferentiated oligodendroglioma, as described herein.

[0218] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade IV glioma, as described herein.

[0219] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of diffuse median glioma, as described herein.

[0220] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of brain metastases, as described herein.

[0221] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of giant cell glioblastoma or glioblastoma multiforme, as described herein.

[0222] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of glioblastoma polymorphism, as described herein.

[0223] In one embodiment, as described herein, a biphase injectable electrode is provided for use in the treatment of solid tumors after surgical resection, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, retinal implantation for vision restoration, regeneration of nerve tissue including the brain, spinal cord, and peripheral nerves, brain / spinal cord / peripheral nerve interfacing, wound healing, treatment of infections (antibacterial / antiviral / antifungal), or augmentation of drug delivery / gene therapy.

[0224] In one embodiment, a two-phase injectable electrode is provided for use in the following electrotherapy treatments after surgical resection, as described herein. Brain tumors (grade I, II, III or IV glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, oligodendroglioma, oligodendroglioma NOS, anaplastic astrocytoma, undifferentiated oligodendroglioma) tumor, anaplastic oligodendroglioma NOS, glioblastoma, giant cell glioblastoma, glioblastoma multiforme, subependymal giant cell astrocytoma, pyromyxoid astrocytoma, pleomorphic xanthoastrocytoma, glioma, oligoastrocytoma, meningioma (gray This includes I, II, or III meningiomas and other neoplasms associated with the meninges (e.g., perivascular cell tumors), pediatric brain tumors (including ependymoma, medulloblastoma, atypical teratomas / rhabdoid tumors (AT / RT), choroid plexus papillomas, choroid plexus carcinomas, intracranial teratomas, and embryonic tumors (ETMRs) with multilayer rosettes), pineal gland tumors (e.g., pineoblastomas), and pituitary gland tumors (e.g., pituitary adenomas, craniopharyngiomas, and chordomas). • Metastases originating from any type of cancer (e.g., brain metastases including those from lung cancer, breast cancer, genitourinary cancer, osteosarcoma, and melanoma) • Lung cancer (including mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, and small cell lung cancer) • Pancreatic cancer (e.g., locally advanced pancreatic adenocarcinoma) • Ovarian cancer (e.g., ovarian cancer resistant to chemotherapy) • Liver cancer (e.g., advanced hepatocellular carcinoma) • Breast cancer • Cervical cancer • Colorectal cancer • Stomach cancer (including gastric adenocarcinoma) • Spinal nerve sheath tumors (including schwannomas, neurofibromas, and gangliomas) Malignant melanoma • Renal adenocarcinoma, and • Transitional cell carcinoma of the urinary tract

[0225] In one embodiment, a two-phase injectable electrode is provided for use in the following electrotherapy treatments after surgical resection, as described herein. • Brain metastases, and • Diffuse median glioma

[0226] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of a solid tumor after surgical resection, as described herein.

[0227] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade I, II, III, or IV gliomas after surgical resection, as described herein.

[0228] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade I glioma after surgical resection, as described herein.

[0229] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of pilocytic astrocytoma after surgical excision, as described herein.

[0230] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade II glioma after surgical resection, as described herein.

[0231] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of diffuse astrocytoma or oligodendroglioma after surgical excision, as described herein.

[0232] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade III glioma after surgical resection, as described herein.

[0233] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of undifferentiated astrocytoma or undifferentiated oligodendroglioma after surgical resection, as described herein.

[0234] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of grade IV glioma after surgical resection, as described herein.

[0235] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of diffuse median glioma after surgical resection, as described herein.

[0236] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of brain metastases after surgical resection, as described herein.

[0237] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of giant cell glioblastoma or glioblastoma multiforme after surgical resection, as described herein.

[0238] In one embodiment, a two-phase injectable electrode is provided for use in electrotherapy treatment of glioblastoma multiforme after surgical resection, as described herein.

[0239] As used herein, the terms “treatment” and “to treat” mean restoring, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more of its symptoms. In some embodiments, treatment may be performed after the onset of one or more symptoms. In other embodiments, treatment may be performed even in the absence of symptoms. For example, treatment may be performed on individuals who are highly susceptible before the onset of symptoms (e.g., by reference to a history of symptoms and / or by reference to genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided to prevent or delay relapse. Treatment may be performed for relapsing diseases, such as relapsing GBM, or for transformative diseases in which gliomas that were previously of a lower grade (e.g., grade II) become of a higher grade (e.g., grade III or IV), or to prevent transformative diseases.

[0240] [Treatment method] In one embodiment, a two-phase injectable electrode is provided for use in a therapeutic method of treating the body of a human or animal, as described herein.

[0241] In one embodiment, a method for electrotherapy in a warm-blooded animal such as a human is provided. The method comprises administering a two-phase injectable electrode described herein to the animal.

[0242] In one embodiment, a method is provided for treating solid tumors, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, retinal implantation for vision restoration, regeneration of nerve tissue including the brain, spinal cord, and peripheral nerves, brain / spinal cord / peripheral nerve interface formation, wound healing, treatment of infections (antibacterial / antiviral / antifungal), or augmentation of drug delivery / gene therapy in a warm-blooded animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0243] In one embodiment, a method is provided for treating the following in a homeothermic animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein. Brain tumors (grade I, II, III or IV glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, oligodendroglioma, oligodendroglioma NOS, anaplastic astrocytoma, undifferentiated oligodendroglioma) tumor, anaplastic oligodendroglioma NOS, glioblastoma, giant cell glioblastoma, glioblastoma multiforme, subependymal giant cell astrocytoma, pyromyxoid astrocytoma, pleomorphic xanthoastrocytoma, glioma, oligoastrocytoma, meningioma (gray This includes I, II, or III meningiomas and other neoplasms associated with the meninges (e.g., perivascular cell tumors), pediatric brain tumors (including ependymoma, medulloblastoma, atypical teratomas / rhabdoid tumors (AT / RT), choroid plexus papillomas, choroid plexus carcinomas, intracranial teratomas, and embryonic tumors (ETMRs) with multilayer rosettes), pineal gland tumors (e.g., pineoblastomas), and pituitary gland tumors (e.g., pituitary adenomas, craniopharyngiomas, and chordomas). • Metastases originating from any type of cancer (e.g., brain metastases including those from lung cancer, breast cancer, genitourinary cancer, osteosarcoma, and melanoma) • Lung cancer (including mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, and small cell lung cancer) • Pancreatic cancer (e.g., locally advanced pancreatic adenocarcinoma) • Ovarian cancer (e.g., ovarian cancer resistant to chemotherapy) • Liver cancer (e.g., advanced hepatocellular carcinoma) • Breast cancer • Cervical cancer • Colorectal cancer • Stomach cancer (including gastric adenocarcinoma) • Spinal nerve sheath tumors (including schwannomas, neurofibromas, and gangliomas) Malignant melanoma • Renal adenocarcinoma, and • Transitional cell carcinoma of the urinary tract

[0244] In one embodiment, a method is provided for treating the following in a homeothermic animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein. • Brain metastases, and • Diffuse median glioma

[0245] In one embodiment, a method for treating solid tumors in a warm-blooded animal such as a human is provided, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0246] In one embodiment, a method is provided for treating grade I, II, III, or IV gliomas in a homeothermic animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0247] In one embodiment, a method for treating grade I glioma in a warm-blooded animal such as a human is provided, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0248] In one embodiment, a method is provided for treating pilocytic astrocytoma in a homeothermic animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0249] In one embodiment, a method for treating grade II glioma in a warm-blooded animal such as a human is provided, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0250] In one embodiment, a method is provided for treating astrocytoma or oligodendroglioma in a warm-blooded animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0251] In one embodiment, a method for treating grade III glioma in a warm-blooded animal such as a human is provided, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0252] In one embodiment, a method is provided for treating undifferentiated astrocytoma or undifferentiated oligodendroglioma in a warm-blooded animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0253] In one embodiment, a method is provided for treating grade IV glioma in a warm-blooded animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0254] In one embodiment, a method is provided for treating diffuse median glioma in a warm-blooded animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0255] In one embodiment, a method for treating brain metastases in a warm-blooded animal such as a human is provided, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0256] In one embodiment, a method is provided for treating giant cell glioblastoma or glioblastoma multiforme in a warm-blooded animal such as a human, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0257] In one embodiment, a method is provided for treating solid tumors after surgical resection in homeothermic animals such as humans, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, retinal implantation for vision restoration, regeneration of nerve tissue including the brain, spinal cord, and peripheral nerves, brain / spinal cord / peripheral nerve interfacing, wound healing, treatment of infections (antibacterial / antiviral / antifungal), or augmentation of drug delivery / gene therapy, the method comprising providing electrotherapy to an animal having a biphase injectable electrode as described herein.

[0258] In one embodiment, a method for treating glioblastoma multiforme in a warm-blooded animal such as a human is provided, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0259] In one embodiment, a method is provided for treating the following in a homeothermic animal such as a human after surgical excision, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein. Brain tumors (grade I, II, III or IV glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, oligodendroglioma, oligodendroglioma NOS, anaplastic astrocytoma, undifferentiated oligodendroglioma) tumor, anaplastic oligodendroglioma NOS, glioblastoma, giant cell glioblastoma, glioblastoma multiforme, subependymal giant cell astrocytoma, pyromyxoid astrocytoma, pleomorphic xanthoastrocytoma, glioma, oligoastrocytoma, meningioma (gray This includes I, II, or III meningiomas and other neoplasms associated with the meninges (e.g., perivascular cell tumors), pediatric brain tumors (including ependymoma, medulloblastoma, atypical teratomas / rhabdoid tumors (AT / RT), choroid plexus papillomas, choroid plexus carcinomas, intracranial teratomas, and embryonic tumors (ETMRs) with multilayer rosettes), pineal gland tumors (e.g., pineoblastomas), and pituitary gland tumors (e.g., pituitary adenomas, craniopharyngiomas, and chordomas). • Metastases originating from any type of cancer (e.g., brain metastases including those from lung cancer, breast cancer, genitourinary cancer, osteosarcoma, and melanoma) • Lung cancer (including mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, and small cell lung cancer) · Pancreatic cancer (e.g., locally advanced pancreatic cancer) · Ovarian cancer (e.g., ovarian cancer resistant to chemotherapy) · Liver cancer (e.g., advanced hepatocellular carcinoma) · Breast cancer · Cervical cancer · Colorectal cancer · Gastric cancer (including gastric adenocarcinoma) · Spinal schwannoma (including neurilemmoma, neurofibroma, and ganglioneuroma) · Malignant melanoma · Adrenal gland cancer, and · Urinary tract transitional epithelial cancer

[0260] In certain embodiments, a method of treating the following in a warm-blooded animal such as a human after surgical resection is provided, the method comprising providing electrotherapy to an animal having the biphasic injectable electrode described herein. · Brain metastasis, and · Diffuse midline glioma

[0261] In certain embodiments, a method of treating a solid tumor in a warm-blooded animal such as a human after surgical resection is provided, the method comprising providing electrotherapy to an animal having the biphasic injectable electrode described herein.

[0262] In certain embodiments, a method of treating grade I, II, III or IV glioma in a warm-blooded animal such as a human after surgical resection is provided, the method comprising providing electrotherapy to an animal having the biphasic injectable electrode described herein.

[0263] In certain embodiments, a method of treating grade I glioma in a warm-blooded animal such as a human after surgical resection is provided, the method comprising providing electrotherapy to an animal having the biphasic injectable electrode described herein.

[0264] In certain embodiments, a method of treating pilocytic astrocytoma in a warm-blooded animal such as a human after surgical resection is provided, the method comprising providing electrotherapy to an animal having the biphasic injectable electrode described herein.

[0265] In certain embodiments, a method for treating grade II gliomas after surgical resection in warm-blooded animals such as humans is provided, the method comprising providing electrotherapy to an animal having a biphasic injectable electrode as described herein.

[0266] In certain embodiments, a method for treating diffuse astrocytomas or oligodendrogliomas after surgical resection in warm-blooded animals such as humans is provided, the method comprising providing electrotherapy to an animal having a biphasic injectable electrode as described herein.

[0267] In certain embodiments, a method for treating grade III gliomas after surgical resection in warm-blooded animals such as humans is provided, the method comprising providing electrotherapy to an animal having a biphasic injectable electrode as described herein.

[0268] In certain embodiments, a method for treating undifferentiated astrocytomas or undifferentiated oligodendrogliomas after surgical resection in warm-blooded animals such as humans is provided, the method comprising providing electrotherapy to an animal having a biphasic injectable electrode as described herein.

[0269] In certain embodiments, a method for treating grade IV gliomas after surgical resection in warm-blooded animals such as humans is provided, the method comprising providing electrotherapy to an animal having a biphasic injectable electrode as described herein.

[0270] In certain embodiments, a method for treating diffuse midline gliomas after surgical resection in warm-blooded animals such as humans is provided, the method comprising providing electrotherapy to an animal having a biphasic injectable electrode as described herein.

[0271] In certain embodiments, a method for treating brain metastases after surgical resection in warm-blooded animals such as humans is provided, the method comprising providing electrotherapy to an animal having a biphasic injectable electrode as described herein.

[0272] In one embodiment, a method is provided for treating giant cell glioblastoma or glioblastoma multiforme in a warm-blooded animal such as a human after surgical resection, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0273] In one embodiment, a method is provided for treating glioblastoma multiforme in a warm-blooded animal such as a human after surgical resection, the method comprising providing electrotherapy to an animal having a two-phase injectable electrode as described herein.

[0274] [Multi-electrode electrotherapy] In one embodiment, a form of electrotherapy is provided having multiple cooperative electrodes embedded in soft tissue. These cooperative electrodes conduct current in one direction under DC conditions and in both directions under AC conditions. This is called "multi-electrode electrotherapy."

[0275] For example, by using multiple cooperating implanted electrodes along the circumference or periphery of the tumor or tumor resection margin, it is possible to reduce the maximum distance between any point in the 3D space within the tumor or resection margin and the nearest implanted electrode. As a result, the minimum electric field strength within the total volume of the tumor or resection margin increases. Consequently, the input voltage and energy demand required to generate a clinically effective electric field are reduced, resulting in advantages in battery life and the overall size of the stimulator. As a result, it becomes possible to fully implant the charge supply device, potentially benefiting the patient's quality of life without affecting the therapeutic effect.

[0276] In one embodiment, multi-electrode electrotherapy can be provided by implanting multiple electrodes.

[0277] In one embodiment, multi-electrode electrotherapy can be provided by implanting / injecting multiple electrodes.

[0278] In some embodiments, multi-electrode electrotherapy has two electrodes. In some embodiments, multi-electrode electrotherapy has three electrodes. In some embodiments, multi-electrode electrotherapy has four electrodes. In some embodiments, multi-electrode electrotherapy has five electrodes. In some embodiments, multi-electrode electrotherapy has six electrodes. In some embodiments, multi-electrode electrotherapy has at least two electrodes. In some embodiments, multi-electrode electrotherapy has at least three electrodes. In some embodiments, multi-electrode electrotherapy has at least four electrodes. In some embodiments, multi-electrode electrotherapy has at least five electrodes. In some embodiments, multi-electrode electrotherapy has at least six electrodes.

[0279] In some embodiments, multi-electrode electrotherapy has electrodes comprising platinum, platinum alloy, platinum wire, iridium oxide, platinum-iridium alloy, carbon, graphene, conductive polymer, conductive composite, and / or the biphasic injectable electrodes described herein.

[0280] In some embodiments, multi-electrode electrotherapy has electrodes comprising the biphasic injectable electrodes described herein and electrodes comprising platinum, platinum alloy, platinum wire, iridium oxide, platinum-iridium alloy, carbon, graphene, conductive polymer, and / or conductive composite.

[0281] In some embodiments, multi-electrode electrotherapy has electrodes comprising platinum.

[0282] In some embodiments, multi-electrode electrotherapy has electrodes comprising platinum alloy.

[0283] In some embodiments, multi-electrode electrotherapy has electrodes comprising platinum wire.

[0284] In some embodiments, multi-electrode electrotherapy has electrodes comprising iridium oxide.

[0285] In some embodiments, multi-electrode electrotherapy has electrodes comprising platinum-iridium alloy. <\

[0286] In one embodiment, multi-electrode electrotherapy has electrodes that have carbon.

[0287] In one embodiment, multi-electrode electrotherapy has electrodes having graphene.

[0288] In one embodiment, multi-electrode electrotherapy has electrodes having a conductive polymer.

[0289] In one embodiment, multi-electrode electrotherapy has electrodes having a conductive composite material.

[0290] In one embodiment, multi-electrode electrotherapy has two-phase injectable electrodes as described herein.

[0291] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having platinum.

[0292] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having a platinum alloy.

[0293] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having a platinum wire.

[0294] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having iridium oxide.

[0295] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having a platinum-iridium alloy.

[0296] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having carbon.

[0297] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having graphene.

[0298] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode as described herein and an electrode having a conductive polymer.

[0299] In one embodiment, multi-electrode electrotherapy comprises a two-phase injectable electrode and an electrode having a conductive composite material, as described herein.

[0300] In one embodiment, multi-electrode electrotherapy is provided for the treatment of solid tumors, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, retinal implantation for vision restoration, regeneration of nerve tissue including the brain, spinal cord, and peripheral nerves, brain / spinal cord / peripheral nerve interface formation, wound healing, treatment of infections (antibacterial / antiviral / antifungal), or enhancement of drug delivery / gene therapy.

[0301] In one embodiment, multi-electrode electrotherapy is provided for the following treatments. Brain tumors (grade I, II, III or IV glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, oligodendroglioma, oligodendroglioma NOS, anaplastic astrocytoma, undifferentiated oligodendroglioma) tumor, anaplastic oligodendroglioma NOS, glioblastoma, giant cell glioblastoma, glioblastoma multiforme, subependymal giant cell astrocytoma, pyromyxoid astrocytoma, pleomorphic xanthoastrocytoma, glioma, oligoastrocytoma, meningioma (gray This includes I, II, or III meningiomas and other neoplasms associated with the meninges (e.g., perivascular cell tumors), pediatric brain tumors (including ependymoma, medulloblastoma, atypical teratomas / rhabdoid tumors (AT / RT), choroid plexus papillomas, choroid plexus carcinomas, intracranial teratomas, and embryonic tumors (ETMRs) with multilayer rosettes), pineal gland tumors (e.g., pineoblastomas), and pituitary gland tumors (e.g., pituitary adenomas, craniopharyngiomas, and chordomas). • Metastases originating from any type of cancer (e.g., brain metastases including those from lung cancer, breast cancer, genitourinary cancer, osteosarcoma, and melanoma) • Lung cancer (including mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, and small cell lung cancer) • Pancreatic cancer (e.g., locally advanced pancreatic adenocarcinoma) • Ovarian cancer (e.g., ovarian cancer resistant to chemotherapy) • Liver cancer (e.g., advanced hepatocellular carcinoma) • Breast cancer • Cervical cancer • Colorectal cancer • Stomach cancer (including gastric adenocarcinoma) • Spinal nerve sheath tumors (including schwannomas, neurofibromas, and gangliomas) Malignant melanoma • Renal adenocarcinoma, and • Transitional cell carcinoma of the urinary tract

[0302] In one embodiment, multi-electrode electrotherapy is provided for the following treatments. • Brain metastases, and • Diffuse median glioma

[0303] In one embodiment, multi-electrode electrotherapy for the treatment of solid tumors is provided.

[0304] In one embodiment, a multi-electrode electrotherapy is provided for the treatment of grade I, II, III, or IV gliomas.

[0305] In one embodiment, multi-electrode electrotherapy for the treatment of grade I glioma is provided.

[0306] In one embodiment, multi-electrode electrotherapy is provided for the treatment of pilocytic astrocytoma.

[0307] In one embodiment, multi-electrode electrotherapy for the treatment of grade II glioma is provided.

[0308] In one embodiment, a multi-electrode electrotherapy is provided for the treatment of diffuse astrocytoma or oligodendroglioma.

[0309] In one embodiment, multi-electrode electrotherapy for the treatment of grade III glioma is provided.

[0310] In one embodiment, multi-electrode electrotherapy is provided for the treatment of undifferentiated astrocytoma or undifferentiated oligodendroglioma.

[0311] In one embodiment, multi-electrode electrotherapy for the treatment of grade IV glioma is provided.

[0312] In one embodiment, multi-electrode electrotherapy is provided for the treatment of diffuse median glioma.

[0313] In one embodiment, multi-electrode electrotherapy for the treatment of brain metastases is provided.

[0314] In one embodiment, a multi-electrode electrotherapy is provided for the treatment of giant cell glioblastoma or glioblastoma multiforme.

[0315] In one embodiment, multi-electrode electrotherapy for the treatment of glioblastoma multiforme is provided.

[0316] In one embodiment, a method is provided for treating solid tumors in warm-blooded animals such as humans, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, retinal implantation for vision restoration, regeneration of nerve tissue including the brain, spinal cord, and peripheral nerves, brain / spinal cord / peripheral nerve interface formation, wound healing, treatment of infections (antibacterial / antiviral / antifungal), or enhancement of drug delivery / gene therapy, the method comprising providing multi-electrode electrotherapy.

[0317] In one embodiment, a method is provided for treating the following in a warm-blooded animal such as a human, and the method includes providing multi-electrode electrotherapy. Brain tumors (grade I, II, III or IV glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, oligodendroglioma, oligodendroglioma NOS, anaplastic astrocytoma, undifferentiated oligodendroglioma) tumor, anaplastic oligodendroglioma NOS, glioblastoma, giant cell glioblastoma, glioblastoma multiforme, subependymal giant cell astrocytoma, pyromyxoid astrocytoma, pleomorphic xanthoastrocytoma, glioma, oligoastrocytoma, meningioma (gray This includes I, II, or III meningiomas and other neoplasms associated with the meninges (e.g., perivascular cell tumors), pediatric brain tumors (including ependymoma, medulloblastoma, atypical teratomas / rhabdoid tumors (AT / RT), choroid plexus papillomas, choroid plexus carcinomas, intracranial teratomas, and embryonic tumors (ETMRs) with multilayer rosettes), pineal gland tumors (e.g., pineoblastomas), and pituitary gland tumors (e.g., pituitary adenomas, craniopharyngiomas, and chordomas). • Metastases originating from any type of cancer (e.g., brain metastases including those from lung cancer, breast cancer, genitourinary cancer, osteosarcoma, and melanoma) • Lung cancer (including mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, and small cell lung cancer) • Pancreatic cancer (e.g., locally advanced pancreatic adenocarcinoma) • Ovarian cancer (e.g., ovarian cancer resistant to chemotherapy) • Liver cancer (e.g., advanced hepatocellular carcinoma) • Breast cancer • Cervical cancer • Colorectal cancer • Stomach cancer (including gastric adenocarcinoma) • Spinal nerve sheath tumors (including schwannomas, neurofibromas, and gangliomas) Malignant melanoma • Renal adenocarcinoma, and • Transitional cell carcinoma of the urinary tract

[0318] In one embodiment, a method is provided for treating the following in a warm-blooded animal such as a human, and the method includes providing multi-electrode electrotherapy. • Brain metastases, and • Diffuse median glioma

[0319] In one embodiment, a method for treating solid tumors in warm-blooded animals such as humans is provided, and the method includes providing multi-electrode electrotherapy.

[0320] In one embodiment, a method is provided for treating grade I, II, III, or IV gliomas in homeothermic animals such as humans, the method comprising providing multi-electrode electrotherapy.

[0321] In one embodiment, a method for treating grade I glioma in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0322] In one embodiment, a method for treating pilocytic astrocytoma in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0323] In one embodiment, a method for treating grade II glioma in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0324] In one embodiment, a method is provided for treating astrocytoma or oligodendroglioma in a warm-blooded animal such as a human, the method comprising providing multi-electrode electrotherapy.

[0325] In one embodiment, a method for treating grade III glioma in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0326] In one embodiment, a method is provided for treating undifferentiated astrocytoma or undifferentiated oligodendroglioma in a warm-blooded animal such as a human, the method comprising providing multi-electrode electrotherapy.

[0327] In one embodiment, a method for treating grade IV glioma in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0328] In one embodiment, a method for treating diffuse median glioma in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0329] In one embodiment, a method for treating brain metastases in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0330] In one embodiment, a method for treating giant cell glioblastoma or glioblastoma multimorphum in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0331] In one embodiment, a method for treating glioblastoma polymorphism in a warm-blooded animal such as a human is provided, and the method includes providing multi-electrode electrotherapy.

[0332] [combination] In one embodiment, the electrotherapy having a two-phase injectable electrode described herein may be provided in combination with chemotherapy and / or radiotherapy.

[0333] In one embodiment, the electrotherapy having a two-phase injectable electrode described herein may be provided in combination with chemotherapy and radiotherapy.

[0334] In one embodiment, the electrotherapy having a two-phase injectable electrode described herein may be provided in combination with chemotherapy.

[0335] In one embodiment, the electrotherapy having a two-phase injectable electrode described herein may be provided in combination with radiotherapy.

[0336] Where the term “combination” is used herein, it should be understood to mean simultaneous, separate, or sequential delivery. In other aspects of this disclosure, “combination” means simultaneous delivery. In one aspect of this disclosure, “combination” means separate delivery. In other aspects of this disclosure, “combination” means sequential delivery. If the delivery is sequential or separate, delays in the delivery of the second element do not negate the benefits of the combination.

[0337] [kit] In one embodiment, a) A two-phase injectable electrode as described herein, b) Opposite poles, c) Probe and, d) A kit is provided that includes a charge supply device.

[0338] In one embodiment, a) A two-phase injectable electrode as described herein, b) Probe and, c) A kit is provided that includes a charge supply device.

[0339] In one embodiment, a) A two-phase injectable electrode as described herein, b) Opposite poles, c) A kit is provided that includes a charge supply device.

[0340] In one embodiment, a) A two-phase injectable electrode as described herein, b) Opposite poles, c) A kit having a probe is provided.

[0341] In one embodiment, a) A two-phase injectable electrode as described herein, b) A kit having a probe is provided.

[0342] In one embodiment, a) A two-phase injectable electrode as described herein, b) A kit is provided that includes a charge supply device.

[0343] In one embodiment, a) A two-phase injectable electrode as described herein, b) A kit having a counter electrode is provided.

[0344] In one embodiment, a) A two-phase injectable electrode as described herein, b) A kit is provided that includes a charge supply device.

[0345] In one embodiment, a) A two-phase injectable electrode as described herein, b) A kit having a counter electrode is provided.

[0346] In one embodiment, a) A two-phase injectable electrode as described herein, b) A kit having a probe is provided.

[0347] In one embodiment, a) Two or more electrodes, b) A kit is provided that includes a charge supply device.

[0348] In one embodiment, a) Three or more electrodes, b) A kit is provided that includes a charge supply device.

[0349] In one embodiment, a) Four or more electrodes, b) A kit is provided that includes a charge supply device.

[0350] In one embodiment, a) Five or more electrodes, b) A kit is provided that includes a charge supply device. [Brief explanation of the drawing]

[0351] [Figure 1]This is a transmission diagram of the two-phase injectable electrode described herein, used for use in surgical resection cavities of the brain. A charge supply device is also shown. The two-phase injectable electrode (3) is inserted into a surgical resection cavity in the brain with a tumor resection margin (4). A probe (1) is inserted into the electrode, and four counter electrodes (2) are embedded in the surrounding brain tissue. A charge supply device (6) is surgically implanted and supplies charge to the probe via a similarly implanted wire (5). [Figure 2] The results from Experiment 1 show the capacitance and charge injection characteristics of the samples. The potential was applied between +1 and -1V, and the results are shown at a scan speed of 500mVs⁻¹. All of these cyclic voltammograms show smooth curves and indicate capacitive charge injection without a Faraday peak. A capacitive potential window of ±1V is the maximum voltage that can be applied without inducing electrolysis of water, and all samples were able to operate under the capacitive charge transfer scheme within this potential window environment. [Figure 3] The results of Experiment 1, specifically the sample cathode charge storage capacity (CSC), are shown. The results are presented at a scan speed of 500 mVs-1. CSC data for several different samples are shown. Charge storage capacity was calculated from cyclic voltammetry results. The CSC results in this experiment exceeded those of currently clinically used designs (SF Cogan; Neural Stimulation and recording electrodes; Annual Review of Biomedical Engineering; 2008). This means that all samples were able to deliver more charge per voltage input compared to currently clinically used designs. [Figure 4]The results of Experiment 2 show the mechanical properties. The mechanical properties of the samples were measured via vibrational rheometry. The results indicate that the samples are very soft and have a storage modulus in the low kPa range. Some samples fall within the stiffness range of brain tissue itself (0.5–2 kPa), and all measured samples are orders of magnitude softer (lower stiffness) than current clinical electrode materials (usually in the range of several hundred GPa) (e.g., Kostarelos et al.; Graphene in design and engineering of next generation neural interfaces; Advanced Materials; 2017. https: / / doi.org / 10.1002 / adma.201700909). [Figure 5] Experiment 3 demonstrates the biocompatibility of the sample to U251 human astrocyte-like cells through the detection of cell viability. The positive control consisted of healthy cells cultured in a well plate without the sample. The negative control consisted of cells grown in a culture well plate without the sample, but the cells were exposed to 5% dimethyl sulfoxide in the culture medium, which is known to have cytotoxic effects on these cells. Cell viability was similar in the sample and the positive control, demonstrating the biocompatibility of the sample. [Figure 6] Experiment 3 demonstrates the biocompatibility of the sample to U251 human astrocyte-like cells through the detection of cell viability. The positive control consisted of healthy cells cultured in a well plate without the sample. The negative control consisted of cells grown in a culture well plate without the sample, but the cells were exposed to 5% dimethyl sulfoxide in the culture medium, which is known to have cytotoxic effects on these cells. Cell viability was similar in the sample and the positive control, demonstrating the biocompatibility of the sample. [Figure 7]Figure 7 is a schematic diagram of the test cell used to perform three-electrode cyclic voltammetry in Experiment 1. The two-phase injectable electrode sample (1) to be examined is housed in a well within a sample holder (3) made for this purpose from a solid block of polytetrafluoroethylene. The sample (1) functions as the working electrode and is connected to a potentiostat via a conductive base (4) formed from a graphite composite. The electrolyte (2) is pipetted onto the sample, immersing it. The counter electrode (5) is inserted into the electrolyte. The measurement is performed using a non-energized reference electrode (6). [Modes for carrying out the invention]

[0352] [Examples] [Overall treatment] The materials and equipment used in the subsequent examples were purchased from the following suppliers.

[0353] [Table 1]

[0354] A two-phase injectable electrode has two components: a solid particle phase and a transporter phase, where the solid particle is distributed within the transporter phase. Examples 1 and 2 describe the production of the solid particle for a two-phase injectable electrode, while Examples 3 and 4 describe the production of the transporter phase. Example 5 provides a schematic description of combinations of both materials for producing a two-phase injectable electrode.

[0355] [Example 1] PEDOT:PSS Solid Particle Production for Two-Phase Injectable Electrodes 1A) The PEDOT:PSS solution was mixed in a glass vial at room temperature for 5 hours before adding DMSO. After mixing for a set period, the PEDOT:PSS / DMSO suspension was cast into a cylindrical mold with a diameter of 127.76 mm or 5 mm. The samples were left overnight at room temperature or on a hot plate set to 60°C, and then placed in an oven set to 60°C until a solid structure was formed. In some samples, EG, GOPS, and DBSA were added as stabilizers.

[0356] To remove excess DMSO, the solid structures were washed with distilled water, phosphate-buffered saline (PBS), and a range of ethanol concentrations (30, 50, 70, and 100%), and stored in PBS until use. To produce PEDOT:PSS beads, the structures were punched out using a spherical punch of the desired size. Bead sizes ranged from 0.1 mm to 1.5 mm (but were not limited to this).

[0357] [Table 2]

[0358] 1B) To form particles, PEDOT:PSS alone, or PEDOT:PSS with additional stabilizers (EG, GOPS, DBSA) and / or PBS was used. A solution of PEDOT:PSS containing optional additional components was dropped dropwise into liquid nitrogen to form particles. The liquid nitrogen was removed, and the frozen particles were freeze-dried overnight. To anneal, the particles were placed in an oven set to 180°C for 1 hour. Fully formed particles were immersed in PBS for 8–24 hours and stored in PBS until use.

[0359] The bead size is between 0.1 mm and 3 mm (but not limited to this), and depends on the syringe / needle used and the flow rate of the solution.

[0360] [Table 3]

[0361] [Example 2] Fabrication of PEDOT:PSS solid particles for two-phase implantable electrodes with added synthetic polymers 2A) One or more polymers were added directly to the PEDOT:PSS solution and mixed at 60°C for 1 hour, then at room temperature for 4 hours. In some samples, EG, GOPS, and DBSA were added as stabilizers. Subsequently, DMSO was added to the PEDOT:PSS / polymer solution and mixed for a set time. The solution was poured into a cylindrical mold (127.76 mm in diameter) and placed in an oven set to 60°C until the structure was completely cured. After complete curing, the solid structure was left at room temperature for 24 hours. The structure was washed with distilled water, PBS, and a series of ethanol dilutions (30, 50, 70, and 100%) to remove excess DMSO and stored in PBS until use (at room temperature). The structure was then punched out using a spherical punch to obtain beads of 0.1–1 mm in size.

[0362] [Table 4]

[0363] 2B) One or more polymers were added directly to the PEDOT:PSS solution and mixed at 60°C for 1 hour, then at room temperature for 4 hours. In some sample EGs, GOPS and DBSA were added as stabilizers. The solution was dropped into liquid nitrogen to form particles. The liquid nitrogen was removed and the frozen particles were freeze-dried overnight. To anneal, the particles were placed in an oven set to 180°C for 1 hour. Fully formed particles were immersed in PBS for 8–24 hours and stored in PBS until use.

[0364] The bead size is between 0.1 mm and 4 mm (but not limited to this), and depends on the syringe / needle used and the flow rate of the solution.

[0365] [Table 5]

[0366] [Example 3] Fabrication of PEDOT:PSS transporter phase for two-phase injectable electrodes 3A) The PEDOT:PSS solution was mixed at room temperature for 5 hours. In some sample EGs, GOPS and DBSA were added as stabilizers. DMSO was added to the PEDOT:PSS solution and mixed at room temperature for 24 hours. The solution was placed in an oven set to 60°C and mixed periodically until a gel-like viscosity was achieved. The samples were left at room temperature for at least 24 hours.

[0367] To remove excess DMSO, the sample was dialysis. Dialysis involved placing the PEDOT:PSS / polymer / DMSO sample into a dialysis tube. The sample tube was placed in a beaker containing 600 ml of distilled water for 24 hours, then in a beaker containing 600 ml of PBS for 24 hours, followed by a series of ethanol washes (30%, 50%, and 70%, 600 ml each) for 1 hour each, and finally the tube was placed in a beaker containing 600 ml of PBS for 24 hours. After that, the sample was removed from the dialysis tube, and the viscosity of the sample was reduced by PBS immersion.

[0368] [Table 6]

[0369] 3B) In a glass vial, PBS buffer (10x) was vigorously mixed with deionized water for 10 seconds. PEDOT:PSS solution was added and immediately mixed vigorously for at least 10 seconds. The vial containing the sample was sealed and placed in a 90°C oven for a set period of time. The sample was removed from the oven and allowed to cool to room temperature.

[0370] [Table 7]

[0371] [Example 4] Fabrication of a PEDOT:PSS transporter phase for a two-phase injectable electrode with added synthetic polymers 4A) One or more polymers were dissolved in a PEDOT:PSS solution and stirred at 60°C for 1 hour, then stirred at room temperature for 4 hours. In some samples, stabilizers containing EG and GOPS were added to the PEDOT:PSS / polymer solution. DMSO was added to the solution and stirred at room temperature for 24 hours. The solution was then transferred to an oven set to 60°C and stirred periodically until a viscous mixture was formed. The samples were left at room temperature for at least 24 hours.

[0372] Excess DMSO was removed from the sample using dialysis. Dialysis involved loading the sample into a dialysis tube and performing a series of 600 ml washes (24 hours with distilled water, 24 hours with PBS, a series of ethanol washes including 30%, 50%, and 70% for 1 hour each, and 24 hours with PBS). The sample was then transferred from the dialysis tube to a glass vial.

[0373] [Table 8]

[0374] 4B) To prepare the methylcellulose stock, water was added to a glass vial and heated to 90°C while stirring. Methylcellulose was gradually added to the heated water and stirred for 15 minutes after it was completely dispersed. The solution was cooled to room temperature while continuing to stir. The vial was then sealed and placed in an ice bath and left to stand for 1 hour. The vial containing the sample was then placed in a refrigerator (4°C) for 24 hours.

[0375] To prepare the transporter phase, methylcellulose stock was mixed with PBS at room temperature for 1 minute. PEDOT:PSS solution was added and stirred until completely mixed.

[0376] [Table 9]

[0377] [Example 5] Combination of solid particles and transporter phase for the manufacture of two-phase implantable electrodes 5A) A two-phase injectable electrode can be prepared by mixing either of the transporter phases in Example 3A and Example 4A with either of the solid particles in Example 1A and Example 2A. Optionally, to optimize the mechanical properties, one or more polymers may be mixed into the transporter phase and heated in an oven set to 120°C for 20 minutes before adding the solid particles. The solid particles are then added to this mixture.

[0378] [Table 10]

[0379] 5B) A two-phase injection electrode can be prepared by mixing either of the transporter phases in Example 3B and Example 4B with either of the solid particles in Example 1B and Example 2B.

[0380] In some cases, to produce a biphasic gel electrode, any of the transporter phases in all the examples may be mixed with any of the solid particles in all the examples.

[0381] [Table 11]

[0382] [result] [Experiment 1] Sample capacitance and charge injection characteristics The charge injection mechanism was evaluated by three-electrode cyclic voltammetry using a Bio-Logic Instruments (France) SP200 potentiostat. The apparatus configuration is shown in Figure 5. 0.4 g of sample was used as the working electrode. The electrolyte was 137 mM NaC phosphate-buffered saline. The counter electrode was an A-002222 platinum counter electrode (Biologic Instruments, France), with an outer diameter of 0.5 mm and a length of 5 cm. This was inserted into the electrolyte to a depth of 0.5 mm, so that the distance between the counter electrode and the sample was 0.5 mm. Measurement was performed using a non-energized reference electrode. The reference electrode was a RE-IB Ag / AgCI reference electrode (Biologic Instruments, France), with an outer diameter of 6 mm and a length of 80 mm. This was inserted into the electrolyte to a depth of 0.5 mm, so that the distance between it and the sample was 0.5 mm. The reference electrode was physically separated from the counter electrode. The sample used was the working electrode and the A-002222 platinum counter electrode (Biologic Instruments, France), with an outer diameter of 0.5 mm and a length of 5 cm. The potential was 500 mVs between +1 and -1 V. -1 The scan speed at which the sample was applied was 0.169 cm². In all cases, the area of ​​the working electrode (sample) was 0.169 cm². 2 The scan speed was 500 mVs. -1 The cyclic voltammetry results are shown in Figure 2. The cathode charge storage capacity was calculated from these results and is shown in Figure 3.

[0383] [Experiment 2] Mechanical properties The storage modulus of the sample was measured using an "FIR-2 Discovery rheometer" (TA instruments). The parallel plates used were 20 mm in shape with a gap of 500 μm. Three amplitude sweep tests were performed per sample with a set immersion time of 180 seconds, a temperature of 37°C, and a frequency of 1.0 Hz. The test was terminated when the vibration strain reached 20% (from the initial 0.01%). The G' value was taken from the linear viscoelastic region and corresponds to the data point at 0.1% strain.

[0384] This data indicates that the samples are very soft and their storage modulus is in the low kPa range. Some samples fall within the stiffness range of brain tissue itself (0.5–2 kPa). All measured samples are orders of magnitude softer (less stiff) than current clinical electrode materials (typically in the range of several hundred GPa). The results are shown in Figure 4.

[0385] [Experiment 3] Sample biocompatibility U251 human astrocyte-like cells were directly seeded into 24-well plates (Corning, UK) using standard culture conditions (modified Eagle medium supplemented with 10% fetal bovine serum and 100 units / mL penicillin-streptomycin, all supplied by Gibco, UK). Figure 5 shows the results using a seeding density of 20,000 cells per well. Cells were allowed to adhere for 3 hours before placing two 0.7mm x 0.1mm disks of sample 2A.5 in each well. Figure 6 shows the results using a seeding density of 50,000 cells per well, with cells allowed to adhere for 24 hours. Five 3mm diameter particles (samples 1B.1 and 2B.1) were added to appropriate wells, and 1 ml of sample 3B.2 was added to appropriate wells. Samples were compared to a positive control for cell health, consisting of cells cultured in well plates without sample disks, which is considered an ideal environment for cell culture. Negative controls were also used, and cells were grown in well plates without electrode samples. Furthermore, 5% dimethyl sulfoxide, a compound known to have cytotoxic activity at a 5% concentration, was added to the culture medium. Cell viability was measured using a resazurin reduction assay (Alamar Blue®, Thermofisher Scientific, UK), and the measurement was performed according to the manufacturer's instructions. Figure 5 shows four different experiments using data recorded at 24 hours, 3 days, 5 days, and 7 days after culture. Figure 6 shows three different experiments using data recorded at 24 hours, 3 days, and 7 days after culture. The results are shown in Figures 5 and 6.

[0386] [statement] Statement 1. A two-phase implantable electrode comprising multiple solid particles and a transporter phase, both of which contain poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0387] Statement 2. The solid particles are two-phase injectable electrodes as described in Statement 1, with a maximum dimension of 1.5 mm.

[0388] Statement 3. The solid particles consist of a gel and are a two-phase injectable electrode as described in Statement 1 or 2.

[0389] Statement 4. A two-phase injectable electrode as described in any one of Statements 1 to 3, wherein the solid particles have at least 90% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

[0390] Statement 5. A two-phase injectable electrode described in any one of Statements 1 to 4, in which solid particles occupy 60-85% v / v of the injectable electrode.

[0391] Statement 6. A two-phase injectable electrode as described in any one of Statements 1 to 5, comprising a shea-thinning gel as the transporter phase.

[0392] Statement 7. A two-phase injectable electrode as described in any one of Statements 1 to 6, wherein the transporter phase comprises clay, polyethylene glycol, polyvinyl alcohol, polydimethylsiloxane, xanthan gum, (3-glycidyloxypropyl)trimethoxysilane, ethylene glycol, dodecylbenzenesulfonic acid, cyclodextrin, and / or polyvinylamine.

[0393] Statement 8. A two-phase injectable electrode as described in any one of Statements 1 to 7, comprising polyvinyl alcohol, (3-glycidyloxypropyl)trimethoxysilane, and / or ethylene glycol.

[0394] Statement 9. The storage modulus of a two-phase injectable electrode is that of a two-phase injectable electrode described in any one of Statements 1 to 8, where the vibrational rheometry is evaluated at a temperature of 37°C and a frequency of 1 Hz, with a vibrational strain of 0.1% and <2 kPa.

[0395] Statement 10. A two-phase injectable electrode as described in any one of Statements 1 to 9, capable of supplying ±1V to human tissue under a capacitive charge transfer method without inducing a Faraday reaction.

[0396] Statement 11. An apparatus for use in electrotherapy, comprising a two-phase injectable electrode as described in any one of Statements 1 to 10, a counter electrode, a probe, and a charge supply device.

[0397] Statement 12. A biphase injectable electrode described in any one of Statements 1 through 10, for use in electrotherapy treatment of solid tumors after surgical resection.

[0398] Statement 13. A two-phase injectable electrode described in any one of Statements 1 through 10 for use in electrotherapy.

[0399] Statement 14. A method for treating glioblastoma multiforme after surgical resection in a warm-blooded animal such as a human, comprising providing electrotherapy to an animal having a biphase injectable electrode as described in any one of Statements 1 to 10.

[0400] Statement 15. Treatment is provided in combination with chemotherapy and / or radiotherapy, using any one of the methods described in Statements 12 through 14, or the method described in Statement 15.

[0401] Statement 16. a) A two-phase injectable electrode as described in any one of statements 1 to 10, b) Opposite poles, c) Probe and, d) A kit comprising a charge supply device.

[0402] Statement 17. A method of electrotherapy having multiple cooperating electrodes implanted in soft tissue.

[0403] Statement 18. The electrotherapy method described in Statement 17, having at least four electrodes.

[0404] Statement 19. A method of electrotherapy according to Statement 17 or 18, comprising a two-phase injectable electrode as described in any one of Statements 1 to 10, and an electrode having platinum, a platinum alloy, a platinum wire, iridium oxide, a platinum-iridium alloy, carbon, graphene, a conductive polymer, and / or a conductive composite material.

[0405] Statement 20. Electrotherapy methods described in any one of Statements 17 to 19 for the treatment of solid tumors, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, retinal implantation for vision restoration, regeneration of nerve tissue including the brain, spinal cord, and peripheral nerves, brain / spinal cord / peripheral nerve interface formation, wound healing, treatment of infections (antibacterial / antiviral / antifungal), or enhancement of drug delivery / gene therapy.

Claims

1. Comprising multiple solid particles and a transporter phase, The solid particles and the transporter phase each contain poly(3,4-ethylenedioxythiophene)polystyrenesulfonic acid, respectively, in a two-phase implantable electrode.

2. The two-phase injectable electrode according to claim 1, wherein the solid particles have a maximum dimension of 4 mm.

3. The two-phase implantable electrode according to claim 1 or 2, wherein the solid particles are composed of a gel.

4. The two-phase implantable electrode according to any one of claims 1 to 3, wherein the solid particles comprise at least 90% v / v poly(3,4-ethylenedioxythiophene)polystyrene sulfonic acid.

5. The two-phase injectable electrode according to any one of claims 1 to 4, wherein the solid particles constitute 40-85% v / v of the injectable electrode.

6. The transporter phase is composed of a shea-thinning gel, as described in any one of claims 1 to 5, for a two-phase injectable electrode.

7. The transporter phase further comprises clay, polyethylene glycol (PEG), poly(ethylene glycol) methacrylate, poly(ethylene glycol) diacrylate, polyvinyl alcohol (PVA), polydimethylsiloxane (PDMS), xanthan gum, (3-glycidyloxypropyl)trimethoxysilane, ethylene glycol, dodecylbenzenesulfonic acid, methylcellulose, hydroxymethylcellulose, guar gum, Pluronic F-127, poly(N-isopropylacrylamide) (PNIPAAM), copper-carrageenan, cyclodextrin, phosphate-buffered saline (PBS), and / or polyvinylamine, as described in any one of claims 1 to 6.

8. The transporter phase further comprises methylcellulose, the two-phase injectable electrode according to any one of claims 1 to 7.

9. The storage modulus of the two-phase injectable electrode is less than 2 kPa when the vibrational strain is 0.1% as evaluated by vibrational rheometry at a temperature of 37°C and a frequency of 1 Hz, according to any one of claims 1 to 8.

10. A two-phase injectable electrode according to any one of claims 1 to 9, capable of supplying ±1V to human tissue under a capacitive charge transfer method without inducing a Faraday reaction.

11. A device used in electrotherapy, A two-phase injectable electrode according to any one of claims 1 to 10, Opposite, probe and, An apparatus comprising a charge supply device.

12. a) A two-phase injectable electrode according to any one of claims 1 to 10, b) Opposite pole, c) Probe and, d) A kit comprising a charge supply device.

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