System and method for electrically stimulating tissue

Abstract

Systems and methods for electrically stimulating biological tissue. A microneedle array formed from a conductive material is adapted to create holes in the tissue surface. A processing unit is configured to determine from a signal that a microneedle in the microneedle array is in a predetermined position in the tissue, or that tissue surrounding one or more microneedles has been excised.

Description

Technical Field

[0001] The present invention relates to medical devices, and more particularly, to devices for electrically stimulating biological tissues and the like.

Background Art

[0002] Electrical stimulation in biological tissues is used to treat chronic and acute medical conditions and can be implemented using implantable electrodes or surface electrodes. Implantable electrodes are generally used to directly stimulate tissue at a desired site. Although effective in stimulating the target tissue, implantable electrodes exhibit significant drawbacks such as infections at the implantation site, electrode failure, and electrode displacement.

[0003] Despite recent improvements in implantable electrode technology, transcutaneous electrical stimulation (TES) is still most frequently applied to stimulate muscle and nerve tissue near the epidermis and is commonly used for pain relief, rehabilitation, and the treatment of migraine headaches. TES utilizes surface electrodes rather than implantable electrodes to transmit electrical signals to tissues such as muscle or nerve tissue. Since surface electrodes do not require an implantation procedure, they avoid some of the drawbacks of implantable electrodes. Transcutaneous electrodes overcome some of the above-mentioned drawbacks of implantable electrodes, but their positioning on the skin surface deflects the direction of the electrical signal from the target tissue (e.g., nerve, muscle) and often forces the electrical signal to penetrate electrically resistive tissue (e.g., the stratum corneum of the skin). Due to these drawbacks of surface electrodes, they are often unsuitable for stimulating deep tissues such as the tibial nerve applied to overactive bladder or the vagus nerve in autoimmune and inflammatory diseases.

[0004] The most significant drawback in the use of surface electrodes arises from the fact that, for many applications, the surface electrodes are too far from the tissue to effectively stimulate. In the case of electrodes on the epidermis, the electrical signal will penetrate the superficial layers of the skin, such as the stratum corneum. In the stratum corneum, much of the signal is dispersed and the electrical signal will not reach the target tissue (nerve or muscle) in the deeper layers.

[0005] U.S. Patent No. 10,688,301 discloses a TES system that utilizes a microneedle array for forming conductive micropores that penetrate the tissue surface. The formation of micropores in the superficial layer of the skin has been found to facilitate the penetration of electrical stimulation into deeper layers of the tissue, thereby overcoming some of the aforementioned drawbacks of standard surface electrode systems. The system disclosed in U.S. Patent No. 10,688,301 substantially improves TES, but the need for a system and method for electrically stimulating tissue using surface electrodes still remains.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

[0007] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in practice or in testing of the present invention, the preferred methods and materials are described below. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0008] The implementation of the method and system of the present invention includes performing or fulfilling a selected operation or step manually, automatically, or a combination thereof. Further, according to the actual apparatus and equipment in the preferred embodiments of the method and system of the present invention, some selected steps can be implemented by hardware, or by software on any operating system in any firmware, or by a combination thereof. For example, for hardware, the selected steps of the present invention can be implemented as a chip or a circuit. For software, the selected steps of the present invention can be implemented as a plurality of software instructions executed by a computer using any suitable operating system. In any case, the selected steps of the method and system of the present invention can be described as being implemented as a data processor, such as a computer platform that executes a plurality of instructions.

[0009] In one aspect thereof, the present invention provides a system for electrically stimulating biological tissue. In one embodiment thereof, the system of the present invention includes an applicator including an array of two or more microneedles. The microneedles are made of a conductive material such as stainless steel and, in addition to opening holes in the tissue surface and entering the tissue, the microneedles also function as electrodes.

[0010] The system further includes a control unit, which includes a processing unit, a signal generator, a power unit, and a switching circuit. The processing unit controls the switching circuit to intermittently connect the various electrodes of the system to the poles of the signal generator during various stages of treatment.

[0011] The system may further include a force detector that can be incorporated into the applicator. This force detector detects the pressure applied to the tissue surface by the tip of the microneedle when the applicator is pressed against the tissue surface while the microneedle penetrates into the tissue.

[0012] The system further comprises one or more surface electrodes. The processing unit also controls the switching circuit to intermittently connect two or more surface electrodes to the poles of the power unit and / or the signal generator.

[0013] During use, the applicator is applied to the first tissue surface that is over a deep second tissue region to be treated. The second tissue may be, for example, a nerve or nerve tissue. For example, in a treatment for stimulating the vagus nerve, the applicator can be placed on an individual's neck over the vagus nerve. When pressure is applied by the applicator, the force detector detects the pressure applied to the tissue surface and generates an electrical signal indicative of the pressure input to the processing unit. The processing unit either constantly monitors or is triggered by the signal input from the force transducer to determine whether the force of the applicator on the tissue surface is at least a threshold pressure. In an alternative embodiment, the force detector closes a switch and sends a signal to the processing unit that pressure has been detected.

[0014] When the pressure of the applicator on the tissue surface is at least a predetermined pressure, this is an indication that the microneedles are applying the required pressure and are in the required position. In the case of the skin, the microneedles are applying the required pressure when the tip of the microneedle is pressed through the stratum corneum of the skin.

[0015] Additionally or alternatively, some or all of the microneedles can be connected to the poles of the signal generator and a ground electrode applied to the tissue surface. A DC or pulsating signal of non-stimulating energy (e.g., 1V or 2mA) is generated by a signal generator that generates an electrical signal between the microneedles and the ground electrode. The current is monitored by the processing unit and the impedance of the tissue is calculated from the electrical signal. An impedance of the tissue that is below a predetermined threshold is an indication of the formation of micropores and that the required pressure is being applied.

[0016] When it is determined that the necessary pressure is being applied, an ablation signal is generated by a signal generator, and on one hand, the ablation signal is applied between one or a plurality of first subsets of the micro needles and, on the other hand, a second subset of the micro needles. The ablation signal is designed to ablate the tissue surrounding the micro needles in the first subset. Since the tissue is essentially elastic, when the micro needles are removed, the micro holes formed by the micro needles tend to close partially or completely. An ablation electrical signal is used to ensure that the micro holes formed by the micro needle array remain open after the micro needles are removed, ensuring that the micro holes remain open.

[0017] When the ablation signal is being applied between two subsets of the micro needles, the processing unit monitors the current flowing between the two subsets of the micro needles to determine whether the ablation around the micro needles in the first subset is satisfactory. A satisfactory ablation of the tissue around the micro needles reduces the total impedance of the tissue and the amplitude of the treatment signal by the surface electrodes required for effective treatment.

[0018] The process is repeated one or more times using various selections in the first and second subsets of the micro needles. Next, the processing unit determines whether all ablations in the tissue are satisfactory. When it is determined that the ablation of the tissue area is satisfactory, the applicator is removed from the tissue surface, and the treatment surface electrodes are placed on the tissue surface covering the micro holes formed in the tissue. Next, a treatment signal is generated between the treatment surface electrodes and passes through the second tissue under the tissue surface. The treatment continues as required for any application.

[0019] The system may include a communication module for wireless communication to an external device (such as a smartphone, computer, etc.) and / or a cloud-based database server. The communication module can be used for storing data (including storing in a cloud-based repository), for software updates, for training, for remote assistance, and for communication between the present system and a doctor. The communication module enables remote access to data and information by health management experts who respond in real time and provide instructions.

[0020] The system can further include sensors for measuring physiological parameters of a subject, such as heart rate, blood pressure, sweat, respiratory rate, and body temperature. These parameters are analyzed to assist in the determination of the type and / or timing of electrical signals transmitted by surface electrodes. For example, it is known that transmitting an electrical signal to the vagus nerve can affect blood pressure. Sensing and analyzing blood pressure can affect the characteristics and timing of the transmitted signal.

[0021] A fluid analysis unit can also be incorporated into / connected to the present system to provide chemical properties of blood, urine, sweat, or saliva. Such analysis can affect the timing and characteristics of the location where an electrical signal is transmitted and the electrical signal transmitted. For example, cytokine analysis from a blood sample can indicate the effectiveness of treatment and whether it is necessary to modify the characteristics and / or timing of the electrical signal to affect cytokine levels.

[0022] The conductive efficacy from the surface electrode into the tissue through the micropores depends on the quality of the micropores (such as depth, diameter, shape, structure, etc.). The present invention enables confirmation that the micropores formed by the microneedle array have desired characteristics. This in turn helps to maximize patient comfort.

[0023] This system can be used for aesthetic treatment (e.g., of facial skin), or for treating various diseases / conditions that can benefit from electrical stimulation, such as muscles or tissues.

[0024] The following is an incomplete list of diseases or conditions treatable by the present invention. (i) Pain relief - back pain, neuropathic pain, carpal tunnel syndrome, shoulder pain, chronic and refractory pain including diabetic neuropathy, complex regional pain syndrome, phantom limb pain, ischemic limb pain, refractory unilateral limb pain syndrome, post-herpetic neuralgia and acute herpes zoster pain. Pain treatment can be carried out via electrical stimulation of the tibial nerve. An exemplary electrical signal can have a current of 10 mA and a frequency of 100 Hz. (ii) Rehabilitation - functional recovery, such as gripping to support daily life tasks. Generation of electrical signals directed at nerves to directly or indirectly stimulate various muscles. An exemplary electrical signal can have a current of 15 mA and a frequency of 50 Hz. (iii) Incontinence (fecal or urinary) and overactive bladder. An exemplary electrical signal can have a current of 5 - 20 mA and a frequency of 20 Hz. (iv) Treatment of epilepsy, depression, Alzheimer's disease, anxiety, obesity, bulimia, tinnitus, obsessive-compulsive disorder, hypertension, or heart failure, by stimulating the neck, face, chest, or stomach, for example adjacent to the vagus nerve or one of its branches. An exemplary electrical signal can have a current of 10 mA and a frequency of 10 Hz. (v) Treatment of cancers, tumors, such as prostate cancer, brain tumors, breast cancer. Treatment of cancers and tumors can be carried out in addition to, and / or in conjunction with, chemotherapy. The system and method of the present invention can enhance the process of chemotherapy. An exemplary electrical signal can have a current of 10 mA and a frequency of 10 Hz. (vi) Regulation of the immune system for the treatment of autoimmune diseases, reduction of systemic inflammation. An exemplary electrical signal can have a current of 10 mA and a frequency of 10 Hz. (vii) Enhancement of hair growth by stimulating the scalp. An exemplary electrical signal can have a current of 5 mA and a frequency of 1 MHz.

[0025] One particular use of the system of the present invention is the treatment of diseases that benefit from stimulating the vagus nerve or one of its branches. Such diseases include, but are not limited to, the following. Substance addiction, anxiety disorders, autism, bipolar disorder, cerebral palsy, chronic headache, cognitive impairment associated with Alzheimer's disease, coma, depression, eating disorders (e.g., anorexia and bulimia), essential tremor, fibromyalgia, heart failure, persistent unilateral headache, juvenile myoclonic epilepsy, migraine, mood disorders, sleep attacks, obesity, obsessive-compulsive disorder, sleep disorders, tinnitus, and Tourette syndrome, hypomanic personality or any other organic hypersomnia, tension headache, alcohol-induced sleep disorder, drug-induced sleep disorder, episodic mood disorder, autism spectrum disorder, obsessive-compulsive disorder, mood-cycling disorder, alcohol dependence syndrome, drug dependence, non-dependent drug abuse, anorexia nervosa, non-organic specific sleep disorder, eating disorder of unknown etiology, tension headache, circadian rhythm sleep disorder, organic abnormal insomnia, organic sleep disorder, essential and other specific forms of tremor, persistent unilateral headache, cerebral infantile paralysis, migraine, fainting spells and sleep attacks, rheumatic heart failure, myalgia and myositis, sleep disorder, bulimia, mood, Parkinson's disease and headache, akinesia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune hereditary autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AMAN), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, pancreatitis, acute pancreatitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neural disorder (AIED), Baló disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman disease (CD), childhood steatorrhea, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis with polyangiitis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia syndrome,Fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, fibrillary glomerulonephritis, Goodpasture syndrome, polyangiitis granulomatosis, Graves' disease, Guillain - Barré syndrome, Hashimoto's disease, hemolytic anemia, Henoch - Schönlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS), hypogammaglobulinemia, IgA nephropathy, IgG4 - related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile type 1 diabetes, juvenile myositis (JM), Kawasaki disease, Lambert - Eaton syndrome, leukocytoclastic vasculitis, lichen planus, ligneous conjunctivitis, linear IgA disease (LAD), lupus erythematosus, chronic Lyme disease, Ménière's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren ulcer, Mucha - Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myelin - oligodendrocyte glycoprotein antibody disease, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, semen & testicular autoimmunity, stiff - person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa - Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo,Vogt-Koyanagi-Harada disease, sepsis, hemorrhagic diseases.

[0026] Treatment can be performed by other branches in the vagus nerve or other nerves that affect the disease. It is performed by being connected to either the vagus nerve or an area that controls the disease.

[0027] Stimulation of the vagus nerve can activate the body's natural inflammatory reflex, suppress inflammation, and improve clinical signs and symptoms. The inflammatory reflex is a neurophysiological mechanism that regulates the body's immune system. It senses infection, tissue damage, and inflammation, transmits this information to the central nervous system, and then reflexively increases nerve signals through the peripheral vagus nerve and splenic nerve, which widely stimulate the spleen and other internal organs. This signal is transmitted to T cells in the spleen, which in turn control effector cells including monocytes and macrophages, reducing the production of mediators that cause and perpetuate inflammation. Inflammation plays a major role in acute and chronic diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis, diabetes, heart disease, and multiple sclerosis.

[0028] In one aspect, the present invention provides a system for electrically stimulating biological tissue. The system includes: (a) A microneedle array in which the microneedles are formed of a conductive material and adapted to pierce the tissue surface; (b) A power unit; (c) One or more surface electrodes configured to be connected to the power unit and transmit electrical stimulation to the biological tissue; (d) A processing unit that, from the input signal: · determines whether the microneedles in the microneedle array are at a predetermined position in the tissue; and · determines whether the tissue surrounding one or more microneedles has been excised, and is configured to determine any one or more of the above, and comprises.

[0029] One or more of the surface electrodes may be wet electrodes.

[0030] The system according to the present invention may further comprise one or more force detectors. Each force detector is one or more of the microneedles in the array and is configured to detect the application of pressure applied by the tissue. This pressure represents the position of the microneedles in the tissue and generates a signal indicating the position of one or more of the microneedles. This signal is input into the processing unit. One or more of the force detectors may comprise a displacement mechanism that activates the force detector when a force is detected by the force detector. The force detector may be a spring-based detector. The degree of compression of the spring indicates the pressure applied by the microneedles in the array. The force detector may be a load cell-based force detector. One or more of the force detectors may comprise a switch. It is closed when a predetermined force is detected by the force detector. Closing the switch generates an electrical signal that is input into the processing unit.

[0031] The processing unit is configured to monitor a time-dependent electrical signal to determine whether the microneedles in the microneedle array are at a predetermined position in the tissue, and may include determining when the pressure applied by the tissue to the microneedles exceeds a predetermined threshold.

[0032] The system of the present invention may further include a switching circuit configured for intermittent electrical connection of one or more selectable subsets of the microneedles to the power unit and for intermittent electrical connection of one or more of the surface electrodes to the power unit.

[0033] The system of the present invention may further comprise a signal generator. The processing unit may be further configured to activate the signal generator to transmit an electrical signal between a selectable first subset of the microneedles and a selectable second subset of the microneedles, or between a selectable first set of the microneedles and at least one of the surface electrodes. The processing unit may be further configured to activate the signal generator to transmit an ablation signal between a selectable first subset of the microneedles and either a selectable second subset of the microneedles and one or more of the surface electrodes. This ablation signal is selected to ablate the tissue surrounding one or more of the microneedles. The processing unit may be further configured to activate the signal generator to transmit an ablation signal only after determining that the microneedle array is in a predetermined position. The processing unit may be further configured to activate the signal generator to generate a test signal between a selectable first subset of the microneedles and either a selectable second subset of the microneedles and one or more of the surface electrodes, and to determine whether the tissue surrounding the selectable first subset of the microneedles has been ablated, which may include analyzing the response of the tissue to the test signal. The processing unit may be further configured to generate a test signal between a plurality of selectable first subsets of the microneedles and either one or more selectable second subsets of the microneedles and one or more of the surface electrodes, and to determine whether the ablation of the microneedles in the array meets a predetermined criterion. The processing unit may be further configured to determine the number of microneedles in the array that have ablated the tissue surrounding them. The predetermined criterion may be determined such that the number of microneedles in the array that have ablated the tissue surrounding them exceeds a predetermined threshold. The processing unit may be configured to transmit an electrical stimulus to the tissue when the predetermined criterion is met.

[0034] The ablation signal may be a voltage signal. The ablation signal may be composed of a series of burst pulses. The ablation signal may comprise square voltage pulses with alternating signs, or a sine wave signal. The ablation signal may have an amplitude of, for example, 200 to 800 volts and a frequency of 1 to 1000 KHz.

[0035] Determining whether the tissue surrounding the microneedles in a selectable first subset has been ablated may include monitoring the tissue's current or impedance response and determining whether this current exceeds a predetermined threshold or whether the impedance falls below a predetermined threshold.

[0036] The system of the present invention may be configured to transmit electrical stimulation through the skin. In this case, a predetermined position of the microneedle is the position when the microneedle penetrates through the stratum corneum of the skin. The system may be configured to transmit electrical stimulation to one or more nerves under the skin surface, such as the vagus nerve.

[0037] A method for electrical stimulation of biological tissue includes the following: (a) Applying a microneedle array to the surface of biological tissue to create holes in the tissue surface and generate micropores in the tissue; (b) Applying one or more surface electrodes over the micropores to the tissue surface and transmitting electrical stimulation through the one or more surface electrodes; (c) For the following: · Whether the microneedles in the microneedle array are at a predetermined position in the tissue; and · Whether the tissue surrounding one or more microneedles has been removed, determining one or more of the above.

[0038] The present invention will be described merely by way of example with reference to the accompanying drawings. Turning now to the drawings in more detail and specifically, it is emphasized that what is shown in detail is an example and is for the purpose of illustratively explaining preferred embodiments of the present invention only, and that the presentation is for the reason of providing an explanation of the principles and conceptual aspects of the present invention that is considered to be the most useful and easily understood. In this regard, no attempt is made to show the structural details of the present invention beyond what is necessary for a basic understanding of the present invention. The description using the drawings clarifies for those skilled in the art how some forms of the present invention can actually be implemented.

Brief Description of the Drawings

[0039]

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Figure 11

Embodiments for Carrying Out the Invention

[0040] The present invention provides a system and method for electrically stimulating biological tissue, which can be used to transmit an electrical signal to the tissue using one or more surface electrodes. The system of the present invention utilizes a microneedle array and a resection signal for forming conductive micropores in the tissue, and a processing unit for confirming that the formed micropores exhibit desired conductive properties.

[0041] Next, referring to the figures, FIG. 1A shows a system 10 for electrically stimulating a biological tissue according to one embodiment of the present invention. The system 10 includes an applicator 13 having an array 15 of two or more microneedles 12 mounted on a support portion 14.

[0042] The support portion 14 can be made of, for example, polycarbonate. The microneedles 12 are made of a conductive material such as stainless steel and, in addition to piercing the tissue surface to enter the tissue as described in detail below, the microneedles 12 also function as electrodes. Each microneedle 12 can have a coating of an insulating material 36 such as polycarbonate. It prevents current leakage through the sides of the microneedle, improves the conductivity of the current to the tip 32 of the microneedle, and creates a depression 39 (FIG. 2) for enhancing the penetration of the microneedle.

[0043] In one embodiment, each microneedle 12 has a base portion 30 (surrounded by an insulating material 36 in FIG. 1A) and a pointed tip portion 32 shaped to pierce through the first tissue to form micropores in the surface layer of the first tissue. The shape of the insulating material 36 may generally be conical (FIG. 2) having a smaller diameter near the tip of the microneedle 32. The base portion 30 may be cylindrical, extending about 10 to 10,000 micrometers and having a diameter of 10 to 500 micrometers. When used to create a hole in the skin covering the area of the vagus nerve, for example, the extension of the tip portion 32 of the microneedle can be 40 to 150 micrometers. The base portion 30 may also have a different shape and diameter than the tip portion 32. This diameter can be enlarged to allow for a more stable base. For example, the microneedle can also have a non-cylindrical shape (e.g., a flat microneedle) with a width of about 40 to 300 micrometers, an extension of about 40 to 8,000 micrometers, and a height extending to about 10 to 10,000 micrometers (FIG. 3C). The microneedle array 12 can cover an area of 0.5 to 5 square centimeters, generally 0.5 to 2 square centimeters, for placement, for example, in the stimulation of the vagus nerve in the neck.

[0044] The microneedle array 15 can be, for example, a 16×16 microneedle array. The microneedles can be held by bonding to the support portion 14 or by friction, for example, by inserting them into sockets in the support portion 14. Alternatively, the support portion 14 can be made integrally with the microneedles 12 using, for example, semiconductor chip assembly techniques known in the art.

[0045] System 10 further includes a control unit 22, which includes a processing unit 25, a memory 21, a signal generator 37, a power unit 41, and a switching circuit 31. The power unit 41 can include power components known in the art, such as a transformer. The processing unit 25 controls the switching circuit 31 to intermittently connect various electrodes of the system to the poles of the signal generator 37, and / or to the power unit 41, and / or to the processing unit 25 during various stages of treatment, as will be described in detail below. The switching circuit 31 includes two or more sets of switches and can be connected to various electrodes. For example, one set can be used to connect the micro-needles 12 to the processing unit 25 and / or the signal generator 37, and / or to the power unit 41. On the other hand, another set is used to connect the surface electrodes 28 to the processing unit 25 and / or the signal generator 37, and / or to the power unit 41. The signal generator 37 can include two or more sets of signal generators for various signals. The power unit 41 can include two or more sets of power units for various signals. The control unit 22 and / or the switching circuit 31 intermittently connect a selectable first subset of the micro-needles 12 in the array 15 to one pole of the power unit 41 and a selectable second subset of the micro-needles 12 in the array 15 to the second pole of the power unit 41. The processing unit 25 also controls the signal generator 37 to generate an electrical signal between the two poles of the power unit 41. The micro-needles 12 can be connected to the switching circuit 31 through a wire 24 or a printed circuit board (PCB). The components of the control unit 22 can be supplied with energy from a battery or an external power source.

[0046] The control unit 22 may further include a display 20 and a user input device 35 such as a keyboard or a touch screen that can be integrated with the display 20. The input device 35 is used to program the processing unit 25 to generate an electrical signal between a selected first subset and a second subset of the micro needles 12, and to generate an electrical signal between the selected first and second surface electrodes 28 having desired characteristics such as, for example, frequency, potential, and signal profile. The control unit 22 also includes a communication unit 42, which can enable remote control of the control unit 22, for example, via Bluetooth.

[0047] The applicator 13 may also include a force detector 16. The detector 16 detects the pressure applied to the tissue surface by the tip 32 of the micro needle 12 when the applicator 13 is pressed against the tissue surface while the micro needle 12 penetrates into the tissue. The micro needle array 15 may include a displacement mechanism that activates the force detector 16 when the micro needle 12 is pressed on the tissue. The force detector 16 can generate a time-dependent electrical signal indicating the pressure input to the processing unit 25. The force detector 16 can be a spring-based transducer, where the degree of compression of the spring indicates the pressure applied to the tissue surface. Alternatively, the force transducer 16 may be a load cell-based transducer. The load cell transducer can be connected to the display 20 of the system 10 and provide a display of the force applied by the tip 32. The galvanic isolation between the micro needle 12 and the control unit 22 can be maintained until a predetermined force is applied by the tip 32. The applicator 13 may include two or more sets of force detectors 16. The force can be measured collectively or at each micro needle. The predetermined force applied to the force detector can be used as a trigger to initiate the ablation signal by the micro needle 12 and to further confirm that at least a predetermined force has been applied while transmitting the ablation signal to the first tissue.

[0048] System 10 further includes a therapeutic surface electrode 28 and a ground surface electrode 26. Electrodes 26 and 28 are surface electrodes connected to a switching circuit 31 via respective wires 27 and 29. Wires 27 and 29 may each include two or more wires for connecting to two or more surface electrodes 26 and two or more surface electrodes 28. Electrodes 26 and 28 can be dry electrodes, wet electrodes, or moist electrodes. A conductive liquid such as physiological saline can be used to wet the surface of the electrodes. The physiological saline can have a concentration in the range of, for example, 0.1 to 25%, preferably 5 to 15%. Electrodes 26 and 28 can have any shape and dimensions required for any application. For example, electrodes 26 and 28 may be square with 2×2 cm and a width of 0.5 centimeters, or other dimensions and shapes suitable for the desired treatment area, such as circular or elliptical. Electrodes 26 and 28 can be disposable or reusable and can include an adhesive surface for attachment to a first tissue (e.g., skin). The processing unit 25 controls the switching circuit 31 to intermittently connect two or more surface electrodes 28 to the poles of the power unit 41 and / or the signal generator 37. The processing unit 25 controls the switching circuit 31 to also intermittently connect one or more surface electrodes 26 to the poles of the power unit 41 and / or the signal generator 37.

[0049] FIG. 11 shows a flowchart of a method for electrical stimulation of tissue using the system of the present invention according to one embodiment of the present invention. In step 50, the applicator 13 is applied to the first tissue at the top of the second tissue region to be treated. The second tissue may be a nerve, and is not limited, but is located in a relatively deep part (for example, deeper than 0.5 centimeters, and may be shallower than that as well) under the first tissue (for example, skin). FIG. 4A shows, as an example, in a treatment for stimulating the vagus nerve (this vagus nerve may be located deeper than 1 centimeter under the skin), the applicator 13 is installed on the individual's neck above the vagus nerve. When pressure is applied by the applicator 13, the force detector 16 detects the pressure applied to the tissue surface and generates an electrical signal indicating the pressure input to the processing unit 25. The processing unit 25 always monitors or is activated by the signal input from the force transducer 16 (step 52), and determines whether the force of the applicator 13 on the tissue surface is at least a threshold pressure pre-stored in the memory of the processing unit (step 54). Although not shown, in an alternative embodiment, when the pressure on the tissue surface is detected by the force detector 16, the force detector 16 closes a switch and sends a signal indicating that the pressure has been detected to the processing unit 25. As shown in FIG. 2, the pressure of the applicator 13 on the tissue surface can deform the tissue 39 and insert the tissue into the space between the microneedle 12 and its coating 36. This deformation has been found to be useful for the penetration of the microneedle 12 into the surface layer of the first tissue, and can also reduce the pressure required for the insertion of the microneedle through the tissue surface.

[0050] If the pressure of the applicator 13 on the tissue surface has not reached a predetermined pressure, the pressure of the applicator on the tissue surface is increased (step 56), and the process returns to step 52. If the pressure of the applicator 13 on the tissue surface is at least a predetermined pressure, this indicates that the microneedle 12 is applying the required pressure, and the process proceeds to step 58. The inventor has found that 0.3 to 2 kg / cm2 pressure within the range of, but generally 0.5 to 1.2 kg / cm 2 It has been found that the pressure within the range indicates that the micron needles are in the required positions. In the case of the skin, when the tip 32 of the micron needle is pressed through the stratum corneum of the skin, the micron needle 12 applies the required pressure.

[0051] Additionally or alternatively, some or all of the micron needles 12 may be connected to the poles of the signal generator 37 via the switching circuit 31, the grounding electrode 26 may be applied to the tissue surface, and may be connected to another pole of the signal generator 37 via the switching circuit 31. A DC or pulsating signal of non-stimulating energy (e.g., less than 1 V or 2 mA) is generated by the signal generator 37 generating an electrical signal between the micron needle 12 and the grounding electrode 26. The current is monitored by the processing unit 25, and the impedance of the tissue is calculated from this electrical signal. An impedance of the tissue that is less than a predetermined threshold is an indication of the formation of micropores and that the required pressure is being applied.

[0052] When it is determined that the required pressure is being applied, the display k is set to 1 and the counter is set to 0 (step 58). This is merely an example, and other methods known in the art for measuring time and activating the switching circuit may be used. Next, in step 60, the k-th subset 1 of the micron needles in the micron needle array 15 (previously stored in the memory 21), and the k-th subset 2 of the micron needles in the micron needle array 15 are recalled from the memory 21 of the control unit 22. The k-th subset 1 and the k-th subset 2 are sets of micron needles where the sets are non-empty and have no common elements with each other. The micron needles in the k-th subset 1 are then connected via the switching circuit 31 to the first pole of the signal generator 37 and / or the power unit 41, and the micron needles in the k-th subset 2 are then connected via the switching circuit 31 to another pole of the signal generator 37 and / or the power unit 41 (step 62).

[0053] In an alternative embodiment, the k-th subset 2 is not used and instead the ground electrode 26 is attached to the second pole of the signal generator.

[0054] Next, the process continues with step 64 where the k-th ablation signal generated by the signal generator 37 is applied between the micro-needles in the k-th subset 1 on the one hand and between the micro-needles in the k-th subset 2 on the other hand. The k-th ablation signal is designed to ablate the tissue surrounding the micro-needles in subset 1. FIG. 3A schematically shows, as a first example, a part of the microneedle array 15 having six micro-needles. In the example of FIG. 3A, the micro-needle 12a is the single micro-needle in the k-th subset 1. The remaining five micro-needles, micro-needles 12b to 12f, constitute the k-th subset 2. The dashed curve in FIG. 3A shows the electrical signal between the micro-needle 12a and each of the micro-needles in the k-th subset 2 when the ablation signal is applied to the first tissue. FIG. 3B schematically shows, as a second example, a part of the microneedle array 15 having six micro-needles where the micro-needles 12g together with 12h constitute the k-th subset 1. The remaining four micro-needles, micro-needles 12i to 12l, constitute the k-th subset 2. The dashed curve in FIG. 3B shows the electrical signal between the micro-needles 12g and 12h and each of the micro-needles in the k-th subset 2 when the ablation signal is applied. This is merely an example and any permutation of subset 1 and subset 2 is possible.

[0055] The upper panel of FIG. 5 shows an example of an ablation signal applied to the first tissue between the microneedles in the k-th subset 1 and the microneedles in the k-th subset 2. The ablation signal shown in the upper panel of FIG. 5 is a pressure signal composed of a series of burst pulses, and each pulse is composed of several square voltage pulses with alternating signs. The square shape is only an example, and other shapes can be used (for example, a sine waveform can also be used). Depending on the tissue being treated, each pulse generally has an amplitude of 25 - 2000 V (generally 200 - 800 V) and a wavelength of 1 - 1000 KHz.

[0056] The pulse train of the ablation signal is applied during duration intervals such as t1, t3, t5, etc. These times can be predetermined or determined during execution, but generally the pulse duration is 1 - 20 milliseconds. These pulses are separated by rest durations such as t2, t4, etc. when the impedance can be measured without the ablation signal being applied.

[0057] Referring again to FIG. 11, when the k-th ablation signal is applied between the k-th subset 1 and subset 2, the processing unit monitors the current flowing between one or more of the microneedles in the k-th subset 1 and one or more of the microneedles in the k-th subset 2 (step 66). The lower panel of FIG. 5 shows a typical current response to an ablation signal such as the ablation voltage signal shown in the upper panel. As ablation progresses, the current rises, indicating a decrease in impedance in the tissue, penetration of the microneedles through the tissue, and the ablation process. The current reaches a peak and then decays. Without wishing to be bound by any particular theory, it is believed that at the current peak and then during the decay of the current, ablated tissue with low conductivity surrounds the microneedles. This can be an indication of the state of the micropores.

[0058] Next, in step 68, the processing unit 25 determines whether the resection around one or more of the micro needles in the k-th subset 1 is satisfactory. A satisfactory resection of the tissue around the micro needle reduces the total impedance of the tissue and reduces the amplitude of the treatment signal by the surface electrode 28 required for effective treatment.

[0059] In one embodiment, the resection around the micro needle in subset 1 is determined to be satisfactory when the peak height of the current response exceeds a predetermined threshold level (represented by the horizontal dashed line in the lower panel and pre-stored in the memory 27). In another embodiment, a change (e.g., a decrease) in the phase of the signal is used to determine whether the resection is satisfactory. If the resection around the micro needle in the k-th subset 1 is satisfactory, a counter that counts the number of micro needles when the tissue surrounded by the micro needle is resected satisfactorily is incremented by the number of micro needles in the k-th subset 1 (step 70).

[0060] Next, the process proceeds to step 72. There, it is determined whether k is equal to the maximum value kmax. kmax is the number of pairs of subset 1 and subset 2 for which the resection of the surrounded tissue is to be considered. If k is not equal to kmax, then in step 74, k is incremented by 1, and the process returns to step 60, where subset 1 and subset 2 for the new value of k are recalled from memory 27. If k = kmax, the process continues to step 76, where it is determined whether the overall resection of the tissue is satisfactory. This is determined from the final value of a counter that counts the number of microneedles when the resection of the surrounded tissue is found to be satisfactory. If the number of microneedles when the resection of the surrounded tissue is found to be satisfactory exceeds a predetermined threshold, the overall resection of the tissue may be considered satisfactory. Otherwise, the overall resection of the tissue is not considered satisfactory. The threshold may be a predetermined ratio such as 0.8 of the number of microneedles in array 15 (i.e., the overall resection of the tissue is satisfactory if at least about 80% of the resection of the microneedles is satisfactory). If it is determined that the resection of the tissue area is not satisfactory, the applicator may be moved to a new location on the tissue surface (step 78). And the process can return to step 52 to start the process again using the applicator at the new location. In another example not shown, another location for generating micropores may be selected to create micropores. Performing the process of creating micropores at two or more locations may enable two or more surface electrodes 28 to be placed covering the micropores (not included in FIG. 11).

[0061] In step 76, when it is determined that the excision of the tissue area is satisfactory, the applicator 13 is removed from the tissue surface (step 80), and the treatment electrode 28 is placed on the tissue surface covering the micropores formed in the tissue (step 82). The quality of the treatment requires good alignment of the surface electrode 28 with the formed micropores. This can be achieved, for example, by marking the tissue surface using the boundaries of the area of the tissue surface to be treated, as well as by applying the microneedle array 15 (step 50) and applying the treatment electrode 28 within the boundary marking (step 82). Another method for ensuring the alignment of the treatment electrode 28 with the micropores is to utilize the device described in U.S. Patent No. 10,688,301, which has an aperture covered by a removable flap in which the treatment electrode 28 is incorporated. This device is adhered to the tissue surface with the aperture over the area of the tissue surface to be treated. This flap can be lifted or removed to expose the skin surface under the aperture. The microneedle array 15 can be pressed into the tissue surface through the aperture of the patch, the thus formed micropores can then be excised and the microneedle array 15 removed, and then the flap can be closed and the surface electrode 28 brought into direct contact with the skin surface over the formed micropores. In another example, the aperture does not include a flap and the surface electrode is separated from the flap.

[0062] Figure 1B shows a system 10 with a treatment electrode 28a and another electrode 28b placed on the tissue surface, where the treatment electrode 28a covers the micropores 33 formed in the first tissue. This is just an example, and micropores can also be created similarly under the surface electrode 28b. The micropores 33 can extend 10 - 300 micrometers into the tissue (but not limited to this), and preferably extend through the keratinized layer with higher resistivity. Figure 4B shows, by way of example, the placement of surface electrodes 28a and 28b on an individual's neck for treatment to stimulate the vagus nerve. The treatment procedure for modifying cytokine levels begins by selecting the target vagus nerve (along the left and / or right side of the subject's neck), and then marking the locations of two surface electrodes 28 placed to cover the tissue surface over the vagus nerve at a suitable distance between the electrodes (e.g., 1 - 10 cm). Other treatments, such as for hypertension, can be similarly implemented with other electrical signal parameters for the treatment. The treatment electrode 28a is positioned to cover the micropores formed in the tissue over the vagus nerve (see Figure 4A). Next, a treatment signal 44 is generated between the surface electrode 28a that passes through a second tissue such as the vagus nerve and the surface electrode 28b (step 84). The presence of micropores under the electrode 28a tends to conduct current through deeper layers of tissue, such as the vagus nerve, in the arrangement shown in Figure 4B. Figure 5B shows the waveforms of two exemplary electrical signals that can be used for electrical stimulation of tissue. These signals can be a controlled voltage or current with a current of 0.1 - 50 mA, a voltage of 0.1 - 100 V, and a frequency of 1 Hz - 1 MHz. The pulse duration may vary from 10 - 1000 microseconds (generally 50 - 500 microseconds).

[0063] The process ends upon completion of the treatment.

[0064] Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art by considering the following examples, which are not intended to be limiting.

Example

[0065] Next, refer to the following examples. Together with the above description, they illustrate the present invention by way of non-limitation. [Example 1] Examination of Rat Cytokines

[0066] The electrical stimulation effect on pro-inflammatory and anti-inflammatory cytokines was examined using a rat model and a prototype of the present system.

[0067] Thirty adult rats were divided into four groups: (i) Lipopolysaccharide (LPS); (ii) Lipopolysaccharide (LPS) + electrical stimulation treatment; (iii) Electrical stimulation treatment only; and (iv) Control group.

[0068] Lipopolysaccharide (LPS, 5 mg / kg body weight) from Escherichia coli was administered to the rats by injection at 0 minutes (Figs. 6 - 9), and blood samples were taken 30 minutes before LPS administration, and 90 minutes and 120 minutes after LPS administration.

[0069] Electrical stimulation was performed using the tissue stimulation system of the present invention, which has a microneedle array with 80 - 160 microneedles and a surface area of 0.5 - 1.5 square centimeters for generating micropores and measuring tissue properties, and two wet surface electrodes with a diameter of 0.5 - 2.0 centimeters for transmitting electrical stimulation and measuring impedance.

[0070] Before treatment, the rats were shaved using a hair trimmer in the neck region, taking care not to damage the skin surface. The treatment site was anatomically determined on the vagus nerve in the neck of the rats, and the insertion site of the microneedle array was marked on the skin. Tissue properties before and after generating micropores were monitored as described above in this specification.

[0071] The micropores were generated in the marked area on the skin surface over the vagus nerve by pressing a microneedle array into the skin. After inserting the microneedle array into the skin, as described above, it was determined that the microneedles had their tip portions penetrating the stratum corneum and were at the required positions. The tissue surrounding each microneedle was then excised as determined above to remove the microneedle array from the skin surface. A therapeutic surface electrode was applied to the skin surface covering the micropores, and a grounding electrode was placed 1 to 10 centimeters away from the therapeutic electrode.

[0072] Rats in groups ii and iii were treated simultaneously using signals having the following parameters: Frequency - 5 to 30 Hz Pulse width - 100 to 500 microseconds Pulse shape - bipolar Interphase - 10 to 100 microseconds Intensity range - 1.0 to 4.0 mA Groups ii and iii were each treated for 10 minutes in 2 sessions. Group iii was not administered LPS. Group iv was not administered LPS and was not electrically treated either.

[0073] These results are shown in FIGS. 6 to 9. FIGS. 6 to 8 show the average measured values of cytokines TNFα, IL6, and IL-1β respectively, and FIG. 9 shows the average measured values of IL-10 at 90 minutes and 120 minutes after LPS administration. The bars indicate the standard deviation.

[0074] (IL-1β: 145 pg / ml and 770 pg / ml; IL6: below the sensitivity level, 852 pg / ml; TNFα: 105 pg / ml, 565 pg / ml; IL-10: below the sensitivity level) is Group i, and Bars 3 and 4 (IL-1β: 20 pg / ml, 214 pg / ml; IL6: below the sensitivity level, 364 pg / ml; TNFα: below the sensitivity level, 280 pg / ml; IL-10: 53 pg / ml, 713 pg / ml) are Group ii. Groups iii and iv were below the detection sensitivity. Statistical calculations showed a decrease in the cytokine levels of TNFα, IL6, and IL-1β in Group ii, which was significant at p < 0.05. The increase in the IL-10 level in Group ii was also significant at p < 0.05. [Example 2] Examination of Rat Blood Pressure

[0075] The effect of electrical stimulation on rat blood pressure was examined in 4 rats using the system of the present invention. As described above, after forming micropores in the skin of the neck, surface electrodes for stimulation were placed covering the micropores, and the vagus nerve was stimulated using a signal having the following parameters. Frequency - 10 to 40 Hz Pulse width - 200 to 1000 microseconds Pulse shape - Bipolar Intermediate period - 10 to 100 microseconds Intensity range - 0.5 to 4.0 mA

[0076] Figure 10 shows the average systolic and diastolic blood pressures of 4 rats and shows the average baseline obtained over 50 minutes or more before treatment. Next, the above treatment was continued for 5 minutes, and then the blood pressure was monitored for 45 minutes. The systolic blood pressure decreased by 15% during the measurement period after treatment, and the diastolic blood pressure decreased by approximately 20% during the same time period.

[0077] It should be understood that certain features of the invention, which have been described separately for clarity in connection with separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that have been described in connection with a single embodiment for brevity may also be provided separately or in any suitable partial combination.

[0078] Although the present invention has been described with reference to its specific embodiments, it will be apparent to those skilled in the art that many alternatives, modifications, and variations will be obvious. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and scope of the appended claims. All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. Additionally, any reference standards or identifiers in this application are not to be construed as an admission that such references are available as prior art to the present invention.

Claims

1. A system for electrically stimulating biological tissue, comprising: (a) a microneedle array in which the microneedles are formed of a conductive material and adapted to create holes in the tissue surface; (b) a power unit; (c) one or more surface electrodes configured to be connected to the power unit and to transmit electrical stimulation to the biological tissue; (d) a processing unit configured to determine, from an input signal, · whether the microneedles in the microneedle array are at a predetermined position in the tissue, and · whether tissue surrounding one or more of the microneedles has been excised, wherein the processing unit is configured to determine any one or more of the foregoing. A system comprising the above components.

2. The system according to claim 1, further comprising one or more force detectors, each force detector being one or more of the microneedles in the array and configured to detect the application of pressure applied by the tissue, wherein the pressure indicates the position of the microneedles in the tissue and is configured to generate a signal indicating the position of one or more of the microneedles, and the signal is input to the processing unit.

3. The system according to claim 2, wherein one or more of the force detectors comprise a displacement mechanism that activates the force detector when a force is detected by the force detector.

4. The system according to claim 2 or 3, wherein the force detector is a spring-based detector, and the degree of compression of the spring indicates the pressure applied by the microneedles in the array.

5. The system according to claim 2 or 3, wherein the force detector is a load cell-based force detector.

6. The system according to any one of claims 2 to 5, wherein one or more of the force detectors comprise a switch that closes when a predetermined force is detected by the force detector, and closing the switch generates an electrical signal input to the processing unit.

7. The system according to claim 6, wherein the processing unit is configured to monitor the time-dependent electrical signal to determine whether the microneedles in the microneedle array are at a predetermined position in the tissue, including determining when the pressure applied by the tissue to the microneedles exceeds a predetermined threshold.

8. The system according to any one of claims 1 to 7 may further include a switching circuit configured for intermittent electrical connection of one or more subsets of the micro needles to the power unit and for intermittent electrical connection of one or more of the surface electrodes to the power unit.

9. The system according to claim 8, further comprising a signal generator, wherein the processing unit is further configured to activate the signal generator to transmit an electrical signal between a selectable first subset of micro needles and a selectable second subset of micro needles, or between a selectable first set of micro needles and at least one of the surface electrodes.

10. The system according to claim 9, wherein the processing unit is further configured to activate the signal generator to transmit an ablation signal between a selectable first subset of micro needles and either a selectable second subset of micro needles and one or more of the surface electrodes, the ablation signal being selected to ablate tissue surrounding one or more of the micro needles.

11. The system according to claim 10, wherein the processing unit is further configured to activate the signal generator to transmit the ablation signal only after determining that the micro needle array is in a predetermined position.

12. The system according to claim 10 or 11, wherein the processing unit is further configured to activate the signal generator to generate a test signal between a selectable first subset of micro needles and either a selectable second subset of micro needles and one or more of the surface electrodes, and to determine whether tissue surrounding the micro needles in the selectable first subset has been ablated, including analyzing the response of the tissue to the test signal.

13. The processing unit is further configured to generate the test signal between a plurality of selectable first subsets of the microneedles and either one or more selectable second subsets of the microneedles and one or more of the surface electrodes, and to determine whether resection of the microneedles in the array meets a predetermined criterion. The system according to claim 11.

14. The processing unit is further configured to determine the number of microneedles in the array when the tissue surrounding the microneedles is resected. The system according to claim 13.

15. The predetermined criterion is determined such that the number of microneedles in the array is greater than a predetermined threshold when the tissue surrounding the microneedles is resected. The system according to claim 14.

16. The processing unit is configured to transmit an electrical stimulus to the tissue when the predetermined criterion is met. The system according to claim 14 or 15.

17. The resection signal is a pressure signal. The system according to any one of claims 10 to 16.

18. The resection signal is composed of a series of burst pulses. The system according to any one of claims 10 to 17.

19. The resection signal is composed of square voltage pulses with alternating signs. The system according to any one of claims 10 to 18.

20. The resection signal is composed of a sine wave signal. The system according to any one of claims 10 to 19.

21. The resection signal has an amplitude of 200 to 800 volts. The system according to any one of claims 10 to 20.

22. The resection signal has a frequency of 1 to 1000 kHz. The system according to any one of claims 10 to 21.

23. Determining whether the tissue surrounding the microneedles in the selectable first subset has been resected includes monitoring the current or impedance response of the tissue and determining whether the current exceeds a predetermined threshold or whether the impedance is below a predetermined threshold. The system according to any one of claims 18 to 22.

24. The system according to any one of claims 1 to 23, configured to transmit an electrical stimulus through the skin.

25. The system according to claim 24, wherein at a predetermined position of the micro needles in the micro needle array, the micro needles penetrate through the stratum corneum of the skin.

26. The system according to claim 24 or 25, configured to transmit an electrical stimulus to one or more nerves under the skin surface.

27. The system according to claim 26, wherein the nerve is the vagus nerve.

28. The system according to any one of claims 1 to 27, wherein one or more of the surface electrodes are wet electrodes.

29. A method of electrically stimulating biological tissue, comprising: (a) applying a micro needle array to the surface of the biological tissue to create holes in the tissue surface and generate micropores in the tissue; (b) determining one or more of the following: - whether the micro needles in the micro needle array are at a predetermined position in the tissue, and - whether the tissue surrounding one or more micro needles has been removed; (c) applying one or more surface electrodes over the micropores to the tissue surface and transmitting an electrical stimulus through the one or more surface electrodes. A method comprising the steps above. ​

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