Systems and methods for treatment of pain

Abstract

A system for the treatment of pain comprising: at least one muscle graft in contact with: an epineural window of a target nerve, and / or a terminus of a target nerve; and at least one electrode.

Description

SYSTEMS AND METHODS FOR TREATMENT OF PAINCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. § 119 of U.S. Provisional Application No. 63 / 608,925 filed December 12, 2023, the contents of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The technology described herein relates to treatment of pain and systems / devices for such purposes.BACKGROUND|0003| Chronic pain conditions, acute injuries, and post-operative discomfort affect millions worldwide, significantly impacting quality of life and productivity. This has created a pressing need for effective and personalized pain management options that go beyond traditional approaches like opioids. As concerns about opioid addiction and side effects mount, patients, healthcare providers, and researchers seek safer, non-invasive. and non-pharmacological interventions. There is an increased need for wearable devices, digital health platforms, virtual reality therapies, biofeedback techniques, and advanced pain-relief technologies that improve on the available therapeutic approaches.SUMMARY

[0004] Prior art methods of using electrical stimuli to activate nerves must overcome significant barriers to activate the target nerve, resulting in the use of high voltages. This leads to heating of the surrounding tissue and / or off-target effects. The inventors have formd that improved nene activation can be achieved by activating the nene indirectly. Instead of providing an electrical stunulus to a nerve, the inventors place a muscle graft near the nerve and provide the electrical stimulus to the muscle graft. The electrical stimulus is then transmitted into the nerve via pathways that more closely mimic natural nen e activation. This permits more effective treatment of pain, the use of lower voltages, and reduces unwanted or harmful side effects such as tissue heating.

[0005] In one aspect of any of the embodiments, described herein is a system comprising: a) at least one muscle graft in contact with:1) an epineural window of a target nene, and / or2) a terminus of a target nene: and b) at least one electrode.In some embodiments of any of the aspects, the muscle graft is denenated at the time of grafting. In some embodiments of any of the aspects, the muscle graft is a skeletal muscle graft. In some embodiments of any of the aspects, the muscle graft is an autograft. In some embodiments of any of the aspects, the muscle graft is an allograft.

[0006] In some embodiments of any of the aspects, the at least one muscle graft is in contact with an epineural window of a target nerve and the epineural window is not located at a terminus of the target nerve.

[0007] In some embodiments of any of the aspects, the at least one electrode is implanted. In some embodiments of any of the aspects, the at least electrode is located hi, underneath, or on the skin of a subject. In some embodiments of any of the aspects, the at least one electrode is connected to a wired or wireless pulse generator or wired or wireless stimulator. In some embodiments of any of the aspects, the pulse generator is a subdermal implanted pulse generator. In some embodiments of any of the aspects, a topical patch comprises the at least one electrode. In some embodiments of any of the aspects, the at least one electrode is topical, or penetrates the stratum comeum, penetrates the stratum corneum greater than 40um, or penetrates up to 2 mm into the skin. In some embodiments of any of the aspects, the topical patch comprises one or more of: c) at least one pulse generator; d) at least one battery; e) a biocompatible gel; andI) at least one adhesive portion.

[0008] In some embodiments of any of the aspects, the system further comprises a biocompatible gel in contact with at least one of the at least one muscle graft and / or the at least one electrode; and / or located at least in part between the at least one muscle graft and / or the at least one electrode. In some embodiments of any of the aspects, the biocompatible gel is an alginate / poly-acry lamide hydrogel.

[0009] In some embodiments of any of the aspects, the biocompatible gel is a conductive gel.

[0010] In some embodiments of any of tire aspects, the system further comprises a conductive gel in contact with at least one of the at least one muscle graft and / or the at least one electrode; and / or located at least in part between the at least one muscle graft and / or the at least one electrode. In some embodiments of any of the aspects, the conductive gel is an alginatc / poly -aery lam ide hydrogel.

[0011] In one aspect of any of the embodiments, described herein is a method of inducing afferent activation in a nerve in a subject in need thereof, the method comprising delivering, to a subject administered a system as described herein, an electrical signal from the at least one electrode to the at least one muscle graft.

[0012] In one aspect of any of the embodiments, described herein is a method of treating neuropathy or pain in a subject in need thereof, the method comprising delivering, to a subject administered a system as described herein, an electrical signal from the at least one electrode to the at least one muscle graft.

[0013] In some embodiments of any of the aspects, the target nerve has or is diagnosed as having neuropathy or is involved in nociception of pain that the subject is in need of treatment for.

[0014] In one aspect of any of the embodiments, described herein is a method of selectively stimulating sensory fibers, die mediod comprising delivering, to a subject administered a system as described herein, an electrical signal from the at least one electrode to the at least one muscle graft.

[0015] In some embodiments of any of the aspects, the sensory fiber is stimulated via the muscle graft and not stimulated via the motor fibers of the target nerve. In some embodiments of any of the aspects, the electrical signal is 50% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft. In some embodiments of any of the aspects, the target nerve innervates the muscle graft. In some embodiments of any of the aspects, the target nerve innervates the muscle graft with multiple sprouts.BRIEF DESCRIPTION OF THE DRAWINGS|0016| Fig. 1 depicts an exemplary system as described herein, e.g., comprising a topical patch.

[0017] Fig. 2 depicts an exemplary system as described herein.

[0018] Fig. 3 depicts an exemplary' system as described herein, e.g., comprising a conductive gel.

[0019] Figs. 4A-4D show the results of tests conducted in rats and described in Example 2.DETAILED DESCRIPTION

[0020] Direct electrical stimulation of nerves has been used to treat certain conditions. The inventors have now found that indirect electrical stimulation of nerves provides multiple advantages and superior therapeutic efficacy as compared to prior art electrical therapies. Specifically, the systems and methods described herein related to delivering an electrical signal or stimulus to a muscle graft that is in contact with the target nen e. This indirect stimulation permits the use of lower voltages, avoids dangerous side effects such as tissue heating, encourages nen e enervation of the muscle graft which improves efficacy over time, and provides a nen e response which is more likely to override nociception and provide effective pain relief.

[0021] In one aspect of any of the embodiments, described herein is a sy stem comprising a) at least one muscle graft 100 in contact with: a) a target nerve 120; and b) at least one electrode 110. In one aspect of any of the embodiments, described herein is a system comprising a) at least one muscle graft 100 in contact with: 1) an epineural window 121 of a target nerve 120, and / or 2) a terminus 122 of a target nerve 120; and b) at least one electrode 110. An exemplary' embodiment of such a system is depicted in Fig. 1

[0022] In some embodiments of any of the aspects, the muscle graft is an autograft. In some embodiments of any of the aspects, the muscle graft is an allograft. In some embodiments of any of the aspects, the muscle graft is an isograft.

[0023] Allografts include tissue or cells from a donor that can be transplanted into a genetically non-identical member of the same species. Transplanted tissue or cells from a genetically identical donor, i.e., an identical twin, is termed an isograft. When a cell or tissue is transplanted from one site to another in the same individual, it is termed an autograft. In contrast, a transplant from anotherspecies is called a xenograft. In some eases, muscle from a human donor is transplanted into another human. Methods of muscle grafting are known in the art.

[0024] In some embodiments of any of the aspects, the muscle graft is denervated at tire time of grafting. In some embodiments of any of the aspects, the muscle graft is a skeletal muscle graft.

[0025] In some embodiments of any of the aspects, the muscle graft is at least 0.1 cm x 0.1 cm. In some embodiments of any of the aspects, the muscle graft is at least 0.5 cm x 0.5 cm. In some embodiments of any of the aspects, the muscle graft is at least 1 cm x 1 cm. In some embodiments of any of the aspects, the muscle graft is at least 2 cm x 2 cm.

[0026] In some embodiments of any of the aspects, the muscle graft is no greater than 20 cm x 20 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 15 cm x 15 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 10 cm x 10 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 7 cm x 7 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 5 cm x 5 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 3 cm x 3 cm.

[0027] In some embodiments of any of the aspects, the muscle graft is at least 0.1 cm x 0.1 cm x 0.1 cm. In some embodiments of any of the aspects, the muscle graft is at least 0.5 cm x 0.5 cm x 0.5 cm. In some embodiments of any of the aspects, the muscle graft is at least 1 cm x 1 cm x 1 cm. In some embodiments of any of the aspects, the muscle graft is at least 2 cm x 2 cm. In some embodiments of any of the aspects, the muscle graft is at least 2 cm x 2 cm and no more than 2 cm in the third dimension.

[0028] In some embodiments of any of tire aspects, the muscle graft is no greater than 20 cm x 20 cm x 2 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 15 cm x 15 cm x 2 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 10 cm x 10 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 7 cm x 7 cm x 2 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 5 cm x 5 cm x 2 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 3 cm x 3 cm x 2 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 5 cm x 3 cm x 2 cm. In some embodiments of any of the aspects, the muscle graft is no greater than 7 cm x 5 cm x 2 cm.

[0029] As used herein, “nerve" refers to a bundle of nerve fibers (also known as axons). A healthy peripheral nerve will have a natural terminus where the nerve forms synapses with a tissue or has a sensory receptor. Between the natural terminus and connection of the nerve to the brain, the nerve has an outer covering of connective tissue called the epineurium. Under the cpincurium is the endoneurium, a tube of collagen and glycocalyx. A tissue which comprises a nerve or portion of a nerve is referred to as “innervated.” A tissue which comprises a nerve or portion of a nerve is referred to as “denervated.”

[0030] As used herein, “terminus” refers to the distal end of a nene (c.g., with respect to the central nervous system). A terminus can be a natural terminus or formed by transection or neurectomy.

[0031] As used herein, a “target nerve” is nerve drat is to be electrically stimulated using the systems and / or methods described herein. In some embodiments of any of the aspects, the target nerve can be a nerve suffering from a disease, disorder, or damage. In some embodiments of any of the aspects, the target nerve can be a nerve that transmits or generates pain that a subject is in need of treatment for.

[0032] As used herein, “in contact with” means that two elements are physically arranged such that an electrical signal in a first element (e.g.. a muscle graft) can be transmitted or communicated to the second element (e.g.. a target nen e).

[0033] In some embodiments of any of the aspects, a muscle graft is in contact with a target nerve if the muscle graft and target nerve are in physical contact with each other. In some embodiments of any of the aspects, a muscle graft is in contact with a target nerve if the muscle graft is in physical contact with the target nerve. In some embodiments of any of the aspects, a muscle graft is in contact with a target nerve if the muscle graft is in physical contact with the endoneurium of the target nerve. In some embodiments of any of the aspects, a muscle graft is in contact with a target nerve if the muscle graft is in physical contact with at least one nerve terminal of the target nerve. In some embodiments of any of the aspects, a muscle graft is in contact with a target nerve if the muscle graft is in physical contact with at least one axon terminal of the target nerve. In some embodiments of any of the aspects, a muscle graft is in contact with a target nene if there is a synaptic space or synaptic cleft formed between the muscle graft and the target nerve. In some embodiments of any of die aspects, a muscle graft is in contact with a target nerve if the target nerve has innervated the muscle graft.

[0034] An cpincural window can be formed in a nerve, c.g., a target nerve by a gap or disruption in the epineurium of the nerve. An epineural window can be formed by surgically removing a portion of the epineurium. An epineural window can also be formed by surgically cutting, slitting, ablating, or tearing the epineurium. An epineural window can provide a muscle graft the ability to transmit electrical signals to a nerve, or to more strongly or efficiently transmit an electrical signal to a nerve. In some embodiments of any of the aspects, the muscle graft is in contact with an epineural window of a target nerve. In some embodiments of any of the aspects, the muscle graft is in contact with an epineural window of a target nen e and the epineural window is not located at a terminus of the target nerve.

[0035] In some embodiments of any of the aspects, the muscle graft is in contact with an epineural window of a target nen e. In some embodiments of any of the aspects, the muscle graft is incontact with a terminus of a target nerve. In some embodiments of any of the aspects, the muscle graft is in contact with an epineural window of a target nerve and a terminus of a target nerve.

[0036] The systems described herein comprise one or more electrodes. As used herein, “electrode” refers to a conductor through which electricity enters or leaves an object, substance, or region. In the systems described herein, the at least one electrode comprises at least one electrode configures to permit electricity to enter the at least one muscle graft.

[0037] The systems described herein can comprise one electrode. In some embodiments of any of the aspects, the systems described herein can comprise two or more electrodes, e.g., at least one active electrode conducting electricity into the at least one muscle graft and at least one return electrode. In some embodiments of any of the aspects, the systems described herein can comprise two or more active electrodes. In some embodiments of any of the aspects, the systems described herein can comprise two or more active electrodes, where a first active electrode conducts electricity into a first muscle graft and a second active electrode conducts electricity into a second muscle graft. In some embodiments of any of the aspects, the systems described herein can comprise two or more active electrodes, where a first active electrode and a second active electrode both conduct electricity into the same muscle graft. In some embodiments of any of the aspects, the systems described herein can comprise tw o or more active electrodes, where a first active electrode and a second active electrode both conduct electricity’ into the same muscle graft concurrently. In some embodiments of any of the aspects, the systems described herein can comprise two or more active electrodes, where a first active electrode and a second active electrode both conduct electricity into the same muscle graft non-concurrently. In some embodiments of any of the aspects, the systems described herein can comprise two or more active electrodes, where a first active electrode and a second active electrode both conduct electricity into the same muscle graft at different locations in the same muscle graft.

[0038] The electrode(s) of the sy stems described herein can be placed in (e.g., implanted or inserted) a subject, or used topically on the subject. Whether the clcctrodc(s) is implanted or used topically may depend on a number of factors, e.g., the location of the target nerve, the size of the muscle graft, the placement of the muscle graft with respect to the target nerve and skin, the voltage to be used. etc.

[0039] In some embodiments, the at least one electrode is implanted. The at least one implanted electrode can be in contact with the muscle graft. In some embodiments of any of the aspects, the at least one implanted electrode is in physical contact with the muscle graft.

[0040] In some embodiments, the at least one electrode is topical. In some embodiments, the at least one electrode is not implanted. In some embodiments, the at least one electrode is located in, underneath, or on the skin of a subject. In some embodiments, the at least one electrode is located in the skin of a subject. In some embodiments, the at least one electrode is located underneath the skin of a subject. In some embodiments, the at least one electrode is located on the skin of a subject. Insome embodiments, the at least one electrode penetrates the stratum comcum. In some embodiments, die at least one electrode penetrates the stratum corneum greater than 40 um. In some embodiments, die at least one electrode penetrates up to 2 mm into the skin.

[0041] In some embodiments of any of the aspects, the at least one electrode is not in contact with the target nerve. In some embodiments of any of the aspects, the at least one electrode is not in physical contact with die target nerve.

[0042] A system described herein can comprise at least 2 electrodes. In some embodiments of any of die aspects, a system described herein can comprise from 2 to 10 electrodes. In some embodiments of any of the aspects, a system described herein can comprise from 2 to 20 electrodes. In some embodiments of any of the aspects, a system described herein can comprise from 2 to 50 electrodes. In some embodiments of any of the aspects, a system described herein can comprise from 2 to 100 electrodes. In some embodiments of any of the aspects, a system described herein can comprise from 2 to 200 electrodes.

[0043] In some embodiments of any of the aspects, the at least one electrode is connected to a power source. In some embodiments of any of the aspects, the at least one electrode is connected to pulse generator, stimulator, or controller that is connected to a power source. In some embodiments of any of the aspects, the power source can be or comprise a battery, e g., a battery in the device, in an implantable pulse generator or stimulator, or a battery in a topical patch. The battery can store electrical energy and supply it to the pulse generator or stimulator. In some embodiments of any of the aspects, the power source can comprise a cord or other means of connection to an electrical power source, such as electrical outlet. The power source can be connected in a wired or wireless manner.

[0044] In some embodiments of any of the aspects, the at least one electrode is connected to a wired or wireless pulse generator or wired or wireless stimulator.

[0045] In some embodiments of any of the aspects, the at least one electrode is connected wirelessly to a pulse generator or stimulator. In some embodiments of any of the aspects, the at least one electrode is comrected wirelessly to a pulse generator. In some embodiments of any of the aspects, the at least one electrode is connected wirelessly to a stimulator.

[0046] In some embodiments of any of the aspects, the at least one electrode is comrected by one or more wires to a pulse generator or stimulator. In some embodiments of any of the aspects, the at least one electrode is connected by one or more wires to a pulse generator. In some embodiments of any of tire aspects, the at least one electrode is connected by one or more wires to a stimulator.

[0047] As used herein, “pulse generator” refers to a device that produces or generates electrical pulses, e.g., rectangular pulses. In the systems described herein, a pulse generator causes an electrical signal or current to flow through the at least one electrode, through the muscle graft, and into the target nerve. The current can then return to the pulse generator via the return electrode and / or the pulse generator case. Implantable pulse generators, and design principles for implantable pulsegenerators arc known in the art, e.g., Sarica ct al. Front. Hinn Ncuroscic 15:708481 (2021), which is incorporated by reference herein in its entirety. Pulse generators can comprise controllers and / or power sources in the pulse generator, e.g.. inside the pulse generator case. In some embodiments of any of the aspects, the at least one electrode is connected to a wired or wireless pulse generator. In some embodiments of any of the aspects, the at least one electrode is connected to a wired pulse generator. In some embodiments of any of the aspects, the at least one electrode is connected to a wireless pulse generator. In some embodiments of any of the aspects, the pulse generator is a subdermal implanted pulse generator.

[0048] As used herein, "stimulator" refers to a device comprising electrodes and a means of producing or generating electrical signals (e.g., a pulse generator). In some embodiments of any of the aspects, the at least one electrode is connected to a wired or wireless stimulator. In some embodiments of any of the aspects, the at least one electrode is connected to a wired stimulator. In some embodiments of any of the aspects, the at least one electrode is connected to a wireless stimulator.

[0049] A system described herein can further a controller configured to control the at least one electrode. In some embodiments of any of the aspects, a system described herein can further a controller configured to control the at least one pulse generator or stimulator. A controller can manage the activation and deactivation of the system, waveforms generated by the pulse generator and / or stimulator, and communication with external devices. In some embodiments of any of the aspects, the topical patch can comprise the controller. In some embodiments of any of the aspects, an implantable device can comprise the at least one pulse generator and / or at least one stimulator and the controller. In some embodiments of any of the aspects, an implantable device can comprise the at least one electrode, at least one pulse generator and / or at least one stimulator, and the controller. In some embodiments of any of the aspects, the controller is wirelessly connected to the at least one pulse generator and / or at least one stimulator. In some embodiments of any of the aspects, the controller has a wired connected to the at least one pulse generator and / or at least one stimulator. In some embodiments of any of the aspects, the controller is physically separate from the one pulse generator and / or at least one stimulator, e.g., except for the wired or wireless connection. For example, the controller could be a separate device or an app or program on a mobile device.

[0050] In some embodiments of any of the aspects, the controller can include a wireless transceiver for receiving commands from a user device, such as a mobile phone or control unit. Although described as a mobile phone, any device capable of sending commands to the controller can be used, such as any computing device, any smart device, etc.

[0051] In some embodiments of any of the aspects, the methods described herein can comprise (or the systems described herein can be operated by) generating the electrical signals or stimuli on- demand in response to receiving a command at the controller. In some embodiments of any of theaspects, the methods described herein can comprise (or the systems described herein can be operated by) generating the one or more electrical signals or stimuli on-demand in response to a command generated by the controller. In some embodiments of any of the aspects, the electrical signals or stimuli are generated continuously during a pre-determined period of time. In some embodiments of any of the aspects, the electrical signals or stimuli are generated periodically during a pre-detennined period of time.

[0052] As used herein, “controller” or computing device refers to a non-human apparatus that is capable of accepting a structured input, processing the structured input according to prescribed rules, and producing results of the processing as output. The controller can include any suitable processing device, such as general purpose computer systems, microprocessors, digital signal processors, microcontrollers, application specific integrated circuits (ASICs), programmable logic devices (PLDs) field programmable logic devices (FPLDs), programmable gate arrays (PGAs), field programmable gate arrays (FPGAs), mobile devices such as mobile telephones, personal digital assistants (PDAs), or tablet computers, local servers, remote servers, wearable computers, or the like. In some embodiments, the controller can comprise or be connected to (or in communication with) a memory device. The memory device can include any suitable memory device and / or machine-readable medium that is capable of storing, encoding, and / or carrying a set of instructions for execution by a processing device and that cause the processing device to perform and / or implement any of the features discussed herein, including solid-state memories, optical media, magnetic media, random access memory (RAM), read only memory (ROM), a floppy disk, a hard disk, a CD ROM. a DVD ROM. flash memory, or other computer readable medium that is read from and / or written to by a magnetic, optical, or other reading and / or writing system that is coupled to the processing device, can be used for the memory or memories.

[0053] In some embodiments of any of the aspects, the sy stem comprises a computing device, a server, a network, and / or a database. In some embodiments, the computing device and server can be connected by a network and the network can be comiected to various other devices, servers, or network equipment for implementing the present disclosure. A computing device can be connected to a display. Computing device can be any suitable computing device, including a desktop computer, server (including remote servers), mobile device, or other suitable computing device. In some examples, algorithm(s) as described herein and other software can be stored in database and run on server. Additionally, data and data processed or produced by said algorithms or programs can be stored in a database.

[0054] It should be understood that the disclosure herein can be implemented with any type of hardware and / or software and can be a pre-programmed general pinpose computing device. For example, the system can be implemented using a server, a personal computer, a portable computer, a thin client, or any suitable device or devices. The disclosure and / or components thereof can be asingle device at a single location, or multiple devices at a single, or multiple, locations that arc connected together using any appropriate communication protocols over any communication medium such as electric cable, fiber optic cable, or in a wireless manner.

[0055] It should also be noted that the disclosure can be illustrated and discussed herein as having a plurality of modules which perform particular functions. It should be understood that these modules are merely schematically illustrated based on their function for clarity purposes only, and do not necessary represent specific hardware or software. In this regard, these modules can be hardware and / or software implemented to substantially perform the particular functions discussed. Moreover, the modules can be combined together within the disclosure or divided into additional modules based on the particular function desired. Thus, the disclosure should not be construed to limit the present technology as disclosed herein, but merely be understood to illustrate one exemplary implementation thereof.

[0056] The computing system can include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other. In some implementations, a server transmits data (e.g., an HTML page) to a client device (e.g., for purposes of displaying data to and receiving user input from a user interacting with the client device). Data generated at the client device (e.g., a result of the user interaction) can be received from the client device at the server. Implementations of the subject matter described herein can be implemented in a computing system that includes a back end component, e.g., as a data server, or that includes a middleware component, e.g., an application server, and / or that includes a front end component, e.g., a client computer having a graphical user interface or a Web browser through which a user can interact with an implementation of the subject matter described in this specification, or any combination of one or more such back end, middleware, or front end components. The components of the system can be interconnected by any form or medium of digital data communication, e.g., a communication netw ork. Examples of communication networks include a local area network (“LAN'’) and a wide area network (“WAN”), an inter-network (e.g., the Internet), and peer-to-peer networks (e.g., ad hoc peer to-peer networks).

[0057] Implementations of the subject matter and the operations described herein can be implemented in digital electronic circuitry, or in computer software, finnware, or hardware, including the structures disclosed herein and their structural equivalents, or in combinations of one or more of them. Implementations of the subject matter described herein can be implemented as one or more computer programs, e.g.. one or more modules of computer program instructions, encoded on computer storage medium for execution by. or to control the operation of, data processing apparatus. Alternatively or in addition, the program instructions can be encoded on an artificially generated propagated signal, e.g., a machine-generated electrical, optical, or electromagnetic signal that isgenerated to encode information for transmission to suitable receiver apparatus for execution by a data processing apparatus. A computer storage medium can be, or be included in, a computer-readable storage device, a computer-readable storage substrate, a random or serial access memorj' array or device, or a combination of one or more of them. Moreover, while a computer storage medium is not a propagated signal, a computer storage medium can be a source or destination of computer program instructions encoded in an artificially generated propagated signal. The computer storage medium can also be, or be included in, one or more separate physical components or media (e.g.. multiple CDs, disks, or other storage devices).

[0058] The operations described in this specification can be implemented as operations performed by a “data processing apparatus” on data stored on one or more computer-readable storage devices or received from other sources. The term "data processing apparatus” encompasses all kinds of apparatus, devices, and machines for processing data, including by way of example a programmable processor, a computer, a system on a chip, or multiple ones, or combinations, of the foregoing. The apparatus can include special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit). The apparatus can also include, in addition to hardware, code that creates an execution environment for the computer program in question, e.g.. code that constitutes processor firmware, a protocol stack, a database management system, an operating system, a cross-platform runtime environment, a virtual machine, or a combination of one or more of them. The apparatus and execution environment can realize various different computing model infrastructures, such as web services, distributed computing, and grid computing infrastructures.

[0059] A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, declarative or procedural languages, and it can be deployed in any form, including as a standalone program or as a module, component, subroutine, object, or other unit suitable for use in a computing environment. A computer program can, but need not, correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub programs, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication netw ork.

[0060] The processes and logic flows described in this specification can be performed by one or more programmable processors executing one or more computer programs to perform actions by operating on input data and generating output. The processes and logic flows can also be performedby, and apparatus can also be implemented as, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit).

[0061] Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor can receive instructions and data from a read only memory' or a random access memory' or both. The essential elements of a computer are a processor for performing actions in accordance with instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g.. magnetic, magneto optical disks, or optical disks. However, a computer need not have such devices. Moreover, a computer can be embedded in another device, e.g., a mobile telephone, a personal digital assistant (PDA), a mobile audio or video player, a game console, a Global Positioning System (GPS) receiver, or a portable storage device (e.g., a universal serial bus (USB) flash drive), to name just a few. Devices suitable for storing computer program instructions and data include all forms of nonvolatile memory', media and memory devices, including by way of example semiconductor memory devices, e.g.. EPROM, EEPROM, and flash memory devices; magnetic disks, e.g.. internal hard disks or removable disks; magneto optical disks; and CD ROM and DVD-ROM disks. The processor and the memory can be supplemented by. or incorporated in. special purpose logic circuitry.

[0062] In some embodiments of any of the aspects, a topical patch 130 comprises the at least one electrode. The topical patch can further comprise other elements of a system described herein, and / or permit replacement and removability of the at least one electrode. In some embodiments of any of the aspects, a topical patch comprises one or more of at least one pulse generator 131; at least one battery 132; a biocompatible gel 133; and at least one adhesive portion 134. The battery 132, pulse generator 131, and at least one electrode 110 can be connected by leads 135. An exemplary embodiment of such a system comprising a topical patch is depicted in Fig. 1. Alternatively, wireless connections can be used.

[0063] As used herein, ‘topical patch” refers to a device placed on the skin to deliver a stimulus and / or agent through the skin. Topical patches typically include at least one adhesive portion and may contain non-adhesive portions. Topical patches can also comprise a backing that protects the patch and its other components from the outer environment. In some embodiments of any of the aspects, a topical patch is a transdermal patch.

[0064] As used herein, the term “gel” refers to the state of matter between liquid and solid. As such, a “gel” has some of the properties of a liquid (i.e., the shape is resilient and deformable) and some of the properties of a solid (i.e., the shape is discrete enough to maintain three dimensions on a two dimensional surface.). A non-limiting example of a gel is a hydrogel. A hydrogel is a substance that is formed when an organic polymer (natural or synthetic) is crosslinked via covalent, ionic, orhydrogen bonds to create a three-dimensional open-lattice structure which entraps water molecules to form a gel. Gels are well known in the art and non-limiting examples are provided below herein.

[0065] As used herein, “biocompatible” refers to materials which do not have toxic or injurious effects on biological functions, e.g., exhibition of essentially no cytotoxicity or immunogenicity while in contact with body fluids or tissues. Exemplary' biocompatible gels include but are not limited to biocompatible gels or hydrogels comprising polymers such as poly(lactide) (PLA), poly(glycolic acid) (PGA), poly(lactide-co-glycolide) (PLGA). and other polyhydroxyacids, poly (caprolactone), polycarbonates, polyamides, polyanhydrides, polyphosphazene, polyamino acids, polyortho esters, polyacetals, polycyanoacrylates and biodegradable polyurethanes; non-biodegradable polymers such as polyacrylates, ethylene-vinyl acetate polymers and other acyl-substituted cellulose acetates and derivatives thereof; polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, polyethylene oxide; albumin, collagen, fibrin, silk, synthetic polyamino acids and prolamines; polysaccharides such as alginate, heparin; and other naturally occurring biodegradable polymers of sugar units. Alternately, combinations of the aforementioned polymers can be used.

[0066] As used herein, “adhesive” refers to a substance that, when applied to one or both surfaces of two elements (e.g., skin and a topical patch), will keep the two elements in contact and resist their separation. The adhesive portion(s) can form a perimeter on the topical patch around any electrodes, pulse generators, batteries, or biocompatible gels. The adhesive portion(s) can also comprise multiple spots or patches of adhesive interspersed across a surface of the topical patch. The adhesive portion(s) can also comprise rings or perimeters around each electrode or groups of electrodes, e.g., to ensure tight contact of the electrodes and the skin.

[0067] Exemplary' adhesives include but are not limited to acry lates, silicones, poly isobutylenes, polysiloxancs, polyacrclyatc copolymers, Dimcthiconol / Trimcthylsiloxysilicatc Crosspolymers, and the like. Further discussion of topical patch adhesives can be found in the art, e.g, Banerjee et al. Adhesion & Adhesives 50:70-84 (2014); Kandavilli et al. Pharrn Technol 62-80 (2002); and Tan and Pfister. Pharrn Sci Technolo Today 2:60-69 (1999); each of which is incorporated by reference herein in its entirety. Adhesives can be pressure-sensitive adhesives.

[0068] In some embodiments of any of the aspects, a topical patch comprises at least one pulse generator 131: at least one battery' 132; a biocompatible gel 133; and at least one adhesive portion 134. In some embodiments of any of the aspects, a topical patch comprises at least one pulse generator 131: a biocompatible gel 133: and at least one adhesive portion 134. In some embodiments of any of the aspects, a topical patch comprises at least one battery 132; a biocompatible gel 133; and at least one adhesive portion 134. In some embodiments of any of the aspects, a topical patch comprises at least one pulse generator 131; at least one battery 132; and at least one adhesive portion134. In some embodiments of any of the aspects, a topical patch comprises at least one pulse generator 131 and at least one adhesive portion 134. In some embodiments of any of the aspects, a topical patch comprises at least one battery 132 and at least one adhesive portion 134. In some embodiments of any of the aspects, a topical patch comprises a biocompatible gel 133 and at least one adhesive portion 134.

[0069] A topical patch can comprise at least 2 electrodes (e.g, stimulation points). In some embodiments of any of the aspects, a topical patch can comprise from 2 to 10 electrodes (e.g., stimulation points). In some embodiments of any of the aspects, a topical patch can comprise from 2 to 20 electrodes (e.g., stimulation points). In some embodiments of any of the aspects, a topical patch can comprise from 2 to 50 electrodes (e.g., stimulation points). In some embodiments of any of the aspects, a topical patch can comprise from 2 to 100 electrodes (e.g., stimulation points). In some embodiments of any of the aspects, a topical patch can comprise from 2 to 200 electrodes (e.g., stimulation points).

[0070] Biocompatible and / or conductive gels are also known in the art and can be used in some embodiments of the systems described herein. In particular, injectable or implantable conductive gels can help transmit electrical signals from the at least one electrode to the muscle graft and the target nerve. In some embodiments of any of the aspects, the system further comprises a conductive gel. In some embodiments of any of the aspects, the system further comprises a conductive gel in contact with at least one of the at least one muscle graft and / or the at least one electrode; and / or located at least in part between the at least one muscle graft and / or the at least one electrode. In some embodiments of any of the aspects, the system further comprises a conductive gel in contact with the at least one muscle graft. In some embodiments of any of the aspects, the system further comprises a conductive gel in contact with the at least one electrode. In some embodiments of any of the aspects, die system further comprises a conductive gel located at least in part between the at least one muscle graft and / or the at least one electrode.

[0071] Such conductive gels are known in the art and include alginatc / poly-acry lamidc hydrogels. In some embodiments of any of the aspects, the conductive gel can comprise a ratio of 50 mg / mL acrylamide and 25 mg / mL alginate with 75% crosslinker concentration. For further discussion, see, e.g., Srinivasan et al. Med 4: 1-13 (2023) and International Patent Publication WO 2023 / 034614; each of which is incorporated by reference herein in its entirety.

[0072] The systems described herein can be used in methods to stimulate nerves and / or control stimulation of nerves. In one aspect of any of the embodiments described herein, a system described herein is for use in a method of inducing afferent activation in a nerve in a subject in need thereof. In one aspect of any of the embodiments described herein, a system described herein is for use in a method of treating neuropathy in a subject in need thereof. In one aspect of any of the embodimentsdescribed herein, a system described herein is for use in a method of selectively stimulating sensory fibers in a subject in need thereof.

[0073] In one aspect of any of the embodiments, described herein is a method of inducing afferent activation in a nerve in a subject in need thereof, the method comprising delivering, to a subject administered a system described herein, an electrical signal from the at least one electrode. In one aspect of any of the embodiments, described herein is a method of inducing afferent activation in a nerve, the method comprising administering to the subject a system described herein; and delivering an electrical signal from the at least one electrode.

[0074] In one aspect of any of the embodiments, described herein is a method of selectively stimulating sensory fibers, the method comprising delivering, to a subject administered a system described herein, an electrical signal from the at least one electrode. In one aspect of any of the embodiments, described herein is a method of selectively stimulating sensory fibers, the method comprising administering to the subject a system described herein; and delivering an electrical signal from the at least one electrode. In some embodiments of any of the aspects, the sensory fiber is stimulated via the muscle graft and not stimulated via the motor fibers of the target nerve.

[0075] The controlled nerve stimulation described herein can provide therapeutic treatment for pain, e.g.,. neuropathy. As used herein, “neuropathy” or “peripheral neuropathy” refers any central nervous system (CNS) or peripheral nervous system (PNS) disease or damage associated with a neuronal or glial cell defect, including neuronal deficiency, neuronal degeneration, neuronal demyelination , Gliosis (e.g., astrocytosis), or neurons or extraneuronal accumulation of abnormal proteins or toxins (e.g.. [1-amyloid or a-synuclein). The term encompasses neuropathy of various etiologies, including, but not limited, to neuropathy caused by, resulting from, or associated with genetic disorders, metabolic / endocrine complications, diabetes, inflammatory diseases, vitamin deficiencies, malignant diseases, and toxicity, such as alcohol, organic metal, heavy metal, radiation, and drug toxicity. As used herein, the term encompasses motor, sensory', mixed sensorimotor, chronic, and acute neuropathy. As used herein the term encompasses mononeuropathy, multiple mononeuropathy, and polyneuropathy.Illustrative causes of neuropathy include, but are not limited to, neuropathy caused by, resulting from, or associated with diabetes, chemotherapy, trauma, malnutrition, alcoholism, autoimmune diseases, cancer, infectious diseases, kidney disease, liver disease, HIV, AIDS, hypothyroidism, hereditary' disorders, and exposure to toxins. Neuropathy often presents with pain symptoms.

[0076] In one aspect of any of the embodiments, described herein is a method of treating neuropathy or pain in a subject in need thereof, the method comprising delivering, to a subject administered a system described herein, an electrical signal from the at least one electrode. In one aspect of any of the embodiments, described herein is a method of treating neuropathy or pain in asubject in need thereof, the method comprising administering to the subject a system described herein; and delivering an electrical signal from the at least one electrode.

[0077] In some embodiments of any of die aspects, the subject is one having or diagnosed as having neuropathy. In some embodiments of any of the aspects, die subject is one having or diagnosed as having a pain disorder. In some embodiments of any of the aspects, the subject is one having or diagnosed as having chronic regional pain syndrome; peripheral nerve pain; visceral pain; neuropathies; spinal cord injury'; spasticity'; ischemic pain; Multiple Sclerosis; or urinary or bowel dysfunction.

[0078] In some embodiments of any of the aspects, the target nen e is one having or diagnosed as having neuropathy. In some embodiments of any of the aspects, the target nerve is one having or diagnosed as being involved in nociception of pain that the subject is in need of treatment for.

[0079] The methods described herein provide multiple advantages over prior art methods of nerve stimulation. For example, in some embodiments of any of the aspects, the electrical signal is 50% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft. In some embodiments of any of the aspects, the electrical signal is 40% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft. In some embodiments of any of the aspects, the electrical signal is 30% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft. In some embodiments of any of the aspects, the electrical signal is 20% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft. In some embodiments of any' of the aspects, the electrical signal is 10% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft.

[0080] The operating advantages of the instant methods and systems can be due in part to innervation of the muscle graft by the target nen e. In some embodiments of any of the aspects, target nen e innervates the muscle graft. In some embodiments of any of the aspects, the target nerve innervates the muscle graft with multiple sprouts. In some embodiments of any of the aspects, target nerve innen ates the muscle graft before delivery' of an electrical signal via the at least one electrode.

[0081] As used herein “delivery" of an electrical signal comprises providing an electrical signal into the at least one electrode which is then transmitted at least into the muscle graft. Delivery of an electrical signal can be controlled by an controller and / or generated by a pulse generator and / or stimulator.

[0082] As used herein, administering a system as described herein comprises implanting or transplanting at least one muscle graft such that it is in contact with the target nen e. The muscle graft can be surgically implanted, e.g., by microsurgery. Administering the system can further comprise placing any further components of the system (e.g., electrodes, pulse generator / stimulator, topical patch, controller) in or on the subject. Some of the further components can be implanted, e.g., electrodes and / or a subdermal pulse generator. Some of the further components by be placed, e.g..removably, as in the ease of a topical patch. Such of the further components can be connected to other components or made to be in communication with other components, e.g., a controller that is wirelessly connected to a pulse generator can be turned on or activated such that it is actively controlling the pulse generator.

[0083] In some embodiments, administration comprises physical human activity, e.g., an injection, act of ingestion, an act of application, and / or manipulation of a delivery device or machine. Such activity can be perfonned, e.g., by a medical professional and / or the subject being treated.

[0084] In some embodiments, the methods described herein relate to treating a subject having or diagnosed as having neuropathy or pain with a system described herein. Subjects having such conditions can be identified by a physician using current methods of diagnosing such conditions. For example, symptoms and / or complications of neuropathy which characterize these conditions and aid in diagnosis are well known in the art and include but are not limited to, numbness, tingling, prickling, pain, touch sensitivity, pain, lack of coordination, muscle weakness, and autonomic dysregulation. Tests that may aid in a diagnosis of. e.g. neuropathy include, but are not limited to. neurological exams, blood tests, imaging tests, nerve function tests, nerve biopsy, and skin biopsy. A family history of neuropathy, or exposure to risk factors for neuropathy can also aid in determining if a subject is likely to have neuropathy or in making a diagnosis of neuropathy.

[0085] The compositions and methods described herein can be administered to a subject having or diagnosed as having neuropathy. In some embodiments, the methods described herein comprise administering an effective amount of an electrical signal or stimulus, e.g. in order to alleviate a symptom of the condition, e.g., neuropathy. As used herein, "alleviating a symptom" is ameliorating any symptom associated with the condition. As compared with an equivalent untreated control, such reduction is by at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more as measured by any standard technique.

[0086] The term “effective amount" as used herein refers to die amount of an electrical signal or stimulus needed to alleviate at least one or more symptom of the disease or disorder, and relates to a sufficient amount to provide the desired effect. The term "therapeutically effective amount" therefore refers to an amount of the electrical signal or stimulus that is sufficient to provide a particular pain relieving or stimulatory effect when administered to a typical subject. An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact “effective amount". However, for any given case, an appropriate “effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

[0087] Efficacy can be assessed, for example, by measuring a marker, indicator, sy mptom, and / or the incidence of a condition treated according to the methods described herein or any other measurable parameter appropriate, e.g. neuropathic pain. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization, or need for medical interventions (i.e ., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and / or are described herein. Treatment includes any treatment of a disease in an individual or an animal (some non-limiting examples include a human or an animal) and includes: (1) inhibiting the disease, e.g., preventing a worsening of symptoms (e g. pain); or (2) relieving the severity of the disease, e.g., causing regression of symptoms. An effective amount for the treatment of a disease means that amount which, when administered to a subject in need thereof, is sufficient to result in effective treatment as that term is defined herein, for that disease. Efficacy of an agent can be determined by assessing physical indicators of a condition or desired response, (e.g. pain). It is well within the ability of one skilled in the art to monitor efficacy of administration and / or treatment by measuring any one of such parameters, or any combination of parameters.

[0088] The amount, duration, and waveform of an electrical signal as described herein can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease the amount, increase or decrease administration frequency, discontinue treatment, resume treatment, or make other alterations to the treatment regimen.

[0089] In one respect, the present invention relates to the herein described compositions, methods, and respective component(s) thereof, as essential to the technology, yet open to the inclusion of unspecified elements, essential or not ("comprising). In some embodiments of any of the aspects, other elements to be included in the description of the composition, method or respective component thereof arc limited to those that do not materially affect the basic and novel charactcristic(s) of die technology (e.g., the composition, method, or respective component thereof “consists essentially of' die elements described herein). This applies equally to steps within a described method as well as compositions and components therein. In other embodiments of any of the aspects, the compositions, methods, and respective components thereof, described herein are intended to be exclusive of any element not deemed an essential element to the component, composition or method (e.g., die composition, method, or respective component thereof “consists of' the elements described herein). This applies equally to steps within a described method as well as compositions and components therein.

[0090] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions areprovided to aid in describing particular embodiments, and arc not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all teclmical 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. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0091] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here.

[0092] The terms “decrease”, “reduced”, “reduction”, or "inhibit” are all used herein to mean a decrease by a statistically significant amount. In some embodiments, “reduce,” “reduction" or “decrease" or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment or agent) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%. at least about 55%. at least about 60%, at least about 65%, at least about 70%, at least about 75%. at least about 80%. at least about 85%, at least about 90%, at least about 95%, at least about 98%. at least about 99% , or more. As used herein,“reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.

[0093] The terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms “increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, a “increase” is a statistically significant increase in such level.

[0094] As used herein, a "subject" means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g.. domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu. ostrich, and fish, e.g., trout, catfish and salmon. In some embodiments,die subject is a mammal, c.g., a primate, c.g., a human. The terms, “individual," “patient” and “subject” are used interchangeably herein.

[0095] Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of neuropathy or pain. A subject can be male or female.

[0096] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment (e g. neuropathy) or one or more complications related to such a condition, and optionally, have already undergone treatment for the condition or the one or more complications related to the condition. Alternatively, a subject can also be one who has not been previously diagnosed as having the condition or one or more complications related to the condition. For example, a subject can be one who exhibits one or more risk factors for the condition or one or more complications related to the condition or a subject who does not exhibit risk factors.

[0097] A “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.

[0098] As used herein, the terms "treat.” "treatment." "treating.” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder, e.g. neuropathy or pain. The term “treating" includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with a condition described herein. Treatment is generally “effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective" if the progression of a disease is reduced or halted. That is, “treatment" includes not just die improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but arc not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (z.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and / or decreased mortality, whether detectable or undetectable. The term "treatment" of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).

[0099] The term “statistically significant" or “significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.

[0100] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages can mean ±1%.

[0101] As used herein, the term “comprising" means that other elements can also be present in addition to the defined elements presented. The use of “comprising” indicates inclusion rather than limitation.

[0102] The term "consisting of refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment

[0103] As used herein the term "consisting essentially of refers to those elements required for a given embodiment. The term pennits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.

[0104] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, "e.g." is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[0105] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0106] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary . The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in biology' can be found in The Merck Manual of Diagnosis and Therapy, 20th Edition, published by Merck Sharp & Dohme Corp., 2018 (ISBN 0911910190, 978- 0911910421); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology' and Molecular Medicine, published by Blackwell Science Ltd.. 1999-2012 (ISBN 9783527600908); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc.. 1995 (ISBN 1-56081-569-8); Immunology by Werner Luttmann, published by Elsevier, 2006; Janeway's Immunobiology. Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), W. W. Norton & Company, 2016 (ISBN 0815345054, 978-0815345053); Lewin'sGenes XI, published by Jones & Bartlett Publishers, 2014 (ISBN- 1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory' Press, Cold Spring Harbor, N.Y., USA (2012) (ISBN 1936113414); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012) (ISBN 044460149X); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN 047150338X, 9780471503385), Current Protocols in Protein Science (CPPS). John E. Coligan (ed.), John Wiley and Sons, Inc., 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons. Inc., 2003 (ISBN 0471142735. 9780471142737), the contents of which are all incorporated by reference herein in their entireties.

[0107] Other terms are defined herein within the description of the various aspects of the invention.

[0108] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0109] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within tire scope of tire disclosure, as those skilled in tire relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0110] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[0111] In some embodiments, the present technology may be defined in any of the following numbered paragraphs:1. A system comprising: a) at least one muscle graft in contact with:1) an epineural window of a target nen e, and / or2) a terminus of a target nerve: and b) at least one electrode.2. The system of paragraph 1, wherein the muscle graft is denervated at the time of grafting.3. The system of any one of paragraphs 1-2, wherein the muscle graft is a skeletal muscle graft.4. The system of any one of paragraphs 1-3, wherein the muscle graft is an autograft.5. The system of any one of paragraphs 1-3, wherein the muscle graft is an allograft.6. The system of any one of paragraphs 1-5, wherein the at least one muscle graft is in contact with an epineural window of a target nene and the epineural window is not located at a terminus of the target nerve.7. The system of any one of paragraphs 1-6, wherein the at least one electrode is implanted.8. The system of any one of paragraphs 1-6, wherein the at least electrode is located in, underneath, or on the skin of a subject.9. The system of any one of paragraphs 1-8, wherein the at least one electrode is connected to a wired or wireless pulse generator or wired or wireless stimulator.10. The system of paragraph 9, wherein the pulse generator is a subdcnnal implanted pulse generator.11. The system of any one of paragraphs 8-9, wherein a topical patch comprises the at least one electrode.12. The system of paragraph 11, wherein the at least one electrode is topical, or penetrates the stratum corneum, penetrates the stratum corneum greater than 40um, or penetrates up to 2 mm into the skin.13. The system of paragraph 11 or 12, wherein the topical patch comprises one or more of: a) at least one pulse generator; b) at least one battery; c) a biocompatible gel; and d) at least one adhesive portion.14. The system of any one of the preceding paragraphs, further comprising a conductive gel in contact with at least one of the at least one muscle graft and / or the at least one electrode; and / or located at least in part betw een the at least one muscle graft and / or the at least one electrode.15. The system of paragraph 14, wherein the conductive gel is an alginate / poly -acrylamide hydrogel.16. A method of inducing afferent activation in a nerve in a subject in need thereof, the method comprising delivering, to a subject administered the system of any one of paragraphs 1-15. an electrical signal from the at least one electrode to the at least one muscle graft.17. A method of treating neuropathy or pain in a subject in need thereof, the method comprising delivering, to a subject administered the system of any one of paragraphs 1-15, an electrical signal from the at least one electrode to the at least one muscle graft.18. The method of paragraph 17, wherein the target nerve has or is diagnosed as having neuropathy, or is involved in nocioception of pain that the subject is in need of treatment for.19. A method of selectively stimulating sensory fibers, the method comprising delivering, to a subject administered the system of any one of paragraphs 1-15, an electrical signal from the at least one electrode to the at least one muscle graft.20. The method of paragraph 19, wherein the sensory fiber is stimulated via the muscle graft and not stimulated via the motor fibers of the target nerve.21. The method of any one of paragraphs 16-20. whereby the electrical signal is 50% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft.22. The method of any one of paragraphs 16-21. whereby the target nerve innervates the muscle graft.23. The method of any one of paragraphs 16-22, whereby the target nerve innervates the muscle graft with multiple sprouts.

[0112] In some embodiments, the present technology may be defined in any of the following numbered paragraphs:1. A system comprising: a) at least one muscle graft in contact with:1) an epineural window of a target nerve, and / or2) a terminus of a target nerve: and b) at least one electrode.2. The system of paragraph 1, wherein the muscle graft is denervated at the time of grafting.3. The system of any one of paragraphs 1-2, wherein the muscle graft is a skeletal muscle graft.4. The system of any one of paragraphs 1-3, wherein the muscle graft is an autograft.5. The system of any one of paragraphs 1-3, wherein the muscle graft is an allograft.The system of any one of paragraphs 1-5, wherein the at least one muscle graft is in contact with an epineural window of a target nerve and the epineural window is not located at a terminus of the target nerve. The system of any one of paragraphs 1-6, wherein the at least one electrode is implanted. The system of any one of paragraphs 1-6, wherein the at least electrode is located in, underneath, or on the skin of a subject. The system of any one of paragraphs 1-8, wherein the at least one electrode is connected to a wired or wireless pulse generator or wired or wireless stimulator. The system of paragraph 9. wherein the pulse generator is a subdennal implanted pulse generator. The system of any one of paragraphs 8-9, wherein a topical patch comprises the at least one electrode. The system of paragraph 11, wherein the at least one electrode is topical, or penetrates the stratum corneum, penetrates the stratum corneum greater than 40um, or penetrates up to 2 mm into the skin. The system of paragraph 11 or 12. wherein the topical patch comprises one or more of: a) at least one pulse generator; b) at least one battery; c) a biocompatible gel; and d) at least one adhesive portion. The system of any one of the preceding paragraphs, further comprising a conductive gel in contact with at least one of the at least one muscle graft and / or the at least one electrode; and / or located at least in part between the at least one muscle graft and / or the at least one electrode. The system of paragraph 14, wherein the conductive gel is an alginatc / poly -acr lamide hydrogel. A method of inducing afferent activation in a nerve in a subject in need thereof, die mediod comprising delivering, to a subject administered the system of any one of paragraphs 1-15, an electrical signal from the at least one electrode to the at least one muscle graft. A method of treating neuropathy or pain in a subject in need thereof, the method comprising delivering, to a subject administered the system of any one of paragraphs 1-15, an electrical signal from the at least one electrode to the at least one muscle graft. The method of paragraph 17, wherein the target nerve has or is diagnosed as having neuropathy, or is involved in nocioception of pain that the subject is in need of treatment for.19. A method of selectively stimulating sensory fibers, the method comprising delivering, to a subject administered the system of any one of paragraphs 1-15, an electrical signal from the at least one electrode to the at least one muscle graft.20. The method of paragraph 19, wherein the sensory fiber is stimulated via the muscle graft and not stimulated via the motor fibers of the target nerve.21. The method of any one of paragraphs 16-20, whereby the electrical signal is 50% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft.22. The method of any one of paragraphs 16-21, whereby the target nerve innervates the muscle graft.23. The method of any one of paragraphs 16-22, whereby the target nerve innervates the muscle graft with multiple sprouts.24. The system of any one of paragraphs 1-15 for use in a method of inducing afferent activation in a nen e in a subject in need thereof.25. The system of any one of paragraphs 1-15 for use in a method of treating neuropathy in a subject in need thereof.26. The system of any one of paragraphs 1-15 for use in a method of selectively stimulating sensory fibers in a subject in need thereof.

[0113] The technology described herein is further illustrated by the following examples which in no way should be construed as being further limiting.EXAMPLESExample 1

[0114] Described herein is an adhesive, wearable electrostimulation patch for chronic pain management through sensory graft activation.

[0115] The pain market need encompasses a growing demand for innovative solutions to manage and alleviate various forms of pain. Chronic pain conditions, acute injuries, and post-operative discomfort affect millions worldwide, significantly impacting quality of life and productivity. This has created a pressing need for effective and personalized pain management options that go beyond traditional approaches like opioids. As concerns about opioid addiction and side effects mount, patients, healthcare providers, and researchers seek safer, non-invasive. and non-pharmacological interventions. The market is witnessing a surge in demand for wearable devices, digital health platforms, virtual reality therapies, biofeedback techniques, and advanced pain-relief technologies that cater to individual preferences and conditions.

[0116] The peripheral neuropathy market addresses a substantial medical need, with an estimated global market size of $6.2 billion in 2021. This neurological disorder, characterized by nerve damage leading to pain, numbness, and weakness in extremities, affects millions of individuals. Factors suchas diabetes, chemotherapy, and aging contribute to its prevalence. The market's growth is driven by increasing awareness, an aging population, and the demand for novel treatments beyond traditional pain medications. Innovative therapies, including nerve stimulation devices, regenerative medicine, and targeted pharmaceuticals, are gaining traction to cater to this growing market, emphasizing the pursuit of effective and tailored solutions for peripheral neuropathy sufferers. However, stimulators for this disease primarily consist of highly invasive implantable devices.

[0117] In one embodiment, described herein is a system and method as follows. A muscle graft (2x2cm) can be placed on an epineural window of a peripheral nen e that is still connected to its distal organ (muscle or visceral organ) or a neuroma / transection site. A muscle graft can also be placed at the terminus of a nerve (in cases of transection, neurectomy). Axons from the peripheral nerve will reinnervate the denervated muscle graft through direct reinnervation and collateral sprouting.

[0118] Stimulation of this muscle graft will create contractions that will be transduced into afferent signals that will be send to the innervating peripheral nerve. These are contemplated herein to counteract pain signals from the distal organ.

[0119] Stimulation of this muscle graft can be carried out by implanted electrodes that are tunneled to a subdermal implanted pulse generator or a transcutaneous stimulator (similar to a peripheral neural stimulation system). The muscle graft, if placed sufficiently superficially, can also be directly stimulated from surface electrodes.

[0120] Alternatively, an adhesive patch placed on skin near the superficial site of the muscle graft will contain several stimulation points (minimum 2 and up to a 100) that can deliver electrical energy arising from onboard electronics containing a pulse generator and battery. A skin-compatible gel will form the contact area between the patch and the skin. This gel will facilitate conduction of the stimulation and protect skin from thermal bums or electrical burns.

[0121] The gel can also coat the muscle graft, over the entire surface, or near the neuromuscular junction. The conductive properties of the gel will heighten stimulation efficacy and capturc / sprcad of die energy from the lead to the graft.

[0122] Stimulation from this patch excites the implanted muscle and afferent signals on that muscle can be used to counteract nociceptive signals on the grafted nerve. These may cancel arising afferent signals or send complimentary signals to the efferents and soothe the distal organ.

[0123] This patch or die electronics on board can be replaced to recharge the system.

[0124] Stimulation points may be on top of the skin, penetrate the stratum comeum or go up to 2 mm into the skin.

[0125] The systems described herein can be used in methods as follows:

[0126] Power delivery for pain blocks: It is known that a voltage differential across a nerve leads to a hyperpolarized nerve, making it more difficult for depolarization to occur - consequently making it more difficult for afferent pain (nociception) to be propagated. DC blocks on nerves arecurrently challenging due to tissue heating constraints. Stimulating nen es from an implanted electrode not directly on the nerve requires relatively high currents that can be challenging to deliver for tissue heating constraints and considerations of portable power transmission / reception. How ever, stimulation of muscle will sustain signaling for longer periods of time. Electrodes can be placed directly in or on muscle with less risk, lowering the required power for stimulation.

[0127] Im roved / naturalistic sensations: Stimulating electrodes on nerves can often generate uncomfortable sensations, lose contact with the nerve or reduce in functionality over time as scar builds up on the nerve and lead site. As a large surface area and biological transducer, the muscle will be able to ‘harvest’ the electrical energy from the implanted or skin based stimulator, and transduce that into more natural signals that can propagate along the nerve. This naturalistic signaling can provide greater chronic efficacy of such a device.

[0128] Selective sensory activation: The inventors have found that sensory nerves reinnervating skeletal muscle grafts leads to the preferential and perhaps selective innervation of sensory organs with the muscle (Spindle and golgi tendon organs). Stimulation of a muscle graft on a neural pain target will allow preferential activation of these afferent fibers as opposed to wholescale activation of afferent and efferent fibers. It is contemplated that this can significantly improve the 1) quality of sensation from peripheral stimulation for pain 2) reduce the power delivery requirements from a given stimulator and 3) facilitate longer blocks or parasthetic stimulation waveforms.

[0129] Such selective activation of afferent fibers can be utilized in the context of other diseases in the body wherein selective afferent activation (which is currently not possible with cuff electrodes) is desired. This will be tested on the vagus nen e, wherein sensory stimulation can lead to direct physiological outcomes or assist in feedback loops requiring sensory activation.

[0130] This patch may also be used on nen es arising from painful areas / organs in the body or in cases of neuropathy to perform direct nen e stimulation, as long as the nen e is sufficiently superficial.

[0131] For patients with neuropathy, this patch may be placed on regions of the body from which neuropathic pain arises and directly stimulate c-fibers terminating in that region.

[0132] Other disease cases for which this would be applicable include: chronic regional pain syndrome; peripheral nerve pain; visceral pain; neuropathies; spinal cord injury; spasticity; ischemic pain; Multiple Sclerosis; and sensory feedback for urinary or bowel dysfunction.

[0133] In some embodiments, a conductive, electrotherapeutic scaffold can be used an injectable gel to provide: 1) minimally invasive implant stimulation hardware and have the electrical impulses more uniformly reach disperse, hard-to-target and or branched neural structures; 2) bridge conduction gaps between a lead and target nerve; and / or 3) maintain an electrical field between a section of the nerve, preventing depolarization of the nerve and thereby preventing the transmission of nociceptive afferent signals. Leads can be placed in the gel. near the gels, on the surface of the skin. Through these leads, electrical pulses can be propagated. Alternatively, an electrical field can be maintained.This gel can be used to inhibit pain signals travelling from distal to proximal and prevent them from reaching the spinal cord / brain.Example 2

[0134] Data in n = 5 rats demonstrates that sensory fibers sprout widely and reinnervate the muscle mechanoreceptors, as seen via imaging. Further, reinnervating nerves transmitted graded afferent signals in response to force and vibration-based mechanoreceptor activation of the muscle (Figs. 4A-4D), demonstrating that they are functionally active.

[0135] Through immunohistochemical imaging, a high volume of fiber terminals colocalized on neuromuscular junctions was also found. Given that these sensory fibers are redirected to tissue targets, albeit muscle, instead of being left to form neuromas, the inventors contemplate a reduction in nociceptive and inflammatory markers in the dorsal root ganglia of the transected nen e, rendering a molecular basis for prevention of pain sensitization.

[0136] These procedures can be implemented in humans. This will permit acquisition of qualitative data on perceptions and painful sensations that cannot be acquired from animal models and to assess the efficacy of such grafts in painful pathologies. In patients with chronic neuropathic pain or sural nen e neuromas undergoing resection, the transected sural sensory nerve can be placed into regenerative skeletal muscle grafts. Biweekly, patients can be asked to report on the sensations at rest and during electrical and vibratory stimulation of the grafts. It is specifically contemplated herein that parasthetic, nonpainful sensations will be elicited from the sensory activation. These results will be compared to a cohort of patients undergoing standard care for painful neuromas or peripheral nerve pain. This surgical strategy can provide a paradigm shift for the treatment of chronic peripheral nerve pain wherein aberrant neural sprouting can be directed, controlled, and subsequent sensations can also be manipulated to replace otherwise painful sensations.

[0137] Current neural interfacing hardware, such as cuff electrodes, arc placed around the nerve and nonselectively activate a large region or the entire ne e, leading to off-target activation in many applications. Despite the development of many electrode technologies, selective nerve stimulation remains a long-standing challenge as it is difficult to sort or identify, a priori, the type of nerve fiber present in each location. Selective activation poses critical functionality for applications such as vagus nene stimulation (VNS). While VNS has demonstrated promise for a range of diseases ranging from depression to gastroparesis, nonselective recruitment yields significant off-target effects (coughing, tachycardia, hoarseness, respiratory anomalies) that preclude widespread patient acceptance and therapeutic efficiency. In prior studies where a transected mixed motor / sensory nerve was presented with dermal and muscle targets, preferential reinnervation of the dermal tissue with sensory fibers and the muscle tissue with motor has been observed. In a similar line of thinking, it is contemplated ehrein that different nerve fiber types (sympathetic, parasympathetic) from an autonomic nerve willpreferentially rcinnervatc each muscle type (skeletal, smooth). As such, stimulation of the reinnervated muscle grafts could provide the capability to independently communicate with sympathetic and parasympathetic tracts, as opposed to activating the entire nerve with direct nen e stimulation.

[0138] The functional feedback loops created by rewired tissue-nerve systems can be identified. For example, smooth (n = 10 rats) and skeletal muscle (n= 10 rats) grafts around the vagus nerve can be created and permitted 3-4 weeks of regeneration. Epimysial electrodes can be implanted on the graft, chest wall, and gastric serosa. Cuff electrodes can be implanted around the proximal vagus nerve. Under anesthesia and in awake conditions, electrical stimulation (10-40Hz. l-3mA stimulation) of the grafts can be performed while monitoring heart, gastric motility, and respiratory rates. It is contemplated herein that skeletal muscle stimulation can selectively activate the reinnervating sympathetic fibers, triggering a feedback loop evidenced by impaired gastric motility and increased heart rate. With smooth muscle stimulation, it is contemplated herein that selective parasympathetic feedback can yield the opposite effects; gastric motility can be impaired and heart rate can increase.

[0139] Such loops can be utilized for targeted neuromodulation of the autonomic organs (via improved VNS) and to provide feedback to counteract pathological physiology. For example. I artificial stretch feedback from the stomach can be generated to create a sense of illusory satiety and reduce food intake by 40% in swine. Using a muscle graft on the abdominal vagus, graft stimulation could similarly activate gastric afferents signaling stretch and minimize feedforward intake signals in a model of obesity. In a third experiment, such grafts can be created using the technique outlined above in n = 7 rats. During a 2-week period, routine stimulation can be performed before mealtimes and then food intake and weight gain monitored. This will be compared to a 2-week control period wherein no stimulation will be performed. Overall, this can expand the foundational knowledge on reinnervation mechanisms and pennit a new surgical strategy for selective activation of nerve fibers, a long-standing challenge for the neural interfacing field.

Claims

What is claimed herein is:

1. A system comprising: a) at least one muscle graft in contact with:1) an epineural window of a target nerve, and / or2) a terminus of a target nerve: and b) at least one electrode.

2. The system of claim 1, wherein the muscle graft is denervated at the time of grafting.

3. The system of any one of claims 1-2, wherein the muscle graft is a skeletal muscle graft.

4. The system of any one of claims 1-3, wherein the muscle graft is an autograft.

5. The system of any one of claims 1-3, wherein the muscle graft is an allograft.

6. The system of any one of claims 1-5, wherein the at least one muscle graft is in contact with an epineural window of a target nerve and the epineural window is not located at a terminus of the target nerve.

7. The system of any one of claims 1-6, wherein the at least one electrode is implanted.

8. The system of any one of claims 1-6, wherein the at least electrode is located in, underneath, or on the skin of a subject.

9. The system of any one of claims 1-8, wherein the at least one electrode is connected to a wired or wireless pulse generator or wired or wireless stimulator.

10. The system of claim 9, wherein the pulse generator is a subdennal implanted pulse generator.

11. The system of any one of claims 8-9, wherein a topical patch comprises the at least one electrode.

12. The system of claim 11, wherein the at least one electrode is topical, or penetrates the stratum corneum, penetrates the stratum comeuin greater than 40um, or penetrates up to 2 mm into the skin.

13. The system of claim 11 or 12, wherein the topical patch comprises one or more of: a) at least one pulse generator; b) at least one batter ; c) a biocompatible gel; and d) at least one adhesive portion.

14. The system of any one of the preceding claims, further comprising a conductive gel in contact with at least one of the at least one muscle graft and / or the at least one electrode; and / or located at least in part between the at least one muscle graft and / or the at least one electrode.

15. The system of claim 14, wherein the conductive gel is an alginate / poly -acrylamide hydrogel.

16. A method of inducing afferent activation in a nerve in a subject in need thereof, the method comprising delivering, to a subject administered the system of any one of claims 1-15, an electrical signal from the at least one electrode to the at least one muscle graft.

17. A method of treating neuropathy or pain in a subject in need thereof, the method comprising delivering, to a subject administered the system of any one of claims 1-15, an electrical signal from the at least one electrode to the at least one muscle graft.

18. The method of claim 17, wherein the target nerve has or is diagnosed as having neuropathy, or is involved in nocioception of pain that the subject is in need of treatment for.

19. A method of selectively stimulating sensory fibers, the method comprising delivering, to a subject administered the system of any one of claims 1-15. an electrical signal from the at least one electrode to the at least one muscle graft.

20. The method of claim 19, wherein the sensory fiber is stimulated via the muscle graft and not stimulated via the motor fibers of the target nerve.

21. The method of any one of claims 16-20, whereby the electrical signal is 50% or less of the voltage required to stimulate the target nerve in the absence of the muscle graft.

22. The method of any one of claims 16-21, whereby the target nerve innervates the muscle graft.

23. The method of any one of claims 16-22, whereby the target nerve innervates the muscle graft with multiple sprouts.

24. The system of any one of claims 1-15 for use in a method of inducing afferent activation in a nerve in a subject in need thereof.

25. The system of any one of claims 1-15 for use in a method of treating neuropathy in a subject in need thereof.

26. The system of any one of claims 1-15 for use in a method of selectively stimulating sensory fibers in a subject in need thereof.

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