Improved selectivity and high frequency blocking for bioelectronic therapies with intrafascicular stimulation of peripheral nerves

Abstract

Systems and methods for selectively blocking neural conduction in fibers in a nerve are disclosed. The methods include (a) associating an intraneural electrode with a fascicle of the nerve and (b) utilizing a stimulator in electrical communication with the intraneural electrode to provide electrical stimulation to the fascicle. The electrical stimulation blocks conduction in the nerve. The systems include (a) an intraneural electrode operational to associate with a fascicle of the nerve and (b) a stimulator in electrical communication with the intraneural electrode. The stimulator is operational to provide electrical stimulation to the fascicle. The electrical stimulation is operable to block neural conduction in neural fibers in the nerve.

Description

PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004TITLEIMPROVED SELECTIVITY AND HIGH FREQUENCY BLOCKING FOR BIOELECTRONIC THERAPIESWITH INTRAFASCICULAR STIMULATION OF PERIPHERAL NERVESCROSS-REFERENCE TO RELATES APPLICATIONS

[0001] This patent application claims priority from and incorporates by reference the entire disclosure of U.S. Provisional Patent Application 63 / 679,585 filed on August 5, 2024.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under R01 EB027584 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure relates generally to bioelectronic therapies and more particularly, but not by way of limitation, to improved selectivity and high frequency blocking for bioelectronic therapies with intrafascicular stimulation of peripheral nerves.BACKGROUND

[0004] This section provides background information to facilitate a better understanding of the various aspects of the disclosure. The statements in this section of this document are to be read in this light, and not as admissions of prior art.

[0005] The network of peripheral nerves presents an extraordinary potential for modulating and / or monitoring the functioning of internal organs or the brain. The nervous system functions by generating patterns of neural activity that underlie sensation and perception as well as control of movement and autonomic system such as, the cardiovascular system, endocrine activity, immune response, and other physiological systems. In bioelectronic therapies, blocking or activating selectively a group of nerve fibers in a targeted nerve is imperative for clinical efficacy. As such, improved selectivity and blocking for bioelectronic therapies is needed.PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004SUMMARY OF THE INVENTION

[0006] This summary is provided to introduce a selection of concepts that are further described below in the Detailed Description. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it to be used as an aid in limiting the scope of the claimed subject matter.

[0007] In an embodiment, the present disclosure pertains to a method of selectively blocking neural conduction in fibers in a nerve. In some embodiments, the method includes (a) associating an intraneural electrode with a fascicle of the nerve and (b) utilizing a stimulator in electrical communication with the intraneural electrode to provide electrical stimulation to the fascicle. In some embodiments, the electrical stimulation blocks conduction of the nerve.

[0008] In another embodiment, the present disclosure pertains to a neuromodulation system operable to selectively block neural conduction in neural fibers in a nerve. In some embodiments, the system includes (a) an intraneural electrode operational to associate with a fascicle of the nerve and (b) a stimulator in electrical communication with the intraneural electrode. In some embodiments, the stimulator is operational to provide electrical stimulation to the fascicle. In some embodiments, the electrical stimulation is operable to block neural conduction in neural fibers in the nerve.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] A more complete understanding of the subject matter of the present disclosure may be obtained by reference to the following Detailed Description when taken in conjunction with the accompanying Drawings wherein:

[0010] FIG. 1A illustrates an example of a method of selectively blocking neural conduction in fibers in a nerve.

[0011] FIG. IB illustrates an example neuromodulation system operable to selectively block neural conduction in neural fibers in a nerve.

[0012] FIG. 2 illustrates a block diagram of the Kilohertz Electrical Stimulation (KES) neuralPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 conduction block system.

[0013] FIGS. 3A-3C illustrate a block diagram of three possible configurations for the KES-G. FIG. 3A shows the KES-G is fully analog and translates analog input waveforms to the KES signals required to drive the intraneural electrodes. FIG. 3B shows the KES-G is hybrid and translates digital input waveforms to the KES signals. FIG. 3C shows the KES-G is equipped with a digital processing core that handles the KES waveform synthesis.

[0014] FIG. 4 illustrates architecture of the KES-G used for proof-of-concept experiments.

[0015] FIGS. 5A-5D illustrate examples of KES controller architectures. FIG. A shows that the KES-C takes inputs from the user and translate it to KES parameters. FIG. 5B shows that the KES-C can also provide indications to the user on the state of the KES-G. FIG. 5C shows that the KES-G can include a scheduler that can be programmed or configured by the user. FIG. 5D shows that the KES-C can gather data from sensors and a decision-making algorithm to adapt the KES parameters accordingly.

[0016] FIGS. 6A-6B illustrate a graphical user interface developed and used for the proof-of- concept studies. FIG. 6A shows basic parameters of the KES that can be configured. FIG. 6B shows that the routine scheduler can be configured to perform timed simulations and parameter sweeps.

[0017] FIGS. 7A-7D illustrate possible combinations of KES neural block and neural activation. FIG. 7A and FIG. 7B show the KES neural conduction block system is combined with an external neurostimulator. FIG. 7C and FIG. 7D show the KES neural conduction block system generates both the KES waveform and the activating waveform. FIG. 7A and FIG. 7C show activation and block waveforms are applied to different electrodes. FIG. 7B and FIG. 7D show activation and block waveforms are applied to the same electrode but with a different timing.

[0018] FIG. 8 illustrates an example of a method for neural conduction block inside a Fascicle.

[0019] FIG. 9 illustrates a zoom on the onset-response induced by KES with intraneural electrodes.PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004

[0020] FIG. 10 illustrates an example of a method for fascicle-selective neural conduction block.

[0021] FIG. 11 illustrates an example of a method for partial neural conduction block.

[0022] FIG. 12 illustrates an example method for fiber-type selective KES neural conduction block.

[0023] FIG. 13 illustrates an example of a method for simultaneous KES neural conduction block and neural activation.

[0024] FIG. 14 illustrates an example of a method for alternated KES neural conduction block and neural activation.

[0025] FIG. 15 illustrates implantation positions of the stimulating proximal and blocking distal longitudinal intrafascicular electrodes.

[0026] FIG. 16 illustrates conventional stimulation applied to the stimulation electrode to generate the muscle twitch and KES waveform applied to the conduction neural block electrode.

[0027] FIG. 17 illustrates force measured (normalized) when the KES amplitude is reaching the conduction neural block threshold.

[0028] FIG. 18 illustrates KES neural conduction block threshold versus KES frequency.

[0029] FIG. 19 illustrates KES-induced and stimulation-induced fatigue.

[0030] FIG. 20 illustrates measured peak force versus KES amplitude, where the simulation electrode is in the common peroneal fascicle, and the neural conduction block electrode is in the tibial fascicle. The drawing illustrates that the KES block in the tibial fascicle does not block neural conduction in the peroneal fascicle.

[0031] FIG. 21 illustrates measured peak force versus KES amplitude.DETAILED DESCRIPTION

[0032] It is to be understood that both the foregoing general description and the following detailedPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 description are illustrative and explanatory, and are not restrictive of the subject matter, as claimed. In this application, the use of the singular includes the plural, the word “a” or “an” means “at least one”, and the use of “or” means “and / or”, unless specifically stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements or components comprising one unit and elements or components that include more than one unit unless specifically stated otherwise.

[0033] The section headings used herein are for organizational purposes and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated herein by reference in their entirety for any purpose. In the event that one or more of the incorporated literature and similar materials defines a term in a manner that contradicts the definition of that term in this application, this application controls.

[0034] The network of peripheral nerves of the autonomic and sensory-somatic nervous system presents extraordinary potential for modulating and / or monitoring the functioning of internal organs or the brain. The nervous system functions by generating patterns of neural activity which underlie sensation and perception as well as control of movement, cardiovascular, endocrine, immune, and other systems. Whereas most bioelectrical therapies use electrical signal to induce neural activity, Kilohertz Electrical Stimulation (KES) allows an instantaneous and reversible block of the propagating neural signal. KES is a promising approach to treat disorders where neural hyperactivity is involved, such as chronic or neuropathic pain, tremors, or phantom pain.

[0035] The present disclosure provides the possibility of inducing neural conduction block using KES through intraneural electrodes. Such an approach enables greater KES selectivity than conventional extraneural electrodes, limiting the side-effects while being suitable for long-term KES therapies. The present disclosure improves the field of electrical stimulation therapies as it enables the use of a graded and localized neural conduction block, whereas previous technologies demonstrated an unspecific “on or off’ neural conduction block. Such improvement greatly reduces KES-induced side effects and facilitates the translation of KES neural block towards clinical trials. The present disclosure also provides the possibility of combining targeted KESPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 neural block with conventional neural activation, with precise timing and spatial selectivity. This will enable the investigation of novel and adaptive therapies to treat complex impairments.

[0036] In some embodiments, illustrated in FIG. 1A, the present disclosure pertains to methods of selectively blocking conduction of a nerve by (a) associating an intraneural electrode with a fascicle of the nerve (Step 1); and (b) utilizing a stimulator in electrical communication with the intraneural electrode to provide electrical stimulation to the fascicle (Step 2), where the electrical stimulation blocks conduction in neural fibers in the nerve (Step 3). Tn some embodiments, the methods of the present disclosure also include steps of: (c) utilizing a stimulator in electrical communication with the intraneural electrode and a signal processing unit to measure neural conduction by the nerve (Step 4); and (d) utilizing a pulse processing unit to adjust the electrical stimulation to the fascicle based on the measurement (Step 5).

[0037] Additional embodiments of the present disclosure pertain to a neuromodulation system operable to selectively block neural conduction in neural fibers in a nerve. In some embodiments, illustrated in FIG. IB, the neuromodulation system 100 includes: (a) an intraneural electrode 101 operational to associate with a fascicle of the nerve; and (b) a stimulator 102 in electrical communication with the intraneural electrode, where the stimulator is operational to provide electrical stimulation to the fascicle, and where the electrical stimulation is operable to block neural conduction in fibers in the nerve. In some embodiments, the neuromodulation systems of the present disclosure also include: (c) a signal processing unit 103 in electrical communication with the intraneural electrode 101 and the stimulator 102, where the signal processing unit is operable to measure conduction by the nerve; and (d) a pulse processing 104 unit operable to adjust the electrical stimulation to the fascicle by stimulator 102 based on the measurement by signal processing unit 103.

[0038] As set forth in more detail herein, the methods and neuromodulation systems of the present disclosure can have numerous arrangements, embodiments, and applications.

[0039] Nerves

[0040] The methods and neuromodulation systems of the present disclosure may be utilized to block the neural conduction in fibers located in various nerves. For instance, in somePCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 embodiments, the nerve includes a peripheral nerve. In some embodiments, the peripheral nerve includes a peripheral nerve of the autonomic nervous system, such as the sympathetic nervous system. In some embodiments, the peripheral nerve includes a peripheral nerve of the sensory- somatic nervous system. In some embodiments, the nerve includes a cranial nerve. In some embodiments, the cranial nerve includes a vagus nerve. In some embodiments, the nerve includes a spinal nerve. In some embodiments, the spinal nerve includes a sciatic nerve.

[0041] Association of Intraneural Electrodes with Fascicles of Nerves

[0042] The methods and neuromodulation systems of the present disclosure may be utilized to associate intraneural electrodes with fascicles of nerves in various manners. For instance, in some embodiments, the association includes associating a single intraneural electrode with a single fascicle of a nerve. In some embodiments, the association includes associating a plurality of intraneural electrodes with a single fascicle of a nerve. In some embodiments, the association includes associating a single intraneural electrode with a plurality of fascicles of a nerve.

[0043] In some embodiments, the association includes associating a plurality of intraneural electrodes with a plurality of different fascicles of a nerve. In some embodiments, the fascicles are within the same nerve. In some embodiments, the fascicles are within different nerves.

[0044] Intraneural Electrodes

[0045] The methods and neuromodulation systems of the present disclosure may utilize various intraneural electrodes. For instance, in some embodiments, the intraneural electrode includes, without limitation, longitudinal intrafascicular electrodes (LIFEs), thin-film longitudinal intrafascicular electrodes (tf-LIFEs), transverse intrafascicular multichannel electrodes (TIMEs), multielectrode intrafascicular arrays (MEAs), Utah electrode arrays (UEA), Utah slanted electrode array (UESEA), or combinations thereof.

[0046] Electrical Stimulation

[0047] The methods and neuromodulation systems of the present disclosure may utilize intraneural electrodes to electrically stimulate neural fibers in the fascicles in various manners. For instance, in some embodiments, the electrical stimulation includes Kilohertz range electricalPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 stimulation (KES). In some embodiments, KES electrical stimulation includes frequencies between 1,000 to 1,000,000 Hertz (Hz).

[0048] In some embodiments, the electrical stimulation occurs in a gradual manner. In some embodiments, the electrical stimulation includes a step graded increase of amplitude, charge, or combinations thereof.

[0049] Electrical stimulation may block the neural conduction in neural fibers in various manners. For instance, in some embodiments, the blocking of neural conduction in neural fibers is reversible. In some embodiments, the blocking of the neural conduction in neural fibers is selective to a fascicle. In some embodiments, the blocking of neural conduction in neural fibers in the nerve does not produce or produces limited unwanted on-set response. In some embodiments, the blocking of neural conduction in neural fibers in the nerve does not produce or produces limited unwanted neural fatigue.

[0050] Neuromodulation Systems

[0051] The neuromodulation systems of the present disclosure can include various components. For instance, in some embodiments, a pulse processing unit of the neuromodulation system further includes a controller. In some embodiments, the controller is operational to control one or more electrical stimulation parameters by an intraneural electrode.

[0052] In some embodiments, the controller includes a programming language. In some embodiments, the programming language includes programming instructions for controlling one or more electrical stimulation parameters by an intraneural electrode. In some embodiments, the controller includes a graphical user interface (GUI). In some embodiments, the GUI is operational to display one or more electrical stimulation parameters by an intraneural electrode.

[0053] Applications and Advantages

[0054] The methods and neuromodulation systems of the present disclosure may have various advantageous applications. For instance, in some embodiments, the methods and neuromodulation systems of the present disclosure may be used in vivo in a subject (e.g., a human being and / or a non-human mammalian).PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004

[0055] In some embodiments, the methods and neuromodulation systems of the present disclosure may be utilized for neuromodulation therapy in a subject. In some embodiments, the methods and neuromodulation systems of the present disclosure may be used to treat or prevent a condition associated with neural hyperactivity in a subject. In some embodiments, the condition includes, without limitation, pain, Parkinson’s disease, Crohn’s disease, obesity, cardiac diseases, epilepsy, depression, inflammation, diabetes, bladder voiding dysfunctions, sexual disorders, or combinations thereof.

[0056] In some embodiments, the condition includes pain. In some embodiments, the pain includes, without limitation, acute pain, chronic pain, neuropathic pain, phantom pain, or combinations thereof.

[0057] The present disclosure provides systems and methods to produce the possibility of inducing neural selective conduction block of nerve fibers within fascicles using KES with intraneural electrodes placed inside fascicles. KES induced block with intraneural electrodes inside fascicles presents many advantages. For example, the systems and methods disclosed produce neural conduction block inside a nerve fascicle. In some embodiments, the neural conduction block is effective in approximately less than 1 second after turning the block signal on. In some embodiments, the neural conduction block is reversible. In some embodiments, the neural conduction within the nerve is restored in approximately less than 1 second after turning the block signal off.

[0058] Additionally, in some embodiments, the systems and methods of the present disclosure generate no, or reduced onset-response, when the KES is turned ON. In some embodiments, the KES signal is charge-balanced and within the safety limit, thereby not affecting the integrity of the nerve or the electrode. Moreover, in some embodiments, the systems and methods of the present disclosure improve the selectivity of the KES neural conduction block. In some embodiments, the neural conduction in the targeted nerve fascicle can be fully blocked without blocking neighboring fascicles within the nerve. In some embodiments, the systems and methods of the present disclosure do not generate undesired neural activity on fibers that are in un-targeted neighboring fascicles.

[0059] In some embodiments, the systems and methods of the present disclosure allow toPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 selectively and gradually block neural conduction in one or multiple subpopulations of neural fibers inside of the fascicle. In some embodiments, the systems and methods of the present disclosure can achieve targeted fiber-type neural conduction block by tuning the signal parameters to selectively block neural conduction in either sensory, motor, or autonomic fibers.

[0060] Additionally, the systems and methods of the present disclosure can be combined with conventional neural activating stimulation. For example, in some embodiments, KES neural conduction and neural activation can be used simultaneously to block the neural conduction of one targeted fiber population while activating another fiber population. In some embodiments, KES neural conduction and neural activation can be alternated between block and activation of subpopulations of nerve fibers using the same electrode site.

[0061] KES conduction block with intraneural electrodes enables greater neural conduction block selectivity than conventional extra- neural electrodes, limiting the side effects while being suitable for long-term KES therapies. As such, embodiments of the present disclosure improve the field of electrical stimulation therapies as it enables the use of a graded and localized neural conduction block, whereas previous technologies demonstrated an unspecific “on or off’ neural conduction block.

[0062] In some embodiments, the systems and methods of the present disclosure produce reversible, instantaneous, and selective true neural conduction block without or with reduced onset response. In some embodiments, such improvements greatly reduce KES-induced side effects and facilitate the translation of KES neural block towards clinical trials. In some embodiments, the present disclosure also provides the possibility of combining targeted KES neural block with conventional neural activation, with precise timing and spatial selectivity. In some embodiments, the systems and methods enable the investigation of novel and adaptive therapies to treat complex impairments.

[0063] In brief, embodiments of the present disclosure: (1) produces an instantaneous neural conduction block; (2) produces a reversible neural conduction block; (3) generates no or reduced onset-response; (4) produces a safe neural conduction block that does not affect the integrity of the nerve nor the electrode; (5) has the capability of selectively block neural conduction in the targeted nerve fascicles without producing conduction block in neighboring fascicles within thePCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 nerve; (6) does not induce any undesired neural activity of fibers that are in un-targeted neighboring fascicles; (7) can achieve targeted fiber-type neural conduction block by tuning the signal parameters to selectively block neural conduction in either sensory, motor or autonomic fibers; (8) allows the selective and gradual block of neural conduction in one or multiple subpopulations of neural fibers inside of the fascicle; (9) can be used simultaneously with conventional neural stimulation to block neural conduction of one targeted fiber population while activating another fiber population; and (10) can be combined with conventional neural stimulation to alternate between block and activation of a subpopulations of nerves fiber using the same electrode site.

[0064] As such, the systems and methods of the present disclosure can have numerous applications. For instance, in some embodiments, the systems and methods of the present disclosure can be used for a neuroprothesis system, a neuropathic pain treatment system, a chronic pain treatment system, a phantom pain treatment system, a Parkinson disease treatment system, a Crohn’s disease treatment system, an obesity treatment system, a cardiac vascular treatment system, an epilepsy treatment system, a depression treatment system, an inflammation suppression treatment system, a diabetes treatment system, a bladder voiding disfunction treatment system, a sexual disorders treatment system, and combinations of the same and like.ADDITIONAL EMBODIMENTS

[0065] Reference will now be made to more specific embodiments of the present disclosure and experimental results that provide support for such embodiments. However, Applicant notes that the disclosure below is for illustrative purposes only and is not intended to limit the scope of the claimed subject matter in any way.

[0066] Example 1. Improved Selectivity and High Frequency Blocking for Bioelectronic Therapies with Intrafascicular Stimulation of Peripheral Nerves

[0067] The network of peripheral nerves presents an extraordinary potential for modulating and / or monitoring the functioning of internal organs or the brain. The nervous system functions by generating patterns of neural activity that underlie sensation and perception as well as control of movement and autonomic system such as, the cardiovascular system, endocrine activity, immunePCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 response, and other physiological systems.

[0068] Most bioelectronic and neuromodulation therapies use electrical stimulation to induce neural activity. In contrast, direct current (DC) or high-frequency (>5 kHz) alternating current (AC)-electrical stimulation strategies are used to suppress neural activity.

[0069] High-frequency stimulation, such as Kilohertz Electrical Stimulation (KES) or Kilo-Hertz Frequency (KHF), allows an instantaneous and reversible block of the propagating neural signal. This inhibition mechanism is also referred to as neural conduction block. The KES-induced conduction block is preferred over DC electrical stimulation strategies because it is safe for the nerve tissue and electrode material, it produces a true neural block instead of neural fatigue, and it is instantaneously reversible.

[0070] KES neural conduction block is a promising approach to treat disorders where neural hyperactivity is involved, such as chronic or neuropathic pain, tremors, or phantom pain. KES neural conduction block has been extensively demonstrated in various animal models, including frogs, rats, cats, pigs, and non-human primates. KES neural conduction block is clinically used in spinal cord stimulation for chronic pain treatment, as well as abdominal vagal nerve stimulation for the modulation of satiety. The ability to block the neural conduction with KES highly relies on the inherent properties of electrodes (material, geometry, configuration) used as the neural interface, as well as the stimulation parameters (frequency, amplitude, and waveform shape) utilized.

[0071] Successful neural conduction block has been reported using both voltage-controlled and current-controlled electrical stimulation, and the lowest value required to block the targeted neural activity is defined as the block threshold. Similar to the activation of neural fibers, axon type (myelinated or un-myelinated), nerve fiber diameter, and distance of the nerve fiber to the stimulating electrode active site have a direct impact on the block threshold. The primary challenges to the current KES neural conduction block technologies are 1) reduction of the onset response, 2) selectively, and 3) gradual blocking of the neural conduction.

[0072] Typically, turning on the KES signal produces an unwanted strong neural activity that lasts for a few seconds to minutes called onset-response. Literature has reported two phases during thePCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 onset-response. Phase-I includes a brief (< Is) sudden period of hyperactivity that can result in an intense muscle twitch. Immediately after phase-I, phase-II includes asynchronous activity inducing tetanic muscle contractions that can last up to 30s. After the unwanted onset response, KES produces a complete or partial neural conduction block. The onset response limits the usability of the KES neural conduction block. Many strategies are currently being investigated to mitigate the onset-response. These include waveform modulation, electrode geometry, or combination with direct current.

[0073] The majority of in vivo studies demonstrating KES neural conduction block have used extra- neuronal interfaces such as nerve cuff electrodes. The nerve cuff electrode array is wrapped around the whole nerve, with the active electrodes arranged spatially around the circumference of the nerve trunk. Due to the fascicular organization of fiber within the nerve, a high degree of selectivity is difficult to obtain with such an extra-neural electrode.

[0074] In bioelectronic therapies, blocking or activating selectively a group of nerve fibers in a targeted nerve is imperative for clinical efficacy. The vagus nerve, one of the primary targets for bioelectronic medicine, includes multiple fascicles (in large animal and human nerves) and innervates many different organs. A complete or indiscriminate conduction block of the vagus nerve can alter critical functionalities or generate significant side effects. Similarly, an unselective pudendal nerve block can induce several side effects, such as incontinence or sexual disorders.

[0075] Due to the organization of the nerves in the peripheral nervous system, a mix of motor, sensory and autonomic fibers, a fiber-selective targeted neural conduction block could also be beneficial for the treatment of neuropathic pain. An appropriate neural interface (electrode) combined with an adequate KES waveform is used to obtain the desired neural conduction block selectivity. An ideal electrode for KES neural conduction block should be able to interface with a specific population of fibers inside the nerve. This targeted population could be a subpopulation within one fascicle (intrafascicular selectivity), or only one fascicle instead of the entire nerve (interfascicular selectivity). This electrode should also be able to block neural conduction of one specific type of fiber (motor, sensory or autonomic) within the targeted population (fiber-type selectivity). A graded (or partial) neural conduction block is achieved when a controlled fraction of the targeted population of neural fibers cannot conduct neural activity and is also desirable forPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 improved and safer therapies.

[0076] Intraneural electrodes, such as longitudinal intrafascicular electrodes (LIFEs), thin-film longitudinal intrafascicular electrodes (tf-LIFEs), transverse intrafascicular multichannel electrodes (TIMEs), or Utah slanted electrode array (UESEA) provide direct access to neural fiber within a fascicle, which enhances stimulation selectivity in comparison to extraneural selectivity. LIFEs, in particular, have proven to be able to selectively and gradually activate a small population of neural fibers within a nerve or a nerve fascicle. LIFEs have a high degree of biocompatibility and have a minimalistic geometry, making them a good candidate for selective KES neural blocking of large and small nerves. Moreover, due to the closeness between the electrode active site and the fibers, a small current stimulus is required to induce neural activity. Thus, it is likely that neural conduction block with LIFEs will also require small currents, which will improve the stimulator lifespan and increase therapy safety.

[0077] This Example presents a system and methodology to selectively and gradually block neural conduction using intraneural electrodes. Intraneural electrodes offer higher selectivity, which will enable the neural conduction block of a subpopulation of fibers inside the nerve translating in reducing the side effects and improving therapeutical outcomes. Bioelectronic therapies using neural conduction blocks will increase their efficacy as it will enable the use of a graded and localized neural conduction block, whereas previous technologies demonstrated an unspecific “on or off” neural conduction block. Such improvement will greatly facilitate the translation of the KES neural block towards clinical trials.

[0078] Example 1.1. Experimental Results

[0079] The KES neural conduction block was tested in vivo and quantified by selectively blocking electrically induced hindlimb muscle contractions of rat.

[0080] Intraneural electrode-making process: Individual LIFEs were fabricated using highly flexible Pt / Ir (90% / 10%) 25 pm diameter wires coated with custom insulation polymer. To form the active site of the electrode, 200 pm to 1000 pm length of the wire was de-insulated. An electrosharpened 2.5 cm, 75pm tungsten needles were welded to one of the ends of the wires to thread the LIFE into a fascicle in a nerve. The other end of the wire was welded to a small metal platePCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004(approximately 2mm x 3mm) for connecting to the KES-G.

[0081] Animal preparation: In vivo experiments were carried out on anesthetized rats. Rats were anesthetized with isoflurane (1.5-2.5% in medical-grade Oxygen) gas anesthesia. The well-being of rats was maintained by applying ophthalmic ointment to the eyes to prevent corneal desiccation, periodically administering saline subcutaneously to prevent dehydration, and placing the body on thermal pads to prevent hypothermia. Throughout the procedure, rodent body temperature was monitored by placing a temperature probe in the rectum, and physiological indicators (respiratory rate, heart rate, and SpO2) were monitored using vital signs monitor (Smith Medical, Model: Surgivet® Advisor® Vital Sign Monitor, OH, USA). The level of anesthesia was periodically assessed with toe pinch, observation of eye blink, and respiration rate. All studies were conducted after approval of the study by an Institutional Animal Care and Use Committee.

[0082] The sciatic nerve was accessed by making a straight incision from the lateral aspect of the thigh to the ankle joint, followed by separating the biceps femoris and gluteus superficialis through minimal dissection techniques. The separated muscles were held using elastic stays and selfretaining retractors (Cooper Surgical, Model: Lone Star, CT, USA) to reach the sciatic nerve. The nerve was isolated by separating it from the surrounding connective tissue. After the isolation of the sciatic nerve, vessel loops (Aspen Surgical, Model: Maxi, MI, USA) were placed around the isolated nerve to manipulate the nerve. LIFEs were implanted in both the tibial and the common peroneal fascicle of the sciatic nerve. For each rat, 3 to 4 proximal stimulating electrodes and 1 to 2 distal blocking electrodes were implanted. Blocking and stimulating electrodes were separated by approximately 0.7 to 1 cm. Proximal stimulation electrodes were used to induce neural activity in the sciatic nerve, while distal blocking electrodes were used to demonstrate the KES neural conduction block (FIG. 15). After implantation, the electrodes were secured to the epineurium proximally and distally with 8-0 non-absorbable sutures.

[0083] Example 1,2, Experimental Setup

[0084] A computer-controlled neurostimulator was attached to the LIFEs and used for both the stimulation and the KES neural conduction block. The neurostimulator is capable of outputting arbitrary waveforms on 8 independent channels, with a maximum current of 1mA per channel. Channels can be ganged to increase the maximum output current. Kilohertz-frequency capabilitiesPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 of the stimulator using LIFEs were previously demonstrated. A DC -blocking circuit was adapted and added between the electrodes and the stimulator outputs to avoid any DC contamination. Components values were adapted to accommodate the higher impedance of the LIFEs.

[0085] Isometric force recordings were conducted with a 6-axis force transducer (JR3, Inc., Woodland, CA, USA). The paw of the rodent was secured to the force transducer via a 3D-printed shoe. The baseline of each axis of the force transducer was adjusted before the experiment using onboard trimmers. The output of the force transducer was sampled at 30kS / s with a dedicated data acquisition system (Scout processor, Ripple Neuro, USA). Acquisition and stimulation were synchronized using the integrated triggers of both systems. Data were digitally high-pass and low- pass filtered (resp. 0.1Hz and 100Hz) during post-processing using the Python language (signal processing using NumPy and SciPy libraries).

[0086] Example 1,3. Method and Results

[0087] Method 1: Neural Conduction Block Inside a Fascicle'. A biphasic square pulse was applied to a proximal stimulation electrode to elicit a muscle twitch. The KES signal was applied to a distal blocking electrode, and the amplitude was progressively increased in variable step size. For each amplitude step, the stimulation pulse and KHF were applied for a total duration of 4s and processed and followed by a 2s resting time to limit the induced neural and muscle fatigue (FIG. 16). A total neural conduction block was obtained when the muscle twitches were not visible anymore (FIG. 17). The neural conduction block was effective in approximately less than one second after turning the KES signal ON. The corresponding KES amplitude was defined as the block threshold. The neural conduction block thresholds were measured with KES frequency ranging from 5kHz to 30kHz (FIG. 18). No phase-II onset response was observed (FIG. 9).

[0088] The KES-induced neural fatigue is assessed by comparing the force profiles before the KES neural conduction block is applied and after the KES signal is turned off. Fatigue induced by KES is not significatively different from fatigue induced by conventional stimulation alone. Moreover, muscle recovers from stimulation-induced fatigue during the neural conduction block phase (KES signal on), and full force is instantaneously recovered when the KES signal is turned off (FIG. 19).PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004

[0089] Method 2: Fascicle-Selective Neural Conduction Block'. A biphasic square pulse was applied to a proximal stimulation electrode located in the common peroneal fascicle to elicit a muscle twitch. The KES signal was applied on an electrode located in the tibial fascicle, and the KES amplitude was progressively increased in a variable step size up to 1.5 times the KES block threshold. The tibial branch was cut for this study to avoid co-contraction and to facilitate the force data analysis. Analysis showed that force induced by stimulation in the peroneal fascicle does not differ than when not KES block is applied (FIG. 20). Thus, conduction block in the peroneal fascicle remains unaffected during KES neural conduction block in the tibial fascicle. Moreover, no onset response in the peroneal fascicle was observed during KES neural conduction block in the tibial fascicle.

[0090] Method 3: Partial Neural Conduction Block: A biphasic square pulse was applied to a proximal stimulation electrode to elicit a muscle twitch. KES signal was applied to a distal blocking electrode, and the KES amplitude was progressively increased in a variable step size. For each amplitude step, the stimulation pulse and KHF were applied for a total duration of 4s and processed and followed by a 2s resting time to limit the induced neural and muscle fatigue (FIG. 16). Force was measured before and during KES neural conduction block. Peak value of the force versus KES stimulation amplitude is shown in FIG.21 for 10kHz, 15kHz, and 20kHz KES signals. The peak-force profile shows a progressive diminution that demonstrates the feasibility of a partial and controlled neural conduction block.

[0091] Method 4: Simultaneous KES Neural Conduction Block and Neural Activation : A biphasic square pulse was applied to an intraneural electrode located in the common peroneal fascicle to activate fibers that elicit a muscle twitch. The KES signal was applied on an intraneural electrode located in the tibial fascicle to block neural conduction in this fascicle. Analysis showed that force induced by stimulation of fibers in the peroneal fascicle does not differ by blocking the neural conduction in the tibial fascicle (FIG. 20).

[0092] Method 5: Alternated KES Neural Conduction Block and Neural Activation: Neural activation with the intraneural electrodes used for KES neural conduction block were verified before and after the neural conduction block trials. The process is illustrated in FIG. 14.

[0093] Example 2. Adapting the KES Signal to Optimize the Neural Conduction BlockPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004

[0094] Additional Examples include adapting the KES signal to optimize the neural conduction block.

[0095] Example 2,1, Reduction of the Onset Response, Power Consumption and Injected Charge to the Tissue

[0096] Reducing the power consumption relaxes the constraint on the battery form factor and facilitates the power circuitry design for implanted wireless neuro-stimulating device. A small amount of injected charge limits the risk of tissue injury and / or electrode degradation over time. Those improvements will further facilitate the translation to clinical application. To achieve these optimizations of KES neural conduction block, the parameters that can be adjusted include the waveform frequency and its shape (sinewave, square wave, asymmetrical rectangular waveform, etc.). The waveforms modulation will also be investigated in future studies as it showed promising results to reduce onset response.

[0097] Example 2.2. Improve Sub-Fascicular Selectivity

[0098] Current and / or field steering strategies can be achieved by using two or multiple longitudinal intrafascicular electrodes in a bipolar or multipolar configuration. This will further increase the selectivity of the KES conduction block and further reduce side-effects.

[0099] Example 2,3. Long Term Effects of KES Neural Conduction Block

[0100] In vivo monitoring of the conduction neural block and reversibility over time can also be conducted. An ex- vivo analysis can be carried out at the end of the long-term study to assess the tissue and longitudinal intra-fascicular electrode degradation.

[0101] Example 2,4, Application to Different Animal and Nerves

[0102] Studies on larger animal models such as rabbits can also be conducted. This will facilitate the monitoring of neural activity inside the targeted nerve before, during and after applying the KES neural conduction block signal. Monitoring neural activity will facilitate the optimization of the KES signal.

[0103] Example 2.5. Description of the drawingsPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004

[0104] This Example provides more detailed descriptions of the supporting drawings.

[0105] FIG. 2 illustrates a block diagram of the Kilohertz Electrical Stimulation (KES) neural conduction block system. The system comprises a KES controller (KES-C), a KES generator (KES-G), and one or more intraneural electrodes. The KES-C serves as an interface with the experimenter, clinician, patient, or an external system to define the KES parameters. The KES-G transforms these parameters into electrical signals that arc delivered to the intraneural electrode. The intraneural electrodes link the KES electrical signals to the targeted neural tissues.

[0106] FIGS. 3A-3C illustrate three possible configurations for the KES-G. FIG. 3A shows a fully analog configuration, where analog input waveforms are translated into the KES signals required to drive the intraneural electrodes. FIG. 3B shows a hybrid configuration, where digital input waveforms are used. FIG. 3C shows a configuration with a digital processing core that synthesizes the KES waveform.

[0107] FIG. 4 illustrates the architecture of the KES-G used for proof-of-concept experiments. This KES-G includes a digital processing core and can drive up to eight intraneural electrodes simultaneously.

[0108] FIGS. 5A-5D illustrate various KES controller architectures. FIG. 5A shows that the KES-C receives user inputs and converts them into KES parameters. FIG. 5B shows that the KES- C can also provide feedback to the user on the status of the KES-G. FIG. 5C shows that the KES- C can include a scheduler programmable by the user. FIG. 5D shows that the KES-C can collect data from sensors and use a decision-making algorithm to adapt KES parameters dynamically

[0109] FIGS. 6A-6B illustrate a graphical user interface developed for the proof-of-concept studies. FIG. 6A shows basic KES parameters that can be configured. FIG. 6B shows that the routine scheduler can be configured for timed simulations and parameter sweeps.

[0110] FIGS.7A-7D illustrate different combinations of KES neural block and neural activation. FIGS. 7A and 7B show that the KES system is combined with an external neurostimulator delivering conventional stimulation. FIGS. 7C and 7D show that the KES system generates both KES and activating waveforms. FIGS. 7A and 7C show that block and activation are applied toPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 different electrodes. FIGS. 7B and 7D show that both waveforms are applied to the same electrode with different timing.

[0111] FIG. 8 illustrates a method for complete and reversible neural conduction block inside a fascicle. No muscle twitches are observed during KES delivery, and muscle twitching recovers in less than one second after KES stops.

[0112] FIG. 9 illustrates a zoom on the short onset-response induced by KES using intraneural electrodes. The response duration is under one second, and no phase-II onset is observed.

[0113] FIG. 10 illustrates a method for fascicle-selective and reversible neural conduction block. The KES effect is limited to the targeted fascicle. Non-targeted fascicles experience neither onset responses nor neural conduction block.

[0114] FIG. 11 illustrates a method for partial neural conduction block. Initially, complete block is achieved, evidenced by full disappearance of muscle twitches. After adjusting the KES parameters, a partial block is achieved, shown by reduced peak muscle twitch force.

[0115] FIG. 12 illustrates a method for fiber-type selective and reversible neural conduction block. For example, only large motor fibers are blocked, while smaller autonomic fibers remain unaffected, with no onset response and no disruption of neural conduction observed.

[0116] FIG. 13 illustrates a method for simultaneous KES neural conduction block and neural activation using two separate electrodes. This allows for selective blocking of certain fibers in one fascicle and activation of other fibers in a different fascicle.

[0117] FIG. 14 illustrates a method for alternating KES-induced neural conduction block and neural activation using a single intraneural electrode. KES is delivered first, resulting in a block, followed by a conventional activation pulse leading to fiber activation.

[0118] FIG. 15 illustrates the implantation positions of the proximal stimulating and distal blocking longitudinal intrafascicular electrodes used in proof-of-concept experiments.

[0119] FIG. 16 illustrates a conventional stimulation protocol used in proof-of-concept experiments, divided into pre-block, block, and post-block phases. Muscle twitches are evokedPCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004 with the stimulating electrode in all three phases to test neural conduction, while KES is applied only during the block phase to block neural conduction.

[0120] FIG. 17 illustrates normalized muscle force measurements when KES amplitude reaches the neural conduction block threshold. This is observed as a near-complete disappearance of muscle twitches during the block phase, with rapid reappearance in under one second after KES stops.

[0121] FIG. 18 illustrates the relationship between KES neural conduction block threshold and KES frequency. It shows how frequency selection allows modulation of the block threshold.

[0122] FIG. 19 illustrates a comparison between KES-induced and stimulation-induced fatigue.

[0123] FIG. 20 illustrates peak force versus KES amplitude in an experiment where the stimulation electrode is placed in the common peroneal fascicle and the block electrode in the tibial fascicle. The data shows that the block applied in the tibial fascicle does not affect conduction in the peroneal fascicle.

[0124] FIG. 21 illustrates the influence of KES parameters on muscle twitch peak force. It plots peak force versus KES amplitude for three different KES frequencies: 10 kHz, 15 kHz, and 20 kHz. The graph shows how KES parameters can be tuned for precise control of neural conduction block.

[0125] Without further elaboration, it is believed that one skilled in the art can, using the description herein, utilize the present disclosure to its fullest extent. The embodiments described herein are to be construed as illustrative and not as constraining the remainder of the disclosure in any way whatsoever. While the embodiments have been shown and described, many variations and modifications thereof can be made by one skilled in the art without departing from the spirit and teachings of the invention. Accordingly, the scope of protection is not limited by the description set out above, but is only limited by the claims, including all equivalents of the subject matter of the claims. The disclosures of all patents, patent applications and publications cited herein are hereby incorporated herein by reference, to the extent that they provide procedural or other details consistent with and supplementary to those set forth herein

Claims

PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004CLAIMS:

1. A method of selectively blocking neural conduction in fibers in a nerve, said method comprising:(a) associating an intraneural electrode with a fascicle of the nerve; and(b) utilizing a stimulator in electrical communication with the intraneural electrode to provide electrical stimulation to the fascicle, wherein the electrical stimulation blocks conduction of the nerve.

2. The method of claim 1, further comprising:(c) utilizing a stimulator in electrical communication with the intraneural electrode and a signal processing unit to measure conduction by the nerve; and(d) utilizing a pulse processing unit to adjust the electrical stimulation to the fascicle based on the measurement.

3. The method of claim 1, wherein the nerve comprises a peripheral nerve.

4. The method of claim 1, wherein the nerve comprises a vagus nerve.

5. The method of claim 1, wherein the nerve comprises a sciatic nerve.

6. The method of claim 1, wherein the associating comprises associating a single intraneural electrode with a single fascicle of the nerve.

7. The method of claim 1, wherein the associating comprises associating a plurality of intraneural electrodes with a single fascicle of the nerve.

8. The method of claim 1, wherein the associating comprises associating a single intraneural electrode with a plurality of fascicles of a nerve.PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-0049. The method of claim 1, wherein the associating comprises associating a plurality of intraneural electrodes with a plurality of different fascicles of the nerve.

10. The method of claim 9, wherein the fascicles are within the same nerve.

11. The method of claim 9, wherein the fascicles are within different nerves.

12. The method of claim 1, wherein the intraneural electrode is selected from the group consisting of longitudinal intrafascicular electrodes (LIFEs), thin-film longitudinal intrafascicular electrodes (tf-LIFEs), transverse intrafascicular multichannel electrodes (TIMEs), multielectrode intrafascicular arrays (MEAs), Utah electrode arrays (UEA), Utah slanted electrode array (UESEA), or combinations thereof.

13. The method of claim 1, wherein the electrical stimulation comprises Kilohertz range electrical stimulation (KES).

14. The method of claim 1, wherein the electrical stimulation occurs in a gradual manner.

15. The method of claim 1, wherein the electrical stimulation occurs in a graded manner.

16. The method of claim 1, wherein the electrical stimulation comprises a step graded increase of amplitude, charge, or combinations thereof.

17. The method of claim 1, wherein the blocking of the neural conduction in neural fibers in the nerve is reversible.

18. The method of claim 1, wherein the blocking of the neural conduction in neural fibers in the nerve is selective to the stimulated fascicle.

19. The method of claim 1, wherein the blocking of neural conduction in neural fibers in the nerve does not produce or produces limited unwanted on-set response.PCT Application Attorney Docket No. AF42186-P053WOUA No. 2024-00420. The method of claim 1, wherein the blocking of neural conduction in neural fibers in the nerve does not produce or produces limited unwanted neural fatigue.

21. The method of claim 1, wherein the method is used in vivo in a subject.

22. The method of claim 21, wherein the method is used for neuromodulation therapy in the subject.

23. The method of claim 21, wherein the method is used to treat or prevent a condition associated with neural hyperactivity in the subject.

24. The method of claim 23, wherein the condition is selected from the group consisting of pain, Parkinson disease, Crohn’s disease, obesity, cardiac diseases, epilepsy, depression, inflammation, diabetes, bladder voiding dysfunctions, sexual disorders, or combinations thereof.

25. The method of claim 23, wherein the condition comprises pain.

26. The method of claim 25, wherein the pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, phantom pain, or combinations thereof.

27. A neuromodulation system operable to selectively block neural conduction in neural fibers in a nerve, said system comprising;(a) an intraneural electrode operational to associate with a fascicle of the nerve; and(b) a stimulator in electrical communication with the intraneural electrode, wherein the stimulator is operational to provide electrical stimulation to the fascicle, and wherein the electrical stimulation is operable to block neural conduction in neural fibers in the nerve.

28. The neuromodulation system of claim 27, further comprising:PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-004(c) a stimulator in electrical communication with the intraneural electrode and the signal processing unit, wherein the signal processing unit is operable to measure conduction by the nerve; and(d) a pulse processing unit operable to adjust the electrical stimulation to the fascicle based on the measurement.

29. The neuromodulation system of claim 28, wherein the pulse processing unit further comprises a controller, wherein the controller is operational to control one or more electrical stimulation parameters by the intraneural electrode.

30. The neuromodulation system of claim 29, wherein the controller comprises a programming language, wherein the programming language comprises programming instructions for controlling one or more electrical stimulation parameters by the intraneural electrode.

31. The neuromodulation system of claim 29, wherein the controller comprises a graphical user interface (GUI), wherein the GUI is operational to display one or more electrical stimulation parameters by the intraneural electrode.

32. The neuromodulation system of claim 27, wherein the intraneural electrode is selected from the group consisting of Longitudinal intrafascicular electrodes (LIFEs), thin-film longitudinal intrafascicular electrodes (tf-LIFEs), transverse intrafascicular multichannel electrodes (TIMEs), multielectrode intrafascicular arrays (MEAs), Utah electrode arrays (UEA), Utah slanted electrode array (UESEA), or combinations thereof.

33. The neuromodulation system of claim 27, wherein the electrical stimulation comprises Kilohertz range electrical stimulation (KES).

34. The neuromodulation system of claim 27, wherein the electrical stimulation occurs in a gradual manner.PCT Application Attorney Docket No. AF42186-P053WO UA No. 2024-00435. The neuromodulation system of claim 27, wherein the electrical stimulation occurs in a graded manner.

36. The neuromodulation system of claim 27, wherein the electrical stimulation comprises a step graded increase of amplitude, charge, or combinations thereof.

37. The neuromodulation system of claim 27, wherein the system is suitable for use in vivo in a subject.

38. The neuromodulation system of claim 37, wherein the system is suitable for use in neuromodulation therapy in the subject.

39. The neuromodulation system of claim 37, wherein the system is suitable for use in treating or preventing a condition associated with neural hyperactivity in the subject.

40. The neuromodulation system of claim 39, wherein the condition is selected from the group consisting of pain, Parkinson disease, Crohn’s disease, obesity, cardiac diseases, epilepsy, depression, inflammation, diabetes, bladder voiding dysfunctions, sexual disorders, or combinations thereof.

41. The neuromodulation system of claim 39, wherein the condition comprises pain.

Images