JP7741066B2 - Systems and methods for providing neural regeneration therapy and reducing chronic post-surgical pain - Google Patents

Description

cross reference

This application claims priority to U.S. Provisional Patent Application No. 62/909,048, filed October 1, 2019, and U.S. Provisional Patent Application No. 63/044,208, filed June 25, 2020, the contents of both of which are incorporated herein by reference in their entireties. Additionally, the entire contents of U.S. Patent No. 10,589,089, filed August 27, 2019, and issued March 17, 2020, are incorporated herein by reference and made a part of this application.

This application relates generally to devices, systems, and methods for locating and/or treating (e.g., regenerating, promoting healing, etc.) damaged tissue, and more specifically to devices, systems, and methods for promoting regeneration of damaged nerves (e.g., nerve regeneration).

Peripheral nerve injuries adversely affect otherwise healthy patients by significantly weakening them and limiting their ability to perform activities of daily living. Peripheral nerve injuries can result from a variety of etiologies, ranging from complex trauma to iatrogenic and compressive neuropathies. However, despite the diverse etiologies, the primary means for repairing peripheral nerve injuries is surgical repair of the severed nerve end or surgical release of the compressed nerve. Unfortunately, even the best surgical procedures typically leave patients with significant disabilities. Furthermore, patients often experience neuropathic pain associated with nerve injury. Pain can be localized at the injury site, radiate along the injured nerve, or, in the case of compression, pain can radiate downstream from the injury site. Given the disability associated with nerve injury, there is a clear need to improve outcomes.

Currently, clinical treatment of injured peripheral nerves is primarily surgical, either by releasing the nerve compression source or by connecting the severed nerve directly or with a graft. While surgery allows for nerve regrowth by reestablishing nerve connections, functional recovery remains inadequate. Nerves generally regenerate slowly (at a maximum rate of approximately 1 mm/day) and require extended periods of time to reconnect with the denervated target muscle or sensory end organ. The window of opportunity for nerve regeneration is short, and the regenerative capacity of injured neurons and regenerative support for distal nerve stumps declines over time and distance. These factors, combined with misdirection of nerve regeneration, often contribute to poor recovery. In addition to poor recovery, patients often experience pain resulting from nerve injury. This pain can clinically manifest as allodynia or hyperalgesia. While this pain may be transient in nature and resolve with tissue reinnervation, it can also become chronic if nerve regeneration leads to the formation of a neuroma. Poor regeneration can result not only in decreased motor function but also in increased chronic pain and residual paresthesia. Promoting nerve regeneration can result in better tissue renervation, which not only improves functional outcomes but also reduces the likelihood of developing chronic or other long-term pain. Chronic or long-term pain can also include pain that persists beyond the normal healing time (e.g., the normal time for a particular type of injury or other cause of pain). As used herein, "chronic pain" or "long-term pain" can include, but is not limited to, pain that lasts for 12 weeks or longer.

According to some embodiments, a method for managing pain associated with peripheral nerve injury in a subject includes, during a regeneration phase, delivering stimulation energy at a first frequency to the target nerve via at least one electrode assembly to produce a nerve regeneration effect in the target nerve resulting in improved tissue reinnervation configured to lead to a reduced likelihood of developing long-term pain, and during at least one neuropathic pain management phase, delivering stimulation energy at a second frequency via at least one electrode assembly for a predetermined period of time to alleviate neuropathic pain in the subject caused by the peripheral nerve injury.

According to some embodiments, the method further includes accessing the target nerve using a paraincision approach, the target nerve being a peripheral nerve suffering from persistent damage, and the frequency of the neuropathic pain management phase is greater than the frequency of the nerve regeneration phase.

According to some embodiments, the method further includes accessing the target nerve using a paraincision approach, the target nerve being a peripheral nerve suffering from a persistent injury.

According to some embodiments, the frequency of the neuropathic pain management phase is greater than the frequency of the nerve regeneration phase. In some embodiments, the pain management treatment includes stimulation in the range of 50-200 Hz (e.g., 50-60, 50-55, 55-60, 52-58 Hz, values between these ranges, etc.). In some embodiments, the frequency of the neuropathic pain management phase is 20 KHz to 500 KHz. In some embodiments, the frequency of the neuropathic pain management phase is 1 KHz to 10 KHz.

According to some embodiments, the step of accessing the target nerve is performed percutaneously.

According to some embodiments, providing stimulation energy during the regeneration phase is sufficient to elicit a response. In some embodiments, the response relates to an action potential or an evoked response in the subject. In some configurations, the elicited response during the regeneration phase is configured to, at least in part, confirm the therapeutic efficacy of the neural regeneration therapy in the subject.

According to some embodiments, providing stimulation energy during the neuropathic pain management phase is sufficient to elicit a response. In some configurations, the response relates to an action potential or an evoked response in the subject. In some embodiments, the elicited response during the neuropathic pain management phase is configured to, at least in part, confirm relief of neuropathic pain in the subject.

According to some embodiments, the system includes one or more components configured to provide stimulation energy at a first frequency and a second frequency to perform any of the methods described above.

In some embodiments, the systems and methods disclosed herein are configured to provide an approach aimed at both treating injured tissue and alleviating neuropathic pain through electrical stimulation by promoting tissue reinnervation.

In some embodiments, the systems described herein can deliver one or more bouts of nerve regeneration therapy and a separate pain management therapy. In other configurations, multiple bouts of nerve regeneration therapy can be delivered, leading to enhanced tissue reinnervation. In such embodiments, the application of pain management waveforms can alleviate short-term acute pain while reducing the likelihood of a patient or other subject developing chronic or other long-term pain.

According to some embodiments, a system (and corresponding method) configured to deliver targeted electrical stimulation therapy to damaged nerves can be easily adapted to a variety of injuries and clinical workflow needs, such as various anatomic regions, damaged nerves, nerve diameters, and types of nerve injury. The system can conveniently provide users with the ability to seamlessly exchange connected neural interfaces (e.g., for nerve regeneration) to deliver nerve regeneration therapy. The embodiments disclosed herein provide users with the flexibility to apply nerve regeneration therapy pre-operatively, intra-operatively, post-operatively, or a combination thereof, as desired or needed.

Additionally, according to some embodiments, the systems and methods allow for confirmation that the stimulation electrodes are functioning properly by providing a means to verify the integrity of the electrodes and/or system through either physical self-verification or an automated verification step. This can be advantageous in situations where a motor nerve is severed and there is no physical response (e.g., muscle contraction), or where a purely sensory nerve is severed and there is no physical response to begin with. This same verification method allows for the safe and continuous delivery of nerve regeneration therapy by monitoring the flow of current through the electrodes.

According to some embodiments, the systems and methods disclosed herein further enable the user to perform nerve localization tasks using the same or a different neural interface prior to initiating nerve regeneration therapy. Furthermore, the system is configured with a single button to control stimulation parameters, system mode, and treatment time, providing a clinician-friendly interface that minimizes training and complexity.

According to some embodiments, a method for stimulating a target nerve in a subject includes, in a first phase, delivering stimulation energy at a first frequency via at least one electrode assembly; and, in a second phase, delivering stimulation energy at a second frequency to the subject via at least one electrode assembly for a predetermined period of time, wherein delivering the stimulation energy to the subject in the second phase produces a regenerative effect (e.g., a nerve regeneration effect) in the target nerve, and delivering the stimulation energy in the first phase is configured to verify at least one substantiating condition. In some embodiments, the second frequency is greater than the first frequency.

According to some embodiments, a method for stimulating a target nerve in a subject includes, in a first phase, delivering stimulation energy at a first frequency via at least one electrode assembly, and in a second phase, delivering stimulation energy at a second frequency via at least one electrode assembly to the subject for a predetermined period of time, wherein delivering stimulation energy to the subject in the second phase produces a neuroregenerative effect on the target nerve, the second frequency being greater than the first frequency.

According to some embodiments, at least one verifying condition is that at least one electrode assembly is functional. In some embodiments, providing stimulation energy in the first stage is configured to activate an indicator that at least one electrode assembly is functional. In some embodiments, the indicator comprises a visual indicator (e.g., an LED or other light source). In other configurations, the indicator comprises a non-visual indicator (e.g., an audible indicator, a tactile feedback indicator, etc.).

According to some embodiments, at least one verifying condition is that at least one electrode is in contact with a target nerve. In some embodiments, providing stimulation energy in a first phase is configured to facilitate localization of the target nerve. In some embodiments, providing stimulation energy at a first frequency in a first phase produces a visible and/or verbal (e.g., verbal) response in the subject. In some embodiments, the visible response includes a twitch, a reflex, a muscle response, or other involuntary movement in the subject.

According to some embodiments, the predetermined period of time is at least 10 minutes. In some embodiments, the predetermined period of time is at least 20 or 30 minutes. In some configurations, the predetermined period of time is between 10 and 60 minutes.

According to some embodiments, the first frequency is between 1 Hz and 40 Hz. In some embodiments, the first frequency is lower than 40 Hz. In some embodiments, the second frequency is between 1 Hz and 100 Hz. In some embodiments, the first frequency is between 1 Hz and 10 Hz, and the second frequency is between 10 Hz and 100 Hz.

According to some embodiments, the method further includes positioning at least one electrode assembly adjacent to the target nerve in the subject.

The method further includes at least partially securing the at least one electrode assembly to the target nerve of the subject. In some embodiments, at least partially securing the at least one electrode assembly to the target nerve includes using at least one of a suture, a barb, a tissue anchor, a flap, and another type of mechanical connector. In one embodiment, at least partially securing the at least one electrode assembly to the target nerve includes using an adhesive.

According to some embodiments, placing at least one electrode assembly adjacent to the target nerve includes not securing the at least one electrode assembly to the subject. In some embodiments, placing at least one electrode assembly adjacent to the target nerve includes aligning the at least one electrode assembly next to or near the target nerve (e.g., with or without an insertion tool).

According to some embodiments, delivering stimulation energy to the subject in the first stage includes delivering stimulation energy in a repeated burst sequence. In some embodiments, the repeated burst sequence includes at least two pulses. In some embodiments, the repeated burst sequence includes at least three pulses.

According to some embodiments, the at least one electrode is included as part of a bipolar electrode assembly. In some embodiments, placing the at least one electrode assembly at or adjacent to the nerve of interest includes advancing the at least one electrode assembly and a lead secured to the at least one electrode through a cannula, sheath, or other device having an internal opening. In some embodiments, in an intraoperative setting, the at least one electrode assembly comprises a cuff electrode.

According to some embodiments, a device for stimulating a target nerve in a subject comprises at least one electrode assembly and a lead physically coupled to the at least one electrode assembly, wherein in a first stage, the at least one electrode is configured to deliver stimulation energy of a first frequency via the at least one electrode assembly, and in a second stage, the at least one electrode is configured to deliver stimulation energy of a second frequency to the subject via the at least one electrode assembly for a predetermined period of time, wherein delivering the stimulation energy to the subject in the second stage produces a neuroregenerative effect on the target nerve, and delivering the stimulation energy to the subject in the first stage is configured to confirm at least one substantiating condition.

According to some embodiments, at least one verifying condition is that at least one electrode assembly is functional. In some embodiments, the device further comprises an indicator, wherein providing stimulation energy in the first stage is configured to activate the indicator, the indicator configured to provide confirmation that the at least one electrode assembly is functional. In some embodiments, the indicator comprises a visual indicator (e.g., an LED or other light source). In some embodiments, the indicator comprises a non-visual indicator (e.g., an audible indicator, a tactile feedback indicator, etc.).

According to some embodiments, at least one verifying condition is that at least one electrode is in contact with a target nerve. In some embodiments, providing stimulation energy in a first phase is configured to facilitate localization of the target nerve. In some embodiments, providing stimulation energy at a first frequency in a first phase produces a visible and/or verbal (e.g., verbal) response in the subject. In some embodiments, the visible response includes a twitch, a reflex, a muscle response, or other involuntary movement in the subject.

According to some embodiments, the first frequency is between 1 Hz and 40 Hz. In some embodiments, the first frequency is lower than 40 Hz. In some embodiments, the second frequency is between 1 Hz and 100 Hz. In some embodiments, the first frequency is between 1 Hz and 10 Hz, and the second frequency is between 10 Hz and 100 Hz.

According to some embodiments, delivering stimulation energy to the subject in the first phase includes delivering stimulation energy in a repetitive burst sequence. In some embodiments, the repetitive burst sequence includes at least two pulses. In some embodiments, the repetitive burst sequence includes at least three pulses. In some embodiments, at least one electrode assembly comprises a cuff electrode.

According to some embodiments, a method for stimulating a target nerve in a subject includes identifying the target nerve, positioning at least one electrode assembly relative to the subject to selectively stimulate the target nerve, and delivering therapeutic stimulation energy to the subject via the at least one electrode assembly for a predetermined period of time to produce a nerve regeneration effect in the target nerve, wherein the predetermined period of time is at least 10 minutes (e.g., 10 minutes, 10-30 minutes, 10-60 minutes, etc.), and the at least one electrode assembly comprises a first electrode positioned immediately adjacent to the target nerve and a second electrode positioned physically separate from the first electrode.

According to some embodiments, the second electrode comprises a patch electrode disposed on the skin surface of the subject. In one embodiment, the first and second electrodes are included as part of a bipolar electrode assembly. In some embodiments, identifying the nerve of interest comprises providing a verification stimulus to the subject to solicit a response from the subject. In some embodiments, the verification stimulus comprises a frequency lower than the frequency of the therapeutic stimulation energy. In some embodiments, the verification stimulus comprises a repetitive burst sequence of at least two pulses. In some embodiments, the repetitive burst sequence comprises at least three pulses.

According to some embodiments, a method of stimulating a target nerve in a subject includes identifying the target nerve, positioning at least one electrode assembly adjacent to the target nerve, verifying that the at least one electrode is electrically activated when exposed to a verified stimulus derived from a verified stimulus source prior to positioning the at least one electrode assembly adjacent to the target nerve, and delivering therapeutic stimulation to the subject via the at least one electrode assembly for a predetermined period of time to produce a neuroregenerative effect in the target nerve, wherein the therapeutic stimulus is derived from the therapeutic stimulus source, and the predetermined period of time is at least 10 minutes.

According to some embodiments, the source of the verification stimulus is the same as the source of the therapeutic stimulus, and thus the source of the verification stimulus and the source of the therapeutic stimulus comprise a single stimulation course. In some embodiments, the single stimulation source comprises a handheld device. In some embodiments, the source of the verification stimulus is different from the source of the therapeutic stimulus. In some embodiments, the verification stimulus comprises a lower frequency than the therapeutic stimulus. In some embodiments, the verification stimulus comprises a repetitive burst sequence of at least two pulses. In some embodiments, the repetitive burst sequence comprises at least three pulses (e.g., three, four, five pulses, six or more pulses, etc.).

According to some embodiments, the present application discloses an electrical stimulation system comprising one or more electrodes that can be used for intraoperative or perioperative neural stimulation. In some embodiments, the system comprises a relatively small size that conveniently fits in the palm of an end user's hand. In some embodiments, one or more of the configurations disclosed herein provide the ability to interface the system with different electrodes. In some embodiments, the system is designed to be single-use and disposable, providing an end user, such as a surgeon or other practitioner, with the possibility to use the system intraoperatively (e.g., if the system is sterilized and packaged in appropriate packaging).

In some embodiments, the various systems, devices, and methods disclosed herein provide practitioners with a way to locate and treat damaged nerves with electrical stimulation. Embodiments can be used intraoperatively or perioperatively.

In some embodiments, the system can be used in a perioperative environment. The system housing can include controls (e.g., one or more sets of controls) for changing stimulation amplitude and/or other settings.

In some embodiments, the system includes one or more controls for starting, stopping, pausing, resuming, and/or otherwise modifying the delivery of energy to heal damaged tissue. In some embodiments, the system further includes circuitry that enables power to the system, thus providing stimulation only when the appropriate interface is connected. Visual indicators may be included on the housing or in the connected interface. These indicators may provide signals to the end user relaying information regarding the status of the system, active interface use, current operating mode, stimulation settings, and/or time remaining for treatment delivery. The indicators may include multiple light-emitting diodes, a graphical display, or similar light-emitting elements. The housing may further include an element used to secure the system to a surgical drape or other structure. This element may be, but is not limited to, an adhesive, a strap, a hook, or a clip.

Further aspects of the system include the ability to provide either monopolar or bipolar stimulation. For intraoperative use, where the exposed damaged tissue is preferably a nerve, the system can be deployed using a bipolar or monopolar electrode device to interface with the damaged nerve. The described electrode device can allow the user to interface with nerves of any diameter by wrapping the electrode carrier body around the nerve and securing the wrapped portion in place using tabs. Deflecting the tab laterally releases the wrap around the nerve, allowing for easy removal of the electrode. One aspect of the electrode device is that it can be shaped in a flat or open configuration, allowing the electrode to spring back to this configuration when wrapped around the nerve. A shaped tab on the electrode allows the head portion of the electrode to be secured below the tab, preventing the electrode from springing back to the flat configuration and maintaining wrap around the interfaced nerve to provide appropriate stimulation therapy.

In some embodiments, for perioperative use, the electrodes are placed during or perioperatively during a surgical procedure using percutaneous methods. In some embodiments, monopolar electrodes can be used, where the electrode interface does not need to directly contact the nerve. In such a configuration, the system can be connected or coupled to a return electrode (which may, for example, include a patch-type electrode placed on the skin and connected directly to the system).

According to some embodiments, an additional aspect of the system includes a stimulation signal (which may include, for example, either a constant voltage pulse or a constant current pulse). In some embodiments, a constant current pulse is used. In some embodiments, the constant current stimulation amplitude is in the range of 0-20 milliamps (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-15, 15-20 milliamps, values within these ranges, etc.).

According to some embodiments, a biphasic pulse output is used for safe stimulation over a period of time. This can help ensure that no net charge is introduced at the electrode interface. In some embodiments, charge balancing is achieved using a passive element (e.g., a capacitor coupled to the stimulator output). In some embodiments, an active method samples the stimulator output offset in a feedback loop and/or corrects for this by generating additional pulses of the correct polarity or injecting a counter offset to ensure that the net charge is zero. Other methods not specifically described herein may also be used.

According to some embodiments, additional aspects of the system include a test mode (e.g., to allow the user to initially deliver low-frequency stimulation (e.g., 0.1-10 Hz) that allows the end user to visualize whether the damaged tissue is responsive to the stimulation). In some embodiments, various configurations allow the user to adjust the stimulation output to a desired level and begin delivering therapeutic electrical stimulation. Additional parameters can be adjusted.

According to some embodiments, additional aspects of the system include modifying the first stage of stimulation and housing to accommodate bipolar probe electrodes to function as a nerve locator. In some embodiments, the test mode can be modified to provide an electrical stimulation pulse sufficient to elicit a strong muscle contraction response after probe connection with a peripheral nerve. In some configurations, the test mode delivers a stimulation doublet pulse (e.g., a doublet) used to exploit muscle capture-like properties where successive stimulations result in fusion contractions. In certain embodiments, the doublet allows for a greater muscle range of motion and can aid in nerve localization.

According to some embodiments, a method for treating damaged tissue (e.g., a nerve) includes first interfacing the tissue with electrodes appropriate for the use case (e.g., intraoperative or perioperative, other procedure, etc.). The method can further include securing or coupling the electrodes to the system, which in some embodiments allows the system to provide test stimuli to verify the tissue's response to the electrical stimulation. In some embodiments, the system is configured to allow a user to modify one or more operating parameters (e.g., amplitude). The method further includes the user initiating nerve regeneration therapy to treat the damaged tissue (e.g., a nerve of interest).

According to some embodiments, the methods disclosed herein are configured to provide a targeted approach to treating damaged tissue through electrical stimulation. In some embodiments, unlike other stimulation systems, the systems, devices, and methods disclosed herein can be configured to allow a user to select whether the system is applied intraoperatively using a predetermined appropriate electrode interface, or perioperatively using an appropriate electrode interface. In some embodiments, the length of the surgical procedure determines how the device is applied.

According to some embodiments, a method for at least partially positioning an electrical lead assembly within a subject's body structure includes percutaneously inserting the electrical lead assembly into the subject's body structure, the lead assembly comprising at least one electrode configured to contact a target tissue of the subject to perform a desired procedure, the electrical lead assembly further comprising an insert and an outer cover, the insert comprising elastic deformability to facilitate shaping or reshaping of the electrical lead assembly, and the outer cover comprising elastic deformability that allows the outer cover to undergo a temporary change in shape when a force is applied to the electrical lead assembly. The method further includes shaping the electrical lead assembly after percutaneous insertion into the subject's body structure by selectively applying a force or moment along at least a portion of the electrical lead assembly, the elastic deformability of the outer cover being less than or equal to (e.g., equal to or less than) a plastic deformability of the insert, and shaping the electrical lead assembly can position at least one electrode of the electrical lead assembly along the target tissue.

According to some embodiments, the distal aspect of the outer cover has a lower durometer or hardness than the proximal aspect of the outer cover, the Shore D durometer of the distal aspect of the outer cover is between 20D and 50D, the Shore D durometer of the proximal aspect of the outer cover is between 50D and 80D, the thickness of the outer cover is between 100 and 400 μm, and the diameter or other cross-sectional dimension of the insert is 100% to 500% of the thickness of the outer cover. In other words, in some embodiments, the diameter or other cross-sectional dimension of the insert is equal to or greater than the thickness of the outer cover or jacket.

According to some embodiments, the outer cover has a uniform or continuous thickness throughout the length of the electrical lead assembly. In some embodiments, the distal aspect of the outer cover has a lower durometer or hardness than the proximal aspect of the outer cover. In some configurations, the Shore D durometer of the distal aspect of the outer cover is between 20D and 50D. In some configurations, the Shore D durometer of the proximal aspect of the outer cover is between 50D and 80D.

According to some embodiments, the thickness of the outer cover is between 100 and 400 μm. In some embodiments, the diameter or other cross-sectional dimension of the insert is between 100% and 500% of the thickness of the outer cover or jacket. In some configurations, the lead assembly is configured to at least partially surround a nerve or nerve bundle of interest.

According to some embodiments, the Shore D durometer of the outer cover is between 20D and 80D, the thickness of the outer cover is between 100 and 400 μm, the insert comprises an annealed metal or alloy, and the diameter or other cross-sectional dimension of the insert is between 100% and 500% of the thickness of the outer cover.

According to some embodiments, the insert comprises an annealed metal or alloy. In some embodiments, the annealed metal or alloy includes copper.

In some embodiments, the diameter or other cross-sectional dimension of the insert is 100% to 500% of the thickness of the outer cover. In other words, in some embodiments, the diameter or other cross-sectional dimension of the insert is equal to or greater than the thickness of the outer cover or jacket.

According to some embodiments, the Shore D durometer of the distal aspect of the outer cover is between 20D and 50D.

According to some embodiments, the lead assembly is configured for use in a nerve regeneration procedure. In some embodiments, the lead assembly is configured for use in a pain management procedure. In some embodiments, the lead assembly is configured for use in both a nerve regeneration procedure and a pain management procedure.

According to some embodiments, the desired treatment includes a nerve regeneration treatment and/or a pain management treatment. In some embodiments, the target tissue includes nerve tissue.

According to some embodiments, an electrical lead assembly configured to be at least partially inserted into a body structure of a subject comprises at least one electrode configured to contact target tissue of the subject to perform a desired procedure, an insert having elastic deformability to facilitate shaping or reshaping of the electrical lead assembly, and an outer cover having elastic deformability that allows the electrical lead assembly to undergo a temporary change in shape when a force is applied to the electrical lead assembly, wherein the electrical lead assembly is configured to be shaped after percutaneous insertion into the body structure of the subject by selectively applying a force or moment along at least a portion of the electrical lead assembly.

According to some embodiments, the shapeable lead assembly is configured to be shaped in a desired manner before and/or during a procedure, such as after the lead assembly is at least partially positioned within a subject's body structure. The shapeable lead assembly can be shaped during a nerve regeneration procedure to contact and/or interface with a target nerve.

According to some embodiments, a shapeable lead assembly includes an insert or other member and an outer jacket or other outer cover. The insert can be configured to facilitate shaping or reshaping of the assembly and can include plastic deformability (e.g., the insert can be configured to deflect when the material is subjected to a specific force and/or stress that exceeds its yield strength and causes it to stretch, bend, twist, etc.). Such deflection can be temporary, allowing the insert or other member to maintain its shape when no external force is applied (e.g., when placed on a table or other surface until a user applies another bending or other reshaping force or moment). The outer jacket or other outer cover of the lead assembly can include elastic deformability (e.g., can be configured to undergo a temporary change in shape when a force is applied to the lead assembly, and thus the outer jacket or cover). Such elastically deformable members are configured to resume their original shape or orientation when the force or moment is removed or reduced (e.g., are at least partially self-reversible).

These and other features, aspects, and advantages of the present application will be described with reference to drawings of specific embodiments, which are intended to be illustrative of, but not limiting of, the concepts disclosed herein. The accompanying drawings are provided for the purpose of illustrating the concepts of at least some of the embodiments disclosed herein and may not necessarily be drawn to scale.

1A-1C show schematic diagrams of various configurations of a system according to one embodiment.

1 illustrates a top view of a handheld nerve locator according to one embodiment.

10A-10C show a top view of a handheld nerve locator according to one embodiment incorporating lateral grooves to facilitate one-handed holding.

10A-10C show side views of a handheld nerve locator according to one embodiment incorporating longitudinal grooves for easy rotation and access to controls using one hand.

10 illustrates a rear view of a handheld nerve locator according to one embodiment showing access to the nerve port.

FIG. 1 illustrates a perspective view of an improved touchproof jack according to one embodiment used to provide contacts for a jack detection circuit.

FIG. 1 illustrates a schematic diagram of a jack detection circuit according to one embodiment configured to detect a medical Touchproof connection.

1 shows a schematic diagram of a main microcontroller and subsystems that interact with the microcontroller to create a system according to one embodiment.

10 shows a graph illustrating dual stimulation pulses of arbitrary amplitude according to one embodiment.

10 shows a graph illustrating biphasic dual stimulation pulses of arbitrary amplitude according to one embodiment.

10 shows a graph illustrating the use of dual stimulation pulses of any amplitude followed by a single charge balancing pulse according to one embodiment.

10 shows a graph illustrating an exponential rise charge balancing pulse following each pulse of a dual stimulation pulse train of arbitrary amplitude according to one embodiment.

FIG. 1 shows a perspective view of an embodiment of a device in which the electrode configuration is monopolar, with a single electrode pad present at the thickest portion of the carrier, according to one embodiment.

1 illustrates a cross-sectional view of a carrier according to one embodiment showing attachment of a single electrode pad to a lead wire, the lead wire being externalized from the carrier at the tail portion.

1 illustrates a perspective view of a device according to one embodiment, with lead cables exiting the carrier from the rear end along the longitudinal axis.

FIG. 10 illustrates a perspective view of a locking mechanism engaged with a carrier wrapped around a tubular structure according to one embodiment.

1 shows a perspective view of a device according to one embodiment, with the lead cables exiting the carrier perpendicular to the longitudinal axis.

1 shows a rear view of a device according to one embodiment, starting from the tail portion of the device and showing a single through-hole used for electrode placement.

3B shows a perspective view of the device shown in FIG. 3A highlighting the exit portion of the through-hole.

FIG. 1 shows a perspective view of an embodiment of a device in which the electrode configuration is bipolar with two electrode pads, according to one embodiment.

FIG. 1 shows a perspective view of an embodiment of a device in which the electrode configuration is tripolar with three electrode pads, according to one embodiment.

FIG. 1 shows a perspective view of one embodiment of a device in which the electrode configuration according to one embodiment is bipolar with two electrode pads made from metal foil and oriented longitudinally along a grooved portion of the carrier.

FIG. 1 shows a perspective view of one embodiment of a device in which the electrode configuration according to one embodiment is tripolar with three electrode pads made from metal foil and oriented longitudinally along a grooved portion of the carrier.

FIG. 1 shows a closer perspective view of one embodiment of the device in which the electrode configuration is bipolar with two electrode pads made from metal foil and oriented longitudinally along a grooved portion of the carrier.

1 illustrates a perspective view of an embodiment in which the locking mechanism is a circular strap, according to one embodiment.

1 shows a perspective view of an embodiment in which the locking mechanism is a series of aperture pairs aligned longitudinally along the carrier and a pair of protrusions or buttons that engage the apertures.

1 shows a perspective view of an embodiment in which an adhesive patch including a visual indicator is coupled to the proximal end of a lead of an electrode device, according to one embodiment.

FIG. 10 shows a perspective view of an embodiment in which an adhesive patch is coupled to a monopolar needle electrode, with the patch acting as a return, according to one embodiment.

FIG. 1 illustrates a top view of the circuit layer of an adhesive patch stimulator device according to one embodiment.

1 illustrates an exploded view of an assembly of an adhesive patch stimulation system with a conductive rubber skin interface, a circuit layer, and an elastomeric protective layer according to one embodiment.

FIG. 1 illustrates a perspective view of one embodiment of a device showing a carrier bound to a polymeric background material used to isolate tissue of interest from surrounding tissue according to one embodiment.

FIG. 10 shows a perspective view of one embodiment of a device showing a carrier bound to a polymer background material used to isolate tissue of interest from surrounding tissue, with a severed nerve positioned on the background material, according to one embodiment.

FIG. 10 shows a perspective view of one embodiment of the device, showing the carrier folded to encase the nerve, but still partially attached to a polymer background material used to isolate the tissue of interest from surrounding tissue, with the severed nerve resting on the background material, according to one embodiment.

1 illustrates one embodiment of an electrical lead.

1 illustrates one embodiment of an electrical lead.

1 illustrates one embodiment of an electrical lead.

1 illustrates one embodiment of an electrical lead.

1 illustrates one embodiment of an electrical lead coupled to a cap element.

1 shows an embodiment of a cap element with an electrical circuit.

1 illustrates one embodiment of an assembly configured to be secured to a cap element.

18C secured to the cap element of FIG. 18B.

1 illustrates an embodiment of an electrical lead with a cap element.

1 illustrates one embodiment of an adhesive patch that includes exposed conductive contacts.

1 illustrates one embodiment of a validation assembly including a conductive element.

1 illustrates one embodiment of a cuff electrode device interfaced with a verification bar.

1 illustrates one embodiment of a cuff electrode device interfaced with a verification bar.

1 illustrates one embodiment of a cuff electrode device interfaced with a verification bar.

1 illustrates an embodiment of an electrode consisting of a percutaneous lead coupled to a housing containing a stimulation source. 1 illustrates an embodiment of an electrode consisting of a percutaneous lead coupled to a housing containing a stimulation source.

1 illustrates an embodiment of an electrode consisting of a percutaneous lead coupled to a housing containing a stimulation source.

Included are flow diagrams illustrating embodiments of methods for using the systems and devices disclosed herein. 1 includes a flow diagram illustrating another embodiment of a method for using the systems and devices disclosed herein.

1 is a flow chart illustrating a process for locating and treating damaged nerves in an intraoperative setting using the described system according to one embodiment.

10 is a flow chart illustrating a process for locating and treating damaged nerves in an intraoperative setting using the systems and devices disclosed herein according to another embodiment.

10 is a flow chart illustrating a process for locating and treating damaged nerves using the systems and devices disclosed herein according to another embodiment.

1 illustrates one embodiment of a procedure diagram showing the process of percutaneously inserting electrodes using an insertion tool and connecting a stimulator to provide nerve regeneration therapy.

1 illustrates an embodiment for percutaneously placing electrodes at various locations on a body structure to provide nerve regeneration therapy. 1 illustrates an embodiment for percutaneously placing electrodes at various locations on a body structure to provide nerve regeneration therapy. 1 illustrates an embodiment for percutaneously placing electrodes at various locations on a body structure to provide nerve regeneration therapy. 1 illustrates an embodiment for percutaneously placing electrodes at various locations on a body structure to provide nerve regeneration therapy.

1 illustrates an embodiment in which percutaneously placed electrode leads connected to a surface patch with integrated electronics are used to stimulate and measure one or more biological signals. 1 illustrates an embodiment in which percutaneously placed electrode leads connected to a surface patch with integrated electronics are used to stimulate and measure one or more biological signals. 1 illustrates an embodiment in which percutaneously placed electrode leads connected to a surface patch with integrated electronics are used to stimulate and measure one or more biological signals. 1 illustrates an embodiment in which percutaneously placed electrode leads connected to a surface patch with integrated electronics are used to stimulate and measure one or more biological signals.

1 shows an embodiment of stimulation using a percutaneously placed electrode lead and measurement of biosignals using a cuff electrode around the nerve, both connected to a surface patch with integrated electrical devices.

FIG. 1 shows a schematic diagram of how a multi-channel electrode can be interfaced to a system according to one embodiment.

1 illustrates a schematic flow diagram of a procedure, protocol, or method for providing nerve regeneration and pain management therapy to a subject, according to one embodiment.

1 illustrates a schematic flow diagram of a procedure, protocol, or method for providing nerve regeneration and pain management therapy to a subject, according to one embodiment.

1 illustrates a schematic flow diagram of a procedure, protocol, or method for providing nerve regeneration and pain management therapy to a subject, according to one embodiment.

1 illustrates a schematic flow diagram of a procedure, protocol, or method for providing nerve regeneration and pain management therapy to a subject, according to one embodiment.

1 illustrates one embodiment of a pain relief waveform applied by a stimulation system.

1 illustrates one embodiment of a system configured to provide both nerve regeneration therapy and pain management therapy to a subject.

1 shows a perspective view of an electrode lead being manually shaped in the surgical field according to one embodiment.

1 shows a perspective view of an electrode lead being shaped using forceps in a surgical field according to one embodiment.

1 illustrates a perspective view of an electrode lead shaped to be offset from the general longitudinal axis of the lead body according to one embodiment.

1 shows a perspective view of an electrode lead shaped to generally surround or encase a neural structure according to one embodiment.

FIG. 10 shows a perspective view of a U-shaped electrode lead according to one embodiment.

1 shows a perspective view of an electrode lead having a distal flat portion used to interface with a nerve according to one embodiment.

FIG. 10 shows a perspective view of an electrode lead interfacing a nerve to a flat rectangular flap used for fixation according to one embodiment.

1 shows a longitudinal cross-sectional view of the distal end of an electrode lead according to one embodiment, where a shapeable insert is visible.

1A and 1B schematically illustrate a longitudinal cross-sectional view of a portion of a shapeable lead assembly according to one embodiment.

1 illustrates a profile view of an electrode lead having two distinct regions according to one embodiment.

1 illustrates an axial view of a multi-lumen lead housing according to one embodiment.

1 illustrates a perspective view of a multi-lumen lead housing showing both a shapeable insert and wires within the lumens according to one embodiment.

10 illustrates a profile view of an electrode lead with grooves suitable for handling with forceps according to one embodiment.

1 shows a profile view of a proximal end of an electrode lead with concentric ring contacts according to one embodiment.

10 shows a profile view of an insertion tool being pulled over the proximal end of an electrode lead having concentric ring contacts according to one embodiment.

1 shows a perspective view of a proximal end of an electrode lead having concentric ring contacts and a keyway according to one embodiment.

1 illustrates a profile view of an electrode lead with a verification condition indicator according to one embodiment.

FIG. 1 shows a perspective view of an electrode lead having bioadhesive tape used for proximal fixation of the conductive elements according to one embodiment.

1 shows a perspective view of an electrode lead having bioadhesive tape used for fixation between conductive elements according to one embodiment.

1 shows a perspective view of a bioadhesive delivery device and a light-based curing device according to one embodiment.

1 illustrates a perspective view of a bioadhesive delivery device according to one embodiment, the bioadhesive delivery device including a light source and a smaller illumination area located at the distal end of the delivery device.

1 illustrates a perspective view of a bioadhesive delivery device according to one embodiment, the bioadhesive delivery device including a light source and a larger illumination area located at the distal end of the delivery device.

1 shows a perspective view of a bioadhesive delivery device according to one embodiment that includes a light source for delivering bioadhesive to secure an electrode lead to a nerve.

1 shows a longitudinal view of an electrode lead with irrigation openings used for delivery of bioadhesive according to one embodiment.

1 shows a longitudinal view of an electrode lead having multiple irrigation openings used for delivery of a bioadhesive according to one embodiment.

The devices, systems, and associated methods described herein can be used during surgical procedures to locate nerve tissue, test the excitability of nerve tissue, and/or provide nerve regeneration therapy (e.g., electrical stimulation) to treat nerve tissue of interest (e.g., damaged nerve tissue). While the embodiments disclosed herein can be used with peripheral nerves, other types of nerves, such as nerves of the autonomic nervous system or nerves of the central nervous system, can also be targeted. For example, peripheral nerves can include the median nerve in the upper limbs, the sciatic nerve in the lower limbs, smaller nerves (e.g., intercostal branches in the thoracic region), etc. Autonomic nerves can include, but are not limited to, the vagus nerve. Central nervous system nerves can be found in the spinal cord or the brain.

In some embodiments, the systems and methods disclosed herein are configured to provide an approach aimed at both treating injured tissue and alleviating neuropathic pain through electrical stimulation by promoting tissue reinnervation.

In some embodiments, the systems described herein can deliver one or more bouts of nerve regeneration therapy and a separate pain management therapy. In other configurations, multiple bouts of nerve regeneration therapy can be delivered, leading to enhanced tissue reinnervation. In such embodiments, the application of pain management waveforms can alleviate short-term acute pain while reducing the likelihood of a patient or other subject developing chronic or other long-term pain.

In some embodiments, systems (and corresponding methods) configured to deliver targeted electrical stimulation therapy to damaged nerves are easily adaptable to a variety of injuries and clinical workflow needs, such as various anatomic regions, damaged nerves, nerve diameters, and types of nerve injury. The systems can conveniently provide users with the ability to seamlessly swap connected neural interfaces (e.g., for nerve regeneration) to deliver nerve regeneration therapy. The embodiments disclosed herein provide users with the flexibility to apply nerve regeneration therapy pre-operatively, intra-operatively, post-operatively, or a combination thereof, as desired or needed. The delivery of nerve regeneration therapy can occur before, during, and/or after the delivery of pain management therapy, as desired or needed.

In addition, the systems and methods allow for confirmation that stimulation electrodes are functioning properly by providing a means to verify the integrity of the electrodes and/or system through either physical self-verification or an automated verification step. This can be advantageous in situations where a motor nerve is severed and there is no physical response (e.g., muscle contraction), or where a purely sensory nerve is severed and there is no physical response to begin with. This same verification method allows for the safe and continuous delivery of nerve regeneration therapy by monitoring the flow of current through the electrodes.

In some embodiments, the systems and methods disclosed herein further allow the user to perform nerve localization tasks using the same or a different neural interface prior to initiating nerve regeneration therapy. Furthermore, the system is configured with a single button to control stimulation parameters, system mode, and treatment time, providing a clinician-friendly interface that minimizes training and complexity.

There is a need for a purposefully designed system that can accommodate an appropriate neural interface for prolonged stimulation and deliver electrical stimulation to injured nerves to accelerate nerve regeneration. Many medical fields may benefit from using the disclosed systems and interfaces to promote nerve regeneration. These fields include, but are not limited to, plastic surgery, orthopedics, otolaryngology, oral surgery, and neurosurgery. Additionally, clinical diagnoses that may be improved from the use of the disclosed devices include, but are not limited to, sharp lacerations, nerve transections, nerve compression, compressive neuropathy, cancerous injury to the nerve, peripheral neuropathy, iatrogenic nerve injury, birth brachial plexus palsy, neonatal brachial plexus palsy, facial palsy, and radiculopathy.

More specifically, the systems and interfaces of the present disclosure are designed for intraoperative and/or perioperative use and are suitable for the following situations: nerve section, nerve decompression, nerve transfer,
Improved surgical outcomes can be achieved in nerve grafts, neurolysis, nerve allografts, thoracic outlet decompression, carpal tunnel release, cubital tunnel release, and tarsal tunnel release: While these listed examples can benefit from the devices of the present disclosure, the list is not exhaustive and merely provides examples of what medical conditions can be treated.

Furthermore, after one or more of the above-listed nerve injuries, patients may experience pain due to incomplete or insufficient nerve regeneration. Pain may manifest as allodynia or hyperalgesia along the damaged nerve pathway and distally connected tissues. The systems and methods of the present disclosure can be used to provide pain management therapy to these damaged nerves.

In some configurations, during certain surgical procedures (e.g., complex or tedious surgical procedures), nerves may not be visible and/or may be surrounded by connective tissue, scar tissue, and/or other types of tissue. A device such as a nerve locator can be used to probe the tissue using electrical stimulation to test and confirm whether the tissue is a nerve. Additionally, nerve locators may be used to test the motor component of a nerve bundle prior to a nerve transfer procedure.

In some embodiments, a nerve may be transected or severed (e.g., partially transected, mostly transected, completely transected, etc.), crushed, and/or otherwise damaged or injured. In such cases, the application of stimulation therapy to the damaged nerve may be beneficial. For example, in some embodiments, applying a short but continuous electrical stimulus to the proximal segment of the damaged nerve can provide therapeutic and/or other benefits to the target nerve. In some embodiments, such therapy can accelerate nerve regeneration of the damaged nerve. This therapy is referred to herein as nerve regeneration therapy.

In some embodiments, the application of a single bout of nerve regeneration therapy can lead to enhanced tissue reinnervation, ultimately resulting in a reduced likelihood that the patient will develop chronic pain, reduced residual paresthesia, and improved fine motor skills, among other benefits and advantages.

In some configurations, the application of multiple bouts of nerve regeneration therapy can lead to enhanced tissue reinnervation, which can ultimately result in a patient's reduced likelihood of developing chronic pain, reduced residual paresthesia, and improved fine motor skills, among other benefits and advantages.

Various embodiments disclosed herein provide one or more advantages. For example, the devices and systems described herein provide the ability to function as handheld, dual-purpose technology designed and configured to provide both nerve localization/testing functionality, nerve regeneration therapy (e.g., continuous stimulation, intermittent stimulation, etc.) for the treatment of damaged nerves (e.g., nerve regeneration), and pain management therapy. A further advantage of the described embodiments is the ability to switch between bipolar and monopolar stimulating nerve probes, as well as other probes or electrodes that can be interfaced with the system.

In some embodiments, a surgeon or other practitioner benefits from using the various devices, systems, and/or methods disclosed herein. For example, the various embodiments disclosed herein may be fully integrated, may replace multiple (e.g., two or more, separate, etc.) devices and/or systems, may be controlled using one hand, and/or may provide one or more benefits or advantages.

Another benefit provided by one or more of the embodiments discussed herein is that the devices/systems of the present disclosure can apply continuous stimulation over a predetermined period of time, allowing the system to be used hands-free (e.g., without the need to operate or use a button or other controller to deliver stimulation energy) when used to treat damaged tissue.

Overall System Overview In one embodiment, the system includes a housing, a neural probe, ports for additional electrodes, a visual indicator, a power source, a stimulation pulse generator/controller, a central processing unit, and user controls. With particular reference to the schematic diagram of FIG. 1 , the system 100 can be configured to function in multiple configurations. Additional configurations of the system may exist, although not specifically shown in FIG. 1 and/or other figures of this disclosure. In any embodiment disclosed herein, the device or system may include fewer components and/or features, as desired or required. For example, in some configurations, the device or system does not include a visual indicator and/or a power source, etc.

In one configuration, the neural probe 102 is bipolar, i.e., comprises two separate electrode conductors internally connected to a stimulus generator. In another configuration, also shown in FIG. 1, the neural probe may be bipolar, i.e., comprises two separate electrode conductors. However, in the configuration shown, the conductors 104 can be internally shorted together to essentially create a single probe. This connected probe can, in some embodiments, function as a monopolar probe when an appropriate return electrode is connected to the system's electrode port 106. As shown schematically in FIG. 1, the return electrode 108 can comprise a needle, a surface pad, and/or another conductive material, so long as a return path exists. Further details regarding such embodiments are provided herein.

In the above-described configuration, system 100 can be used to provide stimulation at or near the neural probe to probe neural tissue. Thus, system 100 can be used as a neural locator or evaluator. Bipolar or monopolar configurations can be advantageous to the surgeon depending on the location of the nerve being probed or the type of surgical procedure being performed.

In yet another configuration, such as the embodiment also shown in FIG. 1, a cuff-type electrode 110 configured to interface (e.g., directly, indirectly, etc.) with a nerve can be connected to the electrode port of the system. Such an embodiment can be advantageous for delivering nerve regeneration therapy to an injured nerve. In such a configuration, the stimulation output may be driven (e.g., entirely) to a pluggable electrode rather than to a neural probe.

In some embodiments, electrodes plugged into the ports may include one or more electrode contacts and may be physically connected to the stimulus generator via the electrode port. Regardless of the exact configuration used, in some embodiments of the present application, the system may be configured to detect whether and which electrodes are plugged into the ports and ensure that appropriate stimulation is output and driven. Further details regarding various embodiments, components, portions, and/or subsystems of the system are presented below.

2A, the system can include a housing 114 that can contain user controls 116, visual indicators 118, a power source, a stimulation pulse generator/controller, a central processing unit, and/or any other components or portions as desired or required. As shown, the housing can include one or more materials, such as, for example, a thermoplastic-type material (e.g., polyethylene, polypropylene, polyvinyl chloride, polystyrene, polyamide, polyester, polyurethane, etc.), a thermoplastic elastomer (e.g., providing a soft, grippable texture in some embodiments), a metal or alloy (e.g., stainless steel, aluminum, other brushed or polished metals or alloys, etc.), and/or a composite material, as desired or required.

In some embodiments, the housing and associated internal components may be configured to be reused. Accordingly, such components or parts may be designed and otherwise configured to be sterilized and/or otherwise cleaned. For example, the system may be sterilized by exposure to ethylene oxide, chlorine dioxide, vaporized hydrogen peroxide, gamma radiation, and/or electron beam, etc.

According to some embodiments, the housing is designed to ergonomically fit the surgeon's hand, as shown in FIG. 2B. Thus, in some configurations, the housing is shaped with grooves or scallops 120 and/or includes an ergonomic shape to facilitate holding regardless of the user's handedness (e.g., right-handed or left-handed). In other embodiments, the housing is specifically designed for a single user's handedness (e.g., right-handed or left-handed). Such grooves or scallops 120 may be symmetrical, asymmetrical, aligned, offset, and/or otherwise configured. As shown, in one embodiment, the deepest portion of the groove 120 may be offset from the widest portion of the housing by 0.1 to 10 mm (e.g., 0.1 to 0.2, 0.2 to 0.3, 0.3 to 0.4, 0.4 to 0.5, 0.5 to 0.6, 0.6 to 0.7, 0.7 to 0.8, 0.8 to 0.9, 0.9 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10 mm, distances therebetween, etc.).

In some embodiments, the groove 120 may be along the longitudinal axis, the horizontal axis, the underside of the housing, or a combination of the above. See, for example, FIG. 2C. In some embodiments, the housing comprises a proximal end 122 and a distal end 124. The distal end 124 may include a visual indicator 118 and a neural probe 102, or a combination thereof. In some embodiments, the proximal end comprises a neural port 106 that may include a neural probe 102.

In some embodiments, the distal and proximal ends may be collinear or offset. For example, in some configurations, the distal and proximal ends are offset by an angle ranging from 1° to 30° (e.g., 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 7-8, 8-9, 9-10, 10-15, 15-20, 20-25, 25-30, 5-25, 10-20°, angles between these ranges, etc.), resulting in an angled distal end (e.g., relative to the proximal end). In some embodiments, such an angled distal end configuration can advantageously facilitate use of the device, as shown, for example, in FIG. 2C. Furthermore, the angular offset can help prevent the housing from rolling (e.g., off a table, cart, other platform, etc.) when placed on a gently sloping or uneven surface, such as when a surgeon or other practitioner sets the housing aside to perform other surgical tasks.

In some embodiments, the length of the housing, or the distance from the proximal end to the distal end, can be 10 to 40 cm (e.g., 10 to 15, 15 to 20, 20 to 25, 25 to 30, 30 to 35, 35 to 40, 15 to 25, 20 to 40 cm, lengths between these ranges, etc.). In other embodiments, the length of the housing can be less than 10 cm or more than 40 cm, as desired or required by a particular application or use. Additionally, the width (e.g., diameter or cross-sectional dimension) of the housing can be 0.5 to 3 cm (e.g., 0.5 to 1, 1 to 1.5, 1.5 to 2, 0.5 to 2, 2 to 2.5, 2.5 to 3 cm, widths between these ranges, etc.).

In some embodiments, the proximal end of the housing includes a hook-like or other curved or angled extension, or a closed ring, physically connected to the housing. In some configurations, the extension can be used to hang the housing from an IV pole and/or another type of hook, etc.

In some embodiments, the housing can include a slot or opening to facilitate a pull tab interfacing with the battery. The pull tab can allow for separation of the battery contacts and prevent power from being delivered to the system. This is advantageous, among other reasons, as it extends the shelf life of the system. In some embodiments, the pull tab slot or opening is located at or along the proximal end of the housing, and the width of the slot can range from 5 mm to 30 mm (or the width of the housing). The height of the slot can range from 0.1 to 2 mm (e.g., 0.1 to 0.2, 0.2 to 0.3, 0.3 to 0.4, 0.4 to 0.5, 0.5 to 0.6, 0.6 to 0.7, 0.7 to 0.8, 0.8 to 0.9, 0.9 to 1, 1 to 1.5, 1.5 to 2 mm, heights between these ranges, etc.).

As shown in FIGS. 2A-2D, the system 100 can include a first set of user-operable controls 116 for adjusting parameters of the delivered stimulation. In some embodiments, the system is configured to allow the user to discretely control stimulation parameters, such as stimulation amplitude or pulse width, to determine nerve activation thresholds (e.g., threshold testing). This can be particularly important when nerves are encased in scar tissue and/or other tissue (e.g., requiring a relatively large stimulation current for depolarization). Dissecting the scar and/or other obstructing tissue can potentially reduce the required activation current.

In one embodiment, the controls may include two buttons. In another configuration, the first set of controls may include a slider or similar feature or device. In yet another configuration, the first set of controls may include a wheel control (e.g., a roller, a wheel, etc.). However, any other type of control (e.g., a button, a dial, etc.) may be incorporated into the device instead of, or in addition to, a slider and/or wheel control. In some configurations, when a wheel control is used, a set of discrete steps may allow adjustment of the amplitude of the stimulation. Thus, the wheel and/or any other control may be configured to move between discrete steps or positions. However, in other configurations, the amplitude of the stimulation may be selected over a range of non-discrete levels (e.g., in a continuous spectrum of amplitudes). In some configurations, the wheel may be coupled to a rotary encoder to discretize the movement of the wheel. In other configurations, the rotary encoder may include detents to provide tactile feedback to the user operating the control.

In some configurations, the system can further include a second set of user-operable controls. Such second controls can be configured to start, stop, and/or pause initiation or interruption of therapy. In one embodiment, the second controls can be used to power the system on and off. In some configurations, the second set of controls can be located near the first set of user-operable controls. In one embodiment, the second controls can be part of the first user control. For example, a slider or wheel control can be coupled to a switch such that depressing the slider or wheel control activates a momentary switch or the like. Any other type of control (e.g., button, switch, foot pedal, touch screen, etc.) can be used.

In one embodiment, the system includes a pull-tab control (e.g., as described herein) for controlling power to the system. In some configurations, the system includes a switch or button that is used to control power to the system.

According to some embodiments, as described in further detail herein, the system may further include a neural port 106 coupled (e.g., physically coupled, operably coupled, etc.) to the housing, thereby allowing a user to connect (e.g., physically or operatively couple) separate electrodes to the system. As a control, the act of plugging or physically connecting separate electrodes to the system may change the operating mode of the system as described above in the configuration of the system.

In some embodiments shown in Figures 2A-2D, the neural port may be included on the proximal aspect 122 of the housing. In some configurations, the neural port may allow for connections parallel to the longitudinal axis of the housing (see, e.g., Figure 2D). In other configurations, the neural port may be provided such that the connectors of the connected components are perpendicular (e.g., exactly perpendicular, roughly perpendicular, or substantially perpendicular) to the longitudinal axis of the housing. In one embodiment, the act of plugging or otherwise physically connecting a separate electrode to the system allows the system to be powered on.

To detect whether an electrode is present and physically connected to the system, a modified jack 130 may be included with the neural port, as shown in FIG. 3. For example, in some embodiments, the jack 130 may comprise a touch-resistant jack (e.g., designed in accordance with IEC 60601). The modified jack may include flexible contacts 132 that can physically contact the main pins 134. However, in such embodiments, the jack may be configured so that the physical connection between the flexible contacts and the main pins is broken when the electrode lead connector is introduced. In some configurations, the jack may include one or more flexible contacts. In other configurations, a polarity standoff 136 may be included with the jack 130 to ensure the correct polarity of the connected plug. In some embodiments, a standard touch-resistant jack 130 with multiple pins/contacts or the like is used. In other embodiments, the jack or coupling 130 may be of a different configuration or design (e.g., with a different set of features or components) as desired or required.

In some embodiments, the contacts on the jack may be wired to a jack detection circuit 142, as shown, for example, in FIG. 4. This circuit 142 may include a microcontroller and passive components that can be used to detect the status of the connection.

In one embodiment, circuitry 142 includes a standard jack detect chip 142 used in the cell phone industry to detect headsets. These chips are NCX8193 manufactured by NXP Semiconductors or Maxim Semiconductor.
Examples of suitable chips include, but are not limited to, the MAX13330 manufactured by Or. In some configurations, the chip can be configured to take advantage of moisture detection, which allows the system to disable full power or other settings if moisture is detected in the jack housing. This may occur, for example, when the system is used in a surgical situation.

Indicators In some embodiments, the system includes at least one set of indicators 118. In one embodiment, the first indicator may include a bar graph-type display formed by placing at least two light-emitting elements (e.g., LEDs) adjacent to one another. In some configurations, the first indicator may include a multi-segment (e.g., seven-segment) display, as shown in FIG. 2A. The multi-segment (e.g., seven-segment) display may include two or more digits and decimal places, as desired or required. In some embodiments, the first indicator may include a liquid crystal display (LCD), a plasma display, a cathode ray tube display (CRT), an organic light-emitting diode display (OLED), a thin film transistor display (TFT), and/or any other type of display.

In one embodiment, the purpose of such a display or indicator is to convey information regarding stimulation parameters, such as, but not limited to, amplitude, pulse width, frequency, duration, and/or other time parameters. In some configurations, the display is configured to provide time information, such as, for example, a timer or countdown clock. Such information can be useful and convenient in determining the remaining or elapsed time for a treatment application and can help guide a surgeon or other practitioner in performing neural regeneration treatment (e.g., brief electrical stimulation, other types of electrical stimulation, etc.) of damaged neural tissue or other target neural tissue. In some configurations, a combination of stimulation parameters, time-related parameters, and/or any other data or information is displayed on the indicator. Regardless of the exact nature of such data and/or information, it may be displayed in an alternating manner, such as by a user-controlled switch. In some configurations, the user can customize the type and/or manner of presentation of data and/or information by the indicator (e.g., what data/information is presented, how it is presented to the user, etc.).

By way of example, according to some configurations, a first set of indicators may be used to indicate power being supplied to the system. In one example, the aforementioned pull tab (or similar feature or component) may be used to control power supply to the system, and when a user pulls the tab, a first indicator may illuminate to indicate that power is being supplied to the system.

In some embodiments, the system includes additional indicators as desired or required. For example, the system may include a second (or additional) set of indicators 118 that can conveniently present additional data and/or information to the practitioner or other user beyond that presented by the first indicator (e.g., time-related data or information, stimulation parameters, etc.). In some embodiments, the system may include a third set of indicators 118. In one embodiment, the third set of indicators 118 are located at or near the distal aspect of the housing. However, the system's indicators may be included anywhere as desired or required, regardless of how many are included, what data/information they are configured to present, etc. By way of example, the third set of indicators may include LEDs located within a cap 126 that functions as a light pipe. Such a cap may be physically coupled (e.g., directly or indirectly) to the housing 114. In some configurations, the cap and light pipe can be designed and/or otherwise configured to allow visibility from all directions, such as when viewing the housing from above, below, the side, and/or behind (e.g., due to an angled distal aspect).

In some embodiments, the indicators (e.g., first indicator, second indicator, third indicator, etc.) can be configured to indicate the status of the system. For example, a first solid color can indicate the status of the output (e.g., active or inactive). In some configurations, the output can be physically connected or coupled (e.g., directly or indirectly) to the neural probe. Thus, for example, in some configurations, the first solid color can indicate whether the neural probe is active. In one specific example, with reference to the system configuration described above, the first solid color can indicate that the neural probe is active in either a bipolar or monopolar configuration.

In some embodiments, a set of indicators (e.g., a third set of indicators) can be configured to flash (e.g., on/off) a first color to indicate the delivery of stimulation. In some configurations, the timing of the flashing can be synchronized with the delivery of stimulation pulses. In some configurations, the flashing can be asynchronous with the delivery of stimulation pulses. Any other type of configuration can be used to provide data and/or other information to the user via indicators (e.g., different text and/or graphic representations, different warning effects, etc.) as desired or required.

In some embodiments, the flashing is replaced with a pulsating output. In some configurations, the pulsating output may include ramping the light intensity from 0 to a predetermined maximum value and then ramping down from the maximum value to 0. In some configurations, the pulsating output begins ramping up from a non-zero intensity value and ends with ramping down from the maximum value to a non-zero intensity value.

In some embodiments, the visual indicators (e.g., the third set of visual indicators) can be configured to flash or pulse to indicate an open circuit between the stimulating electrode and the return electrode. In one particular example, the absence of contact between the bipolar tips of the neural probe indicates an open circuit, which can cause the visual indicator to flash or pulse. In another particular example, when the system is operating in the monopolar configuration described above, the lack of current between the stimulating electrode and the return electrode can cause the visual indicator to flash or pulse. In some embodiments, flashing of an indicator (e.g., the third indicator) having a first color can occur at stimulation settings greater than 0.

In some embodiments, a flashing or pulsating indicator (e.g., a third indicator) may occur in a second color. In some configurations, the second color may be different from the first color. As an example, the flashing or pulsating second color may indicate a closed circuit. In one embodiment, when there is electrical current contact between the bipolar tips of the neural probe, an indication of a closed circuit is provided that causes the visual indicator to flash or pulsate. In another specific example, when the system is operating in the monopolar configuration described above, the flashing or pulsating visual indicator may be activated or initiated when there is electrical current between the stimulating electrode and the return electrode.

In some embodiments, the system is desired for a particular application or use,
Alternatively, a fourth (or additional) set of indicators 118 may be included as desired. In some configurations, the fourth set of indicators may be located next to or near the neural port 106. In some embodiments, the fourth set of indicators may indicate the status of the neural port 106. In some configurations, the fourth set of indicators may function similarly to the third (and/or other) sets of indicators and may include multiple color indicators and/or similar outputs.

The above-described indicators may be incorporated into any embodiment of the devices or systems described herein and may be modified as desired or necessary.

Central Processing Unit In some embodiments, any system configuration described herein may be part of a smart system with various electronic functions, safety mechanisms, etc. Details regarding some of such features, mechanisms, and/or other characteristics are provided herein.

In some embodiments, the control subsystem or central processing unit of the system can be built in association with (e.g., around) the microcontroller 150. In some configurations, the microcontroller is programmed, storing and executing code, and/or otherwise configured to perform specific tasks to operate the system properly and effectively. In some embodiments, the microcontroller includes timing functionality, for example, to enable timed stimulus output. In other embodiments, the microcontroller interfaces with at least one or more of the subsystems 152 described herein (see, e.g., FIG. 5).

Power Source In some embodiments, any of the systems disclosed herein can be designed to be relatively small, disposable, include handheld operation, and/or include other desired or required features. In other configurations, the system may be reusable.

In some embodiments, the system is powered or energized using an energy source such as a battery, AC power, or the like. In some configurations, the power source comprises a battery with a standard lithium coin cell. However, in other configurations, if a higher capacity is required, an N-type battery or other similar alkaline battery may be substituted. In some configurations, the battery may be rechargeable. Any other type of battery or other local power source may be used as desired or required.

In some embodiments, the system may include a power management subsystem. In these embodiments, the power management subsystem may include one or more subcomponents, such as, for example, a low-noise, low-dropout switching regulator for maintaining a stable operating voltage in the range of 3-5V. For example, in some embodiments, a Texas Instruments LP5912 may be used.

In some embodiments, the power management subsystem comprises a second subcomponent having means for generating the higher voltage required for tissue stimulation. In such embodiments, the power management subsystem may be, for example, but not limited to, a Texas Instruments
In some embodiments, the higher voltage range can be between 10-50 V (e.g., 10-15-15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 20-40, 25-35 V, values therebetween, etc.).

In some embodiments, the subcomponents of the power management subsystem are governed (e.g., enabled and disabled) by the microcontroller 150. In other configurations, the act of physically connecting or plugging an electrode into the neural port 106 can enable or disable the subcomponents of the power management subsystem via the jack detection circuitry 142 described herein.

In some embodiments, the power management subsystem may include a tilt sensor. Such a tilt sensor may be configured to provide data and/or other information to a user. For example, the data or information may relate to whether the system is placed on a flat surface or is being held in a non-horizontal position. In some configurations, the output of the tilt sensor may trigger a low power mode via the power management subsystem.

Output Stage In some embodiments, the system includes a stimulation output stage subsystem. In some configurations, the electrical output of such a subsystem is configured to selectively stimulate tissue. The system microcontroller can be configured to generate rectangular stimulation pulses that are regulated by the stimulation output stage subsystem. The stimulation output stage subsystem can be configured to generate the stimulation pulses. In some embodiments, the stimulation pulses include biphasic constant current or voltage pulses.

In some embodiments, the stimulation output stage subsystem includes a capacitively coupled output, for example, to help ensure that the net charge delivered to the tissue is zero. In some embodiments, the stimulation output stage subsystem includes an H-bridge used to switch current polarity. The H-bridge can be coupled to a current source as desired or required. In some embodiments, the current source includes a Howland current pump.

According to some embodiments, the stimulation output stage subsystem is configured to generate stimulation pulses having pulse durations in the range of 1 to 500 microseconds (e.g., 1 to 5, 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70 to 70 to 80, 80 to 90 to 100, 100 to 120 to 120 to 140, 140 to 160, 160 to 180, 180 to 200, 200 to 250, 250 to 300, 300 to 350, 350 to 400, 400 to 450, 450 to 500, 0 to 20, 1 to 30, 0 to 40, 0 to 50, 0 to 100, 50 to 150, 100 to 200, 100 to 300 microseconds, durations between these ranges, etc.). In some configurations, the subsystem is configured to generate stimulation pulse amplitudes in the range of 0-20 mA (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-15, 15-20 mA, values therebetween, etc.). In some configurations, the subsystem is configured to generate pulse trains in the frequency range of 0.1-100 Hz (e.g., 0.1-0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 20-80-40-60, 10-70 Hz, frequencies therebetween, etc.).

According to some embodiments, the pulse train 154 includes one or more pulses of amplitude A separated by a short inter-pulse interval, referred to as a doublet pulse 156, in the range of 1-10 ms (e.g., 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10 milliseconds, intervals therebetween, etc.). One embodiment of such a configuration is shown schematically in FIG. 6A. In some embodiments, the use of doublet pulses allows for the utilization of the natural catch-like properties of muscle, resulting in a larger muscle contraction or visible response.

In some embodiments, the doublet pulses 156 may be individually charge-balanced, i.e., each doublet pulse may be followed by a charge recovery pulse 158 of equal duration but opposite polarity. See, e.g., FIG. 6B. In other configurations, the doublet pulses may be collectively charge-balanced, resulting in a charge recovery pulse 158 of duration equal to the sum of the durations of the individual doublet pulses 156. See, e.g., FIG. 6C. In other configurations, the charge recovery pulses may be passively generated by AC coupling of the stimulator output. Such an embodiment may generate an exponentially decaying charge recovery pulse 158 followed by each output pulse, as shown in FIG. 6D (e.g., each doublet pulse may include a passively generated charge recovery pulse). In some embodiments, the subsystem generates stimulation pulses, amplitudes, and/or trains sufficient to depolarize nerve fibers and elicit action potentials.

Safety Mechanisms To ensure patient safety, in some embodiments, electrical energy is delivered to a stimulating electrode or neural probe 106 in contact with neural tissue only if the impedance is less than 10 kOhm (e.g., less than 10 kOhm, less than 9 kOhm, less than 8 kOhm, less than 7 kOhm, less than 6 kOhm, less than 5 kOhm, less than 4 kOhm, less than 3 kOhm, less than 2 kOhm, less than 1 kOhm, etc.). In some embodiments, electrical energy is delivered to a stimulating electrode or neural probe 106 in contact with neural tissue only if the impedance is between 0-10 kOhm (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10 kOhm, impedances between these ranges, etc.).

In some embodiments, a system according to any of the configurations disclosed herein includes an impedance measurement subsystem. Such a subsystem may include circuitry coupled to a constant current source and further coupled to a set of electrodes, which circuitry may generate a sine wave. In some embodiments, the constant current source may include a Howland current pump.

In some embodiments, the sine wave is generated using a digital-to-analog converter on a microcontroller. In other configurations, the pulse-width modulated output of the microcontroller is used and coupled to a low-pass filter. In some configurations, the low-pass filter comprises passive components, while in other configurations, the filter comprises active components (e.g., an active filter).

In some embodiments, the impedance measurement subsystem includes an instrumentation amplifier coupled to the electrode path used to measure impedance. Impedance measurements can be calculated within the subsystem and transmitted (e.g., digitally) to a microcontroller. In other configurations, the microcontroller samples the analog impedance values and converts the values internally to a digital representation.

In some embodiments, when an electrode is placed in proper contact with neural tissue, the electrode-tissue impedance will be less than the impedance when the electrode is not in contact with tissue. In some configurations, the impedance in such a situation will typically be less than 10 kOhm (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6).
, 6-7, 7-8, 8-9, 9-10, 3-8, 1-10, 4-8 kOhm, impedances between these ranges, etc. Such low resistances can exist because healthy human internal tissue provides a relatively low resistance electrical path through which electrical current can pass. In some embodiments, resistances above a threshold (e.g., 10 kOhm) can be an indicator of improper electrode placement. In some configurations, the system is configured to recognize values above such thresholds.

In some embodiments, the system is configured to periodically detect impedance during continuous application of electrical stimulation. In some configurations, if a relatively high impedance (e.g., high compared to a threshold level or upper limit) is detected, the system can be designed or otherwise configured to pause application of continuous electrical stimulation and alert the operator via indicator 118 on housing 114. In other configurations, the system is configured to terminate (e.g., automatically stop) stimulation output and/or prompt the user. In some embodiments, the indicator comprises a visual indicator, while in other embodiments, the indicator can include an audible indicator and/or any other type of indicator in addition to or instead of a visual display.

As described herein, to further enhance patient safety, in some embodiments, the output of the system is capacitively coupled to prevent net DC charge from flowing into the electrode-tissue interface.

Neural Probes and Electrodes Neural probes 102 can be used to probe tissue to test excitability. Body tissue, such as nerves, when probed using physical means, electrical stimulation, etc., can conduct action potentials to muscles, resulting in muscle twitches, reflexes, or contractions. According to some embodiments, the devices and systems disclosed herein include a neural probe physically coupled to a housing and electrically coupled to a stimulation output stage subsystem.

In some embodiments, the neural probe comprises a single conductive element in the shape of a cylinder or rod extending from the distal end of the housing. In other embodiments, the shape of the conductive element may vary. In some configurations, the neural probe is completely (or nearly completely) electrically insulated, except for a small, uninsulated component in the distal aspect of the neural probe. For example, a majority (e.g., greater than 70%, 70-100%, 80-95%, etc.) of the neural probe is electrically insulated. The uninsulated area may range from 0.1 mm ² to 10 mm ² (e.g., 0.1-0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 2-8, 1-9, 4-8 mm ² , areas within these ranges, etc.). In some embodiments, the insulation can be manually configured to uninsulate the probe by various percentages, such as, for example, 1-30% (e.g., 1-2, 2-3, 3-4, 4-5, 5-10, 10-15, 15-20, 20-25, 25-30%, percentages within these ranges, etc.).

In some configurations, a single conductive element functions as the cathode or stimulation electrode. In such configurations, an appropriate return path for the current to flow is required. In some embodiments, the return path may be provided by connecting a return electrode to the neural port 106. The return electrode may comprise a needle, a surface pad, another conductive element, etc.

In some embodiments, the neural probe comprises multiple conductive elements, in some configurations, one or more of the conductive elements can be designed or otherwise configured to function as a return electrode or anode, while one or more of the conductive elements can be designed or otherwise configured to function as a cathode or stimulating electrode.

In some embodiments, the conductive elements include one or more metals or alloys (e.g., stainless steel, platinum, iridium, gold, etc.). In one configuration, the conductive elements include platinum or 90/10 platinum iridium, gold. The conductive elements can include any other conductive metals, alloys, and/or other materials as desired or required.

In some embodiments, the length of the conductive elements is 0.5 to 10 cm (e.g., 0.5 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 3 to 7, 5 to 10, 0 to 5 cm, lengths within these ranges, etc.). However, the length of the conductive elements may exceed 10 cm to meet the requirements of a particular application or use. The diameter or other cross-sectional dimension of the conductive elements may be 0.1 to 5 mm (e.g., 0.1 to 0.2, 0.2 to 0.3, 0.3 to 0.4, 0.4 to 0.5, 0.5 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 0.1 to 2, 1 to 2 mm, values within these ranges, etc.). However, the diameter (or other cross-sectional dimension) of the conductive elements may exceed 5 mm to meet the requirements of a particular application or use.

In some embodiments, the system does not include a neural probe. Instead, in such configurations, the system can rely on an appropriate electrode device connected to the neural port. In some configurations, the electrode device comprises a monopolar or bipolar catheter-type device. Such a configuration can be particularly advantageous in perioperative situations, allowing the lead to be placed during surgery and, due to its shape, easily removed through a closed incision or percutaneous access point.

In some embodiments, a nerve cuff electrode device is connected to the nerve port. Cuff electrodes can be particularly advantageous in intraoperative situations, allowing for easy access to transected nerves. However, as discussed herein, in any embodiment disclosed in this application, the electrode can include configurations other than a cuff electrode.

Specific embodiments of the nerve cuff electrode device 10 are shown in FIGS. 7-11. As shown, the nerve cuff electrode device 10 can include a carrier body 12. In some embodiments, the carrier body 12 and/or other portions of the device 10 include one or more insulating materials, such as, for example, silicone rubber, other elastomeric and/or polymeric materials, and/or any other material. Instead of or in addition to rubber, one or more materials can be used, such as, but not limited to, thermoplastic elastomers, elastomeric polyurethanes, and the like. In some embodiments, the material included in the device is flexible so that it can bend during movement during use without breaking, fracturing, and/or other damage.

In some embodiments, the electrode device 10 is arranged in a longitudinal configuration, with its length significantly longer than its width. For example, in some embodiments, the length-to-width ratio of the electrode device 10 may be between 1:1 and 20:1 (e.g., 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, ratios within these ranges, etc.). In some embodiments, the electrode device 10 includes two ends: a head portion 16 and a tail portion 26.

As shown in FIG. 7A, device 10 can include a longitudinal axis 11 extending longitudinally or lengthwise along device 10. The length of the device can be 20-80 mm. The width of device 10 (e.g., the dimension perpendicular to longitudinal axis 11) can be 5-30 mm. Thus, in some embodiments, the length of device 10 is 2-5 times the width of the device. However, in other configurations, the width can be greater than or equal to the length. In some embodiments, the thickness of head portion 16 can be 1.5 mm. In some configurations, the thickness can be in the range of 0.1 mm to 5 mm (e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5 mm, thicknesses within these ranges, etc.), as desired or required.

The head portion may be rounded and may include a tapered end 16 that includes gripping structures 18 to aid the surgeon in handling the electrode device. In some embodiments, the gripping structures 18 are present on both sides of the tapered end of the carrier. However, in other embodiments, the gripping structures 18 are included on only one side. In some embodiments, the gripping structures 18 include ridges, recesses, protrusions, etc. In some embodiments, such structures 18 are formed into the surface or body of the device, thus forming an integral structure with the part that includes them. For example, the ridges or other structures 18 may be molded (e.g., injection molded) along with the main portion of the device. However, in other configurations, the gripping structures 18 are separate from the main portion of the device and/or are created after the main portion of the device is formed (e.g., by one or more connection techniques or methods, material removal, etc.). In some embodiments, the gripping structures are replaced with a through-hole or holes through which one or more sutures can be threaded.

With further reference to FIG. 7A , the tail portion 26 of the device 10 may not be tapered. However, in other configurations, at least a portion of the tail portion 26 may be tapered, as desired or necessary. In some embodiments, the tail portion 26 includes rounded or curved corners to facilitate handling of the device. In some embodiments, the tail portion includes one or more regions that are substantially thicker than the head portion to surround a through-hole in the longitudinal axis 11 that allows for placement of an electrode lead. In some embodiments, this thicker region may be more than one time thicker than the head portion (e.g., 1 to 5 times thicker, 1 to 10 times thicker, 1 to 20 times thicker, etc.), but may not be thicker than the grooved body 24. In some embodiments, the increase in thickness of the tail portion may be in the opposite direction to the increase in thickness of the grooved body 24, and may further include a diagonal through-hole from the bottom of the tail portion to the central body to allow for the accommodation of an electrode lead.

As shown in FIG. 7A, the central portion of the carrier can include two features: a grooved body 24 and a winged locking mechanism 20. In some embodiments, the grooved body 24 can be constructed and configured such that when a surgeon places a nerve on the electrode device 10, the longitudinal axis of the nerve is perpendicular (e.g., substantially perpendicular) to the longitudinal axis 11 of the electrode, and the nerve naturally rests against the thinner central portion 28 of the grooved body.

In some embodiments, the winged locking mechanism may be positioned at various longitudinal locations, and each location may include more than one set (e.g., two wings). In some embodiments, the locking wings are positioned in a staggered arrangement.

The thinner central portion 28 of the grooved body 24 can be shaped to facilitate nerve placement, allowing the head portion 16 of the device to be wrapped or bent around (e.g., at least partially around) the nerve. For nerve placement, in some embodiments, the thinner central portion 28 follows a semicircular shape or other circular or curved shape. This can help prevent neural tissue from slipping off the electrode device 10. The radius of curvature of the thinner central portion 28 can range from 1 to 10 mm (e.g., 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 2-8, 4-8, 5-10 mm, radii within these ranges, etc.). In some configurations, the radius of curvature is greater than 10 mm (e.g., 10-15, 15-20, 10-20, 10-50 mm, radii therebetween, greater than 50 mm, greater than 100 mm, etc.), as desired or needed.

In some embodiments, the thinner central portion 28 of the grooved body 24 is flat and tangent to the head portion 16 of the electrode device 10. The thickness of the central portion may range from 0.1 mm to 5 mm. In some configurations, such as the desired curved shapes described above, the thinnest portion may be 0.1 mm (e.g., 0.05 mm to 2 mm). In some embodiments, the thinnest portion may be 10% (e.g., 5-25%) of the thickest portion of the head portion 16 of the electrode device 10. The thickness of the central portion 28 may be designed or otherwise configured to adjust the degree of flexibility of the device when the head portion 16 is wrapped around a nerve.

In some embodiments, the grooved body 24 of the central portion 28 has a uniform or generally uniform thickness. That is, the central portion is of a similar thickness to the connected head portion 16, providing a flat, planar surface. In some configurations, the carrier can include electrodes disposed on the underside of the carrier 12. In some embodiments, the locking mechanism can be engaged in a reverse direction, such that the head portion 16 engages the locking mechanism from the direction of the tail portion when the carrier is folded.

In some configurations, the desired curved shape described herein follows a semicircular shape or other partially rounded or curved shape having a uniform thickness relative to the head portion 16. In some configurations, the base of the semicircular groove can protrude at least partially below the plane of the head portion 16 to form a larger circumference for nerve placement.

In some embodiments, the groove further includes one or more conductive electrodes 30, which may be present in various configurations as further outlined below. In some configurations, the purpose of the groove is to facilitate interfacing with the nerve while preventing or limiting nerve slippage. Such a configuration can, in some embodiments, promote contact between the nerve and the conductive electrodes 30. Once the nerve is in place, the surgeon or other practitioner can grasp the carrier's tapered head portion 16 (e.g., using either forceps, their fingers, other devices or methods, etc.) and encase (e.g., at least partially) the nerve. In some embodiments, the tapered head portion 16 is positioned below a winged locking mechanism 20 to lock the cuff in place. The electrode device can be conveniently configured to accommodate nerves or nerve bundles of various diameters, allowing the surgeon or other practitioner to apply greater or lesser encircling pressure to adequately cover the nerve. To securely lock the tapered head portion 16, the surgeon can laterally deflect the winged locking tab 22, position the tapered head portion 16 underneath, and then release the tab.

In one embodiment, the carrier is molded in a flat or open position. For example, the carrier can be bent and positioned below the locking tab 22. In some embodiments, a natural bias exists that presses or otherwise urges the tapered head portion 16 against the locking tab 22, preventing the tapered portion from sliding further down the longitudinal axis 11 of the device and potentially compressing the interfaced nerve.

In some configurations, when the surgeon or other practitioner is finished using the electrode device 10, the locking tab 22 can be configured to deflect laterally, causing the carrier's tapered head portion 16 to spring back with a biasing force that pushes it back toward its original flat or open configuration. Such a feature can allow for rapid release of the interfaced nerve. Thus, the surgeon or other practitioner can subsequently pull the nerve cuff from the tail portion 26 and slide it out from under the interfaced nerve without damaging the nerve.

With further reference to FIG. 7A, a single conductive electrode pad 30 is disposed in the grooved portion of the carrier 24. In some configurations, this is the thickest portion of the carrier and serves one or more purposes (e.g., providing an insulating barrier to prevent current spread, providing rigidity to reduce the likelihood of electrode pad detachment when bent around a nerve and then released, etc.).

In some embodiments, the electrode pad 30 includes a unipolar, single-contact configuration. A lead wire 32 can be coupled to the electrode pad 30 (e.g., by laser or resistance welding, crimping, using other techniques or techniques, etc.). In some embodiments, a physical, conductive connection is made with the electrode pad. Figure 7B shows a cross-sectional view through the midplane of the electrode device 10. As shown, the electrode pad 30 is coupled to the lead wire 32. The trailing end of the lead 36 can be external to the electrode device.

According to some embodiments, as shown in FIG. 8A, the trailing ends of the leads 36 exit the device from the trailing end of the carrier 26 parallel or generally parallel to the longitudinal axis of the carrier. In some configurations, when interfaced with the nerve 14 (see FIG. 8B), the device 10, with the head portion 16 secured using the winged locking mechanism 20, has the leads positioned conveniently away from the nerve. Accidental pulling or movement of the leads can move the interfaced nerve 14 in a direction closer to perpendicular to the longitudinal axis. In another embodiment, as shown in FIG. 8C, the trailing ends of the leads 36 can exit perpendicular to the longitudinal axis 11 of the carrier 12.

In some configurations, as shown in FIG. 9A, the electrode pads 30 and lead wires 32 are connected to the carrier through through-holes 40. In some embodiments, the through-holes are cut or otherwise created in a thickened portion 42 at the rear end of the carrier 26. In some embodiments, as shown in FIG. 9B, the through-holes may be straight from the rear end of the carrier 26 and exit through holes or other openings 46 in the slotted body 24.

In some embodiments, the through-holes containing the lead wires 32 comprise one or more through-holes with varying angles between their longitudinal axes. Such a configuration can result in a chamber in which the lead wires 32 can be placed similar to the chamber shown in FIG. 7B. In some configurations, the longitudinal axes of the through-holes are at an inclination of 45 degrees (e.g., 30-60 degrees) from one another. In some configurations, such an angle is between 0 degrees and 90 degrees (0-10-10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 45-90, 45-60, 15-45 degrees, angles within these ranges, etc.), as desired or required.

In some embodiments, the electrode pad 30 is secured to the device via an enlarged second electrode area 34 that is substantially larger than the through-hole through which the lead wire is inserted. In some embodiments, the electrode pad 30 protrudes relative to the adjacent portion of the device. In other configurations, the electrode pad may be insert molded flush or recessed relative to the adjacent portion of the device. In other configurations, the electrode pad is secured by the enlarged second electrode area 34 and/or is flush or recessed relative to the adjacent portion of the device, as desired or required.

According to some embodiments, as shown in FIG. 10A, the electrode contact pad of the electrode device 10' is not limited to a single conductive pad. Instead, as shown, the device can include two (or more) pads arranged in a bipolar configuration (e.g., in a manner similar to a single electrode pad 30). The spacing between the bipolar pads can be 5 mm. In some configurations, the spacing can range from 0.1 mm to 5 mm, or from 0.1 mm to the width of the electrode device.

To more precisely or selectively stimulate axons within a nerve, a tripolar electrode pad configuration can be used, as shown in electrode device 10'' in Figure 10B. The spacing between adjacent electrode pads can range from 0.1 mm to 2 mm. In some configurations, multiple electrode pads (four or more) can be implemented with contact spacing ranging from 0.1 mm to as long as the electrode pads fit within the width of the device.

In yet other embodiments, as shown in FIGS. 11A and 11B, the electrode pads may be configured as conductive electrode strips 50, printed on a carrier, adhered to the carrier using an adhesive, and/or disposed on the carrier using some other method or technique. In some embodiments, the electrode pads include metal foil (e.g., platinum-iridium 90/10) arranged in a bipolar configuration (FIG. 11A). In some embodiments, the metal foil may include gold and/or any other conductive material in addition to or instead of platinum-iridium, as desired or required. In some embodiments, a tripolar configuration of foil strips may be used, as shown in FIG. 11B. The spacing between adjacent strips may be similar to the spacing between electrode pads described above.

The conductive electrode strips 50 can be embedded in the carrier body 12, as shown in FIG. 11C. In some embodiments, the carrier includes laser-cut windows or other openings 54 to at least partially expose the metal contacts and allow for interfacing with tissue. According to some configurations, the majority of the foil is located in the thinner central portion 28 or grooved body 24 of the carrier 12. This can be particularly useful for conductive strip electrode placement, in some embodiments, to minimize or reduce the possibility of delamination when the head portion 16 is wrapped around the nerve 14 and interfaced with the winged locking mechanism 20. The conductive electrode strips can be configured in a variety of ways, including array arrangements of multiple electrode strips (e.g., more than three, such as four, five, six, etc.), as desired or required for a particular application or use. In some embodiments, the electrode device 10 can also be used to record tissue or nerve activity and provide electrical stimulation, as described in further detail herein.

FIG. 12 illustrates yet another embodiment of an electrode device. As shown, the locking device can include a strap 60, allowing a surgeon or other practitioner to pull the head portion 16 of the carrier body 12 downward (e.g., using forceps or some other tool). Such movement can allow the surgeon or other practitioner to size the carrier body 12 to properly fit the nerve. As with the above-described embodiment, molding the electrode device 10 in a flat configuration can create a biasing force (e.g., pressing the carrier head portion 16 upward against the strap as it is threaded underneath). Such a biasing force can help prevent or reduce the likelihood of undesired movement of the head portion 16. Additionally, the friction of the elastomeric material can further prevent or reduce the likelihood of movement of the head portion 16 of the carrier body 12 while engaged with the strap 60. In some embodiments, to remove the electrode device from the nerve, a surgeon or other practitioner can cut or otherwise weaken the strap 60. This allows the head portion 16 to be released and the biasing force to return the electrode device 10 to a flat or nearly flat shape.

In some embodiments, a conductive electrode strip 50 may be included in any of the electrode configurations disclosed herein. The strip may extend in one direction to the location of the strap 60 and may extend to the tapered portion of the head portion 16 of the device. The conductive strip 50 may be attached or otherwise coupled to the electrode carrier body 12 (e.g., as previously described). The electrodes are not limited to the strips described above and may include other electrode embodiments previously described.

In some configurations, as shown in FIG. 13, the locking device includes one or more pairs of openings 70 and a pair of corresponding protrusions 72 or buttons with surface projections (e.g., having a larger diameter than the openings). The openings may have a diameter (or other cross-sectional dimension) ranging from 1 to 10 mm (e.g., 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 2 to 8, 4 to 8, 1 to 5, 5 to 10 mm, dimensions within these ranges, etc.). However, the diameter or other cross-sectional dimension may be greater than 10 mm or less than 1 mm, as desired or required for a particular application or use. The corresponding pair of buttons or protrusions 72 may include caps 74 (e.g., hemispherical caps) with a diameter or other cross-sectional dimension that may be equal to or greater than the pair of openings 70. In some embodiments, the protrusions include a cylindrical (or generally cylindrical) portion attached to the carrier body 12 that may be smaller than the hemispherical caps 74.

In some embodiments, one or more different locking mechanisms can be combined to more securely secure the leading and trailing ends. In some embodiments, the head portion 16 is secured to a winged mechanism at a given longitudinal position and then secured to a second mechanism (e.g., the same wing mechanism or another mechanism) to provide additional locking strength in securely holding the head portion. The surgeon or other practitioner can determine whether the use of additional locking mechanisms is necessary at the time of use.

Any of the embodiments disclosed herein may include one or more conductive electrode strips 50. The strips may extend to the last pair or locking opening 70 in one direction and to the pair of buttons 72 in the other direction. The conductive strips 50 may be attached to the electrode carrier body 12 as previously described. Electrodes are not limited to the strips described above, but may include other electrode embodiments described herein as desired or required for a particular application or use.

In some embodiments, the carrier body 12 includes two or more sets of winged locking mechanisms (e.g., positioned on either side of a symmetrical groove in the carrier body). In some configurations, the carrier body can include one or more electrodes within the grooves. The carrier body and associated locking mechanisms can be configured to engage a second carrier body that includes one or more electrodes. In some embodiments, the second carrier body is equal to or longer than the first carrier body. The second carrier body can be placed over the first carrier body, and the locking mechanisms can be engaged to secure a nerve positioned between the carrier bodies.

The distance between the locking mechanism and the groove may be variable or symmetrical about the groove centerline. In some configurations, the locking mechanism includes a strap or locking aperture as described herein.

According to some embodiments, as shown in FIG. 14, an adhesive patch 80 is added to the lead wire 32. This can advantageously help stabilize the electrode device 10 and prevent (or at least reduce the likelihood of) unintended movement. By way of example, such movement may occur if a user accidentally pulls on the lead wire 32 or interacts with the wire during a surgical procedure. The adhesive patch 80 can be attached (e.g., directly or indirectly) to a portion of the body structure near an incision or other area of treatment or interest.

In one embodiment, the adhesive patch 80 comprises carbon-impregnated rubber or a similar elastomeric material. The elastomeric material used in the patch 80 can be impregnated with conductive elements, if desired or necessary. In one embodiment, the adhesive patch 80 (e.g., one side of the patch) can comprise a conductive adhesive gel (e.g., Parker Labs Tensile Conductive Adhesive Gel).

The adhesive patch 80 may include a rectangular shape. For example, in some embodiments, the patch is rectangular and includes a length of 10 mm to 100 mm and a width of 5 mm to 50 mm. Thus, in some embodiments, the length of the adhesive patch 80 is 1.5 to 5 times the width of the adhesive patch 80. In one embodiment, the distance of the adhesive patch 80 to the electrode device 10 may range from 50 mm to 300 mm. The size, orientation, dimensions, and/or other characteristics of the patch may vary from those disclosed herein. For example, in some configurations, the shape of the patch is circular, oval, triangular, other polygonal, irregular, etc.

With further reference to FIG. 14, the adhesive patch 80 may include one or more visual indicators 82, such as LEDs, to provide a status indication to the user. The indicators may be powered by a connected device, such as an electrical stimulator or biological amplifier.

In some embodiments, the display is configured to confirm proper delivery of stimulation pulses or high electrode impedance. In some configurations, the indicator is configured to display a timer or stimulation amplitude level in the case of nerve regeneration therapy. Any other data, information, confirmation, etc. may be configured to be provided to the user as desired or required.

In some embodiments, an adhesive patch 80 including one or more indicators 82 (e.g., visual indicators) can include a molded portion 84 for embedding the indicators. In some configurations, the molded portion includes additional circuitry (e.g., for powering the indicators, controlling the indicators, providing other non-visual cues to the end user, etc.) as needed or desired.

In some embodiments, the electrode device 10 connected to the adhesive patch 80 includes a single electrode contact that provides a monopolar stimulation field. In some configurations, the adhesive patch 80 can function as a return electrode for the monopolar stimulation field.

In other configurations, as shown in FIG. 15A , an adhesive patch 80 can be connected to a unipolar electrode 180 comprising a needle or needle-like device. The adhesive patch 80 includes circuitry for shaping and delivering stimulation pulses to the connected electrode (see, e.g., FIG. 15B ). In some configurations, the patch and circuitry are powered by an included battery source 182. The circuitry can include elements similar to those described herein with respect to other embodiments of the electrical stimulation system, such as a microcontroller 150. In some embodiments, the circuitry includes a timer (e.g., a 555 timer) or similar device, component, or feature used to generate the stimulation pulse. In the above-described embodiments, associated passive elements can also include the circuitry, such as resistors 190 and capacitors 192, as needed or desired.

In some embodiments, the adhesive patch 80, which includes the circuitry used to shape and deliver the stimulation pulses, can include one or more indicators 82 (e.g., visual indicators), as described in further detail herein. In some embodiments, the function of the adhesive patch 80 and built-in circuitry is to test the connection and placement of the monopolar electrode.

In some embodiments, as shown in FIG. 15A, the adhesive patch 80 includes a push button 184 that is used to initiate or deliver one or more stimulation pulses to the electrode 180. In some configurations, such push button 184 may also be configured to change stimulation amplitude and/or other stimulation parameters (e.g., frequency, pulse width, etc.) as desired or required for a particular application or use.

In some embodiments, the adhesive patch 80 can include a multi-segment display (e.g., a seven-segment display). The seven-segment or other multi-segment display can include two or more digits and decimal places, as desired or required. The display can include a liquid crystal display (LCD), a plasma display, an organic light-emitting diode display (OLED), a thin film transistor display (TFT), and/or any other type of display, as desired or required for a particular application or use. The display can provide information such as stimulation parameters, time remaining for treatment, battery power level, operating mode, connectivity to other devices, etc.

In some configurations, the adhesive patch 80 includes a connector 186 that is used to interface with a second stimulation system. Such a connector can function similarly to the neural port embodiments described above. In some configurations, the connector 186 includes a molded part 188 that interfaces (e.g., seamlessly or nearly seamlessly) with the adhesive patch 80. In some embodiments, the second stimulation system includes a larger capacity battery or any other type of system, device, component, etc., as desired or required for a particular application or use. The second stimulation system can include elements similar to the stimulation systems described with respect to other embodiments herein. In some embodiments, the second stimulation system may be incorporated into the adhesive patch.

According to some embodiments, the circuitry present on the adhesive patch may include elements such as a switch 194 or other components or features for directing stimulation output from the first or second stimulation system. In some embodiments, the adhesive patch comprises multiple layers (see, e.g., FIG. 15C). Some of the layers in such a configuration may include a gelled conductive rubber layer 196, a layer incorporating electrical circuitry and other electrical elements 198, an elastomeric protective layer 200, and/or any other layers or components.

In some embodiments, as shown in FIG. 16A, the electrode carrier body 12 is coupled (e.g., directly or indirectly) via one or more small tabs 90 to a polymer or microsurgical background material 92. Such material 92 can typically be used to separate or isolate nerves or other tissue from surrounding tissue, allowing the surgeon or other practitioner to focus (e.g., solely or exclusively) on repairing or dissecting the isolated tissue.

According to some embodiments, as shown in FIG. 16B, the carrier 12 and associated background material are used to isolate an injured nerve 94 (e.g., a severed nerve) while placing the proximal end of the injured nerve on the electrode device 10. The distal end of the injured nerve 94 can be placed on the background material. As an example shown in FIG. 16B, if the severed nerve does not require a nerve graft to bridge the distance between the proximal and distal ends, joining of both nerve ends can be achieved directly on the background material. If a nerve graft is used to fill the gap between the proximal and distal ends of the severed nerve, insertion of the nerve graft can be achieved on the background material.

In one embodiment, prior to (e.g., immediately prior to) repair of the damaged nerve 94, the electrode device 10 can be detached from the background material by cutting (or otherwise weakening) the tab 90. Then, in some embodiments, as shown in FIG. 16C , the detached carrier body 12 can be wrapped around or encircling the damaged nerve 94, and after wrapping the proximal nerve stump, the winged locking mechanism 20 can be engaged to deliver nerve regeneration therapy (e.g., a relatively brief electrical stimulation) to accelerate and promote nerve regeneration. At this time, the surgeon can perform nerve repair or graft placement distally (e.g., immediately distally) to the electrode device, with the distal aspect of the proximal portion of the nerve and the distal severed nerve 94 positioned on the background material 92.

In any of the embodiments disclosed herein or equivalents thereof, the leads 32 connected to the conductive electrode pads 30 can be coupled (e.g., connected) to a stimulation output subsystem. This can serve to deliver stimulation pulses to depolarize axons or electrically stimulate tissue. In other embodiments, the leads can be connected to a biological amplifier to record signals from nerves or other tissue and/or to any other system, subsystem, device, etc., as desired or required for a particular application, indication, or use.

According to some embodiments, a percutaneous electrode lead 250 can be coupled to an adhesive patch 80. The electrode lead can include one or more conductive elements 252, as shown in FIG. 17A. The conductive elements can be located at or near the tip of the lead, as shown in the example of FIG. 17A. In other configurations, the conductive elements 252 can be located along the length of the lead instead of or in addition to being located at or near the tip of the lead, as desired or required.

In some embodiments, the electrode lead has a circular or curved shape (e.g., at least partially circular or curved shape) and an outer diameter (or other cross-sectional dimension) of 0.1 to 5 mm (e.g., 0.1 to 0.2, 0.2 to 0.3, 0.3 to 0.4, 0.4 to 0.5, 0.5 to 0.6, 0.6 to 0.7, 0.7 to 0.8, 0.8 to 0.9, 0.9 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 1 to 4, 0.5 to 4, 1 to 4 mm, ranges therebetween, etc.). In some configurations, the diameter or other cross-sectional dimension is determined (at least in part, e.g., primarily) by the lead housing 254 (e.g., the size, shape, and/or other characteristics of the lead housing). In other embodiments, the electrode comprises a needle.

The lead housing 254 can comprise one or more elastic or semi-elastic materials, such as, for example, silicone rubber (e.g., silicone rubber tubing), polyurethane, other polymeric materials, other types of elastomers or rubber materials, other flexible or semi-flexible materials, etc. The lead can be placed near the nerve through an existing incision or through a percutaneous route (e.g., when a cannulated needle or other sharp object is utilized to provide access to the nerve). The flexibility and/or similar physical properties of the lead housing 254 material/construction can be selected to facilitate easy removal of the percutaneous electrode lead 250. In some embodiments, the lead housing 254 comprises a lead wire 256 physically connected to the conductive element 252, as shown, for example, in FIG. 17B .

In some embodiments, the lead housing can have a uniform or continuous material thickness throughout the length of the lead. In other embodiments, the lead housing includes regions of different thickness that function as bendable joints that can provide additional flexibility for shaping the lead. In some configurations, the desired shape is maintained until another force is applied that changes the shape of the lead, such as manual manipulation or the act of removing the lead. In other embodiments, these joint portions may be constructed from a different material than the rest of the housing. In some embodiments, the joint portions may be more or less flexible than the rest of the lead housing.

In some embodiments, the lead housing can include a coiled wire used to provide shape memory to the lead. This can be particularly advantageous in areas where the lead is required to bend and maintain its shape. In some configurations, the coiled wire spans the entire length of the lead. In other configurations, the coiled wire can span only a first length or portion of the lead (e.g., the first 10 cm or less, e.g., 0-10, 2-8, 1-5, 5-10 cm, lengths between these ranges, etc.). However, the extent of the coiled wire need not be limited to these distances (e.g., it may be greater than 10 cm, as desired or needed). In some embodiments, the coiled wire physically couples (e.g., directly or indirectly) to an electrode. In other embodiments, the coiled wire is not electrically coupled to any stimulating electrode. In some embodiments, the coiled wire is located at the distal end of the lead housing and serves as an electrical connector to other circuitry located along or near the distal end. Depending on the application, the flexibility and memory characteristics required, and/or other design considerations, the spacing between adjacent coils may be zero (e.g., the coils touch each other) or a fixed distance. In some embodiments, the coiled wire may be insulated or uninsulated. In some configurations, the coiled wire is encased in a flexible material such as Pellethane® or Pebax® of various durometers or similar thermoplastic polyurethane or elastomeric materials.

In some embodiments, to provide a longer length when the stimulation unit is located far from the area of placement of the electrode lead 250, the percutaneous electrode lead 250 can be connected to an extension wire, which is then connected to the stimulation unit. The extension wire can have an additional length of 30-100 cm (30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 50-80 cm, distances between these ranges, etc.). The extension wire can have similar or different material properties at at least one end that interfaces with and forms electrical contact with the electrode lead and at least one end that interfaces with and forms electrical contact with the stimulation unit. In some embodiments, once the stimulation unit, extension wire, and electrode lead are connected, they function as an integrated unit and function in a manner similar to that described above.

In some embodiments, the electrode lead housing 254 includes fiducial and/or other markers that serve to indicate distance from the tip of the lead. Other markers (e.g., fiducial markers) can include radiopaque or hyperechogenic markers for image-guided positioning of the lead. Image-guided positioning of the electrode lead 250 can be advantageous in situations where direct visualization of the damaged nerve and/or electrode lead is not possible. Such situations may occur, for example, when a patient is undergoing a nerve repair or decompression procedure under local anesthesia. Axonal depolarization is not possible in the anesthetized area. In some embodiments, it is advantageous to position the electrode lead 250 proximal to the anesthetized area to provide nerve regeneration therapy to the damaged nerve. In some embodiments, for the treatment to be effective (or more effective), the electric field generated by the lead must depolarize the unanesthetized proximal branch of the damaged nerve. In one non-limiting example, a patient may undergo a carpal tunnel release under local anesthesia, a procedure in which the wrist is anesthetized. In some embodiments, the proximal branch of the median nerve, such as in the forearm, is not near the surface, and image-guided placement of the electrode lead 250 may be advantageous for the surgeon to precisely target the proximal component of the injured median nerve. In some configurations, image-guided placement also ensures that blind insertion of the lead does not cause damage to surrounding vasculature.

In another example, insertion of an electrode lead using image guidance may be advantageous in situations where a nerve repair or other surgery may have been performed previously, but the patient was not receiving electrical stimulation therapy at the time of the original repair procedure. In such situations, placement of the used electrode lead using image guidance can occur several hours, days, or weeks after the repair procedure. Electrode placement may also occur prior to the nerve repair procedure. Such placement can produce an electrical stimulation conditioning effect on the cell body. Image guidance can be performed using ultrasound, fluoroscopy, x-ray, or other imaging modalities.

In some embodiments, the marker comprises one or more protrusions and/or recesses (e.g., dimples or inverted dimples). In such configurations, the protrusions, recesses, and/or similar features can serve dual or multiple purposes or functions. For example, such features can not only function as fiducial markers but also serve to regulate (or limit) movement of the lead when placed within an object (e.g., a cannula, a sheath, another cylindrical object, another object having one or more openings, etc.).

In some embodiments, as shown in FIG. 17C , the lead housing 254 includes a textured, ribbed, and/or other non-smooth surface 286. Such a configuration can increase the surface area of contact and aid in improving local fixation of the lead in situ with adjacent tissue. For example, a circular or linear substructure protruding from the surface (e.g., in a wing-like manner) may be included. In addition to or instead of such embodiments, concave features may be included. For example, such concave features may be depressed in the surface of the material. In some embodiments, the substructure may be shaped or sized to limit or more strongly prevent movement in certain directions while facilitating movement in other directions to improve temporary fixation of the lead in situ. In yet another embodiment, the substructure may include single or multiple rings, hook-like structures, and/or any other fixation mechanism or member 288 to improve or otherwise strengthen fixation of the electrode lead, such as by suturing, to adjacent tissue. In other configurations, fibrin glue or similar tissue adhesives may be used to temporarily fixate the electrode lead. Such a design may be advantageous to the user to affix the stimulation lead in close proximity to the target neural tissue, ensure minimal or reduced unintended movement, facilitate lead removal with minimal tissue disturbance after stimulation is completed, and/or provide one or more other advantages or benefits. As an example, the user may position the lead parallel, near parallel, or tangential to the target neural structure and, if desired, engage flexible structures on the lead for fixation to the tissue using standard medical sutures and/or other fixation techniques.

In some embodiments, as shown in FIG. 17D, a percutaneous electrode lead 250 includes multiple conductive elements 252, 258. The conductive elements 252, 258 can include different shapes, sizes, and/or other characteristics, as desired or needed. For example, as shown in FIG. 17D, the conductive elements at the tip 252 of the electrode lead can be shaped in a manner that both caps the electrode lead housing 254 and also provides a larger surface area that can be used to deliver stimulation current to tissue, such as a peripheral nerve. 17D , the second conductive element 258 can be shaped as a ring varying in thickness from 0.1 to 10 mm (e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 2-8, 3-6, 1-3, 3-5, 5-8 mm, ranges therebetween, etc.) and can be physically coupled to a conductive insulated wire 260. In some configurations, the second conductive element 258 can be used as a return electrode for the first conductive element that generates an essentially bipolar stimulation field. In other configurations, the second conductive element is used as a signal path for other circuitry and is combined with additional conductive elements disposed on the lead. Multiple conductive elements can also form an electrical stimulation array that allows the current field to be shaped or otherwise modified or influenced.

In some embodiments, as shown in FIG. 18A , a percutaneous electrode lead 250 is coupled to a cap element comprising an enclosure 262 (e.g., a molded plastic or other elastomeric or non-conductive enclosure or member) and a conductive surface 264. In some configurations, the conductive surface 264 is larger than the enclosure 262. The plastic enclosure 262 may be more than 1 and less than 20 times (e.g., 1-20 times, e.g., 1-5, 2-4, 5-10, 10-20, 5-15, values therebetween, etc.) the diameter of the electrode lead, as desired or required. In some configurations, a percutaneous electrode lead 250 comprising a conductive element at its tip 252 (as previously described herein) can physically contact (e.g., at least partially physically contact) the larger conductive surface 264 present on the cap, effectively creating a larger stimulation surface. As an example, if an electrode lead is coupled to a pulse generator and covered with the cap described above, and the pulse generator outputs long pulses (e.g., pulses having wavelengths greater than 200 μs), the larger conductive surface of the cap can be used to stimulate muscle tissue. In the context of verifying stimulation output, this can be advantageous because a smaller conductive surface (e.g., as included on an electrode lead) may not generate a sufficiently large electric field to induce a visible muscle contraction. The use of a larger conductive surface on the cap to stimulate a muscle may arise, for example, in situations where an intact, undamaged motor nerve is not easily accessible for stimulation. Using the cap to produce a visible contraction in the muscle can provide the user with improved confirmation that stimulation is being output to the electrode.

In some configurations, the cap can be shaped similarly to a pen-like structure for ease of holding, grasping, manipulation, use, etc. In such a configuration, the cap can function as a nerve locator. In some embodiments, the cap can include a monopolar or bipolar probe. These probes can be configured to provide smaller conductive surfaces for subdividing the stimulation field to map the anatomical location of the nerve. These configurations can advantageously enable a multi-function system that provides both nerve localization and nerve regeneration functions.

In some embodiments, the cap includes two or more pieces or portions that snap together around the electrode lead. In other embodiments, any other type of connection or attachment method or technique can be used, such as friction or press fit, couplings (e.g., standard or non-standard), mechanical fasteners, or other mechanical connections.

In some embodiments, the enclosure 262 (e.g., a molded enclosure) includes space for embedded circuitry. In some configurations, the enclosure comprises a molded plastic enclosure. FIG. 18B shows a cross-sectional view of the cap about the plane 265 depicted in FIG. 18A, including potential space for circuitry 266. In some embodiments, such circuitry includes one or more assemblies 270, as shown in FIG. 18C. In one example, as shown, the assembly 270 includes two conductive components, a distal component 272 and a proximal component 280, that interface with a printed circuit board 274. The printed circuit board can include passive and/or active components. In some embodiments, the printed circuit board 274 includes a resistor 276 and an LED 278.

In yet other embodiments, the circuitry includes a combination of indicators and controls, including, for example, one or more LEDs (and/or other indicators) and/or one or more buttons or other controls or controllers. Such a design may be convenient for a user to initiate pulse generation at the tip (e.g., by an illuminating LED) and/or in one or more other ways and verify functional output at the tip. By way of example, a user may connect the electrode lead 250 to a pulse generator, initiate pulse generation using a button on the electrode cap, and verify functionality by observing the LED on the electrode cap. Such a button, control, or other controller may also be configured to change stimulation amplitude and/or one or more other stimulation parameters (e.g., frequency, pulse width, etc.) as desired or required for a particular application or use.

Figure 18D shows an electrode cap 261 with the embedded assembly 270 of Figure 18C. In some embodiments, the distal conductive component 272 is coupled (e.g., physically connected) to a conductive surface 264 on the cap. When the cap is fully assembled to the electrode lead 250, the proximal conductive component 280 of the cap can physically contact the conductive element 258 on the electrode lead, as shown, for example, in Figure 18E.

In some configurations, when the cap is properly shaped or otherwise configured, the connection of the conductive tip 252 of the lead to the distal conductive component 272 and the connection of the second conductive element on the lead 258 to the proximal conductive component 280 can allow current to flow from the lead tip through a circuit within the printer circuit board 274 to the second conductive element 258 on the lead. Such a design can be advantageous in allowing a user to test whether the conductive tip is functional.

As an example, a user can connect the electrode lead 250 to a pulse generator. When a pulse is drawn from the generator, current can flow through the circuit board and activate an LED or other indicator, so long as the conductive tip 252 is intact and the cap is properly interfaced with both the conductive tip 252 and the second conductive element on the lead 258. Thus, visual confirmation that current is flowing through the conductive tip 252 can be provided to the user. In some embodiments, confirmation of current flow to the conductive tip can be provided in one or more forms, including, but not limited to, visual, auditory, tactile, and/or any other manner, including combinations thereof. Such configurations can be incorporated into any of the embodiments disclosed herein or variations thereof.

According to some embodiments, the adhesive patch 80 includes (e.g., at least partially) exposed conductive contacts 282, as shown in FIG. 19. Additionally, the adhesive patch 80 can include one or more LEDs (and/or other visual indicators) 284, which can be coupled (e.g., directly or indirectly) to the conductive contacts via one or more resistors or other elements. By way of example, as shown in FIG. 19, the adhesive patch 80 can include a percutaneous electrode lead 250 (e.g., according to those described herein or their equivalents). In some configurations, to allow a user to test whether the conductive tip of the lead 252 is functional, the practitioner or other user can physically contact (e.g., at least partially physically contact) the tip 252 with the exposed conductive contacts 282 on the adhesive patch. In some embodiments, so long as the patch is outputting stimulation pulses, a specific action by the user (e.g., depressing a switch 184) can activate (e.g., illuminate) the LED or other visual or other indicator 284, thus providing visual confirmation that the conductive tip is functional and capable of passing stimulation current. In some embodiments, confirmation that the conductive elements are functional may include a visual, audible, or tactile indication, or a combination thereof.

In some embodiments, the patch 80 includes a microcontroller and a stimulus generator that outputs a low-amplitude AC waveform that can be used as a validation signal in some embodiments. In some embodiments, the amplitude is, for example, 0.1 μA to 10 μA (e.g., 0.1-0.2, 0.2-0.3, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 0.1-1, 0.5-2, 1-5, 5-10 μA, values therebetween, etc.). In other embodiments, the amplitude is less than 0.1 μA (e.g., 0.01-0.1, 0.005-0.001 μA, less than 0.005 μA, etc.) or greater than 10 μA (e.g., 10-15, 15-20, greater than 20 μA, etc.), as desired or required. The AC waveform can include a square wave, sine wave, or other AC waveform with a frequency greater than 1 Hz (e.g., 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10 Hz, frequencies between these ranges, greater than 10 Hz, etc.) or less than 1 Hz (0.01-0.1, 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-1, 0.3-0.7 Hz, frequencies between these ranges, etc.).

In some embodiments, the stimulus generator couples (e.g., physically (e.g., directly or indirectly), operatively, etc.) to the electrode lead. In some embodiments, the microcontroller is programmed to prevent output of a stimulation pulse (e.g., a pulse such as those described herein) until a verification signal is applied to the exposed conductive contacts 282, as shown, for example, in FIG. 19 . Such an “unlock after verify” feature may be convenient for a user to verify (e.g., directly) the functionality and integrity of the electrode lead 250 and conductive tip 252.

In some embodiments, the electrode lead wires couple to a cuff electrode device 10 (e.g., a device described herein, variations thereof, and/or any other type of cuff electrode, etc.). To verify the output of the cuff electrode, a verification bar 290, such as the verification bar shown in FIG. 20A, can include one or more conductive elements 292 and can be placed inside a wrapped or unwrapped cuff electrode.

According to some configurations, as shown in FIG. 20B , a cuff electrode device 10 having a unipolar electrode configuration (e.g., any of the embodiments described herein) is configured to interface with a verification bar 290 or similar feature or portion. In some configurations, conductive elements within the verification bar make physical contact (e.g., at least partial physical contact) with the unipolar electrode within the cuff. Additionally, conductive elements can be coupled to conductive elements at or near the tip of the bar, as well as in areas not encompassed by the electrode. In some embodiments, a user can selectively verify the stimulation output of the cuff electrode device 10 by placing the exposed conductive tip on an exposed contact surface used for lead testing, such as the aforementioned exposed contacts on a patch used for lead testing 282. This verification process is similar to the process described herein when using a percutaneous lead with a conductive tip and is applicable to any of the embodiments disclosed herein.

In certain embodiments, the verification bar 290 includes one or more LEDs and/or other visual indicators 284 for testing verification. In one example, as shown in FIG. 20C , the verification bar 290 includes conductive elements 292 in contact with the electrodes of the electrode device 10 (e.g., an electrode device described previously herein). The conductive elements 292 of the verification bar 290 can be coupled to an LED or other visual indicator coupled (e.g., operatively, electrically, etc.) to a second conductive element 292. A user can verify the stimulation output of the cuff electrode device 10 by placing the exposed conductive tip on an exposed contact surface used for testing the lead (e.g., the aforementioned exposed contact 282 on a patch used for testing the lead). In some embodiments, activation of the LEDs or other indicators 284 in the verification bar can indicate proper current conduction from the electrode device 10.

In some embodiments, the verification bar 290 is designed or otherwise configured to interface with a multi-contact electrode device. In one example, as shown in FIG. 20D , the verification bar 290 includes two conductive elements 292, each of which physically contacts (e.g., at least partially physically contacts) a separate electrode of the cuff electrode device 10. In some embodiments, a verification bar 290 that interfaces with multiple electrodes can include one or more LEDs and/or other visual or other indicators, as desired or required. With further reference to the example shown in FIG. 20D , verification of stimulation output can be conveniently performed directly at the electrode device level, without using a separate exposed contact surface for lead testing. In some embodiments, the verification bar 290 may be physically coupled to the adhesive patch 80.

In some embodiments, a percutaneous electrode lead 250 having multiple conductive elements 258 (e.g., as described herein) is coupled (e.g., physically, electrically, operatively, etc.) to a stimulation source, which may include circuitry for testing the electrode lead connection and placement. In some configurations, the stimulation source may also be configured to provide neural regeneration therapy (e.g., by providing stimulation energy). One such embodiment, which may be referred to as a functional electrode, is shown in Figures 21A and 21B. In some embodiments, such an electrode may comprise a percutaneous lead coupled to a housing that may include the stimulation source.

In some embodiments, as shown in FIG. 21C, verification of the stimulation output can be performed by inserting one or more conductive elements of the lead into the housing 114 of an electrical stimulator that includes a verification test element, as described herein. In some embodiments, such a stimulator can include one or more visual elements 284 and/or another type of indication to the user (e.g., an audible indication, a tactile indication, etc.) to notify the user that the stimulation output has been verified.

According to some embodiments, the housing of the electrical stimulator includes a pull tab 187 (e.g., as described herein with respect to other embodiments). In some configurations, the stimulator includes one or more verification mechanisms or features that aid in placing the system in an "unlocked" mode (e.g., also as described herein). By way of example, a percutaneous electrode lead having multiple conductive elements may be packaged with one or more conductive elements inserted into a stimulator housing having a pull tab or similar feature. When the user removes the pull tab, the stimulator may notify the user (e.g., immediately, such as within less than one second) of the status of the stimulation output using a corresponding included indicator (e.g., a visual indicator, an audio indicator, a tactile indicator, a combination thereof, etc.). In other embodiments, the user notification may take other forms (e.g., other types of notifications, other time frames, etc.) as desired or needed. The status may be used to "unlock" or turn on the stimulation circuitry or prevent power from being supplied to the circuitry. This can be advantageous to the user in that proper function of the pulse generator and the integrity of the electrode leads can be assessed in a single step without having to place the leads at or near excitable tissue and deliver a stimulation pulse.

In some embodiments, the pull tab may be replaced with a tactile switch 185 or other type of switch. In some configurations, the stimulator includes multiple indicators (e.g., visual, auditory, tactile, other indicators, etc.) that can be used to provide (e.g., display) information including, but not limited to, time and/or relative stimulation amplitude 118.

In some configurations shown in FIGS. 22 and 23, a device or system is used to initially locate a nerve (300, 310) and, if a damaged nerve is found or otherwise detected (302, 312), deliver nerve regeneration therapy (304, 314). In some embodiments, the device or system is used solely as a nerve locator or solely as a regenerative therapy system. However, in some configurations, it is advantageous for the device or system to be configured for both detection and subsequent delivery of energy (e.g., for nerve regeneration therapy). Such features may be incorporated into any of the device or system embodiments disclosed herein.

In some embodiments, the device or system includes a single control button or other control or controller (e.g., which may take some form other than a button) that is used to switch between a first stage of stimulation and a second stage of stimulation. Such a button or other control or controller may also be used to adjust stimulation output parameters, control visual indicators, and/or perform any other function, as desired or needed.

Intra-Surgical Nerve Localization and Treatment According to some configurations, one intended use of the system is in the operating room. Accordingly, the system can be designed, customized, and otherwise configured with such intended use in mind. The various systems disclosed herein can advantageously function and operate as dual-purpose devices that serve the needs of both nerve localization functions and nerve (e.g., nerve regeneration) therapy.

In some embodiments, the system housing includes a bipolar probe-type electrode used for nerve localization purposes, with a port used to connect a cuff-type electrode that can be used to interface with the damaged nerve to administer nerve regeneration therapy to the damaged nerve tissue. The bipolar electrode device may be similar to any of the devices described in more detail herein. In one embodiment, the damaged tissue is a peripheral nerve. However, in other configurations, the damaged tissue may include any other type of nerve, such as an autonomic nerve. In other embodiments, the bipolar electrode may be one of a variety of types familiar to those skilled in the art. In such a configuration and use, a surgeon or other practitioner can physically connect the electrode with the lead wires and connector to a jack or other coupling location located on the housing unit. A flow chart of one embodiment of use of the dual-purpose device is shown generally in FIG. 24 and is described in more detail below.

In one embodiment, as shown in the example of FIG. 24, upon initial power-on of the system (354), a "test" mode is configured to be entered. In one example, the test mode is configured to assist in nerve localization (356). The test mode can include a pulse train, with each stimulation pulse including a doublet pulse (e.g., separated by a particular inter-pulse interval). For example, in some embodiments, the inter-pulse interval may be 5 ms, as described herein and shown, for example, in FIG. 6A. However, in other configurations, the inter-pulse interval may be less than 5 ms or greater than 5 ms (e.g., 0-5 ms, 5-10 ms, greater than 10 ms, etc.), as desired or needed. A pulse train can be applied to a target nerve to test the integrity and function of the connected muscle (358). The doublet pulses can be configured to increase (e.g., maximize) or otherwise enhance the torque time interval and reduce stimulation amplitude requirements.

In some embodiments, pulses are delivered at a frequency of 10 Hz or less to produce tetanic contractions. Frequency ranges can include 0.1 to 40 Hz (e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-10, 10-15, 15-20, 20-30, 30-40 Hz, frequencies within these ranges, etc.).

In some embodiments, the amplitude of the stimulation can be configured to be adjusted (360) until a desired response is achieved (362). If the user is satisfied with the testing of the target nerve, they can selectively choose to test another nerve (364) and repeat the process of adjusting the amplitude. In some embodiments, once the desired response is reached for the nerve being tested, the user can complete use of the system (366).

In some embodiments, and still referring to FIG. 24 , once the user is satisfied with the nerve location and/or determines that the nerve is damaged (e.g., in light of a particular threshold level or response), the practitioner can connect an electrode (e.g., a cuff electrode, any other type of electrode, etc.) to the nerve port located on the housing (370). Any other type of electrode can be used as desired or required. The system can be configured to detect the electrode (372) and appropriately direct stimulation output from the probe to the electrode. When this occurs, the system mode can be switched to nerve regeneration therapy mode (374). The stimulation amplitude can be changed (376) until a desired response is reached (378). The user can then begin treating the damaged nerve using nerve regeneration therapy (380). In some embodiments, the system includes a timer that limits the duration of nerve regeneration therapy (382) and checks to ensure that the total time is not exceeded (384). In such embodiments, the system can be configured to shut down (e.g., automatically, according to a predetermined protocol or algorithm) once a specified or required time requirement has been reached 386. Additionally, the system can be configured to provide appropriate indications or cues (e.g., visual cues, audio cues, and/or any other indication) to the practitioner.

In some embodiments, intraoperative use of the system can include hands-free use (fully or partially hands-free use). For example, the system can be positioned within the surgical field and operated in a mode requiring minimal or no attention from surgical staff during stimulation. As previously discussed, the shape of the housing can be used to prevent the system from rolling off the surgical table or a sterile towel placed on the patient. Additionally, as also described herein, incorporating a specially shaped (e.g., hook-shaped) extension element or other feature can assist the user in coupling the system to an IV pole or other structure relatively close to the patient. Advantageously, these features can enable and facilitate hands-free use that minimizes or reduces intervention from surgical staff. In some configurations, the system is disposable and, therefore, once turned on or otherwise activated, the system can no longer be turned off. For example, in some configurations, once the pull tab is removed and the power source is activated, the device has a finite functional lifespan determined by the battery life. In some embodiments, the pull tab may be replaced with an on/off switch or similar feature or component, making the device reusable.

Perioperative Uses As described herein and in further detail below, any system embodiment disclosed herein can also be used in perioperative settings or applications. For example, in some embodiments, systems according to various configurations described herein can be configured to be connected to a monopolar electrode (e.g., functioning as an active stimulating electrode or cathode). Such monopolar electrodes can have a variety of forms, including, but not limited to, needle electrodes and/or catheter or cylindrical electrodes that can be placed percutaneously near the damaged nerve or placed near the nerve when the damaged nerve is exposed. As disclosed herein, any other type of electrode can be incorporated into the design of the device or system or the implementation of the treatment method.

In some embodiments, a unipolar lead is replaced by a neural probe, and a return electrode is connected to the neural port. In some embodiments, a multi-conductor electrode lead is connected to the neural port. One of the conductors of the system can be connected to a unipolar lead placed in the patient, while the second conductor can be connected to a return electrode, such as a surface pad or needle. In some embodiments, as shown in FIG. 21A, for example, there is no neural probe, and only a connection to the neural port is required to output electrical stimulation pulses. Some embodiments of the system may be advantageous in certain treatments and applications, such as carpal tunnel release.

In both use cases outlined above (e.g., both intraoperative and perioperative settings), the system is not necessarily limited to use in the manner described for those use cases. For example, the perioperative use case may be applied during surgery if the end user determines that stimulation with a unipolar electrode lead or similar lead would be more appropriate.

Figure 25 shows an overview of a flow diagram of one embodiment of the use of a perioperative system (e.g., a patch described herein). In one embodiment, a user places an adhesive patch 80 on a patient's skin (402). The location of the patch is not specific, and in some embodiments, it is sufficient for the patch to be in at least partial physical contact with the patient's or subject's skin. In one embodiment, an internal stimulus generator within the patch is activated by pressing a switch or other controller (404). The switch or other controller may be the same as or similar to the switches or other controllers described herein.

According to some embodiments, the output of the pulse generator includes a single pulse, a pulse train, a doublet pulse train, or any other type of pulse. The pulses may be constant voltage or constant current pulses having an amplitude sufficient to depolarize the nerve or muscle, provided that proper electrode contact and/or other operating parameters are used. In one configuration, once the stimulus generator is activated, the user may wish to verify the stimulus output (406). In some embodiments, such verification is accomplished in one or more steps according to one or more of the configurations described herein.

In some configurations, the user can observe a stimulation output LED 82 located on the patch itself (and/or receive an alert about the stimulation output using another type of visual, audible, tactile, and/or other indicator or output) (408). If an electrode cap is assembled to the electrode lead, as in the embodiments described herein, the user can observe an LED (or other indicator) in the cap that turns on when stimulation is being output (410).

In some configurations where a cap is not present, the user can touch the electrode lead to a conductive surface used to test the output located on the patch itself, and when connected, an LED on the patch will turn on (412). In some configurations where a cap is not present and a cuff electrode device 10 is used, the user can verify the stimulation output by touching exposed contacts (if present) on the verification bar in the cuff to a conductive surface used to test the output located on the patch itself. In some configurations, the cuff device 10 can include multiple electrodes in a bipolar or multipolar configuration. Verification of the stimulation output in this configuration can include observing whether an LED or other indicator on the verification bar is activated (e.g., turned on).

In some embodiments, if any or all of the above verification steps are negative, the user may stop treatment (414) and remove the patch, as a defect in the stimulus generator or electrode lead may exist. However, if one or more of the tests are positive, the user may continue treatment. In one embodiment, for example, during surgery involving an open incision, the user may further verify the output by using the larger conductive surface of the cap or the conductive lead tip to touch an exposed, intact, undamaged nerve or nearby muscle (416).

In some configurations, once the user is satisfied with the output and the cap is connected, the user can remove the cap 418 and place the lead adjacent (e.g., next to) the damaged nerve to be treated with nerve regeneration therapy 420. In some embodiments, the user can complete the surgery 422 and suture the wound closed 424 while keeping the exposed percutaneous lead properly exiting the wound.

According to some configurations, the patient can then leave the operating room, and a user, such as a nurse, can connect a second stimulation unit to the patch connector 426. The second stimulation unit can be turned on, and nerve regeneration therapy of the damaged nerve begins (428). The user can adjust the stimulation amplitude over the course of the treatment (430). Once the desired response is achieved (432) (which can be based on patient feedback, muscle contraction response, or other criteria), the user can, in some embodiments, leave the stimulation unit and complete the treatment. Once the treatment is complete (434), the stimulation unit is turned off (436), the electrode leads are removed from the body (438), and the procedure can be completed (440).

In some embodiments, the first stimulation unit can provide both verification stimulation pulses used to test nerves and/or muscles and/or verify the functionality of the electrodes and/or system, and can also include the hardware necessary to provide nerve regeneration therapy without the need for a second stimulation unit.

A functional flow diagram of such a system is shown in FIG. 26. As shown in the exemplary embodiment of FIG. 26, the system can be configured to operate in a self-verifying state (324) once power is applied to the system, for example, by removing a pull tab (322). Self-verification can include contacting an electrode with exposed contacts on the system housing or placing a lead within the system housing, as described herein. In some embodiments, self-verification involves placing an electrode in exposed or recessed contact with a stimulation source that produces a characteristic frequency pattern used to "unlock" the system. In some configurations, once the system completes self-verification (326), the system can be used to localize (e.g., "test") a nerve (330). In some configurations, an accessory or component of the device or system, such as a cap or handheld attachment, can clip or otherwise attach (e.g., directly or indirectly) to the electrode lead to facilitate grasping and use as a handheld nerve locator.

26 , the damaged nerve is located (332) using the system itself or determined a priori by a user (e.g., a practitioner, a medical professional, or some other mechanism or procedure), and an electrode lead can be temporarily implanted (334) using an insertion tool (e.g., according to embodiments disclosed herein). The implantation method can rely, at least in part, on using tissue (e.g., preferably unincised or uninjured tissue) in the area near the incision to aid in lead fixation and reduce or minimize lateral (e.g., perpendicular to the longitudinal axis of the lead) lead movement. Once implanted, the delivered stimulation amplitude and/or stimulation energy can be adjusted, and a second verification can be performed (336) to ensure proper electrode placement. This verification step can include measuring current between the anode and cathode electrodes, measuring action potentials in the nerve, measuring motor or sensory responses, and/or any other verification step or method as desired or required. Stimulation parameters used in this second verification step can include a repetitive burst sequence having at least two pulses. In some embodiments, the repeating burst sequence includes at least three pulses (e.g., three, four, five, six or more, etc.). When a desired response to the verification occurs (340), nerve regeneration therapy can be initiated for the damaged nerve (342). The system can be configured to provide nerve regeneration therapy to the damaged nerve for an appropriate period of time, as disclosed herein. When such period of time has elapsed (344), the electrode can be removed from the body (346), and both the electrode and stimulation source can be discarded (348).

In some embodiments, the insertion tool can include an over-needle catheter assembly. Such an assembly can be utilized to deploy the electrodes in a series of steps, for example, as outlined and illustrated in FIG. 27. According to some embodiments, to minimize or otherwise reduce the impact on the surgeon's workflow, the insertion tool is used to place the electrodes in the area near the incision, as previously described (FIGS. 27A-27C). In some configurations, this is advantageous for one or more reasons. For example, such a configuration can prevent the lead wire from protruding (e.g., partially or completely) through the existing incision site. Such protrusion generally requires longer suturing and, in the event of removal, can potentially damage underlying structures, such as the repaired peripheral nerve.

According to some embodiments, once an available pathway near the incision has been created using an insertion tool, an electrode lead can be advanced (e.g., routed using such pathway) toward the damaged nerve (see, e.g., FIG. 27D). In some embodiments, a trocar (e.g., a trocar, another type of hollow tube with or without a sharp end, etc.) can be used to create an access point. Such trocars are typically used by creating an access point starting from inside the body and pushing through the tissue toward the skin. In some embodiments, once the trocar emerges from the skin, an electrode can be routed through the trocar to the site of interest. In other embodiments, a robotic surgical unit can be used to percutaneously place the insertion tool or trocar. In some configurations, maintaining the electric field proximal to the nerve injury/repair site is important for therapeutic efficacy.

Electrical stimulation across the nerve gap can be used to slowly increase neurite growth across the gap. These signals can be low-level (e.g., subthreshold) DC currents. In contrast, in some configurations, AC stimulation, which produces an electric field sufficient to generate action potentials in the proximal aspects of the injured nerve that conduct toward the neuronal cell bodies, upregulates regeneration-related genes and results in accelerated axonal regeneration.

Current procedural and therapeutic techniques allow for several methods to provide AC stimulation to promote nerve regeneration. Such methods involve the placement of two (e.g., separate) wires (e.g., fine-gauge stainless steel wires) at the proximal aspects of the injured and repaired peripheral nerve. Typically, the anode is placed at the most distal aspect of the injured proximal nerve stump, while the cathode is placed further proximally. Such anode/cathode placement can be used to avoid or reduce the possibility of inducing anodal block. However, in such embodiments, the wires are placed within the surgical incision, requiring the surgeon to carefully suture around these wires when closing the main treatment incision.

In other clinical studies, monopolar cuff electrodes have been used to provide AC stimulation to promote nerve regeneration. However, in such configurations, the use of cuff electrodes requires that the stimulation procedure be performed intraoperatively, as the cuff electrodes cannot be removed percutaneously without incurring nerve damage.

In a third clinical example, AC stimulation used to promote nerve regeneration utilizes the use of monopolar fine needle electrodes. While needle electrodes can be placed in the area near the incision, the sharp tip used to form a pathway through the tissue can accidentally puncture the injured nerve to be stimulated. Furthermore, needle electrodes are rigid and can easily become dislodged or displaced. In some situations, this creates difficulties for clinicians using AC stimulation to promote nerve regeneration, in that movement of the active electrode can result in a distant electric field that is insufficient to depolarize the injured axons, potentially reducing or eliminating the therapeutic effect (e.g., all or a desired amount of therapeutic effect).

The methods and systems disclosed herein help avoid or at least reduce the potential for negative problems described in the current clinical use of AC stimulation to promote nerve regeneration.

With further reference to FIG. 27D , a verification or validation step can be performed in connection with (e.g., during) placement of the electrode lead. In some embodiments, such a verification or validation step can include measuring current between the anodal and cathodal electrodes, measuring action potentials within the nerve, measuring motor or sensory responses, and/or any other verification step or method as desired or required. In some configurations, once the electrodes are placed and one or more verification steps are completed, a second phase of stimulation can be administered, which can include therapeutic stimulation to promote or otherwise improve nerve regeneration and tissue reinnervation.

In some embodiments, the verification and treatment procedure includes two steps, although such steps need not be completed as two separate events. In some configurations, the verification and treatment occur in two separate events. For example, a verification step (e.g., a first stimulation phase) can occur in the event of nerve localization or measurement of patient response (e.g., sensory, motor, language, etc.), followed by a treatment step (e.g., a second stimulation phase to deliver nerve regeneration therapy). In some embodiments, these two separate events occur consecutively (e.g., consecutively). In other words, while the nerve localization event and the treatment delivery event are separate events, such separate steps still use a biphasic stimulation approach.

Continuing with reference to embodiments in which the verification and treatment stimulation occur sequentially (e.g., back-to-back) as separate steps, the subsequent treatment step can be configured to occur immediately after the end of the verification step. In other configurations, there is a delay between the end of the verification step and the subsequent treatment step. In such embodiments, the time delay between the two steps is 0 to 5 seconds (e.g., 0 to 0.05, 0 to 0.1, 0.1 to 0.5, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 0 to 2 seconds, time ranges between these values, etc.).

However, in other embodiments, the same devices and systems described herein are configured to complete the two-step verification and treatment procedure in one physical event (e.g., rather than separate events). As a specific example, a stimulation system can be implanted and activated (e.g., turned on) to deliver neural regeneration therapy. In some embodiments, where treatment stimulation pulses are delivered every 50 ms, for example, sufficient time can be provided between successive pulses to deliver a verification stimulus, as described further below. The response to the verification stimulus can be used as a decision point to proceed or continue delivering neural regeneration therapy. In some embodiments, such a single event (e.g., implantation and activation of the stimulation device) occurs in one single event, yet still uses two stimulation stages.

In some embodiments, the substantiation condition may be met if the therapeutic pulse itself is of sufficient energy to induce a biological response (e.g., an action potential).

27A-27D illustrate only one example of the use of the described techniques, and the techniques described herein can be applied to any damaged nerve in the body. For example, as shown in FIGS. 28A and 28B, the devices, systems, and methods can be applied to a situation in which the median nerve is at least partially torn (and/or otherwise damaged) and repaired, and percutaneously placed stimulation electrodes connected to a system are used to provide nerve regeneration therapy. Another example is shown in FIGS. 28C and 28D, in which the peroneal nerve is at least partially torn (and/or otherwise damaged) and repaired, and percutaneously placed stimulation electrodes connected to a system are used to provide nerve regeneration therapy. According to some embodiments, the configurations described above and elsewhere in this application are advantageously designed to be amenable to treating damaged nerves anywhere in the body, regardless of anatomy. By way of example, nerves that may be treated using the devices, systems, and methods described herein include, but are not limited to, nerves of the peripheral nervous system (e.g., median, ulnar, radial, peroneal, tibial, sciatic, etc.), nerves of the autonomic nervous system (e.g., visceral, phrenic, vagus, mesenteric, etc.), and nerves arising or originating in the brain (e.g., cranial nerves such as the facial nerve, trigeminal nerve, spinal accessory nerve, etc.).

In some embodiments, the insertion tool includes one or more electrically active components used to verify the verification condition. For example, a needle in an over-needle catheter assembly may be physically connected to a stimulation source and used to verify the verification condition. In other embodiments, the catheter may include one or more (e.g., two, three, four, five, etc.) conductive elements physically connected to a stimulation source used to verify the verification condition.

In some embodiments, conductive elements on the catheter can be used to detect biological signals, such as action potentials of injured nerves. Such action potentials may be in the form of individual action potentials (spikes), compound motor action potentials, compound sensory action potentials, or a mixture of these.

In some embodiments, a percutaneous electrode lead 250 having multiple conductive elements 258 (e.g., as described herein) can be advantageously used to measure action potentials (Figures 29A-29D). In one example, a multi-element electrode lead is placed near the injured nerve. In some configurations, the electrodes can be positioned parallel or generally parallel to the longitudinal axis of the nerve. The proximal conductive element 30 can be configured to measure an evoked response in the injured nerve in response to a stimulus from the distal conductive element. In some configurations, such an "upstream" measurement is used (alone or in conjunction with some other measurement or reference) to confirm a verification condition. In some configurations, the recording electrode configuration comprises a monopolar, bipolar, tripolar, or other configuration, as desired or required by the particular design or application. In some embodiments, the distal conductive tip 252 is configured to generate a monopolar electric field in combination with a distal reference electrode. In some configurations, the distal reference electrode is a surface patch electrode 80 (or some other type of surface electrode) with integrated electronics. In yet another embodiment, the distal conductive tip 252 with other conductive elements 258 is configured to generate a bipolar electric field. In some embodiments, three or more conductive elements (e.g., three, four, five, etc.) are used to more precisely steer or otherwise direct the current to target the damaged nerve, specific fiber bundles within the damaged nerve, and/or other body structures of interest.

In some configurations, a switching mechanism is used to switch the electrodes from stimulating to recording. Such configurations can be applied to any of the electrode embodiments disclosed herein. For example, a distal monopolar stimulating electrode 252 can be used in the first phase of stimulation to deliver a stimulation pulse in conjunction with a distal reference or return electrode, such as the electronics-integrated patch 80. In some configurations, once the stimulation pulse is delivered, the distal stimulating electrode 252 can be switched to be connected to a recording amplifier and used to measure biosignals, such as action potentials, in combination with one or more proximal electrodes 30 and a distal reference electrode, such as the electronics-integrated patch 80. Combinations of these configurations can also be used and are not limited to the configurations described herein.

In some embodiments, the stimulation system includes recording and amplification circuitry for measuring the biosignal. In some embodiments, the amplification circuitry comprises an instrumentation amplifier, filtering circuitry, or other analog amplification components. Such amplification circuitry may be configured to interface with an analog-to-digital converter that converts the measured analog signal into digital form. In some configurations, such digital signals are further manipulated to extract characteristic features. Such features may include, but are not limited to, signal amplitude, area, power, frequency, phase, etc. In some embodiments, such feature extraction occurs on a microcontroller or similar controller or device.

In some embodiments, as shown in FIG. 29E, a cuff electrode assembly 10 can be used to monitor evidence conditions. Such a cuff electrode assembly can be connected to a single system that incorporates the delivery of stimulation and the measurement of action potentials. In some cases, such a system can be configured to deliver neural regeneration therapy.

For any embodiment disclosed herein, the measurement system or assembly may be a separate system from the stimulation system or assembly. In some configurations, the separate measurement system may be configured to wirelessly communicate with the stimulation system (e.g., to confirm evidence conditions during a first stimulation phase, provide information regarding recorded signal characteristics, or gate (e.g., provide start/stop signals) a second stimulation phase, which may include stimulation to enhance nerve regeneration or tissue reinnervation). Wireless communication means may include, but are not limited to, radio frequency protocols (e.g., Bluetooth, Zigbee, Wi-Fi, NFC, etc.), optical communication (e.g., infrared, near-infrared, visible light), or magnetic (inductive link). In other configurations, a wired connection (e.g., via a cable) may be used to enable communication between different systems or assemblies. In some configurations, a separate system may be used to measure muscle action potentials, nerve action potentials, and/or other evoked biosignals, as desired or required. Such potential and other signals may be advantageous or otherwise useful in various injury situations. For example, in the case of compressive nerve injury (e.g., carpal tunnel syndrome), a connected muscle action potential measurement system may be used to measure evoked muscle responses from partially denervated muscles to confirm a telltale condition. In another example, a separate system may be used to measure action potentials from a nerve at a different anatomical location. Such a nerve may be physically connected to the injured nerve (e.g., further upstream from the injury site) but may not be accessible without obstruction. In such situations, the separate system may be used to confirm a telltale condition that may not be possible to confirm using the other described means. In some embodiments, the separate system uses surface or transcutaneous electrodes to obtain measurements.

In some configurations, the stimulation system waits for an external characteristic signature to verify operation (e.g., a verification condition). In some embodiments, such a signature comprises a discrete stimulation pulse provided by a separate stimulation unit. The response measured to the signature can be used to confirm the verification condition. Such a signature may be evoked using electrical stimulation as well as vibration stimulation, sound, or light, or a combination.

In some embodiments, the separate measurement system is adjusted and configured to measure, record, and/or otherwise account for somatosensory evoked potentials or other electrical activity in the brain resulting from tactile stimulation. By way of example, evoked potentials may be evoked by stimulating the injured nerve or connected branches at the proximal stump. This can provoke responses in both the spinal cord and the brain, which may be recorded using a separate measurement system. In some configurations, such separate measurement systems are used to confirm the evidence condition. In any situation, such recordings may utilize surface electrodes located on the surface of the skin, on the dura mater (epidural electrodes), or directly in the spinal cord or brain (subdural electrodes).

In some configurations, the electrode of the surface patch 80 with integrated electronics is used as a reference electrode for measuring biosignals (e.g., action potentials) recorded by proximal conductive elements in the electrode lead. Such a surface patch 80 may include one or more visual indicators 82. In some configurations, such indicators 82 may be used to conveniently provide data and other information to the user, such as time, status, stimulation amplitude, etc.

In some embodiments, the measurement system is configured to wirelessly transmit data to a separate device or component, such as, for example, a smartphone, a tablet, another smart portable device, a separate computing device (e.g., a laptop), etc. The separate device or component may include (or be configured to use) one or more algorithms for analyzing the data, verifying verification conditions, and/or performing any other function. In some configurations, such a smart or other computing device or component may be configured to communicate with one or more stimulators to enable and/or facilitate the performance of neural regeneration therapy.

Regardless of the configuration utilized, in some embodiments, while measuring a biological signal (e.g., an action potential), it may be advantageous to maintain and/or otherwise consider or account for a running average of the characteristic being measured (e.g., amplitude, signal area, signal power, frequency spectrum, phase, etc.) to improve the signal-to-noise ratio or another metric. In some configurations, such an average includes at least two evoked responses.

In some embodiments, measurements of biosignals during the validation or validation step can be used to gate (e.g., provide a start/stop signal) a second or other subsequent stage of stimulation, which may include stimulation to promote nerve regeneration or tissue reinnervation.

To further refine or otherwise supplement or enhance the motor/sensory response during the validation or verification step, in some embodiments, the repetitive burst sequences described herein generate a validation signature or other unique identifier. Such a signature can include stimulation pulses of various characteristics (e.g., different pulse durations, amplitudes, frequencies). In some configurations, the validation signature is configured to be synchronized with a display (or other output) and used for direct patient and/or practitioner feedback (e.g., asking the patient whether the response they feel from the stimulation is similar to the response shown on the display, querying a physician to evaluate the patient's response, etc.). In some embodiments, it is advantageous to use discrete pulses, which may be delivered randomly, during this validation phase. Such a configuration can be advantageous because a constant frequency output (e.g., 20 Hz with a fixed pulse width) can produce a "buzzing" sound, other consistent sensations, and/or other types of sensations in the patient. For example, in cases of severe nerve damage (e.g., transection), such constant sensations from stimulation may be masked or not interpreted as stimulation due to damaged axons that fire randomly or are hypersensitive. In some configurations, discrete pulses can overcome this limitation and provide an objective measure of the evidence condition (e.g., the patient's response to stimulation). Furthermore, it may be advantageous to provide discrete pulses at a frequency lower than the muscle fusion frequency to prevent fused muscle contractions. In some embodiments, the muscle fusion frequency varies depending on the muscle. For example, such a fusion frequency may be greater than 100 Hz for fast-twitch eye muscles and 5-20 Hz (5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 5-10, 10-15, 15-20, 10-20 Hz, frequencies between these ranges, etc.) for slow-twitch muscles such as the soleus. In some configurations, such contractions can occur when a severed nerve is stimulated proximal to the injury and proximal to an uninjured nerve branch. These contractions can also occur in nerves injured by compression, where some distal conduction can occur when the injured nerve is stimulated proximally. Non-tetanic pulse trains can, in some embodiments, be interpreted as discrete events by the patient that can meet the conditions for substantiation.

In some embodiments, a validation signature or other unique identifier is used throughout the entire therapeutic stimulation window (e.g., during one hour of nerve regeneration therapy, treatment of some other duration, etc.). This validation signature can conveniently confirm to the user that the system is providing a therapeutic effect to the injured nerve being stimulated. In some configurations, the validation signature applied throughout the stimulation window can include one or more discrete pulses (e.g., two, three, four, five pulses, etc.) that generate one or more (e.g., two, three, four, five, etc.) evoked potentials. The timing (e.g., pulse frequency) between subsequent pulses can be uniform or non-uniform (e.g., random) as desired or needed. In some configurations, such evoked potentials can be averaged to generate a composite validation response that can confirm to the user whether stimulation is being applied correctly and the system is providing a therapeutic effect to the injured nerve.

Multiple Nerve Injuries In cases where multiple nerves are injured, such as in a brachial plexus injury, it may be desirable to provide nerve regeneration therapy to all injured nerves at once. In such cases and configurations, the system can be designed and configured to output to different electrode configurations. See, for example, FIG. 30.

In some embodiments, an electrode device connector 208 with a system-controlled analog demultiplexer 210 can be connected to the neural port, as shown in the example of Figure 30. In some configurations, this allows the system to provide output to one channel at a time by switching channels 212.

In some embodiments, the neural port includes additional conductive signal paths or lines for carrying power and control information to the analog demultiplexer. In some embodiments, the connector can feature connections for controlling the analog demultiplexer using either a parallel configuration where one control signal line is required for each electrode connected to the system (e.g., ON Semiconductor's MC14067B, Ana
Analog Devices ADG5412, Maxim Integrated MAX4623, or equivalent.) In other configurations, the connector can include three control signals for interfacing to an analog demultiplexer using a serial peripheral interface (SPI) (e.g., Analog Devices ADGS1412).

According to some embodiments, a cable including multiple electrodes can include a connector housing unit including a demultiplexer circuit and an indicator, such as an LED, to indicate an active channel. In yet other configurations, the connector housing unit can include a memory and an energy source (e.g., a relatively small energy source, such as a coin cell battery) for powering the memory. In some configurations, the memory is configured to store information, such as stimulation settings and/or other operating parameters. In some configurations, the connector housing unit can include a memory, an energy source, a demultiplexer circuit, and/or any other features or components, as desired or required. Each lead connected to an electrode device can include a connector housing unit including one or more of the following components described in more detail with reference to any of the embodiments disclosed herein.

Duration of the Treatment Method Regarding the duration of treatment, studies have demonstrated that the optimal duration is as little as 10 or 30 minutes. However, most studies utilize treatment periods of one hour or close to one hour. Thus, the duration of the treatment method can be between 10 and 90 minutes (e.g., 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 10-30, 30-60, 40-80 minutes, times within these ranges, etc.), as desired or needed. In other embodiments, the treatment procedure may require more than 90 minutes or less than 10 minutes.

In some embodiments, treatment of the damaged nerve involves setting up the appropriate electrode device and stimulation parameters, initiating treatment, and maintaining a stimulation amplitude sufficient to depolarize the axons. Furthermore, the treatment need not be applied continuously throughout the entire treatment period, as long as the total treatment time is equivalent to the optimal stimulation period. For example, if the electrode device needs to be moved during a surgical procedure, the end user can pause the treatment using the user-operable controls, as described above. When paused, the system stops delivering electrical stimulation output and resumes only when the pause control is used again. In this particular example, once treatment has been applied for one hour, the indicator described above can notify the user that treatment is complete.

In some configurations, it may be advantageous to deliver multiple bouts of brief electrical stimulation, each bout comprising the previously described duration (e.g., 10-90 minutes) and stimulation parameters. The timing, i.e., rest period, between subsequent bouts of brief electrical stimulation may vary from multiple bouts per day to single bouts delivered one or more days apart. In some embodiments, a single bout of brief electrical stimulation of an injured axon transiently upregulates regeneration-related genes and neurotrophic factors in the cell body of the injured axon. It is contemplated that, according to some embodiments, multiple bouts can prolong, transiently increase, or maintain the upregulated expression of these genes and neurotrophic factors.

The number of bouts to be performed may vary depending on the type and distance of the nerve injury. For example, a proximal shoulder injury may require a minimum of 450 days for damaged axons to regrow from the injury site to the distal muscles of the hand. In situations where daily stimulation is performed, at least 450 bouts would likely be required to provide multiple bouts of stimulation. More distal injuries, such as lacerations of the digital nerve in a human finger, likely require significantly fewer bouts, e.g., 30-60 bouts, for daily stimulation. The number of bouts to be performed depends on the injury and cannot be determined a priori. In some cases, only a few bouts are necessary, as repeated bouts may not be beneficial. The primary effect of stimulation is to promote nerve growth across the injury site; therefore, after a certain number of days, all damaged axons may have crossed the injury site, and further nerve regeneration therapy may not be beneficial. An additional advantage of nerve regeneration therapy is the ability to reinnervate more tissue. In some embodiments, this not only results in greater function, but also reduces the likelihood of developing chronic pain, as regenerating axons can reconnect to tissue and there are fewer stray axon ends that can form neuromas or cause pain.

In some embodiments, the administration of multiple bouts of brief electrical stimulation may require modification of the systems and devices previously described. In one example, a second stimulation system interfacing with connector 186 on adhesive patch 80 may be programmed to monitor, track, or verify whether the appropriate treatment duration and number of treatments have been administered. In some embodiments, the second stimulation system may store patient information, such as a unique identifier, to track patient compliance with treatment.

In another example, the adhesive patch 80 can be configured with an energy source that lasts for the duration of multiple bout deliveries. In such an embodiment, the adhesive patch 80 can include elements that enable it to function as both a verification energy source and a stimulation energy source. Additional elements that may be included in the adhesive patch are indicators or user controls for adjusting stimulation parameters as referenced herein.

In some embodiments, the adhesive patch includes circuitry used for wireless communication with an external device, an implanted device, or a combination thereof. In one exemplary configuration, such a device may include a smartphone or other computing device (e.g., a tablet). In such applications, the smartphone may include software applications used to modify stimulation parameters and verify appropriate treatment duration and application. In another example, such a device may include an implanted electrode lead. In such applications, the electrode lead may include hardware and circuitry for communicating with the patch and performing desired functions, such as electrical stimulation.

Pain Management In other embodiments, the system (and associated methods) can be modified to not only deliver one or more bouts of nerve regeneration therapy, but also to deliver pain management therapy. Such pain management therapy can be provided immediately before and/or immediately after nerve regeneration therapy. Furthermore, delivery of such pain management therapy can occur before, during, and/or after nerve repair surgery, as desired or necessary. However, the delivery of energy for pain management therapy is not limited to this time period and may be provided at a certain time from delivery of nerve regeneration therapy. The certain time period can represent a period of minutes to several hours to days (e.g., 0-10, 0-30, 0-60 minutes, 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-12, 0-12, 0-24 hours, 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-10, 0-20, 0-30 days, more than 30 days, any period within these ranges, etc.) from delivery of nerve regeneration therapy. Furthermore, the delivery of energy for pain management may occur at the time the patient experiences pain associated with nerve injury, without the need for a fixed delivery schedule.

According to some embodiments, the pain management treatment includes stimulation in the range of 50-200 Hz (e.g., 50-60, 50-55, 55-60, 52-58, 50-100, 50-200, 50-150, 100-150, 100-200, 70-130, 80-120, 60-120, 150-200 Hz, values between these ranges, etc.). In some configurations, the frequency of stimulation for pain relief may be between 20 KHz and 500 KHz (e.g., 20-500, 20-100, 50-100, 100-200, 100-300, 100-400, 100-500, 200-400, 200-500 KHz, frequencies between these ranges, etc.) or between 1 KHz and 10 KHz (e.g., 1-10, 2-8, 4-6, 3-7, 1-5, 5-10 KHz, frequencies between these ranges, etc.). In some embodiments, systems can be designed and otherwise configured (and corresponding methods related to such systems can be configured accordingly) to provide optimal, efficient, and/or comfortable frequencies for pain relief. In some embodiments, the frequencies delivered by the system can be configured to adjust the stimulation energy delivered for pain relief as desired or needed (e.g., depending on the particular patient or other subject, during treatment of the particular patient or subject, targeting a particular type of pain, etc.). However, in other embodiments, the stimulation energy delivered by the system to reduce pain can be fixed.

In some configurations, a single bout or treatment round of nerve regeneration therapy may be sufficient to promote tissue reinnervation, leading to a reduced likelihood of developing chronic pain or other types of long-term pain. However, as nerve tissue regenerates, short-term pain may still be present and may persist. Any of the systems described herein can be used to provide continuous or intermittent pain management therapy after one or more bouts of nerve regeneration therapy.

31, 32, 33, and 34 show flow charts of embodiments of steps for providing nerve regeneration therapy and pain management therapy to a subject. These flow charts illustrate various time configurations in which the delivery of nerve regeneration therapy and pain management therapy may be applied. While these flow charts provide some example time configurations for the delivery of these therapies, a practitioner or device user may choose to bypass or not perform one or more steps, replace a shown step with an alternative step, and/or incorporate additional steps, as desired or necessary. For example, a practitioner may choose to apply only one nerve regeneration therapy, but may also choose to apply multiple applications of pain management therapy. Thus, under such circumstances, the practitioner may omit a step in which an additional nerve regeneration therapy may be applied.

FIG. 31 generally summarizes one embodiment of a procedure, protocol, or method for providing nerve regeneration and pain management therapy to a subject. As shown, nerve regeneration stimulation can be applied to a subject (502), such as according to one or more of the various configurations disclosed herein. In the illustrated configuration, the nerve regeneration stimulation is applied (502) after a neurosurgery procedure is initially performed (500). However, as shown in connection with other embodiments disclosed herein (see, e.g., FIGS. 32-34), the nerve regeneration stimulation can be initially applied before a neurosurgery procedure is performed, if desired or necessary. Once delivery of the nerve regeneration stimulation is complete (504), pain management stimulation can be applied to the subject (506). The pain management stimulation can be applied using any of the devices, systems, and/or methods disclosed herein.

With further reference to FIG. 31 , once pain management stimulation has been completed for the subject, the practitioner may determine whether additional pain management treatment is desired or required (510). Similarly, if it is determined that additional pain management treatment is not desired or required, the practitioner may determine whether additional nerve regeneration treatment is desired or required (512). If none of these additional treatments are desired or required, the protocol, procedure, or method may be terminated (514). However, as shown in FIG. 31 , if additional treatments are desired or required, the practitioner may choose to repeat one or more of the steps as desired or required.

FIG. 32 schematically summarizes another embodiment of a procedure, protocol, or method similar to that shown in FIG. 31 for providing nerve regeneration and pain management therapy to a subject. However, in FIG. 32, nerve regeneration stimulation is applied (520) before the performance of neurosurgery (524). In FIG. 32, neurosurgery is performed (524) before the application of pain management stimulation (526). However, in the procedure shown schematically in FIGS. 33 and 34, both nerve regeneration stimulation (540) and pain management stimulation (544) are applied before the performance of neurosurgery (548). In FIG. 33, application of nerve regeneration stimulation (540) occurs before application of pain management stimulation (544). However, alternatively, in FIG. 34, application of pain management stimulation (560) occurs before application of nerve regeneration stimulation (566).

According to some embodiments, pain management therapy can be provided simultaneously with nerve regeneration therapy. That is, pain relief waveforms 602 can be provided between successive pulses 600 in a nerve regeneration paradigm. Such waveforms can include sinusoidal, rectangular, ramped, and/or any other format, pattern, or shape. By way of example, FIG. 35 shows a 1 KHz sine wave interspersed with biphasic 20 Hz rectangular nerve regeneration pulses. However, any other wave/pattern, frequency, and/or other characteristics for the delivery of stimulation energy can be used as desired or needed.

In some embodiments, the presence of percutaneously placed leads and electrodes already interfaced with the injured nerve provides an inherent advantage to the delivery of one or more follow-up stimulation energies for pain relief. Therefore, the requirement for a separate procedure to gain access to the nerve tissue (and/or surrounding anatomic regions) to deliver stimulation energy for pain management is unnecessary. This is important because the site of neuropathic pain is considered to be the site of nerve injury. Other advantages include the ability to verify the therapeutic effectiveness of pain management treatments and to titrate stimulation levels to produce optimal or superior pain control through biosignal recordings.

In some embodiments, as shown in FIG. 36 , a system for providing nerve regeneration therapy (e.g., according to any of the configurations disclosed herein or their equivalents) includes separate actuators, buttons, controls, controllers, and/or other devices, features, or components that aid in providing pain management therapy. In some embodiments, such features or components can be incorporated into one or more other features, components, devices, and/or portions of the system. In other configurations, a separate system 610 can be used to provide pain management therapy and can also include controls and indicators 612. In some embodiments, such separate controls are configured to be enabled or otherwise actuated and/or controlled by the patient, caregiver, medical professional, etc., as desired or needed.

In some embodiments, once nerve regeneration therapy is completed, the system is configured to provide only pain management therapy, while in other embodiments, both nerve regeneration and pain management therapy are available (e.g., intermittently, indefinitely, for a specified period of time, until a specified event or threshold is achieved, as otherwise determined by the system, as directed by a practitioner or other user, and/or as dictated by one or more other factors or conditions).

In some embodiments, a separate device or system can be configured to replace the device that provides nerve regeneration therapy. A nerve regeneration provider device as described herein can be deployed or otherwise activated during or immediately after surgery to repair a damaged nerve. For example, pain management therapy, on the other hand, can be performed in a home environment, or typically in an environment away from a medical setting (e.g., a hospital, clinic, doctor's office, etc.). Thus, under certain embodiments, it may be advantageous to modify or replace the nerve regeneration device with a pain management device that interfaces with an electrode 250 already positioned upstream from the incision site 614 and interfaced with the damaged nerve.

According to some embodiments, in the case of nerve regeneration therapy and/or pain management therapy, the corresponding system may be body-wearable and directly attachable to the limb 616. In some embodiments, the same device or system may be used to provide both nerve regeneration therapy and pain management therapy. In other configurations, different systems may be used to provide nerve regeneration therapy and pain management therapy. Whether the same or different stimulation energy delivery devices or systems are used for nerve regeneration therapy and pain management therapy, such devices or systems may be body-wearable (e.g., directly or indirectly attached to the subject) or non-body-wearable, as desired or required for a particular application or use.

In some embodiments, controls (e.g., devices, systems, components, features, etc.) for enabling, implementing, or otherwise facilitating pain management are triggered or otherwise initiated using a separate device (e.g., remote device) 618, such as a smartphone or other radio frequency (RF), Bluetooth, and/or other wireless/wired transmission capable remote. In an example of a smartphone or other computing device used to enable pain management therapy, such smartphone or other device may be configured to administer or otherwise control the administration of desired or required therapy via an application (e.g., smartphone application or program), which may include information such as a record of delivery time, amount of energy delivered, compliance with therapy, target stimulation level, deviation from stimulation target over time, etc. In some configurations, no physical controls are found in the pain management system, but rather are strictly controlled via software found on a computer, tablet, smartphone, etc. The software may adjust stimulation parameters, treatment time, delivery time, communication with a physician, etc.

In some embodiments, a system used to provide pain management or nerve regeneration therapy can include a battery or similar power source. In other configurations, the system includes a wireless charge transfer mechanism (e.g., an inductively coupled coil or an electromagnetically coupled circuit) that can be used to power the device. In some embodiments, wirelessly transferred power 620 provided from a computing device, such as a computer, tablet, smartphone, or other computing device, can be configured to power (e.g., electrically charge) a charge storage device, such as a capacitor (e.g., a supercapacitor). In some embodiments, a supercapacitor configured to be charged in this manner can be configured to be programmatically charged to provide a set amount of pain management or nerve regeneration therapy. In some embodiments, a supercapacitor can be used in conjunction with a battery to reduce battery voltage drop due to a high current consumption event (e.g., wirelessly transmitting data). For example, in some configurations, the set amount can include a preset amount of charge provided, duration, stimulation settings, etc. In some configurations, a short-range wireless communication protocol utilizing a license-free frequency band, such as 13.56 MHz, can be used to exchange power and/or data with a pain management device or system. However, any other configuration may be used to facilitate the exchange of power and/or data with a pain management device or system as desired or required.

In some embodiments, the computing device/tablet/smartphone can also act as a payment system. In such a configuration, the computing device can unlock or activate pain management treatment once payment is received.

Shapeable Electrode Leads—General Nerve injuries can occur in various parts of the body and are usually unpredictable. Surgical repair of these injuries typically involves an open incision or open surgical field. Interfacing (e.g., reaching, contacting, accessing, approaching, etc.) a nerve to administer nerve regeneration therapy in these situations can involve the use of an electrode (e.g., a cuff electrode). However, known electrodes (e.g., cuff electrodes) typically cannot be removed percutaneously and are suitable only for the duration of the surgical procedure or are permanently implanted. Given the generally temporary nature of nerve regeneration therapy, having a neural interface that can adequately contact a nerve in open surgical situations such as nerve repair and then be removed from the subject's body (e.g., seamlessly, without additional surgical procedures, etc.) can be important and useful for the advancement and/or applicability of such therapy. Furthermore, the use of a shapeable electrode that can be easily withdrawn is advantageous for providing pain management therapy after nerve repair as described herein.

In some embodiments, percutaneously placed electrodes may be suitable for providing nerve regeneration therapy and/or pain management therapy. In some embodiments, the electrode lead may be shaped to fit the particular region of the body structure in which it is placed. Advantages and benefits of the shaped electrode lead include, but are not limited to, the ability to better conform the electrode lead to a region of the body structure; the ability to position the electrode lead along a trajectory that is not parallel to the longitudinal axis of the target nerve; the ability to at least partially encase and/or at least partially surround the target structure and maintain its position; the ability to create a shape that can be used to avoid the body structure while still engaging the target nerve; the ability to position the electrode lead near the target nerve without having to rely on surrounding connective tissue for fixation; the ability to withdraw the electrode without damaging the repaired target nerve; the ability to better localize treatment to the desired site, reducing the current density required to induce treatment (e.g., nerve regeneration therapy and/or pain management therapy); and the reduction or prevention of pain, discomfort, or trauma that would occur with inflexible, rigid, or protruding implant materials.

According to some embodiments, any of the configurations disclosed herein, or equivalents thereof, can include an electrode lead having one or more shapeable portions. In some configurations, only a portion of the electrode lead is shapeable (e.g., includes a shapeable aspect). However, in other embodiments, the entire electrode lead is shapeable.

The surgical field, or the area containing and/or surrounding the targeted injured nerve, may have experienced sufficient trauma (e.g., structural or material changes) that it does not resemble standard anatomy. Furthermore, having a shapeable electrode lead may be advantageous in open surgical procedures, allowing the lead to be shaped (e.g., globally, generally, automatically, manually, etc.) to fit a particular nerve regardless of the overall shape of the anatomy. In some configurations, shaping of one or more portions of the lead body 1100 (e.g., distal aspect 1102 and/or proximal aspect 1104) can be performed manually, as shown in FIG. 37A. In some embodiments, such manual shaping or manipulation can be accomplished using one or more surgical instruments (e.g., forceps) as shown in FIG. 37B, such as by robotic instrumentation. In other embodiments, no surgical instruments and/or instruments are used. In some embodiments, shaping occurs at least partially within the surgical field. For example, the electrode lead body 1100 can be fully or partially shaped as desired or necessary once the lead body 1100 is positioned within the surgical area of interest.

Shaping can involve applying a force to the electrode lead to cause a change in the shape of the lead. By terminating or modifying the force, the electrode lead can maintain the shape created by the applied force.

As shown in FIG. 38A, according to some examples, shaping can include creating a curved element that deviates from the longitudinal axis 1106 of the electrode lead body 1100 about the distal aspect 1102, which may include a conductive element 1108. In other examples, as shown in FIG. 38B, shaping can be used to impart a generally helical shape to the electrode lead body 1100. As shown, such a shape can be configured to surround a target neural structure 1110.

For any embodiment disclosed herein, the ability of a portion of the electrode lead body 1100 (e.g., the distal aspect 1102) to retain its shape can be advantageous, as it allows the electrode to more predictably and reliably contact and maintain contact with the neural structures 1110 (e.g., similar to a cuff electrode, but with flexibility for atraumatic removal).

In yet another configuration, as shown in FIG. 38C, shaping of the electrode lead body 1100 can be used to create one or more U-shaped sections. Only a few examples of shaping that can shape an electrode are illustrated or otherwise disclosed in this application. It should be understood that selective shaping of the electrode lead body 1100 can result in a myriad of shapes, including shapes not discussed in this application, to fit any anatomical situation encountered and/or to meet any other goal or objective.

Existing devices may include one or more limitations and/or other drawbacks relative to the embodiments disclosed herein. For example, in cardiac applications, catheter-type electrode leads are often used to pace the heart (e.g., deliver electrical stimulation or other energy to cardiac tissue), record signals from the heart, etc. Shaping of the distal aspects of these catheter-type leads can be performed before placement within the body. Manufacturers typically produce various models with distal aspects (and/or other portions) that include different shapes. Such various models can be selected based on one or more factors, such as, but not limited to, the insertion method used to enter the subject's anatomy (e.g., femoral or radial artery access), one or more characteristics of the subject's anatomy (e.g., whether the subject's aorta is narrow or wide), etc. Furthermore, such conventional shaping techniques are not limited to catheters with electrodes, but can also include guidewires, guide catheters, or more generally, devices that must pass through the subject's vasculature or other intraluminal anatomy network.

In the field of neurosurgery, electrodes used to interface with the brain (e.g., deep brain stimulation electrodes) or the spinal cord (e.g., spinal cord stimulation electrodes) are currently placed under image guidance to ensure highly accurate localization. These procedures are minimally invasive and do not require open surgery. In such situations, the electrodes are not shapeable but instead are flexible enough to conform to the tissues (e.g., brain or spinal cord) with which they interface. A stylet, metal insert, or other device is typically used in the placement of these leads to provide the necessary stiffness, pushability, and/or other properties within the tissue. Removal of the stylet allows the surrounding tissue to exert a force on the lead, holding it in place. However, in the absence of surrounding tissue, the flexibility of the lead may prevent it from being shaped and used in the context of peripheral nerve repair, where the repair procedure is typically performed in an open surgical field (e.g., or minimally invasive). The ability to shape the lead to fit a specific anatomic region (e.g., during the surgical procedure) is not possible with existing technology.

In some embodiments, the electrode lead can include one or more conductive elements 1108 distributed along one or more portions of the lead (e.g., the distal aspect of the lead). In other configurations, the conductive elements 1108 are located along the entire length of the lead instead of, or in addition to, the distal end of the lead, as desired or required. The conductive elements can include different shapes, sizes, and/or other characteristics, as desired or required. For example, as shown in FIG. 38A , the conductive elements 1108 at the distal end of the electrode lead body 1100 can be shaped in a manner that both caps the electrode lead body 1100 and also provides a larger surface area that can be used to deliver stimulation current to tissue, such as a peripheral nerve. 38A , the second conductive element 1108 positioned away from the tip element can be shaped as a ring varying in width from 0.05 to 5 mm (e.g., 0.05-0.06, 0.06-0.07, 0.07-0.08, 0.08-0.09, 0.09-0.1, 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5 mm, ranges therebetween, etc.) and/or can be physically coupled (e.g., directly or indirectly) to the conductive insulated wire 1122. In some configurations, at least two conductive elements 1108 are used to generate a bipolar stimulation field. Multiple conductive elements can also form an electrical stimulation array that allows the current field to be shaped or otherwise modified or influenced.

In some embodiments, the electrode lead body 1100 having multiple conductive elements 1108 (e.g., as described herein) couples (e.g., physically, electrically, operatively, directly, indirectly, etc.) to a stimulation source, which may include circuitry for testing the electrode lead connection and placement. In some configurations, the stimulation source may also be configured to provide nerve regeneration therapy (e.g., by providing stimulation energy). In other configurations, the stimulation source may also be configured to provide pain management therapy (e.g., management of chronic pain through electrical stimulation).

In some embodiments, the electrode lead has a circular or curved shape (e.g., at least a partially circular or curved shape) and is 0.1 to 5 mm (e.g., 0.1 to 0.2, 0.2 to 0.3, 0.3 to 0.4, 0.4 to 0.5, 0.5 to 0.6, 0.6 to 0.7, 0.7 to 0.8, 0.8 to 0.9, 0.9 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 5
, 1-4, 0.5-4, 1-4, 0.1-5, 4-5, 3-5, 2-5 mm, ranges therebetween, etc.).

In some embodiments, the electrode lead includes multiple sections (e.g., two, three, four, five, six or more, etc.). Each section may include a different shape. However, in some configurations, two or more sections may include similar or substantially similar shapes, as desired or required.

According to some embodiments, as shown in FIG. 39A, the cross-sectional shape of the proximal aspect of the electrode lead may be at least partially circular, cylindrical, and/or otherwise curved, while the cross-sectional shape of the distal aspect may include a thin rectangular shape (or other non-circular or curved shape). In some configurations, the proximal aspect may be shapeable, allowing the user to deflect the electrode lead from the longitudinal path of the nerve while maintaining contact with the nerve at or along the distal end.

In some configurations, the thickness of the electrode lead can vary along its length. For example, the thickness of the lead can be different in one or more sections. For example, a generally flat rectangular shape can be sufficiently thin (e.g., 10 μm to 500 μm) relative to a cylindrical component. This can be advantageous because the thin rectangular section can be positioned below the nerve to non-traumatically interface with the injured nerve, while the cylindrical section facilitates percutaneous placement or delivery and retrieval of the interface with an insertion tool.

In some embodiments, as shown, for example, in FIG. 39B, a thin rectangular shape or flap 1112 can be used to fasten or otherwise secure (e.g., temporarily, permanently, etc.) a cylindrical lead by surface tension (e.g., using fluid located in and/or around the tissue to create surface tension on the flap). In some configurations, the thin rectangular shape comprises one or more flexible (e.g., non-rigid) materials, such as, but not limited to, polymeric and/or elastomeric materials (e.g., silicone rubber, polyurethane, etc.).

In some embodiments, the distal aspect of the electrode lead comprises one or more shapeable materials. In one example, as shown in FIG. 40A , the lead is configured to be shapeable, at least in part, as a result of an insert 1114 that can be located within the electrode lead body 1100. Such an insert 1114 can, in some configurations, be coupled to a conductive element 1108 located at the distal end (e.g., tip) of the electrode lead body. This assembly can then be covered (e.g., with a layer, coating, jacket, other covering 1116, etc.). Such a covering can include one or more polymeric and/or elastomeric materials. In one example, the insert 1114 can be electrically conductive (e.g., at least in part) and can function as a wire or other conductor to carry signals to and from the conductive element.

For any embodiment disclosed herein, as shown schematically in partial longitudinal cross section in FIG. 40B , the electrode lead assembly 100 can be configured to be shapeable or maneuverable using a combination of (1) at least one shapeable (e.g., malleable, bendable, etc.) insert or other member 1114 and (2) at least one softer outer jacket and/or other covering 116. The lead assembly can include additional layers, coatings, members, components, features, etc., as desired or required. For example, the electrode lead can include one or more of electrodes, wires or other conductors, other electrical components, braids, other structural elements or features, lumens or other passageways, etc.

As used herein, electrical wire and conductor are broad terms that may include, but are not limited to, wires, printed circuit boards, conductive tracks, conductive pads, etched conductive features, soldered conductive features, other conductive features, and/or any other device, member, component, or feature configured to be electrically conductive.

40B , for any embodiment disclosed herein, the shapeable insert or member 1114 can be configured to maintain its shape after being shaped by a practitioner or other user. Similarly, the electrode lead 1100 including the shapeable insert or member 1114 can be configured to maintain its shape after being shaped. The shapeable insert or member 1114, and thus the corresponding lead or lead assembly 1100 including them, can be configured to maintain their shape during a procedure. In some embodiments, such a lead 1100 can be configured to be reshaped after initial shaping during use (e.g., during the performance of a therapeutic procedure). For example, the shapeable insert or member 1114 (and, consequently, the entire lead) can be reshaped by applying a force and/or moment to one or more portions of the lead. As described herein, such forces may be applied manually (e.g., using the practitioner's hand) by the practitioner or other user and/or may be applied using one or more tools (e.g., forceps, other surgical instruments or tools, etc.). In another example, the lead assembly can be shaped and/or reshaped by normal forces exerted by surrounding body structures. This can be advantageous in at least two situations, such as during long-term implantation and/or during lead removal procedures.

By way of example, during long-term implantation (e.g., for pain management treatment), forces (e.g., passive forces) applied to the shapeable insert or member (e.g., by surrounding tissue and/or other parts of the body structure, other force sources, etc.) can reshape (e.g., continuously reshape) the electrode lead to allow it to conform to a desired location without creating undue tension or stress on an injured nerve. Also, for purposes of non-limiting illustrative example, upon removal of the lead (e.g., withdrawing the lead from the subject's body structure), forces (e.g., passive forces) applied to the shapeable insert or member (e.g., by surrounding tissue and/or other parts of the body structure, other force sources, etc.) can at least partially deform the lead (e.g., to a straight line, a generally straight line, a smooth curve, etc.) so that the lead can be removed without tangling, buckling, and/or other deformations that could cause damage to the subject's surrounding body structure.

For any embodiment disclosed herein, the insert or other member 1114 of the lead assembly 1100 configured to facilitate shaping or reshaping of the assembly can include plastic deformability. In other words, such an insert or other member 1114 can be configured to distort, e.g., stretch, bend, and/or twist, when a specific force or stress (e.g., tensile, compressive, bending, or torsional force or stress) that exceeds the material's yield strength is applied. Such distortion can be temporary, allowing the insert or other member to maintain its shape when no external force is applied (e.g., when resting on a table or other surface until a user applies another bending or other reshaping force or moment). In some configurations, when the electrode lead is handled (e.g., in air with the distal shapeable aspect unsupported or subject to other external forces), gravity is insufficient to shape the lead, and the lead has sufficient rigidity to maintain the desired shape.

For any embodiment disclosed herein, the outer jacket or other outer covering 1116 of the lead assembly 1100 can include elastic deformability. In other words, such an outer jacket or covering can be configured to undergo a temporary change in shape when a force is applied to the lead assembly, and thus the outer jacket or covering. Such an elastically deformable member is configured to resume its original shape or orientation (e.g., be at least partially self-reversible) when the force or moment is removed or reduced.

In some embodiments, as shown schematically in FIG. 40B, a gap or space 1115 exists between the insert or other member 1114 and the outer jacket or cover 1116. In one configuration, the gap does not contain any material. However, in some configurations, one or more intermediate layers or members (not shown in FIG. 40B) are located in the gap or space 1115. In other configurations, the insert or other member 1114 is configured to at least partially contact the outer jacket or cover 1116, as desired or needed. Thus, in some embodiments, no gap or space exists between the insert 1114 and the outer jacket 1116.

For any embodiment disclosed herein, the shapeable lead assembly 1100 may be configured to include no lumens or other internal openings. However, for any embodiment disclosed herein, the shapeable lead assembly 1100 may be configured to include one or more lumens or other openings. In some embodiments, the shapeable lead assembly 1100 does not include a shapeable tube and/or other at least partially hollow (e.g., non-solid) member. In some embodiments, the lead assembly 1100 includes at least one insert or internal member 1114 that at least partially assists in bending the assembly and maintains the shape of the assembly 1100 after it has been shaped or otherwise manipulated.

With respect to any of the embodiments disclosed herein, the lead assembly 1100 can be configured to be shaped and/or reshaped during a therapeutic procedure (e.g., a nerve regeneration procedure). A practitioner or other user can reshape or reshape the insert after the procedure has begun. For example, the configuration of any of the lead assemblies 1100 disclosed herein can allow a practitioner to change the shape, direction, orientation, etc. of the assembly after the assembly 1100 has been inserted into a subject. In some embodiments, for example, the practitioner can manipulate the assembly 1100 to shape or reshape it to conform to the subject's anatomy (e.g., to contact or be in a desired orientation relative to a nerve, to wrap at least partially around a nerve, or to abut, secure, and/or otherwise approximate another anatomical feature of the subject, etc.).

Manipulation can be achieved by selectively applying force, pressure, moment, and/or any other external influence to one or more portions of the lead assembly 1100. In some embodiments, as described herein, such force or other external influence can be performed manually (e.g., with the hands of a practitioner) using forceps and/or other instruments or tools, and/or robotically, as desired or required.

In some configurations, the insert 1114 can be coupled to a wire or other conductor that is coupled to the conductive element. In other embodiments, the insert 1114 can be coupled to the conductive element at one end and to a wire or other conductor at the other end that is coupled to a connector. Such materials can include various types of metals and/or alloys, such as, but not limited to, copper, silver-coated copper, polyimide-coated copper, platinum-coated tungsten, stainless steel, lead, tin, etc. In some configurations, the metals can be annealed to soften their structure, allowing them to be shaped with less force than before annealing. In some configurations, the metal can be incorporated into the distal aspect of the electrode lead as an insert, which can have a rod- or cylindrical structure. The length of the insert need not be limited to the distal aspect. For example, in some embodiments, the insert spans the entire length of the electrode lead or a majority of the entire length of the electrode lead (e.g., 50-60, 60-70, 70-80, 80-90-90-100, 50-75, 5-90, 60-90% of the length of the electrode lead, percentages between these ranges and values, etc.), as desired or needed.

In some embodiments, the insert can be coupled (e.g., directly, indirectly, etc.) to the conductive element. The insert can be coupled to the conductive element using any suitable technique or method, including, for example, resistance welding, laser welding, soldering, crimping, and/or other techniques/methods used to bond metals to each other.

In some embodiments, the lead housing or jacket may comprise one or more elastic or semi-elastic materials (PEBAX™, Pellethane™, etc.), such as, for example, silicone rubber (e.g., silicone rubber tubing), polyurethane, other polymeric materials, other types of elastomers or rubber materials, other flexible or semi-flexible materials, etc.

In some embodiments, the insert 1114 is configured to undergo deformation (e.g., plastic deformation) when a force is applied to reshape the electrode lead body 1100. In some instances, the jacket 1116 may also undergo similar deformation (e.g., plastic deformation) as a result of the application of such a force. In some embodiments, the jacket may undergo elastic deformation. In such cases, the elastic recoil force of the jacket may be insufficient to overcome the plastic deformation of the insert, and as a result, the electrode lead maintains its shape. In some configurations, the desired shape is maintained until another force is applied that reshapes the lead, such as a force resulting from manual manipulation or the act of removing the lead.

In some embodiments, the lead housing or jacket 1116 can have a uniform or continuous material thickness throughout the length of the lead body 1100. In some embodiments, the jacket can include multiple durometers. For example, as shown in FIG. 41 , a lower durometer material can be used in the distal, shapeable portion 1102 of the lead, while a higher durometer can be used in the proximal portion 1104 (which can be advantageous, for example, in pushing and advancing the lead into tissue). While such an example outlines two segments with two durometers, the lead is not necessarily limited to two durometers and can include multiple segments with varying durometers within or between segments.

Under certain circumstances, the durometer of the distal aspect of the lead may be 20D to 50D on the Shore D scale (e.g., 20D, 25D, 30D, 35D, 40D, 45D, 50D, 20D to 50D, 25D to 45D, 30D to 40D, 20D to 40D, 30D to 50D, values and ranges between these values and ranges, etc.), while the durometer of the proximal aspect may be 50D to 80D on the Shore D scale (e.g., 50D, 55D, 60D, 65D, 70D, 75D, 80D, 50D to 80D, 55D to 75D, 60D to 70D, 50D to 70D, 60D to 80D, values and ranges between these values and ranges, etc.). Thus, in some embodiments, as described herein, the hardness, and therefore the corresponding durometer, of the proximal aspect of the lead can be greater than the hardness, and therefore the corresponding durometer, of the distal aspect of the lead, as desired or needed.

While durometer is one parameter that may affect (e.g., significantly, under certain circumstances) the formability, functionality, and/or other aspects of a formable lead assembly, one or more other properties, such as, for example, material/component wall thickness, may also be influential (e.g., may be important).

In some embodiments, a relatively thick outer jacket and/or other covering may require a relatively large force to shape the lead assembly. Consideration must be given to the fact that, for example, such force must also be sufficient to shape an insert disposed inside the jacket and/or other covering.

By way of example, under certain embodiments, a wall thickness of the lead assembly jacket or other outer covering between 100 and 400 μm can allow for adequate flexibility of the entire lead assembly (e.g., to allow a practitioner or other user to force the lead assembly into a desired or required shape). Thus, in some configurations, the wall thickness of the lead assembly jacket or other outer covering should be between 100 and 400 μm (e.g., 100-150, 150-200, 100-200, 100-300, 200-300, 150-300, 100-400, 100-500, 200-400, 200-500, 300-500, 400-500 μm, values between these ranges, etc.), as desired or needed.

Additionally, the relationship of the wall thickness of the jacket or other outer covering to the diameter (or other cross-sectional dimension) of the corresponding insert can also affect the shapeability and/or other aspects of the function of the lead assembly. For example, in some embodiments, the diameter or other cross-sectional dimension of the insert is equal to or greater than the wall thickness of the jacket or other outer covering of the lead assembly. For example, the diameter or other cross-sectional dimension of the insert is 100% to 500% (e.g., 100-500, 200-400, 100-400, 200-500, 300-500, 150-200, 100-150, 100-200, 200-300, 400-500%, percentages between these ranges, etc.) of the thickness of the jacket or other outer covering.

Under certain circumstances, the thickness of the jacket or other outer covering may be greater than the diameter or other cross-sectional diameter of the insert, and the lead assembly may still achieve the desired or required formability. However, in some embodiments, this may only occur if the jacket material is relatively soft and flexible. Therefore, under these conditions, the pushability of the electrode lead may be adversely reduced, potentially leading to the undesirable effect of tangling.

In some embodiments, a balance can be struck between a combination of jacket durometer, jacket wall thickness, and insert diameter (assuming a cylindrical structure) to achieve the desired properties of the shapeable electrode lead.

In some embodiments, the shapeable component of the electrode lead can be constructed, at least in part, from and/or with coiled wire. In some configurations, the coiled wire spans the entire length of the lead. In other configurations, the coiled wire spans only a portion of the length of the lead. For example, the coiled wire can span only a first length or portion of the lead (e.g., the first 10 cm or less, e.g., 0-10, 2-8, 1-5, 5-10 cm, lengths between these ranges, etc.). However, the extent of the coiled wire need not be limited to these distances (e.g., it can be greater than 10 cm, as desired or needed). In some embodiments, the coiled wire physically couples (e.g., directly or indirectly) to the electrode. In other embodiments, the coiled wire is not electrically coupled to any stimulating electrode. In some embodiments, the coiled wire is located at the distal end of the lead housing and functions as an electrical connector to other circuitry located along or near the distal end. Depending on the application, the required flexibility and memory characteristics, and/or other design considerations, the spacing between adjacent coils may be zero (e.g., the coils touch each other) or a fixed distance. In some embodiments, the coiled wire may be insulated or uninsulated. In some configurations, the coiled wire is at least partially encased in and/or wrapped by a flexible jacket or other covering, as described above. In some embodiments, the coiled wire acts as an electromagnetic shield, providing at least partial noise immunity to the wire or circuitry contained therein.

In some embodiments, a multi-lumen extrusion or other design can be used for the lead housing 1118, as shown in FIG. 42A. Thus, in such embodiments, the lead housing can include two or more lumens extending (e.g., partially, completely) through the lead housing. In some examples, as shown in FIG. 42B, one lumen 1120 can be used to house or otherwise accommodate (e.g., slidably, permanently, temporarily, etc.) the insert 1114, while the other lumen can accommodate wires or other conductors 1122 leading to the conductive elements. In other configurations, the lumens can be configured to accommodate (e.g., replaceable) a stylet to reshape or reposition the distal aspect and/or other portions of the lead housing (e.g., in a perioperative setting).

In some embodiments, the proximal (and/or other) aspects of the lead can have properties that allow it to be highly flexible. In some embodiments, such flexibility is greater than adjacent or other portions of the lead. In some instances, flexibility of one or more portions or aspects of the lead is created using silicone tubing or other soft polymeric/elastomeric materials. Flexibility of the proximal portion or aspects of the lead assembly can be advantageous or beneficial in external fixation situations, where the length of the electrode lead that is external to the body is loosely coiled (e.g., to provide strain relief). Coiling the flexible tubing can result in smaller recoil forces. High recoil forces can lead to undesirable electrode lead dislodgement.

In some embodiments, flexibility of the proximal portion or aspect of the lead assembly is advantageous or beneficial. For example, such a design can help prevent or reduce force transmission to the distal portion or aspect that contacts, is in proximity to, and/or otherwise interfaces with the target nerve. In one example, movement of the flexible aspect of the lead does not result in a corresponding displacement of the distal aspect. This may be primarily due to the different properties of the proximal and distal aspects, such as when the distal aspect includes a shapeable insert. In some embodiments, it is advantageous for the distal tip to not deflect (and/or to have limited deflection) when a force is applied proximally, because tip deflection could hinder the effectiveness of nerve regeneration therapy because the electrode may no longer interface with the nerve.

In some embodiments, as shown in FIG. 43, the distal aspect can include one or more dimples, grooves, recesses, and/or other features 1124 (e.g., to facilitate grasping of the lead with forceps and/or other tools). In some configurations, the dimples or grooves 1124 span the circumference (or other outer extent) of the cylindrical lead. In other configurations, the dimples or grooves 1124 can only partially cover the circumference or other outer extent (e.g., half of the circumference).

In some embodiments, the jackets 1116 at the distal and proximal ends may be different colors. In some configurations, the distal end can have regions of different colors. The colors can indicate different segments (e.g., shapeable or non-shapeable aspects) or can indicate specific lengths, which can be useful in positioning the lead. In some embodiments, line segments corresponding to unit scale can be printed on the lead to serve as a ruler.

In some embodiments, the proximal portion or aspect 1104 of the electrode lead assembly can terminate in a connector. Such a connector can be a standard medical connector (e.g., manufactured by Redel, Lemu, ODU, etc.). However, the connector can be non-standard (e.g., customized) as desired or needed.

In another configuration, shown in FIG. 44A, the connector may include one or more concentric rings 1126 that are electrically conductive. The rings may be configured to completely or partially wrap or otherwise surround the outer circumference of the lead. In some embodiments, ring contacts are more advantageous than standard medical connectors. The benefits of using such contacts may be emphasized when using an inserter (e.g., an over-needle catheter) to percutaneously place the electrode lead within a subject. The ring contacts may allow for straightforward removal of the inserter 1128 by sliding the lumen of the inserter 1128 down the entire length of the lead body and removing it past the proximal aspect of the lead 1104, as shown in FIG. 44B. With a standard medical connector, the device may not need to be removed (e.g., it may need to remain in the lead assembly). In such embodiments, the use of a peelable (or otherwise separable) catheter can overcome this obstacle, but at the expense of increased overall complexity, cost, etc.

In some embodiments, as shown in FIG. 44C, the spaces between the proximal concentric ring contacts that do not span the entire circumference of the cylindrical lead can include grooves or other recesses or features 1130. Such grooves 1130 can be used as a key for inserting the lead into the stimulus generator unit.

In some embodiments, an electrode lead body 1100 having multiple conductive elements 1108 (e.g., as described herein) can be advantageously used to measure action potentials. In one example, a multi-element electrode lead is placed near the injured nerve. In some configurations, the electrode can be shaped to follow the nerve's path in the anatomy. The proximal conductive element can be configured to measure an evoked response in the injured nerve in response to a stimulus from the distal conductive element. In some configurations, such an "upstream" measurement is used (alone or in conjunction with some other measurement or reference) to confirm a validation condition. In some configurations, the recording electrode configuration comprises a monopolar, bipolar, tripolar, or other configuration, as desired or required by the particular design or application. In some embodiments, the distal conductive tip is configured to generate a monopolar electric field in combination with a distal reference electrode. In some configurations, the distal reference electrode is a surface patch electrode (or some other type of surface electrode) with integrated electronics. In yet another embodiment, the distal conductive tip with other conductive elements 1108 is configured to generate a bipolar electric field. In some embodiments, three or more conductive elements (e.g., three, four, five, six, or more, etc.) are used to more precisely steer or otherwise direct the electrical current to target the injured nerve, specific fiber bundles within the injured nerve, and/or other body structures of the subject. The elements may be arranged as circumferential elements (e.g., ring electrodes), segmented elements (e.g., partial ring electrodes), or other shapes. In some embodiments, multiple conductive elements are used to provide electrical stimulation to the target nerve and/or measure bioelectrical signals from the subject at various locations along the length of the target nerve.

In some embodiments, as shown in FIG. 45, the distal end of the electrode lead can include an indicator. Such an indicator can be located along any other portion of the lead in addition to, or instead of, the distal end. In some configurations, the indicator can comprise an LED 1136. In one example, the LED can be used to indicate a validation condition (e.g., successful action potential capture by the proximal electrode conductive element). Because the surgeon's visual attention is directed to the nerve repair site or electrode interface area, it can be advantageous to incorporate the indicator into the surgical field, while the stimulus generator can be located just outside of this field of view. Without distracting the surgeon, the surgeon can manipulate (e.g., move and/or shape) the lead and the indicator can inform the surgeon that a validation condition has been confirmed.

While nerve regeneration therapy has not been shown to be a long-term treatment, it may be advantageous to maintain electrodes in proximity to an injured nerve to provide treatments other than nerve regeneration therapy. Such treatments may include, for example, pain management therapy, which traditionally remains a long-term treatment. Transcutaneous electrical stimulation may be used to provide pain management therapy. Typically, such long-term stimulation frameworks require greater fixation of the neural interface. In the embodiments disclosed herein, a shapeable aspect (e.g., distal aspect) may be utilized to at least partially surround the nerve for long-term neural interfacing, such as in the context of pain management therapy.

Long-Term Implantation In some embodiments, it may be advantageous to be able to apply a bioadhesive for long-term or permanent implantation. Long-term or permanent implantation may be defined as greater than 30 days, after which time frame a chronic inflammatory and foreign body response typically occurs, as defined by ISO 10993-1. The adhesive material may serve as an interface for securing or anchoring the electrode lead body and/or conductive element to the nerve, while maintaining conformable conformance to the surrounding anatomy due to the conformability of the electrode lead as previously described herein.

In some embodiments, the tissue adhesive comprises a biomaterial having some, any, or all of the following properties: at least partially biodegradable, at least partially bioerodible, at least partially bioabsorbable, at least partially biocompatible, at least partially bioinert, etc. The biomaterial can comprise a single material or can comprise two or more materials, for example, but not limited to, polymers, elastomers, composites, particles, molecules, layered materials, gels, etc. In some embodiments, the polymer can be synthetic, natural, hybrid, chemically modified, or the like, as desired or required. Synthetic polymers can include, but are not limited to, polyethylene glycol (PEG), poly(N-isopropylacrylamide) (poly(NIPAAm)), polylactic-co-glycolic acid (PLGA), polyurethane (PU), etc. Natural polymers can include, but are not limited to, fibrin, collagen, gelatin, derivatives thereof, etc. Chemical modifications of the polymer can include, but are not limited to, the attachment, inclusion, or presence of bioadhesive functional groups, such as catecholamines. For example, a bioinspired bioadhesive component is L-3,4-dihydroxyphenylalanine (DOPA), which achieves excellent adhesive properties primarily due to the presence of catechol functional groups.

In some embodiments, the bioadhesive may be tunable or otherwise modifiable, and may reside within the body and function as an adhesive for a controlled or predetermined period of time. Tuning of the bioadhesive to achieve a desired property or response may be a function of its chemical, material, and/or physical properties, or a function of an externally applied stimulus. As used herein, tunability or modifiability of the bioadhesive refers to the design and/or control of any one or more of the aforementioned factors to achieve a desired property or response, such as, but not limited to, biodegradation rate, release profile of a bioactive molecule or substance, adhesive strength, mechanical properties (e.g., shear, compressive, and/or tensile modulus), or response to an external stimulus.

In some embodiments, the bioadhesive may degrade within an acute or relatively short period of time (e.g., less than 30 minutes, 30 minutes to 1 hour, 1 to 6 hours, 6 to 12 hours, 12 to 24 hours, 1 to 30 days, any value between these values or ranges, etc.). As used herein, such acute periods are based on the period typically accepted for acute human implants as defined by ISO 10993-1.

In some configurations, degradation of the bioadhesive during the acute period can be advantageous for applying nerve regeneration therapy, for example, because the bioadhesive secures the lead to the nerve at the beginning of treatment. This can help prevent migration of the lead assembly and ensure optimal or more favorable contact during stimulation. Furthermore, degradation of the bioadhesive during treatment can allow for easy removal of the lead after treatment with little or no resistance from the bioadhesive.

In some embodiments, the bioadhesive can be tailored or otherwise configured to degrade over a longer period of time (e.g., 30-40 days, 40-50 days, 50-60 days, 60-70 days, 70-80 days, 80-90 days, 90-100 days, 100-120 days, more than 120 days, periods in between these ranges, etc.). This may be advantageous in situations requiring long-term implantation of a lead for purposes of nerve regeneration therapy and/or pain management. In such situations, it may be advantageous or desirable to design the implanted material to modulate this host response. Such design considerations may include, but are not limited to, biocompatibility, bioresorbability, use of bioinert materials, delivery of anti-inflammatory or immunosuppressive agents, etc.

Fixation Using Glues or Other Adhesives In some embodiments, the bioadhesive is in the form of a bulk gel or other gel or gel-like material (e.g., hydrogel, glue, other adhesive, other polymeric material, etc.). The gel may be preformed (e.g., prior to implantation), configured to form in situ, or a combination of both. In some configurations, a preformed gel can be applied directly to the target body structure site and/or the surface of the electrode lead (e.g., to achieve adhesion between the lead and the tissue surface) before or during lead implantation. In some embodiments, a preformed bulk gel does not require mixing before application. Such a configuration can function (e.g., instantly, rapidly, etc.) as an adhesive upon contact with the target surface. Such preformed bulk gels can include, but are not limited to, existing commercially available materials (e.g., Dermabond™, Indermil®, Liquidband®, etc.), custom materials, or hybrids thereof.

In some embodiments, the bioadhesive is formed and/or mixed at the time of application. As used herein, in situ formation refers to chemical and/or physical reactions that occur to result in the formation of the final bioadhesive. Chemical or physical mechanisms that cause this to occur include, but are not limited to, interfacial bonding, covalent or ionic bonding, crosslinking (e.g., chemical, physical, enzymatic, photochemical), photopolymerization, thermal curing (e.g., thermosetting), oxidation, etc. In some embodiments, such reactions can be initiated by physical mixing of the components and/or application of an external stimulus. Additional initiation mechanisms can be used instead of or in addition to those set forth in the preceding sentence. In some embodiments, the in situ formed bioadhesive can be an existing commercially available tissue glue or adhesive (e.g., fibrin-based gels such as Tisseel™, PEG-based gels such as Coseal™, etc.), a custom material, or a hybrid thereof.

In other embodiments, the bioadhesive comprises a coating or film on the surface of the electrode lead (e.g., in the form of a coating or film). The coating/film can incorporate or otherwise include physical features (e.g., roughened surface topography, micropatterning, etc.) to promote adhesion of the bioadhesive (e.g., as a primary feature, a complementary feature, etc.). In some embodiments, the adhesive function of the coating/film can be activated before, during, or after implantation of the device. In some embodiments, the bioadhesive is already functional. In some embodiments, activation requires removal of a protective layer that prevents adhesion before application. In some embodiments, the coating/film is adhesive due to uniquely designed chemical and/or physical properties. Such properties can include, but are not limited to, topographical patterns or depressions, surface charge (anionic, cationic, etc.), etc. In some embodiments, the bioadhesive coating can function or activate upon contact of the adhesive with the target surface (e.g., immediately, after a period of time, etc.). In other configurations, the adhesive function is activated by the application of an external stimulus. The stimulus may include, but is not limited to, one or more of the following: electricity or other electrical stimuli, thermal energy, light energy, chemicals, pressure, acoustic energy, other types of energy, etc.

In some embodiments, the fixation of the electrode lead body 1100 may employ or use a form of bioadhesive or other adhesive tape 1300. In some configurations, the tape is included in the electrode lead assembly. In such configurations, it may be advantageous to use a separate device and/or actuator to release or deploy the bioadhesive tape anchor. The bioadhesive tape may include one or more wings/flaps attached to the tip of the lead and configured to unfold or otherwise release in response to a designated control. For example, once the lead assembly is positioned at a desired anatomical location (e.g., on or adjacent to a peripheral nerve, proximal to the site of injury and/or repair), a designated button or other controller on the control system may be actuated (e.g., pressed) to deploy or release the bioadhesive tape at the distal tip of the lead. In some embodiments, the bioadhesive tape may be configured to move (e.g., curl inward toward the lead and flush with the edge of the lead to prevent snagging on tissue during lead placement) prior to deployment. After deployment, the bioadhesive tape can release (e.g., unfold) and conform (e.g., immediately, near-instantly) to the surrounding body structure, adhering the lead to the surrounding body structure. In other configurations, the tape is a separate device that is applied before, during, and/or after implantation of the device.

In some configurations, the tape 1300 is wrapped partially or completely around a portion of a circular or cylindrical body structure in a semicircular or circumferential manner, or interfaces the electrode lead to the portion of the body structure via adhesive features on both sides of the tape. In one example, as shown in FIG. 46A, the tape 1300 can be used to secure the electrode lead body 1100 to the neural structure 1110 by placing the tape 1300 proximal to the conductive elements 1108. In yet another example, shown in FIG. 46B, the tape 1300 can be placed between the conductive elements 1108.

In some configurations, fixation of the lead to a portion of the body structure is achieved with one or more (two, three, etc.) bioadhesive tapes. In some embodiments, the tapes are rectangular, circular, cylindrical, oval, or any other shape.

In some embodiments, the tape is relatively thin (e.g., 1-10 μm, 10-50 μm, 50-100 μm, less than 1 mm, 1-9 mm, any value between these ranges or values, etc.) or relatively thick (e.g., 9-10 mm, 10-15 mm, greater than 15 mm, etc.).

In some embodiments, the tape can have a controlled, tunable biodegradation profile to degrade within a desired time frame to facilitate easy removal of the lead from a portion of the body structure.

In other embodiments, the lead anchor tape may be instantly disabled by device control. In such embodiments, the tape may remain attached to the lead upon removal, but may have materials or physical properties that allow for smooth removal of the lead and bioadhesive through the paraincision site. In other embodiments, the control may result in the tape being expelled from the lead prior to lead removal. In this case, it would be advantageous for the tape to remain in place in the body structure during and after lead removal, but be biocompatible and rapidly biodegradable (e.g., less than 1 hour, 1-2 hours, 2-4 hours, 4-6 hours, 6-12 hours, 12-24 hours, 1-30 days, any value between these values or ranges, etc.) so as not to provoke a negative immune response upon degradation.

Adhesive Delivery and Curing Methods In some embodiments, the bioadhesive comprises a premixed, preformed fluid solution configured to be delivered to the desired body structure site by injection and instantly function as an adhesive. One example can include the preformed bioadhesive being delivered from a reservoir built into or associated with the nerve regeneration stimulation system and flowing (or otherwise provided) through a cannula or other opening (e.g., a lumen) incorporated into or otherwise contained in the corresponding lead. In other situations where the preformed bioadhesive is an existing commercially available product, the bioadhesive solution can be applied to the desired body structure site before and/or immediately after attachment or at least partial fixation of at least a portion of the lead to and/or near the site.

In other embodiments, the bioadhesive is formed and/or functionally activated in situ. In some configurations, in situ formation occurs through physical and/or chemical crosslinking by mixing (e.g., at least partially in situ) two or more compatible polymer precursor solutions. In some configurations, a multi-barrel syringe or extrusion device is built into (or otherwise included in) the stimulation system or is external to (i.e., not included in) the stimulation system. Such a syringe or other delivery device can be configured to separate (e.g., at least partially, completely, etc.) the precursors (or other materials to be combined) so that crosslinking does not occur until use. In some configurations, mixing and crosslinking occurs proximal to the application site. In other configurations, mixing and crosslinking occurs directly at the application site. Two or more (e.g., three, four, five, six, or more, etc.) materials may be configured to be mixed or combined at least partially in situ.

In some configurations, for any embodiment disclosed herein, the lead assembly includes a single lumen or other opening for facilitating the flow of materials and/or other substances (e.g., a single fluid or other solution, two or more fluids or solutions, etc.) to or near the distal tip and the delivery site. In other configurations, multiple lumens, cannulas, and/or other openings are included in the lead assembly to allow for the delivery of separate solutions, fluids, and/or materials to or near the distal tip and at or near the intended delivery site.

In some embodiments, a separate device is used to mix materials or other substances (e.g., precursors) to form crosslinks, and the mixed material is then extruded and applied directly to or near the desired site. The mixed material may be in a fully crosslinked form or partially crosslinked at the time of extrusion. In some embodiments, full crosslinking may be desired to achieve rapid gelation or otherwise rapidly activate the bioadhesive. In other embodiments, it may be advantageous to extrude a partially crosslinked material to allow for a slower gelation time and activate the bioadhesive at a slower rate.

In some embodiments, the bioadhesive solution is applied to a cuff-like device that can function as a local chamber mechanism to at least partially contain the bioadhesive along, adjacent to, and/or near the nerve. The cuff-like device can be configured to function as a mold that allows only a thin layer of bioadhesive to be extruded onto the nerve or encased structure. Such applications are advantageous because delivery of bulk hydrogel can compress the nerve and potentially cause nerve injury. Additionally, such applications can be advantageous because use of the cuff-like device can aid in the separation (e.g., complete, partial, etc.) of the adhesive from the surrounding tissue.

In some configurations, it may be convenient to extrude a prefilled precursor solution from a double-barrel syringe or other delivery device with a mixing tip directly onto a site in the body structure and then adhere a lead to that site. For example, Tisseel™, a widely used commercially available surgical tissue adhesive, can be used to secure a lead to a nerve during long-term nerve regeneration therapy applications because it maintains its adhesive activity and biodegrades within 14 days. It consists of a fibrinogen and thrombin precursor solution that crosslinks to form fibrin (a bioadhesive) upon mixing. It is packaged in a double-barrel syringe system that separately houses the two precursors. As the syringe is extruded, the precursors enter a mixing chamber at the tip of the syringe, where they undergo a chemical reaction that crosslinks the precursors upon contact, resulting in the formation of the fibrin bioadhesive. In some situations, Tisseel™ may be extruded through a cannula within the body of the lead using an adapter. In other situations, Tisseel™ may be applied to the tip of the lead and/or to the surface of a portion of the body structure prior to lead placement to secure the lead to the nerve for treatment.

In one embodiment, the bioadhesive is photocurable and configured to be activated (e.g., photoactivated) by irradiation with light (e.g., light of a particular wavelength and/or other characteristics). An unactivated bioadhesive can be applied to a desired site (e.g., on tissue, on the surface of an electrode lead, a combination thereof, etc.). In some embodiments, once the lead assembly is positioned at a desired location, light can be applied (e.g., for a desired or required period of time) to cure and activate the bioadhesive, ensuring sufficient at least partial fixation of the electrode lead at the desired location. In some embodiments, the bioadhesive is also photodegradable, and the degradation of the material is controlled by irradiation with light of a wavelength (e.g., a wavelength different from that required to cure the adhesive).

In some situations, it may be advantageous for the bioadhesive to contain both photocurable and photodegradable moieties that instantly cure or degrade in response to the application of specific wavelengths. For example, the bioadhesive may include ortho-nitrobenzyl protecting functional groups that react to light in the visible spectrum (400-700 nm wavelength) and cure within seconds of exposure. This may be applied to adhere (e.g., immediately, quickly, within a specific period, etc.) an electrode lead to a proximal nerve segment prior to electrical stimulation treatment. Additionally, the bioadhesive may include di-ortho-nitrobenzaldehyde moieties that are reactive to UV light (10-400 nm) and are configured to degrade (e.g., immediately, quickly, within a specific period, etc.) upon exposure to UV light, allowing for easy lead removal and detachment from the nerve after treatment.

According to some embodiments, as shown in FIG. 47, the bioadhesive delivery device 1310 and light source 1312 may be included as part of a kit, e.g., as individual devices separate from the stimulation system. The bioadhesive delivery device may include a reservoir, opening, and/or other chamber 1314 pre-loaded with bioadhesive that is extruded at a controlled rate through a nozzle 1316 (e.g., syringe dispenser) or using a plunger 1317. The light source may include a power source, a light source, a transmission mechanism (e.g., a bulb, fiber optic cable, etc.), a control 1318 (e.g., a button or switch) for turning on/off or changing the type of light, and/or any other components or features, as desired or required.

In some embodiments, the light source is included in a handheld device or wand 1312 whose tip and/or other portions are configured to emit light. In some configurations, it may be advantageous to transmit the light through the tip of the device to focus the light energy at one location to illuminate a small, localized area of the bioadhesive.

In other situations, particularly when a larger surface area of the bioadhesive needs to be irradiated at one time, it may be advantageous to configure the device to transmit light when at least a portion of the device (e.g., a portion of the device, the entire device, etc.) is held horizontally (or at some other orientation relative to a reference point or surface).

In another embodiment, the light-responsive bioadhesive applicator and light source comprise a single device separate from the stimulation system (or are included in a single device separate from the stimulation system). In one configuration, the device is a handheld tool comprising a bioadhesive reservoir, a power source, a light source, and a transmission mechanism, configured to control or regulate at least one aspect of the delivery of the bioadhesive (e.g., an automatic button dispenser, a manual plunger, etc.), and configured to control or regulate the transmission of light.

According to some configurations, as shown in FIG. 48A, the bioadhesive delivery nozzle tip 1320 includes one or more light sources 1322 (e.g., LEDs). Such light sources 1322 may be configured to be controlled by one or more controllers (e.g., buttons, switches, dials, etc.) on the body of the device, and may be configured to transmit or otherwise provide a desired type of light (e.g., UV or visible light).

In some configurations, it may be advantageous to transmit or otherwise provide light when at least a portion of the axis of the device is held in a particular orientation (e.g., horizontal), as shown in FIG. 48B. In some embodiments, such a configuration may be desirable when a larger surface area of bioadhesive must be irradiated at one time. Bioadhesive delivery controls may allow the user to deliver a certain amount (e.g., a preset amount, a customizable amount, etc.) of adhesive (e.g., up to a maximum reservoir limit).

In some embodiments, as shown in FIG. 48C , the dispenser can be configured to dispense a curable bioadhesive 1330 that can be used to secure the distal aspect of the electrode lead body 1100 or electrode 1102 to the neural structure 1110. The dispenser can also be configured to cure such bioadhesive. The device can include an indicator (e.g., a visual indicator, another type of indicator, etc.), such as, for example, but not limited to, a sensor output to a display (e.g., an LCD screen, other display, other output, etc.). Such a display can be configured to display various information, as desired or needed, such as, but not limited to, a selected or preset amount of bioadhesive to be dispensed, the amount of bioadhesive remaining in the reservoir, etc. Additionally, the visual indicator can be configured to provide additional information, such as, for example, information regarding the light source (e.g., whether the light source is on or off), information regarding the wavelength of light being or to be transmitted, information regarding the duration of irradiation (e.g., elapsed time, time remaining, etc.), etc. In some embodiments, the bioadhesive itself is configured to change color to signal adequate curing (e.g., in real time, after another condition is met, etc.).

In some embodiments, the bioadhesive solution is applied to a cuff-like device that can act as a local chamber mechanism to strategically contain the bioadhesive near or along the nerve (or elsewhere relative to the nerve). The cuff-like device can be configured to function as a mold that allows for the extrusion of only thin, patterned, or multi-patterned layers of bioadhesive onto the nerve or wrapped structure. Additionally, the device may further comprise a light source and/or light diffusing element directed internally at the wrapped structure and utilized to cure the polymer.

In some configurations, it may be advantageous to pre-program the light-responsive bioadhesive applicator and light source system. For example, the system may be operated by one or more preset controls (e.g., built-in or integrated controls) in the following manner to secure the lead tip to the nerve: (1) operate a button or other controller that is pressed or otherwise configured to apply a quantity of bioadhesive (e.g., a controlled amount, a constant flow rate, direct, indirect, uniform, non-uniform, etc.) at or near the surface of the nerve, (2) place or otherwise position the lead on the surface of the nerve, with the bioadhesive as the interface between the two surfaces, and (3) press or otherwise activate another button or other controller to activate one or more light sources (e.g., for a preset, predetermined, or fixed duration (e.g., 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 5-10 minutes, values between these ranges, more than 10 minutes, etc.)). Such a duration may be selected based at least in part on the time required for light curing and activation of the bioadhesive. In some embodiments, the bioadhesive passively biodegrades over a controlled period of time, allowing for easy detachment and removal of the lead at the end of the biodegradation period, hi other embodiments, the bioadhesive degrades instantly or rapidly upon irradiation with light of a wavelength different from that required for curing.

In some embodiments, the bioadhesive application system and light source are integrated or otherwise incorporated into the stimulation system and/or lead. In one configuration, a bioadhesive solution reservoir may be housed within the stimulation unit. In other configurations, the reservoir may be an external component (e.g., not integrated into or part of the stimulation and/or lead assembly), as desired or required. In one configuration, the bioadhesive is a solution extruded or otherwise disposed (e.g., at least partially) through the body of the lead assembly in one or more housed channels, reservoirs, and/or other portions. In some embodiments, the bioadhesive is configured to exit at or near the tip or distal end of the lead assembly.

In one example, as shown in FIG. 49A, the bioadhesive solution is configured to exit near or from the distal portion of the electrode lead body 1102 (e.g., through one or more dedicated irrigation ports, holes, pores, openings, and/or other openings 1340). Such openings can be located at or near the distal end of the electrode lead body between the conductive elements 1108. In some embodiments, the bioadhesive may exit through one or more ports, holes, pores, openings, and/or other openings that may be located along the distal aspect or portion of the electrode lead body or assembly, the proximal aspect or portion, a location between the proximal and distal portions, a combination thereof, etc.

In some configurations, as shown in FIG. 49B, it may be advantageous for the bioadhesive to be configured to exit through multiple (e.g., two or more) openings 1340 located along or near the distal and/or proximal lead body to achieve uniform extrusion over the surface area surrounding the lead tip for optimal adhesion to the body structure. The lead assembly may include any arrangement of openings 1340 to allow delivery of the bioadhesive to specific areas of the lead assembly and/or the subject's body structure.

In another configuration, the bioadhesive comprises a coating or film located on the surface of the lead assembly. In some embodiments, such a coating or film extends from the tip to a predetermined length (e.g., the entire length of the lead, up to half the length of the lead, the distal quarter of the length of the lead, any other portion of the lead, etc.) and can be activated/deactivated by application of light (e.g., light of a specific wavelength) and/or any other activation source.

In some configurations, the light source may be located, at least in part, at and/or near the tip of the lead assembly and may be controlled by one or more controls (e.g., buttons or other controls located on the stimulation unit, another device, etc.).

According to some embodiments, the active light source includes one or more sets of light generators (e.g., one or more LEDs, one or more other light sources, etc.). In other configurations, the light source is contained (e.g., partially or completely) within the stimulation unit housing and/or transmitted through the body of the lead assembly (e.g., via a mechanism such as, for example, an optical fiber, other transmitter, etc.). In some configurations, at least a portion of the lead assembly is at least partially translucent or transparent to allow transmission of light through a dedicated portion or the entirety of the lead body.

In some embodiments, activation and/or deactivation of the bioadhesive is controlled by other external stimuli, including, but not limited to, thermal energy, electrical energy, photoacoustic energy, chemical and/or biochemical stimuli. In some embodiments, the bioadhesive is thermoresponsive or thermosensitive. In such configurations, the bioadhesive may be configured to be inactive in temperature ranges above/below normal physiological temperatures (e.g., ambient hospital storage temperatures), but to become active once exposed to temperatures within the normal physiological range.

In other embodiments, the bioadhesive is responsive to electrical energy stimulation. In some situations, the bioadhesive may be activated or deactivated in response to electrical stimulation of given parameters or within a specified range of parameters. These parameters may include, but are not limited to, differences in stimulation current, voltage, amplitude, pulse frequency, AC or DC, etc. In some configurations, activation of the bioadhesive can be configured to occur in response to electrical stimulation parameters that are the same (or substantially the same) or different from the electrical stimulation parameters of the nerve regeneration therapy. For example, after an electrode lead assembly is positioned at or near a portion of a body structure, with the bioadhesive as the interface between the two surfaces, a controller on the stimulation unit can be used to apply a desired dose (e.g., predetermined, fixed, variable, etc.) of electrical stimulation so that the bioadhesive cures and activates, attaching the lead to the body structure.

In some embodiments, the dose of electrical stimulation delivered to the bioadhesive is the same as, or approximately the same as, the dose used in the nerve regeneration therapy. In some embodiments, such a dose of stimulation is enabled at the beginning of treatment. In other embodiments, the dose for curing may be different from the dose used in the nerve regeneration therapy, e.g., stimulation at the same current output but a lower pulse frequency (e.g., less than 1 Hz, 1 Hz, 1-2 Hz, 2-3 Hz, 3-4 Hz, 4-5 Hz, 1-5 Hz, 5 Hz, 10 Hz, 15 Hz, 25 Hz, 5-10 Hz, 10-15 Hz, 15-20 Hz, 20-25 Hz, frequencies within and/or between these ranges, greater than 25 Hz, etc.). Such a frequency may be equal to, lower than, or higher than the frequency used in the nerve regeneration therapy.

According to some configurations, the bioadhesive is activated upon electrical stimulation. Such activation can occur immediately or at some point after activation of the electrical stimulation. In some configurations, various embodiments disclosed herein can have two stimulation phases: (1) a bioadhesive hardening stimulation phase and (2) a nerve regeneration therapy stimulation phase. In some embodiments, the hardening dose of electrical stimulation is applied over a relatively short period of time, such as less than 5 minutes (e.g., less than 30 seconds, 30 seconds, 1 minute, 2 minutes, 30 seconds to 1 minute, 1 to 2 minutes, 2 to 3 minutes, 3 to 5 minutes, ranges or values therebetween, etc.), to activate the bioadhesive. In other configurations, the hardening dose needs to be applied over a longer period of time (e.g., 5 minutes, 10 minutes, 5 to 10 minutes, more than 10 minutes, ranges or values therebetween, etc.). In some situations, it may be advantageous for the bioadhesive to be activated instantly or within a short period of time following electrical stimulation, so that the total surgical time is minimized or otherwise shortened.

In some configurations, the bioadhesive is activated by electrical stimulation and deactivated by passive biodegradation, allowing for easy removal of the lead assembly (e.g., after a biodegradation period). In certain circumstances, it may be advantageous to design the biodegradation period to be within the time period required for neural regeneration therapy. Thus, the biodegradation period may be equal to or longer than the duration of the neural regeneration therapy.

In some configurations, the bioadhesive is activated and deactivated by electrical stimulation. In such configurations, the application of electrical stimulation to deactivate the bioadhesive may be the same as or different from the application of electrical stimulation required for activation and/or nerve regeneration therapy. In one aspect, the bioadhesive may be activated with a specific curing dose of electrical stimulation, but may be deactivated when exposed to the nerve regeneration therapy electrical stimulation. In another aspect, the bioadhesive may be activated with a specific curing dose of electrical stimulation, remain active during the nerve regeneration therapy, and then be deactivated by applying electrical stimulation of different parameters than the curing dose and nerve regeneration therapy.

In some configurations, deactivation of the bioadhesive by electrical stimulation occurs instantly, or over a short or extended period of time. For example, it may be advantageous to apply electrical stimulation to deactivate the bioadhesive instantly after nerve regeneration therapy in an acute setting to minimize the total time for lead removal.

In some embodiments, the bioadhesive is responsive to photoacoustic and/or other acoustic energy. For example, an ultrasound system can be used in a multifunctional manner during surgery and/or perioperatively. In such a configuration, the ultrasound or other acoustic system can be configured to (1) guide a user in lead placement, (2) allow a user to visualize the lead assembly at least partially within a subject's body structure, (3) activate the bioadhesive, (4) deactivate the bioadhesive, and/or perform any other task. In some configurations, activation/deactivation of the bioadhesive may require the same or different photoacoustic energy parameters.

In some embodiments, the bioadhesive can respond to chemical and/or biochemical stimuli. In one aspect, the bioadhesive is pH-responsive and is activated by exposure to physiological pH (pH 7.4). In some aspects, the bioadhesive is pH-responsive and is activated/deactivated in response to the application of a solution having a pH above or below physiological conditions. For example, the bioadhesive may be placed as an interface between a portion of a body structure and an electrode lead and be activated only when an acidic or basic solution (pH<7.4 or pH>7.4) is applied to that area. Additionally, the bioadhesive may be deactivated by passive biodegradation or in response to a chemical change, such as the application of a solution having a pH different from that of normal physiological conditions.

In some embodiments, the bioadhesive is multifunctional, delivering therapeutic or non-therapeutic substances in response to chemical and/or biochemical stimuli (and/or other stimuli) in addition to securing the lead to a body structure. For example, following fixation of the lead to a nerve, the bioadhesive may be configured to respond when exposed to physiological pH levels and/or other physiological biochemical factors. In such circumstances, a nerve regeneration agent (e.g., nerve growth factor, glial-derived growth factor, tacrolimus, etc.) may be released or delivered at a rate (e.g., a controlled rate) to synergistically enhance and promote the regeneration of injured peripheral nerves in combination with electrical stimulation of nerve regeneration. Additionally or alternatively, the bioadhesive may be configured to release or deliver a pain-modulating agent (e.g., nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen, other medications, etc.) in combination with electrical stimulation of nerve regeneration. Examples of pH-responsive bioadhesives include, but are not limited to, oligo(methyl methacrylate)-grafted poly(acrylic acid), modified poly(ethylene glycol), modified poly(amino ester), and derivatives thereof.

Combination Systems In some embodiments, the bioadhesive is configured to be multifunctional, and configured to deliver bioactive and/or therapeutic molecules (e.g., in addition to maintaining specific adhesive properties and characteristics). Bioactive and/or therapeutic molecules that can be delivered by the bioadhesive include, but are not limited to, anti-inflammatory agents (e.g., ibuprofen, celecoxib, diclofenac, etc.), anesthetic agents (e.g., lidocaine), immunosuppressants (e.g., tacrolimus, cyclosporin A, rapamycin, etc.), antibacterial agents (e.g., ciprofloxacin), steroidal or hormonal agents (e.g., erythropoietin, melatonin, testosterone, estrogen, etc.), neuroactive agents (e.g., lithium, gabapentin, etc.), proteins and neurotrophins (e.g., brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, etc.), cells (e.g., stem cells, Schwann cells, macrophages, etc.), vitamins (e.g., vitamin B12, etc.), delivery vehicles (e.g., nano/microparticles, liposomes, micelles, precipitates, etc.), and the like.

In some configurations, the bioadhesive is tailored to deliver bioactive and/or therapeutic molecules within an optimal or desired time frame. In some configurations, such time frame depends, at least in part, on the molecule, the site of delivery, clearance rate, etc. Delivery may occur according to a regular or irregular frequency (e.g., a constant or non-constant rate), as desired or necessary, depending on the design of the biomaterial and the properties of the molecule or agent and/or one or more other factors or considerations.

In one example, the bioadhesive is used to at least partially secure an electrode lead to a surgically repaired nerve for 60 days or more (e.g., greater than 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300 days, any number of days in between, greater than one year, etc.). In such circumstances, the bioadhesive may be multifunctional and configured to release an immunosuppressant (e.g., cyclosporine A or tacrolimus) at a constant rate while the lead is secured to prevent or reduce the likelihood of severe inflammation or host immune rejection of the implanted lead, which could lead to premature lead removal, ineffective treatment, and pain or other negative or problematic physiological effects in the patient or other subject.

In some configurations, it may be advantageous to deliver a drug or drugs that achieve or otherwise produce a particular desired effect. In some embodiments, two or more desired effects are produced. For example, tacrolimus (also known as FK506, for example), a commercially available immunosuppressant, has also been shown to promote peripheral nerve regeneration in acute and chronic animal nerve injury models. Therefore, under certain circumstances, because the biological mechanism of tacrolimus nerve regeneration differs from that of nerve regeneration electrical stimulation therapy, providing both tacrolimus and electrical stimulation may act synergistically to optimize or otherwise improve peripheral nerve regeneration beyond what can be achieved by applying either individual method alone. Therefore, it may be advantageous to design the electrode lead bioadhesive to also be a therapeutic delivery device that delivers one or more therapeutic agents (e.g., tacrolimus) in a desired manner (e.g., in a controlled manner) to synergistically enhance or improve the nerve regeneration capacity of injured peripheral nerves. This can be done in addition to applying electrical stimulation therapy. Additionally, with the example of tacrolimus in mind, because tacrolimus is an immunosuppressant, delivery of this drug can also help alleviate chronic immune or foreign body responses to any implanted components.

In other aspects, the combination of nerve regeneration electrical stimulation and the delivery of a regeneration-promoting agent may be desirable under certain circumstances (e.g., to produce optimal or superior effects) (e.g., in relation to severe nerve injury models (e.g., chronic axotomy, plexus injury, gap nerve injury, etc.)). Current treatment strategies for gap nerve injury, which require the surgical placement of nerve grafts (e.g., autografts, xenografts, allografts, etc.) or nerve conduits, remain largely inadequate with regard to meaningful regeneration and functional recovery following injury.

Furthermore, some types of nerve grafts, often chosen because of their ease of access and the absence of a secondary surgical site, have also been reported to induce acute and/or chronic host inflammatory or immunogenic responses. In such cases, it may be advantageous or desirable to apply a multifactorial treatment strategy involving surgical nerve gap repair using grafts or conduits, nerve regeneration electrical stimulation, local delivery of anti-inflammatory and/or immunosuppressive agents, and/or application of other materials/treatments to promote regeneration and prevent or reduce the likelihood of graft rejection after nerve gap injury.

In some configurations, the nerve regeneration stimulation system can be implemented following surgical repair of the nerve gap. Leads can be inserted using a paraincision approach and secured in place with a multifunctional bioadhesive (e.g., by any of the techniques and methods described herein). In some embodiments, the bioadhesive can include an immunosuppressant, such as tacrolimus (FK506) or other immunosuppressant substances (e.g., cyclosporin A, rapamycin, etc.).

According to some embodiments, the bioadhesive can at least partially secure the lead to and/or near a location on the nerve (e.g., proximal to the repair site) and can also cover (e.g., completely, partially, etc.) the surface area of the corresponding nerve graft. The bioadhesive can function to anchor or otherwise secure the stimulation lead for the duration and course of nerve regenerative electrical stimulation treatment. In some embodiments, the bioadhesive can be configured to remain in place for treatment or for longer periods of time (e.g., 2 hours, 4 hours, 1-4 hours, less than 1 hour, 4-6 hours, 6-8 hours, 8-12 hours, 4-16 hours, 12-18 hours, 12-24 hours, 18-24 hours, 1-30 days, 30-60 days, 60-90 days, times within these ranges, more than 90 days, etc.) as desired or required for a particular application or use.

Regardless of the exact time frame, over a corresponding period of time, the bioadhesive can be configured to biodegrade and release a therapeutic agent (e.g., tacrolimus (FK506)) at a desired (e.g., controlled) rate. In some embodiments, such embodiments can be configured to provide local immunosuppression during the axonal regeneration and graft remodeling process. As noted above, in addition to being an immunosuppressant, tacrolimus (FK506) can also be a neurotrophic agent, for example. Thus, under certain circumstances, controlled local delivery of a substance (e.g., tacrolimus) in combination with nerve regeneration electrical stimulation therapy can not only prevent host rejection of the nerve graft and/or conduit, but can also synergistically promote axonal regrowth and promote nerve regeneration in gap nerve injury models (and/or produce some other beneficial effect or outcome) beyond what can be achieved with surgery alone.

In another example, the bioadhesive is multifunctional and also serves as a drug delivery system for the purpose of acute and/or chronic pain modulation. In some embodiments, the bioadhesive can function as a local delivery vehicle for pain suppressants or pain preventatives (e.g., anti-inflammatory agents, steroids, local anesthetics, etc.). This drug delivery system may act synergistically or separately with the pain-modulating electrical stimulation. The bioadhesive drug delivery system can be tailored to release the drug payload depending on the optimal therapeutic window. In some embodiments, it may be advantageous for the bioadhesive drug delivery system to rapidly deliver the drug while remaining adhesive and malleable during the lead implantation process.

In some embodiments, it may be advantageous for the bioadhesive drug delivery system to deliver the drug over a slower time course.

In some embodiments, the drug release profile may be continuous, discontinuous, or occur at designed intervals (e.g., pulsed drug delivery). For example, a patient with a peripheral nerve injury may undergo an electrical stimulation phase for nerve regeneration therapy and a second electrical stimulation phase for pain management therapy. A bioadhesive may be used to interface and secure an electrode lead proximal to the nerve injury site during the nerve regeneration therapy phase and throughout the pain modulation therapy phase. Additionally, the bioadhesive may be designed to release a localized dose of an anti-inflammatory and pain modulation agent, such as, but not limited to, ibuprofen, pregabalin, gabapentin, topiramate, or carbamazepine. The release profile of the pain modulation agent from the drug delivery system may be linear, releasing a constant dose and rate of pain modulation agent over time to provide the patient with pain relief during the recovery process, in addition to the pain modulation therapy phase provided by the electrical stimulation. The bioadhesive may be capable of passively degrading during either or both of the timeframes of nerve regeneration therapy or pain modulation therapy, so that at the time of lead removal, the lead is no longer attached to a body structure and can be easily removed.

In some embodiments, the bioadhesive is multifunctional and is composed of or includes a radiopaque element, allowing for image-guided visualization, placement, and/or removal of the radiopaque element or lead. Additionally, the radiopaque element may be an added safety feature for monitoring lead position and placement, particularly in the case of chronic lead implantation. In some configurations, the bioadhesive may include, completely or partially, a radiopaque element and/or a contrast agent, or may include a hybrid of a radiopaque element and/or a contrast agent. Such radiopaque elements may include, but are not limited to, radiopaque polymeric agents, radiopaque agents (e.g., acrylics, inorganic salts, and high atomic number elements such as bismuth, iodine, barium, etc.), contrast agent-eluting nano/microparticles, etc.

In some embodiments, the bioadhesive is conductive and/or piezoelectric. In some aspects, the bioadhesive can include a conductive or piezoelectric material (e.g., polypyrrole, polyaniline, polythiophene, etc.). In other aspects, the bioadhesive can be a composite material including conductive or piezoelectric elements such as, but not limited to, carbon nanotubes, graphene particles, gold nanoparticles, silver nanoparticles, etc. Conductive or piezoelectric material properties can be convenient or otherwise advantageous, for example, to act synergistically with electrical stimulation applied to nerves for nerve regeneration and/or pain modulation therapy, while allowing for more localized charge concentration in the target anatomic region.

In other embodiments, various therapeutic substances can be delivered via the electrode lead body to various locations along a trajectory near or on the damaged nerve of interest. Such substances can act by other mechanisms, act synergistically with nerve regeneration therapy, and/or act to minimize pain and local inflammation, among other things.

In some embodiments, the neural treatment kit includes two or more of a bioadhesive, an electrode lead having at least one electrode, a stimulation system, an insertion tool, and a user manual. In one configuration, the kit can be deployed intraoperatively during or before treatment of a neural injury.

While several embodiments and examples are disclosed herein, the present application extends beyond the specifically disclosed embodiments to alternative embodiments and/or uses of the various inventions and modifications, and/or their equivalents. Furthermore, various combinations or subcombinations of specific features and aspects of the embodiments may be made and still be considered within the scope of the invention. Accordingly, various features and aspects of the disclosed embodiments can be combined with or substituted for one another to form varying aspects of the disclosed invention. Therefore, the scope of the various inventions disclosed herein should not be limited by the specific embodiments described above. The embodiments disclosed herein are susceptible to various modifications and alternative forms, specific examples of which are shown in the drawings and described in detail herein. However, the invention of the present application is not limited to the particular forms or methods disclosed; on the contrary, it embraces all modifications, equivalents, and alternatives included within the spirit and scope of the various described embodiments and the appended claims. Furthermore, the disclosure herein of any specific features, aspects, methods, properties, characteristics, qualities, attributes, elements, etc., associated with one embodiment or embodiment may be used in all other embodiments or embodiments described herein.

In any method disclosed herein, acts or operations may be performed in any suitable order and are not necessarily limited to the particular disclosed order or order recited. Various operations may be described as multiple separate operations in a sequence that may aid in understanding particular embodiments, but the order of description should not be construed to imply that these operations are order dependent. Furthermore, any structures described herein may be embodied as integrated components or as separate components. For purposes of comparing various embodiments, certain aspects and advantages of the embodiments are described. Not necessarily all such aspects or advantages are achieved by a particular embodiment. Thus, for example, an embodiment may be practiced in a manner that achieves or optimizes one advantage or advantages without necessarily achieving other advantages or advantages.

The methods disclosed herein include specific actions taken by a practitioner, but they can also include any third-party direction of those actions, either explicitly or implicitly. For example, actions such as "locating" a nerve, "coupling" or "connecting" an electrode to a nerve, and "initiating" a stimulation treatment include "instructing to locate,""instructing to couple," and "instructing to initiate," respectively. Ranges disclosed herein encompass all overlaps, subranges, and combinations thereof. Terms such as "up to,""atleast,""greaterthan," and "less than" are also used.
Language such as "than,""between," and the like includes the numerical values stated therein. Numerals followed by terms such as "about" or "approximately" are inclusive of the numerical values stated therein and should be interpreted according to the context (e.g., ±5%, ±10%, ±15%, etc., as precisely as reasonably possible under the circumstances). For example, "about 1 mm" includes "1 mm." Phrases followed by terms such as "substantially" are inclusive of the numerical values stated therein and should be interpreted according to the context (e.g., as precisely as reasonably possible under the circumstances). For example, "substantially rigid" includes "rigid," and "substantially parallel" includes "parallel."

Claims (12)

1. An electrical lead assembly configured to be at least partially inserted into a body structure of a subject,
at least one electrode configured to contact a target tissue of the subject to perform a desired treatment;
an insert having elastic deformability for facilitating shaping and reshaping of the electrical lead assembly, the insert extending to a distal end of the electrical lead assembly;
an outer cover having elastic deformability that allows the electrical lead assembly to undergo an elastic change in shape when a force is applied to the electrical lead assembly;
the electrical lead assembly is configured to be shaped and reshaped after percutaneous insertion into a body structure of a subject by selectively applying a force or moment along at least a portion of the electrical lead assembly;
the insert is configured to deflect when subjected to a force that exceeds the yield strength of the insert and selectively bends or twists the insert;
the insert is configured to maintain its shape in the absence of an external force;
a distal aspect of the electrical lead assembly having a lower hardness than a proximal aspect of the electrical lead assembly;
Electrical lead assembly. the thickness of the outer cover is between 100 and 400 μm;
the insert comprises an annealed metal or alloy;
The lead assembly of claim 1 , wherein the diameter or other cross-sectional dimension of the insert is between 100% and 500% of the thickness of the outer cover. The outer cover has a Shore D durometer of between 20D and 80D;
the thickness of the outer cover is between 100 and 400 μm;
the insert comprises an annealed metal or alloy;
The lead assembly of claim 1 , wherein the diameter or other cross-sectional dimension of the insert is between 100% and 500% of the thickness of the outer cover. The lead assembly of claim 2 or 3, wherein the annealed metal or alloy includes copper. The lead assembly of claim 1, wherein the diameter or other cross-sectional dimension of the insert is between 100% and 500% of the thickness of the outer cover. The lead assembly of claim 1, wherein the outer cover has a uniform or continuous thickness throughout the length of the electrical lead assembly. The lead assembly of claim 4, wherein the Shore D durometer of the distal aspect of the outer cover is between 20D and 50D. The lead assembly of claim 4 or 5, wherein the Shore D durometer of the proximal aspect of the outer cover is between 50D and 80D. The lead assembly described in any one of claims 1 to 8, wherein the Shore D durometer of the outer cover is between 20D and 80D. A lead assembly according to any one of claims 1 to 9, wherein the thickness of the outer cover is between 100 and 400 μm. The lead assembly of any one of claims 1 to 10, wherein the insert comprises an annealed metal or alloy. The lead assembly of claim 11, wherein the annealed metal or alloy includes copper.