Human-relevant near-organ neuromodulation of the immune system via the splenic nerve.

Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve-induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.

Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes.

AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents. METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT. RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks. CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord.

UNLABELLED: After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9ß1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a ß1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery. SIGNIFICANCE STATEMENT: The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory-motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient.

Electrical nerve stimulation to promote micturition in spinal cord injury patients: A review of current attempts.

AIMS: In this review, we focus on the current attempts of electrical nerve stimulation for micturition in spinal cord injury (SCI) patients. METHODS: A literature search was performed through PubMed using "spinal cord injury," "electrical nerve stimulation AND bladder," "sacral anterior root stimulation/stimulator" and "Brindley stimulator" from January 1975 to January 2014. RESULTS: Twenty studies were selected for this review. CONCLUSION: Electrical nerve stimulation is a clinical option for promoting micturition in SCI patients. Well-designed, randomized and controlled studies are essential for further investigation.

Electrical Stimulation of the Spinal Dorsal Root Inhibits Reflex Bladder Contraction and External Urethra Sphincter Activity: Is This How Sacral Neuromodulation Works?

INTRODUCTION: Using a rat model, we aimed to confirm the inhibitory effect of dorsal spinal root (afferent) stimulation and test if bilateral stimulation is more effective than unilateral stimulation. External urethral sphincter (EUS) electromyography (EMG) is also assessed in conjunction with cystometrogram. MATERIALS AND METHODS: Eighteen female Sprague-Dawley rats were tested following urethane anesthesia. Via urethral catheterization, the bladder was infused with normal saline to evoke rhythmic bladder reflex contractions (BRC). L6 spinal nerves were isolated and stimulated. RESULTS: L6 stimulation was effective in inhibiting BRC. L6 bilateral dorsal root (DR) stimulation of 50% intensity was required to cause inhibition as compared to unilateral stimulation. In EUS EMG recordings, there was a strong association between EUS EMG activities and bladder contraction. When the bladder contraction was inhibited effectively by L6 DR stimulation, a considerable reduction was also found in the EUS EMG activities. CONCLUSIONS: L6 DR stimulation abolished BRC in our rat model. Bilateral L6 DR stimulation produced a 50% reduction in stimulation intensity, providing a similar BRC block. Abolishing BRC also appeared to coincide with a reduction in EUS EMG, implicating that sacral neuromodulation might act centrally, at least rostrally at the T8-9 spinal level.

The kinesin-2 family member KIF3C regulates microtubule dynamics and is required for axon growth and regeneration.

Axon regeneration after injury requires the extensive reconstruction, reorganization, and stabilization of the microtubule cytoskeleton in the growth cones. Here, we identify KIF3C as a key regulator of axonal growth and regeneration by controlling microtubule dynamics and organization in the growth cone. KIF3C is developmentally regulated. Rat embryonic sensory axons and growth cones contain undetectable levels of KIF3C protein that is locally translated immediately after injury. In adult neurons, KIF3C is axonally transported from the cell body and is enriched at the growth cone where it preferentially binds to tyrosinated microtubules. Functionally, the interaction of KIF3C with EB3 is necessary for its localization at the microtubule plus-ends in the growth cone. Depletion of KIF3C in adult neurons leads to an increase in stable, overgrown and looped microtubules because of a strong decrease in the microtubule frequency of catastrophes, suggesting that KIF3C functions as a microtubule-destabilizing factor. Adult axons lacking KIF3C, by RNA interference or KIF3C gene knock-out, display an impaired axonal outgrowth in vitro and a delayed regeneration after injury both in vitro and in vivo. Murine KIF3C knock-out embryonic axons grow normally but do not regenerate after injury because they are unable to locally translate KIF3C. These data show that KIF3C is an injury-specific kinesin that contributes to axon growth and regeneration by regulating and organizing the microtubule cytoskeleton in the growth cone.

Functional Electrochemistry: On-Nerve Assessment of Electrode Materials for Electrochemistry and Functional Neurostimulation.

Emerging therapies in bioelectronic medicine highlight the need for deeper understanding of electrode material performance in the context of tissue stimulation. Electrochemical properties are characterized on the benchtop, facilitating standardization across experiments. On-nerve electrochemistry differs from benchtop characterization and the relationship between electrochemical performance and nerve activation thresholds are not commonly established. This relationship is important in understanding differences between electrical stimulation requirements and electrode performance. We report functional electrochemistry as a follow-up to benchtop testing, describing a novel experimental approach for evaluating on-nerve electrochemical performance in the context of nerve activation. An ex-vivo rat sciatic nerve preparation was developed to quantify activation thresholds of fiber subtypes and electrode material charge injection limits for platinum iridium, iridium oxide, titanium nitride and PEDOT. Finally, we address experimental complexities arising in these studies, and demonstrate statistical solutions that support rigorous material performance comparisons for decision making in neural interface development.

Splenic arterial neurovascular bundle stimulation in esophagectomy: A feasibility and safety prospective cohort study.

Introduction: The autonomic nervous system is a key regulator of inflammation. Electrical stimulation of the vagus nerve has been shown to have some preclinical efficacy. However, only a few clinical studies have been reported to treat inflammatory diseases. The present study evaluates, for the first time, neuromodulation of the splenic arterial neurovascular bundle (SpA NVB) in patients undergoing minimally invasive esophagectomy (MIE), in which the SpA NVB is exposed as part of the procedure. Methods: This single-center, single-arm study enrolled 13 patients undergoing MIE. During the abdominal phase of the MIE, a novel cuff was placed around the SpA NVB, and stimulation was applied. The primary endpoint was the feasibility and safety of cuff application and removal. A secondary endpoint included the impact of stimulation on SpA blood flow changes during the stimulation, and an exploratory point was C-reactive protein (CRP) levels on postoperative day (POD) 2 and 3. Results: All patients successfully underwent placement, stimulation, and removal of the cuff on the SpA NVB with no adverse events related to the investigational procedure. Stimulation was associated with an overall reduction in splenic arterial blood flow but not with changes in blood pressure or heart rate. When compared to historic Propensity Score Matched (PSM) controls, CRP levels on POD2 (124 vs. 197 mg/ml, p = 0.032) and POD3 (151 vs. 221 mg/ml, p = 0.033) were lower in patients receiving stimulation. Conclusion: This first-in-human study demonstrated for the first time that applying a cuff around the SpA NVB and subsequent stimulation is safe, feasible, and may have an effect on the postoperative inflammatory response following MIE. These findings suggest that SpA NVB stimulation may offer a new method for immunomodulatory therapy in acute or chronic inflammatory conditions.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

Printable microscale interfaces for long-term peripheral nerve mapping and precision control.

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying peripheral interfacing technologies. Here, we present a microscale implantable device - the nanoclip - for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high signal-to-noise ratio recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation within the confines of the small device can achieve multi-dimensional control of a small nerve. These results highlight the potential of new microscale design and fabrication techniques for realizing viable devices for long-term peripheral interfacing.

Quantification of clinically applicable stimulation parameters for precision near-organ neuromodulation of human splenic nerves.

Neuromodulation is a new therapeutic pathway to treat inflammatory conditions by modulating the electrical signalling pattern of the autonomic connections to the spleen. However, targeting this sub-division of the nervous system presents specific challenges in translating nerve stimulation parameters. Firstly, autonomic nerves are typically embedded non-uniformly among visceral and connective tissues with complex interfacing requirements. Secondly, these nerves contain axons with populations of varying phenotypes leading to complexities for axon engagement and activation. Thirdly, clinical translational of methodologies attained using preclinical animal models are limited due to heterogeneity of the intra- and inter-species comparative anatomy and physiology. Here we demonstrate how this can be accomplished by the use of in silico modelling of target anatomy, and validation of these estimations through ex vivo human tissue electrophysiology studies. Neuroelectrical models are developed to address the challenges in translation of parameters, which provides strong input criteria for device design and dose selection prior to a first-in-human trial.

Feasibility of kilohertz frequency alternating current neuromodulation of carotid sinus nerve activity in the pig.

Recent research supports that over-activation of the carotid body plays a key role in metabolic diseases like type 2 diabetes. Supressing carotid body signalling through carotid sinus nerve (CSN) modulation may offer a therapeutic approach for treating such diseases. Here we anatomically and histologically characterised the CSN in the farm pig as a recommended path to translational medicine. We developed an acute in vivo porcine model to assess the application of kilohertz frequency alternating current (KHFAC) to the CSN of evoked chemo-afferent CSN responses. Our results demonstrate the feasibility of this approach in an acute setting, as KHFAC modulation was able to successfully, yet variably, block evoked chemo-afferent responses. The observed variability in blocking response is believed to reflect the complex and diverse anatomy of the porcine CSN, which closely resembles human anatomy, as well as the need for optimisation of electrodes and parameters for a human-sized nerve. Overall, these results demonstrate the feasibility of neuromodulation of the CSN in an anesthetised large animal model, and represent the first steps in driving KHFAC modulation towards clinical translation. Chronic recovery disease models will be required to assess safety and efficacy of this potential therapeutic modality for application in diabetes treatment.

Optimisation of bioimpedance measurements of neuronal activity with an ex vivo preparation of Cancer pagurus peripheral nerves.

BACKGROUND: In mammals, fast neural Electrical Impedance Tomography (EIT) can image the myelinated component of the compound action potentials (CAP) using a nerve cuff. If applied to unmyelinated fibres this has great potential to improve selective neuromodulation ("electroceuticals") to avoid off-target effects. Previously, bioimpedance recordings were averaged from unmyelinated crab leg nerve fibres, but the signal to noise ratio (SNR) needs improving. NEW METHOD: Currently, functional non-invasive neuronal imaging is accomplished through surface electrodes or genetically expressed indicators that provide good spatial, but poor temporal, resolution. Here is an improved method for bioimpedance measurements from a model of unmyelinated fibres to enable optimisation through improvement of the 1) signal processing measurement paradigm, 2) neurophysiology, and 3) electrode-nerve interface. RESULTS: For bioimpedance recordings, the recruitment and necessity of the CAP was quantified and saline significantly improved the SNR. An improved protocol resulted in averaging not being required, as sequentially recorded traces produced bioimpedance changes of -0.232 ± 0.064% that did not show phase or timing related artefacts. COMPARISON WITH EXISTING METHOD: Here, two bioimpedance traces displayed an SNR of ≥3:1, while previously over >100 averages were required with greater inter-experimental variability. 10 paired traces were averaged for an SNR of ≥9:1, or near real-time measurement. CONCLUSIONS: This method facilitates further studies aiming to enable non-invasive localization of fascicular activity in unmyelinated fibres within peripheral nerves. This technique could ultimately produce the first 3-D tomographic images to help guide selective neuromodulation using bioelectric devices.

Cell death after dorsal root injury.

Flow cytometry and terminal deoxynucleotidyl transferase-mediated biotinylated uridine triphosphate nick end-labelling (TUNEL) immunohistochemistry have been used to assess cell death in the dorsal root ganglia (DRG) or spinal cord 1, 2 or 14 days after multiple lumbar dorsal root rhizotomy or dorsal root avulsion injury in adult rats. Neither injury induced significant cell death in the DRG compared to sham-operated or naïve animals at any time point. In the spinal cord, a significant increase in death was seen at 1-2 days, but not 14 days, post injury by both methods. TUNEL staining revealed that more apoptotic cells were present in the dorsal columns and dorsal horn of avulsion animals compared to rhizotomised animals. This suggests that avulsion injury, which can often partially damage the spinal cord, has more severe effects on cell survival than rhizotomy, a surgical lesion which does not affect the spinal cord. The location of TUNEL positive cells suggests that both neuronal and non-neuronal cells are dying.

Imaging fast neural traffic at fascicular level with electrical impedance tomography: proof of principle in rat sciatic nerve.

OBJECTIVE: Understanding the coding of neural activity in nerve fascicles is a high priority in computational neuroscience, electroceutical autonomic nerve stimulation and functional electrical stimulation for treatment of paraplegia. Unfortunately, it has been little studied as no technique has yet been available to permit imaging of neuronal depolarization within fascicles in peripheral nerve. APPROACH: We report a novel method for achieving this, using a flexible cylindrical multi-electrode cuff placed around nerve and the new medical imaging technique of fast neural electrical impedance tomography (EIT). In the rat sciatic nerve, it was possible to distinguish separate fascicles activated in response to direct electrical stimulation of the posterior tibial and common peroneal nerves. MAIN RESULTS: Reconstructed EIT images of fascicular activation corresponded with high spatial accuracy to the appropriate fascicles apparent in histology, as well as the inverse source analysis (ISA) of compound action potentials (CAP). With this method, a temporal resolution of 0.3 ms and spatial resolution of less than 100 µm was achieved. SIGNIFICANCE: The method presented here is a potential solution for imaging activity within peripheral nerves with high spatial accuracy. It also provides a basis for imaging and selective neuromodulation to be incorporated in a single implantable non-penetrating peri-neural device.

Stimulation of peripheral nerves using conductive hydrogel electrodes.

Nerve block via electrical stimulation of nerves requires a device capable of transferring large amounts of charge across the neural interface on chronic time scales. Current metal electrode designs are limited in their ability to safely and effectively deliver this charge in a stable manner. Conductive hydrogel (CH) coatings are a promising alternative to metal electrodes for neural interfacing devices. This study assessed the performance of CH electrodes compared to platinum-iridium (PtIr) electrodes in commercial nerve cuff devices in both the in vitro and acute in vivo environments. CH electrodes were found to have higher charge storage capacities and lower impedances compared to bare PtIr electrodes. Application of CH coatings also resulted in a three-fold increase in in vivo charge injection limit. These significant improvements in electrochemical properties will allow for the design of smaller and safer stimulating devices for nerve block applications.

Carbon fiber on polyimide ultra-microelectrodes.

OBJECTIVE: Most preparations for making neural recordings degrade over time and eventually fail due to insertion trauma and reactive tissue response. The magnitudes of these responses are thought to be related to the electrode size (specifically, the cross-sectional area), the relative stiffness of the electrode, and the degree of tissue tolerance for the material. Flexible carbon fiber ultra-microelectrodes have a much smaller cross-section than traditional electrodes and low tissue reactivity, and thus may enable improved longevity of neural recordings in the central and peripheral nervous systems. Only two carbon fiber array designs have been described previously, each with limited channel densities due to limitations of the fabrication processes or interconnect strategies. Here, we describe a method for assembling carbon fiber electrodes on a flexible polyimide substrate that is expected to facilitate the construction of high-density recording and stimulating arrays. APPROACH: Individual carbon fibers were aligned using an alignment tool that was 3D-printed with sub-micron resolution using direct laser writing. Indium deposition on the carbon fibers, followed by low-temperature microsoldering, provided a robust and reliable method of electrical connection to the polyimide interconnect. MAIN RESULTS: Spontaneous multiunit activity and stimulation-evoked compound responses with SNR >10 and >120, respectively, were recorded from a small (125 µm) peripheral nerve. We also improved the typically poor charge injection capacity of small diameter carbon fibers by electrodepositing 100 nm-thick iridium oxide films, making the carbon fiber arrays usable for electrical stimulation as well as recording. SIGNIFICANCE: Our innovations in fabrication technique pave the way for further miniaturization of carbon fiber ultra-microelectrode arrays. We believe these advances to be key steps to enable a shift from labor intensive, manual assembly to a more automated manufacturing process.

A micro-scale printable nanoclip for electrical stimulation and recording in small nerves.

OBJECTIVE: The vision of bioelectronic medicine is to treat disease by modulating the signaling of visceral nerves near various end organs. In small animal models, the nerves of interest can have small diameters and limited surgical access. New high-resolution methods for building nerve interfaces are desirable. In this study, we present a novel nerve interface and demonstrate its use for stimulation and recording in small nerves. APPROACH: We design and fabricate micro-scale electrode-laden nanoclips capable of interfacing with nerves as small as 50 µm in diameter. The nanoclips are fabricated using a direct laser writing technique with a resolution of 200 nm. The resolution of the printing process allows for incorporation of a number of innovations such as trapdoors to secure the device to the nerve, and quick-release mounts that facilitate keyhole surgery, obviating the need for forceps. The nanoclip can be built around various electrode materials; here we use carbon nanotube fibers for minimally invasive tethering. MAIN RESULTS: We present data from stimulation-evoked responses of the tracheal syringeal (hypoglossal) nerve of the zebra finch, as well as quantification of nerve functionality at various time points post implant, demonstrating that the nanoclip is compatible with healthy nerve activity over sub-chronic timescales. SIGNIFICANCE: Our nerve interface addresses key challenges in interfacing with small nerves in the peripheral nervous system. Its small size, ability to remain on the nerve over sub-chronic timescales, and ease of implantation, make it a promising tool for future use in the treatment of disease.

Conductive Hydrogel Electrodes for Delivery of Long-Term High Frequency Pulses.

Nerve block waveforms require the passage of large amounts of electrical energy at the neural interface for extended periods of time. It is desirable that such waveforms be applied chronically, consistent with the treatment of protracted immune conditions, however current metal electrode technologies are limited in their capacity to safely deliver ongoing stable blocking waveforms. Conductive hydrogel (CH) electrode coatings have been shown to improve the performance of conventional bionic devices, which use considerably lower amounts of energy than conventional metal electrodes to replace or augment sensory neuron function. In this study the application of CH materials was explored, using both a commercially available platinum iridium (PtIr) cuff electrode array and a novel low-cost stainless steel (SS) electrode array. The CH was able to significantly increase the electrochemical performance of both array types. The SS electrode coated with the CH was shown to be stable under continuous delivery of 2 mA square pulse waveforms at 40,000 Hz for 42 days. CH coatings have been shown as a beneficial electrode material compatible with long-term delivery of high current, high energy waveforms.

Chronic multichannel neural recordings from soft regenerative microchannel electrodes during gait.

Reliably interfacing a nerve with an electrode array is one of the approaches to restore motor and sensory functions after an injury to the peripheral nerve. Accomplishing this with current technologies is challenging as the electrode-neuron interface often degrades over time, and surrounding myoelectric signals contaminate the neuro-signals in awake, moving animals. The purpose of this study was to evaluate the potential of microchannel electrode implants to monitor over time and in freely moving animals, neural activity from regenerating nerves. We designed and fabricated implants with silicone rubber and elastic thin-film metallization. Each implant carries an eight-by-twelve matrix of parallel microchannels (of 120 × 110 µm(2) cross-section and 4 mm length) and gold thin-film electrodes embedded in the floor of ten of the microchannels. After sterilization, the soft, multi-lumen electrode implant is sutured between the stumps of the sciatic nerve. Over a period of three months and in four rats, the microchannel electrodes recorded spike activity from the regenerating sciatic nerve. Histology indicates mini-nerves formed of axons and supporting cells regenerate robustly in the implants. Analysis of the recorded spikes and gait kinematics over the ten-week period suggests firing patterns collected with the microchannel electrode implant can be associated with different phases of gait.