A Hydrogel-Based Microfluidic Nerve Cuff for Neuromodulation of Peripheral Nerves

Implantable neuromodulation devices typically have metal in contact with soft, ion-conducting nerves. These neural interfaces excite neurons using short-duration electrical pulses. While this approach has been extremely successful for multiple clinical applications, it is limited in delivering long-duration pulses or direct current (DC), even for acute term studies. When the charge injection capacity of electrodes is exceeded, irreversible electrochemical processes occur, and toxic byproducts are discharged directly onto the nerve, causing biological damage. Hydrogel coatings on electrodes improve the overall charge injection limit and provide a mechanically pliable interface. To further extend this idea, we developed a silicone-based nerve cuff lead with a hydrogel microfluidic conduit. It serves as a thin, soft and flexible interconnection and provides a greater spatial separation between metal electrodes and the target nerve. In an in vivo rat model, we used this cuff to stimulate and record from sciatic nerves, with performance comparable to that of metal electrodes. Further, we delivered DC through the lead in an acute manner to induce nerve block that is reversible. In contrast to most metallic cuff electrodes, which need microfabrication equipment, we built this cuff using a consumer-grade digital cutter and a simplified molding process. Overall, the device will be beneficial to neuromodulation researchers as a general-purpose nerve cuff electrode for peripheral neuromodulation experiments.

Multisite Simultaneous Neural Recording of Motor Pathway in Free-Moving Rats

Neural interfaces typically focus on one or two sites in the motoneuron system simultaneously due to the limitation of the recording technique, which restricts the scope of observation and discovery of this system. Herein, we built a system with various electrodes capable of recording a large spectrum of electrophysiological signals from the cortex, spinal cord, peripheral nerves, and muscles of freely moving animals. The system integrates adjustable microarrays, floating microarrays, and microwires to a commercial connector and cuff electrode on a wireless transmitter. To illustrate the versatility of the system, we investigated its performance for the behavior of rodents during tethered treadmill walking, untethered wheel running, and open field exploration. The results indicate that the system is stable and applicable for multiple behavior conditions and can provide data to support previously inaccessible research of neural injury, rehabilitation, brain-inspired computing, and fundamental neuroscience.

In-vivo application of low frequency alternating currents on porcine cervical vagus nerve evokes reversible nerve conduction block

Background This paper describes a method to reversibly block nerve conduction through direct application of a 1 Hz sinusoidal current waveform delivered through a bipolar nerve cuff electrode. This low frequency alternating current (LFAC) waveform was previously shown to reversibly block the effects of vagal pulse stimulation evoked bradycardia in-vivo in the anaesthetised rat model (Mintch et al. 2019). The present work measured the effectiveness of LFAC block on larger caliber myelinated vagal afferent fibers in human sized nerve bundles projecting to changes in breathing rate mediated by the Hering-Breuer (HB) reflex in anaesthetized domestic swine (n=5). Methods Two bipolar cuff electrodes were implanted unilaterally to the left cervical vagus nerve, which was crushed caudal to the electrodes to eliminate cardiac effects. A tripolar recording cuff electrode was placed rostral to the bipolar stimulating electrodes on the same nerve to measure changes in the compound nerve action potentials (CNAP) elicited by the vagal pulse stimulation and conditioned by the LFAC waveform. Standard pulse stimulation was applied at a sufficient level to induce a reduction in breathing rate through the HB reflex. If unblocked, the HB reflex would cause breathing to slow down and potentially halt completely. Block was quantified by the ability of LFAC to reduce the effect of the HB reflex by monitoring the respiration rate during LFAC alone, LFAC and vagal stimulation, and vagal stimulation alone. Results LFAC achieved 87.2 ±8.8% block (n=5) at current levels of 1.1 ±0.3 mAp (current to peak), which was well within the water window of the working electrode. CNAP showed changes that directly correlated to the effectiveness of LFAC block, which manifested itself as the slowing and amplitude reduction of components of the CNAP. Conclusion These novel findings suggest that LFAC is a potential alternative or complementary method to other electrical blocking techniques in clinical applications.

Selective Facial Muscle Activation with Acute and Chronic Multichannel Cuff Electrode Implantation in a Feline Model

Objectives: Facial paralysis is a debilitating condition with substantial functional and psychological consequences. This feline-model study evaluates whether facial muscles can be selectively activated in acute and chronic implantation of 16-channel multichannel cuff electrodes (MCE). Methods: Two cats underwent acute terminal MCE implantation experiments, 2 underwent chronic MCE implantation in uninjured facial nerves (FN) and tested for 6 months, and 2 underwent chronic MCE implantation experiments after FN transection injury and tested for 3 months. The MCE were wrapped around the main trunk of the skeletonized FN, and data collection consisted of EMG thresholds, amplitudes, and selectivity of muscle activation. Results: In acute experimentation, activation of specific channels (ie, channels 1-3 and 6-8) resulted in selective activation of orbicularis oculi, whereas activation of other channels (ie, channels 4, 5, or 8) led to selective activation of levator auris longus with higher EMG amplitudes. MCE implantation yielded stable and selective facial muscle activation EMG thresholds and amplitudes up to a 5-month period. Modest selective muscle activation was furthermore obtained after a complete transection-reapproximating nerve injury after a 3-month recovery period and implantation reoperation. Chronic implantation of MCE did not lead to fibrosis on histology. Field steering was achieved to activate distinct facial muscles by sending simultaneous subthreshold currents to multiple channels, thus theoretically protecting against nerve damage from chronic electrical stimulation. Conclusion: Our proof-of-concept results show the ability of an MCE, supplemented with field steering, to provide a degree of selective facial muscle stimulation in a feline model, even following nerve regeneration after FN injury. Level of evidence: N/A

Classification of directionally specific vagus nerve activity using an upper airway obstruction model in anesthetized rodents

Electrical signals from the peripheral nervous system have the potential to provide the necessary motor, sensory or autonomic information for implementing closed-loop control of neuroprosthetic or neuromodulatory systems. However, developing methods to recover information encoded in these signals is a significant challenge. Our goal was to test the feasibility of measuring physiologically generated nerve action potentials that can be classified as sensory or motor signals. A tetrapolar recording nerve cuff electrode was used to measure vagal nerve (VN) activity in a rodent model of upper airway obstruction. The effect of upper airway occlusions on VN activity related to respiration (RnP) was calculated and compared for 4 different cases: (1) intact VN, (2) VN transection only proximal to recording electrode, (3) VN transection only distal to the recording electrode, and (4) transection of VN proximal and distal to electrode. We employed a Support Vector Machine (SVM) model with Gaussian Kernel to learn a model capable of classifying efferent and afferent waveforms obtained from the tetrapolar electrode. In vivo results showed that the RnP values decreased significantly during obstruction by 91.7% ± 3.1%, and 78.2% ± 3.4% for cases of intact VN or proximal transection, respectively. In contrast, there were no significant changes for cases of VN transection at the distal end or both ends of the electrode. The SVM model yielded an 85.8% accuracy in distinguishing motor and sensory signals. The feasibility of measuring low-noise directionally-sensitive neural activity using a tetrapolar nerve cuff electrode along with the use of an SVM classifier was shown. Future experimental work in chronic implant studies is needed to support clinical translatability.

Improving the Selectivity of an Osseointegrated Neural Interface: Proof of Concept For Housing Sieve Electrode Arrays in the Medullary Canal of Long Bones

Sieve electrodes stand poised to deliver the selectivity required for driving advanced prosthetics but are considered inherently invasive and lack the stability required for a chronic solution. This proof of concept experiment investigates the potential for the housing and engagement of a sieve electrode within the medullary canal as part of an osseointegrated neural interface (ONI) for greater selectivity toward improving prosthetic control. The working hypotheses are that (A) the addition of a sieve interface to a cuff electrode housed within the medullary canal of the femur as part of an ONI would be capable of measuring efferent and afferent compound nerve action potentials (CNAPs) through a greater number of channels; (B) that signaling improves over time; and (C) that stimulation at this interface generates measurable cortical somatosensory evoked potentials through a greater number of channels. The modified ONI was tested in a rabbit (n = 1) amputation model over 12 weeks, comparing the sieve component to the cuff, and subsequently compared to historical data. Efferent CNAPs were successfully recorded from the sieve demonstrating physiological improvements in CNAPs between weeks 3 and 5, and somatosensory cortical responses recorded at 12 weeks postoperatively. This demonstrates that sieve electrodes can be housed and function within the medullary canal, demonstrated by improved nerve engagement and distinct cortical sensory feedback. This data presents the conceptual framework for housing more sophisticated sieve electrodes in bone as part of an ONI for improving selectivity with percutaneous connectivity toward improved prosthetic control.

Rapid and Low Cost Manufacturing of Cuff Electrodes

For many peripheral neuro-modulation applications, the cuff electrode has become a preferred technology for delivering electrical current into targeted volumes of tissue. While basic cuffs with low spatial selectivity, having longitudinally arranged contacts, can be produced from relatively straightforward processes, the fabrication of more complex electrode configurations typically requires iterative design and clean-room fabrication with skilled technicians. Although facile methods for fabricating cuff electrodes exist, their inconsistent products have limited their adoption for rapid manufacturing. In this article, we report a fast, low-cost fabrication process for patterning of electrode contacts in an implantable peripheral nerve cuff. Using a laser cutter as we have prescribed, the designer can render precise contact geometries that are consistent between batches. This method is enabled by the use of silicone/carbon black (CB) composite electrodes, which integrate with the patterned surface of its substrate—tubular silicone insulation. The size and features of its products can be adapted to fit a wide range of nerve diameters and applications. In this study, we specifically documented the manufacturing and evaluation of circumpolar cuffs with radial arrays of three contacts for acute implantation on the rat sciatic nerve. As part of this method, we also detail protocols for verification—electrochemical characterization—and validation—electrophysiological evaluation—of implantable cuff electrodes. Applied to our circumpolar cuff electrode, we report favorable electrical characteristics. In addition, we report that it reproduces expected electrophysiological behaviors described in prior literature. No specialized equipment or fabrication experience was required in our production, and we encountered negligible costs relative to commercially available solutions. Since, as we demonstrate, this process generates consistent and precise electrode geometries, we propose that it has strong merits for use in rapid manufacturing.

All-Polymer Printed Low-Cost Regenerative Nerve Cuff Electrodes

Neural regeneration after lesions is still limited by several factors and new technologies are developed to address this issue. Here, we present and test in animal models a new regenerative nerve cuff electrode (RnCE). It is based on a novel low-cost fabrication strategy, called “Print and Shrink”, which combines the inkjet printing of a conducting polymer with a heat-shrinkable polymer substrate for the development of a bioelectronic interface. This method allows to produce miniaturized regenerative cuff electrodes without the use of cleanroom facilities and vacuum based deposition methods, thus highly reducing the production costs. To fully proof the electrodes performance in vivo we assessed functional recovery and adequacy to support axonal regeneration after section of rat sciatic nerves and repair with RnCE. We investigated the possibility to stimulate the nerve to activate different muscles, both in acute and chronic scenarios. Three months after implantation, RnCEs were able to stimulate regenerated motor axons and induce a muscular response. The capability to produce fully-transparent nerve interfaces provided with polymeric microelectrodes through a cost-effective manufacturing process is an unexplored approach in neuroprosthesis field. Our findings pave the way to the development of new and more usable technologies for nerve regeneration and neuromodulation.

Compensation Strategies for Bioelectric Signal Changes in Chronic Selective Nerve Cuff Recordings: A Simulation Study

Peripheral nerve interfaces (PNIs) allow us to extract motor, sensory, and autonomic information from the nervous system and use it as control signals in neuroprosthetic and neuromodulation applications. Recent efforts have aimed to improve the recording selectivity of PNIs, including by using spatiotemporal patterns from multi-contact nerve cuff electrodes as input to a convolutional neural network (CNN). Before such a methodology can be translated to humans, its performance in chronic implantation scenarios must be evaluated. In this simulation study, approaches were evaluated for maintaining selective recording performance in the presence of two chronic implantation challenges: the growth of encapsulation tissue and rotation of the nerve cuff electrode. Performance over time was examined in three conditions: training the CNN at baseline only, supervised re-training with explicitly labeled data at periodic intervals, and a semi-supervised self-learning approach. This study demonstrated that a selective recording algorithm trained at baseline will likely fail over time due to changes in signal characteristics resulting from the chronic challenges. Results further showed that periodically recalibrating the selective recording algorithm could maintain its performance over time, and that a self-learning approach has the potential to reduce the frequency of recalibration.

SMoBAICS

Simulation and modelling are powerful methods in computer aided therapy, rehabilitation monitoring, identification and control. The smart modular biosignal acquisition and identification system (SMoBAICS) provides methods and techniques to acquire electromyogram (EMG)- and electroneurogram (ENG)-based data for the evaluation and identification of biosignals. In this paper the author focuses on the development, integration and verification of platform technologies which support this entire data processing. Simulation and verification approaches are integrated to evaluate causal relationships between physiological and bioinformatical processes. Based on this we are stepping up of efforts to develop substitute methods and computer-aided simulation models with the objective of reducing animal testing. This work continues the former work about system identification and biosignal acquisition and verification systems presented in (Bohlmann et al., 2010), (Klinger and Klauke, 2013), (Klinger, 2014). This paper focuses on the next generation of an embedded data acquisition and identification system and its flexible platform architecture. Different application scenarios are shown to illustrate the system in different application fields. The author presents results of the enhanced closed-loop verification approach and of the signal quality using the Cuff-electrode-based ENG-data acquisition system.