A multi-channel stimulator with an active electrode array implant for vagal-cardiac neuromodulation studies.

BACKGROUND: Implantable vagus nerve stimulation is a promising approach for restoring autonomic cardiovascular functions after heart transplantation. For successful treatment a system should have multiple electrodes to deliver precise stimulation and complex neuromodulation patterns. METHODS: This paper presents an implantable multi-channel stimulation system for vagal-cardiac neuromodulation studies in swine species. The system comprises an active electrode array implant percutaneously connected to an external wearable controller. The active electrode array implant has an integrated stimulator ASIC mounted on a ceramic substrate connected to an intraneural electrode array via micro-rivet bonding. The implant is silicone encapsulated for biocompatibility and implanted lifetime. The stimulation parameters are remotely transmitted via a Bluetooth telemetry link. RESULTS: The size of the encapsulated active electrode array implant is 8 mm × 10 mm × 3 mm. The stimulator ASIC has 10-bit current amplitude resolution and 16 independent output channels, each capable of delivering up to 550 µA stimulus current and a maximum voltage of 20 V. The active electrode array implant was subjected to in vitro accelerated lifetime testing at 70 °C for 7 days with no degradation in performance. After over 2 h continuous stimulation, the surface temperature change of the implant was less than 0.5 °C. In addition, in vivo testing on the sciatic nerve of a male Göttingen minipig demonstrated that the implant could effectively elicit an EMG response that grew progressively stronger on increasing the amplitude of the stimulation. CONCLUSIONS: The multi-channel stimulator is suitable for long term implantation. It shows potential as a useful tool in vagal-cardiac neuromodulation studies in animal models for restoring autonomic cardiovascular functions after heart transplantation.

Bioelectronic modulation of carotid sinus nerve to treat type 2 diabetes: current knowledge and future perspectives.

Bioelectronic medicine are an emerging class of treatments aiming to modulate body nervous activity to correct pathological conditions and restore health. Recently, it was shown that the high frequency electrical neuromodulation of the carotid sinus nerve (CSN), a small branch of the glossopharyngeal nerve that connects the carotid body (CB) to the brain, restores metabolic function in type 2 diabetes (T2D) animal models highlighting its potential as a new therapeutic modality to treat metabolic diseases in humans. In this manuscript, we review the current knowledge supporting the use of neuromodulation of the CSN to treat T2D and discuss the future perspectives for its clinical application. Firstly, we review in a concise manner the role of CB chemoreceptors and of CSN in the pathogenesis of metabolic diseases. Secondly, we describe the findings supporting the potential therapeutic use of the neuromodulation of CSN to treat T2D, as well as the feasibility and reversibility of this approach. A third section is devoted to point up the advances in the neural decoding of CSN activity, in particular in metabolic disease states, that will allow the development of closed-loop approaches to deliver personalized and adjustable treatments with minimal side effects. And finally, we discuss the findings supporting the assessment of CB activity in metabolic disease patients to screen the individuals that will benefit therapeutically from this bioelectronic approach in the future.

Beyond the limiting gap length: peripheral nerve regeneration through implantable nerve guidance conduits.

Peripheral nerve damage results in the loss of sensorimotor and autonomic functions, which is a significant burden to patients. Furthermore, nerve injuries greater than the limiting gap length require surgical repair. Although autografts are the preferred clinical choice, their usage is impeded by their limited availability, dimensional mismatch, and the sacrifice of another functional donor nerve. Accordingly, nerve guidance conduits, which are tubular scaffolds engineered to provide a biomimetic environment for nerve regeneration, have emerged as alternatives to autografts. Consequently, a few nerve guidance conduits have received clinical approval for the repair of short-mid nerve gaps but failed to regenerate limiting gap damage, which represents the bottleneck of this technology. Thus, it is still necessary to optimize the morphology and constituent materials of conduits. This review summarizes the recent advances in nerve conduit technology. Several manufacturing techniques and conduit designs are discussed, with emphasis on the structural improvement of simple hollow tubes, additive manufacturing techniques, and decellularized grafts. The main objective of this review is to provide a critical overview of nerve guidance conduit technology to support regeneration in long nerve defects, promote future developments, and speed up its clinical translation as a reliable alternative to autografts.

A soft, scalable and adaptable multi-contact cuff electrode for targeted peripheral nerve modulation.

BACKGROUND: Cuff electrodes target various nerves throughout the body, providing neuromodulation therapies for motor, sensory, or autonomic disorders. However, when using standard, thick silicone cuffs, fabricated in discrete circular sizes, complications may arise, namely cuff displacement or nerve compression, due to a poor adaptability to variable nerve shapes and sizes encountered in vivo. Improvements in cuff design, materials, closing mechanism and surgical approach are necessary to overcome these issues. METHODS: In this work, we propose a microfabricated multi-channel silicone-based soft cuff electrode with a novel easy-to-implant and size-adaptable design and evaluate a number of essential features such as nerve-cuff contact, nerve compression, cuff locking stability, long-term integration and stimulation selectivity. We also compared performance to that of standard fixed-size cuffs. RESULTS: The belt-like cuff made of 150 µm thick silicone membranes provides a stable and pressure-free conformal contact, independently of nerve size variability, combined with a straightforward implantation procedure. The adaptable design and use of soft materials lead to limited scarring and demyelination after 6-week implantation. In addition, multi-contact designs, ranging from 6 to 16 electrodes, allow for selective stimulation in models of rat and pig sciatic nerve, achieving targeted activation of up to 5 hindlimb muscles. CONCLUSION: These results suggest a promising alternative to classic fixed-diameter cuffs and may facilitate the adoption of soft, adaptable cuffs in clinical settings.

Improved Physiochemical Properties of Chitosan@PCL Nerve Conduits by Natural Molecule Crosslinking.

Nerve conduits may represent a valuable alternative to autograft for the regeneration of long-gap damages. However, no NCs have currently reached market approval for the regeneration of limiting gap lesions, which still represents the very bottleneck of this technology. In recent years, a strong effort has been made to envision an engineered graft to tackle this issue. In our recent work, we presented a novel design of porous/3D-printed chitosan/poly-ε-caprolactone conduits, coupling freeze drying and additive manufacturing technologies to yield conduits with good structural properties. In this work, we studied genipin crosslinking as strategy to improve the physiochemical properties of our conduit. Genipin is a natural molecule with very low toxicity that has been used to crosslink chitosan porous matrix by binding the primary amino group of chitosan chains. Our characterization evidenced a stabilizing effect of genipin crosslinking towards the chitosan matrix, with reported modified porosity and ameliorated mechanical properties. Given the reported results, this method has the potential to improve the performance of our conduits for the regeneration of long-gap nerve injuries.

Cardiovascular Response to Intraneural Right Vagus Nerve Stimulation in Adult Minipig.

OBJECTIVE: This study explored intraneural stimulation of the right thoracic vagus nerve (VN) in sexually mature male minipigs to modulate safe heart rate and blood pressure response. MATERIAL AND METHODS: We employed an intraneural electrode designed for the VN of pigs to perform VN stimulation (VNS). This was delivered using different numbers of contacts on the electrode and different stimulation parameters (amplitude, frequency, and pulse width), identifying the most suitable stimulation configuration. All the parameter ranges had been selected from a computational cardiovascular system model. RESULTS: Clinically relevant responses were observed when stimulating with low current intensities and relatively low frequencies delivered with a single contact. Selecting a biphasic, charge-balanced square wave for VNS with a current amplitude of 500 µA, frequency of 10 Hz, and pulse width of 200 µs, we obtained heart rate reduction of 7.67 ± 5.19 beats per minute, systolic pressure reduction of 5.75 ± 2.59 mmHg, and diastolic pressure reduction of 3.39 ± 1.44 mmHg. CONCLUSION: Heart rate modulation was obtained without inducing any observable adverse effects, underlining the high selectivity of the intraneural approach.