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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., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Peripheral neural interfaces facilitate bidirectional communication between the nervous system and external devices, enabling precise control for prosthetic limbs, sensory feedback systems, and therapeutic interventions in the field of Bioelectronic Medicine. Intraneural interfaces hold great promise since they ensure high selectivity in communicating only with the desired nerve fascicles. Despite significant advancements, challenges such as chronic immune response, signal degradation over time, and lack of long-term biocompatibility remain critical considerations in the development of such devices. Here we report on the development and benchtop characterization of a novel design of an intraneural interface based on carbon fiber bundles. Carbon fibers possess low impedance, enabling enhanced signal detection and stimulation efficacy compared to traditional metal electrodes. We provided a 3D-stabilizing structure for the carbon fiber bundles made of PEDOT:PSS hydrogel, to enhance the biocompatibility between the carbon fibers and the nervous tissue. We further coated the overall bundles with a thin layer of elastomeric material to provide electrical insulation. Taken together, our results demonstrated that our electrode possesses adequate structural and electrochemical properties to ensure proper stimulation and recording of peripheral nerve fibers and a biocompatible interface with the nervous tissue., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Conde, Sacramento, Zinno, Mazzoni, Micera and Guarino.)

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.

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., (© 2024. The Author(s).)

Background: The impact of acute unilateral injury on spontaneous electrical activity in both vagus nerves at the heart level is poorly understood. We investigated the immediate neuroelectrical response after right or left cardiac vagal nerve transection (VNTx) by recording spiking activity of each heart vagus nerve (VN)., Methods: Fourteen male Göttingen minipigs underwent sternotomy. Multi-electrode cuffs were implanted below the cut level to record vagal electroneurographic signals during electrocardiographic and hemodynamic monitoring, before and immediately after cardiac VNTx (left: L-cut, n = 6; right: R-cut, n = 8)., Results: Left cardiac VNTx significantly reduced multi-unit electrical activity (MUA) firing rate in the vagal stump (-30.7% vs pre-cut) and intact right VN (-21.8% vs pre-cut) at the heart level, without affecting heart rate, heart rate variability, or hemodynamics. In contrast, right cardiac VNTx did not acutely alter MUA in either VN but slightly increased (p < 0.022) the root mean square of successive RR interval differences (rMSSD), an index of parasympathetic outflow, without affecting hemodynamics., Conclusions: Our study reveals an early left-lateralized pattern in vagal spiking activity following unilateral cardiac vagotomy. These findings enhance understanding of the neuroelectrical response to vagal injury and provide insights into preserving vagal outflow after unilateral cardiac vagotomy. Importantly, monitoring spiking activity of the cardiac right VN may predict onset of left vagal pathway injury, which is detrimental to cardiac patients and can occur as a complication of catheter ablation for atrial fibrillation., (Copyright © 2023. Published by Elsevier B.V.)

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.

Vagus nerve stimulation (VNS) is an FDA-approved technique for the neuromodulation of the autonomic nervous system. There are many therapeutic applications where VNS could be used as a therapy, such as cardiovascular diseases, epilepsy, depression, and inflammatory conditions. Cardiovascular applications are particularly relevant, since cardiovascular diseases are the top causes of death worldwide. VNS clinical trials have been performed in the last 15 years for the treatment of heart failure (HF), achieving controversial results. Typically VNS is applied with a cuff electrode placed around the nerve, in an open-loop or cardiac synchronized design. The effectiveness of this approach is hindered by the multifunctional nature of the VN, which is involved in a variety of homeostatic controls. When a high current is applied, adverse effects arise from the stimulation of undesired fibers. An alternative strategy is represented by intraneural stimulation, which can guarantee higher selectivity. Moreover, closed-loop modalities allow the delivery of electrical current inside the nerves only if needed, with a reduced risk of untargeted nerve activation and lower energy consumption. Here we propose a closed-loop intraneural stimulation of the right cervical VN in a clinically relevant animal model. The intraneural was designed according to the internal structure of the VN. A threshold-based closed-loop algorithm was developed using HR as a control variable to produce a chronotropic effect.Clinical Relevance-This work analyzes the closed-loop intraneural VNS for the treatment of cardiovascular disorders, and supports the possibility of developing fully implantable devices with a high degree of selectivity in stimulation and prolonged lifespan.

Understanding the methane (CH 4 ) emissions that are produced by enteric fermentation is one of the main problems to be solved for livestock, due to their GHG effects. These emissions are affected by the quantity and quality of their diets, thus, it is key to accurately define the intake and fiber content (NDF) of these forage diets. On the other hand, different emission prediction equations have been developed; however, there are scarce and uncertain results regarding their evaluation of the emissions that have been observed in forage diets. Therefore, the objectives of this study were to evaluate the effect of the NDF content of a forage diet on CH 4 enteric emissions, and to evaluate the ability of models to predict the emissions from the animals that are consuming these forage diets. In total, thirty-six Angus steers (x¯ = 437 kg live weight) aged 18 months, blocked by live weight and placed in three automated feeding pens, were used to measure the enteric CH 4 . The animals were randomly assigned to two forage diets (n = 18), with moderate (<50%, MF) and high (>50%, HF) NDF contents. Their dry matter intake was recorded individually, and the CH 4 emissions were measured using the SF 6 tracer gas technique. For the model evaluation, six prediction equations were compared with 29 studies ( n = 97 observations), analyzing the accuracy and precision of their estimates. The emission intensities per unit of DMI, per ADG, and per gross energy intake were significantly lower ( p < 0.05) in the animals consuming the MF diet than in the animals consuming the HF diet (21.7 vs. 23.7 g CH 4 /kg DMI, 342 vs. 660 g CH 4 /kg ADG, and 6.7% vs. 7.5%, respectively), but there were no differences in the absolute emissions ( p > 0.05). The best performing model was the IPCC 2006 model ( r 2 = 0.7, RMSE = 74.04). These results show that reducing the NDF content of a forage diet by at least 10% (52 g/kg DM) reduces the intensity of the g CH 4 /kg DMI by up to 8%, and that of the g CH 4 /kg ADG by almost half. The use of the IPCC 2006 model is suitable for estimating the CH 4 emissions from animals consuming forage-based diets.

The neural stimulation of the vagus nerve is able to modulate various functions of the parasympathetic response in different organs. The stimulation of the vagus nerve is a promising approach to treating inflammatory diseases, obesity, diabetes, heart failure, and hypertension. The complexity of the vagus nerve requires highly selective stimulation, allowing the modulation of target-specific organs without side effects. Here, we address this issue by adapting a neural stimulator and developing an intraneural electrode for the particular modulation of the vagus nerve. The neurostimulator parameters such as amplitude, pulse width, and pulse shape were modulated. Single-, and multi-channel stimulation was performed at different amplitudes. For the first time, a polyimide thin-film neural electrode was designed for the specific stimulation of the vagus nerve. In vivo experiments were performed in the adult minipig to validate to elicit electrically evoked action potentials and to modulate physiological functions, validating the spatial selectivity of intraneural stimulation. Electrochemical tests of the electrode and the neurostimulator showed that the stimulation hardware was working correctly. Stimulating the porcine vagus nerve resulted in spatially selective modulation of the vagus nerve. ECAP belonging to alpha and beta fibers could be distinguished during single- and multi-channel stimulation. We have shown that the here presented system is able to activate the vagus nerve and can therefore modulate the heart rate, diastolic pressure, and systolic pressure. The here presented system may be used to restore the cardiac loop after denervation by implementing biomimetic stimulation patterns. Presented methods may be used to develop intraneural electrodes adapted for various applications.