Stimulation of peripheral nerves has transiently restored lost sensation and has the potential to alleviate motor deficits. However, incomplete characterization of the long-term usability and bio-integration of intra-neural implants has restricted their use for clinical applications. Here, we conducted a longitudinal assessment of the selectivity, stability, functionality, and biocompatibility of polyimide-based intra-neural implants that were inserted in the sciatic nerve of twenty-three healthy adult rats for up to six months. We found that the stimulation threshold and impedance of the electrodes increased moderately during the first four weeks after implantation, and then remained stable over the following five months. The time course of these adaptations correlated with the progressive development of a fibrotic capsule around the implants. The selectivity of the electrodes enabled the preferential recruitment of extensor and flexor muscles of the ankle. Despite the foreign body reaction, this selectivity remained stable over time. These functional properties supported the development of control algorithms that modulated the forces produced by ankle extensor and flexor muscles with high precision. The comprehensive characterization of the implant encapsulation revealed hyper-cellularity, increased microvascular density, Wallerian degeneration, and infiltration of macrophages within the endoneurial space early after implantation. Over time, the amount of macrophages markedly decreased, and a layer of multinucleated giant cells surrounded by a capsule of fibrotic tissue developed around the implant, causing an enlargement of the diameter of the nerve. However, the density of nerve fibers above and below the inserted implant remained unaffected. Upon removal of the implant, we did not detect alteration of skilled leg movements and only observed mild tissue reaction. Our study characterized the interplay between the development of foreign body responses and changes in the electrical properties of actively used intra-neural electrodes, highlighting functional stability of polyimide-based implants over more than six months. These results are essential for refining and validating these implants and open a realistic pathway for long-term clinical applications in humans.
The presented three-dimensional electrode provides an effective anchorage system to the nervous tissue that can improve the stability of the implant for acute and chronic studies.
Objective. Bioelectronic medicine is opening new perspectives for the treatment of some major chronic diseases through the physical modulation of autonomic nervous system activity. Being the main peripheral route for electrical signals between central nervous system and visceral organs, the vagus nerve (VN) is one of the most promising targets. Closed-loop VN stimulation (VNS) would be crucial to increase effectiveness of this approach. Therefore, the extrapolation of useful physiological information from VN electrical activity would represent an invaluable source for single-target applications. Here, we present an advanced decoding algorithm novel to VN studies and properly detecting different functional changes from VN signals. Approach. VN signals were recorded using intraneural electrodes in anaesthetized pigs during cardiovascular and respiratory challenges mimicking increases in arterial blood pressure, tidal volume and respiratory rate. We developed a decoding algorithm that combines discrete wavelet transformation, principal component analysis, and ensemble learning made of classification trees. Main results. The new decoding algorithm robustly achieved high accuracy levels in identifying different functional changes and discriminating among them. Interestingly our findings suggest that electrodes positioning plays an important role on decoding performances. We also introduced a new index for the characterization of recording and decoding performance of neural interfaces. Finally, by combining an anatomically validated hybrid neural model and discrimination analysis, we provided new evidence suggesting a functional topographical organization of VN fascicles. Significance. This study represents an important step towards the comprehension of VN signaling, paving the way for the development of effective closed-loop VNS systems.
Minimizing the foreign body reaction to polyimide-based implanted devices plays a pivotal role in several biomedical applications. In this work, we propose materials exhibiting nonbiofouling properties and a Young's modulus reflecting that of soft human tissues. We describe the synthesis, characterization, and in vitro validation of poly(carboxybetaine) hydrogel coatings covalently attached to polyimide substrates via a photolabile 4-azidophenyl group, incorporated in poly(carboxybetaine) chains at two concentrations of 1.6 and 3.1 mol %. The presence of coatings was confirmed by attenuated total reflectance Fourier transform infrared spectroscopy. White light interferometry was used to evaluate the coating continuity and thickness (between 3 and 6 μm under dry conditions). Confocal laser scanning microscopy allowed us to quantify the thickness of the swollen hydrogel coatings that ranged between 13 and 32 μm. The different hydrogel formulations resulted in stiffness values ranging from 2 to 19 kPa and led to different fibroblast and macrophage responses in vitro. Both cell types showed a minimum adhesion on the softest hydrogel type. In addition, both the overall macrophage activation and cytotoxicity were observed to be negligible for all of the tested material formulations. These results are a promising starting point toward future advanced implantable systems. In particular, such technology paves the way for novel neural interfaces able to minimize the fibrotic reaction, once implanted in vivo, and to maximize their long-term stability and functionality.
functions of nervous system when damages occur. Moreover, in case of physical impairments, the use of artificial tactile sensors is also paramount to ensure the possibility to restore the sense of touch to the patient. Bioinspiration from human natural touch could help in the release of enhanced tactile sensors to be used in neuroprosthetics. Technological and biological advancements brought serious improvements in the quality of these devices, such as miniaturization and increased biocompatibility. This article reviews the essential design criteria, working principles, materials, and technical considerations on neural interfaces and tactile sensors; their clinical application in neuroprosthetics and their future progress toward optimized solutions. Neural InterfacesA neural interface device (NID) is an implantable tool that aims at restoring nervous system functions in case of impairments or communicates with external components (e.g., limb prostheses); its main objective is to record neural signal from a small group of axons/cells or to stimulate a selected area of the nervous system. The clinical potentialities of NIDs range from their applications in central nervous system (CNS) for treating epilepsy seizures, mitigating Parkinson's disease; in peripheral nervous system (PNS) for controlling limb prostheses in amputees and restore sensory feedback; in autonomous nervous system such as vagus nerve to treat drug-resistant epilepsy and chronic depression to finally auditory and vision systems to restore the perception of specific sounds and phosphenes. An ideal NID should be biocompatible, highly selective, low invasive and stable over long time. If intended for clinical applications, the functionality of a NID should be reliable and should last decades. Considering the different implantation sites of interest of the device, various solutions have been proposed to optimize the communication between the NID and the surrounding environment. Figure 1 highlights the main applications of most common used NIDs in neuroprosthetics. With a special focus on implantable neuroprostheses and motor system, this paragraph will portray the design criteria, the materials and technical considerations heretofore used for the development of diverse types of NID used in CNS and PNS.Neuroprosthetics and neuromodulation represent a promising field for several related applications in the central and peripheral nervous system, such as the treatment of neurological disorders, the control of external robotic devices, and the restoration of lost tactile functions. These actions are allowed by the neural interface, a miniaturized implantable device that most commonly exploits electrical energy to fulfill these operations. A neural interface must be biocompatible, stable over time, low invasive, and highly selective; the challenge is to develop a safe, compact, and reliable tool for clinical applications. In case of anatomical impairments, neuroprosthetics is bound to the need of exploring the surrounding environment by fast-responsive and ...
This multi-aisle regenerative electrode may be suitable for neuroprosthetic applications, such as prostheses, for the restoration of hand function after amputation or severe nerve injuries.
Objective: Ultrasound (US) stimulation carries the promise of a selective, reversible, and non-invasive modulation of neural activity without the need for genetic manipulation of neural structures. However, the mechanisms of US-induced generation of action potentials (APs) are still unclear. Methods: Here we address this issue by analyzing intracellularly recorded responses of leech nociceptive neurons to controlled delivery of US. Results: US induced a depolarization linearly accumulating in time and outlasting the duration of the stimulation. Spiking activity was reliably induced for an optimal US intensity range. Moreover, we found that APs induced by US differ in smaller amplitude and faster repolarization from those induced by electrical stimulation in the same cell but display the same repolarization rate. Conclusions: These results shed light on the mechanism by which spikes are induced by US and pave the way for designing more efficient US stimulation patterns.
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