Long-term usability and bio-integration of polyimide-based intraneural stimulating electrodes

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 intraneural 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. (C) 2017 Elsevier Ltd. All rights reserved.

Chronic multichannel neural recordings from soft regenerative microchannel electrodes during gait

Marco Capogrosso, Stéphanie Lacour, Silvestro Micera, Katherine Marie Musick, Shreya Narasimhan, Jacopo Rigosa, Sophie Marie Marthe Wurth

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 x 110 mu m(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.

Nature Publishing Group2015

Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush

Lin Jin, Sylvain Eric Lengacher, Pierre Magistretti, Luc Pellerin

Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. (C) 2014 Elsevier Inc. All rights reserved.

Elsevier2015

Spatial and Functional Selectivity of Peripheral Nerve Signal Recording With the Transversal Intrafascicular Multichannel Electrode (TIME)

Silvestro Micera, Stanisa Raspopovic

The selection of suitable peripheral nerve electrodes for biomedical applications implies a trade-off between invasiveness and selectivity. The optimal design should provide the highest selectivity for targeting a large number of nerve fascicles with the least invasiveness and potential damage to the nerve. The transverse intrafascicular multichannel electrode (TIME), transversally inserted in the peripheral nerve, has been shown to be useful for the selective activation of subsets of axons, both at inter-and intra-fascicular levels, in the small sciatic nerve of the rat. In this study we assessed the capabilities of TIME for the selective recording of neural activity, considering the topographical selectivity and the distinction of neural signals corresponding to different sensory types. Topographical recording selectivity was proved by the differential recording of CNAPs from different subsets of nerve fibers, such as those innervating toes 2 and 4 of the hindpaw of the rat. Neural signals elicited by sensory stimuli applied to the rat paw were successfully recorded. Signal processing allowed distinguishing three different types of sensory stimuli such as tactile, proprioceptive and nociceptive ones with high performance. These findings further support the suitability of TIMEs for neuroprosthetic applications, by exploiting the transversal topographical structure of the peripheral nerves.

Ieee-Inst Electrical Electronics Engineers Inc2016

Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush

Lin Jin, Sylvain Eric Lengacher, Pierre Magistretti, Luc Pellerin

Elsevier2015