Flexible Multielectrode Array for Skeletal Muscle Conditioning, Acetylcholine Receptor Stabilization and Epimysial Recording After Critical Peripheral Nerve Injury.

Complete re-innervation after a traumatic injury severing a muscle's peripheral nerve may take years. During this time, the denervated muscle atrophies and loses acetylcholine receptors, a vital component of the neuromuscular junction, limiting functional recovery. One common clinical treatment for atrophy is electrical stimulation; however, epimysial electrodes currently used are bulky and often fail due to an excessive inflammatory response. Additionally, there remains a need for a device providing in vivo monitoring of neuromuscular regeneration and the maintenance of acetylcholine receptors. Here, an implantable, flexible microelectrode array (MEA) was developed that provides surface neuromuscular stimulation and recording during long-term denervation. Methods: The MEA uses a flexible polyimide elastomer and an array of gold-based microelectrodes featuring Peano curve motifs, which together maintain electrode flexibility. The devices were implanted along the denervated gastrocnemius muscles of 5 rats. These rats underwent therapeutic stimulation using the MEA daily beginning on post-operative day 2. Another 5 rats underwent tibial nerve resection without implantation of MEA. Tissues were harvested on post-operative day 14 and evaluated for quantification of acetylcholine receptors and muscle fiber area using immunofluorescence and histological staining. Results: The Young's modulus was 1.67 GPa, which is comparable to native tendon and muscle. The devices successfully recorded electromyogram data when implanted in rats. When compared to untreated denervated muscles, MEA therapy attenuated atrophy by maintaining larger muscle fiber cross-sectional areas (p < 0.05). Furthermore, the acetylcholine receptor areas were markedly larger with MEA treatment (p < 0.05). Conclusions: This proof-of-concept work successfully demonstrates the ability to combine conformability, tensile strength-enhancing metal micropatterning, electrical stimulation and recording into a functional implant for both epimysial stimulation and recording.

Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations.

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled-release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites-subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

Polyimide Electrode-Based Electrical Stimulation Impedes Early Stage Muscle Graft Regeneration.

Given the increasing use of regenerative free muscle flaps for various reconstructive procedures and neuroprosthetic applications, there is great interest and value in their enhanced regeneration, revascularization, and reinnervation for improved functional recovery. Here, we implant polyimide-based mircroelectrodes on free flap grafts and perform electrical stimulation for 6 weeks in a murine model. Using electrophysiological and histological assessments, we compare outcomes of stimulated grafts with unstimulated control grafts. We find delayed reinnervation and abnormal electromyographic (EMG) signals, with significantly more polyphasia, lower compound muscle action potentials and higher fatigability in stimulated animals. These metrics are suggestive of myopathy in the free flap grafts stimulated with the electrode. Additionally, active inflammatory processes and partial necrosis are observed in grafts stimulated with the implanted electrode. The results suggest that under this treatment protocol, implanted epimysial electrodes and electrical stimulation to deinnervated, and devascularized flaps during the early recovery phase may be detrimental to regeneration. Future work should determine the optimal implantation and stimulation window for accelerating free muscle graft regeneration.