Project Summary Twenty million Americans suffer from peripheral nerve injury, which results in approximately $150 billion health-care expenses annually in the United States. Approximately half of patients treated with nerve grafts have an inadequate level of function. Twenty million Americans suffer from peripheral nerve injury, which results in approximately $150 billion health-care expenses annually in the United States. Among various factors, axon growth rate and the lack of reinnervation and neuromuscular regeneration are two major road barriers. In many cases, during peripheral regeneration, the muscle undergoes atrophy and becomes un-receptive to reinnervation, and even the sprouting axons that regenerate across the gap cannot form functional neuromuscular junctions (NMJs). While most of the previous studies focus on accelerating peripheral nerve growth, novel approaches to maintain the neuromuscular receptivity and delay the degeneration of muscle need to be developed and integrated. Therefore, an integrative approach that combines the acceleration of axon growth and the prevention of muscle degeneration is required to address this unmet medical need, and we propose to use multimodal electrical stimulation (ES) to achieve this goal. Our recent studies have shown that repetitive ES either at the proximal or distal stumps of transected nerve can be more effective than one-time ES to further improve the therapeutic outcome, but their relative contributions to and their combined effects on axon growth, the slow-down of muscle atrophy and reinnervation remain to be investigated. Therefore, to investigate the potential synergistic effects of proximal and distal ES, we hypothesize that programmable ES at the proximal and distal stumps of sciatic nerve following a transection injury can promote axon growth and maintain muscle receptivity respectively and synergize neuromuscular regeneration. We will test this hypothesis by developing a wireless, stretchable, bioresorbable and miniaturized system that allows repetitive ES with versatile protocols. To address the aforementioned challenges and test our hypothesis, we have assembled a multidisciplinary team, and performed pilot studies to demonstrate the feasibility. We propose three Specific Aims: (1) To develop and characterize a bioresorbable, stretchable and wireless bioelectronic device for repetitive electrical stimulation. (2) To determine how the time periods of repetitive proximal and distal ES regulate muscle functional recovery. (3) To investigate the combined effects of proximal and distal ES on neuromuscular regeneration. This proposed project is timely with the recent advancement in regenerative engineering, micro/nanotechnologies, miniaturized wireless point-of-care devices, and bioresorbable and stretchable electrodes. This innovative bioelectronic device provides a novel and minimally invasive approach for neuromuscular regeneration, and will have wide applications in regenerative me...