PROJECT SUMMARY Peripheral nervous system (PNS) injuries impact millions of Americans each year with approximately 20 million people currently living with the effects of such injury. In the case of severe injuries, nerve pathways, connections, and the extracellular matrix (ECM) surrounding the nerve that lead to the distal innervation targets are disrupted. If the injury gap is large enough, functional recovery is extremely limited and adequate clinical therapies don’t exist. A key reason for poor functional recovery is that neurons lack the proper guidance, alignment, and signaling from the damaged ECM to allow for targeted growth across injured tissue. Therefore, our overarching goal is to develop an ultrashock-mediated, bioactive scaffold to address traumatic PNS injury. The scaffold will possess controllable electrical, physical, and chemical signaling capabilities to address guidance, alignment, and cell-ECM communication. Piezoelectric poly(vinylidene fluoride-co-trifluoroethylene)(PVDF-TrFE) is integrated with decellularized ECM and capable of producing controllable electrical stimulation in response to remote ultrashock activation without the need for electrodes due to its piezoelectric capacity. The studies proposed will focus on quantitatively determining and controlling the electric potential of the scaffolds due to ultrashock and mechanical stimulation (Aim 1), analysis of the integration and phenotypic response of Schwann cells to PVDF-TrFE scaffolds (Aim 2), and the ability of the scaffold to minimize immune response while evaluating the ability to repair critical sized nerve gaps in vivo (Aim 3).