Acellular Nerve Perineurium Repairs Peripheral Nerve Injuries in a Rat Model via ECM-Mediated Barrier and Optimization of the Regenerative Microenvironment

Abstract Building upon the clinically established platform of acellular nerve allografts (ANAs), we developed an advanced derivative: acellular nerve perineurium (ANP) grafts. These grafts are characterized by their preservation of the native perineurial barrier architecture and a unique extracellular matrix (ECM) composition, distinct from the endoneurial basement membrane. This distinctive ECM profile endows ANPs with significantly enhanced barrier integrity and robust neuroprotective properties. In vitro evaluations confirmed that ANP provides a highly favorable substrate, effectively supporting the adhesion and active proliferation of dorsal root ganglion neurons. In a rat model of sciatic nerve transection, ANP grafts demonstrated remarkable therapeutic efficacy. They markedly inhibited the deposition of chondroitin sulfate proteoglycans (CSPGs) at the repair site, thereby preventing traumatic neuroma formation. Furthermore, ANP treatment resulted in a doubling of regenerated axon density and a significant increase in target muscle action potential amplitude. Behavioral recovery in ANP-treated animals approached the functional levels observed in crush-injury controls. Multiomics analyses provided mechanistic insight, revealing that ANP-mediated repair activates multiple pro-regenerative signaling pathways. These collective findings position ANP grafts as a highly promising and clinically translatable biomaterial strategy for improving functional outcomes in peripheral nerve repair.