Biodegradable Polyurethane Nerve Conduit Functionalized with NDP-MSH-Loaded Self-Assembling Peptide Hydrogel for Peripheral Nerve Regeneration

Abstract

Autologous nerve grafting remains the clinical gold standard for segmental peripheral nerve repair but it is limited by donor-site morbidity and graft availability. Nerve guidance conduits (NGCs) offer a promising alternative for peripheral nerve repair. In this work, we engineered a fully biodegradable waterborne polyurethane (BWPU) NGC functionalized with a pH-responsive self-assembling peptide (SAP) loaded with [Nle4, D-Phe7]-α-melanocyte-stimulating hormone (NDP-MSH)-an α-MSH analogue that activates melanocortin receptors to confer neuroprotection by attenuating oxidative stress, apoptosis, and neuroinflammation. BWPU (17 mol% PEG) was fabricated into porous conduits and integrated with NDP-MSH-loaded SAP to provide mechanical support for peripheral nerve repair while enabling sustained release of the bioactive peptide during conduit degradation, thereby integrating structural guidance with antioxidant and pro-survival signaling to promote regeneration. In vitro, NDP-MSH at appropriate concentrations attenuated oxidative damage in RSC96 Schwann cells by reducing intracellular reactive oxygen species (ROS) levels and LDH release, thereby exerting cytoprotective effects. In vivo, 10-mm rat sciatic nerve defects were bridged with BWPU, SAP@BWPU, NDP-MSH@SAP@BWPU conduits, or autografts. Early post-implantation, NDP-MSH@SAP@BWPU reduced apoptosis and rapidly shifted the local repair microenvironment toward M2 macrophage dominance compared to other groups. At 60 days post-implantation, the NDP-MSH@SAP@BWPU group achieved sciatic nerve repair outcomes-structurally, functionally, and electrophysiologically-comparable to those of the autograft group. These findings 3 demonstrate that the NDP-MSH-loaded BWPU-SAP system provides an effective, controlled peptide-based release strategy to biofunctionalize biodegradable nerve guidance conduits, offering a viable alternative to autografts for peripheral nerve repair.