Biodegradable polyurethane nerve conduits functionalized with NDP-MSH-loaded self-assembling peptide hydrogels 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 and has been reported to attenuate 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 controlled peptide release, thereby coupling structural support with antioxidant/pro-survival signaling. In vitro, NDP-MSH at appropriate concentrations attenuated oxidative damage in RSC96 Schwann cells by reducing intracellular reactive oxygen species (ROS) and LDH release. In vivo, 10-mm rat sciatic nerve defects were bridged with BWPU, SAP@BWPU, NDP-MSH@SAP@BWPU conduits, or Autograft. Early post-implantation, NDP-MSH@SAP@BWPU reduced apoptosis and promoted an M2-enriched immune microenvironment. At 60 days post-repair, the NDP-MSH@SAP@BWPU group achieved structural, functional, and electrophysiological outcomes comparable to the Autograft group. These findings demonstrate that NDP-MSH delivery via a BWPU-SAP depot-enabled conduit is an effective strategy to biofunctionalize biodegradable NGCs and may offer a viable alternative to autografts for peripheral nerve repair.