Synergistic Integration of Immune Regulation and Bioactive Guidance Cues in Multi-Channel Nanofibrous Nerve Guidance Conduits for Accelerated Peripheral Nerve Regeneration

Peripheral nerve injury presents a significant clinical challenge due to the limited regenerative capacity of the injured nerves, often resulting in permanent functional deficits. A key obstacle to effective nerve regeneration is the inability to modulate the inflammatory response, guide axonal elongation, and promote myelination. To address these challenges, we developed a multi-channel nerve guidance conduit (NGC) that integrated immune-modulating drug with gradient cues to enhance peripheral nerve regeneration. The inner tubes of the conduit were composed of degradable electrospun gelatin methacryloyl/collagen (GelMA/COL) fibers loaded with 1400W, an inducible nitric oxide synthase (iNOS) inhibitor. The outer tube consisted of electrospun polycaprolactone (PCL) fibers decorated with a density gradient of collagen particles encapsulating acidic fibroblast growth factor (aFGF). The release of 1400W enhanced macrophage activity and promoted their polarization from the pro-inflammatory M1 phenotype to the reparative M2 phenotype, thereby creating a pro-regenerative microenvironment conducive to nerve repair. The incorporation of gradient cues guided and promoted Schwann cell migration and neurite extension in vitro. In a rat sciatic nerve injury model, the conduit significantly improved nerve regeneration by sequentially modulating the inflammatory response and guiding axonal elongation, providing both spatial support and biological activity. Furthermore, the conduit promoted organized nerve fiber alignment, enhanced myelination, and achieved functional recovery outcomes that closely resembled those of the autograft. These findings suggest that the integration of immune-regulatory drug release, gradient cues, and a multi-channel structure presents a promising strategy for enhancing peripheral nerve repair.

Graphical Abstract