Synergistic effects of electrical and chemical cues with biodegradable scaffolds for large peripheral nerve defect regeneration

Large-gap peripheral nerve injuries (PNI) are often treated with autografts, allografts, or synthetic grafts to facilitate nerve regeneration, but these options are often limited in their availability or functionality. To address these issues, we developed ionically conductive (IC) nerve guidance conduits (NGCs) of sufficient biodegradability, mechanical strength, and bioactivity to support large-gap nerve regeneration. These chitosan-based NGCs release 4-aminopyridine (4-AP) from embedded halloysite nanotubes, and the NGC's IC properties enable transcutaneous electrical stimulation (ES) without invasive electrodes. <i>In vitro</i>, we found scaffolds with ES+4-AP synergistically enhanced Schwann cell adhesion, proliferation, and neurotrophin secretion, significantly improving axonal growth and neurite extension. <i>In vivo</i>, these scaffolds in large-gap PNI boosted neurotrophin levels, myelination, nerve function, and muscle weight while promoting angiogenesis and reducing fibrosis. Upregulated Trk receptors and PI3K/Akt and MAPK pathway highlight the regenerative potential. This study advances understanding of ES-mediated regeneration and supports innovative strategies for nerve and musculoskeletal repair.