Engineered nerve guide conduit enhances peripheral nerve regeneration by modulating the microenvironment through macrophage-triggered cascade reactions

Nerve regeneration after peripheral nerve injury (PNI) depends on exogenous and endogenous pro-healing signals in the microenvironment. Maintaining immune system homeostasis and remodeling the regenerative microenvironment are crucial prerequisites for promoting nerve regeneration. Here, a double-layer PSM/Gel-SC(IL-4) nerve guide conduit was fabricated by photocrosslinking poly (ethylene glycol) diacrylate (PEGDA) and methacrylic acid-sodium alginate (SAMA) hydrogel as the outer layer, with GelMA encapsulating IL-4 overexpressing Schwann cells as the inner layer. PSM/Gel-SC(IL-4) conduit enabled the sustained release of IL-4, inducing pro-healing macrophages polarization through JAK1/STAT6 pathway <i>in vitro</i>. The polarized macrophages further triggered the cellular cascade reactions, enhancing the pro-healing characteristics of endothelial cells and Schwann cells. In addition, PSM/Gel-SC(IL-4) conduit significantly promoted functional recovery and nerve regeneration in 12-mm rat sciatic nerve defect model, induced pro-healing macrophage polarization at the early stage and accelerated angiogenesis and myelination at the nerve regeneration stage. This study developed a novel immunomodulatory strategy to remodel the regenerative microenvironment, and explored the underlying cellular and molecular mechanism, demonstrating considerable therapeutic potential for long-distance nerve defect.