Oriented nanofibrous P(MMD-co-LA)/Deferoxamine nerve scaffold facilitates peripheral nerve regeneration by regulating macrophage phenotype and revascularization

Delayed injured nerve regeneration remains a clinical problem, partly ascribing to the lack of regulation of regenerative microenvironment, topographical cues, and blood nourishment. Functional electrospun conduits have been established as an efficacious strategy to facilitate nerve regeneration by providing structural guidance, regulating the regenerative immune microenvironment, and improving vascular regeneration. However, the synthetic polymers conventionally used to fabricate electrospinning scaffolds, such as poly(L-lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid), can cause aseptic inflammation due to acidic degradation products. Therefore, a poly[3(S)-methyl-morpholine-2,5-dione-co-lactic] [P(MMD-co-LA)] containing alanine units with good mechanical properties and reduced acid degradation products, was obtained by melt ring-opening polymerization (ROP). Here, we aimed to explore the effect of oriented nanofiber/Deferoxamine (DFO, a hydrophilic angiogenic drug) scaffold in the rapid construction of a favorable regenerative microenvironment, including cell bridge, polarized vascular system, and immune microenvironment. In vitro studies have shown that the scaffold can sustainably release DFO, which accelerates the migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as the expression of genes related to angiogenesis. The physical clues provided by the arranged nanofibers can regulate the polarization of macrophages and reduce the expression of inflammatory factors. Furthermore, the in vivo results demonstrated a higher M2 polarization level of the oriented nanofibrous scaffold treatment group with reducedinflammation reaction in the injured nerve. Moreover, the in-situ release of DFO up-regulated the expression of HIF1-α and SDF-1α genes, as well as the expression of HIF1-α's target gene VEGF, further promoting revascularization and enhancing nerve regeneration at the defect site. The obtained results provide essential insights on accelerating the creation of the nerve regeneration microenvironment by combining the physiological processes of nerve regeneration with topographical cues and chemical signal induction.