Polydopamine-modified hydrogel nanofibers for sustained SFRP2 release: synergistic promotion of angiogenesis and nerve regeneration

Abstract Hydrogel nanofibers provide a regeneration-permissive environment conducive to the regrowth of numerous nerve fibers, thereby enhancing regenerative capacity in cases of peripheral nerve injury and spinal cord injury. However, developing hydrogel nanofiber-based nerve guidance conduits (NGCs) with tailored drug release profiles to synergistically promote angiogenesis and axonal regeneration remains a significant challenge. In this study, novel polydopamine (PDA)-modified gelatin methacryloyl (GelMA) hydrogel nanofibers are developed as an efficient drug delivery platform for sustained release of Secreted Frizzled-Related Protein-2 (SFRP2). This platform aims to promote neurite outgrowth, facilitate nerve function recovery, and enhance angiogenesis through Wnt signaling pathways. Results indicate that PDA coating significantly improves the hydrophilicity and mechanical properties of GelMA hydrogel nanofibers, which were fabricated using a combination of electrospinning and photo-crosslinking technology. This modification enables SFRP2 loading for sustained release through π-π stacking interactions and hydrogen bonding. In vitro experiments demonstrate that SFRP2-loaded hydrogel nanofibers effectively enhance the adhesion, proliferation, viability, and migration of Mouse Schwann Cells (MSCs), while also promoting tube formation and ameliorating the inflammatory microenvironment of Human Umbilical Vein Endothelial Cells (HUVECs). Furthermore, the SFRP2-loaded hydrogel nanofibers are confirmed to exert their functions for angiogenesis and peripheral nerve regeneration via the calcium-dependent calcineurin/NFATc3 signaling pathway. Finally, the hydrogel nanofiber-based NGCs are applied in a mouse model of peripheral nerve injury, and results demonstrate that the SFRP2 ~ PDA@GelMA conduit significantly enhances angiogenesis, promotes peripheral nerve repair, and facilitates target muscle restoration and functional recovery, thus presents a promising therapeutic strategy for patients with peripheral nerve injuries.