Peripheral nerve regeneration: From molecular mechanisms to biomaterial design strategies

• Early macrophage recruitment and myelin debris clearance define key biological constraints for peripheral nerve repair. • Macrophages orchestrate stepwise peripheral nerve regeneration through dynamic interactions with multiple cell types. • Effective nerve repair biomaterials must enable cell infiltration and spatiotemporal control of the regenerative microenvironment. • Injectable hydrogels offer design flexibility to modulate cellular behavior and microenvironmental cues during nerve regeneration. Peripheral nerves possess an intrinsic capacity for regeneration; however, spontaneous functional recovery after severe peripheral nerve injury remains rare in clinical practice. This limitation is largely attributed to the inability to maintain a supportive regenerative microenvironment at the injury site in vivo . Successful peripheral nerve regeneration relies on a tightly regulated microenvironment that orchestrates cellular recruitment, intercellular communication, and tissue remodeling following injury. After nerve damage, dedifferentiated Schwann cells initiate regeneration by recruiting macrophages to the lesion site. Accumulating evidence indicates that macrophages are key regulators of peripheral nerve repair, contributing to debris clearance, angiogenesis, axonal guidance, and Schwann cell redifferentiation. Their functional plasticity and stage-dependent interactions with multiple cell types underscore the importance of spatiotemporal control of the regenerative milieu. These insights highlight macrophage-mediated microenvironmental dynamics as critical design parameters for biomaterials aimed at peripheral nerve repair. Accordingly, various biomaterial-based strategies have been explored, among which injectable hydrogel scaffolds offer unique design flexibility to regulate cellular behavior and microenvironmental cues at the injury site. This review integrates molecular and cellular mechanisms with emerging biomaterial approaches to propose design considerations for next-generation nerve repair materials, emphasizing the importance of macrophage-driven microenvironmental regulation for effective biomaterial design and improved clinical outcomes.