Biomaterial and Hydrogel Strategies for Regenerative Microenvironment Reconstruction in Peripheral Nerve Conduits

Peripheral nerve injury (PNI) poses a major clinical challenge, frequently resulting in chronic pain, muscle atrophy, and long-term functional impairment. While autologous nerve grafting remains the gold standard for repairing long-gap defects, its application is limited by donor-site morbidity and limited tissue availability. Nerve guidance conduits (NGCs) have emerged as promising alternatives; however, their efficacy remains suboptimal, primarily because most fail to recapitulate the spatiotemporally coordinated regenerative microenvironment required for robust axonal extension, timely remyelination, and durable neurovascular integration. Key limitations of current designs include an inability to balance the bioactivity of natural materials with the tunability of synthetic polymers, insufficient nutrient and oxygen delivery for long-gap repair, and a lack of dynamic, stage-specific regulation of the healing process. Consequently, microenvironment reconstruction represents the central bottleneck to achieving effective regeneration. This review synthesizes recent advances in purposefully rebuilding the NGC microenvironment across three interdependent dimensions: (i) activation and functional regulation of Schwann cells; (ii) immunomodulation to resolve inflammation while promoting repair; (iii) angiogenesis to ensure metabolic support. We place special emphasis on biomaterial strategies, particularly advanced hydrogels that integrate physical, biochemical, and dynamic cues for spatiotemporally programmed regeneration. Finally, we outline design principles and translational considerations for next-generation NGCs aimed at closing the efficacy gap with autografts.