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.

Functional regeneration of osteochondral defects remains hindered by poor spatiotemporal coordination, insufficient endogenous stem cell recruitment, oxidative stress, and unresolved inflammatory microenvironments that drive apoptosis. To address this, we designed a magnesium boride (MgB ₂ )-functionalized bilayer scaffold that orchestrates spatiotemporal control over endogenous repair mechanisms. The upper mimics cartilage ECM that GelDA/HAMA hydrogel establishes a chondroinductive niche by recruiting synovial fluid-derived mesenchymal stem cells (SF-MSCs) via dopamine-mediated adhesion and RGD motifs. The lower 3D-printed MgB ₂ @PLGA scaffold mimics bone stiffness and releases Mg ²⁺ and H ₂ in a time-dependent manner, scavenging excess ROS during the early inflammatory phase and polarizing macrophages toward an anti-inflammatory M2 phenotype. The GelDA/HAMA hydrogel enhances stem cell adhesion and extracellular matrix remodeling to establish a pro-regenerative microenvironment. Sustained Mg ²⁺ release subsequently drives SF-MSC chondrogenesis and bone BMSC osteogenic mineralization. In a rabbit full-thickness osteochondral defect model, the scaffold promoted hyaline-like cartilage regeneration and subchondral bone mineralization at 6 and 12 weeks, with higher collagen II deposition at the integration interface compared to controls. This study presents a cell- and growth factor-free strategy that leverages the multifunctional biological properties of MgB ₂ to spatiotemporally coordinate immunomodulation, redox homeostasis, and dual-lineage differentiation.