GelMA–HIF-1α composite hydrogels drive osteogenesis-angiogenesis coupling for bone defect repair

Bone defects remain a major clinical challenge due to limited intrinsic bone regeneration and insufficient vascularization. This study asked whether sustained presentation of hypoxia-inducible factor-1α (HIF-1α) within a biomaterial scaffold could simultaneously couple osteogenesis and angiogenesis to improve bone repair. A GelMA-based hydrogel was engineered by covalently immobilizing HIF-1α via EDC/NHS chemistry to achieve prolonged bioactivity. In vitro effects were evaluated using bone marrow stromal cells (BMSCs) and endothelial cells, and in vivo efficacy was assessed in a rat calvarial defect model. Multi-omics analyses and extracellular acidification rate (ECAR) assays were used to explore underlying mechanisms. The novelty of this work lies in the stable covalent conjugation strategy enabling sustained HIF-1α signaling within a degradable hydrogel, integrated with systems-level mechanistic analysis linking cellular responses to metabolic regulation. Results showed enhanced osteogenic differentiation of BMSCs, increased endothelial migration and tube formation, and significantly improved new bone formation with greater mineral deposition and vascular ingrowth in vivo. Mechanistically, HIF-1α promoted intercellular communication, extracellular matrix remodeling, hypoxia adaptation, and metabolic reprogramming, accompanied by elevated glycolytic activity. Overall, this study demonstrates a biomaterial platform that coordinates vascularized bone regeneration through sustained HIF-1α signaling and metabolic coupling.