Osteogenic GelMA/Calcium Oligophosphate Composite Hydrogel for Bone Regeneration

Critical-sized bone defects (CSDs) represent a major clinical challenge due to their limited self-healing capacity. Conventional hydrogels incorporating crystalline hydroxyapatite (HA) often fail to recapitulate the hierarchical nanostructure of native bone, leading to suboptimal regeneration outcomes. To overcome this, we developed a biomimetic hydrogel by molecularly integrating amorphous calcium phosphate oligomers (CPO) into gelatin methacryloyl (GelMA), enabling a bone-like organic–inorganic hybrid network. This composite exhibits outstanding performance: an ultimate strength of 192 kPa at 18 wt% CPO confirms robust mechanical reinforcement, while 54% mass retention after 56 days underscores exceptional degradation resistance and dose-dependent bioactivity, evidenced by a two-fold upregulation of alkaline phosphatase (ALP) activity. The amorphous CPO facilitates biomimetic HA nucleation within the GelMA matrix, mimicking the natural mineralization process. In a rat calvarial CSD model, the hydrogel promoted 60% bone volume regeneration within 12 weeks, significantly outperforming conventional composites, through seamless host integration, vascularized trabecular bone formation, and a collagen–mineral hierarchy resembling native osteogenesis. This study establishes CPO as a transformative component that converts passive scaffolds into bioactive osteogenic microenvironments, offering a clinically viable strategy for complex bone regeneration.