Injectable oxidized sodium alginate/gelatin (OSA/Gel) hydrogel loaded with MgO/SZS for ion-mediated osteogenesis and macrophage polarization

Injectable OSA/Gel hydrogel with MgO and Sr–Zn–Si silicate bioceramic is developed. • Dual crosslinking enables rapid gelation, stable mechanics, and controlled degradation. • Sustained release of Mg, Sr, Zn and soluble Si species promotes osteogenic responses. • The hydrogel promoted a more anti-inflammatory, pro-regenerative macrophage profile. • Enhanced bone regeneration is achieved in a rabbit calvarial critical-sized defect model. Bone defect healing remains challenging due to trauma-associated microenvironmental disruption, persistent inflammation, and impaired coupling between bone formation and resorption. Here, we developed an injectable, biodegradable oxidized sodium alginate/gelatin (OSA/Gel) hydrogel with tunable gelation kinetics, favorable mechanical performance, and high shape fidelity for defect filling. By incorporating magnesium oxide (MgO) and Sr₂ZnSi₂O₇ (SZS) at different ratios, the formulation was optimized and its cytocompatibility and osteoimmunomodulatory activity were evaluated in vitro and in vivo. The hydrogel can be delivered minimally invasively to irregular defects and rapidly gels in situ into a porous three-dimensional scaffold, enabling sustained release of bioactive ions (Mg 2+ , Zn 2+ , Si 4+ , and Sr 2+ ). These ionic cues promoted osteogenic responses in MC3T3-E1 cells, as indicated by enhanced osteogenesis-related gene expression, increased alkaline phosphatase activity, and mineral deposition, and were concurrently associated with a shift of RAW264.7 macrophages toward a pro-regenerative M2 phenotype. In a rabbit calvarial defect model, the OSA/Gel–MgO/SZS hydrogel induced early osteoid-like tissue deposition and promoted the formation of low-mineral-density newly formed bone spanning the defect margins and extending toward the central region compared with controls. Overall, the OSA/Gel hydrogel containing 1.0% MgO and 0.5% SZS promoted bone regeneration, accompanied by enhanced osteogenic activity and a pro-regenerative immune response, demonstrating strong potential as a functional biomaterial for bone defect repair.