Microenvironment-engineered hydrogels drive osteo-angiogenic coupling to accelerate osteoporotic bone regeneration

Osteoporotic bone defects repair remians significant clinical challenges, characterized by impaired osteogenic differentiation and dysregulated angiogenesis within a microenvironment of oxidative stress and chronic inflammation. Modulating this pathological microenvironment to create favorable conditions is a pivotal strategy for treating osteoporotic bone defects. In this study, we developed a multifunctional composite hydrogel (SMm) through photo-crosslinking, incorporating Metformin (Met) and magnesium oxide nanoparticles (MgO), to promote osteoporotic bone regeneration. The SMm hydrogel demonstrated optimal physicochemical characteristics and excellent biocompatibility in vitro. Through controlled release of Mg²⁺ions and Met, the SMm hydrogel exhibited dual bioactivity: (1) robust osteogenic and angiogenic capacity, as evidenced by upregulation of key markers like Col 1, Runx-2 and VEGF, and (2) potent antioxidant and anti-inflammatory effects, effectively scavenging reactive oxygen species (ROS) and suppressing pro-inflammatory cytokines. Notably, under simulated osteoporotic conditions, SMm hydrogel significantly enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), overcoming the inhibitory microenvironment. In vivo validation using an osteoporotic bone defect model further confirmed the therapeutic efficacy of SMm hydrogel, with micro-CT scans revealing increased new bone formation in the defect area. In summary, this study establishes SMm hydrogel as a promising biomaterial for osteoporotic bone regeneration, leveraging synergistic ion therapy and metabolic modulation to address pathological barriers.