A bioactive magnesium alloy scaffold integrated with BMSCs-Loaded 3D microspheres synergistically promotes femoral head osteonecrosis repair by improving the osteogenic-angiogenic microenvironment

Osteonecrosis of the Femoral Head (ONFH) is primarily characterized by impaired osteogenesis and insufficient vascularization, leading to progressive structural collapse and limb dysfunction. To develop a targeted strategy for regulating the bone-vascular microenvironment in hip preserving treatment, we integrated a three-dimensionally (3D) printed microporous magnesium alloy scaffold with bone marrow mesenchymal stem cells (BMSCs)-loaded 3D microspheres into a composite regenerative system. We then evaluated its therapeutic efficacy and investigated its underlying mechanisms. In vitro, the composite system demonstrated favorable biocompatibility and promoted osteogenic and angiogenic differentiation. In a steroid-induced rabbit model of femoral head necrosis, micro-CT and histological analysis confirmed the system's significant interventional effect. The magnesium alloy scaffold provided adequate mechanical support and released Mg 2+ ions to participate in microenvironmental regulation. The BMSCs-loaded 3D microspheres were firmly integrated with the scaffold, which increased BMSCs loading capacity and provided a protective growth environment that shielded cells from mechanical damage. Further experiments indicated that the composite system modulated the interactions among BMSCs, osteoblasts, and vascular endothelial cells. By activating Extracellular Matrix organization, Focal adhesion, and the PI3K-Akt signaling pathways, it regulated the osteoblast and endothelial cell-related bone-vascular microenvironment to promote femoral head repair. This study demonstrates that combining a bioactive magnesium scaffold with BMSCs-loaded microspheres synergistically promotes femoral head repair, highlighting the therapeutic potential of integrating bioactive ion release with cellular paracrine regulation. • A composite scaffold of BMSCs-loaded 3D microspheres and biodegradable microporous magnesium alloy promotes osteogenesis and angiogenesis in ONFH. • Controlled Mg²⁺ release and BMSCs paracrine effects synergistically remodel the bone regenerative microenvironment. • The composite scaffold may promote ONFH repair by activating the “PI3K/Akt–ECM-receptor interaction–Focal adhesion” axis.