Dual-metal-organic framework and gallic acid incorporated 3D-printed scaffolds: Revolutionizing refractory bone defect repair through immune-angiogenic-neurogenic synergy

Steroid-associated osteonecrosis (SAON)-related bone defects are refractory and present significant therapeutic challenges due to dysregulated multiple cellular functions and disrupted multidimensional microenvironments. Despite progress in regulating immune responses and promoting vascularization for SAON-related bone defects, effective neural innervation strategies remain limited. Notably, immune response, angiogenesis, and neural innervation are interdependent processes that collectively regulate bone regeneration. Herein, we engineered a novel 3D-printed composite scaffold with highly interconnected porosity and multiple bioactivities by integrating magnesium-copper dual-metal-organic framework (MgCu-MOF74), gallic acid (GA) and polylactic acid (PLA). MgCu-MOF74 exhibits antioxidant capacity, controllable release of metal ions, and osteo-angiogenic properties. The composite scaffold demonstrated excellent mechanical properties and degradation characteristics well suited for bone regeneration. More importantly, the incorporation of GA and dual-ion synergy enabled the scaffold to achieve pronounced multicellular modulation by promoting macrophage polarization, inducing endothelial cell-mediated angiogenesis, stimulating Schwann cell morphological maturation, and enhancing the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs), while markedly increasing intercellular crosstalk to optimize the local multidimensional microenvironment. In vivo studies further confirmed that the scaffold effectively facilitates the repair of SAON-related bone defects by harnessing the synergistic interactions among the immune, angiogenic, and neurogenic microenvironments. This work provides an innovative strategy for treating refractory SAON - related bone defects, highlighting the potential of the developed scaffold in modulating diverse cell types and remodeling complex microenvironments.