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Repairing large bone defects effectively requires concurrent osteogenesis and angiogenesis, a significant challenge for conventional biomaterials often limited by suboptimal structural design and an inability to provide spatiotemporally controlled bioactive cues. Here, we report a novel chemophysical dual-responsive system rationally designed to address this osteogenic-angiogenic coupling challenge. This system integrates a structurally engineered bimetallic FeCu-metal-organic framework (FeCu-MOF) within a poly(lactic acid)/hydroxyapatite (PLA/HA) scaffold. The engineered FeCu-MOF architecture enables the programmed and sustained co-release of Fe 3+ and Cu 2+ ions, providing tailored chemical signals. Synergistic pulsed electromagnetic field (PEMF) stimulation was introduced as a physical cue to further enhance the scaffold's bioactivity. The composite scaffolds, featuring interconnected hierarchical porosity and enhanced hydrophilicity due to FeCu-MOF incorporation, demonstrated distinct Fe 3+ /Cu 2+ release profiles. In vitro , these scaffolds exhibited excellent biocompatibility and significantly promoted bone marrow mesenchymal stem cells (BMSCs) proliferation and osteogenic differentiation. Notably, this structure-derived dual-ion release also indicated pro-angiogenic potential. Crucially, daily PEMF treatment synergistically amplified these cellular responses. In vivo evaluation in a rat cranial defect model confirmed the system's efficacy. While FeCu-MOF/PLA/HA scaffolds alone enhanced bone regeneration, their combination with PEMF yielded the most robust outcomes, characterized by markedly superior vascularized bone formation. Comprehensive analysis, including micro-CT, histology, and immunohistochemistry, confirmed these findings by demonstrating improved bone volume, density, and architecture, mature integrated tissue, and enhanced coupled expression of CD31 and osteogenic markers. In summary, the study validates a powerful synergistic strategy for enhanced bone regeneration. This strategy, integrating programmable, structure-derived bimetallic ion release with PEMF stimulation, successfully achieved synergistic angiogenic-osteogenic coupling, offering a promising approach for complex defect scenarios.
Guo et al. (Tue,) studied this question.