An Engineered SIM@ZIF-8 Hydrogel Synergistically Enhances Vascularized Bone Regeneration in an Osteoporotic Environment

To address the coupled impairment of osteogenesis and angiogenesis in osteoporosis, we developed a synergistic two-factor delivery strategy based on photo-cross-linked nanocomposite hydrogels (nSZCSG). This system innovatively integrates simvastatin (SIM) loaded zeolite imidazolate skeleton-8 (ZIF-8) nanoparticles into a methacrylated chitosan-gelatin matrix, endowing the material with controllable mechanical properties and a long-lasting local bioactive factor reservoir. The key breakthrough lies in the synergistic sustained release of Zn 2+ and simvastatin by the ZIF-8 vector, which enables the hydrogel to simultaneously regulate three major regeneration processes: powerful cell recruitment, efficient osteogenesis, and enhanced angiogenesis. This system thus effectively coordinates the “osteogenic–angiogenic coupling” that is often disrupted in the osteoporotic environment and significantly accelerates angiogenic bone regeneration under osteoporotic conditions in both in vitro and in vivo experiments. This study proposes an efficient biomaterial strategy that achieves a breakthrough in the traditional single-factor delivery model by collaboratively targeting multiple pathological dimensions of osteoporotic bone defects.