Bisphosphonate-Functionalized Injectable Hydrogel Microspheres Enable Zinc-Mediated Reconstruction of a Vascularized Osteogenic Microenvironment for Osteoporotic Bone Regeneration

Abstract Osteoporotic bone regeneration remains challenging because impaired vascularization and disruption of the regenerative microenvironment compromise functional bone repair. In this study, we developed an injectable hydrogel microsphere platform with BP-mediated mineral affinity (GH-BZ) for localized and sustained Zn2+ delivery to promote vascularized osteoporotic bone regeneration. GH-BZ microspheres were fabricated using GelMA/HAMA hydrogels integrated with ZIF-8 nanoparticles and bisphosphonate functionalization to provide controlled Zn²⁺ release and potential hydroxyapatite-associated retention. The microspheres exhibited favorable injectability, porous structures, sustained ion release, and good biocompatibility. In vitro studies demonstrated enhanced endothelial migration, tube formation, and osteogenic differentiation following GH-BZ treatment. In an osteoporotic rat femoral condyle defect model, GH-BZ microspheres significantly promoted trabecular bone regeneration, collagen deposition, and neovascularization. Transcriptomic analysis further suggested the involvement of extracellular matrix remodeling and focal adhesion-associated signaling during regeneration. Collectively, these findings indicate that GH-BZ microspheres provide a promising injectable biomaterial strategy for reconstructing the vascularized osteogenic microenvironment and improving osteoporotic bone repair.