An injectable phosphocreatine-grafted hydrogel incorporating hierarchically structured teriparatide/SrZnP-functionalized Zn–Cu particles for osteogenesis–angiogenesis coupling and osteoporotic bone regeneration

Osteoporotic bone defects remain a major clinical challenge due to impaired osteogenesis, insufficient angiogenesis, excessive osteoclast activity, and increased susceptibility to infection. To address these issues, we developed an injectable phosphocreatine-grafted gelatin hydrogel (GGP) incorporating hierarchically structured Zn-Cu particles functionalized with a teriparatide (PTH)/strontium-zinc phosphate (SrZnP) hybrid coating. This multifunctional hydrogel was fabricated via enzymatic and ionic coordination crosslinking, yielding improved mechanical properties and sustained release of Zn²⁺, Sr²⁺, and PTH. In vitro evaluations demonstrated that the hydrogel enhanced BMSC proliferation, osteogenic differentiation, and mineralization, promoted HUVEC migration, tube formation, and angiogenic marker expression, and simultaneously inhibited osteoclastogenesis and bacterial growth. Transcriptomic analysis and inhibitor experiments revealed a dual paracrine mechanism mediating bone-vascular coupling: BMSC-derived HIF-1α-VEGF signaling facilitated angiogenesis, while HUVEC-derived PI3K-Akt-BMP-2 signaling enhanced osteogenesis. In vivo, the PTH/SrZnP@ZnCu-GGP hydrogel significantly accelerated bone regeneration and neovascularization in an ovariectomized rat calvarial defect model, accompanied by upregulated expression of BMP-2, RUNX2, p-Akt, and CD31. Collectively, this injectable hydrogel system offers a robust and translationally feasible strategy for coordinated osteogenesis-angiogenesis coupling, osteoclast suppression, and antibacterial defense, thus holding strong potential for the regeneration of osteoporotic bone defects.