Injectable photo-crosslinked phosphocreatine-functionalized chitosan hydrogel enhanced by ZnSrP nanoparticles for synchronized angiogenesis and osteogenesis in bone defect repair

Repairing critical-sized bone defects remains a significant clinical challenge. Although chitosan (CS)-based hydrogels show promise for bone regeneration, their application is limited by insufficient mechanical strength and inadequate osteogenic and angiogenic properties. Herein, we synthesized Zn- and Sr-containing phosphate particles (ZnSrP) via a sintering and ball milling process, followed by surface modification with polydopamine (PDA) to obtain bioactive nanoparticles. These PDA-coated ZnSrP nanoparticles were incorporated into a phosphocreatine-grafted, photo-crosslinked methacryloyl chitosan (CSMP) hydrogel to form a CSMP&ZnSrP composite system. The resulting hydrogel exhibited enhanced compressive strength and modulus, and enabled sustained release of Zn 2+ and Sr 2+ ions. Mechanistically, Zn 2+ and Sr 2+ promoted angiogenesis in HUVECs via activation of the HIF-1α pathway and osteogenesis in BMSCs through the PI3K/Akt/Sgk1 signaling axis. Notably, the CSMP&ZnSrP hydrogel synchronized the coupling of angiogenesis and osteogenesis between HUVECs and BMSCs. In both the rat calvarial and rabbit femoral condyle critical-sized defect models, the hydrogel significantly accelerated new bone formation, underscoring its potential as an advanced injectable material for critical-sized bone regeneration.