Harnessing copper-strontium synergy in an injectable composite for multi-pathway bone regeneration

Bone regeneration, particularly in critical-sized defects, remains a significant clinical challenge. Hydroxyapatite (HA) is widely used due to its similarity to bone mineral, yet its biological activity often requires improvement. Incorporation of therapeutic metal ions has shown promise, but the combined and mechanistically distinct effects of copper (Cu) and strontium (Sr) remain underexplored. Cu and Sr influenced stem cells via different signaling pathways: Cu enhanced angiogenesis and modulated differentiation, while Sr promoted osteogenesis and bone remodeling. Importantly, these differences extended beyond stem cell regulation; Cu and Sr activated distinct mechanisms in both osteogenesis and angiogenesis. When combined, this dual action resulted in a true synergistic effect, independently enhancing osteogenic and angiogenic outcomes beyond what either ion can achieve alone. To exploit this, we developed an injectable dual-network hydrogel composed of polyvinyl alcohol (PVA) and sodium alginate (SA), incorporating Cu/Sr co-doped HA synthesized via hydrothermal methods. By varying synthesis temperature (80, 120, 160 °C), we revealed the dependence of HA crystallinity on bioactivity and identified 120 °C as optimal for coupling mechanical stability with biological performance. Cytotoxicity assays established the safe Cu threshold and defined the single-ion optima for Cu and Sr. Strikingly, co-doping at these optima yielded a composite with excellent injectability, robust in vitro and ex vivo biocompatibility, and, most importantly, synergistic promotion of both osteogenesis and angiogenesis through complementary mechanisms. This dual-ion strategy provides a novel route for synchronizing bone and vascular regeneration in bone repair.