Strontium-doped Calcium Sulfate–Calcium Phosphate Composite Cement with Bone-Matched Strength and Triple Osteogenic–Angiogenic–Immunomodulatory Functions

Current bone cements for percutaneous vertebroplasty (PVP) suffer from a fundamental mismatch between mechanical stability, degradation behavior, and biological functionality, limiting their ability to support true vertebral regeneration. Here, we report a novel injectable strontium-doped calcium sulfate–calcium phosphate composite cement (Sr-CSC-CPC) that, for the first time, integrates bone-matched mechanical strength, healing-synchronized degradation, and coordinated osteogenic, angiogenic, and immunomodulatory biofunctions within a single injectable system. The Sr-CSC-CPC cement exhibits cancellous bone-level compressive strength (10–15 MPa), low setting temperature, excellent injectability, and a controllable degradation period of approximately 16 weeks, closely matching the temporal requirements of vertebral bone repair. Strontium incorporation further transforms the cement from a passive filler into an active regenerative material by simultaneously enhancing osteogenesis through PI3K/AKT/mTOR pathway activation, promoting angiogenesis, and modulating the immune microenvironment via macrophage polarization toward the pro-regenerative M2 phenotype. Importantly, these three biological processes are synergistically coupled, establishing a regenerative microenvironment that supports both early vascularization and sustained bone formation during cement degradation. Notably, the superior performance of the 5% Sr-CSC-CPC formulation arises from its ability to maintain a favorable local pH microenvironment while providing a sustained Sr²⁺ release within a bioactive concentration window, thereby maximizing osteogenic, angiogenic, and immunomodulatory responses without inducing cytotoxicity or inflammatory imbalance. This work demonstrates a materials-by-design strategy for vertebral bone cements, highlighting Sr-CSC-CPC as a multifunctional alternative to conventional PMMA and providing a paradigm for integrating mechanical, degradative, and immuno-osteogenic-angiogenic functions in injectable bone repair materials. Fig. 1. Schematic illustration of the multifunctional Sr-CSC-CPC bone cement developed for percutaneous vertebroplasty (PVP). The injectable composite exhibits key physicochemical advantages, including biodegradability, cancellous bone-like mechanical strength, excellent injectability, low exothermic setting temperature, and favorable biocompatibility. Biologically, the Sr-CSC-CPC cement promotes osteogenesis via activation of the PI3K/AKT/mTOR signaling pathway, enhances angiogenesis, and facilitates macrophage polarization toward the M2 phenotype. These synergistic effects contribute to an optimal microenvironment for bone regeneration and effective repair of vertebral fractures.