3D printed biomimetic composite scaffolds with sequential releasing of copper ions and dexamethasone for cascade regulation of angiogenesis and osteogenesis

Repairing bone defects is a complex multi-stage physiological process involving the coupling of early angiogenesis and later osteogenesis and is often complicated by infection, therefore, this process remains a major clinical problem. Although functional drug-loaded engineered scaffolds are promising for in resolving this issue, effectively replicating the natural healing cascade via sequential delivery of angiogenic and osteogenic signals remains a challenge. In this study, a vascularized bone scaffold loaded with copper ions (Cu2+) and mesoporous silica nanoparticles (MSNs) preloaded with dexamethasone (DEX) (MSNs@DEX) was fabricated via 3D printing to achieve coupled angiogenesis and osteogenesis. This scaffold promoted early angiogenesis through the rapid release of Cu2+ and later-stage osteogenesis through the gradual release of DEX, thus mirroring physiological bone repair processes. Our systematic characterization revealed that the scaffold exhibited favorable mechanical properties with a compression modulus of 25.49 ± 2.85 MPa to provide mechanical support, and had obvious antibacterial activity, confirming the sequential release of Cu2+ and DEX in vitro. Our in vitro and in vivo experiments further demonstrated that the scaffold had great biocompatibility and promoted angiogenesis and osteogenesis. Hence, our findings underscore the clinical potential of this vascularized bone scaffold for large bone defect repair.