Functionalized 3D-printed porous titanium scaffold induces in situ vascularized bone regeneration by orchestrating bone microenvironment.

• A silicon-doped hydroxyapatite (nSiHA)/titanium dioxide (TiO 2) composite coating with a hierarchical micro/nano-network structure was successfully constructed on Ti scaffold surface, which could achieve the spatiotemporal release of Si ions and vascular endothelial growth factor (VEGF). • The functionalized Ti scaffold significantly promoted osteogenesis in bone marrow mesenchymal stem cells and angiogenesis in human umbilical vein endothelial cells by activating the ERK and HIF-1α signaling pathways. • By orchestrating the two coupled processes of angiogenesis and osteogenesis, the functionalized Ti scaffold was capable of inducing in situ vascularized bone regeneration and consequently accelerating bone defect healing. Titanium (Ti) and its alloys have been extensively explored for treating load-bearing bone defects. However, high-stress shielding, weak osteogenic activity, and insufficient vascularization remain key challenges for the long-term clinical outcomes of Ti-based implants. Herein, inspired by structural and functional cues of bone regeneration, a silicon-doped nano-hydroxyapatite (nSiHA)/titanium dioxide (TiO 2) composite coating with a hierarchical micro/nano-network structure is constructed on the surface of a 3D-printed porous Ti scaffold via a combined strategy of acid-alkali (AA) treatment and electrochemical deposition technique, which not only endows the scaffold with excellent osteoinduction ability but can also effectively immobilize and release vascular endothelial growth factor (VEGF). The results of the in vitro cell experiments show that the functionalized Ti scaffold significantly promotes osteogenesis in bone marrow mesenchymal stem cells (BMSCs) and angiogenesis in human umbilical vein endothelial cells (HUVECs) by activating the extracellular signal-regulated protein kinase (ERK) and HIF-1α signaling pathways. After being implanted into a rat femoral condyle defect model, the functionalized Ti scaffold can induce in situ vascularized bone regeneration by orchestrating the two coupled processes of angiogenesis and osteogenesis. These findings indicate that the functionalized Ti scaffold has great potential in bone tissue regeneration and is a promising candidate for load-bearing bone defect repair. [Display omitted] [ABSTRACT FROM AUTHOR]