Abstract
Personalized porous scaffold materials for bone defect repair, with adjustable mechanical strength and porosity via 3D printing technology, have made significant strides in the bone tissue engineering. However, their ability to regulate the angiogenesis processes at the defect site remains constrained, hindering the effective coupling of angiogenesis-bone regeneration. In this study, we incorporated Nb(2)C MXene as a photothermal agent and enhancer for both angiogenesis and osteogenesis, embedded into a poly (lactic-co-glycolic acid)/β-tricalcium phosphate (PLGA/β-TCP) composite biological ink. Nb releasing and precisely gentle thermotherapy successfully enhanced both angiogenesis and bone regeneration while promoting their coupling. The in vitro experiments demonstrate that the scaffold induces the upregulation of MMP family members, particularly MMP-1, MMP-3, and MMP-10, during the initial stage of bone defect repair under mild hyperthermia conditions. It promotes vascular basement membrane degradation, effectively initiating angiogenesis. Moreover, it directly activates the HIF-1/STAT3/VEGF pathway in HUVECs and triggers HSP90 expression, which stabilizes and activates the PI3K-AKT pathway in BMSCs. Consequently, this sequential linkage between PI3K-AKT and HIF-1 pathways enhances bone formation while facilitating angiogenic bone regeneration, as evidenced by the increased expression of specialized H-type vessels in rat cranial critical defect models. In vivo experimental findings further validate the effective promotion of angiogenic bone regeneration by this precision-designed PTMN scaffold under mild hyperthermia conditions, making it an effective solution for large-area bone defect repair. In summary, the precise design and manufacture of the PTMN scaffold using mild hyperthermia to fix large bone defects is a promising approach that has huge implications.