Hierarchical chirality of bone cement drives osteoinduction via integrin dependent signaling to accelerate critical bone defect regeneration

The biocompatibility and degradability of calcium phosphate bone cement (CPC) make it a potential therapeutic strategy to critical bone defects repair. However, it fails to create a stable extracellular microenvironment for inducing stem cells osteogenic differentiation, which hinders the wider clinical application. Receiving inspiration from chiral structures in biological organisms, particularly skeleton, we incorporated hierarchical chiral hydroxyapatite (CHA) into CPC to fabricate the microenvironment conducive to bone repair. Interestingly, levorotatory hydroxyapatite (LH) cement significantly enhanced osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs), followed by racemic hydroxyapatite (RH) cement. Whereas dextral hydroxyapatite (DH) and achiral hydroxyapatite (HA) cement didn't display a comparable effect. The differentiated osteoblasts and osteogenic proteins on the LH cement continuously recruited stem cells, facilitating the construction of osteoinductive microenvironment. Regard to the underlying mechanism, LH bone cement tightly bound to integrin α9, thereby facilitating the activation of PI3K/AKT pathway and enhancing the expression of osteogenic transcription factors. Following the implantation of LH bone cement into femur defect of rabbits, it exhibited good biocompatibility, enhanced the vascularization of bone defect region, and accelerated new bone formation effectively.