Abstract
BACKGROUND: The treatment of bone defects in the context of osteoporosis encounters numerous challenges. In the osteoporotic microenvironment, bone resorption outweighs bone formation, impeding the self-repair of bone defect areas. Furthermore, the deterioration of osteogenesis-angiogenesis coupling function at the defect sites and excessive inflammatory responses further complicate the treatment of bone defects. Hence, an improved approach is urgently needed to enhance the treatment of osteoporotic bone defects. METHODS: Our efficient strategy has developed a multi-scale biomimetic fusion alendronate sodium cerium ion hydrogel scaffold, integrating 3D-printed tricalcium phosphate (TCP) scaffolds, collagen-methacrylate (COMA) hydrogel, and nanoparticles of alendronate sodium cerium ions. In vitro, we intervened osteoporosis rat derived bone marrow stromal cells (BMSCs) with the extract of TCP-H-Alendronate sodium cerium ion nanoparticles (ACNP) scaffold and detected the osteogenesis-related indicators through alkaline phosphatase (ALP) enzymatic activity staining, alizarin red staining, Western Blot, RT-qPCR and immunofluorescence staining to evaluate the osteogenic differentiation effect of TCP-H-ACNP scaffold. Through transcriptome sequencing, we explored the mechanism of TCP-H-ACNP scaffold affecting osteogenic differentiation of osteoporotic BMSCs. We intervened human umbilical vein endothelial cells (HUVECs) with the extract of TCP-H-ACNP scaffold and evaluated the angiogenic effect of TCP-H-ACNP scaffold through tube formation assay and cell scratch assay. In vivo, we established a distal femoral bone defect model in osteoporotic rats and evaluated the therapeutic effect in vivo through Mirco CT, Hematoxylin and Eosin (H&E) stainin, Masson staining and immunohistochemical staining. RESULTS: The results demonstrated that in vitro, TCP-H-ACNP scaffolds could promote osteogenic differentiation of osteoporotic BMSCs from rats and angiogenesis of HUVECs. In vivo, TCP-H-ACNP scaffolds could promote bone regeneration and repair of distal femoral bone defects in osteoporotic rats and improve local angiogenesis. Mechanistically, TCP-H-ACNP scaffolds could directly promote osteogenic differentiation of osteoporotic BMSCs from rats through the Wnt signaling pathway, and indirectly promote osteogenic differentiation by influencing Ca ion transport and improving mitochondrial function. CONCLUSION: We create a hydrogel scaffold that not only offers adequate mechanical support but also possesses a favorable microenvironment for cell growth and contains biological factors promoting osteogenic and angiogenic differentiation. THE TRANSLATIONAL POTENTIAL OF THIS PAPER: This application represents a pioneering aspect of multi-scale biomimetic hydrogel scaffolds in addressing osteoporotic bone defects, providing a novel direction for the treatment of osteoporotic bone defects.