Icariside II enhances crania defect repair through synergistic angiogenesis and osteogenesis

Vascularized bone tissue engineering for osteogenesis is considered a key approach for the repair of critical bone defects. Icariin(ICA) has been employed in bone tissue engineering for osteogenesis in several studies, demonstrating significant angiogenic and osteogenic effects in vivo in rat models. However, the in vivo angiogenic and osteogenic effects of Icariside II (ICSII), a gastrointestinal metabolite of ICA, remain unclear. Our preliminary study indicated that ICSII upregulated the expression of angiogenic and osteogenic differentiation markers in rat Bone Marrow Mesenchymal Stem Cells(rBMSCs) in vitro. Consequently, we loaded ICA and ICSII onto rBMSCs on Calcium Phosphate Cement(CPC) to construct the complexes CPC/ICA/BMSCs and CPC/ICSII/BMSCs, respectively. Scanning electron microscopy (SEM) revealed that BMSCs exhibited a more favorable morphology for proliferation, adhesion, and spreading on the scaffolds containing ICA and ICSII. Additionally, CPC/ICSII/BMSCs were implanted into a rat bilateral 5-mm critical skull defects model. Micro-CT analysis revealed that the CPC/ICA/BMSCs and CPC/ICSII/BMSCs groups exhibited the most significant promotion of new bone formation and neovascularization. Notably, the CPC/ICSII/BMSCs group demonstrated a significantly stronger neovascularization response than the CPC/ICA/BMSCs group. Histomorphometric analysis further revealed significant collagen fiber, new bone, and neovascularization formation in the CPC/ICA/BMSCs and CPC/ICSII/BMSCs groups, compared to the other groups. Thus, this study concludes that CPC/ICSII/BMSCs, which possess dual osteogenic and angiogenic properties, hold significant potential for repairing critical-size bone defects.