Caffeic Acid‐Deferoxamine Self‐Polymerization Coating on Ti Implant Promotes Osteointegration by Synergetic Regulation of Multi‐Pathways in ONFH Mechanism

Abstract Osteonecrosis of the femoral head (ONFH) is a common but sophisticated multifactorial disease. In this study, the genomic characteristics of ONFH from the sequencing is first analyzed. Excepting ischemia and inflammation, some of differentially expressed genes (DEGs) are connected with autophagy. So, they are taken as the breakthrough points to design an auto polymerization coating of caffeic acid with grafting deferoxamine (DFO) and strontium on Ti substrate. In vitro cells and in vivo immunofluorescence and immunohistochemical results prove that the modified Ti can upregulate the expression of HIF‐1α in mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) by receptors of TGF‐β and TNFR on cell membrane. Interestingly, in MSCs, the upregulated HIF‐1α can promote autophagy to some extent by HIF‐1α/BNIP2 pathway. Meanwhile, appropriate autophagy and HIF‐1α can regulate MSCs proliferation and osteogenic differentiation by STAT3/Notch pathway. However, in HUVECs, although autophagy increases slightly, the upregulated HIF‐1α prefers to increase its downstream target gene VEGF and accelerate angiogenesis by the pathway of HIF‐1α/VEGF. The results of in vivo implantation show that the modified Ti substrate can effectively enhance the integration effect of the implant by osteogenesis and angiogenesis. More significantly, the modified Ti can retard the further deterioration of ONFH by regulation of key genes.