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.

Activating Angiogenesis and Immunoregulation to Propel Bone Regeneration via Deferoxamine-Laden Mg-Mediated Tantalum Oxide Nanoplatform

“…Previous reports indicated that DFO could potentially enhance vascularization and bone regeneration in bone fracture models. , Hypoxia-inducible factor-1 (HIF-1α) is critical for the regulation of genes involved in angiogenesis and osteogenesis. The DFO treatment could activate a range of pro-angiogenic genes critical for angiogenesis, including vascular endothelial growth factor (VEGF) .…”

Deferoxamine-Loaded Chitosan-Based Hydrogel on Bone Implants Showing Enhanced Bond Strength and Pro-Angiogenic Effects

“…As a vascular endothelial relaxing factor, NO serves as a regulatory signal for angiogenesis [8]. Related studies have shown that the pro-angiogenic effects of NO were mainly through promoting embryonic cells to be involved in new blood vessel formation [4].…”

“…Specifically, DFO can simulate a hypoxic environment that up-regulates hypoxia-inducible factor-1α (HIF-1α) signal transduction and the expression level of its downstream angiogenic factor vascular endothelial growth factor (VEGF) [5][6][7]. Li et al [8] loaded DFO via caffeic acid on the Ti surface and demonstrated that DFO upregulated the expression of HIF-1α in MSCs and HUVECs by receptors of TGF-β and TNFR on cell membranes. However, directly loading DFO on an orthopedic Ti implant is challenging in clinical applications as a result of the short half-life of DFO and the initial burst release [9,10].…”