Promotion of osteointegration under diabetic conditions by a silk fibroin coating on 3D-printed porous titanium implants via a ROS-mediated NF-κB pathway

Abstract

Clinical evidence indicates the compromised application of titanium implants (TIs) in diabetics, associated with reactive oxygen species (ROS) overproduction at the bone-implant interface. Silk fibroin (SF) has displayed impressive biocompatibility in the application of biomedical material and optimal anti-diabetic effects in oriental medicine. We proposed that SF-coated titanium implants (STIs) could alleviate diabetes-induced compromised osteointegration, which has rarely been reported before. To confirm this hypothesis and explore the underlying mechanisms, rat osteoblasts cultured on 3-dimensional (3D) -printed titanium implants (TIs) and STIs were subjected to normal serum (NS), diabetic serum (DS), DS with N-acetyl-L-cysteine (a ROS inhibitor) or SN50 (an NF-κB inhibitor). An in vivo study was performed on diabetic sheep with TIs or STIs implanted into bone defects on the crista iliaca. The results demonstrated that ROS overproduction induced by diabetes lead to osteoblast dysfunctions and cellular apoptosis on the TI substrate, associated with the activation of an NF-κB signaling pathway in osteoblasts. Importantly, the STI substrate significantly attenuated ROS production and NF-κBp65 phosphorylation, thereby ameliorating the osteoblast biological dysfunctions. These results were further confirmed in vivo by the improved osteointegration of the STIs, as evidenced by Micro-CT and histological examinations compared with those of TIs. These results demonstrated that the ROS-mediated NF-κB signaling pathway played a crucial role in diabetes-induced implant destabilization. Importantly, the SF coating, as a promising material for biomaterial-engineering, markedly improved the clinical treatment effect of TIs under diabetic conditions, possibly associated with the suppression of the NF-κB pathway.