Sepu-Titanium Enhance Bone Regeneration In Metabolic Disorders Via Nrf2

Titanium (Ti) implants, although widely used in clinical practice, still face challenges such as inflammation and impaired osseointegration, particularly in patients with metabolic disorders like diabetes and osteoporosis, who have higher risks of implant failure. Conventional Ti surface modification methods are limited by complex fabrication processes, poor adhesion strength, and the difficulty of simultaneously regulating immune responses and osteogenesis. In this study, we synthesized selenium-containing polyurethane (SePU) and functionalized Ti surfaces through a simple soaking method. At first, single-molecule force spectroscopy quantified the binding interactions between SePU and Ti. In addition, in vitro experiments assessed SePU’s effects on osteogenesis and macrophage polarization. Then, male SD rats, ZDF rats, and female OVX rats were respectively used to model healthy, diabetic, and osteoporotic conditions. SePU-modified Ti implants were placed in femurs of these rats to evaluate bone formation under different conditions via Micro-CT and histological analysis (Ethical approval: LA2023535). Moreover, RNA sequencing of peri-implant bone tissues explored potential mechanisms, which were further validated. Notably, SePU formed a chemical bond with Ti, induced M2 macrophage polarization, enhanced osteogenic differentiation, and promoted peri-implant bone formation in diabetic and osteoporotic rats. RNA sequencing and validation showed that SePU modulated NRF2-mediated oxidative stress by upregulating GSTM3. This enhanced ROS scavenging, reduced oxidative damage, thereby created an immune microenvironment conducive to regeneration. Our findings offer a novel strategy utilizing selenium to tackle the clinical challenges of Ti implants, especially for metabolic disorders like diabetes and osteoporosis that hinder osteogenesis.