Construction of a reactive oxygen species-responsive biomimetic multilayered titanium implant for in situ delivery of α-melanocyte-stimulating hormone to improve bone remolding in osteoporotic rats

Abstract By exploiting the high reactive-oxygen-species(ROS) level in osteoporosis fractured sites, a ROS responsive biomimetic multilayer onto titanium(Ti) implant composed of gelatin(Gel)/dextran amine (DA) and α-melanocyte-stimulating hormone (α-MSH) has been constructed using layer-by-layer spin self-assembled technique, which was further cross-linked with 4-nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) benzyl carbonate (NBC)-grafted-polyethylene glycol (PEG-NBC) for in situ delivery of α-MSH. The PEG-NBC cross-linked Gel/DA multilayer onto Ti substrate (Ti/LBLNBC-MSH) could be broken down when exposed to ROS-rich pathological environment, thus leading to a sustained release of α-MSH from multilayer in a controlled manner. It could maintain the α-MSH concentration at a constant level to promote in situ MSCs differentiation and inhibit osteoclast activity through regulating GSK-3β/β-catenin signal pathways with Runx2 positive feedback regulation loop. Micro-CT analysis, hematoxylin/eosin (HE) staining and Masson's trichrome (MT) staining further confirmed that new bone has fused into mature lamellar bone and trabecularism along the interface of Ti/LBLNBC-MSH in osteoporotic rats. Therefore, this study offers a new perspective on the development of biofunctional Ti implants as supplementary treatment for osteoporotic fracture repair in a clinical context.