PROJECT SUMMARY/ABSTRACT Post-treatment relapse is one of the most unpredictable limitations of orthodontic therapy. Relapse results in patient's teeth reverting towards their pretreatment positions, which increases the susceptibility to functional problems, dental disease, and substantially increases the financial burden for retreatment. Currently, patient compliance-based retention is the primary method for maintaining post-orthodontic tooth stability, which due to its variable use results in a significant proportion of patients experiencing relapse. Therefore, the objective of this application is to address the clinical need for a translational and clinically relevant approach to increase post-orthodontic tooth stability using approaches that minimize the need for patient compliance. Orthodontic relapse is strongly associated with increased bone-resorbing osteoclast activity and immature bone quality surrounding the teeth. As such, a promising approach to this adverse outcome is to produce a response of net bone accretion by synergistically inducing osteogenesis and inhibiting osteoclastic activity. However, a strategy to produce such synergistic responses in bone has never been explored for this purpose. Our group has found that multiple and single submucosal injections of anti-osteoclastic recombinant OPG protein (OPG-Fc) reduced relapse by 60-70% in a rat model of orthodontic relapse. These biological methods have not been adopted for clinical use presumably due to the lack of effective drug delivery systems that mitigate the need for large bolus doses over long durations that may produce systemic effects. This application aims to develop a clinically relevant osteoconductive hydroxyapatite (HAP)-based drug delivery system for local and sustained release of OPG to mitigate post-orthodontic relapse that will also enhance our understanding of bone regeneration/maturation following mechanically mediated bone turnover through modulation of these responses by HAP and OPG. This project will test the central hypothesis that sustained release of recombinant OPG from hollow hydroxyapatite (HHAP) microparticles will inhibit orthodontic relapse by decreasing osteolysis and promoting bone anabolism. Aim 1 will build on our preliminary data to engineer HHAP microparticles for sustained release of OPG at desired concentrations and validate this system in vitro with OPG and osteoclast activity assays. Aim 2 will validate the use of OPG administered for local and sustained release via HHAP drug delivery microparticles to mitigate relapse in our animal model of orthodontic relapse with minimal systemic effects. Furthermore, this study will characterize potential molecular pathways by which the periodontal tissues and cellular responses result in enhancing bone regeneration and maturation. The successful completion of this project will lead to a translatable method to improve post-orthodontic tooth stability outcomes and provide significant insight into enha...