Local Sustained Delivery of Osteoprotegerin via Hydroxyapatite Microparticles to Enhance Post-Orthodontic Tooth Stability

项目总结/摘要 治疗后复发是正畸治疗最不可预测的限制之一。复发导致 患者的牙齿恢复到治疗前的位置，这增加了对功能性 问题，牙病，并大大增加了重新治疗的经济负担。目前，患者 基于顺应性的固位是维持正畸后牙齿稳定性的主要方法， 其可变的使用导致显著比例的患者经历复发。因此， 本申请旨在解决临床上对转化和临床相关方法的需求， 使用最小化患者依从性需求的方法来提高正畸后牙齿的稳定性。正畸 复发与骨吸收破骨细胞活性增加和未成熟骨质量密切相关 围绕牙齿。因此，一个有希望的方法，这种不利的结果是产生一个反应的净 通过协同地诱导骨生成和抑制骨生长活性来增加骨。然而，战略 在骨中产生这样的协同反应从未被探索用于此目的。我们小组发现 多次和单次粘膜下注射抗骨肉瘤重组OPG蛋白（OPG-Fc） 在正畸复发的大鼠模型中复发60-70%。这些生物学方法尚未被采用， 临床使用可能是由于缺乏有效的药物输送系统， 长时间给药，可能产生全身效应。本申请旨在开发一种临床 相关的基于骨传导性羟基磷灰石（HAP）的药物递送系统， OPG减轻正畸后复发，也将提高我们对骨的理解 在机械介导的骨转换后，通过调节这些 HAP和OPG的反应。 本项目将验证中心假设，即从中空微囊中持续释放重组OPG， 羟基磷灰石（HHAP）微粒将通过减少骨质溶解和促进 骨固定器目标1将建立在我们的初步数据，工程HHAP微粒持续释放 的OPG在所需的浓度，并验证该系统在体外与OPG和破骨细胞活性测定。目的 2将验证通过HHAP药物递送微粒局部和持续释放给予OPG的用途 在我们的正畸复发动物模型中以最小的全身影响减轻复发。而且这 这项研究将描述牙周组织和细胞反应的潜在分子途径， 导致增强骨再生和成熟。该项目的成功完成将导致 可翻译的方法，以改善正畸后牙齿稳定性的结果，并提供显着的洞察力， 增强机械介导的骨转换后的骨再生/成熟。

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 enhancing bone regeneration/maturation following mechanically mediated bone turnover.