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

项目摘要/摘要 治疗后复发是正畸治疗最不可预测的局限性之一。旧病复发导致 患者的牙齿恢复到预处理位，这增加了对功能性牙病的敏感性 问题，牙病，并大大增加了再次治疗的经济负担。目前，患者 基于顺应性的固位是保持正畸后牙齿稳定性的主要方法，这是因为 它的可变使用导致相当大比例的患者复发。因此，它的目标是 这一应用是为了解决临床需要的翻译和临床相关的方法，以增加 使用最大限度地减少患者依从性的方法，使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 围绕着牙齿。因此，对这一不利结果的一个有希望的方法是产生一个净的反应 通过协同诱导成骨和抑制破骨活性来促进骨生长。然而，一种战略 为了在骨骼中产生这样的协同反应，从来没有人探索过这一目的。我们小组已经找到了 多次和单次黏膜下注射抗破骨细胞重组OPG蛋白(OPG-FC)减少 在正畸复发的大鼠模型中复发率为60%-70%。这些生物学方法还没有被用于 临床应用可能是由于缺乏有效的药物输送系统来减轻对大剂量药物的需求 长时间服用可能会产生全身影响的剂量。这个应用程序旨在开发一种临床上的 骨传导羟基磷灰石(HAP)局部缓释给药系统 OPG用于减轻正畸后复发，这也将增强我们对骨骼的了解 通过调节这些因子实现机械性骨转换后的再生/成熟 HAP和OPG的回应。 该项目将检验核心假设，即重组OPG从中空持续释放 羟基磷灰石(HHAP)微粒通过减少骨溶解促进正畸复发 骨骼合成代谢。Aim 1将以我们的初步数据为基础，设计HHAP微粒以实现持续释放 并在体外用OPG和破骨细胞活性检测来验证该系统。目标 2将验证OPG的使用，通过HHAP药物传递微粒进行局部和持续释放 为了在正畸复发的动物模型中减少复发，并将全身影响降至最低。此外，这一点 研究将描述牙周组织和细胞反应的潜在分子途径 促进骨骼再生和成熟。这一项目的成功完成将导致 可翻译的方法来改善正畸后牙齿的稳定性，并提供重要的洞察力 促进机械介导骨转换后的骨再生/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.