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

通过羟基磷灰石微粒局部持续输送骨保护素以增强正畸后牙齿的稳定性

• 批准号: 10418647
• 负责人: Darnell Cuylear
• 金额: $ 4.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418647
• 关键词: Address; Adopted; Aftercare; Anabolism; Animal Model; Back; Biological; Biological Assay; Biological Process; Biological Products; Biological Response Modifier Therapy; Bolus Infusion; Bone Regeneration; Clinical; Data; Defect; Dental caries; Development; Disease; Dose; Drug Delivery Systems; Engineering; Ensure; Esthetics; Financial Hardship; Genes; Goals; Health Care Costs; Hydroxyapatites; Imaging Techniques; Immature Bone; Impairment; In Vitro; Injectable; Injections; Intervention; Kinetics; Knowledge; Mastication; Mechanics; Mediating; Methods; Modeling; Molds; Molecular; Natural regeneration; Oral; Orthodontic; Osteoclasts; Osteogenesis; Osteolysis; Outcome; Pathologic Processes; Pathway interactions; Patients; Periodontal Diseases; Periodontium; Persons; Phase; Positioning Attribute; Predisposition; Property; Proteins; Protocols documentation; Rattus; Recombinants; Relapse; Retreatment; Risk; Site; Speech; Stains; System; Testing; Therapeutic; Therapeutic Uses; Tissues; Tooth Diseases; Tooth Movement; Tooth structure; Translations; Treatment Efficacy; Treatment outcome; Tumor necrosis factor receptor 11b; adverse outcome; alveolar bone; base; biomaterial compatibility; bone; bone metabolism; bone quality; bone repair; bone turnover; chemical property; clinically relevant; compliance behavior; controlled release; crystallinity; experience; experimental study; impression; improved; in vitro activity; in vivo; insight; non-compliance; novel; novel strategies; novel therapeutic intervention; orofacial; repaired; response; transcriptome sequencing; transcriptomics

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.

项目摘要/摘要 治疗后复发是正畸疗法最明显的局限性之一。复发导致 患者的牙齿恢复到预处理位置，这增加了功能的敏感性 问题，牙齿疾病并大大增加了撤退的经济负担。目前，病人 基于合规性的保留是维持后正畸牙齿稳定性的主要方法，这是由于 它的可变使用导致相当一部分患者患有复发。因此，目的 该应用是为了满足转化和临床相关方法增加的临床需求 后正畸牙齿的稳定性使用方法最小化患者依从性的需求。正畸 复发与骨质骨细胞活性和未成熟骨质的增加密切相关 周围的牙齿。因此，这种不利结果的有希望的方法是产生净的响应 通过协同诱导成骨和抑制整骨活性来吸收骨。但是，一种策略 为此目的从未探索过在骨头中产生这种协同反应。我们的小组发现 多次和单一粘膜下粘膜抗粘膜重组OPG蛋白（OPG-FC）降低了 在正畸复发的大鼠模型中，复发增加了60-70％。这些生物学方法尚未采用 临床用途大概是由于缺乏有效的药物输送系统来减轻大量大量的需求 长时间的剂量可能会产生全身作用。该应用程序旨在在临床上开发 相关的骨导导式羟基磷灰石（HAP）基于局部和持续释放的药物输送系统 OPG减轻后正畸复发，这也将增强我们对骨骼的理解 通过调节机械介导的骨转换后的再生/成熟 HAP和OPG的响应。 该项目将测试中心假设，即持续从空心释放重组OPG 羟基磷灰石（HHAP）微粒将通过减少骨溶解和促进来抑制正畸复发 骨变成代谢。 AIM 1将基于我们的初步数据，以设计HHAP微粒以持续发布 在所需浓度下OPG的OPG，并通过OPG和破骨细胞活性测定在体外验证该系统。目的 2将验证使用HHAP药物递送微粒的局部和持续释放的OPG使用 为了减轻我们的正畸复发动物模型的复发，并具有最小的全身效应。此外，这个 研究将表征牙周组织和细胞反应的潜在分子途径 导致增强骨骼再生和成熟。该项目的成功完成将导致 可翻译的方法来改善后正畸牙齿稳定性结果，并为 机械介导的骨转换后增强骨再生/成熟。