Therapeutic microneedles for localized treatment of periodontal tissue

用于牙周组织局部治疗的治疗性微针

• 批准号: 10008033
• 负责人: Song Li
• 金额: $ 28.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2020-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10008033
• 关键词: Address; Adhesives; Adult; Adverse effects; Affect; Anti-Bacterial Agents; Anti-inflammatory; Antibiotics; Bacteria; Bacterial Infections; Biodegradation; Bone Resorption; Caliber; Cells; Chronic; Clinical; Defect; Dimensions; Disease; Dose; Drug Delivery Systems; Encapsulated; Engineering; Ensure; Environment; Gingiva; Gingival Pocket; Gingivitis; Growth Factor; Guided Tissue Regeneration; Heparin; Human; Immune; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Ligature; Mechanics; Mesenchymal; Modeling; Natural regeneration; Needles; Outcome; Patients; Periodontal Diseases; Periodontal Ligament; Periodontal Pocket; Periodontitis; Periodontium; Pharmaceutical Preparations; Phenotype; Polymers; Population; Porphyromonas gingivalis; Production; Property; Proteins; Rattus; Regulatory T-Lymphocyte; Research; Scheme; Site; Solid; Stem cells; Surgical sutures; T-Lymphocyte; Testing; Tetracyclines; Therapeutic; Therapeutic Effect; Tissues; Tooth Loss; Tooth structure; Transdermal substance administration; Transforming Growth Factor beta; Translating; United States; adaptive immune response; alveolar bone; base; biocompatible polymer; biodegradable polymer; biomaterial compatibility; clinical application; clinically relevant; cytokine; healing; human old age (65+); immunoengineering; immunoregulation; in vivo; insight; macrophage; mechanical properties; monocyte; multidisciplinary; nanoparticle; nanoparticle delivery; novel; particle; recruit; seal; small molecule; stem cell differentiation; therapeutic protein; tissue regeneration

Abstract Periodontitis is a prevalent chronic destructive inflammatory disease affecting tooth-supporting tissues in humans which may cause tooth loss. Approximately 35% of adults and 70% of senior population (>65 years old), globally, suffer from periodontal diseases. Currently, no ideal treatment is available for periodontitis. Local administration of antibiotics or anti-inflammatory drugs in different forms can reduce the bacterial infection but it cannot effectively alter progress of periodontium alveolar bone resorption and cannot positively promote the regeneration of periodontal tissue. Here, we will engineer microneedle-based drug delivery platforms for localized and prolonged treatment of periodontal disease by using an immunoengineering approach. Unlike the other products on market, our patches do not need adhesive or suture for sealing. Instead, the microneedles can self-detach from the dissolvable patch upon placement and stay in the gingival tissues for the course of treatment and degrade eventually. We hypothesize that (1) biodegradable microneedles allow effective and sustained and localized delivery of drugs in gingival tissues, and (2) immunoregulatory patches can modulate macrophage phenotype accelerate formation of regulatory T cells and thus inhibit periodontitis and gingivitis progress. (3) The sustained release of growth factor can also facilitate regeneration of periodontal tissue. Specifically, sustained and local co-delivery of immunoregulatory cytokines and growth factors can control the inflammation via formation of regulatory T cells as well as repolarizing pro-inflammatory macrophages toward anti-inflammatory macrophages that can accelerate regeneration of periodontal tissue. The engineered patch is biodegradable and possesses proper mechanical properties ensuring that material is easy to use in the clinical setting. The platform is modular and can load/deliver wide range of therapeutic proteins. To test our hypotheses, three Specific Aims are proposed: (1) To optimize a periodontal patch with detachable and biodegradable solid microneedles for prolonged delivery of nanoparticle-encapsulated antibiotic. (2) To optimize the engineered microneedle patch for co-delivery of immunoregulatory cytokines to reprogram host immune cells (e.g. inflammatory macrophages and T cells) toward anti-inflammatory, regulatory, and pro-healing lineages. (3) To evaluate the functionality of the engineered patches using a ligature-induced periodontal defect model in rats. Successful completion of this project will introduce a novel treatment platform for management of periodontitis, gingivitis and other periodontal diseases. Accomplishment of this project will advance our understanding of how localized alteration of immune system in periodontal environment can control and reverse the adverse effect of periodontitis. The long-term objective of this project is to translate the basic insights gained in this study into important and relevant clinical applications. This is a promising approach reduce inflammation as well as to promote tissue regeneration in periodontitis-related defects, and will have a significant impact on the therapy of periodontal diseases.

抽象的 牙周炎是一种影响人类牙齿支持组织的常见慢性破坏性炎症性疾病 这可能会导致牙齿脱落。全球约 35% 的成年人和 70% 的老年人（>65 岁） 患有牙周疾病。目前，牙周炎尚无理想的治疗方法。地方行政 不同形式的抗生素或抗炎药可以减少细菌感染，但不能 有效改变牙周组织牙槽骨吸收的进程，不能积极促进牙周组织的骨吸收。 牙周组织的再生。在这里，我们将设计基于微针的药物输送平台 使用免疫工程方法对牙周病进行局部和长期治疗。与 市场上的其他产品，我们的贴片不需要粘合剂或缝合来密封。相反，微针 放置后可从可溶性补片上自行脱离，并在整个过程中保留在牙龈组织中 处理并最终降解。我们假设（1）可生物降解的微针可以有效且 在牙龈组织中持续和局部地输送药物，以及（2）免疫调节贴片可以调节 巨噬细胞表型加速调节性T细胞的形成，从而抑制牙周炎和牙龈炎 进步。 (3)生长因子的持续释放还可以促进牙周组织的再生。 具体来说，免疫调节细胞因子和生长因子的持续和局部共同递送可以控制 通过形成调节性 T 细胞以及将促炎性巨噬细胞重新极化为 抗炎巨噬细胞可以加速牙周组织的再生。工程补丁是 可生物降解并具有适当的机械性能，确保材料易于在临床中使用 环境。该平台是模块化的，可以加载/输送多种治疗性蛋白质。为了检验我们的假设， 提出了三个具体目标：（1）优化可拆卸且可生物降解固体的牙周补片 微针用于延长纳米颗粒封装抗生素的输送。 (2) 优化设计 用于共同递送免疫调节细胞因子以重新编程宿主免疫细胞的微针贴片（例如 炎症巨噬细胞和 T 细胞）朝向抗炎、调节和促愈合谱系。 (3) 至 使用结扎诱导的大鼠牙周缺损模型评估工程补片的功能。 该项目的成功完成将为牙周炎管理引入一种新型治疗平台， 牙龈炎和其他牙周疾病。该项目的完成将加深我们对如何 牙周环境中免疫系统的局部改变可以控制和逆转牙周病的不良影响 牙周炎。该项目的长期目标是将本研究中获得的基本见解转化为 重要且相关的临床应用。这是一种有前途的减少炎症以及 促进牙周炎相关缺损的组织再生，将对牙周炎的治疗产生重大影响 牙周疾病。