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 牙周炎是一种流行的慢性破坏性炎症性疾病，影响人类牙齿支持组织 这可能会导致牙齿脱落。大约35％的成年人和70％的高年级人口（> 65岁），全球 患有牙周疾病。目前，没有理想的治疗方法可用于牙周炎。地方政府 以不同形式的抗生素或抗炎药可以减少细菌感染，但不能 有效地改变牙周肺泡骨吸收的进展，无法积极促进 牙周组织的再生。在这里，我们将设计基于微对准的药物输送平台 通过使用免疫工程方法对牙周疾病进行局部和延长治疗。不像 市场上的其他产品，我们的补丁不需要粘合剂或缝合线即可密封。相反，微针 可以在放置时从可溶解的贴片中自我实现，并留在牙龈组织中 治疗和降解。我们假设（1）可生物降解的微针允许有效，并且 牙龈组织中药物的持续和局部递送，（2）免疫调节贴剂可以调节 巨噬细胞表型加速了调节性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也可以促进牙周组织的再生。 具体而言，免疫调节细胞因子和生长因子的持续和局部共同交付可以控制 通过形成调节性T细胞的炎症以及使促炎性巨噬细胞的复制 可以加速牙周组织再生的抗炎巨噬细胞。工程补丁是 可生物降解并具有适当的机械性能，可确保易于在临床中易于使用 环境。该平台是模块化的，可以加载/提供广泛的治疗蛋白。为了检验我们的假设， 提出了三个具体目标：（1）优化具有可分离和可生物降解固体的牙周贴片 微针长时间递送纳米颗粒封装的抗生素。 （2）优化工程 微针斑块，用于对免疫调节细胞因子的共递送，以重编程宿主免疫细胞（例如， 炎症性巨噬细胞和T细胞）朝着抗炎，调节性和亲链谱系。 （3）到 使用结扎诱导的牙周缺陷模型在大鼠中评估工程斑块的功能。 该项目的成功完成将引入一个新颖的治疗平台，用于管理牙周炎， 牙龈炎和其他牙周疾病。完成该项目将提高我们对如何的理解 牙周环境中免疫系统的局部变化可以控制并扭转 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。这是一种有前途的方法减少炎症和 促进与牙周炎相关缺陷的组织再生，并将对 牙周疾病。