Therapeutic microneedles for localized treatment of periodontal tissue

摘要 牙周炎是一种影响人类牙齿支持组织的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%的老年人口(65岁)， 患有牙周病。目前，牙周炎尚无理想的治疗方法。地方行政管理 使用不同形式的抗生素或消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，但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，用于 使用免疫工程方法对牙周病进行局部和长期治疗。不像 市场上的其他产品，我们的贴片不需要粘合剂或缝线来密封。取而代之的是微针 可在放置时从可溶解的贴片中自行分离，并在牙周组织中停留 最终会被治疗和降解。我们假设(1)可生物降解的微针允许有效和 药物在牙龈组织中的持续和局部传递，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周炎 进步。(3)生长因子的持续释放也能促进牙周组织的再生。 具体地说，持续和局部联合传递免疫调节细胞因子和生长因子可以控制 通过形成调节性T细胞和重新极化促炎巨噬细胞向 能加速牙周组织再生的抗炎巨噬细胞。设计的补丁是 可生物降解，并具有适当的机械性能，确保材料易于临床使用 布景。该平台是模块化的，可以装载/输送各种治疗性蛋白质。为了检验我们的假设， 提出了三个具体的目标：(1)优化可分离和可生物降解的固体牙周贴片 用于延长纳米颗粒包裹的抗生素的输送的微针。(2)优化工程建设 用于共同传递免疫调节细胞因子的微针贴片，以重新编程宿主免疫细胞(例如： 炎性巨噬细胞和T细胞)向抗炎、调节和促进愈合的方向发展。(3)至 使用结扎诱导的大鼠牙周缺陷模型评估工程补片的功能。 该项目的成功完成将为牙周炎的管理引入一个新的治疗平台， 牙周炎和其他牙周病。这个项目的完成将促进我们对如何 局部改变牙周环境中的免疫系统可控制和逆转牙周环境的不良反应 牙周炎。该项目的长期目标是将从这项研究中获得的基本见解转化为 重要且相关的临床应用。这是一种有希望的方法，既可以减少炎症，也可以 促进牙周炎相关缺陷的组织再生，并将对牙周炎的治疗产生重大影响 牙周病。

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.