Therapeutic microneedles for localized treatment of periodontal tissue

摘要 牙周炎是一种常见的慢性破坏性炎症性疾病，影响牙齿支持组织 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）， 患有牙周病。目前，没有理想的治疗牙周炎。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 有效地改变牙周组织牙槽骨吸收的进程， 牙周组织再生。在这里，我们将设计基于微针的药物输送平台， 通过使用免疫工程方法局部和长期治疗牙周病。不像 我们的贴片不需要粘合剂或缝线进行密封。相反， 可以在放置时从可溶解贴片上自分离， 治疗并最终降解。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递送，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细胞形成，从而抑制牙周炎和牙龈炎 中求进工作总(3)生长因子的持续释放还可以促进牙周组织的再生。 具体地，免疫调节细胞因子和生长因子的持续和局部共递送可以控制免疫调节细胞因子和生长因子的表达。 炎症通过调节性T细胞的形成以及促炎性巨噬细胞向 消炎的巨噬细胞，可以加速牙周组织的再生。工程补丁是 可生物降解，具有适当的机械性能，确保材料易于在临床上使用 设置.该平台是模块化的，可以装载/递送各种治疗性蛋白质。为了验证我们的假设， 本研究的目的有三：（1）优化牙周补片的制备工艺 微针用于纳米颗粒包封的抗生素的延长递送。(2)为了优化设计的 用于共递送免疫调节细胞因子以重编程宿主免疫细胞（例如， 炎性巨噬细胞和T细胞）向抗炎、调节和促愈合谱系的转化。(3)到 使用结扎诱导的大鼠牙周缺损模型评价工程化补片的功能。 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， 牙龈炎和其他牙周疾病。该项目的完成将促进我们了解如何 牙周环境中局部免疫系统的改变可以控制和逆转 牙周炎本项目的长期目标是将本研究中获得的基本见解转化为 重要和相关的临床应用。这是一种很有前途的方法，可以减少炎症， 促进牙周炎相关缺损的组织再生，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.