Designing non-toxic hydrogels for trans-tympanic drug delivery and treatment of otitis media

该提案的目标是开发一种无毒的水凝胶，以实现经鼓膜递送 治疗中耳炎（OM）的方法。这个平台将非侵入性地提供治疗 穿过鼓膜以根除细菌感染并抑制抗菌素耐药性， 同时避免全身性抗生素暴露引起的副作用。该提案建立在我们的 先前的工作证明了通过聚合物水凝胶成功根除OM， 现在仅使用生物相容性聚合物化学物质（例如已经获得批准的那些 用于局部、口服或静脉内递送）。通过使用 我们的目标是加速下游临床转化。该项目处理 通过重点关注听力和平衡方案的关键支柱-OM，实现NIDCD的使命， 开发新的药物输送系统到中耳治疗中耳和内耳疾病。 在这个项目中，我们将运用我们在功能材料设计，力学， 纳米技术，使成功的发展，并最终部署，这一新的 治疗平台这里使用的独特和广泛的方法范围从基本的 聚合物物理学、流变学和力学，以及离体和体内测试的小角度散射 在一个栗鼠模型。第一个目标集中于基于水凝胶结构的逆向工程 从我们以前的结果发展的标准，以获得最佳的结构和机械 用于有效药物递送和凝胶粘附于鼓膜的性质。的影响 水凝胶结构和机械性能对经鼓室流量，生物相容性， 在第二个目标中，将研究有希望的制剂的生物降解性。第三 aim专注于最佳性能配方，体外研究将评估抗菌 有效性和细胞毒性，以及在灰鼠模型中的体内评估将评价治疗 功效、药代动力学和药效学。 该项目将通过提供新的治疗方法，促进NIDCD的使命， 改善所有人的健康，包括95%的美国儿童受急性OM影响。我们将产生 新的知识，既可以帮助治疗中耳炎，又可以开发新的药物输送平台， 改善对每个人的护理的提供、质量和有效性。短期内这 该项目将有助于加速下游研究成果转化为临床实践， 专注于生物相容性聚合物化学。从长远来看，这种新的药物输送平台 具有降低治疗副作用和抗菌素耐药性的潜力， 通过消除与口服治疗相关的患者依从性障碍来提高治疗效果。

The goal of this proposal is to develop a non-toxic hydrogel to achieve trans-tympanic delivery of therapeutics to treat otitis media (OM). This platform will non-invasively deliver therapeutics across the tympanic membrane to eradicate bacterial infections and curb antimicrobial resistance, while avoiding side effects caused by systemic antibiotic exposure. This proposal builds on our previous work that demonstrated successful eradication of OM through a polymeric hydrogel, by now employing solely biocompatible polymer chemistries (e.g. ones that have obtained approval from the FDA for topical, oral, or intravenous delivery) with safe degradation products. By using these chemistries, we aim to accelerate downstream clinical translation. The project addresses the NIDCD mission by focusing on OM, a key pillar within the Hearing and Balance Program, and on developing new drug delivery systems to the middle ear to treat middle and inner ear diseases. In this project, we will apply our experience in functional material design, mechanics, and nanotechnology to enable the successful development, and eventual deployment, of this new treatment platform. The unique and wide-ranging methods utilized here range from fundamental polymer physics, rheology and mechanics, and small angle scattering to ex vivo and in vivo testing in a chinchilla model. The first aim focuses on reverse engineering the hydrogel structure based on criteria developed from our previous results, to obtain the optimal structure and mechanical properties for effective drug delivery and gel adhesion to the tympanic membrane. The impact of the hydrogel structure and mechanical properties on the trans-tympanic flux, bio-compatibility, and bio-degradation will be investigated for promising formulations in the second aim. The third aim focuses on the best performing formulations, where in vitro studies will assess antimicrobial effectiveness and cytotoxicity, and in vivo assessment in a chinchilla model will evaluate treatment efficacy, pharmacokinetics, and pharmacodynamics. The project will contribute to the mission of NIDCD by providing new treatments that will lead to better health for all, including the 95% of US children affected by acute OM. We will generate new knowledge, both to help treat otitis media and to develop new drug delivery platforms, while improving the delivery, quality, and effectiveness of care for everyone. In the short term, this project will help accelerate downstream translation of research findings into clinical practice by focusing on biocompatible polymer chemistries. In the longer term, this new drug delivery platform has potential to reduce treatment side effects and antimicrobial resistance, while improving treatment efficacy by removing barriers to patient compliance associated with oral therapy.