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

这项提议的目标是开发一种无毒的水凝胶，以实现经鼓室给药 治疗中耳炎(OM)的治疗方法。这个平台将以非侵入性的方式提供治疗 通过鼓膜根除细菌感染并遏制抗菌素耐药性， 同时避免全身暴露抗生素引起的副作用。这项建议建立在我们的 之前的工作表明，通过聚合物水凝胶成功地根除了OM，通过 现在使用完全生物兼容的聚合物化学(例如，已获得批准的聚合物 来自FDA的局部、口服或静脉注射)，具有安全的降解产品。通过使用 在这些化学方面，我们的目标是加速下游的临床翻译。该项目致力于 NIDCD的使命是专注于OM，这是听力和平衡方案的关键支柱，以及 关于开发新的中耳给药系统来治疗中耳和内耳疾病。 在这个项目中，我们将应用我们在功能材料设计、力学和 纳米技术使这一新的成功开发和最终部署成为可能 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、流变学和力学，以及小角度散射到体外和体内测试 穿着栗鼠模型。第一个目标是基于水凝胶结构的逆向工程 根据我们以前的结果制定的标准，以获得最优的结构和机械 具有有效的药物输送性能和与鼓膜的凝胶粘附性。网络的影响 水凝胶的结构和力学性能对经鼓膜通量、生物相容性、 在第二个目标中，将研究有希望的配方的生物降解性。第三 AIM专注于表现最好的配方，其中体外研究将评估抗菌剂 在栗鼠模型中的有效性和细胞毒性，以及体内评估将评估治疗 药效、药代动力学和药效学。 该项目将通过提供新的治疗方法为NIDCD的使命做出贡献， 以增进所有人的健康，包括95%受急性OM影响的美国儿童。我们将生成 新知识，帮助治疗中耳炎和开发新的药物输送平台，同时 改善对每个人的护理的交付、质量和有效性。短期内，这一点 该项目将通过以下方式帮助加快研究成果的下游转化为临床实践 专注于生物相容聚合物化学。从长远来看，这个新的药物输送平台 有可能减少治疗副作用和抗菌素耐药性，同时改善 通过消除与口服治疗相关的患者依从性障碍来实现治疗效果。

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.