"Optical Tympanostomy Tube" for prevention and treatment of tympanostomy tube otorrhea

项目摘要 鼓膜置管术后最常见的并发症是鼓膜置管术后鼓膜穿孔 在儿童中的安置。尽管使用局部抗生素进行标准治疗，但TTO通常是持久性的， 经常性的TT上的生物膜被认为是持续性和复发性TTO的主要原因。抗菌 蓝光（aBL），一种创新的非药物方法，最近引起了越来越多的关注， 其通过光激发天然存在的内源性卟啉而具有显著的抗微生物活性， 细菌产生细胞毒性活性氧物质。在初步研究中，我们证明了aBL是 有效杀死实验生物膜中常见的TTO病原体。本R21提案的目的是 开发了一种新型的光学鼓膜造口管（Optical-TT），它是由生物相容性光散射 光学材料，并从管的整个表面发射aBL，用于预防和治疗TTO。本 最后，我们提出两个具体目标。 在目标1中，我们将进行体外研究，以确定aBL介导的Optical-TT在预防 和根除由代表性TTO病原体形成的光学TT上的实验生物膜，包括 流感嗜血杆菌、金黄色葡萄球菌和绿脓杆菌。为了防止生物膜 Optical-TT，Optical-TT将在细菌接种后30分钟内使用aBL“激活”;而对于 为了消除生物膜，在生物膜在管上成熟后，将使用aBL“激活”光学TT。的 将通过定量菌落形成单位（CFU）计数确定Optical-TT上生物膜的细菌负荷 和定性扫描电子显微镜（SEM）成像。Optical-TT的疗效将是 与环丙沙星溶液和银氧化物浸渍的硅橡胶TT相比。 在目标2中，我们将进行临床前动物研究以确定aBL介导的免疫抑制剂的有效性和安全性。 光-TT在预防和治疗灰鼠实验性TTO中的应用为了防止TTO，Optical-TT 将在细菌接种后30分钟内使用aBL“激活”;而对于TTO的治疗，Optical-TT将 当TTO通过鼓室检查和耳显微镜检查可见时，使用aBL“激活”。上的细菌负荷 将通过CFU计数和SEM成像确定光学TT和中耳大疱。疗效 将与环丙沙星/地塞米松滴耳液进行比较，后者是目前 对TTO的护理。作为安全性研究，将对Optical-TT对听觉功能的耳毒性进行评估。 通过测量听觉脑反应和耳蜗毛细胞存活来确定。 总的来说，成功完成本提案中概述的具体目标将为临床前 确定aBL介导的Optical-TT预防和治疗的有效性和安全性所需的证据， 治疗TTO。这些研究还将演示Optical-TT原型系统的功能。

PROJECT SUMMARY Tympanostomy tube otorrhea (TTO) is the most common complication after tympanostomy tube (TT) placement in children. Despite the standard treatment using topical antibiotics, TTO is often persistent or recurrent. Biofilms on TT are implicated to be the major cause of persistent and recurrent TTO. Antimicrobial blue light (aBL), an innovative non-pharmacological approach, has recently attracted increasing attention due to its prominent antimicrobial activity through photoexcitation of naturally occurring endogenous porphyrins in bacteria to produce cytotoxic reactive oxygen species. In the preliminary study, we demonstrated that aBL was effective in killing common TTO pathogens in experimental biofilms. The objective of this R21 proposal is to develop a novel Optical Tympanostomy Tube (Optical-TT), which is made from a biocompatible light-scattering optical material and emits aBL from the whole surface of tube, for prevention and treatment of TTO. To this end, we propose two Specific Aims. In Aim 1, we will perform in vitro studies to determine the efficacy of Optical-TT mediated by aBL in prevention and eradication of experimental biofilms on Optical-TTs formed by representative TTO pathogens, including Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa. For prevention of biofilms on Optical-TTs, Optical-TTs will be "activated" using aBL within 30 min after bacterial inoculation; while for eradication of biofilms, Optical-TTs will be "activated" using aBL after biofilms have matured on the tubes. The bacterial load of biofilms on Optical-TTs will be determined by quantitative colony-forming units (CFU) counting and qualitative scanning electron microscopic (SEM) imaging. The efficacy found with Optical-TT will be compared with those of ciprofloxacin solution and silver oxide-impregnated Silicone TT. In Aim 2, we will perform preclinical animal studies to determine the efficacy and safety of aBL-mediated Optical-TT in prevention and treatment of experimental TTO in chinchillas. For prevention of TTO, Optical-TT will be "activated" using aBL within 30 min after bacterial inoculation; while for treatment of TTO, Optical-TT will be "activated" using aBL when TTO are visible via tympanometry and otomicroscopy. The bacterial load on Optical-TTs and in the middle ear bullae will be determined by CFU counting and SEM imaging. The efficacy found with aBL will be compared with that of ciprofloxacin/dexamethasone otic drops, which are the current stand of care for TTO. As the safety study, the ototoxicity of Optical-TT to the auditory function will be determined by measurement of auditory brain response and hair cell survival in the cochlea. Collectively, successful completion of the Specific Aims outlined in this proposal will provide the preclinical evidence required to determine the effectiveness and safety of aBL-mediated Optical-TT in prevention and treatment of TTO. The studies will also demonstrate the functionality of a prototype system of Optical-TT.