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

项目总结 鼓膜造瘘管耳漏(TTO)是鼓膜造孔术后最常见的并发症 安置在儿童中。尽管使用外用抗生素进行标准治疗，但TTO通常是持久的或 反复发作。TT上的生物膜被认为是持续性和复发性TTO的主要原因。抗菌剂 蓝光(ABL)，一种创新的非药理学方法，最近由于 通过光激发天然产生的内源性卟啉，使其具有显著的抗菌活性。 细菌产生细胞毒性的活性氧物种。在初步研究中，我们证明了ABL是 有效杀灭实验生物膜中常见的TTO病原体。此R21提案的目标是 利用生物相容光散射技术研制新型光学鼓膜造口管 光学材料，从管子的整个表面发射ABL，用于预防和治疗TTO。对这件事 最后，我们提出了两个具体目标。 在目标1中，我们将进行体外研究，以确定ABL介导的光学-TT在预防 和根除由有代表性的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、金黄色葡萄球菌和铜绿假单胞菌。用于预防生物被膜 在接种细菌后30分钟内，使用ABL对光学TTS进行“激活”； 为了消除生物膜，在生物膜在试管上成熟后，光学TTS将使用ABL进行“激活”。这个 将通过定量菌落形成单位(CFU)计数来确定光学TTS上生物膜的细菌负荷 定性扫描电子显微镜(SEM)成像。光学-TT的功效将是 与环丙沙星溶液和二氧化银浸渍硅胶TT进行比较。 在目标2中，我们将进行临床前动物实验，以确定ABL介导的有效性和安全性。 OPTIC-TT防治龙猫实验性TTO的研究用于预防TTO、光学TT 将在接种细菌后30分钟内用ABL激活；而对于TTO的治疗，光学-TT将 当通过鼓室导纳和耳镜可见TTO时，使用ABL进行“激活”。细菌的载量 通过CFU计数和扫描电子显微镜成像来确定中耳大泡的光学类型和TTS。药效 将发现的ABL与目前流行的环丙沙星/地塞米松滴耳剂进行比较 关爱TTO的立场。作为安全性研究，光学-TT对听觉功能的耳毒性将是 通过测量听觉大脑反应和耳蜗毛细胞存活率来确定。 总体而言，成功完成本提案中概述的特定目标将提供临床前 确定ABL介导的光学TT在预防和治疗癌症中的有效性和安全性所需的证据 TTO的治疗。这些研究还将演示光学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.