Real-Time Monitoring and Scavenging of Reactive Oxygen Species (ROS) to Enhance Cochlear Implantation Outcomes

项目摘要 听力损失是第三大最常见的健康状况，影响所有年龄段的人。对于聋人来说， 或有严重听力损失的患者，人工耳蜗植入（CI）是标准治疗方法。CI通过电恢复听力 用植入的电极阵列刺激耳蜗中残留的有活力的听觉神经纤维。然而，耳蜗 植入总是伴随着手术损伤，这引发了对植入物的急性炎症反应。 电极并诱发残余听觉的开始和进行性丧失。因此，迫切需要 开发实时监测方法，以帮助了解植入期间和植入后的神经状况， 随后的听力损失，以提高术后临床结果。炎症过程诱导氧化 应激（即细胞内活性氧（ROS）水平升高）并减少细胞抗氧化剂 容量大量研究表明，氧化应激在慢性神经炎症中起着关键作用。 因此，我们假设氧化应激是影响CI临床结局的主要因素。在R21中 项目，我们提出开发新的多功能CI电极和方法，可以同时监测 以及耳蜗植入期间和之后氧化应激途径的快速启动。我们将开发 多功能CI，以临床所需的灵敏度实现实时体内传感和清除ROS 和特异性。我们开发先进的多功能CI的方法是利用独特的钯（Pd）和 Pd/Au（即Pd/Au）纳米颗粒，其显示出酶样活性，允许灵敏和选择性地感测 ROS以及将ROS转化为中性分子。与现有的用于听觉的表面技术相比， 神经元保护和再生，我们的贵金属纳米催化剂作为CI电极具有耐腐蚀性， 生物相容性，其独特的表面电化学可以提供连续的（手术期间和手术后） 以高稳定性在体内感测和去除ROS。同时中和活性氧与其 电化学传感反应应该减轻氧化应激相关的细胞死亡，而不破坏细胞的正常功能。 整合的先天抗氧化防御网络，从而改善患有 线人在目标1中，我们将设计和制备多功能CI，并将Pd/Au纳米催化剂集成到一个 柔性聚对二甲苯基电极阵列，用于体外检测和清除ROS。在目标2中，我们将验证 具有集成微通道的多功能CI在大鼠模型中的检测和清除功能。结果 本R21项目中的这些临床前开发和验证研究将构成长期R 01的基础 项目将传感/清除能力完全集成到能够记录，刺激， 传感和清除功能，供长期临床使用。我们还预见到应用这些结果的机会 用于其他神经接口和医疗植入物。我们建立的多学科团队， 成员在体内神经探针、实时化学传感器技术方面拥有20多年的经验， 听觉神经生理学分别，使我们做好准备，成功地在拟议的研究活动。

Project Summary Hearing loss is the third most common health condition, affecting people of all ages. For individuals who are deaf or have significant hearing loss, cochlear implants (CIs) are a standard treatment. CIs restore hearing by electrically stimulating residual viable auditory nerve fibers in the cochlea with an implanted electrode array. However, cochlear implantation is always accompanied by surgical injury, which initiates an acute inflammatory response to the electrode and induces on-set and progressive loss of residual acoustic hearing. Thus, there is an urgent need to develop a real-time monitoring method to help understand the neural conditions during and after implantation and subsequent hearing loss to enhance post-operative clinical outcomes. Inflammatory process induces oxidative stress (i.e. an elevated intracellular level of reactive oxygen species (ROS)) and reduces cellular antioxidant capacity. Numerous studies have shown that oxidative stress plays key roles for chronic neuroinflammation. Therefore, we hypothesize that oxidative stress is the major factor compromising CIs’ clinical outcome. In this R21 project, we propose to develop novel multifunctional CI electrodes and methods that can simultaneously monitor and scavenge initiation of the oxidative stress pathway during and after cochlear implantation. We will develop the multifunctional CIs to achieve real-time in vivo sensing and scavenging of ROS with clinically required sensitivity and specificity. Our approach to develop advanced multifunctional CIs is to utilize the unique palladium (Pd) and Pd bimetallic (i.e. Pd/Au) nanoparticles that show enzyme-like activities allowing sensitive and selective sensing of ROS as well as converting ROS to neutral molecules. In contrast to existing surface technologies for auditory neuronal protection and regeneration, our noble metal nanocatalysts as CIs electrodes are corrosion-resistant and biocompatible, and their unique surface electrochemistry can provide continuous (during and post-operative times) sensing and removal of ROS in vivo with high stability. The simultaneous neutralization of ROS with their electrochemical sensing reactions should mitigate oxidative stress-related cell death without disrupting the well- integrated innate antioxidant defense network, thus, improving post-operative clinical outcomes for individuals with CIs. In Aim 1, we will design and fabricate multifunctional CIs with bimetallic Pd/Au nanocatalysts integrated into a flexible parylene-based electrode array for detecting and scavenging ROS in vitro. In Aim 2, we will validate the detection and scavenging functions of the multifunctional CIs with an integrated microchannel in a rat model. Results from these pre-clinical development and validation studies in this R21 project will form the basis of a long-term R01 project to fully integrate sensing/scavenging capability into CI devices that are capable of recording, stimulation, sensing and scavenging functions for long-term clinical use. We also foresee the opportunities to apply the results gained here to other neural interfaces and medical implants. Our established multidisciplinary team with each member has more than 20 years’ experience with in vivo neuroprobe, real-time chemical sensor technology, and auditory neurophysiology respectively, making us well prepared to be successful in the proposed research activities.