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

项目摘要 听力损失是第三种最常见的健康状况，影响着所有年龄段的人。对于失聪的人来说 或有严重听力损失，人工耳蜗(CI)是一种标准的治疗方法。CI通过电子方式恢复听力 用植入电极阵列刺激耳蜗内剩余的可存活的听神经纤维。然而，人工耳蜗术 植入物总是伴随着手术损伤，这会引发急性炎症反应 并导致残余声学听力的在位和进行性丧失。因此，迫切需要 开发一种实时监测方法，以帮助了解植入期间和术后的神经状况 随后的听力损失，以提高手术后的临床结果。炎症过程诱导氧化 应激(即细胞内活性氧簇(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中起着关键作用。 因此，我们假设氧化应激是影响顺铂临床结局的主要因素。在此R21中 在这个项目中，我们建议开发新型多功能CI电极和方法，可以同时监测 清除人工耳蜗术中和术后氧化应激途径的启动。我们将开发 多功能顺式传感器实现实时体内检测和清除ROS，并具有临床所需的灵敏度 和专一性。我们开发先进多功能CI的方法是利用独特的钯(Pd)和 Pd双金属(即Pd/Au)纳米颗粒，具有类似酶的活性，允许敏感和选择性地传感 ROS以及将ROS转化为中性分子。与现有的听觉表面技术形成对比 神经元保护和再生，我们的贵金属纳米催化剂作为顺式电极具有耐腐蚀和 生物相容，其独特的表面电化学可以提供连续的(术中和术后)时间 体内ROS的传感和去除具有很高的稳定性。ROS与其化合物的同时中和 电化学传感反应应该在不破坏井的情况下减轻氧化应激相关的细胞死亡 整合了天然抗氧化防御网络，从而改善了患者术后的临床结果 顺位。在目标1中，我们将设计和制造多功能顺式分子筛，将双金属钯/金纳米催化剂集成到一个 用于体外检测和清除ROS的柔性对苯基电极阵列。在目标2中，我们将验证 具有整合微通道的多功能顺式通道在大鼠模型中的检测和清除功能。结果 根据这些临床前开发和R21项目的验证研究，将形成长期R01的基础 将传感/清除功能完全集成到能够记录、刺激、 长期临床使用的感应和清除功能。我们还预见到应用结果的机会。 在这里获得了其他神经接口和医疗植入物。我们建立了多学科团队，每个团队 会员在体内神经探头、实时化学传感器技术方面有20多年的经验，以及 听觉神经生理学，使我们为在拟议的研究活动中取得成功做好充分准备。

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.