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

实时监测和清除活性氧 (ROS) 以提高人工耳蜗植入效果

基本信息

批准号：
10515333
负责人：
XIANGQUN ZENG
金额：
$ 18.95万
依托单位：
OAKLAND UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10515333
关键词：
Acoustic Nerve Acoustics Acute Adult Affect Age Anions Antioxidants Apoptotic Auditory Auditory Brainstem Responses Autopsy Benchmarking Biotechnology Cell Death Cessation of life Chemicals Child Chronic Clinical Cochlea Cochlear Implants Cochlear implant procedure Complex Corrosion DNA Detection Development Devices Drug Metabolic Detoxication Elasticity Electric Stimulation Electrochemistry Electrodes Enzymes Excision Failure Fluorescence Free Radicals Gelatin Gene Expression Profiling Goals Hair Cells Health Hearing Histologic Hydrogels Hydrogen Peroxide Hydroxides Hydroxyl Radical Immune response Implant Implanted Electrodes In Situ In Vitro Individual Inflammatory Inflammatory Response Injury Ischemia Ligaments Lipids Measures Mediating Metals Methods Microelectrodes Modeling Modification Modiolus Monitor Natural regeneration Nerve Fibers Neurons Operative Surgical Procedures Organ of Corti Outcome Oxidants Oxidative Stress Oxidative Stress Induction Oxidative Stress Pathway Palladium Performance Peroxonitrite Persons Play Polymers Postoperative Period Process Protective Agents Proteins Rattus Reaction Reactive Nitrogen Species Reactive Oxygen Species Reperfusion Therapy Research Activity Residual state Resistance Sensitivity and Specificity Site Specificity Spiral Lamina Stria Vascularis Superoxides Surface Surgical Injuries Technology Testing Therapeutic Time Tissues Toxic effect Trauma antioxidant therapy biomaterial compatibility deaf design experience flexibility functional restoration hard of hearing hearing impairment hearing restoration immunocytochemistry implantable device implantation improved in vivo in vivo monitoring medical implant member metallicity multidisciplinary nanofiber nanoparticle neural neural implant neural prosthesis neuroinflammation neurophysiology neurotrophic factor novel parylene pharmacologic preclinical development preservation prevent real time monitoring sensor technology spiral ganglion standard care validation studies

项目摘要

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.

项目概要听力损失是第三大常见的健康状况，影响所有年龄段的聋人。或有严重听力损失，人工耳蜗 (CI) 是通过电恢复听力的标准治疗方法。使用植入的电极阵列刺激耳蜗中残留的可行听觉神经纤维。植入总是伴随着手术损伤，从而引发急性炎症反应电极并诱发残余声学听力的开始和渐进性丧失，因此，迫切需要开发实时监测方法以帮助了解植入期间和之后的神经状况随后的听力损失可增强术后临床结果。炎症过程会诱导氧化。压力（即细胞内活性氧 (ROS) 水平升高）并减少细胞抗氧化剂大量研究表明，氧化应激在慢性神经炎症中发挥着关键作用。因此，我们认为氧化应激是影响 CI 临床结果的主要因素。项目中，我们建议开发新型多功能 CI 电极和方法，可以同时监测我们将开发人工耳蜗植入期间和之后氧化应激途径的启动。多功能 CI 可实现实时体内检测和清除 ROS，并具有临床所需的灵敏度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）纳米粒子表现出类似酶的活性，允许灵敏和选择性地传感 ROS 以及将 ROS 转化为中性分子，与现有的听觉表面技术形成鲜明对比。神经保护和再生，我们的贵金属纳米催化剂作为 CI 电极具有耐腐蚀和生物相容性，其独特的表面电化学可以提供连续的（手术期间和术后时间）体内活性氧的高稳定性检测和去除，同时中和活性氧。电化学传感反应应该减轻氧化应激相关的细胞死亡，而不破坏良好的状态。整合先天抗氧化防御网络，从而改善患有以下疾病的个体的术后临床结果在目标 1 中，我们将设计和制造集成有双金属 Pd/Au 纳米催化剂的多功能 CI。用于体外检测和清除 ROS 的柔性聚对二甲苯电极阵列在目标 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。 R21 项目中的这些临床前开发和验证研究将构成长期 R01 的基础该项目将传感/清除功能完全集成到 CI 设备中，这些设备能够记录、刺激、我们还预见到应用结果的机会。我们建立的多学科团队在此获得了其他神经接口和医疗植入物的经验。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了在拟议的研究活动中取得成功的充分准备。