Nanoparticle Coated Microelectrode Arrays for Electrochemically Controlled Gene Editing at the Electrode Site

用于电极位点电化学控制基因编辑的纳米颗粒涂层微电极阵列

基本信息

批准号：
10604904
负责人：
NATHANIEL P WILLIAMS
金额：
$ 7.86万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604904
关键词：
Affect Afferent Neurons Antiinflammatory Effect Area Astrocytes Biocompatible Coated Materials Brain Cell Culture Techniques Cells Cellular Morphology Chronic Cicatrix Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA DNA Sequence Development Devices Electrodes Encapsulated Equipment Malfunction Failure Fluorescence Foreign Bodies Formulation Gene Delivery Gene Expression Gene Modified Gene Transduction Agent Gene Transfer Genes Gliosis Hearing Immune response Implant In Vitro Inflammation Inflammatory Inflammatory Response Intervention Knock-out Life Limb structure Longevity Measures Medicine Metals Microelectrodes Microglia Modification Monitor Mus Neurons Pathway interactions Patients Pattern Perception Performance Play Porosity Property Prosthesis Proteins Reporter Reporter Genes Resolution Role Sensory Silicon Dioxide Site Specificity Structure Surface System Technology Testing Therapeutic Therapeutic Uses Time Tissues Touch sensation Vision Work bioelectronics brain computer interface cell type experimental study gene therapy implantable device implantation improved in vitro testing in vivo knockout gene limb loss loss of function mechanical device nanoparticle neural neuron loss neurotransmission novel prevent prosthesis control recruit response robot control spatiotemporal technology development tool two photon microscopy vector

项目摘要

Abstract Microelectrode arrays (MEAs) have great potential for therapeutic use in direct brain-computer interface (BCI) control of robotic prostheses to improve the lives of patients suffering from debilitating conditions related to loss of limbs or limb function. MEAs also have the potential to restore loss of sensory perception in vision, hearing, and tactile sensation by applying patterned current stimulation to sensory neurons. As promising as these therapies are, there is a major shortcoming to the current state of the art in implanted MEAs in that their recording and stimulation quality degrades over time, and the implants eventually become non-functional. Their use as therapeutic devices to treat chronic conditions that persist for the patient's life requires MEAs that are stable over decades rather than months to years. The underlying mechanisms leading to failure for chronically implanted MEAs have yet to be fully elucidated. One candidate is degradation of the electrode or insulation material leading to mechanical device failure. Another important factor is the host foreign body response. Inflammation due to activation of microglia and astrocytes can lead to gliosis and the formation of a “glial scar” encapsulating the device and preventing efficient recording and stimulation of neurons. Recently, gene therapy-based interventions using CRISPR/Cas systems for gene knockout have shown great promise in modifying the immune response. Recent work in the Cui lab has shown the efficacy of using functionalized silica nanoparticles (SNPs) as a versatile surface modification for microelectrodes. MEAs coated with polyethylenedioxythiophene (PEDOT)/SNP have improved electrochemical properties over standard bare metal electrodes and the capacity to be loaded with therapeutic compounds due to their porous structure with a high surface area. These properties make MEAs coated with PEDOT/SNP an ideal platform for highly targeted gene delivery, as the silica nanoparticles can be efficiently loaded with DNA. This proposal aims to develop this technology to efficiently gene modify microglia locally around implanted MEAs to reduce inflammation and to measure the effect of inflammation on recording quality and stimulation efficiency, as well as long-term device stability. In addition, I will investigate how changes in the foreign body response affect the remodeling of tissue surrounding the implant. I will take the approach of loading SNP coated MEAs with DNA encoding CRISPR gene therapy vectors targeting inflammatory pathways in microglia. The CRISPR vectors will be electrochemically delivered to cells directly interfacing with the implanted devices. The development of this technology has great potential to enhance the therapeutic value of implanted devices by increasing their performance and longevity by reducing inflammation and gliosis and to increase our fundamental understanding of how the brain responds to implanted devices. Once established, this technology will be a versatile platform for highly targeted gene delivery, having both spatiotemporal and cell-type specificity.

抽象的微电极阵列（MEA）在直接脑机接口（BCI）中具有巨大的治疗用途潜力控制机器人假肢，以改善因失去而导致衰弱的患者的生活肢体或肢体功能的 MEA 也有可能恢复视觉、听觉、听觉等感官知觉的丧失。和通过对感觉神经元施加图案化电流刺激来获得触觉。疗法是，目前植入 MEA 的技术水平存在一个主要缺点，即它们的记录随着时间的推移，刺激质量会下降，植入物最终会失去功能。用于治疗患者终生持续的慢性疾病的治疗设备需要长期稳定的 MEA 导致长期植入失败的潜在机制是几十年而不是几个月到几年。 MEA 尚未完全阐明，其中之一是电极或绝缘材料的退化。造成机械装置故障的另一个重要因素是主机异物反应所致。小胶质细胞和星形胶质细胞的激活可导致神经胶质增生并形成包裹神经胶质细胞的“神经胶质疤痕” 最近，基于基因治疗的干预措施。使用 CRISPR/Cas 系统进行基因敲除在改变免疫反应方面显示出巨大的前景。 Cui 实验室最近的工作表明了使用功能化二氧化硅纳米颗粒 (SNP) 作为用于涂有聚乙烯二氧噻吩 (PEDOT)/SNP 的微电极的多功能表面修饰。与标准裸金属电极相比，电化学性能和负载能力得到改善由于其具有高表面积的多孔结构，这些特性使得 MEA 具有治疗性化合物。涂有 PEDOT/SNP 的二氧化硅纳米颗粒是高度靶向基因递送的理想平台该提案旨在开发这项技术来有效地对小胶质细胞进行基因修饰。局部植入 MEA 周围，以减少炎症并测量炎症对记录的影响此外，我将研究如何变化。在异物反应影响植入物周围组织的重塑时，我将采取以下方法。将编码 CRISPR 基因治疗载体的 DNA 加载到 SNP 包被的 MEA 上，靶向炎症途径在小胶质细胞中，CRISPR载体将通过电化学方式传递至与小胶质细胞直接连接的细胞。这项技术的发展具有提高治疗价值的巨大潜力。通过减少炎症和神经胶质增生来提高植入设备的性能和寿命一旦建立，就会增加我们对大脑如何响应植入设备的基本理解。技术将成为高度靶向基因传递的多功能平台，具有时空和细胞类型特异性。