Optimizing Delivery of a Known Therapeutic Agent, Dexamethasone, to Improve Microelectrode Recording Performance

优化已知治疗剂地塞米松的输送，以提高微电极记录性能

基本信息

批准号：
10642761
负责人：
Jeffrey R Capadona
金额：
--
依托单位：
LOUIS STOKES CLEVELAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10642761
关键词：
3-Dimensional Address Amputation Anterior Anti-Inflammatory Agents Antibiotics Behavior Behavioral Bilateral Biological Blood Blood Chemical Analysis Blood Platelets Blood Vessels Body Weight Brain Central Nervous System Cerebrospinal fluid shunts procedure Chronic Cicatrix Data Devices Dexamethasone Dose Drug Delivery Systems Drug Targeting Drug usage Electrodes Engineering Euthanasia FDA approved Failure Frequencies Future Gender Gene Expression Glucocorticoids Goals Health Hemorrhage Hemostatic function High Pressure Liquid Chromatography Human Implant Implanted Electrodes Inflammation Inflammatory Response Kidney Kinetics Left Limb Prosthesis Liver Local Therapy Longevity Lung Measurement Measures Mechanics Mediating Medical Device Medical Research Metabolic Clearance Rate Methods Microelectrodes Motor Motor Cortex Nerve Degeneration Neurons Organ Outcome Pain Paralysed Parkinson Disease Patients Pattern Performance Peripheral Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Prevalence Prosthesis Quality of life Randomized Rattus Rehabilitation therapy Research Research Personnel Rodent Rodent Model Safety Saline Side Signal Transduction Silicon Site Spinal cord injury Spleen Steroids Stroke System Technology Therapeutic Agents Thinking Time Tissues Touch sensation Trauma Treatment Efficacy Tremor Veterans With laterality animal imaging behavior test blood-brain barrier permeabilization brain computer interface chronic pain cohort commercialization delivery vehicle dosage fluorescence imaging functional restoration imaging modality implantable device implantation improved limb movement medical implant nanolabel nanoparticle neural neuroinflammation neuromuscular pharmacokinetics and pharmacodynamics prevent response safety assessment sensor side effect tissue processing treatment comparison

项目摘要

The overall goal of this proposal is to improve the chronic performance of intracortical recording microelectrodes using a targeted drug-delivery approach. Microelectrode-based devices have the potential to resolve many challenges in rehabilitation for Veterans with paralysis and/or amputation. Notably, brain-computer interface (BCI) endeavors within the VA have provided patients the ability to control electromechanical or neuromuscular prostheses using ‘thoughts’ or signals from their motor cortex. BCIs are further being extended by researchers at the VA to restore the sensation of touch by integrating sensors and stimulators into mechanical prosthetic limbs.3-5 While the promises of intracortical microelectrode interfaces are significant, the devices suffer from a key challenge: long term stability and functionality. The failure modes are multifaceted, but a substantial component is attributed to vascular trauma from implantation that initiates bleeding and a prolonged biological response, including inflammation which leads to significant reduction in healthy neurons near recording contacts. Several FDA-approved drugs have demonstrated the ability to reduce the biological inflammatory response and augment microelectrode recording performance in rodents. However, due to limitations of pharmacokinetics and pharmacodynamics, most of the agents reach the implant site in relatively low concentrations, limiting the magnitude of effect and/or requiring frequent dosages to attain meaningful results. Additionally, in the case of steroids and antibiotics, long-term systemic administration is contraindicated due to side effects on peripheral systems. Leveraging a platelet-inspired drug delivery platform currently undergoing commercialization, we have engineered a method for targeting drugs specifically to the microelectrode implantation site. Localizing the drug to the microelectrode site will reduce the systemically administered dose, while minimizing the payload delivered to peripheral organs, e.g., liver and kidneys. During this study, we will focus on delivering the drug, dexamethasone (Dex), which is a potent glucocorticoid steroidal anti-inflammatory drug. While we have demonstrated the ability to target the microelectrode with drug-loaded nanoparticles, further optimization of dosing with Dex and characterization of chronic recordings are needed. Our objective is to establish a safe and effective drug-delivery platform for localized therapy to improve chronic BCI performance. We hypothesize that administration of targeted dexamethasone-loaded nanoparticles (Dex-NPs) will prevent chronic scarring and neurodegeneration associated with improved chronic recording quality of intracortical microelectrodes and associated motor-behavioral function. If proven effective, the platform may be further developed and characterized to release other pharmaceutical payloads that have unique or complementary effects on the system. Additionally since the delivery platform is being commercialized, there is increased potential for scaling the technology to human application.

该提案的总体目标是改善皮质内记录微电极的慢性表现采用靶向药物交付方法。基于微电极的设备有可能解决许多瘫痪和/或截肢的退伍军人康复方面的挑战。值得注意的是，大脑计算机界面（BCI）VA内的努力为患者提供了控制机电或神经肌肉的能力假体使用“思想”或电动机皮质信号。研究人员进一步扩展了BCI 在VA处，通过将传感器和刺激器集成到机械假肢中来恢复触摸感四肢3-5虽然物质内微电极接口的承诺很重要，但设备遭受了主要挑战：长期稳定性和功能。故障模式是多方面的，但很重要组成部分归因于植入引发出血和长时间生物学的血管创伤反应，包括炎症，导致记录接触附近的健康神经元显着降低。几种FDA批准的药物已经证明了降低生物性炎症反应的能力和增强啮齿动物中的微电极记录性能。但是，由于药代动力学和药效学，大多数药物以相对较低的浓度到达植入物位置，从而限制了效果的大小和/或需要剂量经常获得有意义的结果。此外，在类固醇和抗生素，由于对周围的副作用而禁忌长期全身部给药系统。利用当前正在商业化的血小板风格的药物输送平台，我们有设计了一种专门针对微电极植入部位的药物的方法。定位该药物到微电极站点将减少系统施用的剂量，同时最大程度地减少交付的有效载荷到外围器官，例如肝脏和肾脏。在这项研究中，我们将专注于提供药物，地塞米松（Dex），这是一种潜在的糖皮质固醇抗炎药。而我们有证明了用加载药物的纳米颗粒靶向微电极的能力，进一步优化了需要用DEX和慢性记录的表征进行剂量。我们的目标是建立安全和有效的药物分娩平台，用于局部治疗，以改善慢性BCI性能。我们假设这一点给予靶向地塞米松的纳米颗粒（DEX-NP）将防止慢性疤痕和神经变性与改善了皮质内微电极的慢性记录质量有关相关的运动行为功能。如果证明有效，该平台可能会进一步开发，并且特征是释放其他药物有效载荷，这些有效载荷对系统。此外，由于交付平台正在商业化，因此扩展潜力增加人类应用的技术。