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

• 批准号: 10418649
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418649
• 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; Cerebrospinal fluid shunts procedure; Chronic; Cicatrix; Data; Devices; Dexamethasone; Dose; Drug Delivery Systems; Drug Targeting; Drug usage; Electrodes; Engineering; FDA approved; Failure; Frequencies; Future; Gender; Gene Expression; Glucocorticoids; Goals; Health; Hemorrhage; Hemostatic function; High Pressure Liquid Chromatography; Human; Implant; Inflammation; Inflammatory Response; Kidney; Kinetics; Label; 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; Neuraxis; 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; animal imaging; base; behavior test; blood-brain barrier permeabilization; brain computer interface; chronic pain; cohort; commercialization; delivery vehicle; dosage; fluorescence imaging; imaging modality; implantable device; implantation; improved; limb movement; medical implant; nanoparticle; neuroinflammation; neuromuscular; pharmacokinetics and pharmacodynamics; prevent; relating to nervous system; response; sensor; side effect; tissue processing; treatment comparison

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.

本提案的总体目标是改善皮质内记录微电极的慢性性能 使用靶向药物输送方法。基于微电极的设备具有解决许多问题的潜力。 瘫痪和/或截肢退伍军人的康复挑战。值得注意的是，脑机接口 (BCI)VA内的努力为患者提供了控制机电或神经肌肉的能力， 使用来自运动皮层的“思想”或信号的假肢。研究人员正在进一步扩展BCI 通过将传感器和刺激器集成到机械假肢中来恢复触觉 虽然皮质内微电极界面的前景是重要的，但该设备存在以下问题： 关键挑战：长期稳定性和功能性。故障模式是多方面的，但实质上 组件归因于植入引起的血管创伤，引发出血和长期的生物学损伤。 反应，包括炎症，导致记录接触附近的健康神经元显着减少。 几种FDA批准的药物已经证明能够减少生物炎症反应， 增强啮齿动物的微电极记录性能。然而，由于药代动力学的局限性， 由于药效学，大多数药剂以相对低的浓度到达植入部位，限制了药物的有效性。 效果的大小和/或需要频繁的剂量以获得有意义的结果。此外，在 类固醇和抗生素，由于对外周的副作用，长期全身给药是禁忌的 系统.利用目前正在商业化的血小板激发的药物递送平台，我们 设计了一种将药物特异性靶向微电极植入部位的方法。定位药物 将减少全身给药剂量，同时使递送的有效载荷最小化 到外周器官，例如，肝脏和肾脏在这项研究中，我们将专注于药物的输送， 地塞米松（Dex），这是一种有效的糖皮质激素类固醇抗炎药。虽然我们已经 证明了用载药纳米颗粒靶向微电极的能力，进一步优化了 需要Dex给药和慢性记录的表征。我们的目标是建立一个安全和 用于局部治疗的有效药物递送平台，以改善慢性BCI性能。我们假设 靶向地塞米松负载的纳米颗粒（Dex-NP）的施用将防止慢性瘢痕形成， 与皮质内微电极慢性记录质量改善相关的神经变性， 相关的运动行为功能。如果证明有效，可进一步发展该平台， 其特征在于释放对所述药物组合物具有独特或互补作用的其它药物有效载荷。 系统此外，由于交付平台正在商业化，扩展的潜力也在增加 将技术应用于人类。