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: 10217285
• 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/10217285
• 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; 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.

该提案的总体目标是提高皮质内记录微电极的长期性能 使用基于微电极的靶向药物输送方法有可能解决许多问题。 瘫痪和/或截肢退伍军人康复面临的挑战尤其是脑机接口。 (BCI) VA 内的努力为患者提供了控制机电或神经肌肉的能力 研究人员正在进一步扩展使用来自运动皮层的“思想”或信号的假肢。 VA 通过将传感器和刺激器集成到机械假肢中来恢复触觉 3-5 虽然皮质内微电极接口的前景很重要，但这些设备存在以下问题： 关键挑战：长期稳定性和功能性 故障模式是多方面的，但影响很大。 该成分归因于植入引起的血管创伤，导致出血和长时间的生物滞留。 反应，包括炎症，导致记录接触点附近的健康神经元显着减少。 FDA 批准的几种药物已被证明能够减少生物炎症反应和 增强啮齿动物的微电极记录性能然而，由于药代动力学和的限制。 从药效学来看，大多数药物以相对较低的浓度到达植入部位，限制了 在这种情况下，效果的大小和/或需要频繁的剂量才能获得有意义的结果。 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 利用目前正在进行商业化的血小板启发药物输送平台，我们拥有 设计了一种将药物专门靶向微电极植入部位的方法。 到微电极部位将减少全身给药剂量，同时最大限度地减少传递的有效负载 到周围器官，例如肝脏和肾脏 在这项研究中，我们将重点关注药物的输送， 地塞米松（Dex），这是一种有效的糖皮质激素类固醇抗炎药。 能够用载药纳米颗粒靶向微电极，进一步优化 我们的目标是建立一个安全且可靠的方法。 用于局部治疗以改善慢性 BCI 表现的有效药物输送平台。 施用靶向地塞米松负载纳米粒子（Dex-NPs）将预防慢性疤痕和 神经退行性变与皮质内微电极慢性记录质量的改善相关 如果证明有效，该平台可以进一步开发和使用。 其特点是释放其他药物有效负载，这些药物有效负载对药物具有独特或互补的作用 此外，由于交付平台正在商业化，因此扩展的潜力也越来越大。 技术对人类的应用。