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

这项提议的总体目标是改善皮质内记录微电极的慢性性能 使用有针对性的药物输送方法。基于微电极的设备有可能解决许多 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 假肢使用“思想”或来自运动皮质的信号。BCI正在被研究人员进一步扩展 在退伍军人管理局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是重要的，但这些设备受到 关键挑战：长期稳定性和功能性。故障模式是多方面的，但实质上是 成分归因于植入引起的血管损伤，引发出血和长时间的生物学反应 反应，包括炎症，导致录音接触附近的健康神经元显著减少。 FDA批准的几种药物已经证明了降低生物炎症反应和 增强啮齿类动物的微电极记录性能。然而，由于药物动力学和药物动力学的限制 药效学方面，大多数药物在相对较低的浓度下到达植入部位，限制了 效果的大小和/或需要频繁的剂量才能达到有意义的结果。此外，在以下情况下 类固醇和抗生素，由于对外周的副作用，禁止长期全身给药 系统。利用目前正在商业化的血小板激发的药物输送平台，我们已经 设计了一种专门针对微电极植入部位的药物靶向方法。将药物本地化 到微电极部位将减少全身给药剂量，同时最小化所提供的有效载荷 外周器官，如肝脏和肾脏。在这项研究中，我们将重点放在药物的传递上， 地塞米松(Dex)，是一种有效的糖皮质激素抗炎药物。当我们有了 展示了用载药纳米粒靶向微电极的能力，进一步优化了 需要地塞米松的剂量和慢性记录的特征。我们的目标是建立一个安全和 有效的药物传递平台，用于局部治疗，以改善慢性脑梗塞的表现。我们假设 给药靶向地塞米松纳米粒(Dex-NPs)将防止慢性瘢痕和 与皮质内微电极慢性记录质量改善相关的神经退行性变 相关的运动行为功能。如果被证明有效，该平台可能会进一步开发和 其特点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，因此扩展的潜力更大 这项技术对人类的应用。

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.