Flexible Multi-Sensory Mode Neural Devices for Neurochemical Control

 说明： 长期目标是开发先进的、多功能的神经接口，用于与生物环境的局部相互作用。通过预防、检测和控制生物组织，将保持皮质内微电极阵列的长期可靠性 对植入装置的反应。为了实现这一目标，基于在神经组织内无缝集成的材料的微型皮质内神经接口将与微流控药物输送能力和神经化学传感器集成在一起。皮质内神经记录植入物在植入后的几周和几个月内，由于神经记录质量的丧失而受到阻碍。神经炎性组织反应导致植入物周围的神经胶质包被，被广泛认为是导致神经棘波记录质量逐渐丧失的原因。虽然已经通过使用新材料来减少探头与组织的机械失配或通过注射抗炎药来努力延长记录的可靠性，但缺乏一种多方面的方法来消除神经炎性反应。目前还没有实用的技术来跟踪组织的反应活动 植入物-组织界面在包裹发生之前在原位，此时对生物-非生物界面的破坏可能是不可逆的。在缺乏神经炎症活动的原位测量的情况下，通过药物输送来缓和组织反应的治疗干预效果较差。该项目将使用一种新型的聚合物纳米复合材料作为植入结构材料来防止组织反应，使用谷氨酸传感器来检测组织反应，并使用微流控药物传递能力来控制组织反应。这一建议的基本假设是，基于微加工的方法可以用于将机械适应性聚合物纳米复合材料与用于预防和治疗神经植入的生物反应的闭环控制系统所需的功能集成在一起。本研究项目分为两个不同的具体目标。第一个目标是使用电化学法 将传感器集成到皮质内微电极设备中，以评估谷氨酸是组织反应活动的指标的假设。将研究三组同时具有集成神经记录电极和谷氨酸电化学传感器的多模式神经探针：刚性硅控制、高顺应性聚合物纳米复合材料和中等顺应性聚合物纳米复合材料。将探头植入Spraogue-Dawley大鼠的桶状皮质，持续3天、2周或16周。在整个植入过程中，将定期进行电化学阻抗、神经记录和谷氨酸测量。之后，将对固定组织进行免疫组织化学(IHC)分析，以评估组织反应的程度。阻抗、神经尖峰和谷氨酸数据将与IHC数据进行比较，以寻找体内测量和累积组织反应之间的相关性。通过确认这一假设，将识别出一种简单的分析物，它可以用于跟踪组织反应，并作为闭环系统的控制信号。在第二个目标中，微流控药物输送能力将被整合到聚合物纳米复合材料中。机械适应性聚合物纳米复合材料的透湿性将通过可渗透壁微流体通道的设计来开发，以补充纳米复合材料中药物的存储。这将使少量高度定位于植入物周围区域的抗炎剂得以受控、持续释放。然后，这些能力可以与微电子系统结合和集成，以感知和控制局部神经炎性反应。

 DESCRIPTION: The long-term goal is to develop advanced, multi-functional neural interfaces for localized interaction with the biological environment. Long-term, intracortical microelectrode array reliability will be maintained through preventing, detecting, and controlling the biological tissue response to the implanted device. To accomplish this goal, microscale intracortical neural interfaces based on materials that seamlessly integrate within the neural tissue will be integrated with microfluidic drug delivery capabilities and neurochemical sensors. Intracortical implants for neural spike recording are hampered by a loss of neural recording quality in the weeks and months after implantation. The neuroinflammatory tissue response leading to glial encapsulation around the implants is widely hypothesized as the cause of the gradual loss of neural spike recording quality. While efforts to extend recording reliability have been made through the use of novel materials to reduce probe-tissue mechanical-mismatch or by delivery of anti-inflammatory agents, a multi-faceted approach to eliminating the neuroinflammatory response is lacking. There is currently no practical technique to track tissue response activity at the implant-tissue interface in situ before encapsulation has occurred, at which point damage to the biotic-abiotic interface may be irreversible. In the absence of an in situ measure of neuroinflammatory activity, therapeutic intervention to temper the tissue response via drug delivery is less effective. This project will use a novel polymer nanocomposite as the implant structural material to prevent the tissue response, a glutamate sensor to detect the tissue response, and microfluidic drug delivery capabilities to control the tissue response. The primary hypothesis of this proposal is that a microfabrication-based approach can be used to integrate a mechanically-adaptive polymer nanocomposite with the functions required for a closed-loop control system for preventing and treating the biological response to neural implants. This research project is divided into two distinct specific aims. The first aim will use electrochemical sensors integrated into intracortical microelectrode devices to evaluate the hypothesis that glutamate is an indicator of tissue response activity. Three sets of multi-modal neural probes with both integrated neural recording electrodes and glutamate electrochemical sensors will be studied: a rigid silicon control, a highly-compliant polymer nanocomposite, and a moderately- compliant polymer nanocomposite. Probes will be implanted in the barrel cortex of Sprague-Dawley rats for either 3 days, 2 weeks, or 16 weeks. Electrochemical impedance, neural recordings, and glutamate measurements will be made regularly throughout the implant duration. Afterward, immunohistochemical (IHC) analysis will be performed on fixed tissue to assess the extent of the tissue response. Impedance, neural spike, and glutamate data will be compared to the IHC data to look for correlations between in vivo measures and the cumulative tissue response. By confirming the hypothesis, a simple analyte will have been identified that can be used to track tissue response and serve as a control signal for a closed-loop tissue response control system. In the second aim, microfluidic drug-delivery capabilities will be integrated into the polymer nanocomposite. The moisture permeability of the mechanically-adaptable polymer nanocomposite will be exploited with the design of permeable-walled microfluidic channels to replenish the storage of pharmacologic agents within the nanocomposite. This will enable for controlled, sustained release of a small amount of anti- inflammatory agents highly localized to the region surrounding the implant. These capabilities can then be combined and integrated with microelectronic systems to sense and control the local neuroinflammatory response.