Flexible Multi-Sensory Mode Neural Devices for Neurochemical Control

 产品说明： 长期目标是开发先进的多功能神经接口，用于与生物环境的局部交互。通过预防、检测和控制生物组织，将维持长期的皮质内微电极阵列可靠性 对植入设备的反应。为了实现这一目标，基于无缝集成在神经组织内的材料的微尺度皮质内神经接口将与微流体药物递送能力和神经化学传感器集成。用于神经尖峰记录的皮质内植入物受到植入后数周和数月内神经记录质量损失的阻碍。神经炎性组织反应导致植入物周围的神经胶质包囊被广泛假设为神经锋电位记录质量逐渐丧失的原因。虽然已经通过使用新型材料来减少探针-组织机械失配或通过递送抗炎剂来努力扩展记录可靠性，但是缺乏消除神经炎症反应的多方面方法。目前还没有实用的技术来跟踪组织反应活性， 植入物-组织界面在封装发生之前原位，此时对生物-非生物界面的损伤可能是不可逆的。在缺乏神经炎症活性的原位测量的情况下，通过药物递送来缓和组织反应的治疗干预是不太有效的。该项目将使用一种新型聚合物纳米复合材料作为植入物结构材料，以防止组织反应，谷氨酸传感器检测组织反应，以及微流体药物输送能力来控制组织反应。 该提案的主要假设是，基于微加工的方法可以用于将机械自适应聚合物纳米复合材料与闭环控制系统所需的功能集成，用于预防和治疗对神经植入物的生物反应。这个研究项目分为两个不同的具体目标。第一个目标将使用电化学 传感器集成到皮质内微电极装置，以评估假设谷氨酸是组织反应活性的指标。将研究三组具有集成神经记录电极和谷氨酸盐电化学传感器的多模态神经探针：刚性硅控制、高度顺应性聚合物纳米复合材料和适度顺应性聚合物纳米复合材料。将探针植入Sprague-Dawley大鼠的桶皮质中3天、2周或16周。在整个植入期间定期进行电化学阻抗、神经记录和谷氨酸盐测量。随后，将对固定的组织进行免疫组织化学（MHC）分析，以评估组织反应的程度。将阻抗、神经尖峰和谷氨酸数据与IHC数据进行比较，以寻找体内测量值与累积组织反应之间的相关性。通过确认该假设，将识别出可用于跟踪组织反应并用作闭环组织反应控制系统的控制信号的简单分析物。在第二个目标中，微流体药物递送能力将被集成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被利用与渗透壁微流体通道的设计，以补充纳米复合材料内的药物制剂的存储。这将使得能够控制、持续释放高度定位于植入物周围区域的少量抗炎剂。然后，这些能力可以与微电子系统相结合和集成，以感知和控制局部神经炎症反应。

 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.