CD14 facilitates neural device integration and performance

描述（由申请人提供）： 大脑皮层内电极记录的神经元电信号已被人类患者用于与计算机通信和控制机器人肢体。 信号质量和有用信号可以被记录的时间长度是不一致的。 社区的共识是，微电极的炎症反应至少部分地有助于电极的可靠性。 当炎性细胞识别外来生物制剂（即受损/浸润的蛋白质和细胞）时，炎症蛋白被启动。 血清蛋白和血液来源的细胞在器械植入后侵入中枢神经系统。 细胞和组织因器械植入创伤而受损。 在电极表面，促炎分子的积累导致神经元变性并增加血脑屏障的渗透性，使该过程自我延续。 共受体分化簇14（CD 14）已显示协调病原体或受损细胞对至少四种不同的toll样受体（TLR）的结合和识别。 具体地，与CD 14合作，TLR 2和TLR 4也已显示对血清蛋白和坏死细胞具有反应性。 CD 14可能通过识别吸附的血清蛋白和受损的细胞和组织来介导对非生物医疗器械的自我持续神经炎症反应。 我们研究了CD 14、TLR 2和TLR 4在促进神经炎症反应中的作用，这些炎症反应是对植入的皮质内电极的反应。 植入非工作“假”电极的缺乏CD 14、TLR 2或TLR 4的转基因小鼠显示出对植入物的炎症反应的时间依赖性抑制。 CD 14拮抗剂的治疗性给药也减轻了植入物的炎症。 此外，脂多糖对CD 14通路的过度刺激对慢性神经记录的质量产生负面影响。 因此，我们假设CD 14抑制将使皮质内微电极更一致地记录高质量的神经单元。 我们建议首先植入缺乏CD 14共受体的转基因小鼠与功能微电极。 神经信号的质量和稳定性将 与植入对照野生型动物长达16周的相同装置的性能进行比较。 作为临床应用的一个步骤，Aim 2将建立使用CD 14拮抗剂进行全身抑制的时间过程。 最后，目标3将研究局部给药载体的有效性，以最大限度地减少与长期全身给药相关的副作用的可能性。 在所有目标中，组织学评价将跟踪神经炎症和血脑屏障随时间的稳定性，而电生理学评价将神经炎症与器械性能相关联。

DESCRIPTION (provided by applicant): Electrical signals recorded from neurons by intracortical electrodes have been used by human patients to communicate with computers and to control robotic limbs. The signal quality and the length of time that useful signals can be recorded are inconsistent. The consensus view of the community is that the inflammatory response to the microelectrode contributes, at least in part, to electrode reliability. Inflammatin is initiated when inflammatory cells recognize foreign biologics (i.e. damaged/infiltrating proteins and cells). Serum proteins and blood-derived cells invade the central nervous system following device implantation. Cells and tissue are damaged from the trauma of device implantation. At the electrode surface, accumulation of pro-inflammatory molecules causes neuronal degeneration and increases the permeability of the blood-brain barrier, self-perpetuating the process. The co-receptor cluster of differentiation 14 (CD14) has been shown to coordinate the binding and recognition of pathogens or damaged cells for at least four different toll-like receptors (TLR). Specifically, in cooperation with CD14, both TLR2 and TLR4 have also been shown to become reactive towards serum proteins and necrotic cells. CD14 likely mediates the self-perpetuating neuroinflammatory response to non-biological medical devices through recognition of adsorbed serum proteins and damaged cells and tissue. We have studied the role of CD14, TLR2, and TLR4 in facilitating neuroinflammation in response to implanted intracortical electrodes. Transgenic mice lacking CD14, TLR2 or TLR4 implanted with non- working "dummy" electrodes, showed a time dependent inhibition in the inflammatory response to the implant. Therapeutic administration of a CD14 antagonist also attenuated inflammation to the implant. Further, over stimulation of CD14 pathways with lipopolysaccharide negatively impacted the quality of chronic neural recordings. Therefore, we hypothesize that CD14 inhibition will enable intracortical microelectrodes to more consistently record high quality neural units. We propose to first implant transgenic mice lacking either the CD14 co-receptor with functional microelectrodes. The quality and stability of neural signals will be compared to the performance of identical devices implanted in control wildtype animals for up to 16 weeks. As a step towards clinical use, Aim 2 will establish a time course for systemic inhibition using a CD14 antagonist. Finally, Aim 3 will investigate the efficacy of a local delivey vehicle, to minimize the potential for side effects associated with long-term systemic administration. In all aims, histological evaluation will track both neuroinflammation and blood-brain barrier stability over time, while electrophysiological evaluation will correlate neuroinflammation to device performance.