CD14 facilitates neural device integration and performance

通过皮层内电极从神经元记录的电信号已经被人类使用 病人与电脑交流和控制机器人肢体。信号质量和长度 有用信号被记录的时间是不一致的。社会人士的共识是 对微电极的炎症反应至少部分地有助于电极的可靠性。 当炎症细胞识别外来生物制剂（即， 受损/浸润的蛋白质和细胞）。血清蛋白和血液来源的细胞侵入中枢 植入器械后的神经系统。细胞和组织因器械创伤而受损 置入在电极表面，促炎分子的积累引起神经元 这一过程可导致细胞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）已显示协调结合， 识别病原体或受损细胞的至少四种不同的Toll样受体（TLR）。 具体地，与CD 14合作，TLR 2和TLR 4也已显示出变得具有反应性 向血清蛋白和坏死细胞转移CD 14可能介导了自我延续 通过识别吸附的血清对非生物医疗器械的神经炎症反应 蛋白质和受损的细胞和组织。 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， 植入皮质内电极。缺乏CD 14、TLR 2或TLR 4的转基因小鼠植入非- 工作的“假”电极，显示出对炎症反应的时间依赖性抑制， 植入CD 14拮抗剂的治疗性给药也减轻了植入物的炎症。 此外，用脂多糖过度刺激CD 14途径负面地影响了细胞的质量。 慢性神经记录因此，我们假设CD 14抑制将使皮质内 微电极，以更一致地记录高质量的神经单位。 我们建议首先植入缺乏CD 14共受体的转基因小鼠， 微电极神经信号的质量和稳定性将与 将相同的装置植入对照野生型动物中长达16周。作为迈向临床的一步 使用时，目标2将建立使用CD 14拮抗剂的全身抑制的时程。第三，目标 将研究局部给药载体的有效性，以尽量减少副作用的可能性 与长期全身给药有关。在所有目标中，组织学评价将跟踪 随着时间的推移，神经炎症和血脑屏障的稳定性，而电生理评价将 将神经炎症与器械性能相关联。

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. Inflammation 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 delivery 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.