CD14 facilitates neural device integration and performance

描述（由申请人提供）：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械肢体。信号质量和记录有用信号的时间长度不一致。医学界的共识是，对微电极的炎症反应至少在一定程度上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）时，炎症就开始了。植入装置后，血清蛋白和血源性细胞侵入中枢神经系统。细胞和组织因植入装置的创伤而受损。在电极表面，促炎分子的积累导致神经元变性，增加血脑屏障的渗透性，使这一过程自我延续。分化共受体簇14 （CD14）已被证明协调病原体或受损细胞对至少四种不同toll样受体（TLR）的结合和识别。具体来说，在与CD14合作的情况下，TLR2和TLR4也被证明对血清蛋白和坏死细胞产生反应。CD14可能通过识别吸附的血清蛋白和受损的细胞和组织，介导对非生物医疗器械的自我延续的神经炎症反应。我们研究了CD14、TLR2和TLR4在促进皮层内电极植入后的神经炎症反应中的作用。缺乏CD14、TLR2或TLR4的转基因小鼠植入不起作用的“假”电极后，对植入物的炎症反应表现出时间依赖性抑制。治疗性给予CD14拮抗剂也能减轻植入物的炎症。此外，脂多糖对CD14通路的过度刺激会对慢性神经记录的质量产生负面影响。因此，我们假设CD14抑制将使皮质内微电极能够更一致地记录高质量的神经单元。我们建议首先将缺乏CD14共受体的转基因小鼠植入功能性微电极。神经信号的质量和稳定性

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.