CD14 facilitates neural device integration and performance

描述(申请人提供)：由皮质内电极从神经元记录的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。信号质量和可记录有用信号的时间长度不一致。业界的共识是，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物质(即受损/渗入的蛋白质和细胞)时，炎性因子就会启动。植入装置后，血清蛋白和血源性细胞侵入中枢神经系统。植入设备的创伤会对细胞和组织造成损害。在电极表面，促炎分子的积累会导致神经元退化，并增加血脑屏障的通透性，使这一过程自我延续。研究表明，共受体分化簇14(CD14)与至少四种不同的Toll样受体(TLR)协调病原体或受损细胞的结合和识别。具体地说，在与CD14的合作中，TLR2和TLR4也被证明对血清蛋白和坏死细胞具有反应性。CD14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设备的自持性神经炎性反应。我们研究了CD14、TLR2和TLR4在促进皮质内植入电极引起的神经炎症反应中的作用。缺乏CD14、TLR2或TLR4的转基因小鼠被植入非工作的“虚拟”电极，在对植入的炎症反应中显示出时间依赖性的抑制。CD14拮抗剂的治疗性应用也减轻了植入物的炎症。此外，脂多糖对CD14通路的过度刺激对慢性神经记录的质量产生了负面影响。因此，我们假设抑制CD14将使皮质内微电极能够更一致地记录高质量的神经元单位。我们建议首先将CD14共受体缺失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。作为临床应用的一步，Aim 2将建立使用CD14拮抗剂进行全身抑制的时间进程。最后，目标3将调查一种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。在所有目标中，组织学评估将跟踪神经炎症和血脑屏障随着时间的推移的稳定性，而电生理学评估将神经炎症与设备性能相关联。

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.