Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, United States; Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, United States.
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, United States.
Brain Behav Immun. 2024 May;118:221-235. doi: 10.1016/j.bbi.2024.03.004. Epub 2024 Mar 6.
The neuroinflammatory response to intracortical microelectrodes (IMEs) used with brain-machine interfacing (BMI) applications is regarded as the primary contributor to poor chronic performance. Recent developments in high-plex gene expression technologies have allowed for an evolution in the investigation of individual proteins or genes to be able to identify specific pathways of upregulated genes that may contribute to the neuroinflammatory response. Several key pathways that are upregulated following IME implantation are involved with the complement system. The complement system is part of the innate immune system involved in recognizing and eliminating pathogens - a significant contributor to the foreign body response against biomaterials. Specifically, we have identified Complement 3 (C3) as a gene of interest because it is the intersection of several key complement pathways. In this study, we investigated the role of C3 in the IME inflammatory response by comparing the neuroinflammatory gene expression at the microelectrode implant site between C3 knockout (C3) and wild-type (WT) mice. We have found that, like in WT mice, implantation of intracortical microelectrodes in C3 mice yields a dramatic increase in the neuroinflammatory gene expression at all post-surgery time points investigated. However, compared to WT mice, C3 depletion showed reduced expression of many neuroinflammatory genes pre-surgery and 4 weeks post-surgery. Conversely, depletion of C3 increased the expression of many neuroinflammatory genes at 8 weeks and 16 weeks post-surgery, compared to WT mice. Our results suggest that C3 depletion may be a promising therapeutic target for acute, but not chronic, relief of the neuroinflammatory response to IME implantation. Additional compensatory targets may also be required for comprehensive long-term reduction of the neuroinflammatory response for improved intracortical microelectrode performance.
皮质内微电极（IMEs）与脑机接口（BMI）应用结合使用时，其引发的神经炎症反应被认为是导致慢性性能不佳的主要原因。高通量基因表达技术的最新发展使得能够对单个蛋白质或基因进行研究，以确定上调基因的特定途径，这些途径可能有助于神经炎症反应。在 IME 植入后上调的几个关键途径与补体系统有关。补体系统是先天免疫系统的一部分，参与识别和消除病原体 - 这是对生物材料产生异物反应的主要原因。具体来说，我们已经确定补体 3（C3）是一个感兴趣的基因，因为它是几个关键补体途径的交汇点。在这项研究中，我们通过比较 C3 基因敲除（C3）和野生型（WT）小鼠微电极植入部位的神经炎症基因表达，研究了 C3 在 IME 炎症反应中的作用。我们发现，与 WT 小鼠一样，在 C3 小鼠中植入皮质内微电极会导致所有术后时间点的神经炎症基因表达显著增加。然而，与 WT 小鼠相比，C3 耗竭显示术前和术后 4 周的许多神经炎症基因表达减少。相反，与 WT 小鼠相比，C3 耗竭在术后 8 周和 16 周增加了许多神经炎症基因的表达。我们的结果表明，C3 耗竭可能是急性但不是慢性缓解 IME 植入引起的神经炎症反应的有前途的治疗靶点。可能还需要其他代偿性靶点，以实现长期综合减轻神经炎症反应，从而提高皮质内微电极的性能。
