Understanding the Effects of Both CD14-Mediated Innate Immunity and Device/Tissue Mechanical Mismatch in the Neuroinflammatory Response to Intracortical Microelectrodes

Abstract

Intracortical microelectrodes record neuronal activity of individual neurons within the brain, which can be used to bridge communication between the biological system and computer hardware for both research and rehabilitation purposes. However, long-term consistent neural recordings are difficult to achieve, in large part due to the neuroinflammatory tissue response to the microelectrodes. Prior studies have identified many factors that may contribute to the neuroinflammatory response to intracortical microelectrodes. Unfortunately, each proposed mechanism for the prolonged neuroinflammatory response has been investigated independently, while it is clear that mechanisms can overlap and be difficult to isolate. Therefore, we aimed to determine whether the dual targeting of the innate immune response by inhibiting innate immunity pathways associated with cluster of differentiation 14 (CD14), and the mechanical mismatch could improve the neuroinflammatory response to intracortical microelectrodes. A thiol-ene probe that softens on contact with the physiological environment was used to reduce mechanical mismatch. The thiol-ene probe was both softer and larger in size than the uncoated silicon control probe. Cd14-/- mice were used to completely inhibit contribution of CD14 to the neuroinflammatory response. Contrary to the initial hypothesis, dual targeting worsened the neuroinflammatory response to intracortical probes. Therefore, probe material and CD14 deficiency were independently assessed for their effect on inflammation and neuronal density by implanting each microelectrode type in both wild-type control and Cd14-/- mice. Histology results show that 2 weeks after implantation, targeting CD14 results in higher neuronal density and decreased glial scar around the probe, whereas the thiol-ene probe results in more microglia/macrophage activation and greater blood–brain barrier (BBB) disruption around the probe. Chronic histology demonstrate no differences in the inflammatory response at 16 weeks. Over acute time points, results also suggest immunomodulatory approaches such as targeting CD14 can be utilized to decrease inflammation to intracortical microelectrodes. The results obtained in the current study highlight the importance of not only probe material, but probe size, in regard to neuroinflammation.

Differential expression of genes involved in the acute innate immune response to intracortical microelectrodes

“…In order to have a comprehensive molecular analysis of the acute innate immune response, genes involved in the inflammatory cellular markers, the complement response, the cytokine response and the chemokine response were investigated. Since our lab has previously found targeting the TLR/CD14 pathway yields promising results in both improving intracortical microelectrode recording and neuronal density [16,17], it was critical to continue investigation of this pathway. Furthermore, we explored PRRs that could also be potential therapeutic targets, as we have previously shown CD14 to be [18].…”

“…Animals were prepped for surgery using established methods [17]. Briefly, after mice reached surgical plane using isoflurane (3% in 1.0 L/min O 2) , mice were mounted onto a stereotaxic frame for the remainder of the surgical preparations and the surgery itself.…”

“…We have previously shown that the inhibition of specific innate immunity pathways reduces the glial scar and neuronal death and the probe/tissue interface, and improves recording quality [16][17][18]. To connect our previous studies that utilized traditional immunohistochemistry to the gene expression profiles measured here, we first looked at the genes commonly used to code for proteins with immunohistochemistry: astrocytes (Gfap), infiltrating leukocytes (Cd45), and activated microglia/macrophages (Cd68) [13,31,32].…”

“…We have established that two specific pathways are critical to the connection between microelectrode-induced neuroinflammation and microelectrode performance: oxidative stress and innate immunity [16][17][18][19][20][21][22]. Oxidative stress is a result of the intense or prolonged inflammatory response associated with microelectrode implantation [21,22].…”

Tissue Response to Neural Implants: The Use of Model Systems Toward New Design Solutions of Implantable Microelectrodes

“…Genetically engineered animal models are another successful tool in microelectrode research. Mice lacking specific genes involved in neuroinflammation and immunity were employed to investigate the biochemical pathways involved in the foreign body response, the identification of pharmacological targets (Kozai et al, 2014; Bedell et al, 2018b; Hermann et al, 2018a,b) and material testing (Lee et al, 2017). Mice carrying cell specific fluorescent tags have been shown to provide great advantages in the study of the contribution of different cells in a single animal as well as a valuable alternative to immunostaining steps (Sunshine et al, 2018; Eles et al, 2019).…”