Immunohistological and Ultrastructural Study of the Inflammatory Response to Perforated Polyimide Cortical Implants: Mechanisms Underlying Deterioration of Electrophysiological Recording Quality

Abstract

The deterioration of field potential (FP) recording quality and yield by in vivo multielectrode arrays (MEA) within days to weeks of implantation severely limits progress in basic and applied brain research. The prevailing hypothesis is that implantation of MEA platforms initiate and perpetuate inflammatory processes which culminate in the formation of scar tissue (the foreign body response, FBR) around the implant. The FBR leads to progressive degradation of the recording qualities by displacing neurons away from the electrode surfaces, increasing the resistance between neurons (current source) and the sensing pads and by reducing the neurons’ excitable membrane properties and functional synaptic connectivity through the release of pro-inflammatory cytokines. Meticulous attempts to causally relate the cellular composition, cell density, and electrical properties of the FBR have failed to unequivocally correlate the deterioration of recording quality with the histological severity of the FBR. Based on confocal and electron microscope analysis of thin sections of polyimide based MEA implants along with the surrounding brain tissue at different points in time after implantation, we propose that abrupt FP amplitude attenuation occurs at the implant/brain-parenchyma junction as a result of high seal resistance insulation formed by adhering microglia to the implant surfaces. In contrast to the prevailing hypothesis, that FP decrease occurs across the encapsulating scar of the implanted MEA, this mechanism potentially explains why no correlations have been found between the dimensions and density of the FBR and the recording quality. Recognizing that the seal resistance formed by adhering-microglia to the implant constitutes a downstream element undermining extracellular FP recordings, suggests that approaches to mitigate the formation of the insulating glial could lead to improved recording quality and yield.

Inflammatory Foreign Body Response Induced by Neuro-Implants in Rat Cortices Depleted of Resident Microglia by a CSF1R Inhibitor and Its Implications

“…Thus overall, consistent with the vast literature on traumatic brain injuries (TBI) and spinal cord injuries (SCI), the activation of microglia by MEA platform implantation temporally precedes the activation of astrocytes ( Polikov et al, 2005 ; Huang et al, 2020 ) and spatially borders the injury site or the MEA implant ( Polikov et al, 2005 ; Kozai et al, 2012b ; Potter et al, 2013 ; Campbell and Wu, 2018 ; Huang et al, 2020 ).…”

“…Recordings continued for 8 weeks (and in two cases for up to 16 weeks) from control rats and rats continuously fed with PLX5622 chow (Figure 10). As reported by our laboratory (Huang et al, 2020), when using the PPMPs (under control conditions), the number of operating platforms, viable electrodes/PPMP, and recorded FP amplitudes deteriorated with time after implantation. Comparing these parameters among control group (n = 26 rats) and PLX5622 pre-and post-fed rats (n = 8 and 14 rats, respectively) did not reveal significant differences.…”

“…The lines were fitted using the "scatter with smooth line" application (Excel). Kozai et al, 2012b;Potter et al, 2013;Campbell and Wu, 2018;Huang et al, 2020). The temporal and implied causal relationships between microglia and astrocyte activation are also evidenced by studies using PLX5622 as a way to dilute the microglia prior to damage to the CNS.…”

“…For this study, PPMPs were engineered in-house using standard photolithography fabrication methods as detailed earlier by our laboratory ( Huang et al, 2020 ). Two types of single-shaft, 280-μm wide, and 16-μm-thick platforms carrying 15 planar gold electrodes were used, as follows: (a) non-functional platforms for the immunohistological studies and (b) functional platforms for the electrophysiological recordings.…”

“…Using PLX5622 chow and a relatively large footprint perforated polyimide-based multielectrode array platform (PPMP) ( Figure 1 ) which can be thin sectioned for immunohistological examinations along with the surrounding tissue ( Huang et al, 2020 ), we took a basic-research perspective to investigate the prevailing concept that microglia, “the professional phagocytes of the CNS” and a major source of proinflammatory cytokines and chemokines, serve critical downstream functions in sensing and translating damage by MEA platform implantation to what appears to be an orchestrated inflammatory FBR cascade. Specifically, we examined how inflammatory FBR induced by MEA platform implantation develops in rat cortices depleted of 89–94% of their microglia population by the brain permeant CSF1R inhibitor PLX5622.…”