Multiplex immunochemistry for proteins examining neuronal structure or function in NeuN+ regions adjacent intracortical microelectrodes (MEA) more closely matched historic intracortical MEA recording performance than traditional IHC quantification.

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.

The neuroinflammatory response to intracortical microelectrodes (IMEs) is regarded as a major contributor to device performance degradation and failure. Iatrogenic injuries from the craniotomy, IME insertion, and the continued presence of the implanted device all evoke a temporally mediated neuroinflammatory response. Transcriptomic analyses have emerged as a highly sensitive and detailed approach to characterizing and quantifying the neuroinflammatory response to IME implantation. Therefore, we used transcriptomic analyses to update the historic characterization of the component injuries associated with IME devices to differentiate surgical and device-related contributions to neuroinflammation and provide an updated view of a decades-old problem. Four injury profiles - uninjured, craniotomy-only, stab wound, and implant - were applied to each rat in different locations corresponding to traditional IME placement. At 2, 8, or 16 weeks after surgery, tissue was extracted and processed using bulk transcriptomic analysis with a custom panel of 212 genes related to neuroinflammation and neuronal health. Many genes were significantly differentially expressed compared to naïve controls across time points, with highly similar gene and pathway profiles observed across the craniotomy-only, stab wound, and implant groups. Additionally, the uninjured tissue region also exhibited neuroinflammation-related gene expression changes. The results presented here suggest that the neuroinflammatory response due to the intracortical implant can extend to distal brain regions. The persistent and widespread neuroinflammatory response indicates a need for novel strategies to minimize the iatrogenic effects of neural implants and suggests that the placement of additional implants for increased tissue access may come at the cost of exacerbating neuroinflammation.

(1) Background: Intracortical microelectrodes (IMEs) are an important part of interfacing with the central nervous system (CNS) and recording neural signals. However, recording electrodes have shown a characteristic steady decline in recording performance owing to chronic neuroinflammation. The topography of implanted devices has been explored to mimic the nanoscale three-dimensional architecture of the extracellular matrix. Our previous work used histology to study the implant sites of non-recording probes and showed that a nanoscale topography at the probe surface mitigated the neuroinflammatory response compared to probes with smooth surfaces. Here, we hypothesized that the improvement in the neuroinflammatory response for probes with nanoscale surface topography would extend to improved recording performance. (2) Methods: A novel design modification was implemented on planar silicon-based neural probes by etching nanopatterned grooves (with a 500 nm pitch) into the probe shank. To assess the hypothesis, two groups of rats were implanted with either nanopatterned (n = 6) or smooth control (n = 6) probes, and their recording performance was evaluated over 4 weeks. Postmortem gene expression analysis was performed to compare the neuroinflammatory response from the two groups. (3) Results: Nanopatterned probes demonstrated an increased impedance and noise floor compared to controls. However, the recording performances of the nanopatterned and smooth probes were similar, with active electrode yields for control probes and nanopatterned probes being approximately 50% and 45%, respectively, by 4 weeks post-implantation. Gene expression analysis showed one gene, Sirt1, differentially expressed out of 152 in the panel. (4) Conclusions: this study provides a foundation for investigating novel nanoscale topographies on neural probes.

Intracortical microelectrodes allow for the recording of neural signals in the brain but show decreased recording performance over time. This failure is due primarily to the neuroinflammatory response triggered by microelectrode implantation. We have shown that one consequence of the disruption of the blood-brain barrier following microelectrode probe implantation is the invasion of non-native bacteria to the implant site, which exacerbates the neuroinflammatory response. This study investigates the effects of coating non-functional silicon intracortical microelectrodes with an antimicrobial titania nanotube array (TNA) to reduce the relative abundance of invasive microbes and the resulting neuroinflammatory response. TNA-coated probes were implanted into mice for either 4 weeks (N = 4) or 12 weeks (N = 4) and compared to uncoated probes at both time points. We found that the TNA coatings reduce microbe relative abundance at both acute and chronic time points, correlating with fewer significantly expressed neuroinflammatory markers. Coating probes with TNAs allows for the beneficial effects of the antimicrobial coating to persist to chronic time points, in contrast to the detrimental effects of chronic systemic antibiotic administration reported previously. This study establishes antimicrobial TNA coatings as a platform for controlling the microbial environment, reducing invasive bacteria and neuroinflammation at the implant site. By mitigating the neuroinflammatory response, TNA-coated probes address one of the key contributors to intracortical microelectrode failure, thereby providing a strong platform that may support improved chronic recording performance in future functional intracortical microelectrode applications.

(1) Background: Intracortical microelectrodes (IMEs) are an important part of interfacing with the central nervous system (CNS) and recording neural signals. However, recording electrodes have shown a characteristic steady decline in recording performance owing to chronic neuroinflammation. The topography of implanted devices has been explored to mimic the nanoscale three-dimensional architecture of the extracellular matrix. Our previous work used histology to study the implant sites of non-recording probes and showed that a nanoscale topography at the probe surface mitigated the neuroinflammatory response compared to probes with smooth surfaces. Here, we hypothesized that the improvement in the neuroinflammatory response for probes with nanoscale surface topography would extend to improved recording performance. (2) Methods: A novel design modification was implemented on planar silicon-based neural probes by etching nanopatterned grooves (with a 500 nm pitch) into the probe shank. To assess the hypothesis, two groups of rats were implanted with either nanopatterned (n=6) or smooth control (n=6) probes, and their recording performance was assessed over 4 weeks. Postmortem gene expression analysis was performed to compare the neuroinflammatory response from the two groups. (3) Results: Nanopatterned probes demonstrated increased impedance and noise floor compared to controls. However, the recording performance of the nanopatterned and smooth probes was similar, with active electrode yield for control probes and nanopatterned probes being approximately 50% and 45%, respectively by 4 weeks post-implantation. Gene expression analysis showed 1 gene, Sirt1, differentially expressed out of 152 in the panel. (4) Conclusions: This study provides a foundation for investigating novel nanoscale topographies on neural probes.