Depletion of complement factor 3 delays the neuroinflammatory response to intracortical microelectrodes.

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.

Comprehensive proteomic analysis of the differential expression of 62 proteins following intracortical microelectrode implantation.

Intracortical microelectrodes (IMEs) are devices designed to be implanted into the cerebral cortex for various neuroscience and neuro-engineering applications. A critical feature of IMEs is their ability to detect neural activity from individual neurons. Currently, IMEs are limited by chronic failure, largely considered to be caused by the prolonged neuroinflammatory response to the implanted devices. Over the past few years, the characterization of the neuroinflammatory response has grown in sophistication, with the most recent advances focusing on mRNA expression following IME implantation. While gene expression studies increase our broad understanding of the relationship between IMEs and cortical tissue, advanced proteomic techniques have not been reported. Proteomic evaluation is necessary to describe the diverse changes in protein expression specific to neuroinflammation, neurodegeneration, or tissue and cellular viability, which could lead to the further development of targeted intervention strategies designed to improve IME functionality. In this study, we have characterized the expression of 62 proteins within 180 µm of the IME implant site at 4-, 8-, and 16-weeks post-implantation. We identified potential targets for immunotherapies, as well as key pathways that contribute to neuronal dieback around the IME implant.

In Vivo Characterization of Intracortical Probes with Focused Ion Beam-Etched Nanopatterned Topographies.

(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.