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.