Effects of Iron Accumulation in Intracortical Implants and Protection by Iron Chelation

点击翻译按钮获取中文摘要

Microelectrodes (ME) implanted in the nervous system are critical tools for neurophysiological research and in clinical applications that use neuromodulation to treat motor-disability conditions. However, long term stability and functional performance are the critical barriers for implanted ME that have limited their use in clinical applications. Vascular disruption during ME implantation and their continued presence in the brain tissue leads to erythrocyte/hemoglobin entry in the brain parenchyma, which results in iron to be released and accumulated in the tissue. While iron is essential for various physiological functions, an overload of free iron contributes to oxidative and inflammatory mediated cell damage. Our central hypothesis is that iron accumulation in the brain tissue after ME implantation contributes towards chronic oxidative stress, microglial degeneration and neurodegeneration and thus, results in poor neural signal quality. Congruent with our findings, we also hypothesize that chelation of excess free iron can improve long-term functionality of implanted ME. The goal of this proposal is to develop an iron chelation approach, by using the iron chelator deferasirox (DFO), to mitigate the neuroinflammatory response to improve long-term performance of ME implanted in the brain. The study will use multiple techniques that include 1) transcriptomics (qRT-PCR) of the entire brain tissue harboring the ME to provide a macroscopic overview of ongoing inflammatory reactions and not just the tissue at the recording sites which is commonly reported in literature, 2) spatial transcriptomics and proteomics at recording sites, within the same tissue slice, to provide information at high spatial resolution, and 3) immunohistochemistry, all combined with electrophysiology, to produce a comprehensive dataset with readouts of both protein and gene expression in the brain tissue. Further, the study will use materials science and surface chemistry approaches to develop local chelation approach for modulating iron species at the electrode-tissue interface. Aim 1 will determine the effects of iron chelation on microglial degeneration and neurodegeneration and its impact on neuronal recordings. Systemic administration of immunomodulatory drugs is often not the best strategy as 1) drugs need to cross the BBB, which limits their availability at the injury site and 2) require large dosages, which has systemic side effects. Further, studies have shown metal chelators, if present in high concentration, lose their selectivity during systemic chelation therapy, resulting in homeostatic chemical imbalances in which other metal ions are depleted. These concerns provide the rationale to locally modulate the iron species at the electrode-tissue interface. Aim 2 will develop an iron chelator embedded hydrogel coating on ME for modulating excess free iron at the electrode-tissue interface. By studying the dynamics of iron accumulation, with and without chelation, in relation to other inflammation pathways simultaneously, the project has the potential to uncover potential signaling targets that can be immuno-modulated for improving long-term electrode function.