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.