Iron accumulation and the effects of iron dysregulation in intracortical implants

Introduction: Long-term reliability and electrophysiological signal quality recorded by implanted microelectrodes (MEs) is hindered due to the foreign body response triggered at the electrode-tissue interface. Upon ME implantation, there is disruption of the blood-brain-barrier and the vasculature, resulting in release of erythrocytes and activation of immune cells at the implant injury site. As a result of hemolysis due to heme-oxygenase enzyme, erythrocytes degrade to heme and then to free iron. Excess free iron can participate in the Fenton Reaction, producing hydroxyl and superoxide reactive oxygen species (ROS). Iron-mediated ROS production can contribute to the oxidation of lipids, proteins, and DNA, facilitating oxidative stress which can lead to cellular damage, cytotoxicity, and iron-mediated cell death known as ferroptosis.

Materials and

Methods: The objective of this study was to show the iron accumulation and the effects of iron dysregulation that occur at the ME injury sites. We implanted 16-channel ME arrays in the somatosensory cortex of age- and weight- matched male Sprague-Dawley rats. Using qRT-PCR and Western Blot assays, we compared ME-implanted animals to naive controls for markers of iron transport, dysregulation, oxidative stress, and ferroptosis across multiple acute to sub-chronic timepoints post-implantation.

Results, Conclusions, and Discussions: Our results show the effects of ME implantation changes oin iron transport, storage, and accumulation following ME implantation that extended from using qRT-PCR at various acute to sub-chronic time points. . qRT-PCR analysis was used to show changes in iron transporters and storage following ME-implantation at various acute to sub-chronic time points.We observed an unpregulation in mRNA Gene expression of iron importers: transferrin receptor (TfRC) and divalent metal transporter-1(DMT1), exporter: ferroportin (FPN1), and the iron storage protein: ferritin (FTH1) was upregulated at 1 week after implantation. Further, Additional gene expression was completed on ferrireductases: six-transmembrane epithelial antigen of the prostate (STEAP2), STEAP3, ferroxidases: ceruloplasmin (Cp) and hephaestin (Heph), hemolysis: hemeoxygenase-1 (HMOX1). rResults indicated an upregulation of hemolysis, ferrireductases and ferroxidases following injury, which suggests a potential route of iron accumulation and a dynamic iron redox state. The gene expression analysis overall shows an upregulation A transient increase in mRNA expression of in genes related to iron importation and storage, where these results show a transient increase in expression which suggests a period of iron accumulation at the electrode-tissue interface prior to increased cellular uptake of iron. Together, these results are indicative of iron accumulation at the electrode-tissue interface following implantation surgery and a state of iron dysregulation that were observed at all evaluated time-points.

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