Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface

Abstract

(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain–machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application.

Fabrication Methods and Chronic In Vivo Validation of Mechanically Adaptive Microfluidic Intracortical Devices

“…This study also looked at oxidative stress, which is important in cellular health. The delivery of resveratrol resulted in decreased oxidative stress, consistent with previous studies in the laboratory [ 36 ]. Resveratrol’s mechanism of action is twofold: quenching existing reactive oxygen species (ROS) and upregulating endogenous enzymes to prevent future production of ROS [ 16 , 75 , 76 ].…”

“…Meanwhile, the single-outlet design S50-me had decreased oxidative stress response compared to controls at 150–250 µm distances, as you would anticipate with increased efficiency of the delivery of antioxidants to the device-tissue interface [ 28 , 36 ]. Although it seemed as if the D50-me design also may have had a decreased oxidative stress response, the difference was not statistically significant—which may be a result of the low animal numbers.…”

“…Surgical implantation in Sprague–Dawley rats followed our established protocols [ 13 , 36 , 59 , 60 , 61 , 62 ]. Briefly, rats were anaesthetized using 2.5% isoflurane until there was no response to a toe pinch.…”

“…Separately, systemic or ventricular delivery of the natural anti-oxidant resveratrol yielded improved neural density and decreased oxidative stress, indicating decreased neural inflammation [ 16 , 36 ]. Resveratrol-loaded NC implants released over several days post-implant resulted in decreased inflammation compared to non-releasing controls at 2 weeks.…”

Effects of micromachining on anti-oxidant elution from a mechanically-adaptive polymer

“…Neural recording sessions were done to evaluate recording performance from the MARE probes, following established protocols [63][64][65]. Animals were anesthesized with 2.5% isoflurane gas, and the exposed connector was then cleaned with isopropanol.…”