Intracortical brain-machine interfaces (BMIs) offer the promise of providing independence and an improved quality of life to individuals with severe motor dysfunction resulting from neurologic injury or disease. Despite hardware, software, and surgical advances for BMIs, neural spike activity recordings continue to show high variability and unpredictability and ultimately progressive degradation. A neuroinflammatory tissue response that results in astroglial scarring and neuronal process degradation surrounding the implants is widely regarded as a primary cause of neural recording signal variability and degradation. We propose to use a combination of approaches to mitigate the tissue response to improve neural recording quality and stability. Our Microfluidic/Eluting Neural Drug Delivery System (MENDDS) incorporates a mechanically-adaptive intracortical microelectrode implant with a novel microfluidic-aided eluting architecture. A microfluidic channel embedded within a permeable polymer nanocomposite runs down the length of the probe before U-turning and running back up to the back end of the probe. The contents of the channel diffuse through the polymer nanocomposite walls and out to tissue. Drug delivery directly at the implant site facilitates targeted control of local drug concentration without exposing distant tissue and organs to toxic drug levels. Microfluidic-aided elution allows the implant to distribute therapeutic agents uniformly around the implant. Advantageously, this system elutes anti-inflammatory agents along the length of the probe without suffering from the limited release duration of drug-eluting coatings. The key question this proposal will answer is: does local, chronic (>8 week) anti-oxidant elution from a mechanically-compliant implant inhibit the neuroinflammatory response, improve proximity of neuronal cell bodies near to recording microelectrodes, improve neural recording quality, and preserve functional outputs associated with the implanted region of the cortex? To provide insight into this question, we will first optimize resveratrol delivery profile through the MENDDS to maximize neural recording quality and minimize neuroinflammation and adverse local and peripheral effects. We will then quantify the impact of microfluidic-aided elution on chronic neuroinflammation and neural recording quality. Previous resveratrol-related studies have identified a wide therapeutic concentration range of 0 ? 100 M, while large doses of resveratrol that are regularly administered systemically have been associated with adverse side effects, including hemorrhaging. We endeavor to determine an optimal resveratrol concentration within this range for microfluidic-aided elution from the MENDDS. We will implant one MENDDS device into the primary motor cortex of 216 Sprague-Dawley rats across six concentration groups for either 1, 2, or 4 weeks. An osmotic pump will serve drive resveratrol solutions ranging from 0 - 100 M through the MENDDS microfluidic channel at a rate 0.25 L?h-1. Throughout the implant period, neural recording and electrochemical impedance spectra measurement sessions will take place three times weekly. Neuronal density and glial scarring around the implant will be quantified with post-mortem immunohistology. We will determine the optimal resveratrol concentration via a cost function that balances concentration-dependent improvements in neural recording and neuroinflammation versus costs of potential adverse effects of high concentration or prolonged administration. For the chronic delivery experiments, we will implant 100 microelectrode MENDDS into the primary motor cortex of 5 sets of Sprague-Dawley rats for 2 or 16 weeks. Each set will either be assigned to 1) MENDDS probe with microfluidic-aided resveratrol elution, 2) MENDDS probe with resveratrol intraperitoneal (I.P.) injection, 3) MENDDS probe with no resveratrol delivery, 4) silicon- based NeuroNexus probe with I.P. injection, of 5) NeuroNexus probe with no resveratrol delivery. Our objective is to evaluate the effects of sustained anti-oxidant diffuse drug elution at the mechanically-compliant implant interface on the quality and stability of neural recording, the degree of neuroinflammation.
Traumatic injury and disease, particularly from spinal cord injury, can lead to a complete loss of motor function. Spinal cord injury alone affects nearly 50,000 veterans. High-resolution brain-machine interfaces with intracortical electrodes can be used to control computer cursors, robotic arms, or one?s own natural limbs through detection of one?s own thoughts. Unfortunately, the lack of reliability of recordings has prevented this technology from being readily available to our veterans. This proposal takes a multi-faceted approach to improving the reliability of such brain implants by using novel technologies that prevent and treat the inflammatory response that causes implant failure. In doing so, the risk of using these brain-machine interfaces will be drastically reduced, and will provide veterans and other individuals an opportunity to benefit from this technology. Additionally, technologies developed through this research program will improve the reliability and safety of neural implants, such as deep brain stimulation devices and neural interfaces for sensory restoration.
