Microelectrodes for Co-Localized Tunable Drug Delivery and Neural Recording

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Each year, thousands of Veterans experience neurologic injury or disease resulting in severe motor dysfunction, with devastating consequences for the affected individual and their loved ones. Intracortical brain-machine interfaces (iBMIs) offer a compelling solution for restoring volitional control of computer cursors, robotic arms, and functional electrical stimulation-controlled limbs. However, iBMI functionality is reliant upon our ability to detect neuronal signals at indwelling microelectrodes for a period of years to decades. This requirement is challenged by the biological response to the implant, which impedes communication between healthy neurons and the implanted microelectrodes. Successful iBMI clinical translation, and the resulting gains in functional independence for users, hinges upon improving the quality and stability of the biotic-abiotic interface. The standard materials used for intracortical microelectrode devices are rigid materials, such as silicon, which can cause chronic tissue damage that exacerbates the biological response. Some groups have developed flexible polymer-based devices, though these usually require reinforcement to prevent buckling during insertion. Local pharmacologic delivery can also be used to control the tissue response, though is typically either short-lived as drug-loaded coatings are depleted, or requires complex and invasive fluidic systems. Our approach combines advanced structural and microelectrode materials to provide a two-pronged approach to attenuating the inflammatory tissue response without requiring complex fluidic delivery systems. A mechanically-adaptive polymer nanocomposite (NC) provides a structural material that is sufficiently stiff insert into the cortex, yet dramatically softens within minutes of insertion to minimize chronic differential tissue strain. Highly-ordered, vertically-oriented titania nanotube arrays (TNAs) will perform both drug- releasing intracortical microelectrode recording sites. TNAs are highly tunable materials that can efficiently store pharmacologic agents that slowly diffuse into tissue over weeks to months with a release profile governed by the nanotube geometries. Chemical doping processes enhance TNA conductivity to facilitate sensing neuronal activity. We hypothesize that combining soft structural materials with sustained anti-inflammatory drug delivery will lead to synergistic improvements in tissue response and long-term neural recording quality. We will first investigate the relationship between anti-inflammatory release kinetics and the inflammatory response. Devices comprise TNA microsegments integrated into the NC. Dexamethasone, a representative anti- inflammatory corticosteroid, will be loaded into either the NC or into the TNAs to provide rapid and sustained (>8 weeks) release profiles, respectively. Devices will be implanted into wild-type mice for up to 1, 2, 4 or 8 weeks. At each timepoint, local inflammatory markers in tissue will be evaluated for the two experimental groups and for non-releasing and sucrose-releasing controls. This study will be used to evaluate the time course of the inflammatory response to two different release profiles and assess in vivo DEX release from TNAs. In the second study, we will take advantage of both the drug delivery and electrical properties of the TNAs. We will fabricate NC-based neural probes with recording functionality using the TNAs as the recording sites at which neural activity is detected. Probes will be implanted into the primary motor cortex of wild-type mice for 16 weeks. Throughout the implant period, neural activity, electrochemical impedance, and fine motor behavior will be assessed, which will be followed by post-mortem quantification of cell types. We will evaluate the contributions of soft materials, local pharmacologic intervention, and microelectrode recording site material. We expect that sustained (>8 weeks) pharmacologic release directly from the recording sites will result in substantial improvements in neural recording stability that will help to advance iBMI technology toward safe clinical use with long-term reliability.