Patrick A. Tresco, Ph.D. - US grants

DESCRIPTION (provided by applicant): Implantable silicon microelectrode array technology is a promising approach for high-density, high-resolution sampling of neuronal activity with application in both basic research and prosthetic devices. One of the major limitations of the current technology is inconsistent performance in long-term applications, which limits clinical development. Although the brain tissue response to implanted electrodes is believed to be a major cause of electrical instability, the precise mechanisms that cause failure of recordings are not known. Understanding the mechanisms that underlie chronic instability of silicon microelectrode arrays will, therefore, lead to strategies to improve their usefulness for chronic basic science studies and various neuroprosthetic applications. We have observed persistent ED-1 immunoreactivity around silicon microelectrode arrays implanted in the adult rat motor cortex, and observed significant reductions in nerve fiber density and cell bodies in the tissue immediately surrounding implanted silicon microelectrode arrays. Persistent ED-1 up-regulation and neurodegeneration is not observed in microelectrode stab controls indicating that chronic inflammation and neuronal loss is not caused by the initial mechanical trauma of electrode implantation, but is associated with the brain tissue response to the implanted electrode. We find that our observations share biological features of diseases having a neuroinflammatory mediated neurotoxic component. We, therefore, hypothesize that chronically implanted silicon microelectrode arrays lead to persistent macrophage activation at the microelectrode interface resulting in an over production of proinflammatory cytokines and neurotoxic factors that lead to loss of neuronal cell bodies and fibers immediately adjacent to the recording surface. To test our hypothesis, quantitative methods are proposed: a) to determine the temporal histopathological changes at the microelectrode brain tissue interface that coincide with recording failure; in addition 2) we will determine the changes in proinflammatory and neurotoxic factors at the implant site using retrieved probes and a new system that allows sampling of the institial fluid adjacent to the implant over time; and, finally c) we will test the hypothesis that agents that interfere with microglial activation and signaling are effective in attenuating neurodegeneration around the implanted silicon microelectrode arrays. The proposed research is likely to provide insight into the biological mechanisms that underlie chronic instability of silicon microelectrode arrays, and should lead to strategies to improve their usefulness for chronic applications.

DESCRIPTION (provided by applicant): In order to successfully use microelectrode arrays for stimulation in chronic implantation, the neural electrode must have longevity and efficacy. Efficacy of stimulation primarily means injecting enough charge to the targeted tissue to elicit action potentials. However, in doing so, the electrode itself must not (1) degrade, (2) generate harmful substances and (3) provoke significant immune response. Attaining the stated requirements remains a challenge as studies have shown loss of discriminable single unit action potentials on the order of weeks, months, or in rare studies, years. Suitable electrode material or strategies that permit prolonged excitation of neurons for long period of time without injuring the tissue or damaging the electrodes are yet to be developed and demonstrated. For the efficacy of the stimulating electrodes, large charge injection capacity (CIC) is desired. CIC depends on the electrode-tissue interface and is characteristic of electrode material used. Though, much of the microelectrode research during the past 30 years has been directed toward the evaluation of various types of materials with regard to individual stimulus charge density limits, till date, in the scientific literature, there is no single material which can avoi over-stimulation i.e. neural damage. In this application, we present a novel surface modification technique that addresses the longevity and efficacy of the microelectrodes in chronic experiments. The three distinct features of our proposed objectives are (1) novel surface modification technique that produces electrochemical characteristics which are by far superior to any material/technology reported in the literature till date. With the surface modified electrodes we were able to achieve electrode impedance of 188 at 1 kHz and CIC of 24 mC/cm2. The high CIC would lower the potential required for stimulation thereby reducing the chances of neural injury and dissolution of electrode material and toxic remnants. Even with the presence of glial sheath, it would not be necessary to go outside the water window thereby reducing the chances of tissue insult at the site of stimulation. (2) Biocompatible electrode-tissue interface. It has been postulated by researchers that by manipulating the surface structure of the electrode at micro scale one can reduce astrocyte adhesion around the microelectrode, including reducing the proliferation of glial cells, reduced macrophages and preferential neuron sparing at the site of implant. (3) Simple and inexpensive method of obtaining desired electrode characteristics as opposed to any current thin film deposition method. The objective of this research is to develop, validate, examine (in-vitro, in-vivo and histology) and commercialize the proposed surface modification technology for microelectrodes in chronic experiments. The specific aim of our proposed research is to demonstrate (1) manufacturability of the proposed surface modification for use in a microelectrode array; (2) superior electrochemical properties; (3) improved physiological efficacy; and (4) biocompatible electrode-tissue interface i.e. reduced glial proliferation and reduction in neuronal loss at the biotic-abiotic interface. It is envisioned that with the availability of proposed superior electrochemical characteristics in the neural microelectrode arrays there would be a paradigm shift in the neuroscience research and applications. The enabling innovation has clear clinical benefits in such applications as cortical stimulation and recording, deep brain stimulation, cardiac pacing and pain management and therefore has a significant commercial potential.

Intellectual Merit
Implantable medical devices touch virtually every major function in the human body. Cardiac pacemakers and defibrillators, neural recording and stimulation devices, cochlear and retinal implants, etc. Wireless telemetry for these devices is necessary to monitor battery level and device health, upload reprogramming for device function, and download data for patient monitoring. Antennas are inevitably one of the largest if not the largest component of the telemetry communication system and are generally mounted on or in the implanted battery pack, usually in a body cavity. This limited real estate significantly constrains the performance of implantable antennas and results in substantial power loss in the body. Lost power means lost transmit distance and lost battery life.

The proposed research will fundamentally change the design of implantable antennas by tattooing (nearly invisible) conductive nanoparticles in the skin and adjacent fat layer at the body surface, coupling passively to the implant. The antenna will be able to use as much surface area as needed, and dramatically reduce the transmission lost in the body tissues.

This is a fundamental, transformative shift in antenna design for implantable medical devices, enabling the next generation of tiny wireless sensors and devices in the body. This work will evaluate the fundamental options and tradeoffs in implantable antenna design including losses in the antenna (resistive losses), coupled feed system (near field body losses), and antenna radiator (body losses). Both SAR and MedRadio regulations will be taken into account.

Broader Impact
In addition to the direct benefits to improved medical care, this project includes a substantial educational outreach/dissemination component for undergrad/K12 retention and recruitment and general public interest. In addition to traditional scientific dissemination, video tutorials, lab tours, interviews with the research team, etc. will be produced and disseminated broadly following methods currently in use by the PI. Engaging public outreach will leverage this compelling bio-themed NSF research project (having likely appeal to a diverse audience) for use as a recruitment and retention tool in undergraduate programs and high school science/math programs, or just for general interest. This will help students see that their math/science/engineering programs can be used for fascinating science that can make a difference in the world, and will help show the fun and excitement of research and invention.

DESCRIPTION (provided by applicant): Despite substantial progress in implantable recording technology and several proof-of principle experiments demonstrating therapeutic potential as a Brain Computer Interface (BCI), the use of this promising technology is limited by inconsistent performance and eventual recording failure. Although the precise mechanisms are unknown, the foreign body response (FBR) that the brain mounts against the implant is believed to underlie the problems. A major feature of the FBR is chronic inflammation, a property that is also observed in many CNS disorders, where macrophage activation and disruption of the blood brain barrier (BBB) is a self-sustaining cycle that has been observed to relapse and remit, and likely plays a key role in recording instability. Understanding how to reduce the FBR will lead to strategies that improve the biocompatibility of recording microelectrodes and extend their usefulness as a basic science tool and in clinical applications. We hypothesize that cell appropriate ECM coatings can limit blood loss associated with electrode implantation and subsequently reduce neuroinflammation during the indwelling period resulting in a reduction of the FBR that will improve recording consistency and longevity. While it has been known for some time that the extracellular matrix protein, collagen, possesses hemostatic properties, the immunomodulatory properties of ECM has only recently been described. To test the hypothesis, we will use a novel approach to harvest ECM from astrocytes, glial progenitors and mesenchymal stromal cells (MSCs) and screen their effectiveness at blood clotting, platelet aggregation and reducing macrophage activation in vitro. We will then investigate whether such coatings reduce blood loss, lower the FBR, and improve neural recording performance following implantation cortical brain tissue using a rat model. The broad objective of this project is to advance implantable neural recording array technology as a basic science tool and toward increased clinical use.

? DESCRIPTION (provided by applicant): Despite substantial advances in implantable recording technology and several proof-of principle experiments demonstrating its therapeutic potential, the use of this promising technology is limited by inconsistent performance and eventual failure over chronic time frames. To date, the design strategy employed to advance the technology has been largely an empirical `build-and-test' approach with no overarching biologically- informed rationale. While it is widely believed that elements of the foreign body response (FBR) contribute to inconsistent single unit recording performance and failure, current devices in use were designed before much was known about the FBR. The major features uncovered thus far are related to the tissue damage that accompanies high-density recording array implantation and persistent inflammation, a property shared with the FBR to other CNS implants, where macrophage activation and disruption of the blood brain barrier (BBB) is a self-sustaining cycle that has been observed to relapse and remit, and likely plays a key role in single unit recording instability and eventual failure. Understanding how to reduce the initial damage caused by implantation and reduce the impact of the FBR will lead to strategies that improve the biocompatibility of recording microelectrode arrays and extend their usefulness as a basic science tool and in clinical applications. To address this area, our specific aims are directed at: 1) understanding whether it is possible to improve the recording performance of a current FDA-approved technology using a hemostatic and immunomodulation coating strategy; 2) studying how changes in device design influence single unit recording consistency and longevity; and, 3) using CRISPR-based sequence-specific regulation of inflammatory genes to reduce the FBR. The objective of this project is to develop a biologically informed strategy that will advance implantable neural recording array technology as a chronic basic science tool and toward increased clinical usage. The broader goal is to understand how to improve the biocompatibility of all types of chronic indwelling CNS implants.