Brain cells communicate through the generation and transmission of electrical signals. Neurological diseases, such as Parkinson’s disease and Alzheimer’s disease, and injuries can result from faulty or interrupted signaling between networks of brain cells. The development of implanted electrodes, which are medical devices capable of “write-in†or “read-out†of electrical signals to and from the brain, has significantly improved the treatment and understanding of these neurological diseases and injuries. However, following implantation, the body recognizes the implanted device as a foreign object. The tissue response to the implant often results in a build-up of scar tissue and loss of signal-generating cells surrounding the device. This, in turn, is believed to contribute to a loss of function of the implant over time. This CAREER project seeks to answer fundamental questions regarding the tissue response to electrodes implanted in the brain: what are the critical biological events that most strongly impact long-term device performance, and how are they influenced by design features of the electrodes? To answer these questions, new techniques in molecular biology will be applied to reveal biological markers that can predict device performance; then device design choices will be systematically tested to determine the influence of materials and dimensions on these markers. As a result, the project is expected to deliver new understanding of how to design implanted electrodes with optimized biocompatibility and performance. The complementary educational objectives of the project are to strengthen the new graduate curricula in biomedical engineering at Michigan State University through the development of novel assessments of the success of the program, while creating a new peer-mentoring program for undergraduate women interested in entering the field of biomedical engineering.
The Investigator’s long-term research goal is to create fully integrated neural electrode-tissue interfaces. Towards this goal, the goal of this CAREER project is to develop new approaches to understand and control biological responses to brain implants, which are believed to be a key limitation to device function, stability, and lifespan. The Research Plan is organized under three objectives. The FIRST Objective is to identify biomarkers of device-tissue interaction through RNA-sequencing. Laser capture microscopy (LCM) will be used to excise selected portions of brain tissue for extraction of RNA and subsequent sequencing to provide a comprehensive view of possible changes in gene expression induced by single shank, non-functional silicon-based devices implanted in the motor cortex of adult rats. Results will be compared to contralateral tissue samples receiving an insertion injury only (to control for “stab†wound effects), which will enable identification of a subset of genes that will be further screened as potentially key biomarkers of long-term chronic performance. The SECOND Objective is to test biomarker effects on signal detection through knockdown of the three gene expressions that were the most highly differentially expressed at the interface relative to control in the first objective. Knockdown will be via stable, viral-mediated expression surrounding functional, 16-channel, single-shank silicon microelectrode arrays implanted in the motor cortex of rats. Changes will be assessed in terms of the number of “units†detected per device, longevity of detected unit activity, signal-to-noise ratio (SNR), and amplitude of units and local field potentials, in comparison to contralateral control tissue treated with an empty vector. The THIRD Objective is to define design rules via systematic tests of electrode materials and feature sizes. Planar style, single shank arrays, will be fabricated from silicon, Parylene, polycrystalline diamond and polydimethylsiloxane. The impact of device dimensions, Young’s modulus, bending stiffness, and feature size on both traditional histological measures and the expression of biomarkers identified in the first two objectives will be tested. These results will provide guidance on design parameters that should be pursued to optimize the biointegration of electrodes with the brain.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
