R01:Biomimetic Surface for Neural Implant PI: Tracy Cui Implantable microelectrode arrays for neural recording and stimulation have demonstrated tremendous research and clinical potential. Studies of brain tissue response to neural electrode arrays have revealed localized microglia activation, followed by astrocytic scarring and neural degeneration. These reactions are thought to contribute to the low yield and chronic failure of neural recording, although direct links have not been soundly established. Past studies characterizing the CNS response to implants have used postmortem histology at discrete time points. This approach suffers from a large degree of variability and fails to capture the dynamic molecular, cellular and vascular changes of the host. To address this issue, we have developed an experimental set-up to directly image the electrode-tissue interface in live animals using 2-photon microscopy in conjunction with electrical recording. Our previous work indicates that by coating the surface of neural probes with neural adhesion molecules, neuronal density around the device can be promoted while glial reaction attenuated. Meanwhile, neural recording quality is drastically improved. We hypothesize that promoting neuronal growth and health, and/or inhibiting microglia activation will lead to recording improvement. The specific objectives of thi project are to investigate the biological mechanisms of the coating's effect on recording and to evaluate the clinical potential of biomimetic coating in a brain machine interface (BMI) model. First, the acute neuronal and microglia responses to coated probes will be characterized in transgenic animals using two photon imaging and electrical recording for two weeks. Real time tissue characteristics (such as neuronal and neurite density, microglia density and morphology, vasculature change and BBB leakage) will be correlated to recording metrics(such as unit yield, SNR, amplitude of signal and noise as well as impedance). Several biomolecules that promote or inhibit neuronal growth or microglia activation will be immobilized on the Blackrock arrays to test our hypothesis. Secondly, the long-term benefit of the coatings on recording will be determine by testing the optimum coating conditions in rats for 6 months. Explants will be taken monthly to examine the coating longevity, while immunohistochemistry and microarray analysis of the tissue at the interface will be performed to characterize the cellular and molecular change over time. Thirdly, to assess the potential of biomimetic coating for clinical application, coated electrodes will be tested in rhesus monkeys in a brain-machine-interface (BMI) model. Recording metrics such as SNR, signal amplitude, unit yield and stability will be quantified over 2 years and compared to uncoated arrays. A novel functional metric will be developed to assess functionality of the recorded signals. BMI performance will be evaluated based on speed and accuracy. This proposal combines the cutting edge real-time imaging, effective biomaterial strategies and state of the art brain machine interface technology to understand the interactions between neural implants and host tissue. The findings will guide the development of seamless neural interface devices for BMI, visual and auditory prosthesis, deep brain stimulation for Parkinson's disease, depression and epilepsy, to name a few. The knowledge will also benefit other brain implants from biochemical sensing and therapeutic delivery to scaffold and stem cell transplant for treating neurological disorders.

Public Health Relevance

Microdevices can be placed in the brain to restore function and treat neurological disease. The goal of this project is to investigate the novel approaches that can be taken to make the implanted device seamlessly integrate with the brain tissue and thereby obtain improved performance longevity and reliability.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Ludwig, Kip A
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University of Pittsburgh
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
United States
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Michelson, Nicholas J; Vazquez, Alberto L; Eles, James R et al. (2018) Multi-scale, multi-modal analysis uncovers complex relationship at the brain tissue-implant neural interface: new emphasis on the biological interface. J Neural Eng 15:033001
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Woeppel, K M; Zheng, X S; Cui, X T (2018) Enhancing surface immobilization of bioactive molecules via a silica nanoparticle based coating. J Mater Chem B 6:3058-3067
Du, Zhanhong Jeff; Bi, Guo-Qiang; Cui, Xinyan Tracy (2018) Electrically Controlled Neurochemical Release from Dual-Layer Conducting Polymer Films for Precise Modulation of Neural Network Activity in Rat Barrel Cortex. Adv Funct Mater 28:
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