Inhibition of Neural Electrode-mediated Inflammation and Neuronal Cell Death A growing number of implantable neural electrode devices are being developed to map brain circuit or restore function and treat diseases. The performance of these devices hinges on the quality and stability of the electrode-neural tissue interface. Undesirable brain tissue responses, including persistent microglia activation and blood brain barrier breach, glial scarring, neuronal loss and degeneration, have been consistently reported in animal studies. For electrode devices that require intimate contact with host neurons, their performance functionality may be compromised by these responses. As an example, single unit neural recording via microelectrode arrays experiences deterioration in yield and quality over time, which is a major barrier to applications of this technology in long-term neuroscience research and clinical translation. There are many molecules and pathways involved in inflammation and neuronal death. We began our study by focusing on caspase-1, as caspase-1 is a key mediator of both inflammation and programmed cell death. Activation of caspase-1 is the earliest detectable event in neuronal apoptosis in vitro and in brains with ischemic, injury and neurodegenerative conditions. Furthermore, caspase-1 activates interleukin-1 (IL-1), a pro-inflammatory cytokine highly expressed in the tissue surrounding implanted electrodes, especially those that showed poor electrophysiological outcome. IL-1 triggers inflammatory gliosis and exacerbates BBB breach; both are hypothesized causes of chronic recording failure. Therefore, we hypothesize that caspase-1 mediates the neuronal death and inflammation around neural implants and inhibiting caspase-1 may improve neuronal survival, reduce inflammation and lead to improved electrode performance. We have performed a preliminary study comparing the neural recording performance of microelectrode arrays implanted in caspase- 1 knockout (KO) vs. wild-type (WT) mice. The single unit yield and signal quality are significantly greater in the knockout animals over the 6 month time period, strongly supporting the critical role for caspase-1 in maintaining the quality of the electrode-tissue interface. However, closer examination of the recording over time revealed dynamic changes that cannot be interpreted with end-point histology. To better understand the mechanism(s) by which caspase-1-mediated pathways affect recording, we propose to use 2-photon live animal imaging to characterize the cellular and vascular responses to implanted neural probes in conjunction with neural recording and comprehensive tissue and biochemical analyses. Therapeutics targeting caspase-1 or the inflammation/cell death in general will be evaluated in an effort to improve the chronic neural interface. The drugs to be tested are caspase 1 specific inhibitor VX765, melatonin and minocycline. This proposal uses a multidisciplinary approach to uncover the molecular and cellular mechanism contributing to neural recording performance. The findings will increase our scientific understanding of neural implant pathology, and guide the development of therapeutic and/or biomaterial strategy for stable and reliable neural interface. Data and technology developed in this project may also contribute to the study of neuronal degeneration and inflammation in traumatic brain injury, stroke and neural degenerative diseases.

Public Health Relevance

Neural probes are microelectrode devices implanted in the brain for understanding the brain circuitry or treating neurological disorders. This project will investigate the fundamental role of caspase-1 pathways in mediating host tissue responses to implanted neural electrode devices. Therapeutics will be administered to inhibit the neuronal death and inflammation for improved electrode performance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS089688-03
Application #
9306969
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Langhals, Nick B
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Cody, Patrick A; Eles, James R; Lagenaur, Carl F et al. (2018) Unique electrophysiological and impedance signatures between encapsulation types: An analysis of biological Utah array failure and benefit of a biomimetic coating in a rat model. Biomaterials 161:117-128
Golabchi, Asiyeh; Wu, Bingchen; Li, Xia et al. (2018) Melatonin improves quality and longevity of chronic neural recording. Biomaterials 180:225-239
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:
Eles, James R; Vazquez, Alberto L; Kozai, Takashi D Y et al. (2018) In vivo imaging of neuronal calcium during electrode implantation: Spatial and temporal mapping of damage and recovery. Biomaterials 174:79-94
Wellman, Steven M; Kozai, Takashi D Y (2018) In vivo spatiotemporal dynamics of NG2 glia activity caused by neural electrode implantation. Biomaterials 164:121-133
Wellman, Steven M; Eles, James R; Ludwig, Kip A et al. (2018) A Materials Roadmap to Functional Neural Interface Design. Adv Funct Mater 28:
Vazquez, Alberto L; Fukuda, Mitsuhiro; Kim, Seong-Gi (2018) Inhibitory Neuron Activity Contributions to Hemodynamic Responses and Metabolic Load Examined Using an Inhibitory Optogenetic Mouse Model. Cereb Cortex 28:4105-4119
Shen, Yang; Cao, Bin; Snyder, Noah R et al. (2018) ROS responsive resveratrol delivery from LDLR peptide conjugated PLA-coated mesoporous silica nanoparticles across the blood-brain barrier. J Nanobiotechnology 16:13

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