Lawrence Livermore National Laboratory



Nicholas Fischer

Overview

Understanding how the human brain responds to chemical exposure, infection, and disease underpins the development of therapies and therapeutics. Our research focused on developing an experimental model of the human central nervous system that more accurately mirrors the function and physiology of the human brain.

To develop a more accurate experimental model, we evaluated and optimized key elements designed to more precisely recapitulate neuron function. We demonstrated that neuronal function was more robust when neurons were cultured with other neuronal cells as well as complex extracellular matrix molecules. We designed a novel three-dimensional multi-electrode array that provides an unprecedented ability to non-invasively monitor and record neuronal function in 3D, in a reproducible manner. We also optimized an experimental model of the blood-brain barrier, providing an important tool for understanding how this interface regulates the exchange of molecules from the blood to the brain. Underpinning all of these experimental efforts were novel data analytics and modeling approaches. Our in vitro brain-on-a-chip provides critical insight into human brain function in response to chemical exposure and disease.

Impact on Mission

The successful completion of this project expanded Lawrence Livermore National Laboratory's capabilities and expertise in understanding human brain function in the context of the Laboratory's national security mission. This research supports the DOE objective of delivering scientific discoveries and tools that transform our understanding of nature. The results enhance Livermore's bioscience and bioengineering core competencies and advance the Laboratory's chemical and biological security R&D challenge area.

Publications, Presentations, Etc.

Belle, A., et al. 2018. "Evaluation of in vitro Neuronal Platforms as Surrogates for In Vivo Whole Brain Systems." Scientific Reports, 8, 10820. PMID: 30018409. LLNL-JRNL-746078.

Cadena, J., et al. 2018. "Graph-Based Modeling of Neuronal Cultures on a Brain-on-a-Chip Device." Research Symposium, Lawrence Livermore National Laboratory, Livermore, CA, June 2018. LLNL-POST-752566.

——— . 2019. "Temporal Network Modeling of Neuronal Cultures on a Brain-on-a-Chip Device." Research Symposium, Lawrence Livermore National Laboratory, Livermore, CA, April 2019. LLNL-POST-772901.

Enright, H., et al. 2017. "Development and Characterization of Primary Neuronal-Glia Networks." Society for Neuroscience, Washington D.C., November 2017. LLNL-POST-741070.

——— . 2018. "Development and Characterization of Primary Neuronal-Glia Networks." Keystone Symposia-Organs and Tissues on Chips, Big Sky, MT, April 2018. LLNL-POST-748983.

——— . 2018. "Recapitulating Complex Neuronal-Glia Networks in an In Vitro System." Society for Neuroscience, San Diego, CA, November 2018. LLNL-POST-760637.

——— . 2018. "Development and Characterization of Primary Neuronal-Glial Networks." Superfund Research Program Annual Meeting, Sacramento, CA, November 2018. LLNL-ABS-744288.

——— . 2019. "Recapitulating Complex Neuronal-Glia Networks in an In Vitro System for Toxicant Characterization." Military Health System Research Symposium, Orlando, FL, August 2019. LLNL-POST-786859.

Fischer, N., et al. 2017. "Enhancing Cellular Complexity and Architecture of CNS and BBB Experimental Models." Chemical and Biological Defense Science and Technology Conference, Long Beach, CA, November 2017. LLNL-POST-741070.

——— . 2019. "Enhancing Functional Relevance of In Vitro CNS Models by Recapitulating Native Cellular Composition, Extracellular Matrix, and Architecture." Military Health System Research Symposium, Orlando, FL, August 2019. LLNL-POST-785163.

Forde, L., et al. 2019. "Developing a Characterization and Quality Control Process for a 3D Microelectrode Array Brain-on-a-Chip Device." Poster Symposium, Lawrence Livermore National Laboratory, Livermore, CA, August 2019. LLNL-POST-782399.

Jackson, K., et al. 2017. "Brain-on-a-Chip: Detection of Neuron-Specific Proteins Using Western Blots." Poster Symposium, Lawrence Livermore National Laboratory, Livermore, CA, August 2017. LLNL-POST-735261.

Karande, P. et al. 2019. "Detecting Small Objects in Large Microscopy Images." Research Symposium, Lawrence Livermore National Laboratory, Livermore, CA, April 2019. LLNL-POST-772969.

Lam, D. et al. 2017. "Brain-on-a-Chip: Enhancing the Complexity of Cell Culture to Mimic the Cellular and Microenvironment of the Brain." Research Symposium, Lawrence Livermore National Laboratory, Livermore, CA, June 2017. LLNL-POST-733094.

——— . 2017. "Optimizing Cell Encapsulation Condition in ECM-Collagen I Hydrogels to Support 3D Neuronal Cultures." Journal of Neuroscience Methods, PMID: 31626846. LLNL-JRNL-775640.

——— . 2017. "Development and Characterization of Primary Neuronal-Glial Networks." Asilomar Bioelectronics Symposium, Pacific Grove, CA, September 2017. LLNL-POST-738164.

——— . 2017. "Investigation of Primary Rat Neuronal-Glia Networks on Hydrogel Scaffolds Using a 2D Cell Culture System." Society for Neuroscience, Washington D.C., November 2017. LLNL-POST-740994.

——— . 2018. "Extracellular Matrix Enhances Neural Network Formation and Activity on Multi-Electrode Array." Society for Neuroscience, San Diego, CA, November 2018. LLNL-POST-760217.

——— . 2018. "Brain-on-a-Chip: From 2D to 3D Cell Culture Systems." Research Symposium, Lawrence Livermore National Laboratory, Livermore, CA, June 2018. LLNL-POST-752448.

——— . 2019. "Brain-on-a-Chip: Increasing Dimensionality to Probe Neural Network Activity in 3D Space." Research Symposium, Lawrence Livermore National Laboratory, Livermore, CA, April 2019. LLNL-POST-774958.

——— . 2019. "Tissue-Specific Extracellular Matrix Accelerates the Formation of Neural Networks and Communities in a Neuron-Glia Co-Culture on a Multi-Electrode Array." Scientific Reports, 9, 4159. PMID: 30858401. LLNL-JRNL-758714.

——— . 2019. "Optimizing Cell Encapsulation Conditions in ECM-Collagen Hydrogels to Support Long-Term Maintenance of 3D Neuronal Cultures." Society for Neuroscience, Chicago, IL, October 2019. LLNL-POST-792246.

Malik, A. et al. 2018. "Characterizing the Phenotypes of Brain Cells in a 3D Hydrogel Cell Culture Model." Poster Symposium, Lawrence Livermore National Laboratory, Livermore, CA, August 2018. LLNL-POST-755594.

Moya, M., et al. 2016. "Three-Dimensional Dynamic Blood-Brain Barrier Model." Tissue Engineering & Regenerative Medicine: Personalized and Precise Science, Engineering, and Translation, San Diego, CA, December 2016. LLNL-PRES-713825.

——— . 2018. "3D Models to Understand Neurotoxicity." Superfund Research Program Annual Meeting, Sacramento, CA. November 2018. LLNL-POST-763022.

——— . 2018. "Experimental Models with Enhanced Cellular Complexity and Architecture." Blood-Brain Barrier 2018 / 17th Annual World Preclinical Congress., Boston, MA. June 2018. LLNL-PRES-753318.

Petkus, B., et al. 2017. "Determining the Timeline of Oligodendrocyte Precursor Cell Maturation to Aid in Characterization of Complex Cultures." Poster Symposium, Lawrence Livermore National Laboratory, Livermore, CA, August 2017. LLNL-POST-735133.

——— . 2018. "Evaluating Organophosphorus Compounds in a Complex Neuronal System." Poster Symposium, Lawrence Livermore National Laboratory, Livermore, CA, August 2018. LLNL-POST-756057.

Shah, J. et al. 2017. "Evaluating the Organophosphate NIMP on a 3D-Brain-on-a-Chip System." Poster Symposium, Lawrence Livermore National Laboratory, Livermore, CA, August 2019. LLNL-POST-782799.

Soscia, D. et al. 2017. "Brain-on-Chip: Central Nervous System and Blood Brain Barrier." Biomedical Engineering Society, Phoenix, AZ, October 2017. LLNL-POST-739872.

——— . 2018. "Engineering Central Nervous System and Blood Brain Barrier Devices Toward a Brain-on-a-Chip Platform." Keystone Symposia-Organs and Tissues on Chips, Big Sky, MT, April 2018. LLNL-POST-748943.

——— . 2018. "Increasing Complexity of A Brain-on-a-Chip Device Through Engineering and Associated Neuronal Cultures." SELECTBIO, Coronado Island, CA, October 2018. LLNL-PRES-757811.

——— . 2019. "3D Flexible Microelectrode Array for Monitoring Network-Wide Neuronal Electrophysiology In Vitro." Biomedical Engineering Society, Philadelphia, PA, October 2019. LLNL-POST-793157.

White, J., et al. 2018. "Testing Magnetic Actuation of Polyimide-Nickel Probes for a 3D Brain-on-a-Chip Device." Poster Symposium, Lawrence Livermore National Laboratory, Livermore, CA, August 2018. LLNL-POST-755800.