More than a century ago scientists Paul Ehrlich and Edwin Goldman noticed that intravenous administration of blue dye stained all organs except the brain and the spinal cord. Based on this observation, scientists later coined the term blood brain barrier (BBB) to label the layer which protects the vital organ from harmful substances. Funded by the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department, researchers are now developing a novel device to model both the BBB structure and its functions to aid in development of novel warfighter protection.
John P. Wikswo, Ph.D., director of the Vanderbilt Institute for Integrative Biosystems Research and Education, developed a Neurovascular Unit (NVU), which is comprised of primary human cells and allows sampling from both the neural and vascular compartments. The NVU utilizes microfluidics, organs-on-chips and metabolomics to examine the role of inflammation, its effects on BBB functions and metabolic signature of chemical signals.
Inflammation in the BBB is related to the progression of afflictions such as depression and anxiety, and neurological conditions including Alzheimer’s, Parkinson’s, dementia and multiple sclerosis. Since several chemical and biological threats also affect neurological function, modeling the inflammation and human response is vital for understanding chemical threats and increasing warfighter protection.
Researchers have introduced stimulators to provide insights into a dynamic process which helps regulate the protective responses to inflammation within the BBB. In response to stimuli, the unit transports inflammatory cytokines from the vascular to the neuronal compartment, allowing the device to replicate BBB response.
This capability was confirmed a number of ways, including measuring transepithelial electrical resistance, a validated measurement of permeability and structural integrity which maintains the barrier function of epithelial and endothelial monolayers. In addition, the human cells responding to an inflammatory challenge produced cytokines in response to a lipopolysaccharide (LPS) test. The metabolic signature of the NVU in reaction to an LPS or cytokine challenge model indicates a dynamic response over time and reflects an increase in the number of compounds that show this response. The metabolomics profile can be analyzed and compared to the vascular chamber and the neuronal chamber.
Due to its complexity, the medical community has yet to fully assess all the unique aspects of the human brain, especially the BBB. Accurate modeling of interactions among cells, proteins, compounds and inflammatory reactions will allow researchers to deepen their understanding of the brain’s protective barrier. This will aid in comprehending the human response to chemical and biological threats and the development of novel medical countermeasures for our warfighters.
POC: Dale Taylor; dale.e.taylor4.civ@mail.mil