State-of-the-art microchips help understand how sepsis and neurodegenerative diseases damage the brain

In lieu of animal experiments, researchers from the University of Rochester are using state-of-the-art microchips with human tissue to better understand how the brain operates under healthy conditions and is damaged through neurodegenerative diseases or conditions like sepsis.

James McGrath, the William R. Kenan Jr. Professor of Biomedical Engineering and director of the Translational Center for Barrier Microphysiological Systems (TraCe-bMPS), leads a team that develops and leverages tissue chips to study diseases where two different types of tissue meet, including at the blood-brain barrier. A pair of recent studies published in Advanced Science and Materials Today Bio used the chips to identify how the blood-brain barrier breaks down under serious threats, which could lead to new treatments to keep brains healthy.

When inflammation harms the brain

When a patient undergoes a major surgery or contracts an infection such as sepsis, it can excessively inflame organs throughout the body including the brain, sometimes leading to long-lasting cognitive impairment, especially in older patients.

In a study published in Advanced Science, McGrath's team used tissue chips to show what happens at the barrier when the body suffers a cytokinetic storm-when the immune system creates an uncontrollable systemic inflammatory response. Their experiments showed that with a high enough cytokine storm, the blood-brain barrier breaks down, leading to brain injury.

Two different stress signals-blood proteins that leak into the brain, like fibrinogen, together with inflammatory cytokines-can work together to trigger harmful changes in brain support cells called astrocytes. At the same time, we found that the natural force of blood flow helps the blood-brain barrier stay stronger against these challenges. To me, this shows how both biology and engineering principles can come together to give us new insights into how the brain protects itself-and what goes wrong in disease."

Kaihua Chen, a biomedical engineering PhD student and lead author of the study

McGrath says that in the future, the team hopes to integrate more components of the brain on the brain side of the chip, including critical immune cells in the brain known as the microglia, to better understand how neurons are damaged during these inflammatory events. Ultimately, he hopes the chips can be used to prevent brain injuries in patients undergoing cytokine storms.

"We hope that by building these tissue models in chip format, we can arrange many brain models in a high-density array to screen candidates for neuroprotective drugs and develop brain models with diverse genetic backgrounds, including those that may be vulnerable or resilient to cytokine storms," says McGrath.

The researchers also envision their models being used in personalized medicine, tailored to individual patients' needs.

"If a patient is about to undergo a chemotherapy or a major surgery that risks generating cytokine storm, a chip modeling that specific patient's brain tissue could be used to evaluate risk and guide drug choice and dosing to help prevent brain injury as an outcome," McGrath says.

A missing key to brain health

A second study, published in Materials Today Bio, looked at pericytes, which are support cells that play an important but still not fully understood role in maintaining the blood-brain barrier. Previous studies have shown that in cases of systemic inflammation and neurodegenerative diseases, there are far fewer pericytes than in healthy brains, but it was not fully known why.

McGrath's team engineered holes and defects in endothelial tissue-the groups of cells that form blood vessels- and introduced pericytes to see what would happen.

"It's difficult for endothelial cells to create a proper barrier when they're dealing with these large holes," says McGrath. "When we add the pericytes to the membrane, they create a beautiful matrix of structural fibers that fill those holes so the endothelial cells can make their vital barrier function."

Demonstrating the interaction between pericytes and endothelial cells opens the door to therapeutics that can preserve or introduce more pericytes to help keep the blood-brain barrier stable.

"By creating defects in the endothelial cell layer, we're letting the cells interact more directly, allowing the pericytes to provide some of the support they do in the body," says Michelle Trempel, a biomedical engineering PhD student and lead author of the study. "This is important because pericyte loss is implicated in many neurodegenerative diseases, so having a model where pericytes are providing support lets us study the impact of pericyte loss in the future."

Key collaborators on the studies included Harris (Handy) Gelbard, director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center, Professor Niccolò Terrando from the Department of Anesthesiology at the Duke University School of Medicine, and Britta Engelhardt of the Theodor Kocher Institute at the University of Bern. The research was supported by funding from the National Institutes of Health and a pre-doctoral fellowship from the International Foundation for Ethical Research to Kaihua Chen.