Tissue chips to help explore relationship between the lungs and brain

The Biomedical Advanced Research and Development Authority (BARDA), part of the Administration for Strategic Preparedness and Response (ASPR) within the US Department of Health and Human Services (HHS), awarded a three-year contract to researchers at the University of Rochester to develop technology to model respiratory disease effects on the brain and test therapeutic drugs to prevent and treat symptoms.

The project will use so called tissue chips, which are microphysiological systems (MPS) with ultrathin membranes supporting 3D networks of human cells to simulate infection and treatment in vitro.

In a statement, principal investigator Benjamin Miller, a Dean’s Professor of Dermatology at Rochester, said: “This is another step toward making disease modelling and drug discovery focused from the very beginning on more complex, human-relevant systems. These chips can help make the whole drug discovery process faster.”

The project builds on work at Rochester’s Translational Center for Barrier Microphysiological Systems (TraCe-bMPS) to build FDA-qualified drug development tools for studying the body’s barrier functions in combating disease.

Co-investigator James McGrath, the William R. Kenan Jr. Professor of Biomedical Engineering and director of TraCe-bMPS, has been using MPS systems to study the mechanism by which inflammatory factors can enter the brain through the circulation and cause injury. The new BARDA-funded project will link two of McGrath’s modular, mass-producible chips specialised to mimic different organs.

“This project will connect this ‘brain’ chip upstream of a second chip that models a common source of those injurious factors: the infected lung,” said McGrath.

Common viruses including influenza can produce chronic symptoms such as brain fog, fatigue, and enduring pain. The project expects to offer a new way to explore the relationship between the lungs and brain.

“The respiratory tract, with its cellular, humoral and hard-wired conduits to the brain, stands as the first line of defence against emerging infectious threats from zoonotic spillovers,” said co-investigator Harris ‘Handy’ Gelbard, director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center. “We and our collaborators, with the support of the National Institute on Aging, have worked for the past several years to investigate these mechanisms in the hopes of applying therapeutic agents to ameliorate neurologic disease, especially in the elderly that are vulnerable to these infections.”

MORE FROM MEDICAL & HEALTHCARE

David Dean, co-investigator and professor of paediatrics, biomedical engineering, and pharmacology and physiology has studied the disease processes that lead to acute respiratory distress syndrome (ARDS) in the hopes of developing new treatments for this disease.

“Studying this required us to use cultured cells from the lung, but almost always, these are grown and studied by themselves, which is not anywhere close to the situation in the lung where over 40 different cell types co-exist and interact to allow us to live. Thus, this is way too simplistic of a model,” said Dean. “On the other extreme, we have used animal models to test hypotheses and drugs in development, but these models are so hard to control and make sense of because so many different things are going on, and it is difficult to attribute a response to a single pathway, leading to a system that is almost too complicated.”

He said the new approach will allow the researchers to mimic complex interactions between key cell types in the lung, but in a controlled manner.

The team will work with University of Rochester spinout companies Phlotonics to do medium-throughput instrumentation and SIMPore to develop the chips.

By the end of the first year, the team aims to link the tissue chip systems with immune cells, demonstrate that they can infect the lung chip with influenza, and observe an inflammatory response in the brain chip.