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Using an organ-on-a-chip platform, researchers design a potential strategy to treat severe COVID-19 complications

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Using their novel organ-on-a-chip platform, a research team from the University of Toronto’s Faculty of Applied Science and Engineering has identified a molecule with the potential to combat one of the most more severe COVID-19 infections.

The molecule, a new anti-inflammatory peptide called QHREDGS, does not act directly on the virus. Instead, it works to prevent a life-threatening immune reaction known as a cytokine storm.

Cytokine storms are known to occur in some patients with COVID-19, as well as other illnesses. They occur when the body releases large numbers of signaling proteins called cytokines into the blood. Too many cytokines cause the immune system to go into overdrive and can lead to vascular complications, multiple organ failure and even death. One of the biggest challenges for clinicians during the COVID-19 pandemic has been understanding why some people infected with the SARS-CoV-2 virus experience cytokine storms, while others do not.

U of T Engineering Researchers Center for Research and Applications in Fluidic Technologies (CRAFT), co-directed by Professor Milica Radisic from the Institute of Biomedical Engineering and the Department of Chemical Engineering and Applied Chemistry, are using their expertise in organ-on-chip technology to study the problem.

“Organ systems on a chip based on human cells have the unique advantage of allowing us to dissect complex processes by simplifying the system and strategically introducing various types of immune cells to better understand the cascade of events,” says Radisic.

Radisic and his team are experts in growing functional heart tissue outside the human body. These lab-grown tissues allow researchers to model diseases and understand how genetic mutations in heart tissue can cause heart failure.

“During the pandemic, we refocused our cardiac tissue platforms to understand how the SARS-CoV-2 virus can cause vascular dysfunction,” says Rick Ludoctoral student.

In a recent article published in the journal Lab on a chipLu and his co-authors demonstrated how they conducted the study using a specific model tissue platform known as Integrated Vascular System for Dynamic Event Assessment (InVADE) – a survey supported by the U of T Connaught Fund, the Toronto Innovation Acceleration Partners and a donor to the university.

Using the InVADE platform, they infected an on-chip microfabricated perfusable blood vessel with SARS-CoV-2 to understand how the virus triggers inflammation and vascular dysfunction.

They also screened five compounds with anti-inflammatory properties that had already been tested by clinicians to see if any of them showed promise in preventing cytokine storm.

QHREDGS is a peptide that has previously been found to improve cardiomyocyte metabolism and improve endothelial cell survival. In the study, Lu found that it improved vascular functions and repaired the harmful effects of SARS-CoV-2. For example, the function of a vascular structure known as the endothelial barrier was improved by 62% compared to endothelial cells without the peptide, and the secretion of certain cytokine storm molecules was reduced from 1,000 to 10 000 times.

“Vascular dysfunction can allow SARS-CoV-2 to enter a person’s organs, such as the heart, liver, and intestine,” Lu says. “By improving vascular function and reducing inflammation in the body, we hope to prevent the type of organ failure that has been seen in COVID-19 patients.”

The InVADE platform is used for many other investigations in Radisic’s lab, including a study that explores why cancer is rarely found in the heart. Lu and his colleagues are also using the on-chip vasculature system to better understand the causes of myocarditis that have been seen in COVID-19 patients, as well as some people who have been vaccinated against the disease.

The team is currently collaborating with clinicians and researchers in Toronto to find unique biomolecular markers associated with myocarditis.

“We are currently using part of the innate immune system – namely peripheral blood mononuclear cells (PBMC) and neutrophils – to see how these immune cells can interact with heart tissue to understand how they affect heart tissue function” , says Lu.

“We are really excited about this because not only will we be able to identify some of the molecular pathways associated with myocarditis, but we also hope to find potential therapies to reverse this inflammation in the heart.”

Radisic hopes this type of organ-on-a-chip system will allow researchers to predict and better respond to future public health events.

“In addition to eliminating animal studies and ensuring the safety of participants in clinical studies, [the system’s] The small scale also allows us to be efficient in the use of reagents, as well as safe by minimizing the amount of virus needed to complete the experiments,” she says.

“This technology can enable rapid and efficient studies of emerging pathogens and their potential to infect and alter the functioning of various human organs.”