Hesperos Inc.'s Human-on-a-Chip in vitro system demonstrated two types of responses of the immune system in a study conducted with Hoffman-La Roche Pharmaceuticals and the University of Central Florida. The researchers were able to prompt both targeted immune response and one that mimicked a cytokine storm, thought to be a critical factor in severe cases and deaths from COVID-19. The study was published in Advanced Science.

“One application where the immune-system-on-a-chip can be immediately useful is for uncovering how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects multi-organ systems by activating the cytokine storm from inflammatory macrophages and to support the rapid development of therapeutics,” said Hesperos CEO Michael Shuler. “As the global pandemic of COVID-19 continues to grow, this system has the potential to quickly evaluate antiviral and repurposed drugs to help combat this devastating disease.”

The Orlando, Fla.-based company’s technology enables investigators to observe immune response to an assault by pathogens or toxic agents as well as the pro-inflammatory response sometimes triggered by direct activation of immune cells.

The innate immune system is the first part of the body to respond to COVID-19 (or any new pathogen) and is central to protecting the body from disease. Sometimes, however, that immune response becomes overactive, which can cause a cytokine storm in which immune cells move from attacking an invader to destroying healthy cells.

Active debate continues about whether the multiorgan devastation seen in severe COVID-19 cases is caused by the SARS-CoV-2 virus itself or by the body’s immune response to the virus. The Human-on-a-Chip system might help investigators better understand how the coronavirus and the immune system interact and how to mitigate the damage.

That’s something that cannot be effectively studied in animals. “The immune systems in animals is just not reflective of immune systems in humans,” Hesperos Chief Scientist James Hickman told BioWorld. “With Human-on-a-Chip we can gain insight into response and therapies we could not otherwise observe.”

Studying the immune system has also been challenging in other Human-on-a-Chip systems which use pumps or mechanical systems to function as those can activate or damage the immune cells.

The study

The Human-on-a-Chip system used in the study featured an in vitro, pumpless, three-organ system with functional human cardiomyocytes, skeletal muscle, and hepatocytes in a serum-free medium. The system uses gravity to move cells, making it much gentler than other systems, according to Hickman.

To stimulate an immune response, the researchers included recirculating human monocyte THP-1 immune cells, which are critical in wound healing, pathogen response, and activation of the innate immune response.

In the first phase of the study, investigators used the cardiotoxic compound amiodarone to cause damage to the cardiac cells. In the body, such damage would stimulate activation human monocyte THP-1 immune cells.

To simulate that response, the researchers added THP-1 immune cells. The presence of the immune cells plus the amiodarone led to a greater reduction in cardiac force, conduction velocity, and beat frequency compared to amiodarone alone.

The THP-1 cells also infiltrated the damaged cardiac cells and induced a significant increase in expression of cytokine IL-6, indicating an M2 macrophage phenotype.

M2 is a restorative macrophage, Hickman explained. “Some research indicates that these macrophages may be able to turn into stem cells to replace damaged cells,” he noted.

In the second phase of the study, the investigators exposed the three-organ system to lipopolysaccharide (LPS) and interferon gamma (IFN-γ), which provoke monocyte differentiation and activation. Without THP-1 cells in the mix, the addition of LPS/ IFN-γ did not have a discernible effect on the three-organ system.

When the researchers added THP-1 cells, however, the LPS/IFN-γ treatment damaged cells in all three organ components. Alterations included, THP-1 cell infiltration of the liver tissue, reduction in cardiac force and beat frequency, and diminished skeletal muscle force.

The researchers also observed an upregulation of pro-inflammatory cytokines, indicating an M1 macrophage phenotype. The M1 macrophages are destructive, and associated with cytokine storm.

The company

Hesperos is a stage 2 biotech contract research firm that is already using the Human-on-a-Chip technology to individualize treatment for cancer patients and evaluate drug-drug combinations. It was the first company to spin out of the tissue chip program at the National Center for Advancing Translational Sciences (NCATS).

The company now occupies a 14,000 square foot facility and employs 27 people. Hickman said Hesperos was profitable for the first time in 2019, though “the jury’s still out on 2020.”

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