Organ on a chip (Wyss Institute, Harvard Univ.)
09 Nov. 2021. Biomedical engineers found a chip device with intestinal tissue can simulate coronavirus infections and symptoms in the gut, and test possible treatments. A team from the Wyss Institute for Biologically Inspired Engineering at and other departments at Harvard University report their findings in the 25 Oct. issue of the journal Frontiers of Pharmacology.
In the current pandemic, respiratory effects are the best known symptoms of SARS-CoV-2 infections. Yet, the authors cite data showing that six in 10 people with Covid-19 disease also report gastrointestinal or GI symptoms such as nausea and diarrhea. A possible reason for these symptoms is the presence of angiotensin-converting enzyme 2 or ACE2 receptor proteins in cells lining GI tissue, the same primary infection targets for SARS-CoV-2 viruses in the respiratory tract. In addition, lining both respiratory and GI tissue are cells with transmembrane serine protease 2, or TMPRSS2 proteins, also a target for SARS-CoV-2 infections.
Up to now, however, GI symptoms are difficult to model in preclinical studies, since few lab animals have GI organs that work like humans. A team led by Wyss Institute director Don Ingber evaluated a chip device to simulate the workings of a human gut, a field in which the institute has experience. Organs-on-chips are small flexible polymer plastic devices with fine channels etched in the surface or drilled through, lined with live tissue and cells, and designed to simulate the workings of human organs. Three-dimensional tissues on the devices make it possible to predict the behavior of human organs better than animal models like mice, or cells grown in lab cultures.
Similar to gut responses in humans
The intestinal tissue chip in this study uses organ-lining tissue derived from human cells grown into small 3-D tissue fragments called organoids. The chip also has simulated blood vessels with cells found in the lining of veins and arteries. To test the chip’s response to infections, researchers used NL63 viruses, a coronavirus that acts like SARS-CoV-2, causing similar respiratory and GI symptoms.
In their tests, the team found after NL63 virus exposure, tissue lining cells on the GI chip becomes inflamed, recruits peripheral blood cells, and increases cytokine production, similar to gut responses in infected humans. Researchers also tested on the chip current drugs for treating coronavirus infections, with mixed results. The drug remdesivir, approved by FDA for treating patients with Covid-19 disease, shows no reduction of virus on gut tissue, but also damages blood vessel lining cells, a potential toxic effect. The anti-inflammatory drug nafamostat, however, reduces viral load and cytokine production. Nafamostat is a protease enzyme inhibitor currently assessed as a Covid-19 treatment in a clinical trial.
“This study,” says Ingber in a Wyss Institute statement, “demonstrates that we can explore complex interactions between cells, pathogens, and drugs in the human intestine using our intestine chip as a preclinical model. We hope it proves useful in the ongoing effort to better understand the effects of SARS-CoV-2 and to identify drugs that could be used to combat future viral pandemics.”
Ingber is scientific founder of the company Emulate Inc. developing commercial applications for organs-on-chips, including intestine chips, and chairs its scientific advisory board.
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