How new 'lung-on-a-chip' models from Harvard are advancing COVID-19 drug discovery

One of the challenges facing scientists searching for new ways to combat COVID-19 is that pitting drug candidates against the virus in cell cultures doesn’t accurately predict how effective they’ll actually be in the human respiratory tract. Two Harvard University teams have developed new lung-on-a-chip models that they believe could solve that problem—and one of them has already uncovered an existing drug that might be repurposed in fighting COVID-19.

Using a microfluidic device designed to mimic the human lung airway, a team led by Harvard’s Wyss Institute for Biologically Inspired Engineering discovered that the antimalarial drug amodiaquine prevented the SARS-CoV-2 virus that causes COVID-19 from entering lung cells. The researchers validated the results in a small-animal model of the virus, they reported in the journal Nature Biomedical Engineering.

The model the Wyss team created, called the Lung Airway Chip, contains two channels: one is filled with air and the other contains human blood vessel cells and liquid that mimics blood flow. The model, which is about the size of a memory stick, grows airway cells types and develops traits similar to the human lung, the researchers said.

Rather than infecting the Lung Airway Chip with the live SARS-CoV-2 virus, a dangerous proposition, “we designed a SARS-CoV-2 pseudovirus that expresses the SARS-CoV-2 spike protein, so that we could identify drugs that interfere with the spike protein's ability to bind to human lung cells' ACE2 receptors,” explained co-author Haiqing Bai, Ph.D., a postdoctoral fellow at Wyss, in a statement.

Interestingly, the lung model revealed that two antimalarial drugs that generated enthusiasm in the early days of the pandemic—hydroxychloroquine and chloroquine—did not prevent the COVID-19 virus from entering the lungs. But amodiaquine did, as did breast cancer drug toremifene, and infertility drug clomiphene. But amodiaquine was the most potent of the three, reducing infection by 60% in the chips, the researchers reported.

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The second respiratory model, created by researchers at Harvard’s Brigham & Women’s Hospital, was designed to mimic the alveolar tissue found in the lower region of the human lung. The 3D model grew airway cells and was able to simulate human breathing, they reported in the journal Proceedings of the National Academy of Sciences.

The Brigham and Women’s team plans to use the model to study how COVID-19 drugs affect the cells of the lower lung. The researchers believe it will also be useful for studying how emerging SARS-CoV-2 variants travel through the lung and interact with drug treatments. The lung-on-a-chip could also advance research in other pulmonary diseases, including lung cancer, they said.

“In terms of COVID-19, we've had very minimal timelines for developing therapies. In the future, if we have these models ready in hand, we can easily use them to study and test therapeutics in urgent situations where clinical trials are limited,” said co-author Y. Shrike Zhang, Ph.D., associate bioengineer in at Brigham and Women’s, in a statement.

As for the Wyss researchers, they teamed up with scientists at the Icahn School of Medicine at Mount Sinai to test amodiaquine against hydroxychloroquine in animal models of COVID-19. In addition to reducing viral load by 70%, amodiaquine prevented transmission of the virus 90% of the time, they reported. The drug is now being tested in COVID-19 patients in Africa.