Article by Maria Hudock & Roberta Lock
Airway-on-a-Chip Helps to Identify Medications, Faster
A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics, Nature Biomedical Engineering, 2021
LongLong Si et al., Donald Ingber Lab
In urgent situations such as a pandemic, one of the fastest ways to find medications that work but are also safe to put in our bodies is to use medications that already exist. Using information about how an existing drug works, doctors can repurpose a drug used to treat one disease to try to treat a new disease. In 2020, this was done to try to find an existing drug that could be used to treat COVID. However, drugs that worked to treat COVID in lab cell culture models kept failing to work in humans. So, scientists raced to build a better, more realistic model of human airways on which to test potential medications. In this paper, one group of scientists reports on their model and the results of testing medications on it.
What did these researchers do?
In an effort to build a more realistic human lung airway model, these researchers put together different types of human cells (both airway and blood vessel cells) in an microfluidic device that provided air on one side and a flowing blood-like fluid on the other, similar to the environment cells naturally experience in the lungs. They then did a number of experiments to show that their model of the airway, an airway “on-a-chip”, responds to invading viruses and to drugs like animals and humans do.
Human Airway-on-a-Chip platform by D. Ingber Lab
Why is this important?
Having a realistic model for the human airway in the lab to accurately predict which drugs will fight new diseases is extremely important. Simple cell culture models have very limited predictive accuracy and can led to patients being treated with drugs that don't work. More realistic models keep patients safe and help us to discover treatments for diseases faster.
How did the researchers do this?
Before this paper was written, this group of researchers had already built a preliminary version of the Airway-on-a-Chip. In this paper, they upgrade the design by adding larger holes in the membrane between the blood-like chamber and the air chamber. This way, immune cells can leave the blood channel and get into the air channel to fight viruses.
To prove that their airway-on-a-chip acts like a real airway in response to infection, the researchers started with a disease we already understand well: the flu (influenza). Researchers added different influenza viruses into the air channel. They saw damaged airway (epithelial) cells, observed separation of blood vessel (endothelial) cells and leakage of fluid between them, and detected different levels of molecules that signal cell distress (cytokines) in response to different strengths of viruses. Immune cells were able to respond to the cytokines, crawl into the airway, and fight the virus. They also saw that the drug oseltamivir (Tamiflu) worked to help stop flu infection in the airway-on-a-chip on a similar timeline as it works in humans. All of this is good evidence that the airway on a chip acts like a real airway in response to infection.
After that, the researchers were ready to move on to looking for drugs to stop COVID. Since the SARS-CoV-2 virus is dangerous to work with, the researchers made a pseudo-virus that was capable of getting into cells (using COVID’s Spike protein) but not of causing infection. After showing that the pseudo-virus could get into cells, they tested drugs to see which ones would prevent it. Out of six drugs that worked to stop viral entry in cell culture models, only three worked in their airway-on-a-chip.
Finally, they took the drug that worked the best (amodiaquine, another drug that is sometimes used to treat malaria) and tested to see if it also worked to slow down real COVID infections in hamsters. It did! The airway-on-a-chip turned out to be a pretty good predictor of how cells, viruses, and drugs interact in real animals.
What comes next?
While the airway on a chip was a more realistic model for the drug studies, the virus that the researchers used was fake (not the real COVID). The next step for these researchers will be to take their model to a specialized laboratory where the real SARS-CoV-2 can be safely tested on the airway-on-a-chip. The researchers can continue to make their model more realistic (e.g., adding in breathing-like motion to the air channel, adding in new cell types), if needed. They can also use it to study other diseases.
As for the medications that were studied, especially amodiaquine, which was shown to work in hamsters: the next step will be to test the drug on either other animals, or potentially directly on humans. However, amodiaquine isn’t without risks. It currently has a black-box warning from the FDA: a very serious warning that it can cause severe blood and liver damage. These rare but dangerous side effects are so bad that it isn’t really used in the United States, but it is used in areas where malaria is common. This is why it is so important to have good models to establish whether a drug really works to treat a disease: you don’t want to expose patients to a medication and its potential side effects unless you really have to.