Human organ-on-chips: An alternative approach to drug and toxin testing?

Welcome to the new NC3Rs blog, where we discuss and comment on NC3Rs-funded research, our science and topical 3Rs issues. In this first post, our 2012 NC3Rs 3Rs Prize winner, Professor Donald Ingber at the Wyss Institute for Biologically Inspired Engineering, Harvard University, USA, describes how his prize-winning lung-on-a-chip microdevice could change the face of how we test drugs and model human disease in the future. 

The animal models that are currently used for testing drugs and toxins are costly, time-consuming, sacrifice countless animal lives, and they often fail to predict results in humans. That’s why I am excited about the progress we have made at the Wyss Institute at Harvard University, where we are developing human ‘Organs-on-Chips’ – microdevices fabricated with microchip manufacturing that contain hollow channels lined by living human cells. 

These organ chips mimic the three-dimensional tissue–tissue interfaces and unique micro-environment seen in whole living organs, and I believe they provide a tantalising glimpse into what the future of drug and chemical testing might look like. To better understand how this might work, consider the human breathing lung-on-a-chip we recently developed, which is crystal clear, flexible and about the size of a USB memory stick. It contains two parallel, sub-millimeter sized, hollow channels separated by a thin, flexible, porous membrane coated with matrix proteins, which normally hold together cells in tissues. One side of the membrane is lined with living human cells isolated from the air sac of the lung, and air is allowed to permeate into the channel; the other side contains human lung capillary blood cells with medium flowing over their surfaces to mimic blood. A vacuum applied to side chambers recreates the way our tissues physically expand and retract when we breathe.

In a Science article in 2010, we first demonstrated the feasibility of the organ-chip approach by showing that this particular lung chip mimics normal pulmonary physiology, as well as the human inflammatory response to bacterial infection when human white blood cells were introduced into the blood channel. The device also was able to mimic the absorption of tiny airborne particulates, to detect injury and inflammatory responses to these environmental toxins, and it revealed that breathing motions contribute significantly to these responses, something that was not known previously.

New insights into human disease

That was a major step forward; however, recently, we made an even greater leap. We used the lung chip to model a complex human disease – in this case a potentially life-threatening condition called pulmonary edema, or “fluid on the lungs.” One example seen in humans is the shift of fluid and blood proteins into the lungs that is a major side-effect of a chemotherapy drug called interleukin-2 (“IL-2” for short). So we infused IL-2 into the vascular channel of the lung chip, and watched what happened. Sure enough, fluid and blood components leaked across the tissue layers, reducing the volume of air in the other channel, forming blood clots and compromising oxygen transport. Even more impressive was that we observed these responses over the same time course and at the same dose that IL-2 produces these side effects in humans. What’s more, the lung-on-a-chip model led to new insights into this disease that could not easily be obtained with conventional animal studies.

For example, we learned that physiological breathing motions greatly enhance the toxicity of IL-2, which could potentially lead to new ways to minimise this drug side effect in the future. This surprise finding prompted us to test a new drug under development by GlaxoSmithKline, which we found completely prevents the symptoms of pulmonary edema in our chip model. Not only were the results produced by our model as good as those obtained in animal studies, the microchip also enabled high-resolution, real-time imaging and quantitative measurements of fluid shifts and blood clot formation that are not easily performed in animal studies. This is precisely the kind of progress the regulatory government agencies, such as the Food and Drug Administration (FDA) here in the US, and pharmaceutical companies need to see in order to seriously consider an alternative approach to animal models.

Human body-on-a-chip

Given the enormous complexity of human physiology, it is unlikely that organs-on-chips will replace animal testing in the near term; however, these findings increase the likelihood that it will happen over time, likely by replacing one type of animal model one-at-a-time. Our success to date has also spawned a slew of new research in this area, and at the Wyss Institute alone, we are developing more than 10 different organs-on-chips (e.g., gut, liver, heart, bone marrow, etc). Our future goal is to develop a virtual ‘human body-on-a-chip’, as well as an automated instrument that will permit physiological, pharmacokinetic and pharmacodynamic analysis of these linked multi-organ systems in real-time. The door to a new path is open; only time will tell…  

Huh, D., Leslie, D., Matthews, B., Fraser, J., Jurek, S., Hamilton, G., Thorneloe, K., McAlexander, M., & Ingber, D. (2012). A Human Disease Model of Drug Toxicity-Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice Science Translational Medicine, 4 (159), 159-159 DOI: 10.1126/scitranslmed.3004249

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