In the Spotlight
Organs-on-a-Chip gain momentum and support
Published: October 20, 2013
The technology has also captured the attention of the US Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health (NIH), and the Food and Drug Administration (FDA), who are coordinating a multi-institution, nearly $150 million research effort to accelerate development of the chips for use in studies on the effects of chemical and radiation exposures on humans. Approximately $75 million will go to a collaboration between the Wyss Institute and the Massachusetts Institute of Technology (MIT) to develop platforms that will connect ten or more organ chips into an integrated “body-on-a-chip.” The remaining funding is directed at 15 other projects developing tissue or systems components for these devices.
Last spring, another pioneer in organ-on-a-chip technology, the Hurel Corporation, received $9.2 million in private investment from Spring Mountain Capital, along with a research grant from the Humane Society of the United States, in support of the technology’s great potential to reduce animal testing in toxicology. Organ-on-a-chip technologies were also recognized by the UK’s National Centre for Replacement, Refinement, and Reduction of Animals in Research (NC3Rs), which awarded its annual prize for scientific and technical advances to the Wyss Institute’s Founding Director, Dr. Donald Ingber.
What’s the excitement all about?
The Wyss Institute’s Lung-on-a-Chip: an illustrated cross-section of the lung-on-a-chip microdevice used in the Wyss Institute studies of pulmonary edema, a side effect of interleukin-2 (“IL-2” in the illustration). Go here for a video of the device in action.
The “organ-on-a-chip” technology improves on conventional cell culture by adding structural complexity and functionality – creating simple synthetic organ mimics. In toxicity testing and drug development, in vitro cell and tissue culture models have been increasingly supplanting and/or reducing animal tests because they offer significant experimental advantages over in vivo models. The cell-based models allow investigators to test more kinds, concentrations, or mixtures of chemicals, in a fraction of the time, and at a fraction of the cost of testing the same combinations on animals. In addition, in vitro culture models developed using human cells eliminate the need for cross-species extrapolation, facilitate studies of the effect of genetic background on chemical and disease susceptibility, and provide for more mechanistically-based descriptions of cellular responses.
But in vitro models have important limitations, as well. Cultured cells and reconstructed tissues have a relatively short lifespan, making it difficult to assess the effects of long-term or repeated exposures to a test substance. Moreover, the cells and tissues isolated in these in vitro platforms likely behave very differently than they do in the complex physiological environment in which they normally function. It is in that natural in vivo environment – or realistic models of it – that the processes of absorption, distribution, metabolism and elimination (ADME) of a substance can be fully observed. And understanding these processes is essential to determining whether or not, and at what point, a chemical becomes a toxin.
When cultured in vitro cells or tissues are attached to a platform that has been engineered with a microfluidic circulatory system, simulating intra- and inter-cellular processes becomes feasible. “Microfluidics” is the science of the transfer and behavior of minute volumes of fluids (measured in units less than or equal to nanoliters) in minute spaces (geometries measured in units less than or equal to microns). The technology allows for the delivery of nutrients and dissolved gases to cells and tissues, the removal of metabolites, and the observation of inter-cellular chemical communication – thus extending the life of the cells, and the life-likeness of the engineered cellular environment. Ultimately, the combination of microfluidics and microfabrication technologies (for creating miniscule cell and tissue “wells,” fluid channels, and scaffolding) makes possible the creation of fully functional silicon and/or polymer matrices on which cells and tissues can live, grow, and behave, becoming – as these platforms are now widely known – “organs-on-chips.”
What’s happening now?
At Harvard University’s Wyss Institute, several simulated organs are under development, including kidney, spleen, liver, bone marrow, heart, lung, and peristaltic gut-on-a-chip. The foundation of each organ chip is a small, thin polymer rectangle – about the size of a computer “thumb drive” – containing hollow microfluidic channels. A central channel is divided by a thin, flexible, porous material that acts as a membrane. One side of the membrane can be lined with organ-specific human cells; a transport fluid streams across the other side, where it can carry blood cells, nutrients, chemicals-of-interest, bacteria, or any other desired test materials.
When gentle suction is applied cyclically to the sides of adjacent, flexible vacuum channels, the membrane in the central channel stretches and contracts – and the organ cells along with it. This allows researchers to simulate the mechanical effects of, e.g., breathing, peristalsis, or a beating heart. The ability to replicate these processes in vitro greatly enhances the validity of their use in replicating physiologically relevant conditions, e.g., ADME studies. As one example, the Wyss Institute’s lung-on-a-chip tests revealed that the mechanical process of breathing significantly increases absorption of chemicals and gases of the liver tissue – a factor that would not have been observed under more static conditions.
These organ chips can even be linked together to replicate coordinated organ systems. In 2004, Michael Shuler and colleagues described studies with a prototype “animal on a chip,” which linked compartments bearing rat-derived liver cells and lung cells, and replicated the movement of toxic metabolites from lung to liver. Another previously developed multi-organ co-culture model is the IdMOC, which models multiple-organ interaction in one plate by the use of a novel plate platform with discrete and overlaying well capabilities. With DARPA backing, both the Wyss Institute and Linda Griffith’s lab at MIT are working to unite multiple organ chips into a human body-on-a-chip.
Griffith, who created one of the first microfabricated organ models, is also working on tissue engineering – using artificial scaffolds and microfluidics to grow cultured cells into functional, three-dimensional tissues.
Organ-on-a-chip models have the potential to greatly enhance the biological relevance of in vitro approaches to toxicity testing, both in their own right and as complementary to more high throughput systems characteristic of the ToxCast and Tox21 programs. Whether alone or as a part of integrated testing strategies, they can ultimately facilitate the replacement of animal tests altogether, in favor of tests on living human cells exhibiting natural processes comparable to a typically complex in vivo environment. The high costs, inefficiencies, and predictive errors introduced when extrapolating toxicity results from animal models to humans would be greatly reduced or even eliminated.
The appeal of this chip technology is clear; pharmaceutical companies Merck, GlaxoSmithKline, and AstraZeneca are all looking into using lung or liver chips in their drug development research. (In fact, the Wyss Institute and AstraZeneca just announced a partnership to compare human and animal responses in preliminary drug safety tests using Wyss’ chips.) The primary limitation – until recently – has been an issue of scalability: how to produce the chips in the quantity and with the consistency that would make them practical for such industry and regulatory studies. That hurdle has been potentially overcome with the announcement of the Sony DADC/Wyss Institute partnership. With Sony’s production capabilities and extensive global marketing reach, the chip devices will become more accessible and “mainstream,” signaling that organ-on-a-chip technology is rapidly gaining viability and reliability in the areas of drug development, disease modeling, and toxicity testing.
For more information, see “Cell-based Microfluidic Devices for Toxicity Testing,” and “Micro Cell Culture Analogs and What They Can Contribute to the Drug Screening Process.”