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Organs-on-Chips: Rethinking Animal Testing

If a technology developed by a group at Harvard’s Wyss Institute for Biologically Inspired Engineering gains widespread adoption, it could disrupt the entire pharmaceutical research and development industry.

In both academia and industry alike, research involving the discovery and development of drugs and toxins has almost always involved overcoming certain degrees of in vivo animal experimentation and immense financial obstacles. A team of Harvard bioengineers led by the Wyss Institute’s Founding Director Don Ingber hope to change all of that with a novel technology they have developed–a device the size of a USB flash drive capable of modeling and mimicking the complex in vivo mechanics of living organs at a fraction of the cost1.

The organ-on-chip device, bringing together microfabrication techniques with modern tissue engineering in the form factor of a USB flash drive2.

Industry

The biotech industry in the United States invests heavily in the research and development of pharmaceuticals, spending an estimated 68 billion dollars in 2011 on a mere 21 new molecular entities3. A decade earlier the industry invested half that, an estimated 30 billion dollars on the successful approval of 24 new molecular entities4. Despite the skyrocketing costs and increased FDA scrutiny, the impacts of these new medicines are showing increasing yields in survival rates for childhood cancers, heart disease, and previously incurable genetic diseases.

According to PhRMA’s latest industry profile, on average only 20% of marketed drugs were capable of returning revenues that match or exceed the costs incurred to develop them5. Coupled with the fact that the drug development process spans an average of 10-15 years, this underscores the challenges of attracting investment capital and producing acceptable return on such investments.

Having identified the industry constraints, researchers over the past decade have increasingly turned their efforts towards optimizing the current approach to drug development. Thanks to the Harvard bioengineers and their groundbreaking approach, the biotech industry may be ready for a complete renovation. These researchers have engineered human organs, such as the lung, kidney, bone marrow, and gut within microfluidic silicone polymer chips mere centimeters wide. Using microfabrication techniques from computer microchip manufacturing and proprietary microfluidic technologies, this team produced organs-on-chips that mimic the functions, and most importantly, in vivo immunological responses triggered by exposure to particular environments or toxins6.

Technology

Molecular and cellular biologists have spent years developing 2D culture systems, such as tissue culture plates and flasks in order to grow and study cells under a wide variety of conditions. Cell cultures, a common laboratory technique since the mid-1900s, have played a critical role in discoveries ranging from stem and cancer cell research to the development of the first vaccinations. Though 2D culture systems continue to be used for most biological research to this day, a number of scientists have documented the limitations of this method. Researchers focused on drug development therefore still depend on animal testing and clinical trials in order to observe and study natural cellular responses due to inherent limitations to model in vivo cellular environments.

The lack of a 3D cell culture model has promoted significant interest within the scientific community to research and develop that technology7. The goal is to develop highly controlled microenvironments of living organs and tissues that mimic the biology found within humans, allowing for a truly artificial in vivo test environment8.

According to Ingber, previous attempts at engineering organs-on-chips were limited by either mechanical or biological knowledge constraints, and his researchers had to tackle both issues in an interdisciplinary fashion accordingly. The resulting collaboration led to a novel approach involving use of microfabrication techniques to recapitulate the microarchitecture, tissue-tissue interfaces and mechanical microenvironments of specific living organs in vitro.

The fruits of such an interdisciplinary approach can be seen in the development of the first experimental organ system, the human breathing lung-on-a-chip. From a technical approach, the clear, thumb-sized silicone device was engineered with a central microfluidic channel split in two by a horizontal porous membrane coated with extracellular matrix that normally holds cells together in tissues. Human cells from the lung air sac are grown on one side of this membrane with air flowed over them, and human lung capillary blood vessel cells are cultured on the opposite side of the same membrane with culture medium flowing over them to mimic the ‘alveolar capillary interface’; meanwhile, cyclic suction is applied to side chambers that induce the tissue-tissue interface to rhythmically stretch and relax, just as it does during inspiration and expiration in the human lung9,10. This system allows for researchers to flow human immune cells through the vascular channel, and to infuse a wide variety of toxins and closely study in vivo response mechanisms in a controlled environment.

This Organ-on-a-Chip, specifically of a lung, uses living human cells to mimic the lung’s tissue-tissue interface in addition to breathing motions11.

 Relevance

The true significance of this technology is that it enables scientists to perform a wide array of tests and screens in this pseudo-in vivo context that are otherwise impossible. So far, they appear to do such a good job in replicating human organ functions and natural responses that they could serve as vital diagnostic tools for clinical applications, such as the development of safe and effective new therapeutics.

“The goal is to develop an organism-on-a-chip, to have the entire human body modeled by connected in vivo organ chips.” said Ingber, “The goal is to eliminate one animal test at a time, and to shorten clinical development pipeline.”

Animal testing is currently necessary for drug development because it is the only way to obtain in vivo pharmacokinetic and pharmacodynamic response data. However, this approach is burdened by high costs, lengthy testing duration, and is often both controversial ethically and of questionable technical value12.

“We want to replace animal testing, one for ethical reasons, but also because results in animals often don’t accurately predict results in humans,” Ingber said, “We are already making predictions of responses in human organs-on-chips that we have never seen before—things that when we go back to in vivo models, we verify exist.”

Designing drugs utilizing the organs-on-chips platform would address current difficulties in both drug screening and in vivo testing. This may also significantly reduce costs by significantly shortening develoment time. The implications of such a technology are groundbreaking, as we would have a vast database of information on almost every drug – from the most optimal dosages to information on potential side effects.

The industry is ready for a biomimetic system that brings with it lower costs, vast control over individual variables, real-time high-resolution imaging to get direct insight into molecular mechanisms, and a more systematic approach to drug and toxin discovery, testing, and delivery studies.

According to researchers on organ-on-chips platform at the Wyss Institute, the future lies in linking together the various organs in order to develop a physiologically relevant multi-organ system that could hopefully replace animal testing and potentially shorten clinical trials13.

“Harvard is in a unique position in this field” said Ingber, “A lot of research teams are also approaching this field in interesting ways, but I think the interdisciplinary nature of our group and collaborators allow us to really develop exceptional technologies.”

This research has proven to be so significant that the Defense Advanced Research Projects Agency (DARPA) awarded the Harvard researchers 37 million dollars earlier this month to continue to forge ahead with their innovation by building 10 different human organs-on-chips, as well as an automated instrument to carry out pharmacokinetic and pharmacodynamic studies in this ‘human body-on-a-chip’14.

References

  1. Huh, Dongeun, Benjamin D. Matthews, Akiko Mammoto, Martín Montoya-Zavala, Hong Yuan Hsin, and Donald E. Ingber, “Reconstituting Organ-Level Lung Functions on a Chip,” Science 328, no. 5986 (2010): 1662-68, accessed July 25, 2012, doi:10.1126/science.1188302.
  2. CDER, U.S. Food and Drug Administration. “New Molecular Entity Approvals for 2011.” Accessed July 25, 2012.
  3. Food and Drug Administration. “NME 2010 Stats: How Drugs Are Developed and Approved.” Accessed July 25, 2012.
  4. PhRMA. “Pharmaceutical Industry 2011 Profile.” Accessed July 25, 2012.
  5. Baker, Monya. “Tissue Models: A Living System on a Chip.” Nature 471, no. 7340 (2011): 661-65, accessed July 25, 2012, doi:10.1038/471661a.
  6. Huh, Dongeun, Geraldine A. Hamilton, and Donald E. Ingber. “From 3D Cell Culture to Organs-on-Chips.” Trends in Cell Biology 21, no. 12 (2011): 745-54, accessed July 25, 2012, doi:10.1016/j.tcb.2011.09.005.
  7. El-Ali, Jamil, Peter K. Sorger, and Klavs F. Jensen. “Cells on Chips.” Nature 442, no. 7101 (2006): 403-11, accessed August 3, 2012, doi:10.1038/nature05063.
  8. Huh, Dongeun, Yu-suke Torisawa, Geraldine A. Hamilton, Hyun Jung Kim, and Donald E. Ingber. “Microengineered Physiological Biomimicry: Organs-on-Chips.” Lab Chip 12, no. 12 (2012): 2156-64, accessed July 15, 2012, doi:10.1039/C2LC40089H.
  9. Kim, Hyun Jung, Dongeun Huh, Geraldine Hamilton, and Donald E. Ingber. “Human Gut-on-a-Chip Inhabited by Microbial Flora That Experiences Intestinal Peristalsis-Like Motions and Flow.” Lab Chip 12, no. 12 (2012): 2165-74, accessed July 13, 2012, doi:10.1039/C2LC40074J.
  10. Cortiella, Joaquin, Jean Niles, Andrea Cantu, Andrea Brettler, Anthony Pham, Gracie Vargas, Sean Winston, Jennifer Wang, Shannon Walls, and Joan E. Nichols. “Influence of Acellular Natural Lung Matrix on Murine Embryonic Stem Cell Differentiation and Tissue Formation.” Tissue Eng Part A 16, no. 8 (2010): 2565-80, accessed August 1, 2012, doi:10.1089/ten.tea.2009.0730.
  11. Coleman, Robert A. “Human Tissue in the Evaluation of Safety and Efficacy of New Medicines: A Viable Alternative to Animal Models?” ISRN Pharmaceutics (2011): 8, accessed July 13, 2012, doi: 10.5402/2011/806789
  12.   Hansjorg Wyss Institute for Biologically Inspired Engineering at Harvard University. “Wyss Institute to Receive up to $37 Million from DARPA to Integrate Multiple Organ-on-Chip Systems to Mimic the Whole Human Body.” Accessed July 28, 2012.
  13. Image credit (used with permission): Huh, Dan. “Lung-on-a-Chip Microdevice.” Hansjorg Wyss Institute for Biologically Inspired Engineering at Harvard University, 2011.
  14. Image credit (used with permission): Frankel, Felice. “Lung on a Chip.” Hansjorg Wyss Institute for Biologically Inspired Engineering at Harvard University, 2011.

Nikhil Srinivasan is a rising sophomore at Rensselaer Polytechnic Institute majoring in biomedical engineering and chemistry. He is also pursuing a psychology minor and pre-medicine concentration and is interested in the intersection between research, healthcare, and venture. Follow The Triple Helix Online on Twitter and join us on Facebook.

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