Organs-On-Chips for Radiation Countermeasures

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Background | Project Description | Update: Modeling Sex-Specific Responses | Project Outcomes | Publications | Awards

FDA awards contract to Harvard University’s Wyss Institute for Biologically Inspired Engineering to test candidate radiation medical countermeasures, using novel organs-on-chips technology 

Performer: Wyss Institute for Biologically Inspired Engineering at Harvard University

Principal Investigator: Donald E. Ingber, MD, PhD

Initial contract value: $5,625,079

Follow-on study value: $398,000 (Awarded September 27, 2018)

Project dates: September 2013 - April 2019

Background

The development of medical countermeasures to treat acute radiation syndrome (ARS) is a high-priority for the U.S. government. ARS is an illness affecting a combination of organs that occurs when the body receives a high dose of radiation – over a short period of time – as would be expected to occur after a nuclear or radiological incident. 

The development of medical countermeasures to treat ARS presents complex scientific challenges. For example, ARS may involve many organ systems, which makes it difficult to study candidate medical countermeasures that target the radiation effects on one specific organ system in animal models. In addition, certain candidate medical countermeasures cannot be effectively studied in animal models because their activity is specific to humans. 

Project Description

Harvard University’s Wyss Institute for Biologically Inspired Engineering is developing organs-on-chips that mimic the structure, function, and interactions between the living tissues within human organs – such as the lung or intestine – on chips the size of a thumb drive.

Under the contract, Wyss Institute scientists will develop models of radiation damage in their lung, gut, and bone marrow organs-on-chips and then use these models to test candidate medical countermeasures to treat such damage. This will provide a capability to evaluate candidate medical countermeasures for ARS within the specific context of a target human organ system, which may yield valuable information for facilitating development.

Update: Modeling Sex-Specific Responses

Wyss’ earlier work under this contract demonstrated that its bone marrow chip produces human red and white blood cells for up to one month in culture, and faithfully mimics human bone marrow responses to ionizing radiation as well as effects of known chemotherapies and radiation countermeasure drugs. Because scientific evidence indicates that sex differences may play a major role in how bone marrow responds to radiation, 1 ^, 2 in September 2018, FDA awarded a follow-on study to this project to enable the Wyss team to create male and female human bone marrow chips to analyze differences in sex-specific responses to ionizing radiation and a chemotherapeutic drug.

FDA’s Medical Countermeasures Initiative (MCMi), in FDA’s Office of the Chief Scientist and FDA’s Office of Women’s Health (OWH), within the Office of the Commissioner, collaborated to fund this additional research, which will help the scientific community better understand how sex differences impact the body’s response to MCMs for radiological and nuclear preparedness.

Also see: FDA expands award to Wyss Institute for radiation treatment studies using Organ Chips (November 1, 2018), from Wyss

Project Outcomes

This project will:

• Advance the development of microphysiological systems (organs-on-chips) that recapitulate many of the complicated interactions between cells and tissues that occur in the gastrointestinal tract, bone marrow, and lungs
• Characterize how these organs-on-chips systems respond to radiation exposure and compare the responses against those known to occur in people and animals exposed to radiation
• Link together the different organ-on-chips systems (for example, gut chip and bone marrow chip) and expose them to radiation to simulate the interplay between different organ systems exposed to radiation
• Test candidate radiation medical countermeasures in the individual organs-on-chips and linked organ-on-chips systems
• Assess differences in sex-specific responses to radiation exposure and chemotherapeutic agents, as well as the effect of MCMs on that response in the bone marrow chip

This project was funded through the MCMi Regulatory Science Extramural Research program

Publications

• Huh D et al., Microfabrication of human organs-on-chips. Nature Protocols 8:2135-57, 2013 - full text (open access) 
• Torisawa YS et al., Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nature Methods 11:663-9, 2014 - full text (open access)
• Bhatia SN and Ingber DE., Microfluidic organs-on-chips. Nature Biotechnology 72, 201432:760-72, 2014 - full text (open acess)
• Esch EW, Bahinski A, Huh D, Organs-on-chips at the frontiers of drug discovery. Nature Reviews Drug Discovery. doi:10.1038/nrd4539, published online 20 March 2015 - abstract - full text
• Kim HJ, Collins JJ, Ingber DE.  Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. PNAS. 15 Nov 2015 - abstract - full text
• Kim HJ, Lee J, Choi JH, Bahinski, A, Ingber DE. Co-culture of Living Microbiome with Microengineered Human Intestinal Villi in a Gut-on-a-Chip Microfluidic Device. J. Vis. Exp. 2016 Aug 30 (114) – journal link
• Torisawa Y, Mammoto T, Jiang E, Jiang A, Mammoto A, Watters AL, Bahinski A and Ingber DE. Modeling Hematopoiesis and Responses to Radiation Countermeasures in a Bone Marrow-on-a-Chip. TISSUE ENGINEERING: Part C. Volume 22, Number 5, 2016 - abstract -  full text
• Villenave R, Wales SQ, Hamkins-Indik T, Papafragkou E, Weaver JC, Ferrante CT, Bahinski A, Elkins CA, Kulka M, Ingber DE. Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro. PLOS ONE. February 1, 2017 - full text (open access)
• Henry OYF, Villenave R, Cronce MJ, Leineweber WD, Benz MA  and Ingber DE.  Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function. Lab Chip. 2017 Jun 27;17(13):2264-2271 - abstract only
• Jalili-Firoozinezhad S, Prantil-Baun R, Jiang A, Potla R, Mammoto T, Weaver JC, Ferrante T, Jung Kim H, Cabral JMS, Levy O, Ingber DE. Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip. Cell Death & Disease. 9.10.1038, published online 14 February 2018 -full text (open access) 
• Novak, R., Didier, M., Calamari, E., Ng, C. F., Choe, Y., Clauson, S. L., Nestor, B. A., Puerta, J., Fleming, R., Firoozinezhad, S. J., Ingber, D. E. Scalable Fabrication of Stretchable, Dual Channel, Microfluidic Organ Chips. J. Vis. Exp. (140), e58151, doi:10.3791/58151 (2018). abstract
• Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology. Sontheimer-Phelps A, Chou D, Tovaglieri A, Ferrante T, Duckworth T, Fade C, Frismantas V, Sutherland A, Jalili-Firoozinezhad S, Kasendra M, Stas E, Weaver, J, Richmond C, Levy O, Prantil-Baun R, Breault D, Ingber D. Cell Mol Gastroenterol Hepatol. 2019 Nov 25. pii: S2352-345X(19)30163-8. doi: https://doi.org/10.1016/j.jcmgh.2019.11.008

Awards

• Sasan Jalili-Firoozinezhad honored with 2018 Lush Young Researcher award (November 2018)
  In a ceremony held in Berlin, Germany, the Lush Foundation recognized the potential of Wyss Institute’s human intestine chip for replacing animals in the study of radiation injury. The Lush Prize offers a global prize fund across five award categories, with the goal “to bring forward the day when safety testing for drugs, cosmetics and chemicals takes place without the use of animals.”
• Human-organs-on-chips win Design of the Year, from The Guardian (June 22, 2015)

Related Links

• A gut reaction ... on a chip - First study of radiation exposure in human gut Organ Chip device offers hope for better radioprotective drugs (Feb. 2018)
• Organs-on-Chips Technology: FDA Testing Groundbreaking Science (FDA Voice blog, April 11, 2017 - ARCHIVED)
• Organs-On-Chips Technology Infographic (PDF, 389 KB) - Information about organs-on-chips research from FDA's Center for Food Safety and Applied Nutrition
• FDA awards contract to develop promising new technology to test radiation countermeasures (August 12, 2013 - ARCHIVED)

• 1Mell, L. K. et al. Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 70, 1431-1437, doi:10.1016/j.ijrobp.2007.08.074 (2008).
• 2Borgmann, K., Dikomey, E., Petersen, C., Feyer, P. & Hoeller, U. Sex-specific aspects of tumor therapy. Radiat Environ Biophys 48, 115-124, doi:10.1007/s00411-009-0216-1 (2009).