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  1. Preparedness Research

Human organ chips for radiation countermeasure development

Scientists are developing models of radiation damage in lung, gut, & bone marrow organs-on-chips and using these models to test MCMs to treat such damage

Image
The Wyss Institute’s gut-on-a-chip constricts and relaxes, just as in the human body, producing finger-like projections called villi, shown at left. (Credit: Wyss Institute at Harvard University)
Caption
The Wyss Institute’s gut-on-a-chip constricts and relaxes, just as in the human body, producing finger-like projections called villi, shown at left. (Credit: Wyss Institute at Harvard University)

Study expanded to add development and evaluation of new organs-on-chips to aid development of countermeasures for COVID-19 

Background | Project description | 2021 update – COVID-19 response | 2022-2023 update – Radiation countermeasure evaluation | Project outcomes | Additional reading | Publications | Related links

Performer: Wyss Institute for Biologically Inspired Engineering at Harvard University
Principal investigator: Donald E. Ingber, MD, PhD
Initial contract value: $3,588,882
Contract modification value: $1,999,992 (September 2021)
Contract modification value: $835,846 (March 2022)
Contract modification value: $900,000 (June 2023)
Project dates: September 2019 – March 2024

Background

Acute radiation syndrome (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 could occur after a nuclear or radiological incident. The U.S. government has identified a need for safe and effective radiation medical countermeasures (MCMs) for military and civilian applications, as well as to mitigate toxicities associated with medical radiotherapies.

The development of MCMs to treat ARS presents complex scientific challenges. For example, ARS may involve many organ systems, which makes it difficult to study candidate MCMs that target the radiation effects on one specific organ system in animal models. Thus, there is a crucial need for more predictive in vitro models of the effects of ionizing radiation on human tissue and organ function. Closing such knowledge gaps to further MCM development and availability is a key goal of the MCMi Regulatory Science Program.  

Project description

The Ingber Laboratory at the Wyss Institute has developed human organs-on-chips—microfluidic culture devices that replicate human organ-level pathophysiology. This project builds on past FDA-funded work at the Wyss Institute that led to the development of human models of ARS in bone marrow, intestine, and lung organs-on-chips and the application of these tools to the evaluation of ARS MCMs. Under the current project, the Wyss team will advance the use of human organs-on-chips for MCM development by demonstrating biomimicry and defining critical qualification criteria, helping to reduce the reliance on testing in small animals and nonhuman primates (NHPs).  

2021 update – COVID-19 response

In response to the COVID-19 pandemic, FDA partnered with the National Institute of Allergy and Infectious Diseases (NIAID) to develop organs-on-chips and microphysiological systems (MPS) models, to aid development and evaluation of MCMs for COVID-19.  

Under a 2021 contract modification, the Wyss Institute, in collaboration with the UK Health Security Agency (formerly Public Health England), will use their organs-on-chips technology to further develop in vitro (human) models of viral infection, propagation, and pathogenicity. Specifically, the project will also include development of NHP organs on chips to provide a bridge from these models to both clinical and nonclinical data, and to better understand comparability to advance MCM assessment.

2022-2023 update – Radiation countermeasure evaluation (phase II)

Following progress of initial radiation countermeasure work under the base period of this project, FDA awarded a partial option award to continue development and characterization of organ chips for radiation countermeasure research. This option will test effectiveness of radiation countermeasures on organ chips, and screen additional experimental MCM compounds.

Project outcomes

Deliverables from this project include:

  • Assessing the effects of MCMs (FDA-approved and in development) on reducing radiation damage in male versus female bone marrow chips to determine differences in radiation response by sex
  • Analyzing the interplay between human bone marrow organs-on-chips and intestine organs-on-chips that include a complex human gut microbiome in response to radiation exposure
  • Recapitulating radiation-induced pneumonitis and response to existing ARS MCMs in the human lung alveolus chip
  • Using the Wyss computational discovery pipeline with transcriptomics data to support repurposing existing drugs as radiation MCMs
  • Developing NHP (male and female) lung organs-on-chips/MPS
  • Developing NHP COVID-19 lung chip models and comparing to human COVID-19 lung chip models
  • Exploring and assessing the ability of MCMs (including antiviral therapies) to inhibit viral infection and influence host responses in both NHP and human lung chips.

This project was funded through the MCMi Regulatory Science Extramural Research program and is supported through partnership with the Office of Biodefense Research Resources, and Translational Research, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA).

Additional reading

Chou, D. B., Frismantas, V., Milton, Y., et al. (2018). Human bone marrow disorders recapitulated in vitro using organ chip technology. Cold Spring Harbor Laboratory. https://doi.org/10.1101/458935 

Jalili-Firoozinezhad, S., Gazzaniga, F. S., Calamari, E. L., et al. (2019). A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. In Nature Biomedical Engineering (Vol. 3, Issue 7, pp. 520–531). Springer Science and Business Media LLC. https://doi.org/10.1038/s41551-019-0397-0 

Jalili-Firoozinezhad, S., Prantil-Baun, R., Jiang, A., et al. (2018). Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip. In Cell Death & Disease (Vol. 9, Issue 2). Springer Science and Business Media LLC. https://doi.org/10.1038/s41419-018-0304-8 

Kasendra, M., Tovaglieri, A., Sontheimer-Phelps, A., et al. (2018). Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids. In Scientific Reports (Vol. 8, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41598-018-21201-7 

Jain, A., Barrile, R., van der Meer, A., et al. (2017). Primary Human Lung Alveolus‐on‐a‐chip Model of Intravascular Thrombosis for Assessment of Therapeutics. In Clinical Pharmacology & Therapeutics (Vol. 103, Issue 2, pp. 332–340). Wiley. https://doi.org/10.1002/cpt.742 

Torisawa, Y., Mammoto, T., Jiang, E., et al. (2016). Modeling Hematopoiesis and Responses to Radiation Countermeasures in a Bone Marrow-on-a-Chip. In Tissue Engineering Part C: Methods (Vol. 22, Issue 5, pp. 509–515). Mary Ann Liebert Inc. https://doi.org/10.1089/ten.tec.2015.0507

Torisawa, Y., Spina, C. S., Mammoto, T., et al. (2014). Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro. In Nature Methods (Vol. 11, Issue 6, pp. 663–669). Springer Science and Business Media LLC. https://doi.org/10.1038/nmeth.2938

Herland, A., Maoz, B. M., Das, D., et al. (2020). Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. In Nature Biomedical Engineering (Vol. 4, Issue 4, pp. 421–436). Springer Science and Business Media LLC. https://doi.org/10.1038/s41551-019-0498-9

Publications

  • Dasgupta, Q., Jiang, A., Hall, S., Mannix, R., Wen, A. M., & Ingber, D. E. (2023). Hemoxygenase-1 as a key mediator of acute radiation pneumonitis revealed in a human lung alveolus-on-a-chip. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2023.02.13.528339 [preprint]
  • Sontheimer-Phelps, A., Chou, D. B., Tovaglieri, A., et al. (2020). Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology. In Cellular and Molecular Gastroenterology and Hepatology (Vol. 9, Issue 3, pp. 507–526). Elsevier BV. https://doi.org/10.1016/j.jcmgh.2019.11.008
  • Chou, D. B., Furlong, B. A., Posey, R. R., Kyprianou, C., et al. (2022). Differential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors. In Nature Communications (Vol. 13, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41467-022-33672-4
  • Ingber, D. E. (2022). Human organs-on-chips for disease modelling, drug development and personalized medicine. In Nature Reviews Genetics (Vol. 23, Issue 8, pp. 467–491). Springer Science and Business Media LLC. https://doi.org/10.1038/s41576-022-00466-9
  • Grant, J., Lee, E., Almeida, M., et al. (2022). Establishment of physiologically relevant oxygen gradients in microfluidic organ chips. In Lab on a Chip (Vol. 22, Issue 8, pp. 1584–1593). Royal Society of Chemistry (RSC). https://doi.org/10.1039/d2lc00069e
  • Izadifar, Z., Sontheimer-Phelps, A., Lubamba, B. A., et al. (2022). Modeling mucus physiology and pathophysiology in human organs-on-chips. In Advanced Drug Delivery Reviews (Vol. 191, p. 114542). Elsevier BV. https://doi.org/10.1016/j.addr.2022.114542

Related links

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