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The U.S. Department of Defense (DOD) continues to make investments in alternative non-animal methods to develop medical countermeasures to chemical and biological threats. One such effort has led to establishment of the Absorption, Distribution, Metabolism, Elimination, and Toxicology Center of Excellence (ADMET CoE). The ADMET CoE brings best practices from the pharmaceutical industry to DOD, first assessing potential toxicity and efficacy through modeling and in vitro screening mechanisms and then selecting the most promising clinical candidates. This approach could reduce the reliance on animal models for developing medical countermeasures to chemical and biological threats.
The DOD “human-on-a-chip” project aims to develop a platform that uses microphysiological organ systems to mimic all 10 human physiological systems. The platform allows microphysiological systems to interact with each other in a physiologically relevant manner. Recently, this platform demonstrated four interacting microphysiological systems. In the next phase, the goal is to demonstrate seven interacting organ systems and, by the end of the program, 10 interacting microphysiological systems.
While the “human-on-a-chip” focuses on early screening of medical countermeasures, DOD is independently investing in a five-year collaboration known as the XCEL (Ex Vivo Countermeasure Evolution and Licensure) Program, which focuses on chemical and biological threat agent assessment and medical countermeasure research and development. XCEL consists of two multi-institutional program teams that bring together domestic and international talents and leaders in the field of microphysiological systems research. In XCEL, four human primary cell-based organ systems (liver, heart, lung, and kidney/blood vessel) are being integrated into a platform with support of a universal media (blood surrogate), interlinked microfluidics (channels, pumps and valves), in-line sensors (biomedical, immunological, chemical, physical and physicoelectrical sensing), and off-line analytics with on-board data integration. The program will develop the incrementally integrated platform over several years: Year 1, liver; Year 2, liver and heart; Year 3, liver, heart, and lung; Year 4, liver, heart, lung, and kidney/vessel; Year 5, partial validation of the platform by live testing with known threat agents and toxic drugs.
The DOD Rapid Hazard Screening program focuses on developing new approaches to predict and determine the potential health hazards of new chemicals and materials. The program uses high throughput in vitro assays, zebrafish embryos, transcriptomics, and computational predictive modeling, combined with a biological pathway-based hazard/risk screening framework, to rapidly and accurately determine potential human and ecological health hazards of DOD chemicals and materials. These approaches enable extrapolation from exposure concentrations to assay or tissue-dose concentrations, allowing prediction of exposure levels below which no impact would be expected. The methods and framework should provide more accurate hazard-level screening and reduce animal use for in vivo safety tests required for new chemical development. The hazard/risk decision support framework under development will integrate data from the ADMET CoE, “Human-on-a-chip,” and XCEL programs to enable consistent prediction of adverse health impacts with diverse data sets. The Rapid Hazard Screening program is collaborating with the U.S. Environmental Protection Agency and international organizations such as the Organisation for Economic Co-operation and Development to ensure that the approaches being developed are consistent with national and international efforts.
The ADMET CoE, the “human-on-a-chip,” XCEL, and Rapid Hazard Screening programs are concerted, strategic efforts focused on developing new approaches to reduce the reliance on animal models for DOD’s chemical and biological portfolios. Other efforts are aimed at implementing approaches to reduce DOD’s reliance on animal models using, for example, phased approaches to testing and high throughput screening (HTS). In this approach, new candidate compounds undergo a battery of in silico and in vitro testing early in the development process. This approach allows compounds of concern to be eliminated early in the research, development, testing, or evaluation process, reducing the likelihood of testing in an animal model. Phased acute toxicity testing is built on in vitro data, and limited repeat-dose animal testing is focused on targets of toxicity learned from previous in silico and in vitro tests. One effort underway aims to conduct initial screening for toxicity using established cell lines grown in a monoculture or a co-culture with immune cells for the following organs: lung, liver, skin, brain and kidney. With an HTS approach, up to 10 chemicals at three different concentrations can be screened on a 384-well plate with multiple endpoints for analysis, including cell viability, toxicity, nuclear count, oxidative stress, and ATP levels. A three-dimensional, co-culture system for each of the organs of interest is also under development to screen chemicals for these same endpoints. The use of a three-dimensional culture allows for better approximation of the structure and function of each organ system.