Organs-On-A-Chip, Cardiotoxicity of VX and Fentanyl Following Liver MetabolismRuss Dorsey1, Daniel Carmany3, Tyler D.P. Goralski1, Jennifer Horsmon1, Reginald Gray2, Robert Kristovich1, Kyle Glover1, Harry Salem1

1Combat Capabilities Development Command Chemical Biological Center, Aberdeen Proving Ground, MD, 2DTRA , 3Excet Inc.

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Organs–on-a-Chip Platform

Acknowledgements: This research was funded and supported by the Defense Threat Reduction Agency (DTRA)/Joint Science and Technology Office (JSTO). The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Department of Defense or the U.S. Government.

Discussion

To better understand potential effects of chemical agent threats to theWarfighter, 3-D tissue models with multiple linked organoids are beingdeveloped. To demonstrate the utility of this technology, VX and Fentanylwere evaluated in a liver and heart system and shown to produce effectsthat may be life-threatening. These effects are evident immediatelyupon exposure and continue to progress with time. A possible cause maybe a failure of cardiac cells to regulate intracellular calcium. Studies arebeing planned to further investigate the role of calcium on beat rate andwhether or not calcium regulators can counteract the cardio specificeffects such threat agents.

• An integrated model system has successfully been developed using 3D humanorganoids from multiple organ cell types.

• This model system is generating human data on current and emerging chemicaland biological threats.

• These systems can also be used to develop new medical countermeasures againstthreat agents.

XCEL Program Consortium

Conclusions

Abstract

Traditional two dimensional (2D) cell cultures, currently the standard for in vitrotoxicity screening, fail to recapitulate the microenvironment of in vivo tissues.Advancements in cell aggregate culture systems have contributed to theevolution of 3D organoids. The next progression is to combine multiple tissue ororgan types within a single microfluidic device as an organs-on-a-chip platform.This is necessary because tissues and organs in the human body are not isolated,but are instead highly interconnected enabling essential biochemical functionssuch as signaling. Likewise, in toxicity screening, toxic effects in secondarytissues can be as important as effects at the target site. If undetected, theseeffects can result in study inaccuracies which can lead to high rate of drug failure

Human 3-D Tissue Constructs

Liver Cardiac

or withdrawal from the market due tonegative side effects. We investigatedthe use of heart and liver organoids incombination with microfluidics tocreate a multi-tissue platform with aclosed circulatory perfusion system,facilitating inter-organ responses.