By COL. Robin R. Neumeier, Commander, U.S. Army Medical Research Institute of Chemical Defense, USA & Dr. James Dillman, Director of Research, U.S. Army Research Institute of Chemical Defense, USA.
In the event of a chemical warfare agent exposure, the expedient administration of medical countermeasures is critical to prevent life-threatening consequences and facilitate warfighter return to duty. For most chemical nerve agent exposures, the onset of symptoms is immediate, but dermal exposures to some chemical warfare agents can have a latent or pre-symptomatic period, thereby resulting in a delay in providing treatment. Scientists at the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD), a subordinate element of the U.S. Army Medical Research and Development Command, are tackling the problem of diagnosing presymptomatic exposures in innovative and unique ways. The ChemDx Test System is an ultra-portable, easy-to-use point-of-care diagnostic device for nerve agent exposure on the austere battlefield. A skin exposure-detection spray, still in the early phases of development, uses a reactive elastomeric film to indicate the exact sites of cutaneous exposure to chemical agents.
The benefits of the ChemDX Test System
The ChemDx Test System is designed to inform both medical and commander decisions as to the timely use of medical countermeasures, thereby enhancing survivability with respect to medical treatment of chemical casualties on the battlefield and lowering the burden on the medical response. Measuring the activity of acetylcholinesterase in the blood is an extremely sensitive method of determining whether an exposure to chemical nerve agents has occurred. That is because the enzymatic activity of blood cholinesterase enzymes (that is, acetylcholinesterase and butyrylcholinesterase) may become depressed following exposure even prior to the development of overt signs and symptoms.
During this pre-symptomatic window the warfighter can, with minimal training, obtain a real-time assessment of acetylcholinesterase inhibition using the ChemDx Test System. As with a glucometer and glucose strips, the blood sample from a finger stick is applied to a specially configured test strip that is inserted into the device for near real-time determination of the level of acetylcholinesterase activity in circulation. An indication of potential exposure is displayed in 20-40 seconds, depending on ambient temperature.
The ChemDx Test System can also serve as a diagnostic for military working dogs and has potential application for use with civilian first-responders, hospitals, and occupational health specialists.
Every day technology goes from the drugstore to the battlefield
ChemDx was conceived and developed by USAMRICD scientist Dr. Shane Kasten in response to a Department of Defense program to develop wearable sensors to address the need for a low complexity test system to indicate exposure prior to overt symptoms. Upon observing a woman at a restaurant quickly check her glucose levels before eating, Kasten realized that the glucometer/test strip was the most viable diagnostic platform for real-time, far-forward indication of exposure, potentially guiding treatment with a medical countermeasure therapy.
The first step in developing the project was to hack over-the-counter glucose test strips, looking for one whose proprietary chemistry could be replaced with cholinesterase-based chemistry. The successful identification of such a test strip provided proof of concept, and the project received seed funding from the Defense Threat Reduction Agency (DTRA) to begin the development of the reagent formulation and prototypes of the test strips. With full funding by DTRA in 2017, research resulted in the successful demonstration of the capabilities of the first prototype test strips and custom potentiostat to confirm exposure through an acetylcholinesterase assessment prior to the appearance of symptoms. Follow-on studies included reagent formulation optimization, real-time shelf-life testing, and real-time temperature correction.
In 2018 the Department of Defense moved ChemDx to advanced development, which was overseen by the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense. An Other Transactional Authority contract was awarded to MRIGlobal for the development of prototypes, in partnership with the USAMRICD and Conductive Technologies Inc., and for sponsorship of the device’s approval through the Food and Drug Administration.
Through this phase, USAMRICD scientists optimized the system and tuned the algorithm. Additionally, they developed an external control chemistry to use for quality management of the test system prior to deployment. These enhancements and developments allow accurate assessment in the austere conditions of the battlefield while extending to the civilian application of the test system. The USAMRICD provided analytical performance assessment of two successive prototypes of the ChemDx test system. These studies included evaluating the accuracy, linearity, precision, and limits of detection/quantitation, and identifying potential interfering substances. At the end of 2021, the ChemDx effort received the landmark approval of Milestone B after reaching Technology Readiness Level 6.
Adapting the technology to other chemical threats
Research at USAMRICD continues to expand the types of tests the ChemDx can perform to achieve a full platform diagnostic system. Current studies are testing the feasibility of adapting the device to indicate exposure to a synthetic opioid by detecting an opioid metabolite in biological specimens. The project is exploring materials than can provide the sensitivity, specificity, and stability needed for a robust opioid sensor. Future work will continue to optimize the developed sensor, evaluate the sensor’s analytical performance and further integrate it into the ChemDx platform.
Identifying Cutaneous Exposures
Still in the early stages of development at the USAMRICD but showing great potential is a reactive spray-on-film disclosure device that indicates the exact sites of chemical agent contamination on intact skin. The device is comprised of two components that when sprayed, near simultaneously, on the skin polymerize into a gel, or film; contact with the chemical agent on the skin activates color-changing properties of the film, thereby indicating exposure and guiding site specific decontamination. This medical exposure skin spray is envisioned as working in tandem with the ChemDx Test System as a second tier in an integrated layered defense.
The project is a collaboration across several laboratories within the USAMRICD. The research has surpassed proof of concept for nerve agents. The alpha prototype formulation developed for nerve agents can provide color indication of exposure in less than 20 seconds. Additional proof-of-concept studies have demonstrated successful detection of both sulfur mustard and a synthetic opioid (fentanyl) via separate reagent systems. Continuing research on the project will further optimize the formulation and evaluate its utility in an in vivo model. Additionally, the project is evaluating the ability of the polymerized film to trap some of the chemical agent so that it could then be sent to a laboratory for agent identification. The goals of medical countermeasures for chemical agent exposure are warfighter survival and return to duty. Achieving these goals often depends on the prompt administration of these countermeasures, preferably prior to the appearance of symptoms. The USAMRICD is developing diagnostic devices and methods, therefore, to confirm chemical agent exposure as soon as possible and by means amenable to the battlefield environment. With the hand-held, easy-to-use ChemDx Test System, the warfighter can confirm exposure by assessing the level of acetylcholinesterase inhibition in his blood through a simple finger stick. The reactive skin disclosure spray will allow the warfighter to determine the exact location of a dermal exposure and begin stringent site decontamination. Respectively, each diagnostic will facilitate rapid triage and decontamination and trigger, if warranted, the use of medical countermeasures or warfighter fitness to return to duty.
Authors: Bio
COL Robin R. Neumeier is the current commander at the Medical Research Institute of Chemical Defense on Aberdeen Providing Ground, Maryland. Throughout her career, COL Neumeier has served in various medical and operational leadership positions both CONUS and OCONUS. She is a native of Texas and entered the Army as a Nurse Corps Officer commissioned through ROTC at Stephen F. Austin State University, Texas. She received her Bachelor’s in Science degree in Nursing at Stephen F. Austin State University, attended Medical University of South Carolina where she received a Master’s in Nursing; Midwifery in 2001. In 2017, she graduated from Old Dominion University in Virginia with a Doctor of Nursing Practice (DNP) in Executive Leadership. She completed a fellowship with the United States Army War College at the Department of Veterans Affairs in Washington DC.
Dr. James F. Dillman III is currently the Director of Research at the United States Army Medical Research Institute of Chemical Defense. He serves as the Senior Civilian Scientist and oversees a program focused on the research and development of medical countermeasures against chemical and bio- chemical threats to protect Warfighters as well as Civilians. He serves as the Command advisor for scientific and research matters related to medical chemical defense. He served previously as the Chief of the Science Program Analysis and Integration Office and was a Principal Investigator in the Cell and Molecular Biology Branch at the United States Army Medical Research Institute of Chemical Defense. As a Principal Investigator, Dr. Dillman oversaw a research group focused on the development of medical countermeasures to chemical warfare agents. His research group utilized transcriptomics, proteomics and molecular approaches to define the molecular and cellular consequences of chemical warfare agent exposure with the goal of identifying therapeutic targets for development of toxicant medical countermeasures. Dr. Dillman received a B.S. with honors in biology from Lebanon Valley College of Pennsylvania, and his Ph.D. from the Department of Cell Biology at the University of Virginia. He was awarded post-doctoral fellowships from the National Stroke Association and the National Institutes of Health during his time as a research fellow in the Departments of Neurology and Neuroscience at the Johns Hopkins University School of Medicine. He joined the United States Army Medical Research Institute of Chemical Defense as a National Research Council Research Associate and subsequently came on staff as a principal investigator in the Applied Pharmacology Branch at the United States Army Medical Research Institute of Chemical Defense.
