Human exposure to chemicals like ammonia and chlorine can be extremely dangerous, especially when they are in a gaseous form. Port and factory workers are at the greatest risk because of the possibility of incidents happening at their workplace. The threat quickly expands to individuals who protect the homeland such as DHS components, first responders, and others, because it is they who answer the call to an accidental release or planned attack. They run towards the danger, knowing that if they are not able to secure containment immediately, the threat to the general public could be catastrophic.
That’s why S&T is so committed to understanding the risks posed by these chemical agents and it is working to mitigate the effects of exposure to them.
S&T’s mission is to protect the American people, and CSAC’s Chemical Hazard Characterization (CHC) team, in partnership with Probabilistic Analysis for National Threats Hazards and Risks (PANTHR) program’s Chemical Threat Characterization project (CTC) is at the leading edge of that effort with their Organ-on-a-Chip (OOAC) research.
“The Organ-on-a-Chip studies that we are conducting with our partners at the Wake Forest Institute are incredibly important,” said CTC Project Manager Theresa Pennington. “With our OOAC program, we are 3D printing lung organ tissue equivalent (OTE) onto a microchip and then exposing that OTE to the toxic vapors. The reason for this approach is that the OTE more accurately represents how real lung tissue inside the human body reacts to the gaseous chemical agents than anything else we can use.”
“With WFIRM’s innovative Organ-on-a-Chip technologies, we can accurately replicate human responses to toxic chemical exposure,” said WFIRM Director Dr. Anthony Atala. “This groundbreaking research is a vital step toward enhancing safety measures and developing life-saving treatments, ultimately advancing our ability to understand and mitigate the impact of hazardous chemical agents on human health.”
Wake Forest’s 3D printer for OTE represents a major leap forward over standard testing. “With Organ-on-a-Chip, we are able to design a lung tissue system using robotic technology,” said S&T CSAC senior research scientist Rabih Jabbour. “We are able to 3D bio-print a lung model that mimics the microenvironment of a real human model. And it is living human tissue. So, in this case, we are directing a robot to do it, so we eliminate the possibility of human operator error. A robot always wins in terms of precision.”
Following all legal and ethical guidelines, the OOAC team receives primary cells from donors. These cells are placed into a solution that is fed into the 3D bioprinter (the robot) which then designs, creates, and prints a microenvironment that very accurately mimics real human lung tissue.
How small is the microenvironment we’re talking about here? “The entire microchip is only 1×2 inches or even smaller,” said Dr Sean Murphy, WFIRM project co-lead:
“Within a permeable membrane lies the new OTE, and just like a real lung, it has tiny tubes inside it where air travels. These tubules are around 60 microns across, or about the thickness of a human hair. Air that contains the toxic chemical vapors is then pumped through those tubes to simulate as if someone was inhaling the fumes. That’s when the toxin interacts with the cells inside the tubes.”
Jabbour pointed out some of the advantages saying: “The Organ-on-a-Chip model offers a controlled and reproducible environment, enabling high throughput testing and a reduction in the need for animal experimentation. The accuracy of the prediction and translation to human physiology is very high as compared to animal models, where their physiological behavior may not translate well to a human physiological behavior under the same environmental exposures for a variety of reasons.”
One of CTC’s central objectives is to build a comprehensive database of chemicals (and their toxic profiles) that pose a threat to the homeland. The database is there to assist authorities in preparation for or response to an accident or attack.
Pennington further explained the reasons why ammonia and chlorine were selected for this particular research endeavor saying, “Ammonia and chlorine have high toxicity and are also two of the most transported chemicals in the US. Whether it is pipeline, rail car, barge—chlorine and ammonia are up there in terms of transportation. That trend does not appear to be abating, as ammonia is being looked at as one of the future chemicals for fuel, especially maritime fuel. Ammonia is also being used in the storage of hydrogen fuel. Since this may mean an additional increase in ammonia use, transportation, and storage, we need to know how to detect the exposures and quantify levels of exposure in victims. Hopefully, this will lead to research on better countermeasures, as well.”
As for chlorine gas, its deadly effects were seen when it was first used as a chemical weapon during World War I, and it is believed to have been used in other conflicts since then. The word “believed” is significant here, because both chlorine (and ammonia) gas disburse quickly in the environment and in the human body. This means that identifying exposure to these specific toxicants/toxic chemicals is difficult. Currently, health professionals would have to determine the chemical toxicant by using a process of elimination that was based upon the victim’s symptoms, versus a specific and 100% verifiable test. It also means that the level of exposure someone experiences can’t really be measured and thus the best ways to potentially treat that exposure are even murkier.
And that is exactly the current capability gap that S&T’s OOAC research is trying to close.
With OOAC, exhaustive testing can be done where the lung OTEs are exposed to specific concentrations of the chemical agents for set amounts of time. Then the unique type of damage signature from these toxins can be studied and understood. The goal is that if a victim presents with symptoms that track for chemical exposure, tests can be done on the victim. By viewing the type of cellular damage signature to the lung cells, medical staff can understand what chemical it was and the level of exposure. “Having this research may be the only way to determine if someone has been exposed to these toxicants and what their short-term and long-term effects might look like. And the hope is that it may also be able to inform the medical staff’s decisions, so the best course of treatment for the patient can be initiated,” said Pennington.
Determining the toxic exposure agent is a potentially life-saving capability that is needed both domestically and internationally for forensics and attribution purposes.
Recently, the teams from S&T and BMI got together at the Wake Forest lab to hold technical meetings about the progress of the OOAC studies. “S&T selected Wake Forest to partner with because of their global leadership and capabilities in this type of OOAC innovation,” said Jabbour, “and their collaborative approach makes working with them even more rewarding.”
Pennington noted that, “When we talked to Wake Forest, there was a surprise. The chlorine results were very interesting. They actually indicated that there might be an additional mechanism at play that hadn’t been previously considered for chlorine. So, that’s one of the things that we would be looking to expand research on and explore further.”
Other discussions centered around topics like the comparison of damage signatures from ammonia and chlorine, how they interact with human lung tissue, and what biomarkers arose for each agent. Pennington stated that, “We don’t have a lot of data on the biomarkers from chlorine and ammonia damage, and we obviously can’t use human test subjects. There are also a lot of issues with animal testing of this type. They’re just not a great test group when you need accuracy, but we can now get in vitro real human cell response data from the testing because they are real human cells.”
OOAC is a breakthrough because by leveraging the OOAC technology, the team can dramatically speed up the testing process, eliminate human error, and bypass imperfect, laborious, and expensive animal testing. Additionally, it can yield significantly more data (including efficiently testing multiple concentrations of toxic exposure levels as well as the time duration of exposures), all while reducing costs between 20-60 percent.
Jabbour added: “We hope that this research in human response to exposure will assist in the future design and creation of effective medical countermeasures to mitigate or even possibly reverse the effects of these and other toxins so we can save lives.”
There are plenty of other dangerous chemical toxins in the threat space that the team also has on their collective radar. Moving forward, they hope to tackle ones like hydrogen sulfide and phosphine that do not have very accurate toxicity values. “Although this particular effort is wrapping up in December,” said Pennington, “we are hoping to identify additional funding so this incredibly important work can continue.”
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