Scientists trying to make pharmaceuticals that combat multi-organ diseases such as cancer or COVID-19 may have another tool at their disposal, thanks to the University of Central Florida.
UCF Professor James Hickman has been one of the leaders in the development of the Human-on-a-Chip systems for many years. The Human-on-a-Chip systems model how human organs or a series of organs function in the body. The system holds the promise of accelerating medical research and drug testing, potentially delivering life-saving breakthroughs much more quickly than the typical 10-year trajectory most drugs take to get to market.
Hickman, Roche Pharmaceuticals and Hesperos Inc. -the company Hickman cofounded to take the technology to market – conducted a study to see if the Human-on-a-Chip platform could successfully mimic the body’s response to diseases that overwhelm the immune system and attack multiple organs.
The results of the study, which was supported with a National Institutes of Health grant, were published today in the peer-reviewed journal Advance Science.
“It’s very promising,” says Hickman, who also serves as chief scientist at Hesperos. “It’s a major step in our efforts to safely speed up pharmaceuticals development to help patients.”
Diseases that overwhelm the immune system and attack multiple organs present a special challenge to drug makers. The immune system plays an important role in coordinating with other organ systems to combat infection, eliminate damaged cells and repair tissue.
However, modeling immune response following drug treatment in preclinical studies is challenging because of poor predictability, especially for the innate portion of the immune system. As the scientific community begins to turn more towards using multi-organ, human-on-a-chip systems as a cost-effective way to increase efficiency and lower toxicity, many of these models lack a systemic immune component.
In the journal article, the team described an in vitro, pumpless, three-organ system containing functional human cardiomyocytes (healing cells), skeletal muscle and hepatocytes in a serum-free medium, along with recirculating human monocyte THP-1 immune cells. Monocytes are vital immune system cells involved in wound healing, pathogen clearance and activation of the innate immune response, but are also responsible for the cytokine storm -an immune reaction in which the body releases too many cytokines into the blood too quickly – found in conditions such as sepsis.
“One application where the immune-system-on-a-chip can be immediately useful is for uncovering how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects multi-organ systems by activating the cytokine storm from inflammatory macrophages and to support the rapid development of therapeutics. As the global pandemic of COVID-19 continues to grow, this system has the potential to quickly evaluate antiviral and repurposed drugs to help combat this devastating disease,” says Michael L. Shuler, Ph.D., chief executive officer of Hesperos.
In the study, the researchers evaluated two different innate immune responses: targeted immune response following tissue-specific damage, which simulates indirect activation of THP-1 cells, and pro-inflammatory immune response following direct activation of immune cells, mimicking acute inflammation and the cytokine storm.
In the targeted immune response experiments, the cardiotoxic compound amiodarone was used to selectively damage cardiac cells to evaluate how THP-1 immune cells affect the three-organ system. The presence of both amiodarone and THP-1 immune cells led to a more pronounced reduction in cardiac force, conduction velocity and beat frequency compared to amiodarone alone. THP-1 cells were also found to infiltrate the damaged cardiomyocytes and induce significant increases in cytokine IL-6 expression, indicating an M2 macrophage phenotype. No immune-activated damage was reported in the skeletal muscle or liver cells.
“The most striking features of our immune-system-on-a-chip is that it emulates different immune reactions for direct tissue-damage and acute inflammation, as well as distinguishes between M1 vs. M2 macrophage phenotypes,” says Hickman.
The study was initially funded by Roche Pharmaceuticals and completed under an NIH grant from National Center for Advancing Translational Sciences’ Small Business Innovation Research program, which supports studies to advance tissue chip technology toward commercialization.
“Tissue chips are a promising technology for accelerating the preclinical timeline and getting treatments to patients more efficiently,” said Danilo A. Tagle, associate director for special initiatives at NCATS. “Finding improved ways to study immune responses has tremendous implications for drug discovery and the development of more effective personalized medicines in diseases that affect multiple organ systems.”
Teams around the world are researching this chip technology because it could reduce costs, avoid animal testing and hold promise for advancing the field of personalized medicine.
Hickman has multiple degrees from MIT and Pennsylvania State University. He has published over 100 peer reviewed papers, has been awarded 28 patents and has joint appointments at UCF in chemistry, engineering and biomedical sciences. He runs the Hybrid Systems Lab at UCF, which studies the interface between biological and non-biological systems to construct next-generation systems for toxicology, drug discovery and basic biology research.
