Source: Harvard University
Summary: Researchers have discovered Organ-on-a-Chip technology to model coagulation within a human blood vessel in vitro, which opens a door to new anti-inflammatory drug candidates.
Inflammatory responses to injury or disease are very important for recruiting the immune system to help the body heal. Inflammation is one of the most key and fraught processes in the human body but It also can increase thrombin production, which can lead to dangerous blood clots and other conditions. A naturally occurring anti-coagulant and anti-inflammatory protein, Activated protein C (APC) has been used medically to treat severe blood infections and wounds; however, its use is limited because it inhibits thrombin and impacts the ability of the blood to clot which increases bleeding risk. A collaborative team of researchers from the Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center (BIDMC) and the Wyss Institute at Harvard University have discovered synthetic APC-mimicking small molecules called “parmodulins” without interfering with blood clotting, making them attractive new drug candidates. This work was enabled by leveraging the Organ-on-a-Chip technology to model coagulation within a human blood vessel in vitro. The study findings were published in the journal Proceedings of the National Academy of Sciences.
The blood-vessel-on-a-chip consists of microfluidic channels embedded in a clear polymer chip, coated with collagen, and lined by human endothelial cells. Whole blood was perfused through the chip to simulate the flow conditions within human blood vessels, to which were added different pro- and anti-inflammatory compounds to evaluate the response of the endothelium. To evaluate the activity of parmodulins on endothelium, human endothelial cells were incubated with parmodulin-2 in vitro for 4 hours and then exposed them to the thrombin-inducing inflammatory agents lipopolysaccharide (LPS) or tumor necrosis factor– (TNF-). The results indicated that parmodulin exposure blocks the thrombotic response of endothelium to inflammatory stimuli without affecting blood coagulation in humans – a significant improvement over APC.
Prof. Rob Flaumenhaft said, “The discovery of an anti-inflammatory molecule that prevents endothelial thrombosis but also preserves normal blood coagulation is a major step toward an alternative and better approach to treating inflammatory disease.”
Study co-author Dr. Donald Ingber said, “This work provides another example of how organ-on-a-chip technology can enable faster and safer development and evaluation of drugs that could help patients around the world.”
More Information: Karen De Ceunynck et al, “PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury,” PNAS (2018). www.pnas.org/cgi/doi/10.1073/pnas.1718600115