While researchers have made incredible improvements in treating sickle cell disease over the last 50 years, there are still major questions about how the deadly condition affects the body. Some of those answers, however, may come from an unexpected field: fluid dynamics.
Michael Graham
In the May 4, 2020, edition of the journal Physical Review Fluids, Michael Graham, a professor of chemical and biological engineering at the University of Wisconsin-Madison, and graduate student Xiao Zhang investigate the disease through an engineering lens, shedding some light on one of its lingering mysteries.
Sickle cell disease is a disorder of red blood cells that affects 70,000 to 80,000 Americans per year, primarily African Americans and Hispanic Americans. In the disorder, as the cells age, they stiffen and take on a moon-like, or sickle shape—and that leads to all sorts of complications, including anemia, since the cells break down more quickly and reduce oxygen-carrying capacity. The cells can also get stuck in small blood vessels, leading to organ damage. And there’s also inflammation of the endothelial cells that line the blood vessels for reasons that are not yet clear.
The disease is often painful, and the long-term outlook is not good. In the 1970s, the average lifespan for a person with sickle cell was 14 years. Today, with advancing treatments, people often live into their 40s. But there is still more progress to be made.
Over the last decade, Graham’s research group has developed mathematical models to understand how different types of cells circulate in the bloodstream. What the researchers have found is that stiffer cells, like white blood cells and platelets, tend to be driven toward the walls of blood vessels by collisions with red blood cells.
Building on that knowledge, Graham and collaborator Wilbur Lam, a biomedical engineer at Emory University and Georgia Institute of Technology, hypothesized that this process, called “margination,” is also at play in sickle cell disease. In experimental observations, Lam’s research group found that there’s evidence of damage to the cells lining blood vessels in the disease, possibly caused by the stiff, scythe-like cells congregating near the walls.
To confirm this hypothesis, Graham and Zhang examined the ways sickle cells behave in an idealized mathematical model of how the cells deform and collide with one another during blood flow. The simulations indicated that the stiff sickle cells congregate near the endothelial cells lining the vessel walls and undergo a rolling orbit. It’s believed the shear stress created by this affects the nearby cells, which activate inflammatory signals.
“Sickle cells are stiffer than healthy cells and as they move through the bloodstream, they get pushed by the softer, more normal cells toward the walls and that causes damage,” Graham says. “We can actually look in the mathematical model how these disease cells generate stresses that might damage the blood vessel walls.”
While the models are more streamlined than the incredibly complex network of arteries and veins in a human circulatory system, Graham says they are still sophisticated enough to reveal how margination of the sickle cells may cause damage. “We’re trying to keep things simple enough that you can actually make progress in addressing some hypothesis,” he says.
His hope is that the finding will eventually help researchers understand and find new treatment methods for the disease.
“There’s still lots of work to be done, but it’s kind of an exciting direction for sure, and something that hadn’t been addressed previously,” Graham says. “One cool thing about it is that it’s the kind of thing that really comes about from the interaction of someone who knows about fluid mechanics and someone who knows about medicine. I think that was a very interesting aspect of this.”
Graham is a Vilas Distinguished Achievement Professor and Harvey D. Spangler Professor in chemical and biological engineering at UW-Madison.
Xiao Zhang, also of UW-Madison, is first author and performed much of the research described in the paper. Other authors include Christina Caruso of Emory University and Wilbur Lam of Emory University and the Georgia Institute of Technology.