A breakthrough study led by researchers at the University of Minnesota could explain why patients with the same genetic sickle cell mutation experience different levels of pain, organ damage and response to treatment.
Sickle cell disease is an inherited lifelong disorder that affects millions worldwide, causing red blood cells - which are normally flexible and doughnut-shaped - to become stiff and crescent-shaped in low-oxygen environments. This leads to blockages, excruciating pain and reduced life expectancy. Traditionally, blood has been tested using "bulk" measurements that average out the properties of all cells, often missing the subtle but critical differences between individual cells.
The study, published in Science Advances, used advanced microfluidic "chips" that mimic human blood vessels to see how blood flow is disrupted by different types of stiff blood cells. They found:
- The severity of sickle cell disease is not best predicted by the average "thickness" of a patient's blood, but by the specific behavior of a small population of highly stiff red blood cells. These cells reorganize themselves within the flow, pushing their way to the edges of blood vessels. This creates significantly more friction and resistance than flexible cells.
- Blood flow is disrupted in two key ways:
- Margination: Even a small number of stiff cells can move to the vessel walls, drastically increasing wall friction.
- Localized Jamming: At higher concentrations, stiff cells can cause the blood to "jam" in specific areas, creating a sudden and dramatic increase in flow resistance.
- Stiff cells begin to appear at oxygen levels as high as 12% - levels typically found in the lungs and brain. This suggests that the physical processes leading to vessel blockages can start much earlier in the oxygen-depletion process than previously thought.
"Our work bridges the gap between how single cells behave and how the entire blood supply flows," said David Wood, a professor in the College of Science and Engineering and senior author of the study. "By using an engineering approach to measure both individual cell properties and whole blood dynamics, we found that patients with very different clinical profiles all follow the same underlying physical relationship governed by the fraction of stiff cells."
Stiff cells organize within the flow, creating low (left) concentration regions and high (right) concentration regions, which drastically increases flow resistance. Credit: Hannah Szafraniec.
"I am really excited we were able to provide greater insight into the physical mechanisms driving the disease," said Hannah Szafraniec, a Ph.D. candidate in the College of Science and Engineering and lead author on the paper. "This could help the field develop more effective, personalized therapies and new testing that can give early warning for symptoms of sickle cell disease."
The research could also be applied to other blood-related disorders, including malaria, diabetes and certain cancers.
In addition to Wood and Szafraniec, the study was done in collaboration with University College of London, University of Edinburgh, Harvard University, Massachusetts General Hospital and Princeton University.
The research was funded by the National Heart, Lung, and Blood Institute, which is part of the U.S. National Institutes of Health.
About the College of Science and Engineering
The University of Minnesota College of Science and Engineering brings together the University's programs in engineering, physical sciences, mathematics and computer science into one college. The college is ranked among the top academic programs in the country and includes 12 academic departments offering a wide range of degree programs at the baccalaureate, master's, and doctoral levels. Learn more at cse.umn.edu.
