Sickle cell trait is an adaptation that arose in order to offer natural protection against malaria. Unfortunately, 300,000 babies are born each year with a deleterious form of this mutation, known as sickle cell disease (SCD). This causes the hemoglobin in red blood cells to form strands when it delivers oxygen, which cause the cells to take on a rigid sickle shape. The misshapen red blood cells are more likely to stick inside blood vessels, resulting in blockage. A new modeling device will allow researchers to better predict the behavior of sickle cells, which could lead to new treatment methods. Ming Dao of MIT was one of the principal researchers for the paper, which was published in the Proceedings of the National Academy of Sciences.
A common complication of SCD is vaso-occlusive crisis. The condition occurs when sickle-shaped cells get caught in capillaries, choking off oxygen supply to tissues. This can be very painful, but can also have life-threatening consequences. Predicting when or how severe a vaso-occlusive crisis will occur has been very difficult.
“You don’t know exactly when it’s going to happen or how to reliably predict it is coming,” Ming Dao said in a press release.
In an effort to combat this, Dao’s team developed a microfluidic device that mimics the narrow openings of blood vessels and allows the observation of cells as they undergo gas exchange. The device allows for environmental conditions to be altered in order to see what factors contribute to blood cells sticking, and how long it takes before serious consequences occur.
The researchers took blood samples from 25 individuals with SCD, with a range in severity. As the blood samples passed through the device, the team analyzed the relationship between sickling and deoxygenation, how likely the cells were to get stuck, and how quickly the cells normalized after becoming oxygenated again.
Hydroxyurea is the most effective medication to help prevent these blockage events, but 33% of patients are not responsive to it. Introducing the drug to the device revealed that it is most effective on cells with higher densities. These cells contain more hemoglobin, and are more likely to become stuck following a conformational change. The device was also used to test a drug currently in Phase II clinical trials, known as Aes-103. It appears that the drug did help prevent blood cells from becoming stuck in the device.
As the device is refined, the researchers are very optimistic that it could be an integral part in developing and testing the efficacy of drugs in the future. Additionally, it is hoped that it will be useful in diagnosing the severity of disease, allowing for more targeted treatment.
“This technique represents a major advance to further our understanding and treatment of vaso-occlusion due to sickle cell disease,” commented Guruswami Ravichandran of CalTech, who was not involved with the research. “The microfluidic device and technique could also be potentially beneficial in studying and treating other diseases where the deformability of blood cells is affected.”
1