Nature Medicine | Spoonful of Medicine

Chip promises better diagnosis for common blood disorder

For more than fifty years, blood smear tests for sickle cell disease have been the standard diagnostic tool for physicians. But the tests, which show whether the patient’s red blood cells have an abnormal form of the iron-carrying protein hemoglobin that will cause them to take on a crescent shape in response to low oxygen levels in the blood, fails to predict the severity of symptoms. It is a large diagnostic loophole, considering that the symptoms of sickle cell disease, which affects more than 13 million people worldwide, can range from tiredness to life-threatening blood vessel clogs. A new microfluidic chip promises to change that by providing a way to measure the risk of dangerous vascular clogging before it happens.

The microfluidic chip, described today in Science Translational Medicine and pictured here, measures the flow of blood through a silicon capillary measuring just 15 micrometers across. When red blood cells from someone with sickle cell anemia pass through the tiny tube, their signature crescent moon shape makes them stick to each other, which clogs the tube and slows blood flow. By measuring how quickly a person’s blood sample slows down in the tube in response to lowered oxygen levels, the device can predict how severe vascular symptoms will be in that individual. A test of blood samples from 29 patients with sickle cell disease using the chip showed that the more severe a person’s symptoms—as measured by the medical interventions he required over the course of a year—the more his blood slowed down in response to decreased oxygen levels in the chip. In other words, sluggish blood was correlated to more doctor visits.

“We don’t know all the different triggers for clogging—it could be exercise, dehydration, non-physical stress,” says study author Lakshminarayanan Mahadevan, an applied mathematician at Harvard University in Cambridge, Massachusetts who co-developed the technology with colleagues at the Massachusetts Institute of Technology, also in Cambridge. “With so many potential triggers, we realized we needed an integrative marker like blood flow rate that predicts how low oxygen levels caused by any number of triggers will affect the patient.”

The device is not the first to use microfluidics to study sickle cell disease. In 2010, a French team showed that the technology could be applied to rapidly deplete blood samples of oxygen to study what causes diseased red blood cells take on the characteristic sickle shape. And just this January, a team led by hematologist Wilbur Lam from Emory University School of Medicine in Atlanta unveiled a similar microfluidic device that tests how effectively treatments for blood diseases such as sickle cell address microvascular clogging.

Lam’s device looks much like the one developed by Mahadevan and his colleagues, with tiny undulating tubes printed onto a glass microscope slide. But the tubes on Lam’s chip are lined with the same endothelial cells that make up the walls of blood vessels, which means the system can be used to study diseased blood cells in an environment similar to that of the body. “Our system is a good model of small blood vessels,” Lam says.

Photo courtesy of John Higgins, Massachusetts General Hospital

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