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Wednesday, November 29, 2023

This Sticker Absorbs Sweat—and Might Diagnose Cystic Fibrosis

In the Middle Ages, a grim adage sometimes turned up in European folklore and children’s stories: Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die. A salty-headed newborn was a frightful sign of a mysterious illness. The witchcraft diagnosis didn’t hold, of course, but today researchers think that the salty taste warned of the genetic disease we now know as cystic fibrosis.

Cystic fibrosis affects over 30,000 people in the United States, and over 70,000 globally. Mutations in the CFTR gene garble cells’ blueprints for making protein tunnels for chloride ions. Chloride’s negative charge attracts water, so without much chloride meandering into cells, the body’s mucus gets thicker and stickier, making breathing a struggle and often trapping dangerous bacteria in the lungs. It also disrupts digestive enzymes from traveling out of the pancreas and into the gut, causing inflammation and malnutrition.

Salty sweat is a telltale sign. Doctors sometimes meet kids with 10 times higher chloride levels in their sweat than expected. Since the 1960s, measuring chloride has given doctors their clearest diagnoses: They stimulate people’s sweat glands, soak up as much as they can, and send the samples to labs. But the tools are expensive, bulky, and hard to fit onto squirming infants. Sometimes the tests don’t collect enough fluid for a diagnosis. And if a test fails, parents and their newborn often have to wait a couple of weeks to come back.

“That failure to collect enough sweat just delays time to diagnosis,” says Tyler Ray, a mechanical engineer with the University of Hawaii at Mānoa who develops wearable biosensors. That means losing precious weeks when doctors could have prescribed treatments. It also creates a barrier for folks who need to drive for hours—or fly over oceans—to reach a hospital that can run the test. “There are not many throughout the country,” says Ray. “In fact, Hawaii does not have one for the general population.”

Ray's team of engineers and pathologists think they have an alternative: stick-on sweat collectors. In a study published last week in Science Translational Medicine, they report creating a malleable, coin-sized sticker that changes color as it absorbs progressively higher salt concentrations indicative of cystic fibrosis. When tested on babies and adults, the stickers filled with more sweat than traditional devices, and did so faster.

“This is exciting technology and something very new,” says Edward Fong, a pediatric pulmonologist with Hawaii Pacific Health who was not involved in the study. Fong thinks these stickers would make cystic fibrosis diagnosis more accessible. If it lands regulatory approval, he says, “we do not need to send our patients 2,500 miles away to be able to get their sweat tested.”

“Making sweat tests easier would be the one obvious win,” agrees Gordon Dexter, a 36-year-old from Maryland who lives with the condition. Dexter is a moderator for the Reddit community r/CysticFibrosis, where people sympathize about digestive hardships and celebrate triumphs over lung bacteria. “Sweat tests can be kind of ambiguous or just difficult to do, and that is a recurring question that I've seen,” Dexter says.

Ray has had an eye on sweat for years. In 2016, as a postdoctoral fellow, he joined John Rogers' lab at Northwestern University, where researchers had been toying with conducting sweat analysis on wearable sensors. They wanted to create new devices with tiny channels, valves, and dyes that could track body chemistry in real time. Soon after Ray arrived, the lab published a paper demonstrating a wearable sensor that could reveal glucose, lactate, and chloride ion levels in sweat, as well as its pH. That study pitched the sensors as monitors for athletes or military members in training, and the researchers tested it during a long-distance bike race. The tech got a lot of attention: Ray later worked with sports teams like the Chicago Cubs, and Gatorade has used the technology to sell its Gx Sweat Patch. In 2017, the patches were displayed at New York’s Museum of Modern Art and were used to promote hydration at the South by Southwest festival.

Pathologists also noticed. “Right when that paper came out, we were contacted by Lurie Children's Hospital,” says Ray. A researcher at the Chicago institution believed this type of sensor could collect enough sweat to give conclusive diagnoses. Ray’s team agreed that a wearable could probably collect more sweat faster. And to avoid the geographic barriers that come with needing a lab, they could embed most of the lab analysis steps right on the patch.

Their resulting stickers are circular and about one inch across. They can lie flat, hug the wide curve of an adult arm, or conform to small infant’s limbs. (They also look like stickers. Ray’s team placed popular cartoon decals on top, hoping to make them even more kid-friendly.) Sweat soaks up through the center and into thin canals that zigzag out to the sticker’s edge.

To run the test, a clinician uses a weak electric current to drive a sweat-gland-activating gel called pilocarpine into the patient’s skin. This is the standard starting point for sweat tests, but what happens next is different. Five minutes later, the sticker goes on, and the patient’s sweat slips into its tiny capillaries for up to 30 minutes. It immediately mixes with a clear, gel-like pool of silver chlorinalite, a chemical that changes color when it bumps into chloride ions. If the sweat doesn’t contain these ions, the streams stay clear. But progressively higher ion concentrations quickly turn it a pale pink and then a dark violet. Clinicians then snap a picture of the color change, run the photo through an analysis app, and gauge the chloride levels.

Ray’s team wrote algorithms to process images, read up on color theory, and experimented with different overlay hues and reference colors for the sticker. In the end, they found that a green overlay made subtle changes in color more visible: a smartphone could now capture differences down to about one millimolar—roughly the chloride concentration from one teaspoon of table salt dissolved in 100 liters of water—which is potentially accurate enough to make a diagnosis.

In their study, the team tested the device on 51 people, ranging from 2 months to 51 years old. Their main focus was confirming that a flexible sticker would be better than other devices at slurping up sweat, so they compared their sensor to one commonly used in clinics today. On average, the sticker collected 33 percent more sweat, and the team reported no cases of insufficient collection. For one participant, the sticker banked nearly twice as much sweat in 18 minutes as the approved device did in 30.

Ray envisions the sweat sticker as an option for at-home testing and even daily chloride monitoring for people who already have a diagnosis and want to adjust their behavior to keep their levels down, the way that people with diabetes can use wearables to check their glucose. Daily monitoring could help people who want to understand their own response to drugs, exercise, or nutrition through their sweat chloride. (While the study used pilocarpine to make people sweat more, Ray notes that a warm bath could do the same thing naturally.)

No at-home chloride monitors exist today, but Fong wonders if they could be used to detect rising chloride levels, which might be an indicator of worsening symptoms that need medical intervention. He notes, however, that more research is needed to prove whether there is a connection between real-time chloride measures and symptom prediction.

Dexter isn't sold on the utility of at-home monitoring just yet but says that the idea is promising. “I think people haven't even really thought about what they’d do if they had a 24-7 sweat tests,” he says.

But before that can happen, the stickers would need to be approved by the Food and Drug Administration. Ray’s team at Hawaii and Rogers’ at Northwestern are first pursuing approval for use as a one-time diagnostic. They hope to recruit participants for a much larger clinical trial—maybe more than 1,000 people, including newborns—to further test the sensors’ accuracy and consistency.

Still, growing research interest in wearable health sensors has Ray feeling optimistic. L’Oréal debuted a UV exposure tracker in 2018, Rogers reported a clinical trial of wireless neonatal intensive care monitoring last year, and some labs are developing skin bioelectronics to track Covid-19 symptoms. "The idea of just being able to sense what's going on in yourself, simply by looking down at your smartphone or a sensor—it's just amazing,” he says.

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