Researchers have designed a wearable, ring-like biosensor for monitoring the hormone oestradiol in human sweat. The technology is a fast-acting, non-invasive advance over conventional methods for tracking fertility and women’s health.

The single-use sensor, described in a study published on 28 September in Nature Nanotechnology, combines microfluidics and emerging electrode technology with a group of molecules called aptamers to measure hormone levels in real time, feeding into a growing demand for technology that puts personalized health care into the hands of patients¹.

“The paper does a beautiful job, and the fact that they can monitor this hormone non-invasively from sweat is exciting,” says Madhu Bhaskaran, an engineer who develops sensors and wearable technologies for health care at RMIT University in Melbourne, Australia. “You’re trying to make a diagnostic which has a long shelf life but is still sensitive enough and can be used in the home, which is a real challenge.”

Previously, people who needed their hormone levels monitored had to travel to clinics for blood tests or send samples collected at home to a laboratory. But those options tend to be invasive and time-consuming, and although some at-home tests use urine, their results are less precise. Blood remains the gold standard, but researchers are increasingly interested in other fluids and the health information they contain.

“We know, for example, that there are clinically relevant biomarkers present in our sweat, but at extremely low concentrations,” says Wei Gao, a biomedical engineer at the California Institute of Technology in Pasadena and a co-author of the study. So far, no sensors or wearable devices have been developed that specifically target reproductive hormones in sweat. Oestradiol, the focus of the current work, has key roles in fertility and women’s health, areas of research that remain significantly underfunded, despite a “strong demand for technologies that give people more information about their menstrual and fertility status”, he says.

Chemical antibodies

Whereas most biosensors use antibodies or enzymes to target proteins, Gao’s relies on aptamers — short bits of single-stranded DNA or RNA that are designed to fold such that they bind to targets ranging from small molecules to toxins. Although sometimes referred to as chemical antibodies, aptamers are much smaller than most antibodies and can be synthesized chemically, rather than in laboratory animals. Researchers have previously designed aptamers to recognize cortisol², serotonin³, caffeine⁴ and even some types of cancer⁵.

To make the oestradiol sensor, the researchers designed two layers of material to work in tandem — an interface seeded with oestradiol-recognizing aptamers, and a gold-nanoparticle electrode covered in a material called MXene, which further enhances weak electrical signals. The aptamers are preloaded with single-stranded DNA that has been tagged with methylene blue, a dye that in this cases serves as an electrochemical probe.

When placed on a finger, the biosensor generates a small current to jump-start sweat production, then draws the liquid into a tiny reservoir. As sweat fills the chamber, the aptamers exchange the methylene blue-tagged DNA strands for oestradiol. Those DNA strands are then free to travel between the layers and bind to complementary strands on the electrode, where the methylene blue levels are translated into a final measurement. In experiments using artificial sweat, the sensor could detect oestradiol in just 10 minutes, at concentrations as low as 140 nanomolar — near the lower limit of what is typically found in human sweat.

The ring also incorporates sensors that track skin temperature, pH and the sweat’s salt concentration so that it can calibrate the hormone measurements in real time and display them on a mobile phone.

Strong correlation

Gao and his colleagues tested the sensor’s performance on synthetic sweat, before giving it to five women to track their menstrual cycles. Two of the women had blood tests done concurrently to compare with the sweat results. The two sample types rose and fell in tandem, the researchers found, and both matched the expected pattern — oestradiol typically increases at the beginning of a cycle and peaks just before ovulation. A smaller, secondary spike occurs after an egg has been released.

“The correlation they found between blood serum and sweat is really promising,” Bhaskaran says. She adds, however, that the sample size was small, so making sure that the technology “holds up under different conditions in the human body is really essential”.

Although the team developed the ring to track menstrual cycles, oestradiol is also involved in modulating libido, erectile function and spermatogenesis, and Gao says that the sensor could be useful for people undergoing hormone therapy, too.

Aptamers could conceivably be engineered to target almost anything, and Gao aims to develop sensors capable of continuously tracking several hormones at once — including follicle-stimulating hormone, luteinizing hormone, gonadotropin-releasing hormone and progesterone. He is now working to commercialize a suite of sweat-based biosensors.

But although aptamer design has made strides, it hasn’t yet achieved the same mastery as nature, says Kevin Plaxco, a biological engineer at the University of California, Santa Barbara. DNA and RNA are negatively charged, so researchers struggle to bind them to targets that also have strong negative changes, such as fluoride ions. Yet fluoride-binding aptamers have been identified in bacteria and archaea, as part of gene-control structures called riboswitches.

Fluoride “has to be the hardest thing to make an aptamer against, yet there’s a riboswitch that binds fluoride with excellent specificity and affinity”, Plaxco says. “The fact that it exists tells me that when we get sophisticated enough, it’ll be possible to make incredible aptamers.”

*Original full-text article online at: https://www.nature.com/articles/d41586-023-03812-x

Print PDF