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NIST Scientists Enhance Frequency Comb Breathalyzer Enabling It to Detect Multiple Disease Biomarkers

Device could pave the way for real-time, noninvasive breath analysis to detect and monitor diseases and be a new service medical laboratories can offer

Breathalyzer technology is not new, but until now human breath detection devices have not been comparable to clinical laboratory blood testing for disease detection and monitoring. That may soon change and there are implications for clinical laboratories, partly because breath samples are considered to be non-invasive for patients.

Scientists with JILA, a research center jointly operated by the National Institutes of Standards and Technology (NIST) and the University of Colorado Boulder, recently increased the sensitivity of their laser frequency comb breathalyzer one thousand-fold. This created a device that can detect four disease biomarkers simultaneously, with the potential to identify six more, according to an NIST news release.

Medical laboratory scientists will understand the significance of this development. JILA’s enhanced breathalyzer device could pave the way for real-time, noninvasive breath analysis to detect and monitor diseases, and potentially eliminate the need for many blood-based clinical laboratory tests.

The JILA researchers published their findings in the journal Proceedings of the National Academy of Sciences (PNAS), titled, “Ultrasensitive Multispecies Spectroscopic Breath Analysis for Real-Time Health Monitoring and Diagnostics.”

Measuring Light to Spot Biomarkers of Disease

During their research, physicist Jun Ye, PhD, and David Nesbitt, PhD, both Fellows at JILA and professors at University of Colorado Boulder, detected and monitored four biomarkers in the breath of a volunteer:

These chemicals can be indicators of various health conditions. Methane in the breath, for example, can indicate intestinal problems.

The researchers say the JILA breathalyzer also could detect six additional biomarkers of disease without any further modifications to the device. They would include:

Jun Ye, PhD and David Nesbitt, PhD
 
NIST/JILA Research Fellows Jun Ye, PhD (left), and David Nesbitt, PhD (right) of the University of Colorado Boulder, “built a breathalyzer that identifies biomarkers of disease by measuring the colors and amounts of light absorbed as a laser frequency comb passes through breath samples inside a glass tube,” according to an NIST news release. Should they succeed in creating a portable version, their noninvasive device could become an option compared to conventional clinical laboratory blood testing methods used to identify and monitor diseases. (Photos copyright: University of Colorado Boulder.)
 

“Determining the identity and concentration of the molecules present in breath is a powerful tool to assess the overall health of a person, analogous to blood testing in clinical medicine, but in a faster and less invasive manner,” the researchers wrote in PNAS.

“The presence of a particular molecule (or combination of molecules) can indicate the presence of a certain health condition or infection, facilitating a diagnosis. Monitoring the concentration of the molecules of interest over time can help track the development (or recurrence) of a condition, as well as the effectiveness of the administered treatment,” they added.

How the JILA Breathalyzer Detects Biomarkers

According to a 2008 NIST news release, JILA researchers had developed a prototype comb breathalyzer in that year. However, the research did not continue. But then the COVID-19 pandemic brought the JILA/NIST laboratories focus back to the breathalyzer with hopes that new research could lead to a breath test for detecting the SARS-CoV-2 coronavirus and other conditions.

“We are really quite optimistic and committed to pushing this technology to real medical applications,” Ye said in the 2021 NIST news release.

Analytical Scientist explained that JILA’s new and improved breathalyzer system “fingerprints” chemicals by measuring the amount of light absorbed as a laser frequency comb passes back and forth through breath samples loaded into a mirrored glass tube.

JILA’s original 13-year-old prototype comb analyzed colors and amounts of light in the near-infrared band. However, JILA’s recent improvements include advances in optical coatings and a shift to analyzing mid-infrared band light, allowing detection sensitivity up to parts-per-trillion level, a thousand-fold improvement over the prototype. 

Corresponding study author Jutta Toscano, PhD, postdoctoral researcher at the University of Basel in Switzerland and previously Lindemann fellow at JILA, told Physics World the new frequency comb can “probe the molecular fingerprint region where fundamental, and more intense, spectroscopic transitions are found.

“By matching the frequency of the comb teeth with the cavity modes—the ‘standing modes’ of the cavity—we can increase the interaction path length between molecules inside the cavity and laser light by a factor of around 4000, equivalent to an effective path length of a few kilometers,” she added. “We then probe the light that leaks out of the cavity by sending it into an FTIR [Fourier-transform infrared] spectrometer to find out which exact comb teeth have been absorbed and by how much. In turn, this tells us which molecules are present in the breath sample and their concentration.”

Even Hippocrates Studied Breath

Ye noted in the NIST statement that JILA is the only institution that has published research on comb breathalyzers.

In their PNAS paper, the researchers wrote, “Breath analysis is an exceptionally promising and rapidly developing field of research, which examines the molecular composition of exhaled breath. … Despite its distinctive advantages of being a rapid, noninvasive technique and its long history dating back to Hippocrates, breath analysis has not yet been as widely deployed for routine diagnostics and monitoring as other methods, such as blood-based analysis.

“We have shown that this technique offers unique advantages and opportunities for the detection of light biomarkers in breath,” the researchers noted, “and it is poised to facilitate real-time, noninvasive monitoring of breath for clinical studies, as well as for early detection and long-term monitoring of temporary and permanent health conditions.”

Validation of these findings and further design research to make the system portable are required before JILA’s frequency comb breathalyzer can become a competitor to clinical laboratory blood tests for disease identification and monitoring. Nevertheless, JILA’s research brings breathalyzer technology a step closer to offering real-time, non-invasive analysis of human biomarkers for disease.

Andrea Downing Peck

Related Information:

Ultrasensitive Multispecies Spectroscopic Breath Analysis for Real-Time Health Monitoring and Diagnostics

Ultrasensitive Frequency Comb Breathalyzer Targets Real-Time Disease Diagnosis

JILA’s Comb Breathalyzer Is Now a Thousand-Fold More Sensitive to Disease Biomarkers

Breath Analysis with a (Very) Fine Toothed Comb

Optical ‘Frequency Comb’ Can Detect the Breath of Disease

Proof-of-Concept Study at University of Colorado Boulder Shows Dynamic Tattoos Can Help Detect and Track Health Issues

If tattoos can accurately be used in the diagnostic process, might clinical laboratories soon offer these types of diagnostic tattoos at their patient service centers?

Could color-changing tattoos help diagnose illnesses? Researchers at the ATLAS Institute at the University of Colorado Boulder think so. They are working on prototypes of permanent tattoos that can detect chemical changes in the body and smart tattoo ink that would take the concept of wearable medical devices to a whole new level.

Called “dynamic” or “smart” tattoos, these color-changing tattoos have a biomedical purpose. They alert individuals to potential health issues due to changes in the biochemistry in their body. The technology has already been used in animal studies to detect sodium, glucose, electrolytes, and pH levels. Pathologists and clinical lab manager will recognize the value of a relatively non-invasive way to measure and track changes in these types of biomarkers.

The ATLAS Institute published its findings in ACS Nano, a publication of the American Chemical Society, titled, “Solar Freckles: Long-Term Photochromic Tattoos for Intradermal Ultraviolet Radiometry.”

“We developed a photochromic tattoo that serves as an intradermal ultraviolet (UV) radiometer that provides naked-eye feedback about UV exposure in real time. These small tattoos, or ‘solar freckles’, comprise dermally implanted colorimetric UV sensors in the form of nano encapsulated leuco dyes that become more blue in color with increasing UV irradiance,” the ATLAS scientists wrote.

Studies analyzing the efficacy of dynamic tattoos have provided strong evidence that they can be engineered to change color and sense and convey medical information. This field is called “dynamic tattoos” and in recent years various proof-of-concept studies have demonstrated that tattoos can be used to “pick up changes in sodium, glucose, electrolytes or pH levels in animal models,” Labroots reported.

“We demonstrate the tattoos’ functionality for both quantitative and naked-eye UV sensing in porcine skin ex vivo, as well as in human skin in vivo. Solar freckles offer an alternative and complementary approach to self-monitoring UV exposure for the sake of skin cancer prevention,” the researchers explained in their ACS Nano article.

“Activated solar freckles provide a visual reminder to protect the skin, and their color disappears rapidly upon removal of UV exposure or application of topical sunscreen. The sensors are implanted in a minimally invasive procedure that lasts only a few seconds yet remain functional for months to years,” they added.

“These semipermanent tattoos provide an early proof-of-concept for long-term intradermal sensing nanomaterials that provide users with biomedically relevant information in the form of an observable color change,” the ATLAS researchers concluded.

Nanotechnology Gives Dynamic Tattoos Functionality

“When you think about what a tattoo is, it’s just a bunch of particles that sit in your skin,” Carson Bruns, PhD, Assistant Professor, Laboratory for Emergent Nanomaterials, ATLAS Institute, Mechanical Engineering, told Technology.org. “Our thought is: What if we use nanotechnology to give these particles some function?”

The invisible tattoos Bruns and the ATLAS team created turn blue in the presence of harmful levels of ultraviolet radiation to inform wearers that their skin needs protection and to apply or reapply sunscreen.

Carson Bruns, PhD

“I have always been interested in both art and science. My favorite type of art is tattooing and my favorite type of science is nanotechnology,” Carson Bruns, PhD (above), Assistant Professor, Mechanical Engineering, ATLAS Institute, told Inked. “When I had an opportunity to start a new research program, I thought it would be really fun and interesting to try and put the two together.” Might innovative medical laboratories one day operate “tattoo parlors” in their patient service centers to provide patients with tattoos that monitor key biometrics? (Photo copyright: Inked.)

The tattoo ink used for these tattoos contains a UV-activated dye inside of a plastic nano capsule that is less than a thousandth of a millimeter in size, or several sizes smaller than the width of a human hair. The capsules protect the dyes from wear and tear while allowing them to sense and respond to biochemical changes in the body. These tattoos are implanted into the skin using tattoo machines, much like getting a regular tattoo.

“I call them solar freckles because they’re like invisible freckles that are powered by sunshine,” Bruns told Inked, adding, “Millions of cases of preventable skin cancer are treated every year. I hope that the UV-sensitive tattoo will help us reduce the number of those cases by reminding people when their skin is exposed to unsafe levels of UV light.”

Dynamic Tattoos May Help People Lead Healthier Lives

One downside to these tattoos is that they only last a few months before they begin to degrade, requiring the wearer to get a “booster” tattoo.

The researchers hope that someday similar tattoo technologies will be applied to a wide variety of preventative and diagnostic applications. The goal is to enable people to detect health issues and allow them to lead healthier lives. 

“We want to make tattoos that will allow you to, for example, sense things that you can’t currently sense,” Bruns told Inked. “Sometimes I joke that we want to make tattoos that give you superpowers.”

The ATLAS scientists imagine a future where tattoos can detect things like blood alcohol levels or high/low blood sugar levels or other changes in a person’s biochemistry.

“More generally, I hope that smart tattoos will help people stay healthy and more informed about their body, while also giving people new ways to express themselves creatively,” Bruns said.

Using Dynamic Tattoo to Detect Cancer

In 2018, a team of biologists created a tattoo comprised of engineered skin cells and an implantable sensor which could detect elevated blood calcium levels that are present in many types of cancers. These cancer-detecting tattoos were tested on living mice and would darken to notify researchers of potential problems.

Scientists at the Department of Biosystems Science and Engineering at the Swiss Federal Institute of Technology Zurich (ETHZ), Switzerland, developed a biomedical tattoo that uses bio sensitive ink and changes color based on variations in the body’s interstitial fluid. It recognizes four widespread cancers:

  • breast,
  • colon,
  • lung, and
  • prostate.

“Nowadays, people generally go to the doctor only when the tumor begins to cause problems. Unfortunately, by that point it is often too late,” Martin Fussenegger, PhD, Professor of Biotechnology and Bioengineering at the Department of Biosystems Science and Engineering (D-​BSSE) of the ETH Zurich in Basel as well as at the University of Basel, told Medical News Today.

“For example, if breast cancer is detected early, the chance of recovery is 98%,” he continued. “However, if the tumor is diagnosed too late, only one in four women has a good chance of recovery.”

Fussenegger and his team hope their specialized biomedical tattoo may help detect the presence of cancer cells early and significantly improve patient outcomes. They published the results of their research in the journal Science Translational Medicine, titled, “Synthetic Biology-Based Cellular Biomedical Tattoo for Detection of Hypercalcemia Associated with Cancer.”

Though it appears that dynamic tattoos may be a functional and decorative way to track health, rigorous research and safety testing on human subjects will be required before clinical laboratories can set up diagnostic tattoo parlors in their offices.

Nevertheless, this concept demonstrates how different technologies under development may provide clinical laboratories with innovative and unusual diagnostic tools in the future.

JP Schlingman

Related Information

A Smart Tattoo That Could Save Your Life

‘Smart’ Tattoo Inks That Could Save Your Life

Color-changing Tattoos? One Could Save Your Life

Solar Freckles: Long-Term Photochromic Tattoos for Intradermal Ultraviolet Radiometry

Inked Talks to the Creator of the New “Smart Tattoo” That Can Indicate When You Need to Reapply Sunscreen

‘Chameleon’ Tattoos Change Color, May Help Diagnose Illness

Dynamic Tattoos Promise to Warn Wearers of Health Threats

Epidermal Electronics—A Step Closer to Wearable Diagnostic ‘Labs’

‘Biomedical Tattoo’ Might Catch Cancer Early

Synthetic Biology-based Cellular Biomedical Tattoo for Detection of Hypercalcemia Associated with Cancer

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