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'On Vivo' and 'In Vivo' Wearable Diagnostics Advancing to Clinical Use

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WearableTech

NEW YORK – By transforming disease detection and monitoring from static data points into continuous data streams liberated from a healthcare setting, medical-grade wearable technologies could herald a revolution in diagnostics, according to some industry experts.

Wearables that detect analytes in biosamples — particularly in sweat, interstitial fluid, and exhaled breath — are moving ever closer to clinical use, with successes in adjacent spaces teasing the commercial potential. Wearable devices that sample multiple biophysical biomarkers are also rapidly migrating from the health and wellness arena into the clinical space with potential as diagnostic or patient monitoring tools.

The ways in which continuous, remote, real-time, quantitative detection — as opposed to episodic testing with long delays in results reporting — may change clinical diagnostics are uncertain. But while wearable diagnostics still face validation and regulatory hurdles, ever-increasing consumer acceptance of wearable tech and cost-saving advances in materials are forging pathways for accelerated clinical adoption.

Wearables diagnostics reduce the need for recurring sample collection and testing in centralized labs, as noted in a review of the space published in July in Advanced Science, and instead empower the "wireless and remote practice of personalized medicine," the authors wrote.

One major catalyst for this revolution is the fact that the divide separating consumer and medical wearable devices is "increasingly blurred," Can Dincer, an associate professor of sensors and wearables for healthcare at the Technical University of Munich, and colleagues wrote in a review of wearable diagnostics published in Nature Reviews Materials two years ago.

Now with an updated review in press focusing on clinical uses for wearables, Dincer said in a recent interview that wearable clinical diagnostics are moving closer to commercialization, with a few particularly promising projects and startups emerging in the last few years.

The field is moving so quickly that even the vocabulary to describe it is in flux. Consulting firm Health Advances attempted to tackle the vernacular tumult last year in a white paper, breaking the overall digital health tech field into eight subdomains — including digital diagnostics — based on factors like primary stakeholders and intended claims.

Still, "there's not a universal language," Health Advances Partner Jeff Abraham said. Even though academics and companies are out ahead pioneering these new technologies, overall, "digital is still a little bit fluid — which is the fun part."

The Health Advances team chose the term "digital diagnostics" to encompass validated tools within digital medicine for detecting and characterizing disease or for measuring disease status, response, progression, or recurrence.

James Nichols, medical director of clinical chemistry and point-of-care testing at Vanderbilt University, is among those currently using the term mobile health, or mHealth, to describe the overall clinical wearables space.

Dincer and his colleagues, meanwhile, dubbed digital-only, body-worn sensors as first-generation wearables. In contrast, second-generation wearables involve biochemical and multimodal monitoring of biofluids, including those that do so noninvasively through on-skin patches, contact lenses, baby diapers, and even tattoos, as well as more invasive microneedles and injectable devices.

Wearables that perform on-device analysis of biofluid samples are not considered in vitro diagnostics, since that term, by definition, requires a sample to be placed in a (glass) dish or tube. Hence the term "on vivo diagnostics," signifying devices worn on the body, to sample sweat or exhaled breath condensate (EBC), for example, was suggested in a review five years ago, with "in vivo diagnostics" designating devices that sample body fluids, like interstitial fluid, by penetrating the skin.

But be they in vivo or on vivo, diagnostic wearable technologies need to be scalable, low cost, and demonstrate clinical utility to be widely adopted.

Here, the onslaught of AI in healthcare coupled with newer advanced materials, like graphene sheets and flexible electronics, is quickly overcoming data analysis and cost obstacles.

Even with those catalysts not yet in full force, products like Abbott's continuous glucose monitors (CGMs) — housed within its "biowearables" business — and Gatorade's Gx Sweat Patch may foreshadow the commercial potential of diagnostic wearables.

However, as Vanderbilt's Nichols emphasized, data transfer and interoperability remain critical issues for wearable clinical diagnostics, as continuous measures generate continuous data streams.

Martha O'Neill, VP at Health Advances, concurred. With wearables diagnostics, "we need to figure out how to use the data, what the actual workflows and efficiencies are to get that information to the people that need it so that it can impact patient care and patient outcomes," she said.

Nichols is also chair of the Federation of Clinical Chemistry and Laboratory Medicine's Committee on Mobile Health and Bioengineering in Laboratory Medicine. While a survey by IFCC-C-MHBLM in 2021 revealed that laboratory medicine specialists are enthusiastic and proactively approaching digital innovations and transformation with high expectations for collaboration, earlier this year the committee also published a position statement recommending, among other things, that biosensor-based diagnostics interface to a patient's electronic medical record, Nichols said.

CGMs lead the way

In some ways, continuous glucose monitors are paving the way for other wearable technologies as they have revolutionized diabetes care over the past decade. Gone are the multiple daily finger sticks, replaced by a wearable device that measures glucose just under the surface of the skin in interstitial fluid (ISF).

The market is vast and growing. In the US, there were an estimated 38 million people with diabetes in 2021, according to the US Centers for Disease Control and Prevention. Globally, there were 828 million cases in 2022, the authors of a study published this week in the Lancet estimated, while for the prior year, diabetes led to more than 2 million deaths and nearly $1 trillion in healthcare expenditure, based on figures from the World Health Organization and the International Diabetes Federation.

Abbott is one of four leading CGM manufacturers, along with Dexcom, Medtronic, and Eversense, that use needlebased enzyme electrodes to detect glucose, according to a review in Bioengineering and Translational Medicine. Leveraging, in part, core IP that it acquired with its purchase of TheraSense for $1.2 billion in 2004, Abbott launched its FreeStyle Libre in the US in 2017, and in 2022, the company said it is developing a dual sensor to monitor both glucose and ketones.

Abbott's sales of continuous glucose monitors exceeded $1.6 billion in the third quarter of 2024, and the firm said it expects 2024 annual sales to exceed $6 billion. Meanwhile, the company is on track for $10 billion in cumulative CGM sales by 2028. It also announced its fifth partnership with an insulin dosing pump manufacturer to connect its CGM sensor with automated insulin delivery systems.

There are now 10 million CGM users globally, Abbott Chairman and CEO Robert Ford said on a call with investors to discuss the company's Q3 2024 results, and more than 100 million diabetics in the developed world. "I think this is a market that's got mass market potential to it," he said, "as long as you stay ahead from a technology perspective," as well as from a scale and cost perspective.

Biosensor-based in vivo or on vivo diagnostics generally, and glucose biosensors in particular, tend to come in five flavors, according to a 2023 review of CGMs: tissue-based sensors, enzymatic and non-enzymatic sensors, immunosensors, and nucleic acid sensors.

Modification of the recognition element of CGM biosensors could potentially enable them to detect "diverse analytes like lactate, cholesterol, ketones, and various metabolites," the authors wrote in their study published in Alexandria Engineering Journal, adding that this multifunctionality "opens avenues for wearable devices to expand their scope beyond glucose monitoring, potentially enabling comprehensive health monitoring in real time."

Indeed, Abbott said in 2022 that it plans to add other analytes, like ketones and lactate, to its Libre systems, which use needles to access patient samples.

Meanwhile, ongoing academic and commercial efforts are attempting to adapt wearable glucose and other metabolite monitoring to even more minimally invasive wearables, like microneedle patches.

Sweating the small stuff

John Rogers, a researcher at Northwestern, is interested in completely noninvasive diagnostics, in part because invasive sample types, like blood, urine, and even interstitial fluid, have been well explored, he said in an interview. Among noninvasive sample types, he noted, tears can be physically challenging to monitor, urine is not continuous, and saliva can easily get contaminated.

"So, we decided to focus on sweat," he said.

Sweat happens to be the clinical gold standard sample type to diagnose cystic fibrosis, he said, and is a rich source of biochemical information. Indeed, his research team's sweat sticker for cystic fibrosis diagnosis in infants was recently described in Science Translational Medicine.

"Pretty much anything that's in interstitial fluid and blood plasma will be reflected in sweat," he said, through the process of diffusion.

Reasoning that sweat had been under-explored due to sample collection issues, Rogers' lab developed a "lab-in-a-sticker" device made of soft materials that captures pristine sweat and is powered by the natural pumping action of sweat glands themselves. Initially described in 2016, the team went after colorimetric readouts of hydration and electrolyte concentration as a first application.

"We were contacted by the president of Gatorade like a month after the paper published, and of course, they have a lot of interest in sweat in the context of athletics, so they were interested in working with us to make a product," Rogers said.

The result was the Gx Sweat Patch, which currently retails for $24 for a two-pack.

"It's a great way to get the technology out of the academic setting and begin to think about how we establish a manufacturing line that I think, ultimately, will intersect with medical applications," Rogers said.

The technology is now being commercialized by Epicore Biosystems, in partnership with oil and gas manufacturers, to monitor workers whose jobs require vigorous physical activity or who work in hot environments, as well as for drug testing of athletes in partnership with the US Anti-Doping Agency, Rogers said.

Other than industrial safety and fitness, the technology can be used in clinical research, as there are 800 unique proteins in sweat, according to a study in the Journal of Proteomics, and more than 32,000 endogenous peptides. In this business arm, patches serve as collection devices, and samples are analyzed in the lab to generate discovery data reports on sweat biomarker levels and trends.

Rogers noted that some current one-off sweat measures — like chloride detection in cystic fibrosis or levodopa medication concentration in Parkinson's treatment — can also potentially be adapted to become continuous measures to monitor treatment response.

Clinical use of sweat-based wearables will require extensive validation and trials, he said, but "I don't see any fundamental engineering barrier."

Similar work from a handful of other labs is now creating a critical mass of research, Rogers said, that is driving the field forward. For example, teams at UC San Diego's Center for Wearable Sensors recently described in Nature Electronics a "fingertip-wearable" biosensor that could detect glucose, vitamin C, lactate, and levodopa over extended periods of time.

Research by scientists at the California Institute of Technology, meanwhile, seeded a spinout company called Persperity that is currently commercializing noninvasive continuous monitoring of estradiol, progesterone, and luteinizing hormone. The firm recently emerged from stealth with $1 million in seed funding and a $3 million ARPA-H Spark Award to develop a wearable sweat sensor for chronic pain.

The Persperity technology relies on an aptamer nanobiosensor and target-induced strand displacement, as described in September in Nature Nanotechnology.

Meanwhile, Dallas-based EnLiSense Cofounder and CEO Sriram Muthukumar, inspired by Abbott's CGM technology, said in an interview that Abbott's CGM technology made him think, "if you could measure glucose, you could measure a lot of other biomarkers."

Founded in 2014 and recently emerged from stealth mode, EnLiSense is commercializing multiple wearable devices using capture probe-based biosensors. The firm went after a number of biomarkers in sweat, but its focus on the clinical space constrained it somewhat to indicators for which a specific disease claim could be possible.

With support from the Crohn's and Colitis Foundation, EnLiSense hopes to commercialize a wearable called IBD Aware that detects interleukin-6 and C-reactive protein in sweat for continuous monitoring of inflammatory bowel disease.

"We are designing it to address the gap between payors, patients, and providers," Muthukumar said, since the test intervals for chronic disease monitoring are otherwise a bit of a guessing game. The assay is currently in clinical trials with collaborators at the Icahn School of Medicine at Mount Sinai.

However, it is also still working on nonclinical, consumer-facing assays, including a wearable sweat tracker called Corti that measures cortisol, melatonin, and inflammatory markers for people with chronic diseases, shift workers, and health enthusiasts. "Track your stress in real time," it tells consumers on its website.

The EnLiSense tech can also measure brain-derived glial fibrillary acidic protein and interleukin-6 in sweat as a potential mechanism to manage traumatic brain injuries.

Sweat sensors are even being adapted for wearable detection of analytes implicated in psychiatric diseases like bipolar disorder and schizophrenia.

Digital-only Dx

Following the success of the Oura sleep monitoring ring and other wearable sensors in predicting COVID infection during the pandemic, digital-only wearables seem to be moving even more quickly into clinical applications.

For example, a recent multisite prospective study of a wrist-worn infrared sensor from RCE Technologies showed the device can detect elevated high-sensitivity cardiac troponin-I — a protein biomarker of heart attacks — within three minutes and with a high sensitivity, specificity, and negative predictive value compared to central lab testing. The firm plans to launch a clinical trial next year, according to its website, and launch the system for emergency department use in 2026.

Rogers' team at Northwestern played a role in the development of wearable technology now being commercialized by startup Sibel. Its Anne device, which was cleared by the US Food and Drug Administration in 2021, wirelessly tracks a wide range of biophysical biomarkers in the home or hospital setting, including ECG waveforms, heart rate, respiratory rate, activity, fall detection, body position, and skin temperature. Its Adam device, meanwhile, tracks vocal biomarkers, sleep metrics, scratch events, swallow count, body motion, cough count, heart rate, body position, respiratory rate, skin temperature, and step count.

Sibel also adapted its platform for continuous neonatal and maternal health monitoring, with FDA clearance for the former and the latter among the winners of a recent National Institutes of Health Rapid Acceleration of Diagnostics (RADx) challenge.

Body-worn sensors can also potentially track, or even predict, degenerative neurological diseases with long presymptomatic phases, like Huntington's and Parkinson's diseases.

For example, in 2013 through 2015, the UK Biobank asked 103,712 of its participants to wear a 3D motion-tracking accelerometer from Axivity for one week each. As described last year in Nature Medicine, pairing this prospectively collected data with outcomes information — including 196 people who were diagnosed with Parkinson's disease within the subsequent seven years — enabled researchers to develop an algorithm to predict who would develop PD and when this diagnosis might be expected from accelerometry data alone.

Exhaled breath and beyond

Exhaled breath is also an intriguing noninvasive sample type that is now being explored by several companies, including DiagMetrics, which won federal funding last year for its exhaled breath condensate mask-based assay using semiconductor biosensors coupled with nano clostridial antibody mimetic proteins, or nanoCLAMPs.

In August, Wei Gao and colleagues at Caltech published a proof-of-concept study in Science describing an exhaled breath condensate "smart mask" that uses microfluidics and a low-cost, printable wireless electrochemical biosensor array to simultaneously monitor analytes such as alcohol, nitrate, pH, and temperature. The smart mask "revealed rich personalized health information at the molecular level," the authors wrote. In terms of clinical applications, it is capable of continuous monitoring and could potentially be used as an "inflammometer" and as a measure of airway acidification in asthma and higher serum urea in patients with chronic obstructive pulmonary disease.

Meantime, microneedle patches have been used to detect nucleic acids in interstitial fluid, including Epstein-Barr virus cell-free DNA, an important biomarker of nasopharyngeal carcinoma.

Devices that use microneedles only need to penetrate the skin about one-tenth as deeply as a needle-based sensor and can accommodate sensors for multiple analytes. Startup Biolinq, for example, is developing a microneedle-based wearable for glucose and other analyte sensing.

Ali Yetisen, a researcher at Imperial College London, and his colleagues also recently described a microneedle array using Förster resonance energy transfer (FRET)-based hydrogel sensors. That wearable patch has the potential to detect polysaccharides, proteins, and electrolytes by changing biomarker-specific receptors in hydrogel-based biomedical photonics, the authors said in Biosensors and Bioelectronics, with fluorescent signals automatically converted and wirelessly transmitted.

In addition, a review in ACS Nano this year on microneedle-based wearables suggested they can both detect disease and deliver therapy. As such, microneedle patches can potentially be adapted into theranostics.

Along these lines, a tattoo-based biosensor using encapsulated engineered bacteria has the potential to detect analytes, and perhaps also release therapeutics. Similarly, EnLiSense is collaborating with Mayo Clinic on its $42.8 million ARPA-H project called Engage Assess SecretE (EASE) aiming to encapsulate living genetically modified cells that can detect inflammatory biomarkers and generate monoclonal antibodies to treat IBD.

Finally, the antidote to an opioid overdose — naloxone — is so cheap and easy to administer that it is now even available in vending machines. Yet, more than 80,000 people die in the US each year from opioid overdoses in part because the drug requires another person nearby to administer it the moment the overdose is happening. An implantable device described last month in Science Advances can continuously monitor people, and when the signature of an overdose is detected, it can pump out naloxone and alert emergency services. Northwestern's Rogers and researchers from many other labs developed the device and are now looking for industry partners to commercialize it, Rogers said.

With research and development in wearable technologies booming, the wearables movement may reshape diagnostics.

As Nichols noted, continuous monitors like CGMs provide clinical data over time, which manual episodic testing simply cannot do. These trends can in turn inform treatment, for example, by helping a patient stay within a range or admonishing her to eat before she becomes hypoglycemic. "In the long run, that extends your lifespan and prevents other diabetic-related health concerns like end-stage renal disease," he said.

The "quantified self" trend — in which individuals track their health with technology and share their data with other people and device makers to improve health and well-being — is not likely to go away any time soon, and in the health and wellness space, consumers are ever more greedy to track their own health on a granular, molecular level. EnLiSense's Muthukumar suggested that the significant consumer demand for wearable medical devices seems likely to usher these technologies to market sooner rather than later.

This past summer, Abbott launched Lingo, its FDA-cleared over-the-counter health and wellness wearable. "No matter your health goals, glucose management is important," the Lingo website tells consumers, and last year, Abbott said it plans to add ketone and lactate detection to Lingo.

Vanderbilt's Nichols said he is seeing more and more nondiabetic colleagues wearing CGM devices to help with metabolic control. As an n-of-one experiment, they ask, "Hey, if I go out and eat a pizza, does that spike my sugar more than if I ate a steak or a healthy salad?" he said.

While Dincer of Technical University of Munich is planning to launch a company soon to commercialize his amplification-free multiplex CRISPR-based diagnostic and eventually adapt it into a device to measure circulating nucleic acids and a mask-based wearable, he also believes there is still a ways to go to get wearables into clinical use. "If you look at the literature, you will see a lot of wearables claiming to solve a lot of problems," he said, yet a closer inspection shows they were "tested on, like, five students."

Besides bigger studies, the field also needs "better sensors," specifically ones that can withstand literal wear and tear and can more readily reversibly detect analytes like aptamers. 

While the pace of wearable Dx publications and startups emerging from stealth mode seems to be accelerating, Health Advances' Abraham cautions that traditional IVD and diagnostics makers should expect the process to take some time.

"Innovation is fast," he said. "Integration is slow."