Coming Soon: Third-Wave Diagnostics

When is it appropriate to attach the moniker “stone age” to a previous era of science and medicine? You could easily argue that pathology was in just such a stone age before biofluid- and tissue-based diagnostics came of age. So when will our present-day capabilities be similarly relegated?

The last century produced the first wave of modern diagnostics based on collected biosamples that had to be sent to a laboratory for analysis. More recently, we have seen a second technological wave of point of care diagnostics that put the lab right in the hands of the doctor. This second wave brings added convenience and can even allow the doctor to validate a diagnosis while in the presence of the patient. Despite these advances, the remaining gaps in patient care are so significant that – one day not too far in the future – we may agree that pathologists in 2018 were in the “stone age” of medical diagnostics. To visualize the gaps, it may help to start thinking about what might soon be possible…

Imagine personalized therapeutics, where the dosing is adjusted in real time based on each individual’s unique rates of absorption and metabolism and their treatment responsiveness. Or something even simpler: knowing for certain that the patient is actually taking the drug at all. Imagine a complete, continuous biochemical view of lifestyle choices for a cardiac patient, measuring potassium and brain natriuretic peptide continuously on both good and bad days. Imagine mental or stress disorders without the need for biased self-reporting, with treatment based instead on quantitative cortisol responses to daily stressors. Or imagine a workforce safety system in which chemical toxin exposure is reliably recorded as internal exposure and organ loading, not just in terms of what volume of toxin may have breached protective clothing.

Imagination may soon become reality with the third wave of diagnostics – one that allows patients to take the laboratory with them in the form of wearable biochemical monitoring systems. That’s what prompted our research group (in partnership with Air Force Research Labs) to seek not a technological solution, but rather to first uncover the fundamental questions and challenges that would face such diagnostics. It led us to a biofluid that was at the time underused, but arguably had the highest upside potential: eccrine sweat. Seven years after that first inspiration, we have now demonstrated a wearable device that can locally stimulate sweat for multiple days, wick a tiny sweat sample up off the skin surface, and transport it within minutes to a Bluetooth-connected array of sensors that can continuously report analyte concentrations. In essence, we are extracting blood-level information continuously and noninvasively, with less than five-minute time stamps. And it works exceptionally well for small, hydrophobic analytes that partition readily through the tissue layers between blood and the sweat glands (such as steroid hormones or small-molecule drugs). Proteins and antibodies are larger and therefore more challenging because they are highly diluted in sweat, but we can now pre-concentrate such analytes by several orders of magnitude – also continuously and within minutes.

With this device, we hope to ride the crest of that third wave. Our goal is something even more powerful than continuous biochemical data for a patient; we want that data to be contextual. As doctors, you know just how limited a single data point can be – and you know that, in many cases, you would find it more powerful to trade absolute concentration accuracy for the ability to closely monitor relative changes in chemical analytes. Measuring such changes can be particularly powerful when they are placed into context. Coming back to the cardiac patient from earlier – was the spike in blood pressure due to eating a cheesesteak sandwich or because of a daily stress event? Or did the patient simply stop taking their statins? For many diseases, the coming wave will make current diagnostics look like interpreting a connect-the-dots picture before the connecting lines have been drawn.