Sensing the Tiniest Change

Molecules that are essential for the body, such as proteins and hormones, can often yield significant insight into a patient’s health status. But many of these molecules are present in the blood in pico- or nanomolar concentrations. The best-known assay to measure such low concentrations outside the body is an elaborate, multi-step process that yields a single concentration value: ELISA. In contrast, continuous monitoring dynamically follows biomarker concentration in solution, leading to a stream of data rather than an isolated result. For continuous monitoring to work, molecular binding must be reversible and lead directly to a measurable signal without consumption or production of chemical reactants. The sensing principle should be self-contained, reversible, and stable over a long period of time. Still, the assay should be as sensitive and as specific as ELISA. And that’s the challenge my colleagues at Eindhoven University of Technology and I are addressing (1).

BPM refers to “Biomarker monitoring based on sensing of Particle Mobility.” The technique exploits the fact that tiny particles in liquid are constantly in random motion because water molecules collide with them. What we did is couple the particles to a substrate via a flexible molecular tether, so that the particles wiggle back and forth. To detect a specific biomarker, the particles and the substrate are provided with affinity molecules; this enables specific, reversible interactions with the biomarker molecules in solution. When a biomarker molecule attaches to both particle and substrate, they form a molecular sandwich bond that greatly reduces the particle’s mobility. When the biomarker is released, the particle regains its original mobility. So these mobility changes, which we detect via dark-field optical video microscopy, indicate the capture or release of a single biomarker molecule – and the number of changes per minute reveals, with high sensitivity and specificity, the concentration of the biomarker in the liquid.

The beauty of the BPM sensor technology is that increases and decreases in biomarker concentration can be precisely monitored over time. We have demonstrated its use in monitoring protein and DNA, but the technology is widely applicable; affinity molecules such as antibodies and aptamers are available for almost all biomarkers.

We think that BPM sensing can become an early warning system that signals patient deterioration – useful for postoperative, immunocompromised, or chronically ill patients, as well as those in critical condition. Furthermore, patients who receive potent drugs with a narrow therapeutic range might benefit from a sensor that enables rapid and robust dosing regulation. Before that can become a reality, though, we need to develop assays for several medically relevant biomarkers and demonstrate the required analytical performance. This will be followed by clinical proof-of-concept studies, which should give solid ground for subsequent development of a product. In total, we expect the process to take five to 10 years. We are now defining key applications and markets to determine our technical and clinical direction. Are we going to focus on measuring early warning markers, or on therapy monitoring? What patient group will we target? What value will we add? The answers to these questions will define our work in the coming years.

Continuous biomarker monitoring will go through several stages of maturity – and, in the future, may be as easy to perform as today’s blood pressure or heart rate measurements. As technology development increasingly focuses on important medical needs, we have an interesting road ahead.