Dynamic Tracking Biosensors: Finding Needles in a Haystack

Accurate detection of target molecules at low concentrations in the presence of undesired molecules in abundance is a major challenge for biosensors. Nonspecific binding of undesired molecules to receptors limits the minimum detectable concentration of the target significantly. Dynamic tracking (DT) of binding and unbinding events allows us to overcome this challenge and provides a remarkable improvement in the minimum detectable target concentration. Through a combination of theoretical analysis and detailed statistical simulations, here we show that, with aggressive scaling, DT sensors are capable of fM detection limits even if the undesired molecules are present at nM concentrations, which is several orders of magnitude better than traditional endpoint (EP) biosensors. In addition, we propose a novel unconstrained detection scheme that does not rely on a priori knowledge of the dissociation constants and also allows facile back-extraction of critical parameters. Indeed, this work provides a theoretical basis for DT sensors and demonstrates its suitability to usher in a new paradigm on biosensing in hostile environments.