Electrochemical aptamer-based sensors: a platform technology supporting seconds-resolved, real-time molecular monitoring in the living body

Abstract

Introduction: Interstitial fluid and sweat are the leading biofluid contenders for continuous and minimally invasive biosensing of chemical biomarkers1. Wearable devices are now able to continuously sample these biofluids (Fig. 1), and importantly provide blood-correlated data for: glucose in interstitial fluid accessed by indwelling needles and microneedles1; ethanol in sweat accessed by sweat-stimulating and wicking patches2. Although these are important accomplishments, they also reveal that the field has not made significant progress beyond enzymatic sensing of simple metabolite biomarkers. It is clear at this point, that additional sensing modalities such as electrochemical aptamer-based sensors are required if continuous biosensing is to live up to its full promise, including monitoring of performance and injury. Electrochemical aptamer-based sensors are ready to support biosensing beyond metabolites, as they have been demonstrated in-vivo for dozens of biomarkers, even in circulating whole blood3. Together, electrochemical aptamer sensors and rapidly advancing wearable device platforms (Fig. 1) now place the field in technological position to achieve that long sought-after watershed moment of the ability to pursue the continuous measurement of a wide spectrum of small molecule and protein biomarkers. However, even with appropriate sensor technology, not all biomarkers in sweat and interstitial fluid will provide meaningful information (i.e., strong correlation with blood in both time and concentration). Future directions: This presentation will review progress to-date in minimally invasive biofluid access with emphasis on interstitial fluid and sweat. For sweat, the presentation will focus on the need for reliable sweat stimulation, dealing with miniscule sample volumes, effects of variable pH and salinity, and the limited biomarkers that work well in sweat such as small hydrophobic molecules (i.e., drugs, steroid hormones). For interstitial fluid, the presentation will focus primarily on the need for diffusion-based coupling of sensor to the dermis (i.e., indwelling sensors or porous microneedles), and the molecular weight dilution curve that begins to dilute biomarkers in interstitial fluid that are 10s of kilodaltons or greater in molecular weight. With biosensing device technology rapidly maturing, and an improved fundamental understanding of what biomarkers are most feasible for blood correlation, interstitial fluid and sweat are now at the point where we can credibly pursue continuous sensing of biomarkers of performance and injury in the warfighter. Acknowledgements: Biosensor research in Prof. Heikenfeld’s group at the Univ. of Cincinnati has been supported by the U.S. Office of Naval Research, the U.S. Airforce Office of Scientific Research, and the U.S. National Science Foundation. References 1Heikenfeld J, Jajack A, Feldman B, et al. Accessing analytes in biofluids for peripheral biochemical monitoring. Nat Biotechnol 2019; 37:407-419. PubMed PMID: 30804536. 2Hauke A, Simmers P, Ojha YR, et al. Complete validation of a continuous and blood-correlated sweat biosensing device with integrated sweat stimulation. Lab Chip 2018; 18:3750-3759. https://doi.org/10.1039/C8LC01082J 3Arroyo-Currás N, Dauphin-Ducharme P, Scida K, et al. From the beaker to the body: translational challenges for electrochemical aptamer-based sensors. Anal Meth 2020; 12:1288–310. https://doi.org/10.1039/D0AY00026D