Passively Addressable Electrochemical Sensor for Detection of Chloride Ions in Ultra-Low Volumes of Human Sweat




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Sweat chloride serves as the gold standard biomarker for diagnosis of Cystic Fibrosis (CF), a lethal progressive, genetic disorder of childhood. Quantification of chloride concentration in human sweat can also be used to reliably monitor and control hydration levels in an individual within homeostatic limits. There sweat chloride monitors currently available in the commercial or research space, require large sweat volumes for reliable sensing which is achieved by physical, chemical or electrical stimulation of sweat glands. This work demonstrates a novel electrochemical biosensor for the detection of chloride ion levels in ultra-low volumes (1-3 microliters) of passively expressed human sweat. We present here a sweat chloride monitor, that the pediatric, geriatric and other immune-compromised or physically inactive/ sedentary population cohort, can utilize for whom the current methods of chloride quantification based active stimulation of sweat glands through iontophoresis or treadmill runs are unsuitable. In this work, non-faradaic electroanalysis using gold microelectrodes deposited on flexible nanoporous substrate, for high nanoscale surface area to volume enhancement, was leveraged to operate in ultra-low sweat volumes of <3µL eluted at natural rates. Specific chloride ionophore based affinity of chloride ions resulted in the modulation of charge transfer within the Electrical Double Layer at the electrode-sweat buffer interface, which was transduced using Electrochemical Impedance Spectroscopy (EIS) and Chronoamperometry (CA). Linear calibration dose responses with R-squared values of 0.9746 and 0.9403 for EIS and CA respectively were obtained for a dynamic range of 10-100 mM. The surface charge and the binding chemistry of the capture probe were studied using Zeta potential studies and UV-Vis. The dynamic sweat chloride tracking capability of the sensor was evaluated for a duration of 180 minutes. Studies were conducted to probe the efficacy of the developed sensor for passive ultra-low sweat chloride assessment on human subjects (n=3). Misclassification of an acute disease condition as chronic and vice versa by electrochemical sweatbiomarker sensors can cause significant psychological, emotional and financial stress among patients. To achieve higher accuracy in distinguishing between a chronic condition from an acute condition, there is a need to establish a reference biomarker to index the actual chronic disease biomarker of interest by combinatorial sensing. The developed sensor was also used to demonstrate the first technological proof of leveraging the chloride ion content in sweat for combinatorial sweat biomarker benchmarking scheme. In this scheme, the sweat chloride ion has been demonstrated as the reference/ indexing biomarker while sweat cortisol has been studied as the disease biomarker of interest. The electrochemical stability of the fabricated electrodes was studied by Open Circuit Potential measurements and Attenuated Total Reflectance- Fourier Transform Infrared Spectroscopy was used to validate the crosslinker-Antibody binding chemistry. Calibration dose responses for the sensor for cortisol (5-200 ng/mL) and chloride (10- 100 mM) detection was evaluated in synthetic (pH 6) and pooled human sweat(R2>0.95). The variation in the cortisol sensor response due to fluctuations in sweat chloride levels and the significance of reporting normalized biomarker levels was demonstrated to further emphasize on the need for biomarker benchmarking in electrochemical sensors. Thus, proposed indexing scheme based on sweat biomarker normalization discussed in this work takes us a step closer to more precise sweat diagnosis, particularly for at-home monitoring medical devices.



Wearable technology, Perspiration, Impedance spectroscopy, Biological monitoring, Biochemical markers


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