(Invited) Calibration-Free Ion-Selective Electrodes and Optodes for Decentralized Electrolyte Monitoring
Authors: Wang Xuewei 
Published: February 2024

Ionophore-based ion-selective sensors have been used in hospital analyzers for decades to measure electrolytes. Recently, there has been growing interest in affordable and accessible electrolyte measurements via at-home sensors, wearable sensors, transdermal sensors, and implantable sensors. However, the commercial success of ion-selective sensors in these new sensing modalities is hindered by the need for technically demanding on-site calibration. In fact, all ionophore-based sensors in clinical analyzers need to be calibrated with standard solutions at the point of use. We are developing calibration-free ionophore-based sensors, including ion-selective electrodes and optodes, to enable decentralized electrolyte measurements for the management of chronic heart, renal, and parathyroid diseases.
In the first approach, we have designed self-calibrating solid-contact ion-selective electrodes. Due to microheterogeneities and variabilities in multiple phases and interfaces of the indicator and reference electrodes, the absolute electromotive force (EMF) varies among identically fabricated and stored sensors. We create an EMF baseline that corrects for the EMF variabilities by connecting two electrodes using an appropriately formulated ionic conductor. Upon the introduction of a sample, such as a drop of blood, the EMF change relative to this baseline allows for ion measurements with high sensor-to-sensor consistency in the absence of any calibration protocols. Surprisingly, when the cross-sectional area, viscosity, and formulation of the ionic conductor are precisely controlled and the ionic conductor is insulated from the sample, its presence does not compromise the Nernstian response slope of the primary ion in the sample. In other words, this built-in ionic bridge serves for one-point calibration before the sample addition but does not need to be removed for the sample testing, representing a novel self-calibration strategy for electrochemical sensors.
In the second approach, we have for the first time functionalized the oil stream of droplet microfluidics with sensing chemicals to convert oil segments to sensors for adjacent aqueous droplets. Ionophores, ion exchangers, and dyes are dissolved in the oil to form highly selective fluorescent ion sensors. Analyte ions from the aqueous droplets are extracted into the oil segments to alter their fluorescence and absorbance. The composition of all oil segments is highly consistent, as they are from the same homogenous solution, avoiding the need for any on-site calibration. As the optical property of the oil segment is measured in a fashion that is spatially and temporally separated from the aqueous sample, this biphasic sensing method works for complicated samples such as undiluted whole blood.
In the third approach, we have designed a home-use sensor based on a calibration-free oil sensor contained in a capillary tube. Only one segment of sensing oil is used for analysis of one segment of sample of a few microliters. By continuously alternating the relative position of the oil and the sample controlled by a stepper motor, efficient mass transfer between two phases is obtained. The color of the oil segment is acquired and analyzed by a smartphone to indicate the electrolyte concentration in an aqueous sample. The accuracy and precision of an at-home calcium monitor in this format have been validated in > 50 human blood samples.