Ultrasensitive Ionophore-Based Liquid Sensors for Colorimetric Ion Measurements in Blood

The self-monitoring of electrolytes using a small volume of capillary blood is needed for the management of many chronic diseases. Herein, we report an ionophore-based colorimetric sensor for electrolyte measurements in a few microliters of blood. The sensor is a pipet microtip preloaded with a segment of oil (plasticizer) containing a pH-sensitive chromoionophore, a cation exchanger, and an ionophore. The analyte is extracted from the sample into the oil via a mixing protocol controlled by a stepper motor. The oil with an optimized ratio of sensing chemicals shows an unprecedentedly large color response for electrolytes in a very narrow concentration range that is clinically relevant. This ultrahigh sensitivity is based on an exhaustive response mode with a novel mechanism for defining the lower and higher limits of detection. Compared to previous optodes and molecular probes for ions, the proposed platform is especially suitable for at-home blood electrolyte measurements because (1) the oil sensor is interrogated independent of the sample and therefore works for whole blood without requiring plasma separation; (2) the sensor does not need individual calibration as the consistency between liquid sensors is high compared to solid sensors, such as ion-selective electrodes and optodes; and (3) the sensing system consisting of a disposable oil sensor, a programmed stepper motor, and a smartphone is portable, cost-effective, and user-friendly. The accuracy and precision of Ca²⁺ sensors are validated in 51 blood samples with varying concentrations of total plasma Ca²⁺. Oil sensors with an ultrasensitive response can also be obtained for other ions, such as K⁺.