Ion-selective electrode membranes based on hydrophobic materials doped with chemically selective host molecules are an attractive sensing technology but normally suffer from a limited sensitivity, given by the Nernst equation, and a direct reliance on the reference electrode potential, which makes miniaturization difficult. These fundamental problems are addressed here by imposing a multipulse electrochemical excitation signal onto ion-selective membranes that lack ion-exchange properties. Current pulses are responsible for the generation of ion fluxes in the direction of the membrane, which give reproducible super-Nernstian response slopes that originate from depletion processes at the membrane surface. Membranes may also be measured at zero current after this pulse, giving super-Nernstian response regions at lower concentrations. Difference potentials obtained from subsequent pulses give about 10-fold higher sensitivities than predicted on the basis of the Nernst equation.

Ion-selective electrodes ideally operate on the basis of the Nernst equation, which predicts less than 60- and 30-mV potential change for a 10-fold activity change of monovalent and divalent ions measured at room temperature, respectively. Typical concentration ranges in extracellular fluids are quite narrow for the electrolytes of key importance. A range of 2.2-2.6 mM for calcium ions, for instance, translates into just a 2.2-mV potential change. The direct potentiometric measurement of physiological electrolytes is certainly possible with direct potentiometry and is done routinely in clinical analyzers and handheld measuring devices. It places, however, strong demands on the precision of the reference electrode and requires careful temperature control and frequent calibration runs. In this paper, a robust 10-20-fold sensitivity enhancement for calcium measurements is attained by departing from the classical response mechanism and operating in a non-Nernstian response mode. Stable and reproducible super-Nernstian responses of these so-called pulstrodes in a narrow calcium activity range can be controlled by instrumental means in good agreement with theory. The potentials may be measured during a galvanostatic excitation pulse (mode I) or immediately after it (mode II), under open-circuit conditions. Subtraction of the potentials, sampled at different times during a single pulse, allows one to obtain a sensitive differential peak-shaped signal at a critical and fully adjustable analyte activity range. Calcium pulstrodes based on the diamide ionophore AU-1 were characterized and applied to the measurement in model physiological liquids. Super-Nernstian responses exceeding 700 mV/decade were observed in a physiological range of calcium concentration. Such remarkable sensitivity of the pulstrodes, complemented with the well-documented high selectivity of these potentiometric sensors, may provide a significant increase in the accuracy and precision of electrolyte measurements in clinical analysis.