Potentiometric Sensing - American Chemical Society

Review Cite This: Anal. Chem. 2019, 91, 2−26

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Potentiometric Sensing Elena Zdrachek* and Eric Bakker*

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Department of Inorganic and Analytical Chemistry, University of Geneva, Quai Ernest-Ansermet 30, CH-1211 Geneva, Switzerland

CONTENTS

Reference Electrodes Solid-Contact Ion-Selective Electrodes Solid-Contact Based on Conducting Polymers Poly(3,4-ethylenedioxythiophene) (PEDOT) Polypyrrole Poly(3-octylthiophene) (POT) Polyaniline (PANI) and Other Polymers Solid-Contact Based on Other Materials Carbon Materials Molecular Redox Couples Intercalating Compounds Other Materials Theory of Potentiometric Response New and Nonclassical Readout Principles for IonSelective Electrodes Amperometry and Coulometry Chronopotentiometry Ion-Transfer Voltammetry Optical Readout Sensor Materials Membrane Materials Ion-Exchange Nanopore Membranes Ionic Liquids Molecular Imprinted Polymers (MIP) Ionophores Anion-Selective Ionophores Cation-Selective Ionophores Miniaturized Ion-Selective Electrodes Paper-Based and Microfluidic Potentiometric Devices Wearable Sensors Miniaturized pH Sensors Ion-Selective Microelectrodes Ion-Selective Field Effect Transistors Analytical Applications and Methodologies Environmental Analysis Clinical Analysis Polyion Sensing Surfactant Analysis Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments References

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January 2016 and August 2018. January 2016 was when the last fundamental review covering the topic of potentiometric sensors appeared in the special issue of Analytical Chemistry and was set as the start date. The contributions were sourced from the scientific citation indexing service Web of Science by searching for relevant keywords and author names of recognized experts in the field. We also manually screened the tables of contents of selected journals known for publishing quality work related to electroanalytical chemistry. Owing to the significant number of contributions that are published in the field of potentiometric sensing, we may have overlooked some of them or otherwise chosen not to report on it. This contribution should therefore be appreciated as an opinion piece that gives our view on the current state of the field. It is not a comprehensive discussion of all contributions that deal with potentiometric sensors. We would like to apologize if someone feels that his or her contribution was unfairly discarded. The field of potentiometric sensors is experiencing solid growth. It is inspiring to see how research blurs the boundaries between the disciplines and explores new readout principles for traditional potentiometric sensors. Progress in material science offers researchers new ion-to-electron transducing materials that bring the field ever closer to robust, calibration-free, and miniature sensors. The application scope of potentiometry is constantly broadening by combining it with bioassays, corrosion monitoring, in situ environmental analysis, and clinical diagnostics. The idea of developing affordable, scalable, and disposable sensors for point-of-care and in-field applications stimulates important research activity in the domain of paper-based potentiometric sensors. The combination of potentiometric sensors with wearable technologies has become a new important trend in the field. The authors aimed to briefly describe the content of the cited works and to underline their strong and weak points. Our goal was not to offend anyone with these comments but, on the contrary, to raise important questions for critical discussion and to stimulate future progress in the field. This Review starts with a description of progress in the development and improvement of reference electrodes, which represent an indispensable part of any electrochemical cell and has a particularly important influence on the accuracy of potentiometric measurements. It continues with an overview of recent achievements and discoveries in the domain of solidcontact ion-selective electrodes. This section was structured mainly by the type of ion-to-electron transducing material

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Special Issue: Fundamental and Applied Reviews in Analytical Chemistry 2019

his Review describes, with 187 references, progress in the field of potentiometric sensing in the period between © 2018 American Chemical Society

Published: October 17, 2018 2

DOI: 10.1021/acs.analchem.8b04681 Anal. Chem. 2019, 91, 2−26

Analytical Chemistry

Review

divinylbenzene develops a framework of nanochannels into which the former phase is kinetically trapped. The resulting reference electrodes demonstrated potentials that varied by less than 3 mV over almost five orders of KCl concentration. The authors also tested the 24 h potential stability of their electrodes in deionized water. While the initial potential changed by up to 6 mV over 1 h, the subsequent potential drift was on the order of 1.5 mV/h. Other reports were conceptually more conservative and were based on electrodes of the second kind, typically of the Ag/ AgX type. Lewenstam and co-workers described a solid-contact reference electrode with Ag nanoparticles, AgBr, and KBr suspended in a tetrahydrofuran solution of polyvinyl chloride (PVC) and bis(2-ethylhexyl) sebacate (DOS) and deposited on a silver electrode or another substrate covered with Ag, by drop casting.5 An insensitivity of the developed reference electrode to repeated changes in the sample composition, pH, and the presence of redox species was found. The role of the PVC coating is not perfectly clear, but it may be assumed that it functions as a diffusion barrier and therefore effectively traps the added KBr. Zhao et al. presented a flexible Ag/AgCl microreference electrode with an internal electrolyte reservoir based on a rather traditional design.6 The reference electrode was less than 20 mm long and based on a microfabricated parylene tube structure, which was filled with saturated KCl solution in contact with Ag/AgCl element. The distal end of the tube was filled with KCl saturated agarose gel. The potential drift over a 10-h period was found to be less than 2 mV. The total operation time of the device has exceeded 100 h, but this is expected to depend on the solution composition. An IrOx pH indicating electrode was monolithically integrated on top of this reference electrode to complete a miniaturized combination pH probe. Li et al. built an all-solid-state ISFET pH sensing system using solid-state thin-film reference electrodes fabricated on a plastic substrate. The Ti/Au/Ag/AgCl multilayer structure is covered with a polyvinyl butyral membrane containing a high concentration of NaCl to maintain a constant concentration of chloride.7 The achieved potential drift of this reference element was reported to be less than 1.7 mV per hour. Mechaour et al. studied the effect of the Ag wire diameter and the surface morphology of deposited AgCl on the stability of the resulting microscale Ag/AgCl elements.8 Bühlmann’s group had shown earlier that the permselective properties of nanoporous glass junction materials called Vycor may result in large errors upon contact with dilute electrolyte solutions. They continued this work by investigating different available liquid junction materials such as Teflon, polyethylene, and two porous glasses sold under the brand names CoralPor and Electroporous KT.9 It was shown that materials with larger pore sizes of >10 nm are not affected by electrostatic ion screening and exhibit more modest potential changes as a function of sample composition (less than 10 mV). However, the increase of the pores size also accelerates the flow through the junction material, which can cause significant contamination of the sample by the reference electrolyte. The authors also emphasized difficulties related to the wetting of the polymeric frits during electrode fabrication and use that are caused by the hydrophobic nature of these materials.

discussed. Next, insights into modern theory of potentiometry is given, describing the use of numerical simulation to predict time-dependent potential changes at ion-selective membranes as well as new protocols for determining the selectivity coefficient. Subsequently, new and nonclassical readout principles for ion-selective electrodes are presented. It is followed by a section dedicated to new materials exploited for ion-selective electrodes (ISEs), including membrane materials, ion-exchange nanopores, room temperature ionic liquids, molecular imprinted polymers, and new ionophores. Recent developments in the area of miniaturized ISEs, including paper-based devices, wearable sensors, miniaturized pH sensors, ion-selective microelectrodes, and ion-selective field effect transistors (ISFET), are discussed in the next section. The review ends with a discussion of some analytical applications for potentiometric sensors, including polyion detection and environmental, clinical, and surfactant analysis. We mention relevant reviews published in the announced time period in the sections dedicated to the corresponding topic. However, we refer here to a recently published encyclopedia chapter on the fundamentals of potentiometric sensing1 that may be specifically useful for readers new in the field to gain basic knowledge about the technique.

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REFERENCE ELECTRODES The reference electrode is an essential element for any potentiometric measurements. Historically, scientists have been mostly focused on improving the performance of the ISEs because the established Ag/AgCl or Hg/Hg2Cl2 reference electrodes usually provided a stable and reliable potential response during measurement. However, these reference electrodes are rigid and bulky and suffer from a need for bulky electrolyte solutions. With the growing demand to develop miniaturized electrochemical systems such as lab-onchips and wearable sensors, it has become even more important to develop miniature solid-state reference electrodes. Some examples of implementing previously developed solid-state liquid-junction free reference electrodes into small portable and/or disposable potentiometric devices are also discussed in the section dedicated to miniaturized ion-selective electrodes. One may broadly distinguish truly novel reference electrode concepts that make use of conducting polymers, ionic liquids or other materials, and more traditional Ag/AgCl elements in contact with a salt solution. Bühlmann and coworkers published a review discussing all-solid-state ISEs and reference electrodes and discussed important aspects that should be considered when designing such sensors for specific applications.2 Another review published by Sophocleous and Atkinson describes various attempts to produce functionally more traditional but screen printed Ag/AgCl reference electrodes.3 The paper provides an overview of details of the electrode’s construction and an analytical comparison of its performance. Bü hlmann’s group built on an innovative approach introduced originally by Kakiuchi that made use of the selfpartitioning of ionic liquids between two phases to realize a novel class of reference electrodes. Here, the ionic liquid-based reference electrodes were fabricated by polymerization-induced microphase separation,4 which gives, in a single step approach, self-supported and mechanically and thermally robust reference electrodes. During the polymerization, the ionic liquid partitions into a compatible phase, poly(methyl methacrylate) (PMMA). A simultaneous cross-linking by added styrene and 3



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Review

SOLID-CONTACT ION-SELECTIVE ELECTRODES

The development of new solid-contact materials for ISEs remains consistently one of the most active topics in the field of potentiometric sensors. The realization of all-solid-state indicator electrodes with liquid and polymeric membranes is indeed very attractive for a range of applications and promises to simplify electrode design. Conceptually, a solid contact requires an ion to electron transducing layer between ionselective membrane and electron conductor that gives operationally stable potentials. The quality of such materials is typically evaluated with drift measurements, water layer tests, impedance analysis, and galvanostatic perturbations. Solid-Contact Based on Conducting Polymers. The conducting polymers poly(3,4-ethylenedioxythiophene) (PEDOT), polypyrrole, and poly(3-octylthiophene) (POT) represent the oldest group of the solid-contact materials. As they are still widely used for potentiometric applications, progress with these materials is discussed first. Chemical derivatives of these materials with improve characteristics have also been reported. Poly(3,4-ethylenedioxythiophene) (PEDOT). Lindner’s group focused their attention on the rate determining processes during the equilibration of ISEs based on poly(3,4ethylenedioxythiophene):polystyrenesulfonate (PEDOT(PSS)).10 The influence of the thicknesses of conducting polymer film and electrode substrates (Au, GC, and Pt) was investigated by recording potential−time transients upon first contact with aqueous solution. It was possible to minimize the conditioning time of the ISEs at first use, which is important for disposable sensor systems, by optimizing the thicknesses of the solid contact layer and overlaying membrane. K+-SE based on PEDOT(PSS) deposited on Au or Pt electrodes exhibited different equilibration times, which was studied by electrochemical quartz crystal microbalance. Under the otherwise same conditions, the rate of PEDOT(PSS) polymer growth was found to be significantly faster on Au compared to Pt, resulting in a thicker deposited polymer film.11 The same group later explored a highly hydrophobic derivative of PEDOT, namely, PEDOT-C14, as a solid contact for H+, Na+, and K+-SEs.12 All electrodes demonstrated exceptional performance characteristics, including a theoretical response slope, short equilibration time, and excellent potential stability. The superhydrophobic properties of this polymer were confirmed by contact angle measurements (136 ± 5°), which should prevent the accumulation of an aqueous film between membrane and solid contact. The authors emphasized that recording the potential drifts of solid-contact ISEs with pHsensitive membranes in samples containing different CO2 levels may be a faster and more reliable protocol for detecting the presence of a water layer between ion-selective membrane and solid contact than the one that is widely used today (see Figure 1).12 Plawinska et al. found that PEDOT layers exhibited a reduced capacitance when they were covered with polymeric sensing membrane.13 This was ascribed to the low amount of transferable ions across the solid contact/membrane interface. Some procedures and pretreatment methods were proposed to minimize the effect. The groups of Gyurcsanyi and Bobacka synthesized a 3D nanostructured PEDOT(PSS) film with 750 nm-diameter interconnected pores by means of 3D nanosphere lithography and electrosynthesis.14 The authors aimed to combine the beneficial properties of a large surface area

Figure 1. Lindner’s test for the presence of a water layer between an H+-selective membrane and the transducer layer.12 If a water layer is present, an increasing CO2 sample concentration results in diffusive transport through the membrane and into the water layer. This will result in a pH change at the backside of the membrane and a significant negative potential drift.

capacitive material with that of molecular redox probes. The voids in the conducting polymer film were loaded with a moderately lipophilic redox mediator (1,1-dimethylferrocene), and the resulting material gave a reduced variation in the standard potential for a series of silver-selective electrodes to within ±4 mV, which is however still not the best in class. Also, this approach may be used only with a low diffusivity silicone rubber matrix as the extraction of redox mediator into the plasticized PVC-based ion-selective membrane was found to greatly deteriorate the slope and selectivity of the sensor. Polypyrrole. The groups of Lindfors, Höfler, and Gyurcsanyi reported on solid-contact ISEs with excellent potential reproducibility (standard deviation of E0 of only ±0.7 mV) based on polypyrrole.15 This was achieved by the incorporation of a highly hydrophobic perfluorinated anion (perfluorooctanesulfonate, PFOS−) as doping anion. Moreover, before applying the ion-selective membrane, the oxidation state of the electrodeposited polypyrrole was adjusted by polarization to the value of the open-circuit potential of the solid contact in 0.1 M KCl determined in advance. The obtained standard deviation of E0 is the smallest value reported up to now for conducting polymers. However, the authors conceded in an interlaboratory study that the variation increases with different batches of electrodes. Michalska’s group synthesized polypyrrole nanospheres (about 40 nm) from poly(n-butyl acrylate) microspheres to deliver the monomer (pyrrole) to the oxidant (iron(III) nitrate) aqueous solution.16 Ultimately, polypyrrole films were obtained by drop casting aqueous dispersions of these nanoparticles. Cyclic voltammetry and electrochemical impedance spectroscopy experiments demonstrated a high charge transfer reaction rate compared with electrochemically grown polypyrrole. The resulting solid contact in K+-selective electrodes demonstrated reasonably stable Nernstian response. Later, Michalska and co-workers investigated the influence of the doping ion (nitrate or sulfate), and the manner releasing the pyrrole monomer was released on the electrochemical properties of the resulting nanospheres.17 Besides the enhanced electrochemical activity, the polypyrrole nano4



Review

that POT is distributed throughout the membrane and at a relative high level of 0.5 wt %. Polyaniline (PANI) and Other Polymers. Liu et al. demonstrated the significant improvement in the analytical characteristics of solid-contact Pb2+-SE by using electrospun PANI/PMMA microfibers as a transducer layer.23 The electrodes prepared with electrospun microfibers did not have evidence of water layer formation, presumably due to the enhanced adhesion between the PVC membrane and PMMA containing transducer layer. The detection limit was improved by 1 order of magnitude (6.3 × 10−10 M) in comparison with the electrodes based on drop-cast PANI/PMMA film. The reproducibility of E0 values of the prepared ISEs was unfortunately not given. Abramova et al. reported on a PANI derivative doped with methacrylamide groups as a new solid contact material that can be subsequently copolymerized with polyurethane acrylate membrane matrix upon exposure to UV light.24 The material was tested for ionophore based-Ca2+-SEs providing enhanced sensor stability (standard potential drift of less than 2 mV/day) and lifetime (up to 3 months of constant contact with calcium solution) and a reduced pH sensitivity (no response to pH change in the range of 4−9) in comparison with conventional PANI. Other sensor characteristics (sensitivity, detection limit, and selectivity) were comparable to the ones reported earlier for similar membrane composition. No evidence of an aqueous layer between membrane and solid contact was observed. The group of Lindfors introduced a composite of a few-layer exfoliated graphene and electrically conducting PANI as a solid contact in Ca2+-selective solid-contact electrodes with a silicone rubber membrane.25 The transducer layer was deposited by drop casting from a graphene-PANI dispersion in N-methylpyrrolidone. The presence of graphene significantly improved the reproducibility of the standard potential of the electrodes compared to the neat PANI-based electrodes (±4 mV vs ±24 mV (n = 3) in the best case) and increased the hydrophobicity of the solid contact material (ca. 30° higher water contact angle). The achieved detection limit was 5 × 10−8 M. The groups of Lindfors and Gyurcsanyi characterized lipophilic polyazulene as a solid contact film for K+-SEs suitable for clinical applications.26 The authors performed a polarization of polyazulene before coating with plasticized poly(vinyl chloride) sensing membrane to increase the reproducibility of the E0 values of ISEs. Unfortunately, the achieved standard deviation value of ±7.9 mV (n = 4) was still worse than the state of art. Nevertheless, the prepared K+-SEs showed a good detection limit (0.7 nM), selectivity, and a close to Nernstian slope. The absence of the aqueous layer between solid contact and sensing membrane was also confirmed. The K+-SEs gave an accurate estimation of potassium levels in serum. Solid-Contact Based on Other Materials. Carbon Materials. Carbon materials such as graphene, graphene oxide, and carbon nanotubes (CNTs) are widely used as a solid contact material in potentiometric sensors owing to their high lipophilicity and high capacitance value. Cuartero et al. gave the first direct spectroscopic evidence for capacitive charging of CNTs-based solid contact ISEs using synchrotron radiation-X-ray photoelectron spectroscopy and synchrotron radiation valence band spectroscopy.27 Michalska and coworkers studied the dispersing agent used to prepare CNTsbased solid contact layer for ISEs.28 The authors tested two such commonly used reagents, an anionic (dodecylbenzenesul-

particles can be easily applied even on nonconductive supports such as paper because the polypyrrole nanoparticles serve as electrical lead and ion-to-electron transducer. Disposable, K+selective electrodes on paper support were prepared by painting with a polypyrrole nanoparticle suspension and covered by the ion-selective membrane. The analytical parameters (slope, detection limit) were found to be comparable to those of classical ion-selective electrodes.18 Bobacka and co-workers explored the possibility of using polypyrrole/zeolite composites as solid contact material in K+ISEs.19 The anionic groups on the zeolite framework served as counterions for the electrochemically synthesized polypyrrole. The zeolite endowed the polypyrrole with higher hydrophobicity and gave lower detection limits after conditioning for 1 week, while the electrochemical characteristics were found to be otherwise similar to that of chloride-doped polypyrrole. Poly(3-octylthiophene) (POT). POT is often used in potentiometric sensors as a solid contact material by virtue of its high hydrophobicity and ease of its deposition on the electrode surface (drop casting from solution or electrosynthesis). Lindner’s group pointed out ambiguous drifts and poor potential reproducibilities of POT-based ISEs sometimes described in literature and analyzed possible reasons for these contradicting results.20 To further improve the potential stability of POT-based K+-SEs, the authors doped the POT film with a 7,7,8,8-tetracyanoquinodimethane (TCNQ/ TCNQ−) redox couple, imposing a 1:1 molar ratio of TCNQ/TCNQ− by potentiostatic control. This pretreatment resulted in a decrease of the long-term potential drift from −1.4 to −0.1 mV/h but did not improve the sensor-to-sensor potential reproducibility. Bakker’s group presented for the first time a solid contact ion-selective electrode for the sequential sensing of cations (tetrabutylammonium) and anions (hexafluorophosphate), achieved by electrochemical switching on POT-based solidcontact membrane electrodes.21 This became possible with a reduced thickness of the sensing membrane (about 200 nm) and the redox properties of the underlying POT film. The switchable ISE was based on plasticized polyurethane membrane containing a cation exchanger and lipophilic electrolyte (ETH 500). The ISE was formulated to naturally respond to cations. The conversion of POT into POT+ during an oxidative current treatment removed the cation exchanger from the membrane to pair with POT+, resulting in an anionresponsive membrane. A reductive current pulse restored the original cationic response. This is a potentially promising approach, but alternative ion to electron transducing layer may be more advantageous for this concept because POT-based solid contact ISEs are known to not be optimal for the detection of anionic species. Michalska and co-workers reported on an experimental approach for the visualization and quantitation of spontaneous POT partitioning into the ion-selective membrane phase.22 The approach is based on fluorescence microscopy as well as recording the absorption and emission spectra for membranes that were peeled from the electrode surface and subsequently dissolved in THF. Absorbance estimates total POT concentration while fluorescence emission quantifies the reduced (semiconducting) form of POT. This combination of techniques allowed the authors to quantify the change in the molar ratio between oxidized and reduced forms of POT while ISEs are in use. Fluorescence microscopic imaging suggested 5



Review

on the standard potential reproducibility for the electrodes from different batches would be advisable. Yin et al. developed an interesting approach for the preparation of solid-contact ISEs with reduced graphene oxide as transducer layer, avoiding drop casting from solution.35 It is based on physical adsorption of the graphene oxide powder modified with Fe3O4 to a magnetic gold electrode. The amount of graphene oxide self-assembled on the electrode surface was controlled by mass. The ion-selective membrane was glued on top of the transducer layer with a PVC/THF slurry. The resulting electrode gave comparable potential stabilities to other graphene-based solid contact ISEs. At the same time, He et al. developed an inkjet-printing process with postprint thermal annealing for graphene deposition to serve as a solid contact for ISEs.36 The group of Kounaves reported on solid-contact ISEs suitable for measurements at high pressure (about 100 bar).37 They were fabricated using robust microporous carbon as the ion-toelectron transducer, which was impregnated with an ionophore/additive cocktail before covering it with a PVC membrane to prevent premature sensor aging. Molecular Redox Couples. The incorporation of a redox couple at the back side of the membrane is a well-known approach for increasing stability of SC ISEs. The group of Paczosa-Bator reported on a graphene-tetrathiafulvalene/ tetrathiafulvalene cation (TTF/TTF+) nanocomposite as a promising transducing layer for solid-contact ISEs. The improved potential stability and reproducibility of nitrateselective electrodes were found to relate to the high double layer capacitance of graphene and the presence of the TTF/ TTF+ redox couple.38 Later, the same group used a similar approach by combining carbon nanomaterials with TCNQ and its sodium salt to prepare an ion-to-electron transducer for solid-contact ISEs.39 The possibility to improve the Na+-SEs sensitivity, linear range, and detection limit, by changing the NaTCNQ/TCNQ ratio was demonstrated in this work. Paczosa-Bator and co-workers also showed that reproducible standard potentials and low detection limits could be achieved for K+- and NO3−-SEs using the well-known charge transfer salt TTF-TCNQ as ion-to-electron transducer.40 The group of Michalska and Paolesse presented what appears to be a redox buffer in the absence of a molecular redox couple. A mixture of cobalt(II) porphyrin and cobalt(III) corrole together with CNTs, drop cast from solution, appears to be a promising transducer layer for solid-contact ISEs.41 Although the cobalt complexes have different oxidation states, they cannot be electrochemically driven one to another, and so, their function is not immediately evident. The transducer layer was tested on K+SEs and revealed a significant improvement of the analytical performance of the sensors (linear response range, detection limit, and selectivity) with increased amounts of the porphyrinoid compounds. The potential stabilizing effect was attributed to the spontaneous partitioning of cobalt(II) porphyrin and cobalt(III) corrole into the buried half of the membrane, as corroborated by laser ablation ICPMS. The sensors showed an excellent reproducibility of the E0 values with a standard deviation of just ±0.7 mV (n = 4) between different sensor batches. Intercalating Compounds. The group of Schuhmann explored an interesting approach to achieve a well-defined interfacial potential between the solid-contact material and the ion-selective membrane by using an intercalation compound as

fonate) and cationic (cetyltrimetylammonium chloride) surfactant. Thorough washing (about 30 min in excess of deionized water) of the CNT films after deposition increased their hydrophobicity (contact angle measurements) and improved the K+-SEs characteristics significantly in terms of slope and detection limit. The impedance spectra of these electrodes were however changing with time, presumably caused by detachment of the sensing membrane from the solid contact. To avoid these problems, the authors proposed carboxymethylcellulose as alternative polymeric dispersing agent. This resulted in potentiometric sensors with good analytical characteristics, improved potential reproducibility (±2 mV) compared to the other reagents, and no evidence of membrane detachment. Qin and co-workers presented a CNT-based potentiometric solid-contact sensor for the detection of bisphenol A and explained the analytical signal by a change of surface charge.29 The proposed sensor was prepared by layer-by-layer assembly of carboxylated multiwall carbon nanotubes, the polycationic poly(diallyldimethylammonium chloride), and the polyanionic aptamer on the electrode surface. Bisphenol A was thought to induce a detachment of the aptamer from the electrode surface, resulting in a change of surface charge (from negative to positive) that presumably resulted in the potential change. We note that earlier work with alternating polyelectrolyte layers on ion-selective membranes gave no measurable potential change as a function of surface charge, rendering this explanation potentially problematic. Bisphenol A was shown to be measured in the concentration range from 3.2 × 10−8 to 1.0 × 10−6 M with a detection limit of 1.0 × 10−8 M. Yin et al. developed a solid-contact Ca2+-SE with good analytical characteristics (sensitivity, lower detection limit, and potential stability) based on hydrophobic octadecylaminefunctionalized graphene oxide uniformly dispersed in the membrane phase.30 The authors suggested that functionalized graphene oxide not only acts as a transducer layer but also immobilizes the ionophore through hydrophobic interactions, as evidenced by FT-IR spectroscopy. Paczosa-Bator et al. reported on a drop cast graphene supporting platinum nanoparticle layer used as a solid contact material for K+SEs.31 The resulting electrodes showed predictable Nernstian slope and a micromolar level detection limit but also attractive potential drifts (10.8 μV/h within 96 h) and excellent reproducibility of the standard potential values (±1.5 mV (n = 3)). Li et al. synthesized a three-dimensional graphenemesoporous platinum nanoparticle composite and used it as a solid contact material for Cd2+-SE.32 The transducer layer was drop-cast on the electrode surface from aqueous solution. The achieved detection limit value was 10−8.8 M. A good reproducibility of the standard potential values of ±2.5 mV (n = 3) was demonstrated. The group of Niu proposed monolayer protected gold clusters as ion-to-electron transducer.33,34 Gold clusters formed a separate layer by drop casting from solution on the electrode surface33 or were directly incorporated into the membrane cocktail.34 The obvious advantage of this material is its hydrophobicity, large capacitance, and good solubility in the membrane matrix. The mechanism of the potential stabilization at the membrane/glassy carbon electrode was, however, not clarified. Nevertheless, the prepared K+-selective electrodes showed reasonably stable Nernstian responses and typical detection limit and selectivity coefficients. Additional studies 6



Review

a transducer layer.42 The authors applied lithium iron phosphate, LiFePO4, as a solid contact for Li+-SEs. LiFePO4 can reversibly intercalate and deintercalate Li+ ions upon electrochemical reduction and oxidation of the Fe(II)/Fe(III) redox centers. In this configuration, one would expect the membrane potential to depend on the difference in the activities of the analyte ions in the sample solution and intercalating material, but since the activity of ions of interest in the intercalating material is assumed to be constant if it is chemically stable, the membrane potential would be a function of the ion activity in the sample solution only. Lithium iron phosphate was applied on the electrode surface as a slurry prepared by mixing it with an electron conductor (graphite powder), a binding polymer, and N-methyl-2-pyrrolidone as a solvent. A potential value drift of just −1.1 μV/h was reported, with a standard deviation of E0 of just ±2.0 mV (n = 3) while the achieved standard deviation of the potential measured in 10−1 M LiCl during 42 days was only ±1.5 mV. Komaba et al. demonstrated the efficiency of this approach by using different intercalating compounds, namely, Na0.33MnO2 and KxMnO2· nH2O, as a transducer layer for solid-contact Na+- and K+SEs.43 Lately, Schuhmann’s group also presented a family of Prussian Blue analogues as a promising transducer layer for solid-contact ISEs owing to their known capability to intercalate different ions.44 It was shown that potassium nickel hexacyanoferrate, sodium nickel hexacyanoferrate, and calcium nickel hexacyanoferrate can be used as solid contact materials for K+-, Na+-, and Ca2+-SEs, correspondingly. All electrodes had similar analytical characteristics (slope, detection limit, selectivity coefficients, and standard potential reproducibility) as their counterparts with inner reference solution. The electrodes provided stable reproducible potentials for at least 2−3 months. Other Materials. The group of Qin proposed to use molybdenum oxide (MoO2) microspheres45 and three-dimensional molybdenum sulfide (MoS2) nanoflowers46 as ion-toelectron transducers for solid contact ISEs. Both materials were applied by drop-casting from THF solution. The authors suggested that the transduction mechanism of these materials is based on forming an electrical double layer at the interface between the polymer membrane and MoO2 or MoS2. The lower detection limit of the resulting K+-SEs was similar to the values typically achieved for this membrane composition. No evidence of water layer formation was found. Unfortunately, the reproducibility of the standard potential of the electrodes was not reported.

influence of the boundary conditions and simulation parameters to find a solution for this problem.48 The reason for the failure is that mass transport does not account for concentration changes at both sides of the phase boundary, just at one. This means that the model allowed for ions to be generated (or lost) out of nowhere, which is chemically implausible. This group proposed to modify the established calculation protocol and termed it an interface equilibriatriggered time-dependent diffusion model.49 It postulates that the concentration gradients in both membrane and sample solution phases determine the diffusion of the components inside the corresponding phases but not the transfer across the interface. Transfer of the components across the interface at any time is determined by the corresponding local interphase equilibria. Independent of Egorov’s group, Bakker’s group found the same type of failures and used the super-Nernstian potential jump for a membrane initially void of analyte ion as an illustrative example.50 Here, the authors overcame the problem by treating the two boundary elements, one at either side of the sample−membrane interface, as a combined entity for mass transport purposes. While these two elements are linked by an equilibrium treatment, mass transport into and out of the combined entity is correctly described. Both Egorov’s and Bakker’s approaches are conceptually similar, give a good correlation to experimental data, and make the calculations much more robust than the original model. Sanders et al. used a rigorous Nernst−Planck−Poisson (NPP) model, where assumption of local equilibrium across the interface is not required, to simulate the behavior of ion sensors with blocked interfaces, such as coated-wire electrodes and ion-selective field effect transistors (ISFETs).51 This work demonstrates the first application of the NPP model to predict the response of AlGaN/GaN ISFETs with ionophore-doped membranes. Zdrachek and Bakker revisited an old problem of describing the potential response of ion-selective electrodes in solutions containing competing ions of different charge. It is well established that the Nikolsky-Eisenman equation does not adequately describe this case. The authors compared and analyzed five different approaches to describe this problem.52 It included the Nikolsky-Eisenman equation and its permutated form, the most rigorous self-consistent model, which is however mathematically complex, and two different approximations valid for cases of low level of interference. One of these approximations was introduced for the first time. An interesting outcome of the study was that the mathematical average of the Nikolsky-Eisenman equation and its permutated form give reasonably accurate results and might be practically useful because a single equation can be used to treat any number of charge combinations (see Figure 2). The new approximation mentioned above was used by the same authors to develop a time-dependent extrapolation method for the determination of unbiased low selectivity coefficients for two of the most prevalent cases of multivalent ions (zi = 2, zj = 1 and zi = 1, zj = 2).53 This method is based on eliminating the primary ion concentration near the membrane by extrapolating the linearized time dependencies of selectivity coefficients determined by the separate solutions method as a function of t−1/3 or t−1/6, depending on the charge combination of the two ions, to infinite time. The approach is an extension of earlier work by Egorov’s group that only treated equally charged ions. Jasielec et al. used the NPP model to confirm the validity and limits of the method proposed by

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THEORY OF POTENTIOMETRIC RESPONSE The use of numerical simulation, typically by finite element analysis, is an established way to predict time-dependent concentration and associated potential changes at ion-selective membranes. The aspect unique to such membranes is the formulation of the jump condition at the sample−membrane interface, which is typically treated by a local ion-exchange equilibrium treatment. A popular approach was based on Morf’s work, but two independent research groups have identified some weakness and put forward conceptual improvement to overcome them. Egorov’s group used finite difference analysis based on the diffusion layer model to compare methods recommended by IUPAC for the determination of selectivity coefficients.47−49 It was found that in some cases the earlier model shows principal limitations that may lead to failure of the calculations.47 The authors studied the 7



Review

electrochemical (amperometry, coulometry, chronopotentiometry, ion-transfer voltammetry) or optical methodologies. This may allow one to obtain additional analytical information and/ or to improve the system’s robustness and performance characteristics, such as operational reversibility, sensitivity, and selectivity. Amperometry and Coulometry. Bobacka’s group developed an interesting new coulometric readout principle for solid-contact ISEs (see Figure 3).58 Here, the electro-

Figure 2. Simplified ion-selective electrode selectivity theory for ions of different charge. The two traces show the calculated fraction of primary ion remaining in the membrane phase after ion exchange as a function of sample composition, calculated according to the selfconsistent equilibrium model and by a simpler, averaged NikolskyEisenman equation. Top: monovalent primary and divalent interfering ion. Bottom: divalent primary and monovalent interfering ion.52 To average, the second Nikolsky-Eisenman equation is written to treat the interfering ion as the primary one as vice versa. This averaged Nikolsky-Eisenman equation provides results that are in excellent agreement with the values predicted by the most rigorous model for the entire range of ion exchange.

Figure 3. Coulometric readout principle for solid-contact ISEs with a capacitive layer as a transducer material between electrode surface and ion-selective membrane.58 The electrochemical cell is held at a constant potential. Any potential change at the sample−membrane interface that is driven by a change in primary ion sample activity is compensated by an opposite potential change at the transducing layer. As shown on the right, this results in a transient current response until a new equilibrium state is reached. A linear relationship between accumulated charge and the logarithmic primary ion activity change is observed and serves as the analytical signal.

Egorov and co-workers.54 The calculations showed that this method works well in the range of medium selectivity coefficients values, provided that the primary ion contamination of the sample (for example, from the impurities in the interfering ion salts) can be avoided. Unfortunately, for very high selectivity coefficients values (Log KijPot < −7.0), the extrapolation gives negative results, and other methods should be used. Mikhelson’s group presented a simple theoretical model that can describe quantitatively the entire response range of ISEs including the domains of lower and upper detection limits by taking into account the coextraction processes from the inner reference solution and/or sample solution.55 This is a simplified model; thus, it allows one to predict the potential values of ISEs only for an arbitrarily chosen time. The same group studied the increase in the bulk resistance of ionophorebased ISEs observed with decreasing analyte concentration in the sample.56 It was suggested that the observed change in the bulk resistance originates from the difference in the membrane water uptake determined by the sample composition. The groups of Chumbimuni-Torres and Radu suggested that the conditioning step of ISEs can be eliminated by loading the membrane cocktail directly with primary ion solution.57 The applicability of this approach was confirmed for I−-, Ag+-, and Na+-SEs yielding functional electrodes with submicromolar detection limits.

chemical cell is held at constant potential. Any change of the indicator electrode potential must now be compensated by an opposite potential change at a transducing element, which happens to be a capacitive conducting polymer layer, PEDOT(PSS). This results in a transient current response until a new equilibrium state is reached. The accumulated charge is proportional to the logarithmic primary ion activity change. The authors showed that the analytical signal could be significantly amplified by increasing the PEDOT(PSS) film capacitance, which however is at the cost of increased response time. The same group studied the influence of the electrode geometry on the coulometric analytical signal of PEDOT PSSbased K+-SEs.59 Here, glassy carbon electrodes of different surface area were covered with PEDOT layers of the same capacitance, which was controlled by keeping the polymerization charge constant. The thickness of the covering K+selective membrane was also kept constant, giving lower membrane resistance with increasing electrode area. The response time significantly decreased with increasing electrode area. In collaboration between Bakker’s and Bobacka’s groups, the application of a coulometric readout mode was extended to the detection of anions using PEDOT doped with chloride ions as the ion-to-electron transducer.60 As part of the work, a theoretical model was proposed to predict the coulometric response and correlated with impedance analysis. The model showed good correlation with experimental data obtained for Cl−-SE and provided explicit explanations for the previously observed influences of the transducer layer capacitance or membrane resistance on coulometric response. This coulometric readout principle could be very useful in applications where very small concentration changes (down to 0.2%)

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NEW AND NONCLASSICAL READOUT PRINCIPLES FOR ION-SELECTIVE ELECTRODES Recent research has demonstrated that the applicability of ISEs can be significantly expanded by interrogating them by other 8



Review

ions from the sample, and increasing the solution pH to the desired value. Ion-Transfer Voltammetry. Another readout technique for ISEs that has been widely used over the last three years is ion-transfer voltammetry, which can today be applied at solid contact ISEs. The readout mode is based on the oxidation/ reduction of a conducting polymer (POT or PEDOT) transducer layer in solid contact ISEs that initiates ion-transfer processes across the overlaid membrane/sample interface (see Figure 4).

should be detected which is rather challenging with direct potentiometry. Höfler and co-workers proposed an amperometric detection mode in order to enhance selectivity and detection limit of traditional ISEs.61 The cell is divided with separate ionselective membranes into three isolated compartments. The measurement principle is based on detecting a current flow between two Ag/AgCl elements that are placed in the outer compartments of the cell, imposed by an asymmetry in the phase-boundary potential change of two ion-selective membranes with and without an ionophore upon their contact with a sample solution in the middle compartment. In some analogy to the coulometric readout principle outlined above, this amperometric mode may sense much smaller concentration changes than conventional potentiometry. The results were corroborated by NPP finite element simulations. It should be noted here that the use of membranes without ionophore may not be practical for the measurement of variable and unknown samples because they exhibit limited selectivity. Chronopotentiometry. Chronopotentiometry remains a popular readout mode for conventional ISEs. The group of Qin in particular has developed a number of bioassays exploiting chronopotentiometry as a readout mode of polymer based-ISEs.62,63 The principle is based on the polarization of the polymeric membrane doped with lipophilic electrolyte (i.e., tetradodecylammonium tetrakis(4-chlorophenyl)borate) triggered by oxidation/reduction of underlying PEDOT(PSS) film. The authors recently demonstrated the sequential detection of two oppositely charged biomolecules using a single electrode with this readout mode.63 The same group applied this electrochemical protocol by combining it with surface imprinting.64 The recognition reaction between the imprinted polymer surface and bioanalyte molecule is thought to block the flux of an indicating (reference) ion to the membrane, thereby modulating its response. Afshar et al. developed a chronopotentiometric protocol for the detection of a wide range of different analytes (calcium, chloride, alkalinity, acidity, and protamine) by polymer membrane based-ISEs in continuous flow conditions without requiring one to stop the flow.65 In this work, a nonpolarizable Donnan exclusion anion-exchanger membrane served as a separator to the reference/counter electrode. Such membranes sustain high current densities and exhibit stable potential values in electrolyte solutions. The power of chronopotentiometric readout mode for providing important information on chemical speciation was demonstrated by Jansod et al. for the ionizable drug phenytoin.66 Zero current potentiometry with membranes doped with an anion exchanger can sense only the ionized form of the analyte but chronopotentiometry allows one to estimate the total amount of analyte present in the solution by the imposed ion flux. A sequential operation allows one to measure both with the same membrane electrode. An elegant approach for tackling speciation analysis was also reported by Jansod et al. for the potentiometric detection of free and total carbonate.67 In this work, the total carbonate concentration was obtained as a result of the electrochemically triggered alkalinization of a thin layer sample (about 100 μm) formed as a restricted volume between a pH responsive polymer membrane electrode (so-called “proton sink”) and the carbonate-selective membrane electrode. Alkalinization was achieved by potentiostatic polarization of the pH-SE based on polymer membrane, removing hydrogen

Figure 4. Ion transfer at the membrane−solution interface resulting from the oxidation/reduction of a redox probe in the transducing layer as an analytical tool for ion sensing.68−77 On the right, two response regimes are identified depending on the analyte concentration range. At low sample concentrations, the peak current linearly depends on concentration (diffusion limitation) while at high concentration the peak position exhibits a Nernstian shift with analyte activity change.

Bakker’s group focused their attention on POT as a transducer layer for these experiments.68−72 It was shown that a single thin (only 200 nm) polymer membrane doped with up to three different ionophores and deposited on the top of a POT layer allows one to achieve the simultaneous detection of three different hydrophilic cations (lithium, potassium, and sodium) when interrogated by cyclic voltammetry.68 Peak position serves here as the analytical signal, resulting in response curves that are in analogy to potentiometry. The simultaneous detection of several ions with a single membrane is of course a significant advantage of such a voltammetric readout mode compared to potentiometry. The ion-transfer charge in this configuration is chemically limited by the quantity of added ion exchanger; its concentration should therefore be carefully optimized. While the first iontransfer experiments with this principle used conventional plasticized PVC membranes, further studies showed that this polymer matrix suffers from a significant deterioration of the signal after rinsing the electrode surface, apparently due to chemical loss of the membrane components and some physical detachment of the membrane. Bakker’s group performed a comparative study of different polymer matrices and found that plasticized polyurethane is a much more suited material.69 Further experiments showed that one of the limiting conditions for ion-transfer voltammetry experiments is the thickness of the POT layer, as an increase of the conducting polymer film completely suppresses the ion-transfer process.70 The mechanism of the POT thickness/POT surface roughness dependence on the ion-transfer reaction was elucidated by cyclic voltammetry, electrochemical impedance spectroscopy, ellipsometry, scanning electron microscopy, atomic force 9



Review

diaza[6]helicene functionalized with two bromine atoms was identified as the most promising candidate. The reduction of [6]helicene cation to [6]helicene radical triggers ion transfer. For cation transfer, the membrane should be doped with a cation exchanger76 while for anion transfer the presence of lipophilic electrolyte ETH500 (tetradodecylammonium tetrakis(4-chlorophenyl)borate) is necessary.77 Unfortunately, it was found that the ionophore-based cation-selective membrane was losing its sensitivity with time, presumably owing to an ion exchange between the [6]helicene and analyte cations, which reduces the scope of possible applications. Additional optimization of the molecular structures of the proposed redox probes is needed to obtain a stable analytical response and to decrease the concentration of the redox probes in the membrane phase. Cuartero et al. rationalized the mechanism of the previously observed irreversible electrochemical behavior followed by complete loss of redox reactivity of ferrocene-based redox probes in thin polymer films.78 It was shown that the chloride anion is linked to this irreversible ferrocene electrochemistry owing to the conversion of ferrocene into nonlabile and nonreducible FeCl4− species at the glassy carbon/membrane buried interface. This process would affect the behavior of thin membrane films more than for thicker ones as a result of the limited amount of available ferrocene. The explanation was strongly supported by synchrotron radiation-X-ray photoelectron spectroscopy and near edge X-ray absorption fine structure measurements. Cuartero et al. also studied redox molecule valence states implicated in the electron hopping mechanism of ethynylferrocene in unplasticized poly(methyl methacrylate)−poly(decyl methacrylate) membranes using synchrotron radiation-valence band spectroscopy.79 The authors found Fe 3d valence states at high concentrations of ethynylferrocene that can be explained by electron hopping between ferrocene moieties of neighboring redox molecules. Optical Readout. A new principle that converts potential changes at ISEs into a color change was recently reported by Bakker’s group (see Figure 5).80 It was achieved with a closed bipolar electrode at a constant applied potential where the ionselective component is confined to one end of the electrode while color is generated at the opposite pole in a thin layer

microscopy, and synchrotron radiation-X-ray photoelectron spectroscopy. Ion-transfer at the membrane−solution interface can be exploited for ion sensing in two principal regimes: (1) peak current linearly depends on concentration or (2) the peak position describes a Nernstian shift with increasing ion activity (see Figure 4). The applicability of these two regimes depends on the analyte concentration range. Yuan et al. presented a detailed model that allows one to predict the voltammetric current and peak position for a wide concentration range of analyte by considering diffusional mass transport at the membrane−solution interface.71,72 Using this model, one can readily estimate the limit of detection of the technique as well as the concentration level at which the switching between the two mentioned sensing regimes will be observed. Amemiya’s group explored the use of PEDOT films to trigger the ion transfer across the thin plasticized PVC membranes doped with ionophores and lipophilic electrolyte (tetradodecylammonium tetrakis(pentafluorophenyl)borate). They reported on a multiion voltammetric detection with a membrane doped only with one ionophore and reinforced it with a theoretical model and calculations.73 In contrast to the independent ion-transfer mechanism described above where ionophores give rise to selectivity, the mechanism of the secondary ion detection here is different. Once an ionophore becomes exhaustively depleted upon transfer of the most favorable ion, a less favorite one can be extracted at more extreme potentials. One of course may question the selectivity for this secondary extraction. In other work, Amemiya demonstrated a significant kinetic improvement of ISE selectivity (up to 7 orders of magnitude) exploited in a voltammetric readout mode in comparison to potentiometry where selectivity tends to be given by ion-exchange equilibria.74 This principle was put forward for Na+ and Li+ionophore-based membranes. It was shown that the ionophore-facilitated transport across the membrane/water interface of more hydrophilic alkaline earth metal cations (like Ca2+, Sr2+, and Ba2+) is significantly slower than in case of the corresponding primary ions (Na+ or Li+), which is manifested by the negative peak potential shift and increased peak separation. The selectivity coefficients calculated according to the peak positions observed in separate solutions turn out to be smaller. The observed kinetically hindered transport for more hydrophilic ions was intuitively explained by their partial dehydration with the formation of the adduct with a “water finger” prior to complexation with an ionophore at the membrane/water interface. Unfortunately, the concept was not demonstrated in real world samples containing a mixture of ions. The group of Bakker introduced new molecular redox probes for the ion-transfer voltammetry sensing mode of ISEs, which was originally limited to the use of POT and PEDOT. They can be dissolved in the membrane phase and mediate the ion transfer across the interface upon their reduction or oxidation.75−77 Jansod et al.75 demonstrated the applicability of the dinonyl bipyridyl Os(II)/Os(III) complex for mediation of ion transfer for its oxidation/reduction process. The ratio between the concentrations of added cation exchanger and redox probe was found to determine the voltammetric anion or cation response of this system. Cationic diaza, azaoxa, and dioxa[6]helicenes and their derivatives were introduced as another family of molecular redox probes for voltammetric cation76 and anion77 detection by Jarolimova et al. Cationic

Figure 5. Potential change of a potentiometric sensing probe can be visualized by the color change of redox indicator using a closed bipolar electrode configuration.80 If a constant potential is applied across the bipolar electrode, the potentiometric signal change at the sample side results in an opposite potential change at the detection side, which imposes a new concentration ratio of the redox indicator that results in a visible color change. A colorimetric calibration curve of the bipolar electrode is shown on the right. Reproduced from Jansod, S.; Cuartero, M.; Cherubini, T.; Bakker, E. Anal. Chem., 2018, 90, 6376−6379 (ref 80). Copyright 2018 American Chemical Society. 10



Review

was shown that owing to the high concentration of exchangeable ions hydrophilic ion-exchange membranes exhibit an excellent resistance to Donnan failure (the co-ion transfer into the sensing membrane resulting in the upper detection limit) in comparison with traditionally used hydrophobic membranes. The ion-exchange selectivity of such ion-exchange membranes is otherwise rather limited. Michalska and co-workers introduced the concept of socalled potentiometric bilayer membranes. Authors described the bilayer membranes as a sequence of poly(hexyl acrylate) and/or poly(lauryl acrylate) layers characterized by different ionic mobilities.85 It was found that careful tailoring of such membrane architecture allows one to compensate the spontaneous ion fluxes across the membrane phase and improve the lower detection limit of ISEs. Ion-Exchange Nanopore Membranes. Nanopores represent a versatile sensing platform that has been known for a number of years. The principle of their response is based on the selective alteration of the flux of ions passing through preconditioned pores by the chemical and physical properties of the interior pore surface. While the majority of nanoporebased sensors are used to pass ionic current as an analytical signal, an alternative potentiometric readout mode has recently captured some attention. A potentiometric readout allows for simpler instrumentation and higher signal to background noise ratio. The potentiometric response of nanopores can be understood using the concept of permselectivity in some analogy to conventional polymer membrane ISEs. The membranes with charged nanopores exhibit permselectivity behavior by rejecting ions of the same charge sign and transporting those of opposite charge (see Figure 6). The

compartment. The bipolar electrode configuration allows one to physically separate the sample compartment from the detection compartment. If an electric potential is imposed across the bipolar electrode, the potentiometric signal change at the sample side results in an opposite potential change at the detection side, which is coupled to the turnover of a redox indicator and subsequently a color change. The validity of this approach was confirmed in separate experiments with a chloride responsive Ag/AgCl element and a liquid membrane-based calcium-selective membrane electrode, using the redox indicator ferroin in the detection compartment. This is a promising direction that widens the area of potentiometric sensor applications and paves the way for optical ion sensing in colored and turbid solutions. Ding et al. reported on another optical ion sensing platform utilizing ISEs.81 In this work, a fixed potential difference was applied between glassy carbon electrode modified with an ironalginate-horseradish peroxidase and conventional ISE which are placed in separate compartments of the cell connected with a salt bridge. The change in analyte concentration in the sample compartment results in a potential change of the ISE, which induces the enzyme release and subsequent color change in the detection compartment. The application of this optical ion sensing platform for detecting both cations and anions was successfully demonstrated.

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SENSOR MATERIALS Membrane Materials. Polymeric membrane ISEs are traditionally prepared with PVC as sensing matrix. To enhance the robustness and analytical characteristics of potentiometric sensors, scientists have been looking for an appropriate replacement for PVC for many years. Fluorous liquid membranes are particularly promising because their poor solvent properties can translate into dramatically enhanced selectivity (up to 16 orders of magnitude for an ion-exchange membrane vs 8 orders usually obtained for PVC membranes) and chemical robustness. As an example, Bühlmann’s group recently demonstrated the stability of pH electrodes made of ionophore-doped fluorous membranes (Teflon AF2400) by exposing them to harsh on site cleaning protocols used in many industrial processes.82 To mimic this type of treatment, the electrodes were repeatedly exposed for 30 min to a 3.0% NaOH solution at 90 °C. The application of fluorous liquids that have to be infused into a porous Teflon disc as a mechanical support to prepare the membrane is only compatible with fluorophilic ionophores and ion exchangers. Carey et al. reported on newly synthesized semifluorinated polymers suitable for ISEs membrane fabrication.83 It was found that ion-exchange membranes based on these semifluorinated polymers provide a smaller selectivity range (about 8 orders of magnitude) in comparison with fluorous liquids. However, their advantage is that they can be doped both with fluorophilic ionophores and traditional lipophilic ionophores. Moreover, the membranes prepared with cross-linked semifluorinated polymers can be cast and used in the same way as conventional PVC membranes. This material also exhibits superior thermal stability: a Nernstian response was maintained after exposure to a boiling aqueous solution for 10 h. Bühlmann and co-workers focused their attention on the application of hydrophilic ion-exchange membranes for potentiometric sensing and compared the performance of ISEs based on this material with their hydrophobic counterparts doped with an ionophore and/or an ion exchanger.84 It

Figure 6. Representation of permselectivity properties of solid-state modified gold nanopores.86,87 The gold surface may be modified with thiol terminated compounds that contain ion-exchanger groups. As a result, ions of the same charge sign are rejected and those of opposite charge are being readily transported. Further chemical functionalization endows the sensing probe with desired chemical selectivity.

selectivity of this ion transport can be enhanced by using a selective complexing agent (ionophore), together with ionexchanger sites, grafted to the surface of the nanopore. Gyurcsanyi’s group made significant contributions to the development of potentiometric nanopores using solid-state gold nanopore structures.86,87 The group presented a new potentiometric method for the selective detection of nucleic acids,86 which is based on a charge inversion in the sensing zone of a nanopore that is triggered by the selective binding of negatively charged microRNA strands to positively charged complementary peptide-nucleic acid (PNA) modified nanopores. The initial anionic permselectivity of PNA-modified nanopores is gradually changed to cationic permselectivity, which is detected by measuring the potential across the nanoporous membrane. The same group developed a Cu2+selective potentiometric sensor based on a 5 nm diameter gold nanopore modified with a glycine−glycine−histidine peptide.87 This is a very hydrophilic ionophore that would normally not 11



Review

selective recognition properties toward the compound of interest. The preparation of MIPs is based on the polymerization of a functional monomer and a molecule used as a template in the presence of a cross-linking agent, which is followed by the removal of a template molecule before use. MIPs have shown to be useful in different analytical applications and became recently rather popular as recognition elements incorporated in the polymer membranes of ISE. MIPs were used for the potentiometric detection of the insecticide dinotefuran,92 1-hexyl-3-methylimidazolium,93 acetylcholine,94 lactic acid,95 2-naphthoic acid,96 taurine,97 bisphenol S,98 and bisphenol AF.99 Unfortunately, it appears that the authors sometimes overestimate the sensing power of MIP materials and tend to disregard some fundamental principles of potentiometry. For example, it is surprising to see reports on MIP-based potentiometric sensors without any ion exchanger in their membrane composition. The phase boundary potential is determined by the ratio of analyte ion activity in the aqueous and membrane phases. To observe a correlation between measured phase boundary potential and the concentration in the membrane phase, one needs to keep the analyte ion activity in the organic phase constant, which is usually achieved by incorporating a lipophilic ion exchanger into the organic phase. Abdel-Ghany at al. explored the possibility of using MIPs synthesized with acrylamide or methacrylic acid (MAA) as a functional monomer and ethylene glycol dimethacrylate (EGDMA) as a cross-linker for the potentiometric determination of the insecticide dinotefuran.92 The authors claimed that the developed sensors exhibited a close to Nernstian response slope with an appealing detection limit of 0.35 μg L−1, but the proposed membrane composition did not include any cation exchanger. Thus, one is left to wonder about the origin of the observed response. Zhuo and co-workers reported on a potentiometric sensor based on MIPs for determination of the cationic 1-hexyl-3-methylimidazolium.93 The authors prepared the MIP material using MAA and EGDMA as the functional monomers and cross-linking agent. Surprisingly, it was concluded that the optimal membrane composition should be the one without added anionic lipophilic sites since membranes with added sodium tetraphenylborate were found to give a higher detection limit. Nevertheless, this membrane gave a Nernstian slope (58.9 mV) and a detection limit of 2.8 × 10−7 mol kg−1. One might question the role of the MIP in this sensor since ISEs based on a nonimprinted polymer also demonstrated a rather high response slope of 48−52 mV. The group of Sales used MIPs for acetylcholine detection that was synthesized by bulk polymerization in a composite matrix of multiwalled carbon nanotubes (MWCNTs) and aniline.94 Unfortunately, the technical quality of this work was rather low and the authors even tried to estimate the selectivity coefficients of the sensor over some neutral species like glucose, which is not possible. A strong pH influence on the performance characteristics was found that might be caused by the pH sensitivity of the polyaniline material. Unexpectedly, the authors came to the conclusion that pH 4.0 provides the best operating characteristics for the sensor with a super Nernstian slope of 84 mV while the same electrode exhibited a slope of 49 mV at pH 6.0. Acetylcholine detection in spiked artificial serum samples was demonstrated. Alizadeh et al. introduced a MIP-based sensor for lactic acid sensing in dairy products.95 MIP was synthesized using allyl amine and EGDMA as functional monomer and cross-linker.

be functional in conventional ISEs as it would not be compatible with the sensing matrix and likely leach out of the membrane. In this nanopore application, the problem was solved by modifying the complexing tripeptide with a terminal cysteine and a glycine spacer and attaching it to the gold surface. This approach allowed one to construct ISEs with an extraordinary Cu2+ selectivity. This should pave the way for the use of hydrophilic ionophores for ion sensing that were not appropriate thus far. Ionic Liquids. Room temperature ionic liquids (ILs) are promising materials for potentiometric sensors, even though their role in potentiometric sensors is not yet fully understood: they have been promoted as inert plasticizers and/or nonspecific ion exchangers and even as ionophores. Radu’s group investigated the effect of trihexyl(tetradecyl) phosphonium-based ILs as plasticizers for PVC membranes doped with anion exchanger.88 The response characteristics toward ten different anions were evaluated for membranes prepared with six phosphonium-based ILs. The results were compared with membranes based on two classical plasticizers: bis(2-ethylhexyl) sebacate (DOS) and 2-nitrophenyl octyl ether (NPOE). Deviations of the observed selectivity coefficients from the well-known Hofmeister series were found, suggesting binding functionalities of the IL.88 Schazmann et al. reported on a solid-contact anion-SE based on the family of imidazolium salts covalently linked to PVC.89 Here, the IL, with chloride as a counterion, served as an anion exchanger and a salt bridge, stabilizing the interfacial potential between the Ag/AgCl electrode substrate and the membrane. The resulting electrodes exhibited close to Nernstian slopes and stable and reproducible signals to different inorganic anions. The handling protocols of these sensors can be significantly simplified since it takes only 1 h to condition them and they can be stored dry between measurements. Rzhevskaia et al. demonstrated the use of low-melting ionic liquids based on the cationic 1,3-dihexadecylimidazolium and a range of counteranions such as chloride, iodide, and thiocyanate for the fabrication of screen-printed solid-state electrodes for the detection of the corresponding anions.90 The ILs were drop cast in a molten state on the surface of a carbon working electrode and quickly solidified to form a robust layer on the surface. All sensors exhibited slopes close to Nernstian and good selectivity. The applicability of the developed electrodes for the potentiometric determination of iodide in pharmaceutical formulations and thiocyanate in human saliva was demonstrated. Mendecki et al. reported on the development of a novel solid-contact iodide-SE based on covalently attached 1,2,3 triazole-based IL with iodide as a counterion.91 The iodide-SE was prepared by casting a triazole-based IL copolymerized with lauryl methacrylate on top of POT used as an ion-to-electron transducer. The IL was assumed to play the role of an iodide ionophore. The electrodes exhibited high selectivity toward iodide anions over a number of inorganic anions and near-Nernstian behavior in a wide concentration range with a lower detection limit of 8 ppb. The inherent presence of the iodide in the membrane reduces the need for electrode conditioning. The sensor was used to determine iodide concentration in human urine, but the calculated concentration was 50% lower than the one evaluated by ICPMS. The possible reasons for this discrepancy were unfortunately not discussed. Molecular Imprinted Polymers (MIP). Molecular imprinted polymers (MIPs) are tailor-made materials with 12



Review

MIP-based sensor. The selectivity gain over other phenols was also observed in the case of a soluble MIP. Kupis-Rozmyslowicz et al. reported on MIP materials for potentiometric sensing with electrodeposited films. A molecularly imprinted conducting polymer film for taurine detection was electrodeposited from an aqueous solution containing 3,4ethylenedioxythiophene, acetic acid thiophene, flavin mononucleotide, and taurine.97 After removal of the template, the sensor showed close to Nernstian response slope (53.8 mV) toward the protonated form of taurine in the concentration range of 10−4 to 10−2 M. Ionophores. Anion-Selective Ionophores. Pankratova et al. examined a series of fluorinated tripodal compounds as potential ionophores for the fabrication of ISEs for chloride analysis in serum samples.100 It was found that ISEs based on tren tris-urea bis(CF3)[C33H27F18N7O3] exhibit the best selectivity for chloride over major lipophilic anions such as salicylate and thiocyanate that are commonly present in biological fluids. This electrode was successfully applied for chloride determination in undiluted human serum while the slope of the linear calibration in a relevant background of interfering ions was close to Nernstian (49.8 mV). Nuclear magnetic resonance titrations, potentiometric sandwich membrane experiments, and computational studies were performed to determine the binding constants and complexation stoichiometry for the new ionophore with chloride ions. Yagi at al. used a zirconium(IV) complex with octaethylporphin as a charged carrier exhibiting high selectivity to triphosphate against other hydrophilic anions including diphosphate and phosphate.101 In this work, the HP3O104− species was apparently detected at pH 1.5. The structure of the complex was suggested as [Zr(octaethylporphin) 2+ ] 4 [HP3O104−]2 where each HP3O104− is neutralized by two Zr(octaethylporphin)2+ units. In this supramolecular organization, the remaining proton of the triphosphate ion is utilized for the intermolecular hydrogen bonding of two units to make the porphyrin rings serve as a lipophilic shell for triphosphate. The group of Bachas presented a pentagonal macrocyclic compound with an electropositive cavity, so-called cyanostar, which is able to bind anions by CH-based hydrogen bonding.102 The size of the cyanostar’s cavity and its planarity favor the formation of a 2:1 sandwich complex with larger anions, like perchlorate, discriminating the smaller ones like chloride. ISEs of optimized membrane composition demonstrated a response to ClO4− with a slope of −57.0 mV and a detection limit of 50 nM, but unfortunately, complex formation constants were not reported. It is apparent that altering the size of the central cavity and its functionalization might result in the design of new various anion-selective ionophores. Shehab and Mansour introduced a Co(III) complex of (1H-benzimidazol2-ylmethyl)-N-(2-chloro-phenyl)-amine as a new ionophore for salicylate sensing.103 ISEs based on this neutral carrier exhibited good selectivity over the range of different inorganic anions, close to Nernstian response slope, and a detection limit of 0.4 μM, but no complex formation constants were reported. The applicability of the sensors was tested for determination of salicylate ions in human plasma and pharmaceutical formulations. Abdel-Haleem et al. synthesized two new Mn(III)− and Mn(IV)−salophen complexes and used them as charged carrier for thiocyanate.104 Both sensors exhibited very good selectivity toward thiocyanate, as the logarithmic selectivity coefficients over the very lipophilic perchlorate were about −2.

The sensor exhibited a Nernstian slope of 30.3 mV in the concentration range of 10−1−10−6 M with detection limit of 7.3 × 10−7 M. It was successfully used to estimate lactate anion concentration in samples of milk and yogurt. Li et al. reported on the development of a screen-printed potentiometric sensor for determination of 2-naphthoic acid using MIPs and a reduced graphene-oxide as a transducer layer.96 MIP nanobeads were prepared from acrylamide as a functional monomer, methyl methacrylate as a comonomer, and divinylbenzene and trimethylolpropanetrimethacrylate as cross-linkers. The proposed sensor exhibited a Nernstian response of 59.0 mV over the concentration range of 1.0 × 10−5−3.0 × 10−4 M with a detection limit of 2.2 μM. To satisfy the needs of trace-level analysis, the authors aimed to enhance the sensitivity of the ISE by exploiting a nonequilibrium superNernstian response, also known as the Hulanicki effect. Under these conditions, a linear concentration range of 1.0 × 10−10− 5.0 × 10−9 M with a detection limit of 6.9 × 10−11 M was achieved. As these are transient conditions, the authors should have specified in detail the specific measurement conditions used, such as time interval and stirring conditions. Qin and coworkers also developed an all-solid-state MIP-based potentiometric sensor for determination of bisphenol S by using a nanoporous gold film as a solid contact.98 The ISE was characterized with close to Nernstian response (28.8 mV) toward dianion of bisphenol S in the concentration range of 3 × 10−3 to 1 × 10−5 M and the detection limit of 3 × 10−6 M at pH 10.2. The authors proposed a way to improve the sensitivity of the sensor based on previously reported super Nernstian anionic potential responses of polymeric membranes doped with quaternary ammonium salt generated in the presence of electrically neutral phenols. The sensing mechanism is thought to be based on the extraction of neutral phenol ArOH into the membrane phase, accompanied by the formation of Q+X−·ArOH complex and subsequent proton dissociation of the complexed ArOH with ejection of acid HX into the aqueous phase. The authors used the potential difference between the baseline potential values and those measured at a fixed time of 250 s after bisphenol S addition at pH 5.0 for quantitation. It was shown that with this protocol the sensor has a linear concentration range from 0.1 to 2 μM with a detection limit of 0.04 μM. It is well-known that owing to the rigid and highly crosslinked structure MIPs cannot be easily dissolved in the membrane phase. For this reason, they are normally dispersed in the membrane matrix to form a heterogeneous mixture. This heterogeneity may result in a decrease of the amount of the available binding sites as well as the increase of the membrane impedance in comparison with the homogeneous membranes. The group of Qin introduced for the first time a soluble MIP as a receptor for bisphenol AF.99 The plasticized PVC soluble MIP was prepared by swelling the traditional MIP (synthesized from MAA as a functional monomer and divinylbenzene as cross-linker) in 1,2,4-trichlorobenzene at a high temperature. The same protocol as described above was used for sensing neutral bisphenol AF. The sensor exhibited a linear response in the narrow concentration range of 0.1 to 1 μM with a detection limit of 60 nM at pH 6.0, but the detected potential differences were very small (4.93 mV/μM), which may result in an increased error. Nevertheless, it was demonstrated that the sensor based on a soluble MIP exhibits an improved sensitivity toward bisphenol AF compared to the conventional 13



Review

were about −3.5 over Pb2+ and Cd2+ and about −4.5 over Zn2+ and Ni2+. While the ionophores were considered to be neutral carriers, it is not clear why the incorporation of anionic lipophilic sites into the membrane composition deteriorated the ISE response. Kumar et al. reported on an Fe2+-selective electrode based on (E)-3-((2-aminoethylimino) methyl)-4H-chromen-4-one as a neutral carrier.111 The sensor exhibited close to Nernstian slope of 27 mV and a good detection limit of 2.5 × 10−8 M but rather modest selectivity. Pb2+, Ni2+, and Ag+ were found to be the most interfering ions with logarithmic selectivity coefficients of about −2. Rezayi et al. explored the use of methylcalix[4]resorcinarene as an ionophore for Ti3+ sensing in its predominant form TiOH2+ in the pH range of 1.0− 2.5.112 The detection limit of ISE with optimized membrane composition was 8.9 × 10−7 M. The reported logarithmic selectivity coefficients estimated for a wide range of different cations ranged from −4.6 to −1.6. The selectivity coefficients were measured with the matched potential method, which cannot directly be compared to data obtained by other protocols. Zahran et al. showed that the incorporation of cyclosporine A into polymer membrane gave ISEs with a pronounced selectivity toward calcium ions.113 The selectivity gain over sodium, potassium, and magnesium ions was up to about 3 orders of magnitude in comparison with an ion-exchange membrane without ionophore, which is modest compared to the current state of the art. The authors also demonstrated electrospray ionization mass spectrometry for obtaining data about the distribution of complexed species in a mixture of ionophores and ions. Using these data, one can estimate the efficiency of ion binding for a number of different ionophores in a short period of time, which can be very useful for the screening of new molecules. Mass spectrometry produced data that was consistent with potentiometric selectivity. The groups of Andrade and Ballester reported on a synthetic receptor, aryl-substituted calix[4] pyrrole with a monophosphonate bridge, for sensing the cationic creatininium ion.114,115 The receptor works by including the creatininium cation in its deep and polar aromatic cavity and establishing directional interactions in three dimensions. The logarithmic binding constant of the ionophore with creatininium in the polymeric membrane was estimated as 6.60.115 Creatininiumselective electrode exhibited a close to Nernstian slope with a linear range from 1 μM to 10 mM and detection limit of 10−6.2 M.114 The operating pH range of the sensor is rather narrow from 2.8 to 3.8.115 The developed potentiometric sensor demonstrated an improved selectivity over Na + (log + Pot KPot Creatininium, Na+ = −3.7) and K (log KCreatininium, K+ = −2.5) which may allow its use for the analysis of biological liquids.114,115 The authors validated this application for diluted urea and plasma samples. Khaled et al. showed that calix[4]arene could be a promising ionophore for gentamicin detection.116 The proposed sensor demonstrated Nernstian slope of 30.5 mV and detection limit of 7.5 × 10−8 M. Bliem et al. developed a serotonin-selective electrode incorporating an ion-pair complex of protonated serotonin cation and a carborane anion [Co(1,2-C2B9H11)2]− into plasticized PVC membrane.117 The ISE exhibited a near Nernstian response in the concentration range from 2.25 × 10−5 to 1.00 × 10−2 M and a micromolar detection limit. Unfortunately, the very modest selectivity of this sensor over Na+ and K+ results in an increase of the observed detection

The values of the binding constants of the ionophore with thiocyanate in the polymeric membrane were estimated as 1014.1 and 1012.5 for Mn(III)− and Mn(IV)−salophen complexes, respectively. The analytical application of the sensor was successfully demonstrated in saliva samples. Cyclodextrin derivatives possessing a cage-like supramolecular structure remain very popular in chemical sensing and have been explored as possible ionophores for anion sensing. Lenik and Nieszporek reported on the use of heptakis (2,3,6tri-O-benzoyl)-beta-cyclodextrin as an ionophore for ibuprofen (2-(4-isobutylphenyl)propionic acid) detection.105 The electrode exhibited a Nernstian slope of 59.9 mV but in a rather modest concentration range from 10−5 to 10−2 M. Although authors reported good selectivity, the small electrode slopes for interfering ions suggest a significant experimental bias in the data. Cation-Selective Ionophores. Porphyrins have been used as ionophores in potentiometry for a long time. The free base porphyrins are known to be cation-selective while metalloporphyrins are normally anion-selective. Lisak et al. studied porphyrin dimers as ionophores for anion and cation sensing and discovered that porphyrin dimers carrying both metal and freebase porphyrin units can exhibit either anion or cation sensitivity with respect to adding either liopophilic anion or cation exchanger to the membrane.106 Perchlorate and silver were chosen as primary ions for this selectivity study. With cation-sensitive sensors, the selectivity was significantly improved with porphyrin dimers instead of single porphyrin molecules. The selectivity coefficient values depended on the order of porphyrin units in the dimer. These interesting discoveries will likely stimulate the application of complex porphyrin systems with more than one porphyrin unit. Juarez-Gomez et al. presented a new Hg2+ ionophore, O,O′(2,2′-biphenylene)dithiophosphate methyl.107 An ISE based on this neutral carrier exhibited a Nernstian response of 29.8 mV and an attractive detection limit of 9.1 × 10−10 M. While the authors demonstrated a stable potential in the pH range from 0 to 6.0, they chose rather surprisingly an extreme pH of 0 as being optimal for further measurements. The reported logarithmic selectivity coefficients measured by the fixed interference method over Pb2+ and Cu2+ were remarkably good (−6.9 and −5.3, respectively). The sensor was successfully used as an indicating electrode during potentiometric mercury titration with EDTA. Said et al. used bis[1benzyl-benzimidazoliumethyl]-4-methylbenzenesufonamide bromide as Ag+ ionophore,108 but the calculated selectivity coefficients of the prepared sensor were very modest and resulted in an unattractive detection limit of 2 × 10−6 M. Omran et al. reported on another Ag+ ionophore, p-tertbutylthiacalix[4]arene with two triazole rings.109 An ISE based on this carrier exhibited a close to Nernstian response slope in the concentration range from 7.0 × 10−6 to 8.0 × 10−3 M and a very modest detection limit of 3.9 × 10−6 M. Unfortunately, the proposed modification of the calix[4]arene structure did not result in a significant improvement of the selectivity toward Ag+, and the worst selectivity was observed over potassium and sodium. A family of four Cu2+ ionophores based on [14]tetraazaannulene derivatives was synthesized and characterized in ion-selective membranes by Kawakami and co-workers.110 A Nernstian response was observed in a rather narrow concentration range between 10−6 and 10−4 M. For the best membrane composition, the logarithmic selectivity coefficients 14



Review

limit to the level of 10−4 M in the artificial biological liquid sample while serotonin concentration in body fluids ranges from 0.3 to 0.7 μM. This fact makes the real-world application of this ISE very difficult.

heptakis(2,3,6-tri-o-methyl)-β-cyclodextrin ionophore on top of a layer of carbon ink. The reference electrode membrane was composed of poly(methyl methacrylate-co-butyl methacrylate) doped with KCl on top of an Ag/AgCl layer. The sample was added to the sampling pad, and the device was folded along the fold-lines following the specific sequence to allow for the monitoring of the EMF change. The origami paper-based device exhibited a 0.06 nM detection limit for methyl parathion. Radu’s group proposed an alternative approach for the fabrication of paper-based electrodes by preparing an electron conductive layer by mechanical abrasion of household pencil onto a modified acetate sheet.120 The applicability of this approach was tested for sodium-, nitrate-, and ammoniumselective electrodes and a solid-contact reference electrode by covering a graphite layer with POT and the corresponding ion selective/reference electrode membrane. A PVC-based membrane doped with tetrabutylammonium tetrabutylborate was used as the reference electrode. The ISEs exhibited a wide dynamic response range, fast response time, and satisfactory long-term stability. The same methodology was used to prepare a single strip device consisting of a reference electrode and a series of nitrate- and ammonium-selective electrodes. This device was tested for the analysis of natural water samples and gave results that corresponded well to the data obtained with other traditionally used techniques. Sjörberg et al. reported on a paper-based planar electrode platform where working and reference electrodes were printed using ink based on a stable suspension of gold nanoparticles.121 These electrodes were subsequently covered with PEDOT(PSS) layer as solid contact by inkjet printing, giving conducting polymer films with comparable characteristics as electropolymerized or drop-casted ones. The reference electrode was prepared by covering the PEDOT layer with a plasticized PVC membrane doped again with tetrabutylammonium tetrabutylborate. The indicator electrode was a K+selective valinomycin based-membrane. The analytical characteristics were promising, but the sensors were unfortunately not tested in complex real world samples. The group of Chumbimuni-Torres developed a single strip paper-based ion sensing platform based on solid-contact working and reference electrodes.122 The paper-based substrate was prepared by coating it with a suspension of single-walled carbon nanotubes. At the bottom of each paper sheet, a 0.5 cm diameter orifice was spluttered with gold and covered with POT and polymer membrane by drop-casting. The reference electrode membrane consisted of methyl methacrylate-co-decyl methacrylate and ionic liquids ethyl-3methylimidazolium bis(trifluoromethane sulfonyl)amide in the ratio of 50:50. Na+,- K+-, and I−-selective PVC-based membranes were used as indicator electrodes. The singlestrip sensor exhibited a Nernstian response toward all tested ions with submicromolar limits of detection. The possibility of exploiting this platform for multiplexed ion analysis was demonstrated for simultaneous detection of K+ and I−. Andrade’s group recently reported on the interesting potentiometric hydrogen peroxide detection with Pt electrodes. It was found that Nafion not only can serve as an effective permselective barrier for some charged interfering species, such as ascorbate, but also can significantly enhance the sensitivity to hydrogen peroxide in solutions of high ionic strength.123 Pt electrodes covered with Nafion membrane were found to exhibit a linear dependence with logarithmic concentration of

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MINIATURIZED ION-SELECTIVE ELECTRODES Paper-Based and Microfluidic Potentiometric Devices. Paper has recently become increasingly popular as a substrate for sensor fabrication. Its simplicity, affordability, and ease of scaling and fabrication make a disposable paper-based potentiometric sensor an attractive choice for low-cost pointof-care and in-field testing applications. Bühlmann’s group reported on a disposable planar paperbased potentiometric ion-sensing platform.118 It contained an ISE and a reference electrode embedded into the paper substrate. Clinical applications were demonstrated with Cl− and K+ selective membranes. A commercial hydrophilic highcapacity anion-exchange membrane and valinomicyn-doped PVC membrane were used for Cl− and K+ detection. The reference membrane was doped with ionic liquid. Sensing and reference membranes were facing each other and separated the sample and reference solution zones. In complete analogy to a traditional ISE, the authors used a stencil-printed Ag/AgCl in contact with 0.1 M KCl for inner and reference electrolytes to finalize the electrochemical cell. The aqueous channels were formed by depositing polyurethane-based hydrophobic barriers. The required sample volume was just 20 μL. While the sensors worked well even in blood serum and exhibited only a few millivolts variation in their E0 values, the lower detection limit was unusually high (10−3 M) for both membranes. Further improvements are required to achieve calibration-free ion sensing. Ding et al. developed a three-dimensional origami paperbased device for potentiometric biosensing of organophosphate pesticides (see Figure 7).119 The bioassay is based on the

Figure 7. Three-dimensional origami paper-based device for potentiometric biosensing of organophosphate pesticides.119 Left: The device consists of one test pad with electrodes and three folding pads, each for the deposition of sample, enzyme, and substrate reagents, respectively. The folding sequence is identified as Steps I, II, and III. Right: The EMF difference observed between samples with and without analyte resulting from the ability of organophosphate pesticides to inhibit the activity of the enzyme is used to calculate analyte concentration.

known ability of organophosphate pesticides to inhibit the activity of butyrylcholinesterase. The device exhibited a test pad containing ISE and reference electrodes and three folding pads: a sampling zone pad, a pad with an immobilized enzyme, and one containing substrate reagents. The ISE for butyrylcholine was fabricated by casting the membrane doped with 15



Review

H2O2 in the 10 μM to 1 mM concentration range with a slope of −125.1 mV, more than 4 times the value predicted by the Nernst equation. The origin of this high response was not clearly understood. The authors suggested that the coupling between the redox potential on the Pt electrode and the Donnan potential of the Nafion membrane may play a role. The approach was put to work by developing a potentiometric paper-based device for detecting glucose in biological liquids124 where hydrogen peroxide is generated as a result of the enzymatic reaction. The working electrode was built using a platinized filter paper coated with a Nafion membrane that entrapped the glucose oxidase. The reference electrode was fabricated by casting a polyvinylbutyral/NaCl composite onto a conductive paper. The device was equipped with a sampling module that allowed one to perform the analysis in a single drop of blood. Under optimum conditions, a sensitivity of −95.9 mV/dec in the range of 0.3−3 mM was achieved in artificial serum samples. A good correlation between glucose concentration measured by the potentiometric paper-based platform and a commercial glucometer or colorimetric method used in clinical laboratories was demonstrated. Because the linear response range of the sensor was narrower than the physiological range of interest, a 10-fold dilution of the sample was unfortunately required. The same group presented a modified paper-based biosensor for monitoring glucose levels in beverages.125 In complete analogy with the previous approach, the sensing principle was based on the potentiometric detection of the hydrogen peroxide generated by an enzymatic reaction, but the working electrode was constructed by covering a platinized paper substrate first with Nafion membrane and subsequently with a polymeric membrane made of a mixture of poly(vinyl alcohol) and chitosan containing glucose oxidase. This approach appeared to facilitate enzyme immobilization and was found to increase the stability of the sensor over time. A commercial double junction reference electrode was used for measurements. The results of glucose determination in commercial orange juices were demonstrated and validated with an alternative analytical technique. The group of Citterio developed a fully inkjet-printed disposable paper-based device for potentiometric Na+ or K+ sensing.126 Ion selective electrodes were fabricated by using ink containing PEDOT(PSS)/graphite composite as the solid-state contact and overprinting it with the corresponding ion selective ionophore-based membrane ink. A pseudoreference Ag/AgCl electrode was prepared first by printing a layer of Ag nanoparticle ink followed by covering it with a printed layer of FeCl3 solution and reference membrane. A plasticized PVC membrane containing tetrabutylammonium tetrabutylborate was used as a reference electrode membrane. In order to make the potential of the reference electrode stable upon exposure to chloride solutions with different concentration, the authors overprinted the reference electrode membrane with 3 M KCl. The device exhibited a close to Nernstian response slope toward both Na+ (62.5 mV/dec) and K+ ions (62.9 mV/dec) with a detection limit of 32 and 101 μM, respectively. A rather small standard deviation of the E0 values of a few millivolts was achieved. A separate paper-based device was used for each measurement without any electrode preconditioning step. The device was successfully used for human urine analysis and required a 20 μL sample volume. Nery and Kubota reported on a paper-based potentiometric electronic tongue system for analysis of beer and wine

samples.127 The system was composed of ionophore-based sodium-, calcium-, ammonium-, and potassium-selective electrodes and simpler ion-exchanger-based electrodes. The electrodes were prepared by painting a paper substrate with conductive silver paint and covering it with the corresponding membrane composition. Ag/AgCl served as a reference electrode and was prepared by oxidizing the underlying Ag electrode with sodium hypochlorite. A set of five electrodes was fixed on laminated foil and applied to the analysis of 34 beer and 11 wine samples. The sample volume could be reduced to 40 μL by placing a small piece of paper impregnated with the analyzed solution on top of the electrodes. Paper can be used not only as a sensor substrate but also as a versatile sampling and separation platform. Ding et al. developed a paper-based microfluidic sampling and separation device for chloride sensing in the presence of interfering salicylate ions.128 The device was fabricated by combining two pieces of paper of different pore size (12−25 μm for detection zone and 2 μm for separation zone). The piece of filter paper used for the separation was modified with Fe3+ as a complexing agent for salicylate ions. Two pieces of paper were joined together, and a sample of 150 μL was added to the separation zone. The complex formation rendered salicylate ions less mobile whereas chloride ions were easily wicked into the detection zone. A solid-contact Cl−-selective electrode and a commercial single junction Ag/AgCl reference electrode were pressed against the filter paper in the detecting zone to measure the EMF values. Farzbod and Moon presented a digital microfluidic platform with an ion-selective electrode array.129 The novelty of this work was the demonstration of on-chip electrode fabrication, sampling, and measurement using electrowetting-on-dielectric droplet-based microfluidics. The on-chip fabrication of ionselective electrodes included electroplating of Ag followed by its chemical oxidation to form an AgCl layer and the deposition of a thin layer of polymeric ion selective membrane. Ag/AgCl served as a pseudoreference electrode. The fabricated potassium-selective electrode exhibited a Nernstian slope of 58 mV down to 5 μM. Gosselin et al. proposed a microfluidic potentiometric device for monitoring DNA amplification, using pH change as analytical signal.130 Screen-printed polyaniline-based indicator electrodes, applied by drop-casting, and Ag/AgCl chloride reference electrodes were used. A linear response to pH was observed, with a slope of −83 mV/pH. When monitoring loopmediated isothermal amplification reaction, the device was found to give comparable results to fluorescence measurements. Wearable Sensors. The development of wearable sensors recently became a very active research field owing to society’s need for personalized healthcare (see Figure 8). Electrochemical sensors are an attractive choice for wearable sensing platforms primarily owing to their ease of miniaturization and their low energy consumption. Sweat is the most popular sample substrate for wearable sensors as its composition is linked to various physiological processes that makes it suitable for the diagnostics of health status and sports performance. Sweat analysis is also noninvasive. Zhang’s group developed a wearable sweatband sensor platform for Na+ detection.131 The authors used a gold nanodendrite as a solid contact for PVC-based Na+-selective electrode, which was motivated by their high surface area and 16



Review

The electrode fabrication process was very similar to the previous work, but it is surprising that the authors used PEDOT electrochemically deposited from the monomer solution in pure 1-ethyl-3-methylimidazolium tris(pentafluoroethyl) trifluorophosphate as solid-contact, while they previously had shown that this material deteriorates the response characteristics (response slope and linear response range). Roy et al. reported on the development of a wearable sensor based on the CNT electrodes array for monitoring Na+ concentration in sweat.135 Solid-state Na+-SEs were fabricated by drop casting plasticized PVC doped with ionophore and ion exchanger on CNT electrodes. The authors claimed that CNT electrodes provided stronger attachment of the sensing membrane in comparison with Au, Pt, or carbon electrodes, which renders the sensor more robust and reliable. Reference electrodes were prepared by coating CNT electrodes with a colloidal dispersion of Ag/AgCl, agarose hydrogel with 0.5 M NaCl, and a passivation layer of PVC doped with NaCl. This configuration ensured low sensitivity (−1.7 mV/dec) toward the NaCl solution and high repeatability of the reference electrode. While the sensitivity and selectivity of the sensors seem to satisfy the requirements, the key challenges for wearable sensor developments may be insufficient mechanical resistance and large-scale fabrication. The groups of Andrade and Wang reported on a highly stretchable and printable textile-based potentiometric sensor array for the simultaneous Na+ and K+ detection in sweat.136 Na+- and K+-selective electrodes were fabricated by applying Ag/AgCl and MWCNTs inks and subsequently covering them with polyurethane ionophorebased membranes. The reference electrode was prepared by covering Ag/AgCl ink with a polyvinyl butyral layer containing a NaCl dispersion. An implemented serpentine sensor design and Ecoflex cover layer further rendered the sensors stretchable. Mechanical deformation by up to 100%, crumpling, or prolonged washing did not influence the potentiometric response. This sensing platform can be easily printed onto conventional textiles such as underwear, watch straps, and elastic bands. The performance of the potentiometric sensor array printed on different substrates was close to Nernstian from 10−3 to 10−1 M for both Na+ and K+. Choi et al. developed a wearable potentiometric chloride sensor for sweat analysis with two Ag/AgCl wires inserted into PDMS housing as reference and working electrodes.137 The reference element was immersed into the closed chamber and connected to the sample area through a salt bridge, both of which contained 1 M KCl. An increase of the length of the salt bridge and a decrease of its diameter was found to reduce equilibration time. One may wonder why the authors decided to use a chloride containing electrolyte for the salt bridge as it will likely cause sample contamination. Zoerner et al. developed a portable device for the analysis of ammonium in human sweat.138 They used screen-printed NH4+-selective and reference electrodes connected to an evaluation board for data acquisition and transfer. The NH4+selective membrane contained PVC, dibutyl sebacate, ion exchanger, and nonactine as an ionophore. The reference electrode was composed of Ag/AgCl covered with polyvinyl butyral/NaCl composite. The accuracy of the calculated ammonium concentration was validated using an enzymatic assay with glutamate dehydrogenase available with a commercial analyzer. It was shown that the sensor should be

Figure 8. Wearable potentiometric sensors for the real-time monitoring of electrolyte level in sweat have become an important direction of research.

high double layer capacitance. The gold nanodendrite array was fabricated on a microwell patterned chip by one-step electrodeposition. Increased surface area of the gold nanodendrite material gave improved potential stability. The lowest potential drift (0.22 mV h−1) was achieved for a surface area of 7.23 cm2. The sensors exhibited stable and reproducible calibration curves for at least two months. The solid-state reference electrode consisted of a poly(vinyl acetate)/KCl composite membrane on top of Ag/AgCl. The developed sweatband sensor platform was used for a real-time monitoring of sodium in sweat during indoor exercise. Andrade’s group reported on the use of commercial carbon fibers for the fabrication of wearable potentiometric sensors for monitoring of Na+ levels in sweat.132 Carbon fibers were used to build both working and reference electrodes. The Na+-SE was fabricated by dipping the fiber into a PVC-based membrane cocktail while the reference electrode carbon fiber was first covered with Ag/AgCl ink and subsequently with polyvinyl butyral/NaCl composite. The integrated sensing platform exhibited a close to Nernstian slope in the concentration range from 10−3 to 10−1 M in artificial sweat samples. The system demonstrated good potential stability within 4.5 h (drift of −0.4 ± 0.3 mV/h). This material is very attractive for wearable applications as such fibers and can easily be integrated into textile materials. Diamond’s group presented a potentiometric microfluidic chip for detecting sodium concentration in sweat.133 The sensing platform consisted of a solid-state Na+-selective electrode and reference electrode fabricated as screen-printed disposable strips. Different PEDOT films were tested as solidcontact material for Na+-SE, paying attention to sensitivity, linear response range, and within-batch reproducibility. Electrochemically deposited PEDOT from monomer solution in pure 1-ethyl-3-methylimidazolium bis(trifuoromethanesulfonyl) imide offered the best the potential stability (−0.04 mV/min drift within 4 h) and a standard potential reproducibility of a few millivolts. The sensing platform was tested during a real-time exercise session but unfortunately not cross-correlated with any other technique. The same group reported on a new platform design that allows one to harvest sweat samples more efficiently.134 After entering the device, the sweat sample was passed over the solid-state sodium-selective and reference electrodes and was collected in a storage area containing an adsorbent material. Fluid transport through the system was driven by capillary forces arising in the absorbent material. This configuration allows one to control the flow rate through the device, and the sweat stored during analysis can be used to report the harvested sweat volume, which is valuable for validation. Moreover, the electrodes and the high capacity adsorbent material can be easily replaced. 17



Review

contact layers.143 Later, the same group studied the influence of RuO2 material thickness and discovered that in order to obtain a pH sensor with 0.01 pH units of precision the electrode should be covered with the RuO2 film of at least 500 nm thicknesses.144 Jovic et al. adopted a layer-by-layer inkjet printing methodology for the fabrication of a miniaturized pH sensor on a flexible ITO/PET substrate.145 The electrode was fabricated by printing alternating layers of positively charged polydiallyldimethylammonium and negatively charged IrOx citrate-stabilized nanoparticles. Five printed bilayers were found to give the best performance characteristics with a slope of 58.4 mV in the pH range of 3−10. Inkjet-printing technology was also used by Pol et al.146 to prepare miniaturized sulfide-selective electrode of the second kind. The sensor fabrication involved printing a silver electrode over the PEN substrate and electrochemically depositing sulfide from Na2S solution by applying a constant current pulse. The Ag/Ag2S electrode exhibited a Nernstian slope in the concentration range of S2− from 20 μM to 50 mM. The sensor could be used for analysis of river/sea-spiked environmental samples and samples from a bioreactor for reduction of sulfate to sulfide. Ion-Selective Microelectrodes. Originally introduced by life scientists, ion-selective microelectrodes have become an indispensable tool for the in situ visualization of highly localized ion concentration changes, not only in living cells and tissues but also at the solid/liquid interface in many technical systems (i.e., metal corrosion). Toczylowska-Maminska et al. reported on an all-solid-state potentiometric sensor array for the simultaneous measurement of four physiologically important ions (K+, Na+, H+, and Cl−) in cells and tissues.147 The ISEs studied in this work were prepared with plasticized polyurethane-based membranes doped with appropriate ionophores and ion exchangers. The membrane cocktails were deposited directly on the surface of an Ag/AgCl transducer. The reference electrode was fabricated by covering Ag/AgCl with a plasticized polyurethane matrix doped with ionic liquid (1-dodecyl-3-methylimidazolium) chloride, which likely responds to chloride. The sensor array exhibited a close to Nernstian response slope in the concentration range of 10−4−10−1.5 M for Na+, K+, and Cl− and a pH range of 5.5−7.5 for the pH probe. The standard potential reproducibility was a rather modest ±11 mV. One would expect that the use of an appropriate solid-contact transducer layer between ion selective membrane and Ag metal contact would improve this value. The system was successfully applied for ion flux studies in a human colon epithelium Caco2 cell line. Addressing a similar problem, Lewenstam’s group developed a flat multimicroelectrode platform for monitoring sodium, potassium, hydrogen, and chloride ions.148 With a diameter of 12 mm, it could operate with a sample volume as small as 10 μL. The miniaturized ISEs were prepared rather conventionally by applying an appropriate PVC-based membrane cocktail on the top of the electrode body and filling it with an inner filling solution composed of 1% agar, 5% glycerine, and the electrolyte of choice. All electrodes exhibited a close to Nernstian response slope in a concentration range suitable for biological studies. The authors showed that by applying two platforms one can study the simultaneous transport of four ions across a layer of epithelial cells. Church et al. developed a solid contact Zn2+-selective microelectrode to monitor in situ zinc transport in sour orange

calibrated in artificial sweat solutions in order to eliminate errors resulting from interfering ions, primarily Na+ and K+. The lower detection limit observed in artificial sweat samples was 0.3 mM. Real sweat samples were measured only ex situ by putting a drop of collected sweat sample onto the sensor. Andrade’s group demonstrated a miniature disposable paper-based electrochemical cell for monitoring total electrolyte level in sweat.139 A Nafion membrane cast on a paper coated with carbon-ink was used as a working electrode while polyvinyl butyral/NaCl composite cast on a paper coated with Ag/AgCl-ink served as a reference electrode. The established empirical relationship between EMF signal and the measured logarithm of conductivity for a series of artificial sweat dilutions was used for analysis. The authors faced an unusual potential drift in calibration and sample solutions for some sensors. The conductivity values obtained by the device in real sweat samples were in a good correspondence with the ones obtained with a conductivity meter, but larger discrepancies between the values were observed during on-body monitoring. Miniaturized pH Sensors. Conventional glass electrodes are known to be rather bulky and resistive, which hinders their application in small sample volumes and motivates the development of alternative miniaturized potentiometric pH sensors. Metal oxide pH sensors remain one of the most attractive alternatives owing to their solid-state configuration and ease of miniaturization. Unfortunately, the response of such pH sensors can be affected by other redox species in solution. Uria et al. produced miniaturized pH probes on a silicon chip by depositing thin layers of IrOx or Ta2O5 on a platinum metal contact.140 Two different methods were used for metal oxide deposition, electrodeposition for IrOx and e-beam sputtering for Ta2O5. To finalize the device, a reference Ag/ AgCl thick film electrode was screen-printed on the chip. The reference electrode potential was kept indifferent by a constant concentration of chloride ions in all measurements. Ta2O5based pH sensors exhibited a Nernstian slope in the pH range of 4 to 7.5 while the IrOx-based sensor showed a superNernstian slope of 72 mV. The sample volume could be reduced down to 50 μL. The application of the fabricated pH sensors for the detection and quantification of bacterium Escherichia coli (E. coli) was demonstrated, exploiting the fact that the metabolic activity of microorganisms can result in pH changes of the culture medium. Salazar et al. developed a metal oxide pH sensor based on an amorphous nanocolumnar porous thin film of WO3 deposited by reactive magnetron sputtering in an oblique angle configuration onto indium tin oxide (ITO) or gold screen printed electrodes.141 To fabricate a combination solid-state pH sensor, the authors used an Ag/ AgCl electrode covered with polypyrrole as reference electrode. This solid-state pH sensor exhibited a Nernstian behavior in the pH range of 1.0 to 12.0. Manjakkal et al. reported on a miniaturized potentiometric pH sensing platform based on a thick film RuO2−Ta2O5 sensing electrode and Ag/AgCl/KCl reference electrode screen printed on an alumina substrate.142 The device was fabricated using thick film and so-called low temperature cofired ceramics technology. The sensor was found to exhibit a close to Nernstian response slope in the pH range of 2 to 12, and the electrode remained functional after 1 year. Lonsdale et al. found that pH sensors based on RuO2 thin-film sputtered on mesoporous carbon required less conditioning time and exhibited higher accuracy than their counterparts employing Pt and carbon as 18



Review

seedlings using a microelectrode ion flux estimation technique.149 The authors constructed two types of microelectrodes with a commercially available micropipette tip (tip size of 540 μm) or a borosilicate glass micropipette (of 40 μm) as a support. To fabricate the electrodes, a gold wire coated with POT was fixed inside the corresponding micropipette and the PVC-based membrane cocktail doped with ionophore was inserted through capillary action, forming a phase boundary at the end of the tip. Both sensors exhibited a close to Nernstian response slope with micromolar detection limit. To perform the measurements, the microelectrode tip was moved perpendicularly to the leaf surface and the results measured at different height above the surface were compared. One could observe the decrease of the zinc concentration when approaching the surface if ions were taken up by living cells. Ma et al. used a Pb2+-selective microelectrode for in situ monitoring of lead leaching from a galvanic joint in a prepared chlorinated drinking water environment.150 To fabricate the microelectrode, a glass micropipette was backfilled with an internal solution and the Pb(II) PVC-based cocktail was inserted into the front tip by capillary force. The response slope of Pb2+-selective microelectrode was close to Nernstian (22 mV/dec) in the concentration range from 10−6 to 10−3 M. In this work, the authors demonstrated a substantial nonuniform increase of Pb2+ concentration across the lead anode surface which was dependent on the local surface pH. Mao’s group proposed a carbon fiber-based H+-selective microelectrode (tip size of 20 μm) with a high antifouling property for in vivo monitoring of pH in the central nervous system.151 The electrodes were fabricated by covering carbon fiber microelectrodes with a plasticized PVC-based H+selective membrane doped with ionophore and an ion exchanger. The carbon fiber microelectrodes were carefully immersed and rolled into a droplet of membrane cocktail in THF until the solvent was evaporated. The sensor exhibited a Nernstian response slope in the evaluated pH range of 6.0 to 8.0 and a fast response time of less than 1 s. This sensor provided a stable and reproducible response in the vivo monitoring of pH change in the live brain of rats. Moon et al. proposed a dual amperometric/potentiometric microsensor (428 μm diameter) for sensing nitric oxide (NO) and potassium ion.152 The dual microsensor was prepared using Pt and Ag microwires inserted into a theta-type glass capillary. The Pt electrode was used for amperometric detection of NO while the Ag electrode partially oxidized to AgCl and covered with K+-selective membrane served for potentiometric potassium detection. The dual sensor exhibited a close to Nernstian response slope (51.6 mV/dec) to K+ from 10−5 to 10−1 M. The authors demonstrated the simultaneous monitoring of NO and K+ in a living rat brain. Filotas et al. reported on a dual potentiometric microsensor probe for the simultaneous detection of Zn2+ and pH to study localized corrosion processes by scanning electrochemical microscopy (SECM).153 The dual sensor was fabricated using two intertwined borosilicate capillaries. A PEDOT coated carbon fiber was inserted into one capillary, which was filled with Zn2+-selective cocktail containing PVC, plasticizer, ionophore, and ion exchanger. The second capillary was used to prepare an antimony pH electrode. The distance between the two tips in the final configuration was about 10−15 μm. Both sensors exhibited Nernstian behavior in a wide concentration range, namely, pZn 2−5 for the Zn2+-selective electrode and pH 4−10 for the pH probe. The data obtained

with the dual sensor for a model galvanic Fe−Zn system corresponded well to previous results observed with separate single probes. Ummadi et al. developed a solid-state carbon-based Ca2+selective microelectrode (25 μm in diameter) that can be used both as an amperometric sensor (to build an approach curve) and as a potentiometric sensor (to map the ion distribution on the surface) in SECM.154 This is an interesting approach, although the dual amperometric/potentiometric function appears not to be completely understood and optimized at this stage. The membrane cocktail containing ionophore, ion exchanger, PVC, plasticizer, and Vulcan carbon powder was pushed into the capillary tip. The back end of capillary was filled with Vulcan carbon/DOS composite to make the contact with an inserted copper wire. The Ca2+-selective microelectrode was found to have a close to Nernstian response slope of 28 mV/dec in the concentration range from 5 μM to 200 mM with a detection limit of 1 μM. The logarithmic selectivity coefficients were about −6 over Mg2+, Na+, and K+. The authors used the developed sensor to map the process of Ca2+ leaching from bioactive glass. Zhu et al. reported on an all-solid-state pH microelectrode fabricated by anodic electrodeposition of an iridium oxide film onto a 10 μm platinum ultramicroelectrode.155 The sensor exhibited a response slope of 61 mV in a wide pH range and remained functional for at least 110 days. This sensor was successfully applied to study the localized pH distribution during the corrosion of stainless steel in NaCl solution by SECM. The same group proposed a dual solid-state microelectrode that can be used in both amperometric and potentiometric SECM modes.156 As above, the amperometric mode allows one to control tip−substrate distance while the potentiometric mode provides information on ion distribution. The sensor consisted of two 25 μm diameter Pt wires placed in a borosilicate theta capillary. One of the two Pt wires was modified with iridium oxide film to serve as a pH potentiometric sensor, while the other Pt remained unmodified and was used as amperometric sensor. Freeman et al. demonstrated the feasibility of potentiometric redox measurements in subnanoliter solution droplets (between 280 and 1400 pL) using a nanoporous gold electrode.157 It was prepared by dealloying gold leaf with concentrated nitric acid followed by its chemisorption to a standard microscope coverslip with (3-mercaptopropyl)trimethoxysilane. The gold was further modified with 1hexanethiol to improve its hydrophobicity. The close to Nernstian behavior was confirmed with different redox couples (potassium ferricyanide/ferrocyanide, ferrous/ferric ammonium sulfate, benzoquinone/hydroquinone), and the system was also tested for only one form of the redox couple present in appreciable concentrations (potassium ferricyanide and ascorbic acid). Small volumes allowed for faster equilibration and reducing analysis time. Shortening the contact of the electrode surface to the sample solution can also be beneficial in complex samples for preventing electrode surface passivation by other species. Ion-Selective Field Effect Transistors. Asadnia et al. developed an ISFET based on AlGaN/GaN high electron mobility transistor with the gate area covered with a PVCbased membrane for Ca2+ detection.158 The proposed AlGaN/ GaN-based device was claimed not to require a reference electrode, but a constant background of 10−2 M KCl or NaCl was used for the device to exhibit a close to Nernstian response 19



Review

in the concentration range of Ca2+ from 10−7 to 10−2 M. The selectivity coefficients of the sensor were determined by simply fitting the response curves measured in a background of interfering ion with the Nikolsky-Eisenmann equation. Unfortunately, the selectivity coefficient values obtained for all tested ions were several orders of magnitude higher than the one reported previously for the same basic membrane composition. The use of one of the protocols recommended by IUPAC for selectivity estimation of the sensor would be advisable. To avoid the effects of light, all measurements had to be performed in a dark environment, which may not always be practical. Using ISFET technology, Kaisti et al. developed a hand-held multiplexed discrete transistor-based sensing system that can be coupled wirelessly to a smartphone.159 The performance of the developed system was tested with a K+selective membrane. A close to Nernstian slope to potassium with a detection limit of 10−4.8 M was observed. To improve the stability of potential over time with the solid contact electrodes, polyaniline doped with dinonylnaphtalene sulfonic acid was used as a inner transducer layer. Briggs et al. reported on an ISFET-based sensing platform for the reagent-less simultaneous measurement of pH and total alkalinity.160 The authors combined an ISFET-based pH sensor with one presented earlier and commercialized by Orion for the diffusive titration coupled to electrolytic titrant generation, also known as flash titration. The device was shown to perform a nanoliterscale acid−base titration in less than 40 s. The authors demonstrated the applicability of the sensing platform for seawater analysis. Andrianova et al. developed an n-channel ISFET based on phosphotriesterase enzyme for organophosphorus pesticide detection.161 Phosphotriesterase caused the cleavage of the pesticide molecules and was immobilized on the surface of the transistor, resulting in detectable pH changes. The device was coupled to a microfluidic system for analyte delivery and was successfully applied for the detection of paraoxon, parathion, and methyl parathion with detection limits of 0.1, 0.5, and 0.5 μM, respectively. Melzer et al. reported on the direct simultaneous detection of two products of enzymatic urea conversion (NH4+ and H+) using a sensor array based on spray-coated carbon nanotube field-effect transistors.162 The direct simultaneous detection of both products of the enzymatic reaction was possible owing to the immobilization of urease enzyme on the sensor surface and modification of the corresponding active interfaces with polymeric NH4+- and H+-selective membranes. A detection limit for urea of less than 50 μM in dilute phosphate buffer was reported.

potentially important interfering agent. To suppress hydroxide and chloride interferences, additional sample acidification and chloride removal steps are sometimes required before analysis. Bakker’s group reported on three different approaches to locally acidify the sample at the electrode surface during measurement.164 In the first approach, 1 M acetic acid solution was used as an inner filling solution of the PVC-based membrane indicating electrode, which resulted in a significant acid gradient across the membrane and in the desired decrease of pH at the electrode surface. In the second approach, the passive acid diffusion was across a second membrane placed in front of the anion selective electrode. This arrangement formed a thin layer gap where acidification occurred and allowed one to tune both membrane materials to their respective tasks. An ISE with fast diffusive doped polypropylene membrane and a concentrated acetic acid inner solution served as the external proton source. The third approach exhibited a similar configuration, but the protons were released from the external proton source by electrochemical control, applying a potentiostatic pulse. It was demonstrated that all three protocols allowed one to successfully suppress the hydroxide interference and improve the limit of detection of nitrite and dihydrogen phosphate by more than 2 orders of magnitude. Nonetheless, the efficiency of the principles may not be sufficiently high in strongly buffered samples. The same group later proposed an in-line sample acidification approach based on cation exchange/counterdiffusion across an ion-exchange Donnan exclusion membrane.165 Alkali metal ions from the sample are exchanged with hydrogen ions across the membrane, in analogy to an ion suppressor in ion chromatography. Natural water samples with millimolar sodium chloride levels (freshwater, drinking water, and aquarium water, as well as dechloridized seawater) were modified to about pH 5, depending on experimental condition. In situ measurements are most attractive for the study of biogeochemical processes as they can provide real-time concentration profiles with the desired spatial and temporal resolution. Cuartero et al. described a new submersible probe that is fully autonomous during the deployment and provides data storage and computer visualization of the data in real time (see Figure 9).166,167 The probe was explored for marine monitoring in two configurations: (1) simultaneous detection of nitrate, nitrite, and chloride;166 (2) simultaneous detection of carbonate, calcium, and pH.167 Potentiometric detection was performed in a custom-made flow cell with all-solidcontact membrane electrodes using functionalized multiwalled carbon nanotubes (f-MWCNTs) as a solid contact. The detection of nitrate and nitrite was accomplished after suppressing hydroxide, as described above, and chloride interferences. Chloride concentration was drastically reduced by addition of a microfluidic desalination module that consisted of two plated silver sheets that served as working and counter electrodes. Electrochemical oxidation of the silver electrode in contact with the sample film removed chloride as plated AgCl while the sodium counterions were transported away from the sample across the cation-exchange membrane to the reference solution. This decreased the chloride concentration in seawater down to millimolar levels. The electrochemical protocol allowed one to also use the desalination cell as a coulometric, calibration-free electrochemical sensor for chloride/salinity detection. The in situ measurement data were validated using on site and ex situ techniques. In some cases, the correlation was difficult. Re-equilibration with atmospheric

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ANALYTICAL APPLICATIONS AND METHODOLOGIES Environmental Analysis. Potentiometric sensors can be easily miniaturized and exhibit reasonably fast response times, simple operation, and low energy consumption. For this reason, they may be attractive as sensing components in ex situ and in situ environmental monitoring systems. Cuartero and Bakker published a critical review that highlights recent examples of membrane electrode applications in water analysis.163 The complex composition of environmental water samples may make it difficult to deploy potentiometric sensors directly. With a pH range between 6.5 and 8.5, hydroxide interference may be a significant concern with ionophore-based anion sensors. In seawater samples, the high NaCl content acts as a 20



Review

act as “open cages”, where fluoride ions can be trapped apparently without restriction of electrostatic attraction or site binding. The process is reversible and was shown to be eliminated by a centrifugation pretreatment of the sample. Clinical Analysis. Machado et al. described a potentiometric flow injection method for iodide and iodate in urine samples with a commercially available combination iodideselective electrode.172 This was achieved by the sequential determination of iodide and the sum of iodate and iodide, after iodate conversion to iodide with a reducing agent in a separate flow channel. The detection limits were around 1 μM. Lindner’s group developed and validated a protocol for the measurement of urinary CO2 of septic shock patients using a Severinghaus-type CO2 probe.173 The protocol included: (1) sampling urine from a Foley catheter in an intensive care unit setting, (2) storing samples until analysis at a separate facility, (3) calibration of the Severinghaus-type CO2 sensor, and (4) measuring urinary CO2 levels. It was shown that pH does not significantly influence the accuracy of the results so that the measurements can be performed without sample pH adjustment. Nevertheless, the use of the urinary catheter equipped with an in-line thermometer was recommended to correct for the differences in bladder temperature and the equilibration temperature used for the preparation of the standards. The groups of Meyerhoff and Malinowska presented a potentiometric approach for monitoring the release rate of nitric oxide from NO donor-doped polymer films and electrochemical NO generating systems used as parts of medical devices.174 The proposed approach is based on the conversion of NO into nitrate in the presence of oxyhemoglobin with subsequent nitrate detection with a polymeric membrane anion-selective electrode. To minimize the interference of oxyhemoglobin on the detection of nitrate, the membrane was prepared using asymmetric cellulose triacetate instead of PVC. Unfortunately, the potentiometrically measured NO concentration values and the ones from the reference chemiluminescence method gave significant discrepancies. A possible reason was assumed to be the low reaction efficiency for the purged NO with the oxyhemoglobin to form nitrate. A correction was performed with empirically estimated reaction efficiencies based on the results of the chemiluminescence analysis. As reaction efficiencies may depend on experimental conditions (temperature or purge rate of NO), the implementation of this approach is likely difficult. Ortuño’s group described a potentiometric approach for monitoring enzymatic reactions.175 Potentiometry possesses a number of advantages over traditionally used spectrophotometric methods, such as the use of the enzymes’ natural substrates and the possibility of doing measurements under physiological conditions. As a proof-of-concept, kinetic and inhibition studies were performed using electrodes selective to ionic substrate involved in the enzymatic reaction catalyzed by acetylcholinesterase and butyrylcholinesterase. Urbanowicz et al. reported on a miniature multisensor platform (10 mm in diameter) based on solid contact ionselective electrodes for the detection of Na+, K+, Ca2+, Mg2+, and Cl− in fresh, unstimulated, and stimulated human saliva samples.176 PEDOT(PSS) was used as a transducer layer for the corresponding ionophore-based electrodes. An Ag/AgCl electrode in contact with KCl dispersed in polyvinyl acetate was used as a reference electrode. The concentrations determined by the multisensor platform corresponded well

Figure 9. Submersible probes containing ion-selective sensing probes are deployed in marine environments for the in situ potentiometric monitoring of macronutrients166 and species relevant to the carbon cycle.167 The probes were integrated in a titanium cage containing pumps, electronics, sensors, and an additional multiparameter CTD module for simultaneous conductivity, temperature, and depth measurements.

CO2 after sampling can introduce errors, as can be the use of apparent thermodynamic constants for speciation calculations. Athavale et al. reported on the application of solid contact ammonium and pH selective electrodes for the in situ vertical high-resolution profiling in a eutrophic freshwater lake,168 using f-MWCNTs as a solid contact. The sensors were found to be insensitive to strong redox changes, high sulfide concentrations, and bright daylight conditions during application in the lake. Ding et al. presented a solid-contact potentiometric sensor for detection of total ammonia nitrogen (free ammonia plus the ammonium ion) in seawater.169 In this system, a POT-based polymeric membrane ammoniumselective electrode was combined with a poly(vinyl alcohol) hydrogel buffer film of pH 7.0 and a gas-permeable membrane. The proposed sensor exhibited a detection limit of 6.4 × 10−7 M and was successfully applied to the ex situ detection in seawater. Chango et al. proposed a potentiometric chip-based multipumping flow system for the simultaneous determination of fluoride, chloride, pH, and redox potential in water samples with commercially available reference and sensing electrodes.170 The system was equipped with a set of four solenoid micropumps to deliver solutions to the electrode surface. One of the pumps supplied a total ionic strength adjusting buffer. The system was applied for the analysis of water samples from wells and pools, giving a satisfactory correlation for chloride and fluoride concentrations between ISE and ion chromatography. Shen and co-workers demonstrated that the accuracy of fluoride determination by ion-selective electrodes is significantly affected by the aggregation of humic substances that are representative of natural organic matter in water.171 The authors reported on a negative error of detected fluoride concentration up to 19% in the presence of humic substance aggregates. The authors supposed that the formed aggregates 21



Review

cationic analyte into the membrane accompanied by the ejection of Na+ ions into the aqueous phase. It was found that the recorded change of the phase boundary potential can also yield the information about the charge density of different analytes. Reversible potentiometric polyion sensors, also known as “pulstrodes”, were presented for the first time by Bakker’s group in 2003. Meyerhoff’s group adopted this principle for the detection of four polyquaterniums mentioned above.182 A plasticized PVC membrane was doped with a salt of two oppositely charged lipophilic ions. A short (1 s) galvanostatic pulse polarized the membrane, allowing the polyion analyte to be extracted into the membrane yielding a detectable phase boundary potential change. In a second step, a long (15 s) potentiostatic pulse resulted in the ejection of the polyion back into the sample phase. Meyerhoff’s group developed “pulstrode” protocols for polyquaternium detection by exploiting direct and indirect potentiometric (titration) measurements in the beaker. The possibility of performing measurements in a flow injection analysis system was also demonstrated. Potentiometric polyion sensors can be also used for the indirect detection of biomolecules and biological species. Gemene’s group used a polyion-selective electrode to determine the activity of a proteolytic enzyme thrombin.183 It was achieved with a synthetic polypeptide substrate and a flash chronopotentiometry protocol. An applied cathodic current caused the extraction of polypeptides into the membrane while the square root of the transition time at which the depletion of the polypeptides at the membrane− sample interface occurs was found to be proportional to its concentration. The addition of thrombin resulted in proteolysis of the polypeptide substrate and a shortening of the transition times. Qin’s group reported on the potentiometric aptasensing detection of a marine bacterium Vibrio alginolyticus using again a polyion sensor.184 In the presence of the target, the aptamer on the DNA nanostructure-modified magnetic beads specifically binds to the target and results in a disassembly of the DNA nanostructures. The resulting magnetic beads were then incubated with protamine, and after magnetic separation, the unreacted protamine was detected using the “pulstrode” protocol. Surfactant Analysis. Surfactants contain a hydrophilic headgroup and hydrophobic chain (tail) and are commonly used in everyday items (soap, toothpaste, washing liquid, laundry detergents) and many industrial processes. The development and improvement of analytic tools for their control and monitoring remains an active research field, and potentiometric sensors are often used in the titrimetric determinations of surfactants. The titration of ionic surfactants is based on the reaction of two oppositely charged large lipophilic ions resulting in the formation of a sparingly soluble ion-associate that becomes extractable into the membrane. Mikysek et al. reported on a low resistive (10 Ω) coated-wire ion-selective electrode for the potentiometric detection of anionic surfactants.185 The electrode was prepared by dipping an Al conductor into a homogenized mixture of the graphite powder, PVC, and NPOE in THF. In this work, didecyldimethylammonium chloride was used as a cationic titrant to provide titration curves with a larger potential jump than ones obtained with conventionally used titrants. Galovic et al. presented a new all-solid-state membrane ISE for the determination of anionic surfactants.186 The membrane was

to the ones obtained by separately measured ion-selective electrodes. Biofouling of ion-selective membranes owing to protein adsorption is a known limitation for the long-term application of potentiometric sensors in complex biological samples such as blood, serum, or urine. Biofouling often results in an increase of signal noise or loss of signal. Goda et al. studied the influence of the adsorption of bovine serum albumin on the performance characteristics of several ion-selective microelectrodes.177 An Ag/AgCl electrode with protein adsorbed lost sensitivity for chloride concentrations lower than 10−2 M. However, this work indicated that Ir/IrOx microelectrodes are promising for local pH measurements in complex samples containing biomolecules as they maintained adequate pH response in the pH range from 4 to 9. Lisak et al. proposed a way to monitor the kinetics of biofouling of ion-selective membranes by combining in situ potentiometry and null ellipsometry.178 The authors used their approach to monitor the adsorption of bovine serum albumin at the surface of the custom-made solid-contact K+-SEs with 6-(ferrocenyl)-hexanethiol attached to a gold surface as a transducer layer. Polyion Sensing. Polyanions are widely used in medicine (e.g., heparin and protamine), food (e.g., carrageenan), and cosmetics (e.g., polyquaterniums). The first polyion potentiometric sensor was a heparin-selective electrode developed in the early 1990s. Meyerhoff’s group recently published a thorough review about key accomplishments in electrochemical and optical sensing of polyions over the past 25 years.179 The authors discussed the basic sensing principles of single-use and fully reversible polymeric membrane-type potentiometric polyion sensors, voltammetric polyion-sensitive electrodes, and single-use polyion-sensitive optodes. In the last two years, the same group significantly contributed to the development of the analytical protocols for the quantification of polyquaterniums (PQs), polymeric quaternary ammonium salts.180−182 They are found to be widely used in cosmetics but may be toxic for certain aquatic species. The detection of the quaternized hydroxyethylcellulose compound, PQ-10, was demonstrated using titration with dextran sulfate monitored by polyanion-sensitive polymeric membrane-based electrodes.180 In this method, once all of the PQ-10 species have been bound by the titrant, the excess polyanion will be extracted into the plasticized PVC membrane and exchange with the Cl−. As a result, the observed equivalence point is directly proportional to the amount of PQ-10 in the sample. The method was shown to detect PQ-10 down to 20 μg mL−1. It was also shown that sodium lauryl sulfate, which is often present in cosmetic samples together with PQ-10, can be readily separated using an anion-exchange resin (the amount of which may need to be adjusted depending on the sample). The authors also discovered that the increase of pH results in a change of the shape of the titration curve. The pH of the sample solution should therefore be closely monitored, especially after pretreatment with anion-exchange resin. In subsequent work in buffered samples, the authors showed that various quaternary ammonium salts (PQ-2, PQ-6, PQ-10, and poly(2-methacryloxy-ethyltrimethylammonium) chloride) can be titrated with the same titrant, dextran sulfate.181 Here, a syringe pump was used to deliver the titrant at a fixed rate.181 The direct potentiometric detection of the analytes was also demonstrated using polycation sensitive membrane electrodes.181 In this case, one measures the change of the phase boundary potential resulting from the extraction of poly22


Analytical Chemistry applied on the screen-printed electrode based on carbon by drop-casting. The membrane composition included the dimethyldioctadecylammonium−tetraphenylborate ion pair, a graphene nanopowder, PVC, and NPOE. The sensor exhibited close to Nernstian responses for dodecylbenzenesulfonate and dodecyl sulfate in the concentration range of 2.5 × 10−7−4.5 × 10−3 M with detection limits of 1.5 × 10−7 and 2.5 × 10−7 M, respectively. One may wonder about the role of the ion pair incorporated into the membrane phase here as the ion-pair complex does not have ions in common neither with the analyzed anionic surfactants nor with the titrant. As this compound is composed of a hydrophobic cation and anion, it does not seem to possess ion-exchanger properties and so its function is unclear, other than decreasing the resistance of the membrane phase. Khaled et al. demonstrated an enzymatic approach for surfactant analysis.187 As the surfactants are known to inhibit the activity of some cholinesterase enzymes, the authors used this characteristic to determine the surfactant concentration. The enzymatic activity of acetylcholinesterase was measured by monitoring the hydrolysis of acetylcholine with a disposable acetylcholine potentiometric sensor. The inhibition degree of the enzyme was found to be proportional to surfactant concentration. This method was shown to be applicable to the analysis cationic, anionic, and nonionic surfactants.

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ACKNOWLEDGMENTS

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REFERENCES

Review

The authors thank the Swiss National Science Foundation for supporting research in this field.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Eric Bakker: 0000-0001-8970-4343 Notes

The authors declare no competing financial interest. Biographies Elena Zdrachek was born in Belarus and studied at Belarusian State University in Minsk, where she obtained her Bachelor degree in Chemistry in 2010. She received her Ph.D. in Analytical Chemistry from the Belarusian State University in 2015 under the guidance of Prof. Vladimir V. Egorov. She then worked as a Senior Research Fellow at the Research Institute for Physical Chemical Problems of the Belarusian State University. In 2016, she moved to Switzerland for a postdoctoral stay at the University of Geneva in the group of Prof. Eric Bakker. E.Z.’s main research interests are in the development and theory of electrochemical sensors. In particular, she focuses on the influence of equilibria at the membrane/solution interface on electrode response and the theory of selectivity. Eric Bakker pursued his doctoral studies with Wilhelm Simon at the Swiss Federal Institute of Technology (ETH) in Zurich (1990−1993) and spent two years at the University of Michigan before starting his independent career at Auburn University (1995−2005) where he eventually rose to the rank of full professor. In 2005−2007, he spent time at Purdue University (West Lafayette, IN), and in 2007−2010, he was at Curtin University (Perth, Western Australia) before coming back to Switzerland in 2010 as a chair of Analytical Chemistry at the University of Geneva. His research interests are in analytical chemistry, chemical sensors, ion sensors, membrane electrodes, and their bioanalytical and environmental applications. 23



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Potentiometric Sensing - American Chemical Society

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