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Self-Calibrated Ion-Selective Electrodes
Abstract
Ion-selective electrode (ISE) potentiometry is reliable only if on-site calibration using a standard solution is performed before ion measurements. The complex device and operation required for calibration hinder the implementation of ISEs in decentralized sensing. Reported herein is a new type of ISE that is calibrated by a built-in component of the sensor without requiring any fluid handling processes. The indicator and reference electrodes are connected by a thin ionic conductor such as an aqueous phase containing the measuring ions in a capillary tube. This connection establishes a baseline electromotive force (EMF) that incorporates phase boundary potentials across multiple interfaces of the electrochemical cell and serves as a one-point calibration. Unlike conventional ISEs that rely on one EMF reading for each measurement, the proposed sensor utilizes a sample-induced EMF change relative to the baseline for each ion measurement. The variability in relative EMF is found to be <2.0 mV for multiple full potentiometric sensors consisting of plasticizer-based K+ ISEs and hydrogel-based Ag/AgCl reference electrodes. This value is significantly smaller than the variability of absolute EMF readouts in similar sensors without the self-calibration design. Moreover, when the ion-conducting calibration bridge has a low concentration of primary ions, low ion mobility, and/or a small contact area with the indicator and reference phases, it does not compromise the Nernstian response slope toward the analyte ions in the sample and therefore does not need to be removed for sample testing. The accuracy of the single-use self-calibrated K+ sensor in testing undiluted human blood samples is validated using a commercial blood gas analyzer as the reference method. Although this study focuses on disposable sensors consisting of tubes, the fluidics-free self-calibration strategy may be adapted to other sensor configurations such as planar sensors.
... As depicted in Figure 3c, [102] potentiometric sensors are often utilized for pH measurement and ion-selective electrodes (ISEs) for specific ion detection. [106,107] Common applications of potentiometric biosensors include the detection of glucose, neurotransmitters, and environmental monitoring. ...
Electrochemical (EC) analysis has emerged as a high‐sensitivity, reliable, cost‐effective, and rapidly evolving technique that has garnered significant attention across diverse domains. Furthermore, EC‐based techniques hold great potential for miniaturization and integration. The integration of EC techniques with diverse mode/signal (such as light, magnetic, and thermal signals, etc.) provides unique opportunities for biosensors to acquire more information through a single sensing platform. By coupling multiple signals or processing them logically, the detection accuracy can be further improved, and the probability of false positives or negatives can be minimized. In this review, a thorough analysis of multi‐ mode/signal sensors in the field of EC sensing is conducted, along with their integration with various sensing techniques (e.g., fluorescence, photothermal, colorimetry, microfluidic, etc.). The aim is to delve into the latest advances, potential applications, as well as challenges in multi‐mode/signal biosensors, where the utilization of multiple sensing modalities helps enhance accuracy, sensitivity, and selectivity. This review provides new insight into the synergistic effects of integrating EC sensing with other techniques, aiming to shed light on the near‐future developments in EC‐integrated multi‐mode/signal biosensors.
Monitoring human health is of considerable significance in biomedicine. In particular, the ion concentrations in blood are important reference indicators related to many diseases. Microneedle array-based sensors have enabled promising breakthroughs in continuous health monitoring due to their minimally invasive nature. In this study, we developed a microneedle sensing-array integrated system to continuously detect subcutaneous ions to monitor human health status in real time based on a fabrication strategy for assembling planar microneedle sheets to form 3D microneedle arrays. The limitations of preparing 3D microneedle structures with multiple electrode channels were addressed by assembling planar microneedle sheets fabricated via laser micromachining; the challenges of modifying closely spaced microneedle tips into different functionalized types of electrodes were avoided. The microneedle sensing system was sufficiently sensitive for detecting real-time changes in Ca ²⁺ , K ⁺ , and Na ⁺ concentrations, and it exhibited good detection performance. The in vivo results showed that the ion-sensing microneedle array successfully monitored the fluctuations in Ca ²⁺ , K ⁺ , and Na ⁺ in the interstitial fluids of rats in real time. By using an integrated circuit design, we constructed the proposed microneedle sensor into a wearable integrated monitoring system. The integrated system could potentially provide information feedback for diseases related to physiological ion changes.
6 Flexible wearable sweat sensors allow continuous, real-time, noninvasive detection of sweat 7 analytes, provide insight into human physiology at the molecular level, and have received 8 significant attention for their promising applications in personalized health monitoring. 9 Electrochemical sensors are the best choice for wearable sweat sensors due to their high 10 performance, low cost, miniaturization, and wide applicability. Recent developments in soft 11 microfluidics, multiplexed biosensing, energy harvesting devices, and materials have advanced 12 the compatibility of wearable electrochemical sweat sensing platforms. In this review, we 13 summarize the potential of sweat for medical detection and methods for sweat stimulation and 14 collection. This paper provides an overview of the components of wearable sweat sensors and 15 recent developments in materials and power supply technologies and highlights some typical 16 sensing platforms for different types of analytes. Finally, the paper ends with a discussion of the 17 challenges and a view of the prospective development of this exciting field. 18 19 20 3
Solid-contact ion-selective electrodes (SCISEs) can overcome essential limitations of their counterparts based on liquid contacts. However, attaining a highly reproducible and predictable E0, especially between different fabrication batches, turned out to be difficult even with the most established solid-contact materials, i.e., conducting polymers and large-surface-area conducting materials (e.g., carbon nanotubes), that otherwise possess excellent potential stability. An appropriate batch-to-batch E0 reproducibility of SCISEs besides aiding the rapid quality control of the electrode manufacturing process is at the core of their "calibration-free" application, which is perhaps the last major challenge for their routine use as single-use "disposable" or wearable potentiometric sensors. Therefore, here, we propose a new class of solid-contact material based on the covalent functionalization of multiwalled carbon nanotubes (MWCNTs) with a chemically stable redox molecule, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). This material combines the advantages of (i) the large double-layer capacitance of MWCNT layers, (ii) the adjustable redox couple ratio provided by the TEMPO moiety, (iii) the covalent confinement of the redox couple, and (iv) the hydrophobicity of the components to achieve the potential reproducibility and stability for demanding applications. The TEMPO-MWCNT-based SC potassium ion-selective electrodes (K+-SCISEs) showed excellent analytical performance and potential stability with no sign of an aqueous layer formation beneath the ion-selective membrane nor sensitivity toward O2, CO2, and light. A major convenience of the fabrication procedure is the E0 adjustment of the K+-SCISEs by the polarization of the TEMPO-MWCNT suspension prior to its use as solid contact. While most E0 reproducibility studies are limited to a single fabrication batch of SCISEs, the use of prepolarized TEMPO-MWCNT resulted also in an outstanding batch-to-batch potential reproducibility. We were also able to overcome the hydration-related potential drifts for the use of SCISEs without prior conditioning and to feature application for accurate K+ measurements in undiluted blood serum.
The two most promising approaches for preparing solid contacts (SCs) for polymeric membrane based ion‐selective electrodes (ISEs) are based on the use of large surface areas conducting materials with high capacitance (e. g., various carbon nanotubes) and redox active materials (e. g. conducting polymers). While many of the essential requirements for the potential stability of SCISEs were addressed, the E⁰ reproducibility and its predictability, that would enable single use of such electrodes without calibration is still a challenge, i. e., the fabrication of electrodes with sufficiently close E⁰ and slope values to enable the characterization of large fabrication batches through the calibration of only a small number of electrodes. The most generic solution seems to be the adjustment of the E⁰ potential by polarization prior to the application of the ion‐selective membrane. This approach proved to be successful in case of conducting polymer‐based solid contacts, but has to be still explored for capacitive solid contact based ISEs, which is the purpose of this paper. We have chosen a well‐established highly lipophilic multi‐walled carbon nanotube (MWCNT), i. e. octadecane modified MWCNT (OD‐MWCNT), that is investigated in the comparative context of a similarly lipophilic conducting polymer solid contact (a perfluorinated alkanoate side chain functionalized poly(3,4‐ethylenedioxythiophene)). While, the OD‐MWCNT based SCISEs had inherently small standard deviation of their E⁰ values (less than 5 mV) this could be further improved by external polarization and short circuiting the SCISEs.
Management of diabetes insipidus is usually facilitated by an intact thirst mechanism prompting water ingestion in times of rising osmolality. Maintenance of eunatremia can be quite difficult in patients with diabetes insipidus and adipsia because of the absence of this homeostatic mechanism. Few published protocols for management of these complex patients exist. We report a case of a 16-year-old woman who was diagnosed with craniopharyngioma with preoperative hypopituitarism and central diabetes insipidus. She underwent transsphenoidal resection in 2013 and additionally developed postoperative cognitive impairment and hypothalamic dysfunction, including adipsia. She subsequently experienced widely dysregulated sodium levels, requiring inpatient care approximately 30% of days in 2014 and 2015. We created a novel protocol for management of this patient which uses a fixed daily dose of subcutaneous DDAVP combined with daily modulation of fluid intake based on daily serum sodium measurement. The protocol provides guidance for the day’s fluid intake based on both the current sodium result and the rate of change from the previous day. Since the adoption of the protocol in June 2016, the patient has had a dramatic reduction in hospitalizations. Use of a protocol for providing recommendations for fluid intake based on the sodium level and rate of change may help to maintain normal sodium levels in such patients, decreasing hospitalization and improving quality of life.
A fundamental limitation of potentiometric ion sensors is their relatively low sensitivity due to the logarithmic dependence between potential and activity. Here we address this issue by exploring a recently developed coulometric transduction method for solid-contact ion-selective electrodes (SCISEs). Spin-coated thin-layer ion-selective membranes are used to lower the membrane resistance and shorten the response time of the SCISEs. When using coulometric transduction, an optimized design of the K+-SCISE is able to detect a concentration change of 5 μM at a concentration level of 5 mM, corresponding to a 0.1 % change in K+ activity. This indicates that SCISEs can provide extremely high sensitivity when employing coulometric transduction. Impedance measurements show that the coulometric transduction process for the K+-SCISE is limited by diffusion even for very thin ion-selective membranes. On the other hand, the H+-SCISE shows a low impedance and a fast coulometric response that is related to the high mobility of H+ in the H+-selective polymeric membrane as well as in the solid contact layer. The coulometric transduction method was used to detect small changes of pH in seawater and found to improve the sensitivity compared to classical potentiometry. The coulometric method was briefly tested also for determining activity changes of K+ in a serum sample.
Wearable potentiometric ion sensors (WPISs) have become an exciting analytical platform that combines chemical, material and electronic efforts to supply physiological information during certain human activities. The real possibility of wearing an analytical device with diverse configurations—sweatband, patches, garments—without disturbing the welfare of the carrier has enabled potentiometric ion sensors both as health quality and sport performance controllers. Recent studies show a large involvement of WPISs in the following of critical biomarkers (timely or continuously), such as sodium, potassium, calcium, magnesium, ammonium and chloride, which are present at relatively high concentrations in sweat (∼mM levels). Certainly, the non-invasive nature of WPISs and other significant features, e.g., simplicity and cost-effectiveness, have broadened new horizons in relation to applied analytical chemistry. This has been pointed out in the literature over the last decade with the predominance of two analytical outcomes: (i) the improvement of sport performance as a result of continuous detection of ions in sweat (health status of the individual) while decreasing physiological complications (injuries, muscle cramps, fatigue and dehydration) during practice; and (ii) advancements in clinical diagnostics and preventive medicine as a consequence of the monitoring of the health status of patients suffering from any kind of disorder. Beyond the undeniable importance of the integration of WPISs to satisfy current societal needs, the following crucial questions about misleading and missing analytical features need to be answered: To what extent is WPIS technology a reliable analytical tool for the quantification of ions? Is cross-validation the current bottleneck toward further progress? Which are the fundamental steps involving the ion-selective electrode side that would benefit WPIS outcomes? Why is sweat the main (and almost the only) biological fluid to be monitored by WPISs? What is the best sampling strategy to be incorporated into WPIS devices for on-body monitoring of sweat? Which precision limits should be considered to assure a reliable decision-making process? Accordingly, this review focuses on the progression of WPISs from an analytical perspective—merely our vision of the field—within the period between 2010 and 2018. An updated search using specific keywords (wearable, ion, potentiometry, sensor) provided 43 contributions, which are herein highlighted, with a sustainable acceleration over the last three years. Thus, this review describes the current state of WPIS technology, the construction of wearable all-solid-state potentiometric sensors, critical requirements of potentiometric sensors to be fulfilled in a wearable configuration and key features regarding the ideal implementation of WPISs as reliable messengers of physiological information in real scenarios.
In this review, the importance of water in hydrogel (HG) properties and structure is analyzed. A variety of methods such as 1H NMR (nuclear magnetic resonance), DSC (differential scanning calorimetry), XRD (X-ray powder diffraction), dielectric relaxation spectroscopy, thermally stimulated depolarization current, quasi-elastic neutron scattering, rheometry, diffusion, adsorption, infrared spectroscopy are used to study water in HG. The state of HG water is rather non-uniform. According to thermodynamic features of water in HG, some of it is non-freezing and strongly bound, another fraction is freezing and weakly bound, and the third fraction is non-bound, free water freezing at 0 °C. According to structural features of water in HG, it can be divided into two fractions with strongly associated and weakly associated waters. The properties of the water in HG depend also on the amounts and types of solutes, pH, salinity, structural features of HG functionalities.
Objective:
Hypoparathyroidism is a rare disorder characterized by hypocalcemia and absent or deficient parathyroid hormone. This report presents a summary of current information about epidemiology, presentation, diagnosis, clinical features and management and proposes guidelines to help clinicians diagnose, evaluate and manage this disorder.
Participants:
Participants in the First International Conference on the Management of Hypoparathyroidism represented a worldwide constituency with acknowledged interest and expertise in key basic, translational and clinical aspects of hypoparathyroidism. Three Workshop Panels were constituted to address questions for presentation and discussion at the Conference held in Florence, Italy, May 7-9, 2015. At that time, a series of presentations were made followed by in-depth discussions in an open forum. Each Workshop Panel also met in closed sessions to formulate the three evidence-based reports that accompany this summary statement. An Expert Panel then considered this information, developed summaries, guidelines, and a research agenda that constitutes this summary statement.
Evidence:
Preceding the conference, each Workshop Panel conducted an extensive literature search as noted in the individual manuscripts accompanying this report. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature.
Consensus process:
This report represents the Expert Panel's synthesis of the conference material placed in a context designed to be relevant to clinicians and those engaged in cutting-edge studies of hypoparathyroidism.
Conclusions:
This document provides not only a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our understanding of hypoparathyroidism.
Wearable sensor technologies play a significant role in realizing personalized medicine through continuously monitoring an individual’s health state. To this end, human sweat is an excellent candidate for non-invasive monitoring as it contains physiologically rich information. Previously reported sweat-based and other non-invasive biosensors either can only monitor a single analyte at a time or lack on-site signal processing circuitry and sensor calibration mechanisms for accurate analysis of the physiological state. Given the complexity of sweat secretion, simultaneous and multiplexed screening of target biomarkers is critical and full system integration to ensure the accuracy of measurements is a necessity. Here, a mechanically flexible and fully-integrated perspiration analysis system is presented that simultaneously and selectively measures sweat metabolites (e.g. glucose and lactate) and electrolytes (e.g. sodium and potassium ions), as well as the skin temperature to calibrate the sensors' response. Our work bridges the technological gap between signal transduction, conditioning, processing and wireless transmission in wearable biosensors by merging plastic-based sensors that interface with the skin, and silicon integrated circuits consolidated on a flexible circuit board for complex signal processing. The envisioned application could not have been realized by either of the technologies alone due to their respective inherent limitations. This wearable system is used to measure the detailed sweat profile of human subjects engaged in prolonged indoor and outdoor physical activities, and infer real-time assessment of the physiological state of the subjects. The platform enables a wide range of personalized diagnostic and physiological monitoring applications.
We describe an open source software which we have realized and made publicly
available at the website http://jljp.sourceforge.net. It provides the potential
difference and the ion fluxes across a liquid junction between the solutions of
two arbitrary electrolytes. The calculation is made by solving the
Nernst-Planck equations for the stationary state in conditions of local
electrical quasi-neutrality at all points of the junction. The user can
arbitrarily assign the concentrations of the ions in the two solutions, and
also specify the analytical dependence of the diffusion coefficient of each ion
on its concentration.
A promising method for the elimination of undesired capacitive currents in view of realizing a potentially calibration free coulometric ion detection system is presented. The coulometric cell is composed of a porous polypropylene tube doped with a liquid calcium-selective membrane and a silver/silver chloride wire as an inner electrode, forming a thin layer sample between wire and tubing. The total charge passed through the system during potential controlled electrolysis of the thin layer sample is indeed found to be proportional to the amount of calcium present, but non-Faradaic processes do contribute to the obtained signal. We introduce here a multi-pulse procedure that allows one to perform a second excitation pulse at the same excitation potential after exhaustive ion transfer voltammetry of calcium has taken place. The intercept of the calibration curve after background subtraction is found as 20.6 +/- 0.6 muC, significantly lower than the value of 54.1 +/- 0.8 muC for the uncorrected curve. Changes in sample temperature (from 23 degrees C to 38 degrees C) did equally not affect the background corrected coulometric readings, supporting that the procedure renders the readout principle more robust.
More than ten different approaches for improving the lower detection limit of polymeric membrane ion-selective electrodes have been suggested during the recent years. In this contribution, their principles are briefly summarized with a focus to their general practical applicability. The methods that are the most rugged and the easiest to implement in a routine laboratory will be highlighted.
In potentiometric sensing, the preparation of the electrodes preceding a measurement is often the most time-consuming step. Eliminating the conditioning process can significantly speed up the preparation procedure, but it can also compromise the need for proper pre-equilibration of the membrane. We propose here a symmetric setup to address this challenge with an identical indicator and reference elements measured against each other, thereby compensating for potential drift. This strategy allows one to achieve potentiometric measurements using non-conditioned all-solid-state ion-selective electrodes for the detection of nitrate and potassium ions with Nernstian response slopes and detection ranges identical to those of conventional systems. To establish symmetry, a set of solid-contact ion-selective electrodes placed in a reference cell is measured against a set of identical electrodes in a sample cell. By subtracting the potentials between the two cells, potential instabilities not directly relevant to the measuring sample are eliminated, giving minimal potential drifts and stable 5-day potential responses. The E0 value of the nitrate-selective electrodes in the symmetric setup had a standard deviation of just 3 mV for the 5-day period in contrast to 19 mV in the asymmetric system, clearly demonstrating the influence of the conditioning step which is almost eliminated in the former system. During the 20 h potential monitoring experiments, the drift dropped to below 0.3 mV/min in less than 6 min, as opposed to an average time of 35 min for the asymmetric system. The applicability of the proposed setup was successfully demonstrated with the measurement of nitrate in a river water sample, where a potential drift lower than 0.1 mV/min was reached in less than 5 min of first contact with solution.
Solid-contact ion-selective electrodes (ISEs) have the inherent advantage of being miniaturized in addition to maintaining high selectivity and sensitivity of the ionophore-based ISE. The major disadvantage of ISEs is the necessity of performing a calibration curve (varying the intercept in the linear calibration curve equation) each time before running experiments, which limits their application as one-time disposable sensors or for use in remote water sample analysis. To overcome these challenges, we designed a unique back contact made of 3,4-ethylenedioxythiophene (EDOT) and 4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl-methoxy)-1-butanesulfonic acid, sodium salt (EDOT-S). The calibration-free ISEs showed near Nernstian responses of 57.2 ± 0.2 mV/log [K+] and 28.5 ± 0.3 mV/log [Ca2+], while maintaining their respective selectivity against major interfering ions. The detection limits for Ca2+ and K+ ISEs were 0.45 ± 0.01 and 1.68 ± 0.18 μM, respectively. The charging cycles of the PEDOT: PEDOT-S back contact allowed us to fix the background potential at a desired fixed intercept value across different ionophores (K+, Ca2+). This protocol was used to determine the K+ and Ca2+ contents in creek water samples. The activity and concentration of [Ca2+] and [K+] in a local creek was found to be 257 ± 7.3 and 28.1 ± 1.1 μM, respectively.
Calibration-free coulometric determination of K⁺ ions was realized using an all-solid-state thin-layer laminated cell with a simple laminate structure. The fabricated cell consists of a Ag/AgCl electrode, a plastic spacer for positioning the aqueous sample solution, an organic ion-selective membrane, and a conducting polymer/carbon electrode. An originally prepared conducting-polymer-dispersed ink was cast on a conductive carbon sheet (a screen-printed graphite electrode or carbon paper) to fabricate the conducting polymer/carbon electrode. The cell achieved complete mass transport of the target ion from a 1 mm³ drop of the aqueous sample to the organic ion-selective membrane under a constant potential between the Ag/AgCl electrode and the conducting polymer/carbon electrode, which generated electrical current for enabling the ion transfer. The electric charge obtained by integrating the electric current was used to estimate the molar amount of the target ion in the sample drop. For tetraethylammonium cations (TEA⁺; 20–200 μmol dm⁻³), the evaluated molar amounts corresponded to 92%–94% of the initial mole amounts. The repeatability estimated using the same cell was ±4%–6%, and the device-to-device reproducibility was ±4% for five cells. In terms of K⁺-ion detection (0.1–0.8 mmol dm⁻³) in sample drops containing NaCl (14 mmol dm⁻³), the evaluated molar amounts corresponded to 86%–92% of the initial molar amounts, indicating the promise of the all-solid-state thin-layer laminated cell for achieving the calibration-free determination of K⁺ ions in a 1 mm³ drop of ten-fold-diluted serum.
In recent years, an important aspect of research into the improvement of ion-selective electrodes (ISEs) has been the development of solid-contact ISEs for calibration-free measurements, with the goal of sensors that can be implemented with ease for long-term, in situ analysis with very limited or no maintenance. This review discusses the definition of the term “calibration-free” in this context, and it gives suggestions as to what types of information should be reported if a claim of calibration-free usage is made. Relevant literature in this field is reviewed, with a focus on different mechanisms of ion-to-electron signal transduction. Different types of redox-active, capacitive, and mixed-mechanism transduction modes are discussed in view of the reproducibility and stability of the potential responses they provide.
The solid contact ion-selective electrodes (SC-ISEs) have been extensively studied in the field of ion sensing as they offer the possibility of miniaturization, are relatively inexpensive in comparison to other analytical techniques and allow straightforward and routine analysis of ions in a number of clinical, environmental and industrial process samples. In recent years, a significant interest has grown in the development of SC-ISEs with well-defined interfacial potentials at the membrane, solid contact, and substrate electrode interfaces. This has resulted in the development of interesting SC-ISEs exhibiting high electrode-to-electrode potential reproducibility, for those made in a single batch of electrodes, some approaching or exceeding those observed in liquid-contact ISEs. The advancement in the potential reproducibility of SC-ISEs has been partially achieved by scrutinizing insufficiently reproducible fabrication methods of SC-ISEs, or by introducing novel control measures or modifiers to components of the ISEs. This paper provides an overview of the methods as well as the challenges in establishing and maintaining reproducible potentials during the fabrication and use of novel SC-ISEs. The rules outlined in the works reviewed may form the basis of further development of cost-effective, user-friendly, limited calibration or calibration-free potentiometric SC-ISEs to achieve reliable ion analyses here and now.
Porous glass frits are frequently used to contain the salt bridges through which reference electrodes interface samples. Prior work with widely used glass frits with 4 - 10 nm diameter pores showed that, when samples have a low electrolyte strength, electrostatic screening of sample ions by charged sites on the glass surface occurs. This creates an ion-specific phase-boundary potential at the interface between the sample and frit, and it biases the potential of the reference half-cell. Use of frits with much larger pores eliminates this problem but results in the need for frequent replenishing of the bridge electrolyte. A methodical study to determine the optimum pore size has been missing. We show here that charge screening of sample ions occurs when the pore size of nanoporous glass frits is on the order of 1 - 50 nm and samples have a low electrolyte strength. An increase in pores size to 100 nm eliminates charge screening in samples with ionic strengths in the 1.0 M to 3.3 × 10-4 M range. However, the rates of electrolyte solution flow through frits with 1, 5, 20, 50, and 100 nm pores are still low, which makes diffusion the dominant mode of ion transport into and out of these frits. Consequently, the flow of bridge electrolyte into samples is not fast enough to prevent diffusion of ions and electrically neutral components from the sample diffusing into the salt bridge, which can result in cross contamination among samples.
Body-interfaced sensors have received tremendous attention due to a broad and diverse collection of potential applications, from monitoring of health status to managing and preventing disease conditions. In this review article, we highlight the emerging sensing modalities and advanced materials/device designs in body-integrated flexible platforms capable of capturing and analyzing biofluids. In particular, we discuss different chemical sensors and biosensors for real-time noninvasive monitoring and analysis of metabolites and electrolytes in sweat, tears, saliva, and interstitial fluid. Finally, we show several techniques that could be integrated with body-interfaced sensors for data acquisition, signal processing, display, and communication.
Peripheral biochemical monitoring involves the use of wearable devices for minimally invasive or noninvasive measurement of analytes in biofluids such as interstitial fluid, saliva, tears and sweat. The goal in most cases is to obtain measurements that serve as surrogates for circulating analyte concentrations in blood. Key technological developments to date include continuous glucose monitors, which use an indwelling sensor needle to measure glucose in interstitial fluid, and device-integrated sweat stimulation for continuous access to analytes in sweat. Further development of continuous sensing technologies through new electrochemical sensing modalities will be a major focus of future research. While there has been much investment in wearable technologies to sense analytes, less effort has been directed to understanding the physiology of biofluid secretion. Elucidating the underlying biology is crucial for accelerating technological progress, as the biofluid itself often presents the greatest challenge in terms of sample volumes, secretion rates, filtration, active analyte channels, variable pH and salinity, analyte breakdown and other confounding factors.
Background
Hypo- and hyperkalemia in clinical settings are insufficiently characterized and large-scale data from Europe lacking. We studied incidence and determinants of these abnormalities in a large Swedish healthcare system.
Methods
Observational study from the Stockholm CREAtinine Measurements project, including adult individuals from Stockholm accessing healthcare in 2009 (n = 364,955). Over 3-years, we estimated the incidence of hypokalemia, defined as potassium < 3.5 mmol/L, hyperkalemia, defined as potassium > 5 mmol/L, and moderate/severe hyperkalemia, defined as potassium > 5.5 mmol/L. Kidney function was assessed by estimated glomerular filtration rate (eGFR).
Results
Of 364,955 participants, 69.4% had 1–2 potassium tests, 16.7% had 3–4 tests and the remaining 13.9% had >4 potassium tests/year. Hypokalemia occurred in 49,662 (13.6%) individuals, with 33% recurrence. Hyperkalemia occurred in 25,461 (7%) individuals, with 35.7% recurrence. Moderate/severe hyperkalemia occurred in 9059 (2.5%) with 28% recurrence. The frequency of potassium testing was an important determinant of dyskalemia risk. The incidence proportion of hyperkalemia was higher in the presence of diabetes, lower eGFR, myocardial infarction, heart failure (HF), or use of renin angiotensin-aldosterone system inhibitors (RAASi). In adjusted analyses, women and use of loop/thiazide diuretics were associated with lower hyperkalemia risk. Older age, lower eGFR, diabetes, HF and use of RAASi were associated with higher hyperkalemia risk. On the other hand, women, younger age, higher eGFR and baseline use of diuretics were associated with higher hypokalemia risk.
Conclusion
Hypo- and hyperkalemia are common in healthcare. Optimal RAASi and diuretics use and careful potassium monitoring in the presence of certain comorbidities, especially lower eGFR, is advocated.
To understand the rate determining processes during the equilibration of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate-based (PEDOT(PSS)-based) solid contact (SC) ion-selective electrodes (ISEs), the surfaces of Pt, Au, and GC electrodes were coated with 0.1, 1.0, 2.0 and 4.0μm thick galvanostatically deposited PEDOT(PSS) films. Next, potential vs. time transients were recorded with these electrodes, with and without an additional potassium ion-selective membrane (ISM) coating, following their first contact with 0.1M KCl solutions. The transients were significantly different when the multi-layered sensor structures were assembled on Au or GC compared to Pt. The differences in the rate of equilibration were interpreted as a consequence of differences in the hydrophilicity of PEDOT(PSS) in contact with the substrate electrode surfaces based on X-ray photoelectron spectroscopy (XPS) and synchrotron radiation-XPS (SR-XPS) analysis of 10 to 100nm thick PEDOT(PSS) films. The influence of the layer thickness of the electrochemically deposited PEDOT(PSS)-films on the hydrophilicity of these films has been documented by contact angle measurements over PEDOT(PSS)-coated Au, GC, and Pt electrode surfaces. This study demonstrates that it is possible to minimize the equilibration (conditioning) time of SC ISEs with aqueous solutions before usage by optimizing the thickness of the SC layer with a controlled ISM thickness. PEDOT(PSS)-coated Au, and GC electrodes exhibit a significant negative potential drift during their equilibration in an aqueous solution. By coating the PEDOT(PSS) surface with an ISM, the negative potential drift is compensated by a positive potential drift related to the hydration of the ISM and activity changes at the PEDOT(PSS)|ISM interface. The potential drifts related to activity changes in the ISM have been determined by a novel adaptation of the “sandwich membrane” method.
Electrically conducting polymers (ECPs) are one of the most popular types of materials to interface ion-selective membranes (ISMs) with electron conducting substrates to construct solid contact ion-selective electrodes (SCISEs). For optimal ion-to-electron transduction and potential stability, the p-doped ECPs with low oxidation potentials such as PPy need to be generally in their conducting form along with providing a sufficiently hydrophobic interface to counteract the aqueous layer formation. The first criterion requires that the ECPs are in their oxidized state, but the high charge density of this state is detrimental for the prevention of the aqueous layer formation. We offer here a solution to this paradox by implementing a highly hydrophobic perfluorinated anion (perfluorooctane sulfonate, PFOS⁻) as doping ion by which the oxidized form of the ECP becomes hydrophobic. The proof of concept is shown by using polypyrrole (PPy) films doped with PFOS⁻ (PPy-PFOS) as the solid contact in K⁺-selective SCISEs (K⁺-SCISE). Prior to applying the plasticized poly(vinyl chloride) ISM, the oxidation state of the electrodeposited PPy-PFOS was adjusted by polarization to the known open circuit potential of the solid contact in 0.1 M KCl. We show that the pre-polarization results in a hydrophobic PPy-PFOS film with a water contact angle of 97±5º, which effectively prevents the aqueous layer formation under the ISM. Under optimal conditions the K⁺-SCISEs had a very low standard deviation of E⁰ of only 501.0±0.7 mV that is the best E⁰ reproducibility reported for ECP-based SCISEs.
Preparation of ISEs often requires long and complicated conditioning protocols limiting their application as tools for in field measurements. Herein, we eliminated the need for electrode's conditioning by loading the membrane cocktail directly with primary ion solution. This proof of concept experiments were performed with iodide, silver and sodium selective electrodes. The proposed methodology significantly shortened the preparation time of ISEs yielding functional electrodes with submi-cromolar detection limits. Moreover, it is anticipated that this approach may form the basis for the development of minia-turized all-solid-state ion-selective electrodes for in situ measurements.
Ion-selective electrodes (ISEs) are widely used tools for fast and accurate ion sensing. Herein their design is simplified by embedding a potentiometric cell into paper, complete with an ISE, a reference electrode, and a paper-based microfluidic sample zone that offer the full function of a conventional ISE setup. The disposable planar paper-based ion-sensing platform is suitable for low-cost point-of-care and in-field testing applications. The design is symmetrical and each interfacial potential within the cell is well defined and reproducible, so that the response of the device can be theoretically predicted. For a demonstration of clinical applications, paper-based Cl(-) and K(+) sensors are fabricated with highly reproducible and linear responses towards different concentrations of analyte ions in aqueous and biological samples. The single-use devices can be fabricated by a scalable method, do not need any pretreatment prior to use, and only require a sample volume of 20 μL.
Little is known about the frequency and patterns of hyperkalemia in clinical settings. We evaluated the association between baseline antihypertensive medications that may affect potassium levels (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, loop/thiazide diuretics, and potassium-sparing diuretics) and hyperkalemia, defined by potassium >5 mEq/L and >5.5 mEq/L, over a 3-year time period in 194 456 outpatients in the Geisinger Health System, as well as actions taken after an episode of hyperkalemia. The proportions of patients with 0, <2, 2 to 4, and ≥4 potassium measurements per year were 20%, 58%, 16%, and 6%. Potassium levels >5 mEq/L and >5.5 mEq/L occurred in 10.8% and 2.3% of all patients over the 3-year period; among patients with ≥4 measurements per year, corresponding values were 39.4% and 14.6%. Most cases of hyperkalemia occurred only once during follow-up. The antihypertensive medication class most strongly associated with hyperkalemia was angiotensin-converting enzyme inhibitors. Among patients with a measurement of potassium >5.5 mEq/L, only 24% were seen by a nephrologist and 5.2% were seen by a dietician during the 3-year period. Short-term actions after a potassium measurement >5.5 mEq/L included emergency room visit (3.1% within 7 days), remeasurement of potassium (44.3% with 14 days), and change in a potassium-altering medication (26.4% within 60 days). The most common medication changes were discontinuation/dose reduction of an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or potassium-sparing diuretic, which occurred in 29.1% and 49.6% of people taking these medications, respectively. In conclusion, hyperkalemia is common. Future research may enable optimal renin-angiotensin-aldosterone system inhibitor use with improved management of hyperkalemia.
A novel approach to signal transduction concerning solid-contact ion-selective electrodes (SC-ISE) with a conducting polymer (CP) as the solid contact is investigated. The method presented here is based on constant potential coulometry, where the potential of the SC-ISE vs the reference electrode is kept constant using a potentiostat. The change in the potential at the interface between the ion-selective membrane (ISM) and the sample solution, due to the change in the activity of the primary ion, is compensated with a corresponding, but opposite change in the potential of the CP solid contact. This enforced change in the potential of the solid contact results in a transient reducing/oxidizing current flow through the SC-ISE. By measuring and integrating the current needed to transfer the CP to a new state of equilibrium, the total cumulated charge that is linearly proportional to the change of the logarithm of the primary ion activity, is obtained. In this work, different thicknesses of poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly(styrenesulfonate) (PSS) were used as solid contact. Also, coated wire electrodes (CWEs) were included in the study to show the general validity of the new approach. The ISM employed was selective for K+ ions, and the selectivity of the membrane under implementation of the presented transduction mechanism was confirmed by measurements performed with a constant background concentration of Na+ ions. A unique feature of this signal readout principle is that it allows amplification of the analytical signal by increasing the capacitance (film thickness) of the solid contact of the SC-ISE.
Potentiometric sensing, which requires the use of ion-selective electrodes (ISEs) and reference electrodes, is used to determine electrochemically the concentration of target ions in a variety of chemical environments. In view of the need for more affordable and portable analytical devices with small sample volumes, all-solid-state ISEs and reference electrodes, in which a solid contact is used as ion-to-electron transducer, are highly desirable. This review describes how all-solid-state ISEs and reference electrodes function and presents important aspects that should be considered when designing such sensors for specific applications. Approaches to improving reproducibility, the stability of the emf response, lowering detection limits, and novel sensor designs are discussed along with specific examples from the recent literature. Emphasis is placed on the ion-to-electron transduction mechanism and the development of new solid contact materials, with a particular view to miniaturized ion-sensing devices with low cost and calibration-free sensing.
We report the manufacturing and performance of miniaturized reference electrodes (MREs) of wide applicability, with highly stable potential in both aqueous and organic media, and minimal low sensitivity to Cl- ions (- 3.4 mV/log acl-) and pH (0.082 mV/pH). These MREs are based on an Ag/AgiX internal reference element (IRE), where AgiX is a low solubility silver salt (X = Cl-, SCN-, or PO43-). IREs are imbedded in a photopolymerized acrylic hydrogel, with no solid salt supply present in the system. Polymer matrices were tested for swelling/dissolution, and for loss of both electrolyte and silver ions. MREs have a potential stability of ±0.5 mV over 30 h, and a low temperature coefficient of 0.15 mV K-1 (in the range of 281.8-298.6 K).
This work addresses the well-known problem of variations in the standard potential (E degrees) of solid-contact ion-selective electrodes (SC-ISEs) that have a conducting polymer (CP) as ion-to-electron transducer covered by a polymeric ion-selective membrane. Poly(3,4-ethylene dioxythiophene) doped with poly(sodium 4-styrenesulfonate), i.e. PEDOT(PSS), was electrodeposited on glassy carbon (GC) disk electrodes and used as the solid contact for three different types of PVC-based membranes in order to elucidate the possibility to electrochemically control E degrees for this type of SC-ISE. The GC/PEDOT(PSS) electrode was thus coated with potassium-selective membranes with and without the lipophilic salt tetradocedylammonium tetrakis(4-clorophenyl)borate (ETH-500) and by a cation-sensitive membrane without ionophore. The results show that the standard potential of the studied types of SC-ISEs can be shifted by applying a potential that deviates from the open-circuit potential of the electrode in the chosen electrolyte solution or by applying current pulses in the nA range.
A simple, instrument-free method to control the standard potential (E°) of potentiometric solid-contact ion-selective electrodes (SC-ISE) is described. In this method, the electrode potential of a SC-ISE is reset by short-circuiting the electrode with a metallic wire to a conventional Ag/AgCl/3MKCl reference electrode (RE) in a solution containing primary ions. The method is studied experimentally for SC-ISEs where the conducting polymer poly(3,4-ethylenedioxythiophene) doped with the bulky anion poly(sodium 4-styrenesulfonate), PEDOT(PSS), is used as solid contact. Three different types of ion-selective membranes (ISMs) are studied: two potassium-selective membranes, with and without the lipohilic additive tetradodecylammonium tetrakis(4-chlorophenyl)borate (ETH-500) and a cation-sensitive membrane without ionophore. When short-circuiting the SC-ISE with the RE, the PEDOT(PSS) layer is oxidized or reduced, thereby shifting the potential of the SC-ISE to the proximity of the potential of the RE so that the potential difference between these two electrodes becomes zero or close to zero. The slope of the calibration curve is preserved after the short-circuit treatment of the SC-ISEs. The short-circuiting method is an important step towards calibration-free potentiometric analysis.
We report here on a significant improvement in lowering the low detection limit of thin layer coulometric sensors based on liquid ion-selective membranes, using a potassium-selective system as a model example. Various possible processes that may result in an elevated residual current reading after electrolysis were eliminated. Self-dissolution of AgCl on the Ag/AgCl inner element may result in a residual ion flux that could adversely affect the lower detection limit. It was here replaced with an Ag/AgI inner pseudoreference electrode where the self-dissolution equilibrium is largely suppressed. Possible residual currents originating from a direct contact between inner element and ion-selective membranes were eliminated by introducing an inert PVDF separator of 50 μm diameter that was coiled around the inner element by a custom-made instrument. Finally, the influence of electrolyte fluxes from the outer solution across the membrane into the sample was evaluated by altering its lipophilic nature and reducing its concentration. It was found that this last effect is most likely responsible for the observed residual current for the potassium-selective membranes studied here. For the optimized conditions, the calibration curves demonstrated a near zero intercept, thereby paving the way to the coulometric calibration-free sensing of ionic species. A linear calibration curve for the coulometric cell with valinomycin potassium-selective membrane was obtained in the range of 100 nM to 10 μM potassium in the presence of a 10 μM sodium background. In the presence of a higher (100 μM) concentration of sodium, a reliable detection of 1-100 μM of potassium was achieved.
The detection limit of carrier-based ion-selective electrodes is explained by the presence of a locally elevated concentration of measuring ions at the sample−membrane phase boundary. Since ion-selective electrodes are responsive to phase boundary activities, such elevated concentrations render the potentiometric sensor insensitive to dilute bulk concentration changes. Different mechanisms for the continuous release of measuring ions from the membrane are conceivable. The extraction of inner electrolyte into the backside of the ion-selective membrane is predicted to lead to a concentration gradient of electrolyte across the membrane and therefore to a net flux of measuring ions from the inner filling solution to the sample. This effect is described by an extended model that respects the relevant extraction and diffusion processes. The extent of coextraction at the backside is predicted on the basis of potentiometric measurements on the range of anion interference. These predictions are found to relate well to experimental results with valinomycin electrodes. The presence of lipophilic anions in the inner electrolyte is found to increase detection limits owing to the increased extraction into the membrane. An upper limit apparently exists beyond which the detection limit is no longer increased upon increasing the inner filling solution concentration. Stirring the sample decreases the detection limit owing to increased mass transport from the membrane surface to the bulk sample.
A polymer membrane system composed of 30 wt.% cellulose acetate (CA) and polyurethane (PU) has been developed for the fabrication of mass producible solid-state reference electrodes. The CA/PU membrane exhibits appropriate adhesion to common substrates (e.g., ceramic and silicon chips) of miniaturized electrochemical sensors, allows quick hydration of internal hydrogel layer (3 M KCl with a 6 wt.% water soluble polymer) deposited on micro-patterned electrodes resulting in fast preconditioning time (∼100 s), and provides a stable reference potential for an extended period (use-lifetime: 25–90 min) by limiting the diffusion of internal electrolytes. The potentiometric responses of the CA/PU membrane-based solid-state reference electrodes drifted rapidly (40–90 mV/h) after their use-lifetime; the results suggest that the internal electrolyte slowly fills the micro-channels of the outer membrane while maintaining stable potential, and begins to diffuse away at an increased rate from the membrane/aqueous solution interface. The potentiometric responses of the polymer membrane-based ion-selective electrodes (for Na+, K+, Ca2+, Cl− and H+) formed on the same chip with the CA/PU membrane-coated Ag/AgCl reference electrode were examined both in aqueous and physiological samples; their analytical performance closely matched that of sensors measured against a conventional reference electrode.
Comparison of potentials stability of different types of solid contact lead selective electrodes is presented. Conducting polymer based sensors (hydrophilic and conducting - poly(3,4-ethylenedioxythiophene) or hydrophobic and semiconducting-polyoctylthiophene) were studied in parallel with coated wire and hydrogel (poly(hydroxyethylmethacrylate)) contact electrodes. The within day and between days potential stability was compared, highlighting the effect of sensor storing conditions. The obtained results clearly demonstrate that different conclusions on stability of sensors' potential can be drawn depending on experimental protocol applied. Polyoctylthiophene based contacts show superior within day stability with no influence of dry storage. On the other hand, a chronopotentiometric method of stability evaluation clearly prefers poly(3,4-ethylenedioxythiophene) based sensors, pointing to smallest resistance and polarizability. It is clearly shown that the choice of experimental conditions applied to test stability can favor particular type of contact used. The inductively coupled plasma mass spectrometry with laser ablation (LA-ICP-MS) experiments conducted for different arrangements tested has shown that for poly(3,4-ethylenedioxythiophene) and poly(hydroxyethylmethacrylate) type contacts longer contact time with lead(II) solution results in changes in the elemental composition of the transducer layer. On the other hand, in line with high stability observed under potentiometric conditions, no changes were seen for polyoctylthiophene based transducer.
The response of ion-selective electrodes (ISEs) can be described on the basis of two different theoretical approaches. On one hand, the phase-boundary model is based on the assumption of local equilibria at the aqueous/organic interface. The phase-boundary model allows the description of all practically relevant cases of steady state and even transient responses with sufficient accuracy. Moreover, it has the advantage of relating simple thermodynamic parameters to the response function of the electrodes and hence allowing an intuitive interpretation of many observed facts. On the other hand, the comprehensive but quite involved dynamic model requires knowledge of mobilities and ion transfer rate constants. It has never been applied to ionophore-based electrodes in its full complexity. Both models were first suggested decades ago but have been recently extended to explain so far poorly understood aspects of ionophore-based ISEs. Due to space restrictions, only the most important original references are given in this paper, which summarizes the major assumptions of the phase-boundary potential model and discusses the usefulness and limits of this approach. Recent applications are discussed towards understanding sensor selectivity, upper and lower detection limits (even when concentration polarizations are relevant), the so-called sandwich membrane method to determine thermodynamic parameters, apparently non-Nernstian responses, potential drifts with solid contact electrodes, polyion sensors, and galvanostatically controlled ion sensors.
Hydrogel membranes formed by interfacially photopolymerizing poly(ethylene glycol) (PEG) diacrylate precursor solution were prepared from PEG diacrylate of molecular weights (MW) ranging from 2000 (2K) to 20000 (20K) with concentrations ranging from 10% to 30% w/w. The effects of PEG diacrylate MW and concentration in the membrane precursor solution upon the diffusivities of vitamin B12, myoglobin, ovalbumin, albumin, and IgG were determined. Regardless of the concentration of the PEG diacrylate in the precursor solution, hydrogels prepared with PEG 2K, 4K, and 8K diacrylate were impermeable to proteins with a size equal to or larger than myoglobin (22 kDa), while hydrogels prepared with PEG 20K diacrylate were impermeable to proteins with a size equal to or larger than ovalbumin (45 kDa). Similarities between hydrogels formed from PEG 2K, 4K, and 8K diacrylates were also seen in calculations of the molecular weight between crosslinks and the mesh size, with values in the range of 150-750 g/mol and 15-35 A, respectively, depending on PEG diacrylate concentration. In contrast, hydrogels formed from PEG 20K diacrylate had molecular weight between crosslinks ranging from 1150 to 2000 g/mol and mesh sizes ranging from 45-70 A, with larger values being observed in membranes polymerized from more dilute PEG diacrylate precursor.
This study features the fabrication of a planar-form, solid electrolyte modified, (PSEM) Ag/AgCl reference electrode using a screen-printing method. The PSEM Ag/AgCl reference electrode uses agar gel as the inner electrolyte and chloroprene rubber for the liquid junction and insulator. These common low-cost materials and the simple fabrication processes involved render the proposed reference electrode an ideal candidate for cost-efficient mass production. It is shown that the developed reference electrode is insensitive to most of the physiologically important ionic species, including Na+, K+, Li+, Ca2+, NH4+, and Cl-, under continuous measurement conditions. Moreover, as with conventional commercial reference electrodes, the proposed reference electrode exhibits a reversible response, which is maintained until the agar gel dries out. The PSEM Ag/AgCl reference electrode is integrated with an iridium oxide modified Pt-based pH indicator electrode to form a chip-type pH biosensor. The performance of this biosensor is consistent with that obtained from a pH meter based on a macroscopic commercial Ag/AgCl reference electrode. The experimental results confirm that the proposed biosensor is capable of providing precise pH measurements of various real samples. Accordingly, the PSEM Ag/AgCl reference electrode presented in this study provides a viable alternative to the macroscopic Ag/AgCl reference electrode used in many conventional chip-based pH sensors.
The important subgroup of electrochemical sensors is the potentiometric ion sensors or ion-selective electrode (ISEs), which is based on polymeric membranes that contains neutral or charged carriers. Characterized by small size, portability, low-energy consumption, and low cost, the ISEs are available for the determination of a large number of inorganic and organic ions. This article focused on recent achievements and emphasizes the results from the last five years; provides a critical overview on the theory of the potentiometric response; deals with recent advances in the field of solid contact ISEs and recent developments in the area of miniaturized ISEs; and finally, new wave of ISEs. As the result, the response of potentiometric ion sensors is a complex time-dependent phenomenon. However, in obtaining solid-contacts ISEs with reproducible standard potentials is still a challenge. Both conventional and solid-contact ISEs miniaturized versions have been used in a variety of applications. The chemical sensing abilities of ISEs has resulted in a "new wave of ion-selective electrodes", and with the advances made by a number of research groups worldwide, it is concluded that the future of potentiometric ion sensors seem very prospective.
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