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Ultrasensitive Ionophore-Based Liquid Sensors for Colorimetric Ion Measurements in Blood
Abstract
The self-monitoring of electrolytes using a small volume of capillary blood is needed for the management of many chronic diseases. Herein, we report an ionophore-based colorimetric sensor for electrolyte measurements in a few microliters of blood. The sensor is a pipet microtip preloaded with a segment of oil (plasticizer) containing a pH-sensitive chromoionophore, a cation exchanger, and an ionophore. The analyte is extracted from the sample into the oil via a mixing protocol controlled by a stepper motor. The oil with an optimized ratio of sensing chemicals shows an unprecedentedly large color response for electrolytes in a very narrow concentration range that is clinically relevant. This ultrahigh sensitivity is based on an exhaustive response mode with a novel mechanism for defining the lower and higher limits of detection. Compared to previous optodes and molecular probes for ions, the proposed platform is especially suitable for at-home blood electrolyte measurements because (1) the oil sensor is interrogated independent of the sample and therefore works for whole blood without requiring plasma separation; (2) the sensor does not need individual calibration as the consistency between liquid sensors is high compared to solid sensors, such as ion-selective electrodes and optodes; and (3) the sensing system consisting of a disposable oil sensor, a programmed stepper motor, and a smartphone is portable, cost-effective, and user-friendly. The accuracy and precision of Ca2+ sensors are validated in 51 blood samples with varying concentrations of total plasma Ca2+. Oil sensors with an ultrasensitive response can also be obtained for other ions, such as K+.
... Alternatively, anion-selective optodes are sensing systems that involve the immobilisation of a fluorophore/chromophore into a hydrophobic matrix (usually a polymer membrane or nanoparticle), combined with ionophores that can extract the ion from an aqueous solution into the organic polymer [19][20][21][22][23][24][25][26]. So far, there are few examples of optode-like systems that use liquid-liquid extraction, and they have only been demonstrated for the detection of cations [27,28]. For anion sensing, most optodes employ a pH-dependent dye as the fluorophore/chromophore, which relies on the co-extraction of H + along with the anion of interest (or sometimes a solvatochromic dye). ...
Anions play an important role in our life, from storing our genetic code on the polyanion DNA, to being the active ingredient in agricultural fertilizers and other industrial processes. Consequently, chemists have been designing systems that can sense anionic species through a variety of methods, such as unimolecular chromophores or sensor arrays. Nonetheless, most existing sensing approaches still have some drawbacks, particularly related to obtaining adequate selectivity and achieving sensing of anions in aqueous environments. In this manuscript, we report a liquid–liquid extraction (LLE)-based sensing approach that allows the conversion of non-selective optical anion sensors that only work in organic media, into selective sensing systems that allow detection of anions in water. We tested this approach on deprotonation-based anion sensors (alizarin, naphthol AS, 4-nitrophenol, BI-Lawsone, and chromophore 1) and hydrogen bonding-based anion sensors (1,2-diaminoanthraquinone and 4-nitro-1,2-phenylenediamine). In general, the deprotonation-based sensors could be converted from a non-selective sensor for basic anions (NCO¯, H2PO4¯, AcO¯ and F¯) to a selective sensing system for NCO¯ with the aid of carefully chosen tetraalkylammonium salts as extracting agents. On the other hand, the hydrogen-bonding based sensors could be converted to a selective sensing system for the hydrophobic anion ClO4¯ using similar tetraalkylammonium salts.
In this work, we explored the impact of zwitterionic surfactants, sulfobetaine 16 (SB-16) and a PEG- phospholipid conjugate (DSPE-PEG), on nanosensor performance. We fabricated four sensors (for Na+, K+, Al3+,...
Portable optical biosensors have emerged as revolutionary tools in point-of-care diagnostics, bringing the healthcare sector to the next level. Developing cutting-edge portable optical sensors represents significant advances in disease detection and monitoring. This review includes classifying optical sensors based on their transduction mechanism, addressing challenges such as sensitivity, specificity, miniaturization, cost considerations, regulatory approvals associated with portable optical biosensors for point-of-care diagnostics, and potential solutions to address these challenges. Miniaturization strategies and the importance of innovative materials and substrates in designing point-of-care diagnostic devices are investigated. The review further explores the recent advancements in miniaturization that have led to the development of portable optical devices for their recent applications in rapid point-of-care diagnostics, focusing on detecting various bioanalytes associated with various health conditions. Portable optical biosensors can revolutionize healthcare by enabling rapid, accurate, and personalized diagnoses, improving disease management, healthcare outcomes, and global diagnostic accessibility through technological advancements.
Potassium is an important bodily electrolyte which is kept within tight limits in health. Many medical conditions as well as commonly-used drugs either raise or lower blood potassium levels, which can be dangerous or even fatal. For at-risk patients, frequent monitoring of potassium can improve safety and lifestyle, but conventional venous blood draws are inconvenient, don't provide a timely result and may be inaccurate. This review summarises current solutions and recent developments in point-of-care and self-testing potassium measurement technologies, which include devices for measurement of potassium in venous blood, devices for home blood collection and remote measurement, devices for rapid home measurement of potassium, wearable sensors for potassium in interstitial fluid, in sweat, in urine, as well as non-invasive potassium detection. We discuss the practical and clinical applicability of these technologies and provide future outlooks.
We report here on a new generation of optical ion-selective sensors benefiting from cubosomes or hexosomes–nanostructural lipid liquid phase. Cubosome as well as hexosome optodes offer biocompatibility, self-assembly preparation, high stability in solution, and unique, tunable analytical performance. The temperature trigger reversibly changes the lipid nanoparticle internal structure–changing analyte access to the bulk of the probe and ultimately affecting the response pattern. Thus, cubosome or hexosome optodes are highly promising alternatives to conventional polymeric based optical nanoprobes.
Ionophore-based nanosensors (IBNS) are tools that enable quantification of analytes in complex chemical and biological systems. IBNS methodology is adopted from that of bulk optodes where an ion exchange event is converted to a change in optical output. While valuable, an important aspect for application is the ability to intentionally tune their size with simple approaches, and ensure that they contain compounds safe for application. Lipidots are a platform of size tunable lipid nanoemulsions with a hydrophobic lipid core typically used for imaging and drug delivery. Here, we present LipiSensors as size tunable IBNS by exploiting the Lipidot model as a hydrophobic structural support for the sensing moieties that are traditionally encased in plasticized PVC nanoparticles. The LipiSensors we demonstrate here are sensitive and selective for calcium, reversible, and have a lifetime of approximately one week. By changing the calcium sensing components inside the hydrophobic core of the LipiSensors to those sensitive for oxygen, they are also able to be used as ratiometric O2 sensitive nanosensors via a quenching-based mechanism. LipiSensors provide a versatile, general platform nanosensing with the ability to directly tune the size of the sensors while including biocompatible materials as the structural support by merging sensing approaches with the Lipidot platform.
Fluorescence technologies have been the preferred method for detection, analytical sensing, medical diagnostics, biotechnology, imaging, and gene expression for many years. Fluorescence becomes essential for studying molecular processes with high specificity and sensitivity through a variety of biological processes. A significant problem for practical fluorescence applications is the apparent non-linearity of the fluorescence intensity resulting from inner-filter effects, sample scattering, and absorption of intrinsic components of biological samples. Sample absorption can lead to the primary inner filter effect (Type I inner filter effect) and is the first factor that should be considered. This is a relatively simple factor to be controlled in any fluorescence experiment. However, many previous approaches have given only approximate experimental methods for correcting the deviation from expected results. In this part we are discussing the origin of the primary inner filter effect and presenting a universal approach for correcting the fluorescence intensity signal in the full absorption range. Importantly, we present direct experimental results of how the correction works. One considers problems emerging from varying absorption across its absorption spectrum for all fluorophores. We use Rhodamine 800 and demonstrate how to properly correct the excitation spectra in a broad wavelength range. Second is the effect of an inert absorber that attenuates the intensity of the excitation beam as it travels through the cuvette, which leads to a significant deviation of observed results. As an example, we are presenting fluorescence quenching of a tryptophan analog, NATA, by acrylamide and we show how properly corrected results compare to the initial erroneous results. The procedure is generic and applies to many other applications like quantum yield determination, tissue/blood absorption, or acceptor absorption in FRET experiments.
Droplet microfluidics is an enabling platform for high‐throughput screens, single‐cell studies, low‐volume chemical diagnostics, and microscale material syntheses. Analytical methods for real‐time and in situ detection of chemicals in the droplets will benefit these applications, but they remain limited. Reported herein is a novel heterogeneous chemical sensing strategy based on functionalization of the oil phase with rationally combined sensing reagents. Sub‐nanoliter oil segments containing pH‐sensitive fluorophores, ionophores, and ion‐exchangers enable highly selective and rapid fluorescence detection of physiologically important electrolytes (K⁺, Na⁺, and Cl⁻) and polyions (protamine) in sub‐nanoliter aqueous droplets. Electrolyte analysis in whole blood is demonstrated without suffering from optical interference from the sample matrix. Moreover, an oil phase doped with an aza‐BODIPY dye allows indication of H2O2 in the aqueous droplets, exemplifying sensing of targets beyond ionic species.
Background:
Adequate monitoring of patients using lithium is needed for optimal dosing and for early identification of patients with (potential) ADEs. The objective was to internationally assess how health care professionals monitor patients treated with lithium for bipolar disorder.
Methods:
Using networks of various professional organizations, an anonymous online survey was conducted among health care professionals prescribing lithium. Target lithium serum levels and frequency of monitoring was assessed together with monitoring of physical and laboratory parameters. Reasons to and not to monitor and use of guidelines and institutional protocols, and local monitoring systems were investigated.
Results:
The survey was completed by 117 health care professionals incorporating responses from twenty-four countries. All prescribers reported to monitor lithium serum levels on a regular basis, with varying target ranges. Almost all (> 97%) monitored thyroid and renal function before start and during maintenance treatment. Reported monitoring of other laboratory and physical parameters was variable. The majority of respondents (74%) used guidelines or institutional protocols for monitoring. In general, the prescriber was responsible for monitoring, had to request every monitoring parameter separately and only a minority of patients was automatically invited.
Conclusions:
Lithium serum levels, renal and thyroid function were monitored by (almost) all physicians. However, there was considerable variation in other monitoring parameters. Our results help to understand why prescribers of lithium monitor patients and what their main reasons are not to monitor patients using lithium.
Optical nanoparticle (NP)-based sensors have been widely implemented as tools for detection of targeted ions and biomolecules. The NP sensing platform offer a modular design that can incorporate different sensing components for greater target specificity and the ability to tune the dynamic range, as well as encapsulation of multiple dyes to generate a ratiometric signal with varying spectra. Despite these advantages, demonstrating quantitative ion imaging for intracellular measurement still possess a major challenge. Here, we describe fundamentals that enable intracellular validation of this approach using ion-selective nanosensors for investigating calcium (Ca²⁺) as a model ion. While conventional indicators can improve individual aspects of indicator performance such as Kd, wavelength, and ratiometric measurements, the use of NP sensors can achieve combined benefits of addressing these issues simultaneously. The nanosensor incorporates highly calcium-selective ionophores and two fluorescence indicators that act as signal transducers to facilitate quantitative ratiometric imaging. For intracellular Ca²⁺ application, the sensors are fine-tuned to physiological sensing range, and live-cell imaging and quantification are demonstrated in HeLa cells loaded with nanosensors and their responsiveness to carbachol-evoked store release (~400 nM). The current nanosensor design thus provides a promising sensing platform for real-time detection and optical determination of intracellular ions.
While the titrimetric assay is one of the most precise analytical techniques available, only a limited list of complexometric chelators is available as many otherwise promising reagents are not water soluble. Recent work demonstrated the successful titrimetry with ion-exchanging polymeric nanospheres containing hydrophobic complexing agents, so-called ionophores, opening an exciting avenue in this field. However, this method was limited to ionophores of very high affinity to the analyte and exhibited a relatively limited titration capacity. To overcome these two limitations, we report here on solvent based titration reagents. This heterogeneous titration principle is based on the dissolution of all hydrophobic recognition components in a solvent such as dichloromethane (CH2Cl2) where the ionophores are shown to maintain a high affinity to the target ions. HSV (hue, saturation, value) analysis of the images captured with a digital camera provides a convenient and inexpensive way to determine the endpoint. This approach is combined with an automated titration setup. The titrations of the alkali metals K+, Na+ and Li+ in aqueous solution are successfully demonstrated. The potassium concentration in human serum without pretreatment was precisely and accurately determined as 4.38 mM ± 0.10 mM (automated titration), which compares favorably with atomic emission spectroscopy (4.47 mM ± 0.20 mM).
Hypoparathyroidism is a rare endocrine disorder in which parathyroid hormone (PTH) production is abnormally low or absent, resulting in low serum calcium and increased serum phosphorus. The most common cause of hypoparathyroidism is parathyroid gland injury or inadvertent removal during thyroid surgery. Current treatments include supplementation with calcium and active vitamin D, with goal albumin-corrected serum calcium level in the low-normal range of 8–9 mg/dl. Complications of the disease include renal dysfunction, nephrocalcinosis, kidney stones, extracellular calcifications of the basal ganglia, and posterior subcapsular cataracts, as well as low bone turnover and increased bone density. Until January 2015, hypoparathyroidism was the only classic endocrine disease without an available hormone replacement. Recombinant human PTH 1-84, full-length PTH, is now available for a selected group of patients with the disease who are not well controlled on the current standard therapy of calcium and active vitamin D. In addition, the role of PTH replacement on quality of life, intracerebral calcifications, cataracts, improving bone turnover, and reduction of renal complications of the disease remains to be further investigated.
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.
This review describes recent advances in the miniaturization of ion selective optodes into microscale and nanoscale sensors. The topics include a comparison between film-based and miniaturized ion optodes, equilibrium and exhaustive detection modes, recent preparation methodologies and applications of microscale and nanoscale ion optodes, criteria for the design of optode sensors, and other future perspectives. Graphical Abstract Ion selective optodes are attractivre optical sensing tools for ionic species. This review highlights recent advances with this class of ion selective optical sensors with a focus on miniaturization, characteristics and applications of micrometer and nanometer sized optode sensors
Blood glucose monitoring has been established as a valuable tool in the management of diabetes. Since maintaining normal blood glucose levels is recommended, a series of suitable glucose biosensors have been developed. During the last 50 years, glucose biosensor technology including point-of-care devices, continuous glucose monitoring systems and noninvasive glucose monitoring systems has been significantly improved. However, there continues to be several challenges related to the achievement of accurate and reliable glucose monitoring. Further technical improvements in glucose biosensors, standardization of the analytical goals for their performance, and continuously assessing and training lay users are required. This article reviews the brief history, basic principles, analytical performance, and the present status of glucose biosensors in the clinical practice.
Fluorescence is an established technology for studying molecular processes and molecular interactions. More recently fluorescence became a leading method for detection, sensing, medical diagnostics, biotechnology, imaging, DNA analysis, and gene expression. Consequently, precise and accurate measurements in various conditions have become more critical for proper result interpretations. Previously, in Part 1, we discussed inner filter effect type I, which is a consequence of the instrumental geometrical sensitivity factor and absorption of the excitation. In this part, we analyze inner filter effect type II and discuss the practical consequences for fluorescence measurements in samples of high optical density (absorbance/scattering). We consider both the standard square and front-face experimental configurations, discuss experimental approaches to limit/mitigate the effect and discuss methods for correcting and interpreting experimental results.
Chemical sensors based on distance changes are attractive for point-of-care analysis especially in resource-limited regions. We report here a distance-based detection approach for calcium ions by entrapping ionophore-based calcium-selective organosilica nanoparticles in agar hydrogels. The nanoparticles, containing a chromoionophore, an ion-exchanger, and a calcium ionophore, respond to calcium ions in the exhaustive mode, resulting in sensitive and tunable detection of Ca²⁺ in range of both 1 to 5 mM and 0.1 to 0.5 mM. While a distance change from 0.26 to 0.53 mm was readily observed only 2 min after adding 0.1 to 0.5 mM of CaCl2, linear calibration was observed after a waiting time of 1 h, confirming the exhaustive mode in the hydrogel. The exhaustive mode made the approach pH independent (from pH 5.5 to 8.6). The methodology was validated by measuring the calcium levels in chicken blood and serum. Hydrogels with multiple sensing layers were also fabricated for semi-quantitative analysis of calcium with a long shelf life of at least 49 days.
The optical technology presents non-invasive, non-destructive, and non-ionizing features and has the ability to display various chemical components in tissues to provide useful information for various biomedical applications. Regarding selection of light wavelengths, second near-infrared (NIR-II, 900-1700 nm) light is a much better choice compared to both visible (380-780 nm) and traditional near-infrared (780-900 nm) light, because of its advantages including deeper penetration into biological tissues, less tissue scattering or absorption, and decreased interference by fluorescent proteins. Thus, using optical nano-agents that absorb or emit light in the NIR-II window can achieve deeper tissue optical imaging with higher signal-to-background ratios and better spatial resolution for diagnosis. What's more, some of these nano-agents can be further applied for imaging guided surgical removal, real-time monitoring of drug delivery, labeling lymphatic metastasis, biosensing, and imaging guided phototherapy. In this review, we attempt to summarize the recent advances of various NIR-II nano-agents (including single-walled carbon nanotubes, quantum dots, rare-earth doped nanoparticles, other inorganic nanomaterials, small organic molecule-based nanoparticles, and semiconducting polymer nanoparticles) in both bioimaging and therapeutic applications, and discuss the challenges and perspectives of these nano-agents for clinical practice in the near future.
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.
Magnesium is one of the most important elements in the human body and is involved in a number of biochemical processes crucial for the proper functioning of the cardiovascular, alimentary, endocrine, and osteoarticular systems. It also plays a vital modulatory role in brain biochemistry, influencing several neurotransmission pathways associated with the development of depression. Personality changes, including apathy, depression, agitation, confusion, anxiety, and delirium are observed when there is a deficiency of this element. Rodents receiving a diet deficient in magnesium displayed depressive behaviour that was reversed by antidepressant drugs. Poor nutrition, gastrointestinal and renal diseases, insulin resistance and/or type 2 diabetes, alcoholism, stress, and certain medications may lead to magnesium deficiency. Since the extracellular concentration of magnesium ions may not reflect their intracellular level, none of the current methods of evaluating magnesium status is regarded as satisfactory. The mood-improving potential of magnesium compounds have been confirmed by the results of numerous pre-clinical and clinical studies. It seems that magnesium supplementation is well-tolerated and enhances the efficacy of conventional antidepressant treatments, and as such could be a valuable addition to the standard treatments for depression, although differences in bioavailability between inorganic and organic compounds should be taken into consideration.
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.
Ion selective optical sensors are typically interrogated under conditions where the sample concentration is not altered during measurement. We describe here an alternative exhaustive detection mode for ion selective optical sensors. This exhaustive sensor concept is demonstrated with ionophore-based nanooptodes either selective for calcium or the polycationic heparin antidote protamine. In agreement with a theoretical treatment presented here, linear calibration curves were obtained in the exhaustive detection mode instead of the sigmoidal curves for equilibrium-based sensors. The response range can be tuned by adjusting the nanosensor loading. The nanosensors showed average diameters of below 100 nm and the sensor response was found to be dramatically faster than that for film-based optodes. Due to the strong binding affinity of the exhaustive nanosensors, total calcium concentration in human blood plasma was successfully determined. Optical determination of protamine in human blood plasma using the exhaustive nanosensors was attempted, but was found to be less successful.
This review provides an overview of the key aspects of designing ionophore-based optical sensors (IBOS). Exact response functions are developed and compared with a simplified, generalized equation. We also provide a brief introduction into less established but promising working principles, namely dynamic response and exhaustive exchange. Absorbance and fluorescence are the main optical readout strategies used in the evaluation of a sensor response, but they usually require a robust referencing technique for real-world applications. Established referencing schemes using IBOS as well as those from other optical sensors are also discussed. Finally, the power of recently developed photoresponsive ion extraction/release systems is outlined and discussed in view of dynamically switchable IBOS or regenerative exhaustive exchange IBOS.
This review provides information on application of potentiometric ion-sensors in routine clinical analysis. The text comprises sensor design, way-of-use, conventions and practical recommendations, and elements of IS response theory. An instrument producer point of view, based on direct industrial involvement of the author, is emphasized.
Bulk optode-based ion selective optical sensors work on the basis of extraction equilibria and their response towards the analyte ion is known to dependent on the sample pH. This pH dependence has been one of the major disadvantages that have hampered the broad acceptance of bulk optodes in chemical sensing. We present here for the first time the use of exhaustive Ca2+- selective nanosensors that may overcome this pH dependent response. The nanosensors were characterized at different pH and the same linear calibration was obtained in the Ca2+ concentration range from 10-7 M to 10-5 M.
This article summarizes the application of fluorescent sensors to in vitro diagnostic systems measuring critical care analytes in whole blood. We discuss recent advances in fluorescent chemosensor technologies employing fluorescence indicators used for this application. This paper touches on key materials, structure-property relations, and design considerations for maximum utility in low-cost portable systems. In this application the optical sensor technology demonstrates precision and stability comparable or better than that of the best-available conventional technologies employing electrochemical sensors.
We proposed here a potassium selective optode incorporating NaYF:Er,Yb upconverting nanorods and chromoionophore ETH 5294 together in hydrophobic polymer matrixes and the response of the optode is based on changes in the upconverting luminescence intensity induced from the absorption change of the proton sensitive chromoionophore. The optode was used for determination of the potassium content in the whole blood sample for the first time. Because the excitation source of 980 nm, as well as the emission wavelength, lies in the near-infrared region, the background absorption and autofluorescence of the biological sample could be eliminated, and ensure the sensitivity and selectivity of the sensor. The potassium levels of sheep plasma and whole blood samples obtained by the optode were comparable with the results obtained by ICPMS and ISE methods, providing possibilities for further application in clinical diagnosis.
A large variety of new optical ion-sensor constructions (optodes) can now be realized by using a poly (vinyl chloride) (PVC) membrane that incorporates a cation-selective neutral ionophore, a specially tailored H+-selective neutral chromolonophore, and lipophilic anionic sites in the same plasticized PVC membrane. Such membranes generally combine the advantages of a highly selective and reversible recognition of given ionic substrates and of a straightforward optical transduction of the recognition process. The present membrane exhibits the theoretically expected absorbance response to Ca2+ activities in different pH-buffered samples. Dynamic range, reproducibility, response time, long-time stability, and selectivity of the new optode membrane are discussed.
Integration of a neutral ionophore-based ion pair extraction reaction onto a glass microchip was performed. Since the liquid microspace provides a short molecular diffusion distance and a large specific interfacial area of the liquid−liquid interface, novel attractive analytical features arise such as extremely fast ion sensing and ultrasmall reagent solution volume. In contrast to the slow response time of a standard ion optode, in which the response time is basically governed by slow diffusion of ionic species in the viscous polymer membrane, that of the on-chip ion-sensing system is clearly faster due to the short molecular diffusion distance and low viscosity of organic solution. In this case, the organic solution containing a neutral ionophore and a lipophilic pH indicator dye and the aqueous solution containing sample ion were independently introduced into microchannel to form an organic−aqueous interface. Then determination of the ion was performed by thermal lens microscopy at the downstream of the organic phase under continuous-flow conditions. The response time and minimum required reagent solution volume of the on-chip ion-sensing system are about 8 s and 125 nL, respectively, indicating the advantages of using the liquid microspace. Other advantages of the on-chip ion pair extraction system arising from using the liquid microspace and microfluidic system are also discussed in detail.
A simple method for doping ion-sensing ingredients into silanized silica particles (∼3.5 μm) was developed to fabricate carrier-based ion-selective microsphere optical ion sensors. These ion sensors operate according to established bulk optode principles. Na+-selective microsphere optical sensors were prepared with the ionophore tert-butylcalix[4]arene tetraacetic acid tetraethylester, the H+-chromoionophore 9-(diethylamino)-5-octadecanoylimino-5H-benzo[a]phenoxazine (ETH 5294), the ion exchanger sodium tetrakis[3,5-bis(tri-fluoromethyl)phenyl]borate (NaTFPB), PVC and the plasticizer bis(2-ethylhexyl)sebacate (DOS). For Ca2+ sensing, the grafted Ca2+ ionophore AU-1 in poly(n-BA) was applied with ETH 5294, NaTFPB and DOS. Fluorescence microscopy and flow cytometry were used for characterization. The resulting microsphere optical ion sensors were found to obey bulk optode theory with reliable response, high selectivities, dynamic ranges suitable for physiological measurements and a shelf time of over 6 months. The measuring ranges (logarithmic molar concentrations) at pH 7.4 were −3.5 to −1.5 for the fabricated Na+-selective optical-sensing microspheres, and −4.5 to −1.5 for Ca2+-selective optical-sensing microspheres. Corresponding thin optode films and regular PVC/DOS-based microspheres were prepared for comparison and showed similar response characteristics. The fabricated microsphere optical ion sensors were also deposited on an optical fiber bundle, and reproducible fluorescence signals were observed.
A segmented sandwich membrane method is used to determine complex formation constants of 18 electrically neutral ionophores in situ in solvent polymeric sensing membranes. These ionophores are commonly used in potentiometric and optical sensors, and knowledge of such binding information is important for ionophore and sensor design. In this method, two membrane segments are fused together, with only one containing the ionophore, to give a concentration-polarized sandwich membrane. Unlike other approaches, this method does not require the use of a reference ion in the sample and/or a second ionophore in the membrane, and is typically pH insensitive. The following ionophores responsive for the common cations lithium, sodium, potassium, magnesium and calcium are characterized and discussed: valinomycin, BME-44, bis[(benzo-15-crown-5)-4′-ylmethyl]pimelate, ETH 157, ETH 2120, bis[(12-crown-4)methyl]dodecylmethylmalonate], 4-tert-butylcalix [4] arene tetraacetic acid tetraethyl ester, ETH 149, ETH 1644, ETH 1810, 6,6-dibenzyl-14-crown-4, N,N,N′,N′,N″,N″-hexacyclohexyl-4,4′,4″-propylidyne tris(3-oxabutyramide), ETH 1117, ETH 4030, ETH 1001, ETH 129, ETH 5234, and A23187. The logarithmic complex formation constants range from 4.4 to 29 and compare well to published data for ionophores that were characterized earlier. From the observed complex formation constants, maximum possible selectivities are calculated that would be expected if interfering ions show no binding affinity to the ionophore, and the values are compared with experimental findings. Each ionophore is characterized in poly(vinyl chloride) membranes plasticized either with a polar (NPOE) or a nonpolar plasticizer (DOS). Membranes based on NPOE always show larger complex formation constants of the embedded ionophore.
The binding properties of neutral or charged chromoionophores and anion ionophores in solvent polymeric membranes were characterized in situ by the so-called sandwich membrane method. Acidity constants (pK(a)) of eight chromoionophores (ETH 5294, ETH 2439, ETH 5350, ETH 5418, ETH 5315, ETH 7061, ETH 7075, ETH 2412) were measured in bis(2-ethylhexyl)sebacate (DOS) and o-nitrophenyloctylether (NPOE) plasticized poly(vinyl chloride) (PVC) membranes commonly used in optical and potentiometric ion sensors. The pK(a) values of all chromoionophores in DOS membranes are by 2-3 orders of magnitude smaller than in NPOE membranes. The weak alkali metal ion binding properties with neutral H(+)-chromoionophore and anion binding with electrically charged chromoionophores were also studied quantitatively. The complex formation constants of the commercially available Co(III)cobyrinate nitrite ionophore and the organomercury chloride ionophore, ETH 9009, were also measured. The very low stability constant observed for ETH 9009 (logbeta(2)=3.60+/-0.03 in PVC-DOS and 3.61+/-0.01 in PVC-NPOE) was explained by the decomposition of the ionophore in contact with chloride samples. On the other hand, the electrically charged nitrite ionophore showed strong complexation with nitrite ions, with logbeta=10.58 and 10.59 in DOS and NPOE membranes, respectively. In contrast to cation ionophores, the stability constant of the NO(2)(-) ionophore does not change with different plasticizers.
A sequential ion-sensing system using a single microchip was successfully realized. The system developed here involves intermittent pumping of plural organic phases into a microchannel, followed by contact with a single aqueous phase to form a stable organic-aqueous two-layer flow inside the microchannel. Because the plural organic phases created by intermittent flow contain the same lipophilic pH indicator dye but different ion-selective neutral ionophores, different ions can be sequentially and selectively extracted into the different organic phases, where they can be determined by thermal lens microscopy (TLM). We used KD-A3 as the lipophilic pH indicator dye and valinomycin and DD16C5 as neutral ionophores to demonstrate sequential ion sensing of potassium and sodium ions by measuring the deprotonated dye caused by the ion extraction. The integrated microfluidic system proposed here allows multi-ion sensing, which is not easily demonstrated by conventional ion sensor technology using a solvent polymeric membrane. The minimum volume of single organic phase needed to obtain an equilibrium response without dilution by cross dispersion of two organic phases was ca. 500 nL in our system, indicating that the required amounts of expensive reagents in one measurement could be reduced to 1.7 ng and 2.8 ng for the dye and ionophore molecules, respectively.
Hypercalcemia is a disorder commonly encountered by primary care physicians. The diagnosis often is made incidentally in asymptomatic patients. Clinical manifestations affect the neuromuscular, gastrointestinal, renal, skeletal, and cardiovascular systems. The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. Some other important causes of hypercalcemia are medications and familial hypocalciuric hypercalcemia. An initial diagnostic work-up should include measurement of intact parathyroid hormone, and any medications that are likely to be causative should be discontinued. Parathyroid hormone is suppressed in malignancy-associated hypercalcemia and elevated in primary hyperparathyroidism. It is essential to exclude other causes before considering parathyroid surgery, and patients should be referred for parathyroidectomy only if they meet certain criteria. Many patients with primary hyperparathyroidism have a benign course and do not need surgery. Hypercalcemic crisis is a life-threatening emergency. Aggressive intravenous rehydration is the mainstay of management in severe hypercalcemia, and antiresorptive agents, such as calcitonin and bisphosphonates, frequently can alleviate the clinical manifestations of hypercalcemic disorders.
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