pH-regulated single cell migration.

Over the last two decades, extra- and intracellular pH have emerged as fundamental regulators of cell motility. Fundamental physiological and pathological processes relying on appropriate cell migration, such as embryonic development, wound healing, and a proper immune defense on the one hand, and autoimmune diseases, metastatic cancer, and the progression of certain parasitic diseases on the other, depend on surrounding pH. In addition, migrating single cells create their own localized pH nanodomains at their surface and in the cytosol. By this means, the migrating cells locally modulate their adhesion to, and the re-arrangement and digestion of, the extracellular matrix. At the same time, the cytosolic nanodomains tune cytoskeletal dynamics along the direction of movement resulting in concerted lamellipodia protrusion and rear end retraction. Extracellular pH gradients as found in wounds, inflamed tissues, or the periphery of tumors stimulate directed cell migration, and long-term exposure to acidic conditions can engender a more migratory and invasive phenotype persisting for hours up to several generations of cells after they have left the acidic milieu. In the present review, the different variants of pH-dependent single cell migration are described. The underlying pH-dependent molecular mechanisms such as conformational changes of adhesion molecules, matrix protease activity, actin (de-)polymerization, and signaling events are explained, and molecular pH sensors stimulated by H+ signaling are presented.

Polarization Conforms Performance Variability in Amorphous Electrodeposited Iridium Oxide pH Sensors: A Thorough Surface Chemistry Investigation.

Electrodeposited amorphous hydrated iridium oxide (IrOx) is a promising material for pH sensing due to its high sensitivity and the ease of fabrication. However, durability and variability continue to restrict the sensor's effectiveness. Variation in probe films can be seen in both performance and fabrication, but it has been found that performance variation can be controlled with potentiostatic conditioning (PC). To make proper use of this technique, the morphological and chemical changes affecting the conditioning process must be understood. Here, a thorough study of this material, after undergoing PC in a pH-sensing-relevant potential regime, was conducted by voltammetry, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Fitting of XPS data was performed, guided by raw trends in survey scans, core orbitals, and valence spectra, both XPS and UPS. The findings indicate that the PC process can repeatably control and conform performance and surface bonding to desired calibrations and distributions, respectively; PC was able to reduce sensitivity and offset ranges to as low as ±0.7 mV/pH and ±0.008 V, respectively, and repeat bonding distributions over ~2 months of sample preparation. Both Ir/O atomic ratios (shifting from 4:1 to over 4.5:1) and fitted components assigned hydroxide or oxide states based on the literature (low-voltage spectra being almost entirely with suggested hydroxide components, and high-voltage spectra almost entirely with suggested oxide components) trend across the polarization range. Self-consistent valence, core orbital, and survey quantitative trends point to a likely mechanism of ligand conversion from hydroxide to oxide, suggesting that the conditioning process enforces specific state mixtures that include both theoretical Ir(III) and Ir(IV) species, and raising the conditioning potential alters the surface species from an assumed mixture of Ir species to more oxidized Ir species.

Chemometric-Assisted Litmus Test: One Single Sensing Platform Adapted from 1-13 to Narrow pH Ranges.

A novel 3 × 4 colorimetric sensing platform, named the chemometric-assisted litmus test (CLT), has been developed by covalently anchoring commercial pH indicators to ethylene vinyl alcohol (EVOH). The proposed device can be exploited for pH determinations in a wide range from 1 to 13 and in specific narrow ranges, achieving sufficient accuracy and errors below 0.5 pH units. The experimental procedure is simple, quick and reliable; equilibration is reached in less than 2 h, CLT pictures are acquired by a camera, and data treatment is performed applying chemometric techniques such as principal component analysis (PCA) and partial least square regression (PLS) to RGB indices.

A novel aggregation-induced emission fluorescent probe with large Stokes shift for sensitive detection of pH changes in live cells.

The detection of intracellular pH is crucial for elucidating the pathological process of cancers, as well as for medical diagnostic applications. Here, we developed an aggregation-induced emission active pH-responsive fluorescent probe (TPE-DCP) for sensitively detecting cell pH changes. The probe shows obvious pH-sensing properties at ~615 nm, with a pKa value of 6.82 and a good linear pH response ranging from 8.5 to 4.5. TPE-DCP holds advantages such as excellent anti-interference performance, good photostability, and low cytotoxicity, and has been successfully used to image intracellular pH changes in cells.

New Sensors for Monitoring pH and Corrosion of Embedded Steel in Mortars during Sulfuric Acid Attack.

The sulfuric acid attack is a common form of degradation of reinforced concrete in contact with industrial wastewater, mine water, acid rain, or in sewage treatment stations. In this work, new pH-sensitive IrOx electrodes were developed for monitoring the pH inside mortar or concrete. To test their ability, the pH sensors were embedded in mortar samples at different depths and the samples were exposed to sulfuric acid solution. In another set of experiments, iron wires were placed at the same depths inside similar mortar samples and their corrosion was monitored as the acid attacked the mortar. Severe acid attack led to cement dissolution and formation of gypsum. The new pH sensors succeeded in measuring the pH changes inside the mortars. The pH gradient, from the high acid environment to the high alkaline mortar interior, occurred in a narrow region. Corrosion of the iron electrodes started only when the acidic solution was in their close vicinity.

A Review of Stimuli-Responsive Smart Materials for Wearable Technology in Healthcare: Retrospective, Perspective, and Prospective.

In recent years thanks to the Internet of Things (IoT), the demand for the development of miniaturized and wearable sensors has skyrocketed. Among them, novel sensors for wearable medical devices are mostly needed. The aim of this review is to summarize the advancements in this field from current points of view, focusing on sensors embedded into textile fabrics. Indeed, they are portable, lightweight, and the best candidates for monitoring biometric parameters. The possibility of integrating chemical sensors into textiles has opened new markets in smart clothing. Many examples of these systems are represented by color-changing materials due to their capability of altering optical properties, including absorption, reflectance, and scattering, in response to different external stimuli (temperature, humidity, pH, or chemicals). With the goal of smart health monitoring, nanosized sol-gel precursors, bringing coupling agents into their chemical structure, were used to modify halochromic dyestuffs, both minimizing leaching from the treated surfaces and increasing photostability for the development of stimuli-responsive sensors. The literature about the sensing properties of functionalized halochromic azo dyestuffs applied to textile fabrics is reviewed to understand their potential for achieving remote monitoring of health parameters. Finally, challenges and future perspectives are discussed to envisage the developed strategies for the next generation of functionalized halochromic dyestuffs with biocompatible and real-time stimuli-responsive capabilities.

Highly Sensitive Fluorescent pH Microsensors Based on the Ratiometric Dye Pyranine Immobilized on Silica Microparticles.

Pyranine (HPTS) is a remarkably interesting pH-sensitive dye that has been used for plenty of applications. Its high quantum yield and extremely sensitive ratiometric fluorescence against pH change makes it a very favorable for pH-sensing applications and the development of pH nano-/microsensors. However, its strong negative charge and lack of easily modifiable functional groups makes it difficult to use with charged substrates such as silica. This study reports a methodology for noncovalent HPTS immobilization on silica microparticles that considers the retention of pH sensitivity as well as the long-term stability of the pH microsensors. The study emphasizes the importance of surface charge for governing the sensitivity of the immobilized HPTS dye molecules on silica microparticles. The importance of the immobilization methodology, which preserves the sensitivity and stability of the microsensors, is also assessed.

A Novel Lab-on-Chip Spectrophotometric pH Sensor for Autonomous In Situ Seawater Measurements to 6000 m Depth on Stationary and Moving Observing Platforms.

We report a new, autonomous Lab-on-Chip (LOC) microfluidic pH sensor with a 6000 m depth capability, ten times the depth capability of the state of the art autonomous spectrophotometric sensor. The pH is determined spectrophotometrically using purified meta-Cresol Purple indicator dye offering high precision (<0.001 pH unit measurement reproducibility), high frequency (every 8 min) measurements on the total proton scale from the surface to the deep ocean (to 600 bar). The sensor requires low power (3 W during continuous operation or ∼1300 J per measurement) and low reagent volume (∼3 µL per measurement) and generates small waste volume (∼2 mL per measurement) which can be retained during deployments. The performance of the LOC pH sensor was demonstrated on fixed and moving platforms over varying environmental salinity, temperature, and pressure conditions. Measurement accuracy was +0.003 ± 0.022 pH units (n = 47) by comparison with validation seawater sample measurements in coastal waters. The combined standard uncertainty of the sensor in situ pHT measurements was estimated to be ≤0.009 pH units at pH 8.5, ≤ 0.010 pH units at pH 8.0, and ≤0.014 pH units at pH 7.5. Integrated on autonomous platforms, this novel sensor opens new frontiers for pH observations, especially within the largest and most understudied ecosystem on the planet, the deep ocean.

Chemical Sensors for Farm-to-Table Monitoring of Fruit Quality.

Farm-to-table operations produce, transport, and deliver produce to consumers in very different ways than conventional, corporate-scale agriculture operations. As a result, the time it takes to get a freshly picked fruit to the consumer is relatively short and the expectations of the consumer for freshness and quality are high. Since many of these operations involve small farms and small businesses, resources to deploy sensors and instruments for monitoring quality are scarce compared to larger operations. Within stringent power, cost, and size constraints, this article analyzes chemical sensor technologies suitable for monitoring fruit quality from the point of harvest to consumption in farm-to-table operations. Approaches to measuring sweetness (sugar content), acidity (pH), and ethylene gas are emphasized. Not surprisingly, many instruments developed for laboratory use or larger-scale operations are not suitable for farm-to-table operations. However, there are many opportunities still available to adapt pH, sugar, and ethylene sensing to the unique needs of localized farm-to-table operations that can help these operations survive and expand well into the future.

Manufacturing of Microfluidic Devices with Interchangeable Commercial Fiber Optic Sensors.

In situ measurements are highly desirable in many microfluidic applications because they enable real-time, local monitoring of physical and chemical parameters, providing valuable insight into microscopic events and processes that occur in microfluidic devices. Unfortunately, the manufacturing of microfluidic devices with integrated sensors can be time-consuming, expensive, and "know-how" demanding. In this article, we describe an easy-to-implement method developed to integrate various "off-the-shelf" fiber optic sensors within microfluidic devices. To demonstrate this, we used commercial pH and pressure sensors ("pH SensorPlugs" and "FOP-MIV", respectively), which were "reversibly" attached to a glass microfluidic device using custom 3D-printed connectors. The microfluidic device, which serves here as a demonstrator, incorporates a uniform porous structure and was manufactured using a picosecond pulsed laser. The sensors were attached to the inlet and outlet channels of the microfluidic pattern to perform simple experiments, the aim of which was to evaluate the performance of both the connectors and the sensors in a practical microfluidic environment. The bespoke connectors ensured robust and watertight connection, allowing the sensors to be safely disconnected if necessary, without damaging the microfluidic device. The pH SensorPlugs were tested with a pH 7.01 buffer solution. They measured the correct pH values with an accuracy of ±0.05 pH once sufficient contact between the injected fluid and the measuring element (optode) was established. In turn, the FOP-MIV sensors were used to measure local pressure in the inlet and outlet channels during injection and the steady flow of deionized water at different rates. These sensors were calibrated up to 140 mbar and provided pressure measurements with an uncertainty that was less than ±1.5 mbar. Readouts at a rate of 4 Hz allowed us to observe dynamic pressure changes in the device during the displacement of air by water. In the case of steady flow of water, the pressure difference between the two measuring points increased linearly with increasing flow rate, complying with Darcy's law for incompressible fluids. These data can be used to determine the permeability of the porous structure within the device.

Plasmonic Elastic Capsules as Colorimetric Reversible pH-Microsensors.

There is a crucial need for effective and easily dispersible colloidal microsensors able to detect local pH changes before irreversible damages caused by demineralization, corrosion, or biofilms occur. One class of such microsensors is based on molecular dyes encapsulated or dispersed either in polymer matrices or in liquid systems exhibiting different colors upon pH variations. They are efficient but often rely on sophisticated and costly syntheses, and present significant risks of leakage and photobleaching damages, which is detrimental for mainstream applications. Another approach consists of exploiting the distance-dependent plasmonic properties of metallic nanoparticles. Still, assembling nanoparticles into dispersible colloidal pH-sensitive sensors remains a challenge. Here, it is shown how to combine optically active plasmonic gold nanoparticles and pH-responsive thin shells into "plasmocapsules." Upon pH change, plasmocapsules swell or shrink. Concomitantly, the distance between the gold nanoparticles embedded in the polymeric matrix varies, resulting in an unambiguous color change. Billions of micron-size sensors can thus be easily fabricated. They are nonintrusive, reusable, and sense local pH changes. Each plasmocapsule is an independent reversible microsensor over a large pH range. Finally, their potential use for the detection of bacterial growth is demonstrated, thus proving that plasmocapsules are a new class of sensing materials.

Bifunctional DNA Duplexes Permit Efficient Incorporation of pH Probes into Liposomes.

Enzyme-mediated proton transport across biological membranes is critical for many vital cellular processes. pH-sensitive fluorescent dyes are an indispensable tool for investigating the molecular mechanism of proton-translocating enzymes. Here, we present a novel strategy to entrap pH-sensitive probes in the lumen of liposomes that has several advantages over the use of soluble or lipid-coupled probes. In our approach, the pH sensor is linked to a DNA oligomer with a sequence complementary to a second oligomer modified with a lipophilic moiety that anchors the DNA conjugate to the inner and outer leaflets of the lipid bilayer. The use of DNA as a scaffold allows subsequent selective enzymatic removal of the probe in the outer bilayer leaflet. The method shows a high yield of insertion and is compatible with reconstitution of membrane proteins by different methods. The usefulness of the conjugate for time-resolved proton pumping measurements was demonstrated by using two large membrane protein complexes.

High-throughput extracellular pH monitoring and antibiotics screening by polymeric fluorescent sensor with LCST property.

Monitoring extracellular pH (pHe) is important for biology understanding, since pHe and its homeostasis are closely relevant to cellular metabolism. Hydrogel-based pHe sensors have attracted significant attention and showed wide application, while they are tedious with significant time-cost operation and reproducibility variations for high-throughput application. Herein, we synthesized two polymers for pHe monitoring which are soluble in water at room temperature with easy operations and high reproducibility among various micro-plate wells for high-throughput analysis. P1 (P(OEGMA-co-MEO2MA-co-pHS)) and P2 (P(OEGMA-co-pHS)) were synthesized via the Reversible Addition Fragmentation Chain Transfer (RAFT) copolymerization of oligo(ethylene glycol) methacrylate (OEGMA), 2-(2'-methoxyethoxy) ethyl methacrylate (MEO2MA) and the pH sensitive fluorescence moiety N-fluoresceinyl methacrylamide (pHS). P1 is soluble in water at room temperature (25 °C) while insoluble at the temperature above 33 °C, indicating its feature of lower critical solution temperature (LCST) at 33 °C. Further P1 showed higher pH sensitivity and photostability than P2 (without LCST property) when used at physiological temperature (37 °C). Thus, P1 was chosen to in-situ monitor the micro-environmental acidification of E. coli, Hela and Ramos cells during their growth, and the metabolism inhibiting activity of a representative antibiotic, ampicillin. Cell concentration-dependent cellular acidification and drug concentration-dependent inhibition of cellular acidification were observed, demonstrating that the LCST polymer (P1) is suitable for real-time cellular acidification monitoring as well as for high-throughput drug screening. This study firstly demonstrated the use of a LCST polymeric sensor for high-throughput screening of antibiotics and investigation of cell metabolism.

Double Role of Diphenylpyridine Derivatives as Fluorescent Sensors for Monitoring Photopolymerization and the Determination of the Efficiencies of the Generation of Superacids by Cationic Photoinitiators.

Novel fluorescent sensors with electron-donating or electron-withdrawing substituents incorporated into a chromophore group based on 2,6-diphenylpyridine were designed and synthesised. The spectroscopic properties of these compounds were studied. Moreover, the positive solvatochromism of 2,6-bis-(4-methylsulphanylphenyl)pyridine (PT-SCH3) in selected solvents was studied by measurement of the absorption and emission spectra and analysed using the Dimroth-Reichardt solvent parameter set. After that, the performance of a series of 2,6-diphenylpyridine derivatives as fluorescent molecular sensors for monitoring free-radical and cationic photopolymerization processes by the Fluorescence Probe Technique (FPT) was studied. As a consequence of this stage of research, the effect of substituents on the sensitivity of the 2,6-diphenylpyridine derivatives as sensors during photopolymerization has been evaluated and discussed. It has been found that compounds containing strong electron-donating substituent (PT-SCH3) slightly shift their fluorescence spectrum during the free-radical polymerization of monomer, which enables the monitoring of the polymerization progress using the fluorescence intensity ratio measured at two different wavelengths as the progress indicator. The position of the fluorescence spectrum of 2,6-diphenylpyridine derivatives with electron-withdrawing substituents is practically insensitive to changes occurring in their environment. Hence, it is recommended to use these compounds with different indicators of the progress of the photopolymerization process based on normalised intensity of fluorescence (Imax/I0). Among the compounds studied, 2,6-bis(4-methylsulphanylphenyl)pyridine (PT-SCH3) turned out to be the best fluorescent sensor for the purpose of monitoring free-radical polymerization by FPT. Consequently, the dual application of the selected 2,6-diphenylpyridine derivatives is proposed: (a) as fluorescent sensors for monitoring the free-radical photopolymerization progress, and (b) as spectroscopic sensors for the determination of efficiencies of the generation of superacids by cationic photoinitiators during the cationic photopolymerization process. Finally, a new method for determining the relative efficiency of the photogeneration of superacids during the photo cleavage of onium salt has been devised and applied for the evaluation of the performance of 2,6-diphenylpyridine derivatives.

Bioinspired Heterocyclic Partnership in a Cyanine-Type Acidichromic Chromophore.

A new red hair-inspired 1,4-benzothiazine-based scaffold is disclosed herein, built upon a modular D-π-A architecture via condensation of the easily accessible 3-phenyl-2H-1,4-benzothiazine with indole-3-carboxaldehyde. The compound was obtained in around 50% yields and was characterized by complete spectroscopic analysis. The new benzothiazine-based cyanine displayed a characteristic reversible acidichromic behavior with a marked bathochromic shift upon acidification. The chromophore resisted at least fifteen hydrochloric acid/sodium hydroxide cycles without appreciable alterations. The expedient and scalable synthetic procedure together with the pH sensitive chromophoric properties would make the new compound an attractive prototype for novel modular chromophore for pH-sensing and other applications.

Pyranine-Modified Amphiphilic Polymer Conetworks as Fluorescent Ratiometric pH Sensors.

The fluorescent dye 8-hydroxypyrene-1,3,6-trisulfonate (pyranine) combines high photostability with ratiometric pH detection in the physiological range, making it a prime candidate for optical sensors in biomedical applications, such as pH-based chronic wound monitoring. However, pyranine's high water solubility and the difficulty of covalent attachment pose severe limitations in terms of leaching from sensor matrices. Herein, pyranine-modified nanophase-separated amphiphilic polymer conetworks (APCNs) are reported as fluorescent ratiometric pH sensors. The thin, freestanding APCN membranes composed of one hydrophilic and one hydrophobic polymer provide an optically transparent, flexible, and stable ideal matrix that enables contact between dye and aqueous environment. An active ester-based conjugation approach results in a highly homogeneous and stable pyranine modification of the APCN's hydrophilic phase. This concept effectively solves the leaching challenge for pyranine without compromising its functionality, which is demonstrated by ratiometric pH detection in the range of pH 5-9.

Dynamic pH Sensor with Embedded Calibration Scheme by Advanced CMOS FinFET Technology.

In this work, we present a novel pH sensor using efficient laterally coupled structure enabled by Complementary Metal-Oxide Semiconductor (CMOS) Fin Field-Effect Transistor (FinFET) processes. This new sensor features adjustable sensitivity, wide sensing range, multi-pad sensing capability and compatibility to advanced CMOS technologies. With a self-balanced readout scheme and proposed corresponding circuit, the proposed sensor is found to be easily embedded into integrated circuits (ICs) and expanded into sensors array. To ensure the robustness of this new device, the transient response and noise analysis are performed. In addition, an embedded calibration operation scheme is implemented to prevent the proposed sensing device from the background offset from process variation, providing reliable and stable sensing results.

Engineering a pH-Sensitive Liposomal MRI Agent by Modification of a Bacterial Channel.

MscL is a bacterial mechanosensitive channel that serves as a cellular emergency release valve, protecting the cell from lysis upon a drop in external osmolarity. The channel has an extremely large pore (30 Å) and can be purified and reconstituted into artificial membranes. Moreover, MscL is modified to open in response to alternative external stimuli including changes in pH. These properties suggest this channel's potential as a triggered "nanopore" for localized release of vesicular contents such as magnetic resonance imaging (MRI) contrast agents and drugs. Toward this end, several variants of pH-triggered MscL nanovalves are engineered. Stealth vesicles previously been shown to evade normal in vivo clearance and passively accumulate in inflamed and malignant tissues are reconstituted. These vesicles are loaded with 1,4,7,10-tetraazacyclododecane tetraacetic acid gadolinium complex (Gd-DOTA), an MRI contrast reagent, and the resulting nanodevices tested for their ability to release Gd-DOTA as evidenced by enhancement of the longitudinal relaxation rate (R1 ) of the bulk water proton spins. Nanovalves that are responsive to physiological pH changes are identified, but differ in sensitivity and efficacy, thus giving an array of nanovalves that could potentially be useful in different settings. These triggered nanodevices may be useful in delivering both diagnostic and therapeutic agents.

Smart Bandage for Monitoring and Treatment of Chronic Wounds.

Chronic wounds are a major health concern and they affect the lives of more than 25 million people in the United States. They are susceptible to infection and are the leading cause of nontraumatic limb amputations worldwide. The wound environment is dynamic, but their healing rate can be enhanced by administration of therapies at the right time. This approach requires real-time monitoring of the wound environment with on-demand drug delivery in a closed-loop manner. In this paper, a smart and automated flexible wound dressing with temperature and pH sensors integrated onto flexible bandages that monitor wound status in real-time to address this unmet medical need is presented. Moreover, a stimuli-responsive drug releasing system comprising of a hydrogel loaded with thermo-responsive drug carriers and an electronically controlled flexible heater is also integrated into the wound dressing to release the drugs on-demand. The dressing is equipped with a microcontroller to process the data measured by the sensors and to program the drug release protocol for individualized treatment. This flexible smart wound dressing has the potential to significantly impact the treatment of chronic wounds.

Optical Sensor for Real-Time pH Monitoring in Human Tissue.

This article reports on a fiber-based ratiometric optical pH sensor for use in real-time and continuous in vivo pH monitoring in human tissue. Stable hybrid sol-gel-based pH sensing material is deposited on a highly flexible plastic optical fiber tip and integrated with excitation and detection electronics. The sensor is extensively tested in a laboratory environment before it is applied in vivo in a human model. The pH sensor performance in the laboratory environment outperforms the state-of-the-art reported in the current literature. It exhibits the highest sensitivity in the physiological pH range, resolution of 0.0013 pH units, excellent sensor to sensor reproducibility, long-term stability, short response time of <2 min, and drift of 0.003 pH units per 22 h. The sensor also exhibits promising performance in in vitro whole blood samples. In addition, human evaluations conducted under this project demonstrate successful short-term deployment of this sensor in vivo.