Miniaturized electrochemical sensors and their point-of-care applications

Most of the current analytical methods depend largely on laboratory-based analytical techniques that require expensive and bullky equipment,potentially incur costly testing,and involve lengthy detection processes.With increasing requirements for point-of-care testing(POCT),more attention has been paid to miniaturized analytical devices.Miniaturized electrochemical(MEC)sensors,including different material-based MEC sensors(such as DNA-,paper-,and screen electrode-based),have been in strong demand in analytical science due to their easy operation,portability,high sensitivity,as well as their short analysis time.They have been applied for the detection of trace amounts of target through measuring changes in electrochemical signal,such as current,voltage,potential,or impedance,due to the oxidation/reduction of chemical/biological molecules with the help of electrodes and electrochemical units.MEC sensors present great potential for the detection of targets including small organic molecules,metal ions,and biomolecules.In recent years,MEC sensors have been broadly applied to POCT in various fields,including health care,food safety,and environmental monitoring,owing to the excellent advantages of electrochemical(EC)technologies.This review summarized the state-of-the-art advancements on various types of MEC sensors and their applications in POCT.Furthermore,the future perspectives,opportunities,and challenges in this field are also discussed.     

Alkaline Phosphatase-based Electrochemical Analysis for Point-of-Care Testing

Point-of-care testing (POCT) devices have evolved to provide beneficial information about an individual's health whenever needed. Enzyme-based analytical devices have facilitated the highly selective detection of numerous biological molecules and ions. Enzymes are commonly used as the tags of recognition components, such as antibodies, to generate and amplify detection signals. Particularly, alkaline phosphatase (ALP) is one of the most widely used enzymes because of its high turnover number and low cost. Rapid response time and the incorporation of many sensors fabricated by micro/nano processing technologies are the advantages in using electrochemical devices as analytical tools. Therefore, ALP-based electrochemical devices have potential applications for more practical POCT platforms. This review summarizes recent research progress of ALP-based electrochemical devices for POCT. In addition to ALP substrates, the application of ALP-based immunosensors, aptasensors, and DNAzyme sensors are discussed.     

Cardiac markers: a clear cause for point-of-care testing

Point-of-care testing (POCT) in patients with ischemic heart disease is driven by the time-critical need for fast, specific, and accurate results to initiate therapy instantly. According to current guidelines, the results of the cardiac marker testing should be available to the physician within 30 min (“vein-to-brain” time) to initiate therapy within 60–90 min (“door-to-needle” time) after the patient has arrived at the emergency room or intensive care unit. This article reviews the current efforts to meet this goal (1) by implementing POCT of established biochemical markers such as cardiac troponins, creatine kinase MB, and myoglobin, in accelerated diagnosis and management workflow schemes, (2) by improving current POCT methods to obtain more accurate, more specific, and even faster tests through the integration of optical and electrochemical sensor technology, and (3) by identifying new markers for the very early and sensitive detection of myocardial ischemia and necrosis. Furthermore, the specific requirements for cardiac POCT in regard to analytical performance, comparability, and diagnostic sensitivity/specificity are discussed. For the future, the integration of new immunooptical and electrochemical chip technology might speed up diagnosis even further. However, every new development will have to meet the stringent method validation criteria set for corresponding central laboratory testing.     

Nitric Oxide Release for Enhanced Biocompatibility and Analytical Performance of Implantable Electrochemical Sensors

The real-time, continuous monitoring of glucose/lactate, blood gases and electrolytes by implantable electrochemical sensors holds significant value for critically ill and diabetic patients. However, the wide-spread use of such devices has been seriously hampered by implant-initiated host responses (e. g., thrombus formation, inflammatory responses and bacterial infection) when sensors are implanted in blood or tissue. As a result, the accuracy and usable lifetime of in vivo sensors are often compromised. Nitric oxide (NO) is an endogenous gas molecule able to inhibit platelet adhesion/activation, inflammatory responses and bacterial growth. As such, the release of NO from the surfaces of in vivo sensors is a promising strategy for enhancement of their biocompatibility and analytical performance. In this review, the physiological functions of NO to improve the biocompatibility of implantable electrochemical sensors are introduced, followed by a brief analysis of chemical approaches to realize NO release from such devices. A detailed summary of the various types of NO releasing electrochemical sensors reported to date and their performance in benchtop and/or in vivo testing are also provided. Finally, the prospects of future developments to further advance NO releasing sensor technology for clinical use are discussed.     

Quality and timeliness in medical laboratory testing

In terms of testing, modern laboratory medicine can be divided into centralized testing in central laboratories and point-of-care testing (POCT). Centralized laboratory medicine offers high-quality results, as guaranteed by the use of quality management programs and the excellence of the staff. POCT is performed by clinical staff, and so such testing has moved back closer to the patient. POCT has the advantage of shortening the turnaround time, which potentially benefits the patient. However, the clinical laboratory testing expertise of clinical staff is limited. Consequently, when deciding which components of laboratory testing must be conducted in central laboratories and which components as POCT (in relation to quality and timeliness), it will be medical necessity, medical utility, technological capabilities and costs that will have to be ascertained. Provided adequate quality can be guaranteed, POCT is preferable, considering its timeliness, when testing vital parameters. It is also preferred when the central laboratory cannot guarantee the delivery of results of short turn-around-time (STAT) markers within 60 or (even better) 30 min. POCT should not replace centralized medical laboratory testing in general, but it should be used in cases where positive effects on patient care have been clearly demonstrated.     

An Overview of Wearable and Implantable Electrochemical Glucose Sensors

Electrochemical glucose sensors have garnered considerable attention because of their attractive prospect in point-of-care testing (POCT). In this review, we firstly introduce the principles and challenges of electrochemical glucose sensors. Subsequently, we present an overview of the application of electrochemical glucose sensors and discuss their advantages and drawbacks. Wearable and implantable devices based on diverse target biofluid and platforms provide a considerable prospect of accurate and continuous monitoring. Thus, we believe that the future development direction of electrochemical glucose sensors is non-invasive, wearable devices and implantable devices with minimally invasive for continuous glucose monitoring in real time.     

Isothermal nucleic acid amplification technologies for point-of-care diagnostics: a critical review

Nucleic Acid Testing (NAT) promises rapid, sensitive and specific diagnosis of infectious, inherited and genetic disease. The next generation of diagnostic devices will interrogate the genetic determinants of such conditions at the point-of-care, affording clinicians prompt reliable diagnosis from which to guide more effective treatment. The complex biochemical nature of clinical samples, the low abundance of nucleic acid targets in the majority of clinical samples and existing biosensor technology indicate that some form of nucleic acid amplification will be required to obtain clinically relevant sensitivities from the small samples used in point-of-care testing (POCT). This publication provides an overview and thorough review of existing technologies for nucleic acid amplification. The different methods are compared and their suitability for POCT adaptation are discussed. Current commercial products employing isothermal amplification strategies are also investigated. In conclusion we identify the factors impeding the integration of the methods discussed in fully automated, sample-to-answer POCT devices.     

Electrochemical Biosensors Based on Micro-fabricated Devices for Point-of-Care Testing: A Review

Point-of-care testing (POCT) is becoming a hot research topic that allows rapid, on-site, and non-professional measurements outside the central laboratory. The micro-fabricated devices prepared by various micro-machining technologies have shown the advantages of low reagent consumption, high-throughput samples, and wearability. This review presents the recent progress of electrochemical biosensors based on various micro-fabricated devices for POCT and the corresponding electrochemical techniques. Signal amplification strategies based on enzyme and nanotechnology are also illustrated for the more sensitive POCT applications of these micro-fabricated devices. Consequently, the trends and challenges of electrochemical biosensors based on micro-fabricated devices in POCT diagnosis are discussed.     

Recent advances in the development of colorimetric analysis and testing based on aggregation-induced nanozymes

Colorimetric sensing strategies as a powerful point-of-care testing(POCT) tool have attracted significant interest in various chem/biosensing applications.Taking the excellent bare-eye-detectable signaling feature,nanozymes-based colorimetric sensors enable more potential applications and have been a new forefront in the colorimetric POCT analysis toward different target analytes.However,the low catalytic activity of nanozymes in most cases limits their practical application.Recent efforts demonstrate that the aggregation-induced nanozymes provide a general means to modulate nanozymes activity and enhance colorimetric sensing performances of some nanozymes-based colorimetric sensors.But there are few reports are explored to discuss and review such aggregation-induced nanozymes and their colorimetric sensing applications.To highlight the advances and progress in aggregation-induced nanozymes based colorimetric assays,we herein summary the fundamentals,classify and applications of this newlydeveloping field,focusing on the aggregation-induced activity enhancement of nanozymes(AIAEnanozymes) with a significant "signal-on" feature and aggregation-induced activity inhibition of nanozymes(AIAI-nanozymes) with a dramatical "signal-of" characteristics.Finally,we also propose the current challenges and the future prospects on both AIAE-nanozymes and AIAI-nanozymes.     

A mini-review on MXenes as versatile substrate for advanced sensors

MXenes have emerged as versatile 2D materials that are already gaining paramount attention in the areas of energy,catalyst,electromagnetic shielding,and sensors.The unique surface chemistry,graphene-like mo rphology,high hydrophilicity,metal-like conductivity with redox capability identifies MXenes,as an ideal material for surface-related applications.This short review summarizes the most recent reports that discuss the potential application of MXenes and their hybrids as a transducer material for advanced sensors.Based on the nature of transducing signals,the discussion is categorized into three sections,which include electrochemical(bio) sensors,gas sensors,and finally,electro-chemiluminescence fluorescent sensors.The review provides a concise summary of all the analytical merits obtained subsequent to the use of MXenes,followed by endeavors that have been made to accentuate the future perspective of MXenes in sensor devices.     

S‐Click Reaction for Isotropic Orientation of Oxidases on Electrodes to Promote Electron Transfer at Low Potentials

Electrochemical sensors are essential for point‐of‐care testing (POCT) and wearable sensing devices. Establishing an efficient electron transfer route between redox enzymes and electrodes is key for converting enzyme‐catalyzed reactions into electrochemical signals, and for the development of robust, sensitive, and selective biosensors. We demonstrate that the site‐specific incorporation of a novel synthetic amino acid (2‐amino‐3‐(4‐mercaptophenyl)propanoic acid) into redox enzymes, followed by an S‐click reaction to wire the enzyme to the electrode, facilitates electron transfer. The fabricated biosensor demonstrated real‐time and selective monitoring of tryptophan (Trp) in blood and sweat samples, with a linear range of 0.02–0.8 mm . Further developments along this route may result in dramatic expansion of portable electrochemical sensors for diverse health‐determination molecules.     

Quality in point-of-care testing: taking POC to the next level

Point-of-care testing (POCT) is a complex system with many opportunities for error. Delivering quality POCT requires multidisciplinary coordination and an understanding of the preanalytic, analytic, and postanalytic processes that are necessary to deliver a test result and take clinical action. Most errors in laboratory testing occur in the pre and postanalytical phases and many mistakes that are referred to as lab error are actually due to poor communication, actions by others involved in the testing process, or poorly designed processes outside the laboratory's control. POCT requires significant operator interaction with analysis and documentation of calibration and quality control, unlike other medical devices. Clinicians often interpret POCT as equivalent to core laboratory testing, only faster, and mistakenly utilize the results interchangeably despite the differences in test methodologies. Taking quality of POCT to the next level involves looking beyond the analytical phase and integration of POCT into the entire pathway of patient care to understand how POCT relates to medical decision-making at specific points during the patient's care. A systematic review of the literature by the National Academy of Clinical Biochemistry is currently being conducted to draft guidelines for best practice that link the use of POCT to improved patient outcomes.Presented at the 10th Conference Quality in the Spotlight, March 2005, Antwerp, Belgium.     

Design of portable electrochemiluminescence sensing systems for point-of-care-testing applications

Point-of-care testing(POCT) technology is highly desirable for clinical diagnosis, healthcare monitoring,food safety inspection, and environment surveillance, because it enables rapid detection anywhere, anytime, and by anyone. Electrochemiluminescence(ECL) has been widely used in chemo-/bio analysis due to its advantages such as high sensitivity, simplicity, rapidity and easy to control, and is now attracting increasing attention for POCT applications. However, to realize the accurate on-site q...     

Toward sensitive, quantitative point-of-care testing (POCT) of protein markers: miniaturization of a homogeneous time-resolved fluoroimmunoassay for prostate-specific antigen detection

Point-of-care testing (POCT) systems which allow for a sensitive, quantitative detection of protein markers are extremely useful for the early detection and therapy progress monitoring of cancer. However, currently commercially available POCT devices are mainly limited to the qualitative detection of protein markers. In this study we demonstrate the successive miniaturization of a sensitive and fast assay for the quantitative detection of prostate-specific antigen (PSA) using a well established and clinically approved homogeneous time-resolved fluoroimmunoassay technology (TRACE?) on a commercial plate-reader system (KRYPTOR?). Regarding the initial requirements for the development of POCT devices we applied a 30-fold assay volume reduction (150 μL to 5 μL) to achieve a reasonable lab-on-a-chip volume and a 24-fold and 120-fold excitation pulse energy reduction to achieve reasonable pulse energies for low-cost miniature excitation sources. Due to highly efficient optimization of key POCT parameters our miniaturized PSA assay achieved a 30% increased sensitivity and a 2-fold improved limit of detection compared to the standard plate-reader method. Our results demonstrate the successful implementation of key parameters for a significant miniaturization and for cost reduction in the clinically approved KRYPTOR? platform for protein detection. The technological alterations required are easy-to-implement and can be immediately adapted for more than 30 diagnostic protein markers already available for the KRYPTOR? platform. These features strongly recommend our assay format to be utilized in innovative, sensitive, quantitative POCT of protein markers.     

Optical sensors for determination of heavy metal ions

A review is given on optical means for single shot testing (probing) as well as continuous monitoring (sensing) of heavy metal ions (HMs). Following an introduction into indicator based approaches, we discuss the types of indicator dyes and polymeric supports used, as well as existing sensing schemes for HMs. The wealth of information is compiled in the form of tables and critically reviewed. Notwithstanding the tremendous work performed so far, it is obvious that still severe limitations do exist in terms of selectivity, limits of detection, dynamic ranges, applicability to specific problems, and reversibility. On the other hand, such sensors have found — and will find — their application whenever rapid and cost-effective testing is required, where personnel is scarce or unskilled, and in field tests. Despite their limitations, the number of such sensors (and of irreversible probes) for HMs is likely to increase in future.     

Point-of-care testing (POCT): Current techniques and future perspectives

Point-of-care testing (POCT) is a laboratory-medicine discipline that is evolving rapidly in analytical scope and clinical application. In this review, we first describe the state of the art of medical-laboratory tests that can be performed near the patient. At present, POCT ranges from basic blood-glucose measurement to complex viscoelastic coagulation assays. POCT shortens the time to clinical decision-making about additional testing or therapy, as delays are no longer caused by transport and preparation of clinical samples, and biochemical-test results are rapidly available at the point of care. Improved medical outcome and lower costs may ensue.Recent, evolving technological advances enable the development of novel POCT instruments. We review the underlying analytical techniques. If new instruments are not yet in practical use, it is often hard to decide whether the underlying analytical principle has real advantage over former methods. However, future utilization of POCT also depends on health-care trends and new areas of application. But, even today, it can be assumed that, for certain applications, near-patient testing is a useful complement to conventional laboratory analyses.     

Highly sensitive immunodiagnostics at the point of care employing alternative recognition elements and smartphones: hype,trend, or revolution?

Immunodiagnostic tests performed at the point of care (POC) today usually employ antibodies for biorecognition and are read out either visually or with specialized equipment. Availability of alternative biorecognition elements with promising features as well as smartphone-based approaches for signal readout, however, challenge the described established configuration in terms of analytical performance and practicability. Assessing these developments’ clinical relevance and their impact on POC immunodiagnostics is demanding. The first part of this review will therefore give an overview on suitable diagnostic biosensors based on alternative recognition elements (such as nucleic acid-based aptamers or engineered binding proteins) and exemplify advantages and drawbacks of these biomolecules on the base of selected assays. The second part of the review then focuses on smartphone-connected diagnostics and discusses the indispensable considerations required for successful future clinical POCT implementation. Together, the joint depiction of two of the most innovative and exciting developments in the field will enable the reader to cast a glance into the distant future of POC immunodiagnostics.

     

Ion-selective potentiometric sensors with silicone sensing membranes: A review

Ion-selective electrodes (ISEs) are used widely in mainframe analyzers for clinical chemistry, but there is also an increasing interest in the development of paper-based devices, wearable and implantable sensors, and other miniaturized ISEs. This trend is spurring much research in developing solid contact materials that enable miniaturization. The development of suitable polymeric matrixes for such sensors has only received less attention. In particular, in spite of lifetime limitations and toxicity concerns, polymeric matrixes comprising plasticizers are still commonly used. To that end, we note the benefits of silicone materials as alternative polymeric matrixes and, in particular, their promise for enhanced biocompatibility. While there has been steady progress in the development of ISEs with silicone membranes, this topic has not been reviewed for many years. This review critically discusses key fundamental characteristics of ISEs with silicone sensing and reference membranes, including their biocompatibility, adhesion to device substrates, water uptake, polarity, common impurities, and commercial availabilities. This is followed by a discussion of specific types of silicones and their use in ISEs, with the goal to inform and stimulate future research efforts into such devices.     

Can the progress in quality management tools for POC tame the fiends from Pandora's box?

POCT provides the opportunity to significantly improve the overall quality of blood testing in an organization. The design of the product, the redesign of the testing process and the tools used to manage a completely distributed testing process, are key to the quality implementation of POCT. Both theoretical considerations and practical outcomes are discussed in this paper, using the i-STAT^® System as an example of a POCT system.