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Point-of-Care Platforms Gunter Gauglitz ¨ Institute of Physical and Theoretical Chemistry, University of Tuebingen, D-72076 Tuebingen, Germany; email: [email protected]

Annu. Rev. Anal. Chem. 2014. 7:297–315

Keywords

The Annual Review of Analytical Chemistry is online at anchem.annualreviews.org

recognition elements, biomarkers, assays, biosensors, transduction elements, applications

This article’s doi: 10.1146/annurev-anchem-071213-020332 c 2014 by Annual Reviews. Copyright All rights reserved

Abstract Point-of-care applications are gaining increasing interest in clinical diagnostics and emergency applications. Biosensors are used to monitor the biomolecular interaction process between a disease biomarker and a recognition element such as a reagent. Essential are the quality and selectivity of the recognition elements and assay types used to improve sensitivity and to avoid nonspecific interactions. In addition, quality measures are influenced by the detection principle and the evaluation strategies. For these reasons, this review provides a survey and validation of recognition elements, assays, and various types of detection methods for point-of-care testing (POCT) platforms. Common applications of clinical parameters are discussed and considered. In this ever-changing field, a snapshot of current applications is needed. We provide such a snapshot by way of a table including literature citations and also discuss these applications in more detail throughout.

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1. INTRODUCTION


In the past, laboratory testing of patient samples was centralized at large hospitals or community laboratories to improve cost-effectiveness, to cope with economic pressure, and to reduce health care costs. This resulted in higher effectiveness and high-quality analytical results. However, the need for a rapid turnaround time (TAT) and the “permanent” availability of local general practitioners not only during the day but also on nights and weekends has caused a recent trend toward more decentralized diagnostic approaches such as the so-called point-of-care testing (POCT) occurring at the patients’ bedside, in operation theatres, in emergency rooms, and at accident sites (1–4). Fast and easy availability of analysis and portable and easy-to-use instruments have to compete with high-quality, specialized, and central labs with highly skilled personnel. Thus, in recent literature, POCT terminology, effectiveness, appropriate parameters to be tested, training of operators, economics, and management of POCT are discussed in detail (5). These necessities and advantages must be balanced with aspects of quality assurance and regulations and problems with data management (6–8). Several recent articles consider the aspects of instrumentation and detection principles in these POCT approaches, discussing strip-based methods, lateral-flow strips, and parameters available for these measurements, as well as applications and commercially available devices (3, 9–11). Accordingly, various detection methods in biosensing (e.g., electrochemical, electronic, and optical) enable POCT to utilize several detection platforms—however, only some meet POCT requirements (3, 12–16).

2. PRINCIPLES OF A POINT-OF-CARE TESTING PLATFORM 2.1. Setup The easiest way to obtain information about one’s health is to use standard test strips. They consist of a porous matrix in which dried sections are embedded onto a carrier element. The most common form of test strips is urine test strips, which measure pathological changes in urine. Changes occur once the stick layer has been penetrated and soaked. Normally, detection is done by simple visualization. A qualitative influence of the sample on the stick is a change in color, which can be measured by comparison with a colored scale (9; see also http://groeptms1316.wordpress.com/ 2013/04/04/market-trends-in-lateral-flow-immunoassays/, http://en.wikipedia.org/wiki/ Urine_test_strip). A more complex approach is a lateral-flow test, which also attempts to detect in a simple way the presence of a target analyte in a sample (including matrixes) without requiring specialized and costly equipment. Such lateral-flow tests are used for point-of-care diagnostics at home, a typical example being home pregnancy tests. The support materials are the porous paper or polymer in which capillary beds transport the fluid. There is an excess of sample fluid in the first area. This fluid migrates to the next area where a conjugate (a bioactive particle) is stored in a special matrix to support an optimized chemical reaction between the target molecule and the bioactive particle, which is normally an antibody (sometimes attached to particles). During the transport process, the sample fluid dissolves the matrix and the embedded particles, then both mix and flow along the porous structure. The analyte of the sample can bind to the antibody during the migration process; this leads to a third area where a third molecule is immobilized by the manufacturer. The complex of analyte and antibody-particle will bind to this third capture molecule. During this transport process, this area (sometimes called a stripe) changes color. Normally, there is a second stripe that is used as a control and has a capture molecule that can interact with any particle in this sample. Thus, the interaction is shown to work fine, in contrast to the second stripe 298

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Specific binding Nonspecific binding

Recognition elements SHIELDING LAYER


TRANSDUCER

Figure 1 Shielding layer for avoiding nonspecific interactions on top of the transducer (normally covalently bound by siloxanes) to which recognition elements are immobilized to supply specific binding sites for analytes.

where only a specific interaction between selective capture molecules and the particle complex is demonstrated (17; see also http://www.rapid-diagnostics.org/tech-lateral.htm). As expected, the market for lateral-flow tests has grown drastically in recent years (18). A recent market trend demonstrates that a huge demand for decentralized availability of diagnostic tests exists (19). These lateral-flow stripes use various types of assay formats and are, on the one side, simple realizations of biosensor techniques and, on the other, capillary techniques for modern, more sophisticated biosensor platforms. Immunodiagnostics (20) or the integration of lateral-flow and microarray technologies (21, 22) and even the use of magnetic nanoparticles (23) are typical realizations of these techniques. Even simple lateral-flow stripes use principles of biosensing related to the assay and to some extent to the readout as well. However, in many cases pure dip sticks and lateral-flow stripes offer only qualitative or (at best) semiquantitative results. For this reason, especially in the point-of-care approaches, and less for home tests, biosensors have gained more and more interest for a profound diagnosis. In contrast to physical sensors (thermometers, photodiodes, etc.), chemical and biochemical sensors add to the nonselective transducer a recognition layer that more or less selectively detects specific analytes. This is demonstrated in Figure 1, which shows the transducer and on top of it the recognition layer, shielded in between by a biopolymer layer that is tailored to reduce nonspecific binding. This shielding layer is also used to immobilize as many recognition elements as possible, which selectively bind the analytes in question. Besides electronic data acquisition, computer control, and a display, a biosensor platform relies mainly on the transduction principle, the recognition elements, and, of course, the shielding layer. For this reason, the transducer surface (e.g., glass, metal, or electrode) is usually silanized, and onto these siloxane groups, e.g., a hydrogel is covalently bound. Aminodextran or carboxydextrans is used normally, providing good shielding effects and several sites where recognition elements can be immobilized. Approximately 20 ng/mm2 binding capacity of proteins is possible via either an aminodextran or carboxydextran group. Polyethylene glycol (PEG) is another very useful shielding layer. It has a lower binding capacity of just 5 to 6 ng/mm2 for proteins given that it forms only a monolayer. However, in many cases, especially in complex matrixes such as blood, PEG better reduces nonspecific binding. Some more biopolymer layers are known, such as biotin-(strept)avidin biolayers, polyelectrolyte layers, histidine tags or membranes, or even biomimetic membranes (24–27). In Reference 28, applications of hydrogel films in biosensing are reviewed. www.annualreviews.org • Point-of-Care Platforms

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a

Direct assay

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c Signal

Competitive test format

1

2

3

Signal

No signal

SHIELDING LAYER


TRANSDUCER

b

Sandwich assay

1

2

3

d

Binding inhibition test

1

2a

3a

2b Signal

3b No signal

Figure 2 (a) Direct assay: The recognition element is immobilized to the shielding layer, allowing direct detection of the analyte. (b) Sandwich assay: interaction between the immobilized recognition element, the analyte, and a secondary recognition element (antibody). (c) Competitive test format. (d ) Binding inhibition test (processes 2a and 3a: no analyte concentration in the sample; 2b and 3b: high concentration of analyte in the sample).

The tasks of the shielding layer are (a) to reduce the nonspecific binding of the unwanted molecules; (b) to allow a high number of recognition sites that specifically detect the interesting analytes in the sample, even in complex matrixes; and (c) (preferably) to be stable enough for regeneration not to destroy this layer and the recognition element.

2.2. Assay As mentioned above, the biomolecular interaction process between the recognition elements and the analyte can be monitored in homogeneous phase assays or at the heterogeneous interface of the transducer. In the first case, the interaction equilibrium can be measured using scattering, fluorescence quenching, or fluorescence resonance transfer. Figure 2 shows the most interesting of the many heterogeneous assays and the interaction processes between recognition elements immobilized to the shielding layer and the analytes. Figure 2a illustrates the most interesting assay type: a direct assay, which just needs to immobilize the recognition layer at the surface of the shielding layer and requires no other reagent. Unfortunately, this interesting assay can be used only if the analyte to be detected either has fluorescence itself or is large enough to be monitored by the various direct optical detection methods, which has a large effect on the refractive index or the physical thickness of the increasing layer (during interaction). However, the assay normally consists of three steps: an equilibrium in the homogeneous phase area, a transport process to the surface, and the interaction at the surface between the interacting partners. The relevant assay types are shown in Figure 2b,c. Normally, establishing the equilibrium in the homogeneous phase 300

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area is fast compared to the other two steps. In contrast, the mass transport–limited process of diffusion of a partner to the surface, where its interaction with the immobilized partner in a third step is measured, can either have a rate-determining step such as the transport process or the forming of the equilibrium at the surface. If the number of recognition sites at the surface is large, transport limits the establishing of the equilibrium at the surface. For this reason, the diffusion process is the rate-determining step. If the number of binding sites at the surface is small, the kinetics of establishing the equilibrium at the surface is rate determining and is not restricted by the diffusion process. Accordingly, two different types of binding curves can be realized: In the first, the binding curve starts with a linear slope; in the second, the kinetics at the surface produces curvature according to a curve given by a factor of (1 − e−kt ). This means that tailoring the number of recognition sites to the surface can allow one to determine the kinetic constants of the equilibrium at the surface or to use the linear slope of the diffusion process for direct measurement of the concentration of the analyte in the homogeneous phase (29, 30). In any case, in a graph signal versus logarithm of concentration, a sigmoid calibration curve is formed to which a multiparameter curve can be fitted (31). If no direct assay is possible given that the interaction between analyte and recognition element at the surface cannot be measured in high quality, a secondary analyte can be used, a process that is comparable to the first steps of an enzyme-linked immunosorbent assay (ELISA) approach (see Figure 2b). Better established is a competitive test format, where the interaction of a recognition element at the surface with a labeled analyte (e.g., biofluorescence marker) is substituted by the analyte. This depends on the relative concentration of both partners and the relative binding constants. Accordingly, an inverse signal is achieved: A high concentration of the analyte to be detected causes a low signal, whereas for a low concentration, the labeled analyte at the surface is not replaced, exciting a high signal. Because this process depends to a large degree on the relative binding constant, a modification of this assay, called the binding inhibition assay, is preferable. In a preincubation step, the sample with the analyte is mixed with a recognition element in the homogeneous phase. In parallel, a derivate of the analyte is immobilized to the surface of the shielding layer. Then, the homogeneous phase is flashed across the interaction partner at the shielding layer—in most cases in a flow injection–type system. If only a few analyte molecules are present in the sample, they block only a small number of recognition elements. The nonblocked recognition elements (e.g., antibodies) can be transported via diffusion to the surface and will interact with the immobilized analyte derivatives. This results in a high signal (Figure 2d, processes 2a and 3a). If, however, the amount of analyte in the sample is large, then most of the recognition elements are blocked during the preincubation step and cannot go to the surface. Accordingly, no signal or only a poor one will be monitored (Figure 2d, processes 2b and 3b). This assay also results in an inverse signal-to-concentration relationship. Because in many cases optical POCT platforms are used in combination with microfluidics, flow injection analysis is used, which for many years has been known for immunoanalyses (32, 33). Flow injection analysis has been reviewed in several publications (34–37). References 38–40 review special applications to clinical and pharmaceutical analysis. Its application especially to POCT is discussed in References 41 and 42. Sandwich assays are used in ELISA (43). Typically, in a polystyrene microtiter plate, a known quantity of capture antibody is bound, the nonspecific binding sites on the surface of the plate are blocked using bovine serum albumin (BSA), and the analyte-containing sample is added to the plate, which is washed to remove unbound analyte afterwards. A specific enzyme-linked secondary antibody is added and binds to the analyte. The plate is washed to remove the unbound antibody-enzyme conjugates. The enzyme converts an added chemical into a color or fluorescence. The signal is proportional to the enzyme activity. It is measured to determine the presence and quantity of the analyte via a calibration curve. www.annualreviews.org • Point-of-Care Platforms

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The historical background and the impact of ELISA on clinicians and their patients, medical laboratories, in vitro diagnostics manufacturers, and worldwide health care systems are considered in Reference 44.

2.3. Recognition Elements


In biosensing, a wide variety of recognition elements exists (45, 46). Typically, immunoreactions are used, and long-time experience with antibody-antigen interaction is commonly applied in most biosensor approaches in POCT, too. Recent trends in antibody-based sensors are discussed with respect to different detection principles in a schematic way (47). From experience, many groups realized that the effectiveness of the interaction process depends on the orientation of the antibodies at the biosensor surface (48). A general review of the molecular biology techniques for the generation and improvement of antibodies is provided in Reference 49. An upcoming trend is the use of recombinant antibodies that can be genetically engineered to self-assemble on biosensor surfaces. They can be immobilized at high densities and correctly oriented to enhance the interaction capacity (50). Aptamers have found interesting applications in biosensors over the past few years. These aptamers have some advantages over antibodies. They can be screened via in vitro processes against a synthetic library. Therefore, even for small inorganic irons or intact cells, targets can be found. No cell lines or animals have to be used in the production process. As soon as the aptamer is selected, a subsequent amplification by polymerase chain reaction (PCR) can produce a large amount with large purity (51–54). Another approach is to use polypeptide conjugate binders as hybrid molecules for protein recognition. Polypeptides are covalently linked to small organic molecules that form conjugates that bind proteins with high affinity and selectivity (55). Therefore, robust high-affinity and highselectivity binders can be developed. Introducing DNA nanostructure scaffolds can improve the probe-target recognition properties (56). These systems also provide higher stability than antibodies, but their binding constants are smaller. However, by modifying slightly the linker and the binder, it is possible to shift the binding constants over a large working range. A step further is the use of molecularly imprinted polymers as a biomimetic for antibodies. These polymers are synthesized in the presence of macromolecular templates (57, 58). Carbon nanotubes have long been considered materials with future perspectives, and various types exist. Single-walled nanotubes (SWNTs) are interesting, as they consist of a single graphite sheet seamlessly wrapped into a cylindrical tube. Multi-walled nanotubes (MWNTs) are an array of such SWNTs that form a concentric shape. Reference 59 reviews electronic properties, synthesis, and characterization with an outlook for potential applications. Different techniques to immobilize and align carbon nanotubes have been discussed recently (60) and classified into three main categories: chemical immobilization and alignment, physical immobilization and alignment, and the use of external fields for alignment. This possibility of special alignment in particular makes these elements of biosensing very interesting. Accordingly, some of the advantages of biosensors are reported (61, 62). Even label-free detection of viruses on carbon nanotube thin films with field-effect devices is possible (63). A further development is in the area of lattice-like nanostructures such as graphene oxide, which is believed to have advantageous characteristics as a biosensor platform. Photoluminescence with energy transfer is also considered (64). In combination with recognition elements, some nanostructures and nanoparticles (in most cases made of gold) are used to enhance the readout. This is another area of high research interest (65), which allows application, on the one side, of surface-enhanced Raman scattering techniques (66–68) and, on the other side, of localized surface plasmon resonance (LSPR) techniques (69–71). 302

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For many applications, magnetic particles are introduced that provide ultrasensitive biosensors suitable for clinical diagnostics either by signal amplification or, better, by additional possibilities to achieve enrichment (72). Finally, the chemical modification of nanoporous silicon and its use in enzyme electrodes, hybridization studies, and the detection of immunoglobulins or bacteria and viruses have been reviewed recently (73).


2.4. Transducer, Readout, and Detection The biomolecular interaction process is guided by various analytical principles. Thus, electrical, piezoelectric, electrochemical, optical, and thermomechanical mechanisms can be used in biosensing. Some of them are competitive, and in many cases the quality of the results depends on the application. For this reason, many applications using different types of transduction mechanisms are described in the literature. No general statement is possible, but a general introduction to the different methods used in POCT is provided in References 3, 9, 25, and 74. 2.4.1. Electrochemical sensors. The principles of several electroanalytical methods are described in the literature (75, 76). Electrochemical sensors use amperometric or potentiometric methods, ion-sensitive field-effect transistors, and chemical field-effect transistors. Conductometry and capacitance can also be measured to obtain information on the quantity of the biomolecular interaction process. Recommendations for the definition and the nomenclature used in classifying electrochemical biosensors have been published (77). In the past, the most common of electrochemical biosensing applications was glucose biosensors. However, because of innovations in nanomaterials with gold nanoparticles and hybrid materials in recent years, more detection platforms for improved point-of-care diagnostic systems have been developed (78, 79). Reference 80 provides a survey on various experimental aspects and immunological procedures, considering different materials such as magnetic beads and enzymatic labels, as well as instrumentation. Reference 81 provides realizations of techniques and the literature concerning several analytes such as glucose, lactate, cholesterol, urea, creatinine, and cancer marker assays. Nanostructured material and especially metal nanoparticles (which can be embedded in a polymer framework) have attracted high interest for future applications in electrochemical detection. Biosensing based on such new material is discussed for glucose, creatinine, cholesterol, urea, sensors and even neurotransmitters (82). It has been demonstrated that polyelectrolytecoated gold nanoparticles can be used in syphilis screening for point-of-care diagnostics (23). The effects of neurotoxic compounds can be electrochemically monitored via the acetylcholinesterase square wave voltammetry (22). The development of novel and improved electrode surfaces and nanomaterials has paved way for such biosensors. They will serve as potential next-generation point-of-care diagnostic devices (83). Electrochemical transduction and optical transduction are often presented in separate platforms. However, a dual platform combining both transduction methods allows one to optimize the detection of multianalyte samples. In principle, this approach has future perspectives (84). Miniaturization of the devices, the possibility to easily interface them with simple data-stations, and application in homecare demonstrate growing interest. They allow transmission of data to servers for control and trend analysis by experts. Accordingly, prototypes for POCT that implement cyclic voltammetry in a miniaturized electrochemical cell, powered by USB and thus suitable for field testing with any portable personal computer, are discussed in the literature (85). Recently, immunoassays on microfluidic paper-based analytical devices have been introduced. By using multi-walled carbon nanotubes, sensitive diagnosis of several tumor markers simultaneously in real clinical serum samples has been achieved (86). Even the combination of an electrochemical chip and an iPhone has been proposed. On a microfluidic chip, a microcontroller www.annualreviews.org • Point-of-Care Platforms

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is combined via a USB host controller with a smartphone, which allows the user to control the analytical process (87).


2.4.2. Mass-sensitive sensors. A quartz crystal microbalance (QCM) is a mass-sensitive sensor. The resonance of the quartz is disturbed by adding or removing small amounts of analyte at the surface of the acoustic resonator. The frequency measurements are made easily at high precision, making them suitable even for a few interaction partners. QCMs with dissipation provide a realtime and label-free method for studying adsorption or interaction on various surfaces with high sensitivity. Therefore, this type is very suitable for immunosensing (88, 89). An increasing number of publications involving piezoelectric acoustic sensors are reviewed especially with consideration to applications involving carbohydrates, proteins, nucleic acids, viruses, bacteria, cells, and membrane interfaces. Special publications deal with the development of QCM-based sensors for DNA analysis (90, 91). The dependence on the morphology of the sensing layer, which might influence the viscoelasticity, is considered in Reference 92. In surface acoustic wave (SAW)-based devices, the reflectivity of an acoustic wave at the crystal surface depends on the impedance of the adjacent medium. Accordingly, the waves depend on the interaction process. Even single cells can be monitored using SAW devices in lab-on-a-chip systems (93). Cantilevers use the shear stress of nanostructured bridges. The structures are based highly on torque and are mechanically damageable. The sensing applications have been reviewed recently (94). The integration of microcantilevers in microfluidic platforms gives a new technological solution to exploit real-time monitoring of biomolecular interactions, which is interesting for point-of-care devices (95). 2.4.3. Optical sensors. 2.4.3.1. Detection of labeled partners. Optical detection platforms can be classified according to techniques that use labeled compounds and techniques with direct optical detection of the biomolecular interaction process to quantify the analyte. Currently, most assays are based on fluorescence methods. A survey and trends of these methods can be found in References 96 and 97. The assays were classified according to whether they were homogeneous or heterogeneous at the transduction element. The homogeneous ones can only be used if at least one of the partners (either the recognition element or analyte) is labeled. In this case, the quenching effect of the labeled molecule during the interaction must be considered, or a competitive test format can be used. Another possibility is the use of fluorescence resonant energy transfer (98). This measurement procedure continues to be improved. Recent applications are provided in Reference 99, and Reference 100 provides a discussion of the advantages and limitations. Bioluminescence resonance energy transfer also can be used (101). For heterogeneous phase assays, different fluorescence techniques for heterogeneous phase assays are currently well established. They demonstrate low limits of detection and allow the readout of arrays (102). A typical one is the transduction based on Total Internal Reflection Fluorescence (TIRF) where only fluorophores are excited close to the transduction surface; i.e., only those interacting with immobilized recognition partners provide a quantitative readout. However, labeling requires efforts and causes costs; in addition the interaction process can be influenced and can reduce bioactivity. Chemoluminescence and bioluminescence can be used to detect lower amounts of molecules, especially in the case of miniaturized devices; the detection of lower amounts of molecules (103) can be advantageous in comparison to normal fluorescence methods (104). A survey of next-generation chemoluminescent-based technologies has been provided recently (105). 304

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2.4.3.2. Direct optical detection. Direct optical detection methods can use either reflection or refraction. The latter relies on the evanescent field of electromagnetic radiation, which is totally internally reflected in waveguides (106, 107). Waveguide-based transducers (either planar or in an optical fiber) can be combined with prism couplers, grating couplers (108), mode couplers (109), SPR (110), Mach-Zehnder interferometers (111), or Young devices (112). Above the critical angle, radiation propagates in a waveguide as total internal reflection. This guided wave couples to a decaying evanescent field outside the waveguide, which depends on the refractive index close to the waveguide. Any changes in this refractive index caused by changes in the solvent or any type of interaction process at the surface of the waveguide will be influenced also by coupling back to the guided wave inside the waveguide. Accordingly, at the end of the waveguide an attenuation can be measured if the interaction area is long and intense enough (113). A better readout of this effect on the guided wave can be achieved with the other methods, of which SPR is commercially the most advanced and is the most frequently used in research. All these methods have been reviewed recently (15) and have been discussed in detail (114, 115). In Reference 116, microarrays are discussed and compared with respect to fluidics, detection, and applications. Because the refractive index depends on temperature, related equipment has to be very well thermostated and referenced. Reflectivity can also be directly used to measure the kinetics to reach equilibrium in homogeneous phase and the kinetics of interaction processes at the heterogeneous surface of the transduction element. As known from ellipsometry (117), reflected radiation at thin layers causes an interference spectrum by the superimposed partially reflected beams at both interfaces of the thin layer. Superimposition and accordingly the status of the interference depend on the optical thickness of this layer (the refractive index multiplied by the physical thickness of the layer). Changes within or at the layer will cause a shift in the modulation of this interference spectrum. Accordingly, sensitive time-resolved monitoring of any interaction process is possible (15). Because the temperature dependence of the refractive index is compensated by the temperature dependence of the change in thickness of the layer, the overall temperature dependence of this method can be neglected. Another advantage in comparison to evanescent field techniques is that they monitor the distance from the surface of the transduction element with an exponential decay (the evanescent field has decayed to 1/e at ∼250 nm in the visible range). Reflectometric interference spectroscopy (RIfS), however, demonstrates a linear dependence of the physical thickness in homogeneous media. Whereas fluorescence arrays have been known for quite some time, direct optical detection methods to implement arrays that allow the parallel measurement of several spots emerged only a few years ago. For refractometric methods, imaging is possible by utilizing polarization contrast and advanced referencing for a total of 120 sensing areas (118). Recent progress in nano-optics has led to the development of highly sensitive and label-free optical transducers using the LSPR of metal nanostructures. Reference 71 describes principles and biosensor applications—and the additional aspect of parallelization. Imaging RIfS allows measurement up to 700 spots/cm2 (120). All these methods (reflectometric and refractometric) show in various applications and with real samples very similar limits of detection. These are normally higher than those of fluorescence readout.

3. PARAMETERS AND EXAMPLES Several parameters for diagnostics are given in the literature. Such biomarkers have been proposed for use in hospitals and clinical applications (121). Many of these are introduced increasingly into point-of-care applications. Some are mentioned and cited in Section 2. Articles are published www.annualreviews.org • Point-of-Care Platforms

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weekly that propose biomarkers are suitable in POCT applications, in many cases in combination with specific detection methods. C-reactive protein (CRP) is used normally as a new or modified detection method given that this parameter is generally correlated with inflammation and sepsis and the limit of detection is not very low. Even methods that are not well established are able to quantify this (nonspecific) biomarker. Accordingly, several methods and instruments for its measurement are available. Table 1 provides a selection of some POCT-relevant parameters and clinical parameters. In many cases it is difficult to classify the parameters to a specific disease, given that especially inflammatory parameters can be measured for many diseases. The information is extracted from the literature, especially from References 121 and 122. There are a limited number of citations in this article, but References 121 and 122 provide several more citations to related works. Some more specific ones are cited in the table together with some commercially available instruments. These also have been reviewed in, for example, Reference 122. Most of the listed biomarkers can be measured with many different detection principles. In some cases, more than one commercial setup with different detection methods is available on the market. The most common analyte is the measurement of glucose concentration. The accuracy of different glucometers has been systematically compared recently (123). In 2013, the American Diabetes Association published a detailed market survey that provided the most recent advances in blood glucose meters and a 2013 consumer guide (http://forecast.diabetes.org/ meters-jan2013?loc=lwd-tc-bgmeters). A review on biosensors for measuring analytes of clinical interest has been updated (124). In combination with an award lecture delivered to the Royal Society of Chemistry, a personal overview of the field of biosensors has been published recently that opens the applications to nanotechnology and implantable sensors (125). In the future, these might allow permanent monitoring during surgery and in postoperative surveillance during intensive care (http://nanodem.ifac.cnr.it/). The different types of POCT instruments and devices have been classified according to the applied analytical principle and the analyte, especially with regard to measuring blood or urine (10). A recent review offers information on methods and analytical principles as well as on POCT applications of clinical parameters and commercially available devices (122). The same authors have reviewed the market also with respect to strip-based POCT testing, benchtop blood-gas analyzers and new unit-use analyzers (9). Examples for single- and multipad stick tests are also given in Reference 10. Screening the Internet, the products of several companies are found. A recent review is given on POCT diagnostic tests/kits, POCT analyzers, and general POCT equipment (http://www.selectscience.net/point-of-care/product-directory/). The different aspects of microfluidic material substrates, fluid handling, multiplexing, and surface modification strategies are reviewed and discussed (126). One urgent issue is finding simple and practical front-end sample processing techniques for blood-producing plasma (127). Standardization and quality control are ongoing issues for POCT (128, 129). Presentations at conferences dealing with future aspects of POCT and actual and future aspects regarding quality control or standardization also can be found (130). As demonstrated in Table 1, several biomarkers exist for the detection of inflammation and sepsis. They are also used on many POCT platforms. Because they are mostly more general markers for inflammation, they are often affected by other diseases. Typically, most can be used to monitor cardiac injuries and cardiovascular diseases (121, 122). Reference 131 discusses in detail their special application in POCT. Because sepsis is defined as the systematic inflammatory response in association with an outbreak of infection such as hyperinflammation, many of the inflammation biomarkers are also used in sepsis control for higher parameter concentrations. Severe sepsis is combined with organ dysfunction, hypoperfusion, and hypotension and ends with


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Table 1 Biomarkers for clinical parametersa,b


Biomarker

Markers for

CRP IL TNF Myeloperoxidase

inflammatory markers

Creatine kinase-myocardial band Myoglobin cTN Heart-type fatty–acid binding protein

myocardial cell injury

B-type natriuretic peptide Adrenomedullin

cardiac stress

Creatinine Serum cystatin C Urinary cystatin C Urinary albumin Urinary β2-microglobulin

Disease

Literature

cardiac

Reference 121, pp. 119–55 122, pp. 211–30 131

novel kidney safety

kidney

121, pp. 237–80 138

CRP TNF-α IL Nitrosylated tyrosine Procalcitonin Neopterin Activated protein C

inflammation

general

135

Higher level of inflammation markers

sepsis

general

Pancreatic lipase

pancreatitis

pancreas

139, 140

D-dimer Gamma-carboxyglutamyl protein content activated protein C TAT-complex

coagulation

general

122, pp. 98–118 122, pp. 195–210

IL2 Neopterin

immune system activity/inflammation

transplant rejection

129, 133, 134

PSA

tumor

prostatic carcinoma

143

TSH FT3 and FT4 tests

regulation of thyroid hormone levels

hypo-/hyperthyroidism

http://www.thyroid.org/wpcontent/uploads/patients/ brochures/FunctionTests_ brochure.pdf

Neopterin

immune activity

HIV

133, 134

Anti-transglutaminase antibody (IgA, IgG)

autoimmune activity

celiac disease

120, 141, 142

Glucose

insulin deficiency

diabetes

122, pp. 65–77

Lactate

lactate status

test of fitness

137

pH, CO2 , O2 , HCO3 −

blood gas

intensive care

122, pp. 76–97

a

Some of these are also used in POCT. Abbreviations: CRP, C-reactive protein; cTN, cardiac troponin; FT, free thyroxine; POCT, point-of-care testing; PSA, prostate-specific antigen; TAT, turnaround time; TNF, tumor necrosis factor; TSH, thyroid-stimulating hormone.

b

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100


Signal slope (%)

80

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Cystatin C (mg/L) Figure 3 Typical calibration of an immunoreaction in a matrix of human cystatin C–free serum. For the binding inhibition test, cystatin C is immobilized covalently via an aminodextran-layer to the surface of the transducer. 1.5 mg/L of cystatin C antibody is inhibited by nine different concentrations of cystatin C in the sample, ranging from 0 to 10 mg/L. Every concentration is determined threefold (graph taken from Reference 137, with kind permission of Springer Science + Business Media). Abbreviations: MDC, minimum detectable concentration; RDL, reliable detection limit.

septic shock (132). Further details can also be found in Reference 133. Neopterin especially is considered to be more selective than CRP and is a very good marker to realize transplant rejection (134). A detailed review on inflammatory markers, the critical time for fast and effective diagnosis and therapy, and potential future candidates for POCT application are discussed in Reference 135. As it provides information on immune activity, neopterin is also a key marker for HIV monitoring (136). In the case of transplant rejection, the detection of an increase of inflammatory markers such as neopterin or interleukin (IL) 2 can be late. An interesting approach for obtaining information about immune suppression is the continuous monitoring of the blood of patients treated with tacrolimus or cyclosporine A (http://nanodem.ifac.cnr.it/). In intensive care units, another interesting parameter is lactate (137). Recently, amateur and leisure sports have drawn interest to this parameter as well. Therefore, many POCT-like setups are expected in the near future. For the detection of renal failure, creatinine is usually quantified. However, the marker depends strongly on the personal status of the patient. For this reason, cystatin C has been proposed recently as a better biomarker (121). It has been quantitatively determined using a biosensor (138). In Figure 3, the calibration in serum is given as a sigmoid graph of the slope of the binding curve versus the cystatin C concentration using the direct optical detection principle RIfS (15). Fast quantitative results can be obtained within minutes at clinically relevant levels. Pancreatitis is currently an urgent problem. The levels of triglycerides in the serum of apparently healthy persons and persons suffering from cardiovascular disease and pancreatitis have been measured by an amperometric sensor (139). Another approach is the measurement of amylase and lipase concentration. For the latter, a biosensor has been developed (140). 308

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Another widespread disease symptom is thyroid dysfunction. Clinicians and practitioners are interested in simple tests measuring regulation of thyroid hormone levels. Therefore, many tests are considered, and the American Thyroid Association follows up with laboratory medicine practice guidelines for the diagnosis and monitoring of thyroid disease and has given a description of thyroid function tests [thyroglobulin, thyroid-stimulating hormone (TSH), T3, and T4] (http:// www.thyroid.org/wp-content/uploads/patients/brochures/FunctionTests_brochure.pdf ). Easy determination of anti-transglutaminase antibody is of high interest, also, given that celiac disease influences the daily lives of many people. Accordingly, biosensors for the detection of biomarkers for this disease have been developed (141, 142), and imaging techniques are applied to find optimum matching sequences for either recognition elements or blocking drugs (120). The use of prostate-specific antigens (PSAs) for prostate cancer screening is one highly relevant example. The growing rate of prostate cancer in Asia and as a leading cause of male cancer-related fatalities in the United States furthers interest in POCT (143).

4. CONCLUSION AND OUTLOOK In POCT, various detection principles, recognition elements, assays, and instrumental realization exist. Thus, many platforms have been developed in research projects and transferred into commercially successful instrumentation using nanotechnology, modern biotechnology, and microfluidics. On the one side, new biomarkers require new research and development to improve these platforms; on the other side, new instrumental developments allow the detection of new biomarkers, even at low limits of quantification, and pave the way for new preclinical diagnostics. Biomarker research and recognition element development as well as improved electronic and detection methods will certainly influence future diagnostic tools. However, in recent years, urgent problems, especially in the area of recognition elements, optimal surface modification, and fluidics, have been identified. Future interest in web-based home care and in ambient-assisted living will influence platform development and telemetry and will strengthen the position of POCT in diagnostics. Because POCT is a rapidly changing field, this review can only provide a snapshot, subjective opinion, and interpretation of the rapidly increasing literature.

DISCLOSURE STATEMENT The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

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135. Pfaefflin A, Schleicher E. 2009. Inflammation markers in point-of-care testing (POCT). Anal. Bioanal. Chem. 393(5):1473–80 136. Hanafiah KM, Garcia M, Anderson D. 2013. Point-of-care testing and the control of infectious diseases. Biomarkers Med. 7(3):333–47 137. Martin J, Blobner M, Busch R, Moser N, Kochs E, Luppa PB. 2013. Point-of-care testing on admission to the intensive care unit: lactate and glucose independently predict mortality. Clin. Chem. Lab. Med. 51(2):405–12 138. Bleher O, Ehni M, Gauglitz G. 2012. Label-free quantification of cystatin C as an improved marker for renal failure. Anal. Bioanal. Chem. 402(1):349–56 139. Narang J, Bhambi M, Pundir CS. 2010. Fabrication of an amperometric triglyceride biosensor based on PVC membrane. Anal. Lett. 43(1):1–11 140. Krieg AK, Gauglitz G. 2012. Detecting pancreatic lipase using a new strategy for bio-functionalization of the sensor surface. Proc. Europtrode (Barcelona) XI:191 141. Ortiz M, Fragoso A, O’Sullivan CK. 2011. Detection of antigliadin autoantibodies in celiac patient samples using a cyclodextrin-based supramolecular biosensor. Anal. Chem. 83:2931–38 142. Cennamo N, Varriale A, Pennacchio A, Staiano M, Massarotti D, et al. 2013. An innovative plastic optical fiber-based biosensor for new bio/applications. The case of celiac disease. Sens. Actuat. B 176:1008–14 143. Okada H, Hosokawa K, Maeda M. 2011. Power-free microchip immunoassay of PSA in human serum for point-of-care testing. Anal. Sci. 27(3):237–41 144. Gauglitz G, Moore D, eds. 2014. Handbook of Spectroscopy. Weinheim, Ger.: Wiley-VCH. 2nd ed.

www.annualreviews.org • Point-of-Care Platforms

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Contents

Annual Review of Analytical Chemistry Volume 7, 2014

A Life in Electrochemistry Allen J. Bard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Biologically Inspired Nanofibers for Use in Translational Bioanalytical Systems Lauren Matlock-Colangelo and Antje J. Baeumner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23 Analytical Approaches for Size and Mass Analysis of Large Protein Assemblies Joost Snijder and Albert J.R. Heck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p43 Nano/Micro and Spectroscopic Approaches to Food Pathogen Detection Il-Hoon Cho, Adarsh D. Radadia, Khashayar Farrokhzad, Eduardo Ximenes, Euiwon Bae, Atul K. Singh, Haley Oliver, Michael Ladisch, Arun Bhunia, Bruce Applegate, Lisa Mauer, Rashid Bashir, and Joseph Irudayaraj p p p p p p p p p p p p p p p p p p p65 Optical Imaging of Individual Plasmonic Nanoparticles in Biological Samples Lehui Xiao and Edward S. Yeung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89 Mass Spectrometric Analysis of Histone Proteoforms Zuo-Fei Yuan, Anna M. Arnaudo, and Benjamin A. Garcia p p p p p p p p p p p p p p p p p p p p p p p p p p p p 113 Ultrafast 2D NMR: An Emerging Tool in Analytical Spectroscopy Patrick Giraudeau and Lucio Frydman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129 Electroanalysis at the Nanoscale Karen Dawson and Alan O’Riordan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 163 Light-Emitting Diodes for Analytical Chemistry Mirek Macka, Tomasz Piasecki, and Purnendu K. Dasgupta p p p p p p p p p p p p p p p p p p p p p p p p p p p p 183 Energetics-Based Methods for Protein Folding and Stability Measurements M. Ariel Geer and Michael C. Fitzgerald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209

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Ambient Femtosecond Laser Vaporization and Nanosecond Laser Desorption Electrospray Ionization Mass Spectrometry Paul Flanigan and Robert Levis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 229 Engineered Proteins for Bioelectrochemistry Muhammad Safwan Akram, Jawad Ur Rehman, and Elizabeth A.H. Hall p p p p p p p p p p p p 257


Microfluidics-Based Single-Cell Functional Proteomics for Fundamental and Applied Biomedical Applications Jing Yu, Jing Zhou, Alex Sutherland, Wei Wei, Young Shik Shin, Min Xue, and James R. Heath p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 275 Point-of-Care Platforms Gunter ¨ Gauglitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 297 Microfluidic Systems with Ion-Selective Membranes Zdenek Slouka, Satyajyoti Senapati, and Hsueh-Chia Chang p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317 Solid-Phase Biological Assays for Drug Discovery Erica M. Forsberg, Clémence Sicard, and John D. Brennan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 337 Resonance-Enhanced Multiphoton Ionization Mass Spectrometry (REMPI-MS): Applications for Process Analysis Thorsten Streibel and Ralf Zimmermann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 361 Nanoscale Methods for Single-Molecule Electrochemistry Klaus Mathwig, Thijs J. Aartsma, Gerard W. Canters, and Serge G. Lemay p p p p p p p p p p 383 Nucleic Acid Aptamers for Living Cell Analysis Xiangling Xiong, Yifan Lv, Tao Chen, Xiaobing Zhang, Kemin Wang, and Weihong Tan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405 High-Throughput Proteomics Zhaorui Zhang, Si Wu, David L. Stenoien, and Ljiljana Paˇsa-Tolić p p p p p p p p p p p p p p p p p p p p 427 Analysis of Exhaled Breath for Disease Detection Anton Amann, Wolfram Miekisch, Jochen Schubert, Bogusław Buszewski, Tomasz Ligor, Tadeusz Jezierski, Joachim Pleil, and Terence Risby p p p p p p p p p p p p p p p p p p 455 Ionophore-Based Optical Sensors Gunter ¨ Mistlberger, Gastón A. Crespo, and Eric Bakker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 483 Resistive-Pulse Analysis of Nanoparticles Long Luo, Sean R. German, Wen-Jie Lan, Deric A. Holden, Tony L. Mega, and Henry S. White p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 513 Concerted Proton-Electron Transfers: Fundamentals and Recent Developments Jean-Michel Savéant p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 537

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Annual Reviews It’s about time. Your time. It’s time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application Volume 1 • Online January 2014 • http://statistics.annualreviews.org


Editor: Stephen E. Fienberg, Carnegie Mellon University

Associate Editors: Nancy Reid, University of Toronto Stephen M. Stigler, University of Chicago The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as well as all scientists and users of statistics about major methodological advances and the computational tools that allow for their implementation. It will include developments in the field of statistics, including theoretical statistical underpinnings of new methodology, as well as developments in specific application domains such as biostatistics and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

Complimentary online access to the first volume will be available until January 2015. table of contents:

• What Is Statistics? Stephen E. Fienberg • A Systematic Statistical Approach to Evaluating Evidence from Observational Studies, David Madigan, Paul E. Stang, Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage, Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema, Patrick B. Ryan

• High-Dimensional Statistics with a View Toward Applications in Biology, Peter Bühlmann, Markus Kalisch, Lukas Meier • Next-Generation Statistical Genetics: Modeling, Penalization, and Optimization in High-Dimensional Data, Kenneth Lange, Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel

• The Role of Statistics in the Discovery of a Higgs Boson, David A. van Dyk

• Breaking Bad: Two Decades of Life-Course Data Analysis in Criminology, Developmental Psychology, and Beyond, Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca

• Brain Imaging Analysis, F. DuBois Bowman

• Event History Analysis, Niels Keiding

• Statistics and Climate, Peter Guttorp

• Statistical Evaluation of Forensic DNA Profile Evidence, Christopher D. Steele, David J. Balding

• Climate Simulators and Climate Projections, Jonathan Rougier, Michael Goldstein • Probabilistic Forecasting, Tilmann Gneiting, Matthias Katzfuss • Bayesian Computational Tools, Christian P. Robert • Bayesian Computation Via Markov Chain Monte Carlo, Radu V. Craiu, Jeffrey S. Rosenthal • Build, Compute, Critique, Repeat: Data Analysis with Latent Variable Models, David M. Blei • Structured Regularizers for High-Dimensional Problems: Statistical and Computational Issues, Martin J. Wainwright

• Using League Table Rankings in Public Policy Formation: Statistical Issues, Harvey Goldstein • Statistical Ecology, Ruth King • Estimating the Number of Species in Microbial Diversity Studies, John Bunge, Amy Willis, Fiona Walsh • Dynamic Treatment Regimes, Bibhas Chakraborty, Susan A. Murphy • Statistics and Related Topics in Single-Molecule Biophysics, Hong Qian, S.C. Kou • Statistics and Quantitative Risk Management for Banking and Insurance, Paul Embrechts, Marius Hofert

Access this and all other Annual Reviews journals via your institution at www.annualreviews.org.

Annual Reviews | Connect With Our Experts Tel: 800.523.8635 (us/can) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: [email protected]

Force platforms as ergometers.

Experimental platforms for computational photography.

High-throughput platforms for metabolomics.

Analytical platforms in vitreoretinal proteomics.

Microfluidic platforms for biomarker analysis.

Engineering alternative isobutanol production platforms.

Engineering virus-like particles as vaccine platforms.

Accuracy of Next Generation Sequencing Platforms.

Ras nanoclusters: Versatile lipid-based signaling platforms.

Next generation platforms for high-throughput biodosimetry.

In vitro platforms for evaluating liver toxicity.

Complex Particulate Biomaterials as Immunostimulant-Delivery Platforms.

Internet-based platforms for science communication.

MARTX toxins as effector delivery platforms.

Robustness of Massively Parallel Sequencing Platforms.

Applications of thin-film sandwich crystallization platforms.

Particle-based platforms for malaria vaccines.

Election 2015: party platforms on health issues.

Building terpene production platforms in yeast.

Bispecific antibody platforms for cancer immunotherapy.

Assessing Agreement between miRNA Microarray Platforms.

Conformal Visualization for Partially-Immersive Platforms.

Network-Based Protein Biomarker Discovery Platforms.

Should we "reef" obsolete oil platforms?