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Detection platforms for point-of-care testing based on colorimetric, luminescent and magnetic assays: A review
Accepted Manuscript Detection platforms for point-of-care testing based on colorimetric, luminescent and magnetic assays: A review Jinchuan Yang, Kan Wang, Hao Xu, Wenqiang Yan, Qinghui Jin, Daxiang Cui PII:
S0039-9140(19)30443-6
DOI:
https://doi.org/10.1016/j.talanta.2019.04.054
Reference:
TAL 19853
To appear in:
Talanta
Received Date: 14 January 2019 Revised Date:
3 April 2019
Accepted Date: 20 April 2019
Please cite this article as: J. Yang, K. Wang, H. Xu, W. Yan, Q. Jin, D. Cui, Detection platforms for pointof-care testing based on colorimetric, luminescent and magnetic assays: A review, Talanta (2019), doi: https://doi.org/10.1016/j.talanta.2019.04.054. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Detection platforms for point-of-care testing based on colorimetric, luminescent and magnetic assays: A review
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Jinchuan Yang1, Kan Wang1*, Hao Xu2, Wenqiang Yan1, Qinghui Jin3,4 and Daxiang Cui1 *Correspondence: [email protected] 1
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Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai Engineering Research Center for Intelligent diagnosis and treatment instrument, Key Laboratory of Thin Film and Microfabrication (Ministry of Education), Shanghai 200240, China. 2
School of Naval Architecture, Ocean & Civil Engineering, Shanghai Jiao Tong University, Shanghai 200240, China. 3
4
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State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050, P. R. China
Faculty of Electrical Engineering and Computer Science, Ningbo University, Ningbo 315211, P. R. China
Jinchuan Yang, [email protected]
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Co-authors Email:
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Kan Wang, [email protected] Hao Xu, [email protected]
Wenqiang Yang, [email protected] Qinghui Jin, [email protected] Daxiang Cui, [email protected]
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Abstract
Along with the considerable potential and increasing demand of the
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point-of-care testing (POCT), corresponding detection platforms have attracted great interest in both academic and practical fields. The first few generations of conventional detection devices tend to be costly,
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complicated to operate and hard to move on account of early limitations in the level of technological development and relatively high
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requirement of performance. Owing to the requirements for rapidity, simplicity, accuracy and cost controlling in the POCT, reader systems are urgently needed to be developed, upgraded and modified constantly,
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realizing on-site testing and healthcare management without a specific place or cumbersome operation. Accordingly, numerous rapid detection platforms with diverse size and performance have emerged such as
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bench-top apparatuses, handheld devices and intelligent detection
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devices. This review discusses various devices developed mainly for the detection of lateral flow test strips (LFTSs) or microfluidic strips in the POCT and summarizes these devices by size and portability. Furthermore, on the basis of various detection methods and diverse probes usually containing specific nanoparticles composites, three most common aspects of detection rationale in the POCT are selected to elaborate each kind of detection platforms in this paper: colorimetric
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assay, luminescent detection and magnetic signal detection. Herein, we focus on their structures, detection mechanisms and assay results, accompany with discussions and comments on the performances, costs
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and potential application, as well as advantages and limitations of each technique. In addition, perspectives on the future advances of detection platforms and some conclusions are proposed.
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Keywords: Point-of-care testing (POCT); Nanoparticles; Detection
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platforms; Colorimetric; Luminescent; Magnetic
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1. Introduction The point-of-care testing (POCT) is an in vitro detection method that is able to obtain detection results instantly at the sampling site by
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utilizing rapid and convenient analytical instruments as well as
supporting reagents. By collecting and analyzing samples such as whole blood, serum, urine, saliva, viruses, bacteria and other proteins, the
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POCT is capable of performing healthcare, disease management,
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therapy assistance and food safety monitoring in a hospital, clinic, doctor’s office or at home [1-11]. Up to now, this technology can be applied in different areas for various testing purposes, such as food safety (detection of food allergen [12], Listeria monocytogenes [13] and
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nitrite [14]), disease diagnostics (determination of pathogen [15], breast cancer biomarkers [16] and Giardia lamblia cysts [17]), environmental
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monitoring (wastewater treatment [18], Vibrio fischeri assay [19] and K+ quantification [20]), clinical guidance (measurement of non-vitamin
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K antagonist oral anticoagulants [21], therapeutic drugs[22] and addictive drugs [23]). In the studies of POCT technology, lateral flow test strips (LFTSs) [24-36] and microfluidic chips [37-48] are widely used as carriers for the reaction, and for characterization and detection of samples. The first application of the strip assay was the pregnancy test which detected human chorionic gonadotropin (HCG) level [49]. Benefiting from the utilization of a membrane strip as the
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immunosorbent, the macroscopic detection results allowed the analytical platform to perform one-step, rapid and low-cost analysis [50].
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In order to improve the sensitivity and specificity of detection, researchers have investigated a variety of materials serving as immunoprobes [51], where colloidal gold is widely used in the
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colorimetric assay, the most common method. The source of colorimetric
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signals is basically derived from colored immunoreaction labels such as colloidal gold nanoparticles (NPs) [52-56], carbon NPs [57-61], and colloidal selenium NPs [62-65]. The preparation process of such colored NPs has been relatively mature, which provides great convenience for detection.
Besides,
with
the
development
of
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immunolabeling
nanotechnology, luminescent NPs have also been widely utilized in the POCT due to their optical stability and applicability in immunoassays,
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and include quantum dots (QDs) [66-69], dye-doped NPs [70-73] and
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up-converting NPs [74-77]. Fluorescent immunolabeling technology based on fluorescent nanoparticles has made great progress due to its robust photo-stability and high specificity. In addition, magnetic NPs especially superparamagnetic NPs, due to their unique magnetic properties, have also been applied in the POCT [78-81]. In particular, advances in magnetic activated cell sorting (MACS) and microfluidics have led to a successful combination of immunology, cytobiology and
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magnetomechanics. Early research on LFTSs and microfluidic chips using the naked eye only obtained qualitative information in terms of negative or positive
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results. Although qualitative or semi-quantitative detection was performed rapidly and conveniently, accurate values of analyte concentrations and reliable detection results are of great significance in
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the application of the POCT [82]. Accordingly, corresponding diagnostic
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platforms are required for the quantitative detection of analytes of interest in LFTSs or microfluidic chips. These detection systems usually need to meet the following requirements: (a) rapid test process, (b) high accuracy and sensitivity, (c) simple to operate, (d) steady working conditions, and
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(e) automatic analysis and data transmission. Hence, a number of analysis platforms with different measurement mechanisms were developed.
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On the basis of the foregoing, there are far more methods applied in the POCT. For example, electrochemical methods are generally applied in
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various detection devices [83-85], where impedance detection is an effective means for rapid detection [86-88], even considering portability and instrument limitations in the POCT. This paper discusses the progress and work on detection platforms in the POCT over the past few years. We focus on three common types of detection methods colorimetric assay, luminescent detection and magnetic signal detection
for study and
evaluation in detail through discussing and reviewing various devices
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developed for the detection of LFTSs or microfluidic strips. These devices are categorized into three types according to their size and operational complexity: normal or bench-top apparatuses, portable or
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handheld devices, and intelligent detection platforms. Based on different rationales of detection, each size category consists of colorimetric detection, fluorescence intensity assay or magnetic signal measurement. A
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summary of the various detection platforms of the POCT is shown in
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Table 1. 2. Normal or bench-top apparatuses
Normal and commercial bulky apparatuses have been developed and updated for generations through numerous applications and user
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feedback. They are able to achieve high accuracy, desirable sensitivity and reliable results, consequently tend to be standard equipment for
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various detection. On the other hand, in order to obtain effects that were more ideal or to adapt particular contents of a study, custom-developed
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instruments appeared to analyze LFTSs or microfluidic chips. Various apparatuses, both purchased from commercial companies and self-developed by research personnel are discussed below. 2.1.
Colorimetric assay
In numerous studies, the color density information of the test or control lines on the immunochromatographic strips and colorimetric
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signals of the micro-channels in the microfluidic chips is represented by an optical density value or color intensity. Generally, an instrument detecting color signals contains a robust image sensor such as a
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complementary metal oxide semiconductor (CMOS) camera or charge-coupled device (CCD) to capture the images of samples on
LFTSs or microfluidic chips. The established reader software is able to
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identify the accurate position of the test line, control line or
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microchannel, minimize the background noise and calculate image parameters such as gray value, peak value, area integral and line distance. Therefore, the concentration of analyte is calculated and the quantification of samples achieved. In addition, the strip holder of the
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reader can be adjusted according to different dipsticks and cassettes. Generally, light source together with image sensors such as CMOS or CCD is strongly required in the colorimetric assays. For the
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quantification of colorimetric signals of samples on LFTSs, Kim et al.
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developed a test strip reader for the immunochromatographic assay [89]. A schematic of the reader is illustrated in Fig. 1A. A custom-designed optical head and a linear movement mechanism of a standard CD (compact-disk)-ROM (read-only memory) deck were used in assembly of the reader. The optical head contained a light-emitting diode (LED), photodiode and anodized aluminum. A stepping motor was driven by the CD-ROM deck at the full step mode. The reader performance was
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demonstrated by the detection of hepatitis B virus (HBV), with a detection limit of 1.25 ng/mL. Based on an embedded Linux operation system, another LFTS reader (Fig. 1B) was designed by Mei et al. [90].
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A green LED served as the light source and a high-resolution CMOS sensor was used to capture LFTS images. A touch screen on the panel
was included to realize the display function and user control
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simultaneously. A thermal printer was assembled to print detection
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reports. By measuring the concentration of cocaine fluid, the reader achieved an accuracy of 1 ng/mL. In addition, the instrument was able to detect various types of LFTSs.
In order to control the time consumption of researches and obtain
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results fast and accurately, a great deal of research groups turn to commercial apparatuses for testing and characterizing. Yang et al.
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utilized the test strip reader, DT1030 [91] purchased from Shanghai Kinbio Tech Co., Ltd.. DT1030 uses a CMOS sensor as the imaging
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component and a USB interface to transmit data to the PC to compute the gray value of the control and test lines, thereby realizing quantification of the detection results. The system was established to realize the quantitative immunoassay of immunoglobulin G (IgG). Sandwich-type LFTSs were prepared based on gold nanocages (GNCs). Combined with the GNC-based LFTS, the reader completed the assay within 15 min. It was demonstrated that the linear detection range of
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IgG concentration ranged from 0.5 to 50 ng/mL, and the limit of detection (LOD) was 0.1 ng/mL. DT1030 was widely used to detect analytes labeled by colored markers. For example, Mao et al. proposed
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a nucleic acid biosensor based on a LFTS to detect deoxyribonucleic acid (DNA) in plasma [92]. Blue dye-doped latex beads were selected
as the colored label. In association with the strip reader DT1030,
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synthesized DNA detection had a linear range from 0.25 to 50 nM of
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DNA, and a detection limit of 3.75 fM in 50 mL human plasma. In another example, Huang et al. utilized DT1030 to record colorimetric signals of the LFTS [93]. Combined with magnetized carbon nanotubes as labels, the protocol was able to realize the visual detection of proteins
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in whole blood without pretreatment of samples. As a result, the detection limit was 10 ng/mL of proteins and the linear range was 10 to
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200 ng/mL of proteins.
Besides the extensive application of DT1030, a number of
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commercial bench-top detection instruments for the POCT have also emerged. The Alere™ Reader manufactured by Abbott (Chicago, USA) is a typical lateral flow test reader [94]. The reader consists of a built-in camera to capture the strips, a barcode scanner to record the information on the strips, a color touch screen for manipulation, and a standard strip for calibration. The Alere™ Reader can be used in laboratories for research and in the POCT. Combined with specific testing cards, the
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Alere™ Reader was able to detect various diseases such as Legionella pneumophila antigen [95], Streptococcus pneumoniae antigen [95], influenza A and B nucleoprotein antigens [96], respiratory syncytial
The above-mentioned examples
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virus [97] and Streptococcus pyogenes Group A antigen [98]. while not limited as these are
typical bench-top equipment for practical colorimetric assay in the
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POCT. With regard to the normal or bench-top apparatuses, the bulky
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size and complicated operation may prevent their popularity, while their excellent detection performance has promoted their popularity in immunoassays by professional personnel. Luminescent detection
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2.2.
Along with the increasing requirement in detection and the improvement of testing approaches, numerous assays in the POCT
determine
fluorescent
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To
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based on luminescent detection especially fluorescence have emerged.
immunoreaction,
plenty
of
intensity
in
bench-top
the
biochemistry
devices
are
and
developed.
Fluorescence and color detection differ in their requirement for an excitation light source, conversion of the fluorescent density into optical density and recording the optical density signals. The excitation light source at certain wavelengths (usually ultraviolet (UV) rays) enables the invisible fluorescent substance to emit light with a longer wavelength,
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which is in the visible light band, rather than incident light. Instruments are able to detect the optical intensity of fluorescence and analyze the image information, similar to the aforementioned method for color
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signals. Luminescent detection is performed to capture the fluorescent signal from luminescent NPs, as aforementioned in the Introduction part before, such as QDs, dye-doped NPs and up-converting NPs etc.
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For instance, Huang et al. developed an optical reader to capture
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upconverting phosphor particles on LFTSs [99]. The reader protocol was based on upconverting phosphor technology (UPT). Fig. 1C shows a schematic of the reader. The excitation source was a 980 nm laser and was focused on a spot on the LFTSs. The slit can prevent stray light
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from the photomultiplier tube. This detection system was used to measure Yersinia pestis F1 antigen at various concentrations, with a
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sensitivity of 5 ng/mL and dynamic range of 150 ng/mL. For the quantitative measurement of fluorescence intensity from
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QDs on the LFTS, Gui et al. developed a CCD-based reader to detect the concentration of cytotoxin-associated protein (CagA), a typical biomarker of gastric carcinoma [100]. A CCD image sensor (29 × 29 × 29 mm3) and arrays of UV LEDs as the excitation source with a wavelength of 365 nm were assembled inside the integrated reader. The image information on the test strips was captured by the CCD sensor and transmitted to a laptop for analysis and processing using customized
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software. Fig. 2A shows the CCD image sensor and the integrated reader as well as the matched laptop. In this research, an image-processing
algorithm
of
weighted
threshold
histogram
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equalization (WTHE) was used as the core method for data analysis. It was demonstrated that this device was ultrasensitive with a detection limit of 20 pg/mL for CagA detection.
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Not limited to self-built instruments, commercial equipment is also
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widely utilized for fluorescent assays in the POCT. A fluorescent microfluidic chip reader known as Triage MeterPlus (Fig. 2B) has been reported [101]. A silicon photodiode inside the device serves as the detector to measure emission light at a wavelength of 760 nm. The
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standard curve and detection principle of fluorescence, which were stored in the memory unit and the built-in signal processing unit,
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respectively, converted fluorescent intensity into electrical signals and then transformed them into sample concentrations. Triage MeterPlus
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was able to identify the microfluidic test strips by reading barcodes printed on the strip case. Furthermore, each diagnostic result was displayed on a liquid crystal display (LCD) screen. The results were printed by a built-in printer, and automatically transmitted to the health care information system. During manipulation of the assay, operating personnel, according to their different requirements, can autonomously change the detection parameters such as the cut-off value, user or
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patient identification and times of repetition. The Triage MeterPlus device due to its robust performance is widely used in the POCT for the detection of various analytes, such as B-type natriuretic peptide
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[102-105] and cardiac troponin I (cTnI) [106]. Another example of a commercial desktop reader is ESE-Quant (Fig. 2C) [107] manufactured by ESEGmbH of Stockach, Germany. This
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cost-efficient device contains a simple LED as the light source, a
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miniaturized optoelectronic core and a digital processing unit. With this device, 1,500 data points are acquired per second and one scan only takes several seconds. During detection, the reader automatically identifies the peak value of the control line and up to 16 test lines and
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stores the data in the internal memory. The results are displayed on the screen. As an example of its application, Chamorro-Garcia et al. utilized
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the ESE-Quant to quantitatively detect parathyroid hormone-like hormone in cancer cell cultures [108]. In addition, combined with the
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reader, Takalkar et al. detected DNA using a fluorescent carbon NP-based LFTS by measuring the fluorescent intensities of the test zone and control zone [109]. A detection limit of 0.4 fM DNA was achieved. In order to decrease or even eliminate the time spent on the reaction between analytes and labels, Challa et al. developed an intrinsic fluorescence visualization platform to excite and detect the unlabeled protein
molecules
and
protein
complexes
flowing
in
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polydimethylsiloxane (PDMS) channels of the microfluidic chips [110]. A photograph and schematic of the system are shown in Fig. 2D. Ultraviolet excitation light generated by a LED at a wavelength of 280
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nm was transmitted through a series of optical components and finally focused on the microfluidic chip to excite the analytes. Accordingly, the
fluorescence from analytes was collected by an electron multiplying
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charge-coupled device (EMCCD) camera through a specific optical path.
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Black carbon NPs were applied before measurement to eliminate the background interference due to autofluorescence from other materials under the 280 nm excitation light. Combined with diffusional sizing on a micron-scale, this apparatus was able to detect the hydrodynamic
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radius of each single protein and the complexes, respectively. On the basis of these representative examples, by detecting
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fluorescent signals from the immunoprobes, quantitative detection results with higher sensitivity and lower detection limits can be obtained
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compared with colorimetric assays. 2.3.
Magnetic signal detection
Conventional optical detection methods may be biased due to the
uneven distribution of NPs and the unstable performance of image sensors. Compared with colored NPs and fluorescent markers, which only detect reflected light or fluorescence within the two-dimensional
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top layer of the capture regions, magnetic NPs are able to represent the entire volume magnetic signal in the test areas. Furthermore, magnetic LFTSs show low magnetic background signals of analytes.
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In general, a specific sensing component is required to realize the detection of magnetic signals. One of the quantitative methods used is
the detection of the magnetic flux generated by magnetic NPs on the
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LFTSs and microfluidic chips. As an example, the MAR Assay
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Development System (magnetic assay reader, MAR) [111], which was developed and sold by Magna Biosciences LLC (CA, USA), is widely utilized to quantify magnetic NPs labeled samples such as HCG [112], parvalbumin [113], Listeria monocytogenes [114], Bacillus anthracis
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spores [115] and human immunodeficiency virus (HIV) type 1 p24 antigen [116]. The MAR and a schematic illustration of the detection mechanism are shown in Fig. 3A. A C-shaped electromagnet inside the
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MAR generates a magnetic field to excite superparamagnetic NPs. In
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addition, a set of thin film induction coils serve as measurement units for magnetic measurement. The intensity of the measured magnetic signal is proportional to the amount of accumulated magnetic NPs on the test strip and is represented by relative magnetic units (RMU). The improvements in hardware would reach a chock point on the detection performance, which might be effectively addressed by some advanced data processing algorithms. For example, Yan et al. [117]
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presented a machine learning-based magnetic biosensing system named MIR to improve the performance of magnetic immunoassays on LFTSs. The protocol managed to demonstrate the excellent sensitivity by the
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LOD of HCG down to 0.014 mIU/mL. Also, Hong et al. [118] utilized the same magnetic reader platform to simultaneously quantify multiplex cardiac markers including cTnI, creatine kinase isoenzyme MB
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(CKMB), and myoglobin (Myo), with the detection limit of 0.0089
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ng/mL, 0.063 ng/mL, and 0.05 ng/mL respectively.
Besides the reader model of MAR and MIR, another detection strategy is to measure magnetization saturation generated by magnetic NPs through magnetic sensors. Of the research articles on magnetic
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biosensor technology for lateral flow immunoassay, the giant magnetoresistance (GMR) sensing method has been widely used in the
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quantification of analytes labeled by magnetic NPs. For example, Ryu et al. detected the cardiac marker troponin I using a GMR sensor, with a
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sensitivity of 0.01 ng/mL [119]. Furthermore, Marquina et al. presented a general method for monitoring the magnetoresistive response generated from a spin valve GMR sensor which was placed close to the magnetic NPs on the test strip [120]. The measurement equipment used is shown in Fig. 3B. The GMR sensor measured 9 × 9 mm2, and the outer diameter of the circumjacent Helmholtz coils used to provide the magnetic field for polarization of the spin valve, was 150 mm. The
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lateral flow assay test strip, after the immune reaction, was placed on a plastic wheel that enabled switchable situations: either to maintain a soft contact between the sensor and strip or to allow a 2 mm distance from
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the magnetoresistive sensor in the vertical orientation (z direction). The test line on the strip was moved by a step motor in 1 mm steps on the
tangential orientation of the wheel (x direction). The voltage or
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magnetoresistance output signal was generated when the test line
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coincided with the sensor. Furthermore, the stray magnetic field of NPs validated the different sensor resistances in the switchable situations. Meaningful signals produced in the distance interval of 1.5 mm approximately corresponded to the width of the test line. The
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measurement results were obtained within 5 min. In addition, Serrate et al. utilized the GMR protocol to quantitatively detect HCG using highly
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sensitive magnetic LFTSs [78].
Another example of magnetic measurement was based on tunneling
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magnetoresistance (TMR) sensing. Lei et al. developed a contactless sensing system to quantitatively detect magnetic NPs bound on the LFTSs [121]. Fig. 3C shows a photograph of the prototype. A C-shaped magnetic core, which contains a cross-section of 16 × 16 mm2 as well as a gap of 8 mm, was applied by a direct current. Two parallel and adjacent TMR components (TMR2705) were added to form a differential structure in the gap region where a perpendicular magnetic
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field (approximately 300Oe) existed generated by the C-shaped magnetic core. This differential structure was sensitive to variation in the stray magnetic field due to magnetic NPs in the x direction. During
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detection, as depicted in Fig. 3D, the LFTS was moved in the x direction by a sliding rail and the TMR sensors then transformed the changes in magnetic signals into voltage information. Combined with
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the detection of HCG, the device showed a LOD of 25 mIU/mL and the
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ability to measure a stray magnetic field of 0.247 mOe from the test line of the LFTS, which was invisible to the naked eye.
Of the above-mentioned detection devices, MAR is not able to detect positioning and required manual correction of position. In the
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GMR method, the structure of the test strips may be damaged when placed on the detection wheel. Therefore, this method does meet the
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requirements for clinical use. The TMR sensor is bulky and the distance between the two side-by-side sensor chips is about 1 cm; thus, it was
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not capable of detecting multiple test lines simultaneously. In addition, electromagnetic interference from the external environment should be taken into account, which is also a bottleneck restricting the miniaturization of magnetic detection equipment. Overviewing the normal or bench-top apparatuses for colorimetric and luminescent detection, large but accurate image sensing element such as CCD is usually selected to obtain results with more reliability.
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Similar to desktop magnetic detection equipment, larger or even more groups of magnetic sensing components are also preferable to complete the measurement of magnetic signals with high accuracy. Such a setup
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will certainly increase the manufacturing cost of bench-top devices, energy consumption and professional resource devotion. Although this
type of instrument with high stability and repeatability has undergone
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numerous technological innovations and modifications, portability and
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flexibility of testing equipment are significant factors to meet the requirements of the POCT, especially in the community clinics, mobile testing, and other fields’ detection. Therefore, analytical devices that are accurate, compact in size and easy to operate come into being in the
examples.
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POCT. Handheld portable detection devices are excellent and competent
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3. Portable and handheld devices
With the development of medical care, clinical diagnostics have
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gradually evolved from large hospitals to community clinics, family doctors and rapid on-site detection. Therefore, the demand for portable detection devices has increased. Compared to bulky and bench-top devices, handheld and portable analysis instruments are more integrated, easy-to-handle and time-saving, without considerable loss of accuracy and sensitivity. Generally, the handheld devices contain integrated sensors and a signal transmission unit. The detection results are stored
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in the memory, or wirelessly transmitted and uploaded to central servers or other terminals via Bluetooth, Wireless Local Area Networks (WLAN) and mobile communication. The above characteristics enable
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these devices to perform rapid, accurate and on-site analysis of LFTSs and microfluidic chips. Colorimetric assay
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3.1.
Handheld devices for colorimetric assays due to their portability and
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uncomplicated operation are somewhat more promising than bench-top apparatus. One of the examples is the widespread application of glucose monitoring. For instance, an early glucometer [122] introduced by Johnson & Johnson is a low-cost and advanced blood glucose analyzer
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that provides rapid, precise, convincing and professional results in real time. There is a matched test strip containing glucose oxidase which
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reacts with glucose in blood to cause changes in color. After the time, the blood drop on the strip (1.4 µL usually) was wiped off and then
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placed in the glucometer to obtain the blood glucose level by measuring the chromatogram. The detection results can be displayed after 15 seconds. Although measuring more rapidly and requiring less blood sample compared to biochemical analyzers, glucometers that rely solely on color analysis have been basically eliminated in the market with the introduction of photochemical, electrochemical and chemiluminescent techniques.
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Combining with optoelectronic technology, Cetin and Coskun et al. [123] proposed a handheld on-chip sensing platform (Fig. 4A) realizing computational imaging by an optoelectronic sensor array and a CMOS
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imager chip without any lens. An LED, a battery, a plasmonic chip and a CMOS imager are integrated in the light-weight device. The sensing
platform is capable of detecting protein monolayers with label-free
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condition and quantitatively analyzing the binding of protein in various
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biomolecule concentration. Furthermore, an image reconstruction method allows the platform much adaptive in diagnostics in the POCT. In the respect of handheld detection platforms for the POCT, colorimetric or chemical colorimetry seems a good start. And this kind
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of devices draw numerous attention in the market due to the principle and simple operation. Nevertheless, with the growth of detection
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requirements and constant exploration of other detection methods, colorimetric detection has been unable to meet the increasing
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requirements and has been gradually overrode by other methods such as electrochemistry, chemiluminescence, bioluminescence and magnetic detection. Additionally, multiple detection might be more excellent than singly colorimetric detection. 3.2.
Luminescent detection
Similar to colorimetric testing, luminescent detection carrying on
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handheld devices requires image component with high performance, small size and high precision. The external natural light or white light generated from the device is usually used for colorimetric detection to
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illuminate the region of interest (ROI), while fluorescence detection requires an excitation light source with a specific wavelength when
analyzing the intensity of fluorescence, which is a crucial feature in
Moreover, handheld devices for luminescent
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handheld devices.
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detection have many benefits in relation to accuracy compared to bench-top apparatuses. For example, the FluoVisualizer (Fig. 4B) is a handheld, pocket-size device for lateral flow immunoassays [124]. The device contains an illumination source and a filter. Users can view the
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test results directly by the naked eye. Due to no electronic recording of data and simplicity of design and fluorescent detection, the visualizer is cost-effective and is capable of multiplex detection. During operation,
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users insert the strip, turn on the excitation source and can then view the
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luminescent control and test lines. Unfortunately, the FluoVisualizer can only be used for qualitative detection instead of quantitative detection. In order to obtain quantitative results under the POCT condition, a
handheld fluorescent reader named portMD-113 [125] was developed, which achieved comparable LOD against a commercial modern benchtop laser scanner, with agreement of R2 = 0.995. Fig. 4C depicts the overall view of portMD-113. The device is made up from several
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cost-effective, handy and small components. Inside the detection platform, biological sample is spotted onto a cyclic olefin copolymer film waveguide in a grid pattern. A laser diode (λ = 635 nm) together
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with a collimator and a prism generates laser to irradiate the waveguide edge. Through a built-in CCD chip, test results are captured for evaluation by a designed algorithm in MATLAB. The portMD-113
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device completes measurement within 20 second and allows physicians
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detecting out of hospitals and laboratories, which meets the needs of the POCT.
A recent study by Qin et al. demonstrated a handheld diagnostic system named Handing [126], to rapidly quantify the QDs-labeled
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tumor marker CEA on lateral flow immunoassay strips (Fig. 4D). Combined with a customized data server, the detection terminal based on embedded technology can realize the following series of functions:
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fix test strips, form a closed detection environment, generate UV light
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for fluorescent excitation, manipulate the touch screen, obtain and process images, store data and query results. The detection of clinical samples demonstrated that the platform showed excellent performance with a detection limit of 0.049 ng/mL and an analysis range of 1–100 ng/mL, and the total time for each procedure including sampling, analysis and obtaining the results was no more than 15 min. Although the aforementioned handheld devices can perform
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stand-alone detection and data storage, the test results for most devices still need to be uploaded to the host computer through various transmission methods to manage and share the data. Moreover, the
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limitation of a single excitation light source and cumbersome development of the embedded system, as well as the emergence of
handheld fluorescent detection equipment. Magnetic signal detection
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3.3.
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smartphone-based devices, may foster the slow development of
Attributed to the development of integrating physical sensing components such as magnetic induction coil and electromagnet, magnetic detection on miniaturized handheld devices is also an
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attractive task for researchers in the POCT, resulting the magnetic NPs-based immunoassay with high detection sensitivity more portable
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and flexible.
As shown in Fig. 5A, Rettcher et al. designed a handheld magnetic
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reader containing a touch screen and an integrated detection device measuring 10 × 23 × 7 cm [127]. A cluster of four coaxial coils were assembled in the detecting device, two for detection, one for driving with a frequency of 61 Hz and the other for excitation with a frequency of 49 kHz. Based on the magnetic immunoassay detection methodology of frequency mixing [128], the superparamagnetic particles functionally bound with virus in the sample solution are immersed in the mixed
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frequency magnetic field. The driving coil generates a strong low-frequency magnetic field, in which a positive and negative anode drive the magnetic beads at magnetic saturation status. The detection
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coils, containing two neighboring compartments with opposite rotation direction, weaken the direct induction generated by the excitation coil through their differential winding. Furthermore, subsequent steps
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include amplifying the voltage induced by the detection coils, and
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demodulation of the hybrid frequency through multiplication and low-pass filtering. The detection performance of the complete system ranges from 6 ng/mL to 20 fanleaf virus concentration.
g/mL for the detection of Grapevine
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In another example of a magnetic detection device, Shipunova et al. utilized a handheld magnetic particle quantification (MPQ) reader to achieve accurate quantification of the interactions between iron oxide
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NPs and eukaryotic cells [129]. The portable MPQ reader with
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dimensions of 18 × 10 × 4 cm performed measurements at room temperature and detection was at the sub-nanogram level. It was demonstrated that the MPQ device achieved a sensitivity limit of 0.33 ng of magnetic NPs. In addition, the quantification method associated with the MPQ reader did not require costly and sophisticated measurement apparatus or a professional operator and realized rapid diagnostics in field conditions within several seconds for each
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measurement. Combining
200
nm
magnetic
NPs
as
labels
and
immunochromatography technology, Orlov et al. further utilized the
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MPQ reader to quantify prostate specific antigen (PSA) in human serum [130]. In Fig. 5B, after the immune reaction, the LFTS was placed
across the measuring induction coil of the MPQ reader to read the
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quantity of magnetic NPs on the test line and control line. In the
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modified MPQ reader, the excitation magnetic fields were enhanced to 144Oe and 56Oe, respectively, for the low and high frequency components, which resulted in a wider dynamic detection range and high sensitivity and linearity. In this work, the measurement device
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showed a sensitivity limit of 60 zeptomoles of magnetic NPs in a 0.2 mL volume. In addition, the whole detection process registered
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magnetic NPs in a three-dimensional spatial domain rather than a layer plane, which reinforced the capture sensitivity for magnetic nanolabels.
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In order to improve the performance of the MPQ reader and to
fulfill multiplex measurements and assays, Orlov et al. incorporated three measurement inductive coils, which were all read by a single processing unit in the MPQ reader [131]. A schematic of this detection system is shown in Fig. 5C. The three inductive coils in parallel corresponded to the diverse positions of the test line of the three LFTSs, respectively. This particular structure enabled the system to
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simultaneously detect three types (A, B and E) of botulinum neurotoxin (BoNT). As previously mentioned, the magnetic quantification system detected entire magnetic signals of the capture region; thus, ensuring
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high detection accuracy. The developed multiplex biosensing system showed a LOD of 0.20, 0.12, and 0.35 ng/mL for BoNT-A, B, and E, respectively. The multiplex detection system exhibited the expected
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performance in the detection of orange and apple juice, and milk.
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Among the examples of magnetic signal detection in miniaturized devices, mini magnetic induction coils or multiple groups of coils are employed to monitor the intensity of magnetic field. Although the handheld devices might not be as excellent as commercial magnetic
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detection instruments and even might be interfered by external electromagnetic fields, they could also collect the weak magnetic
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signals from magnetic NPs. Compared with the colorimetric and fluorescent analysis, handheld magnetic detection could obtain results
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with favorable accuracy and high reliability. In general, electrochemistry and electrochemiluminescence are the
potential alternative for handheld instruments. It seems that handheld magnetic testing devices dominate in terms of innovation and novelty, while cost might increase. Furthermore, with the advent of intelligent devices (especially smart phone) and the rapid development of information technology, the advantages of handheld test terminal might
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be gradually overwhelmed by intelligent diagnostic devices and systems. Nonetheless, it does not mean that there is no worth on exploring handheld test equipment. In the detection of LFTSs or simple structure
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microfluidic chips, handheld detection equipment still exerts the handsome features and advantages of the POCT technology.
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4. Intelligent detection devices and platforms
Compared with most conventional bulky equipment, intelligent
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devices such as smartphones, smart wearable devices and other mobile devices are ideal processing tools in the POCT due to their portability, intelligent interaction, openness of the operating system, abundant sensors and wireless communication. Furthermore, the number of users
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of these intelligent devices has increased dramatically and will continue to do so, which will enable smart device-based biosensor systems to be
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robust tools for POCT applications. Notably, compared with other intelligent devices, smartphone drawn tremendous attention due to the
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advanced central processing unit, intuitive human-machine interaction, simplified
operation,
open-source
operating
system,
prevalent
availability and bountiful sensing components. Combined with specially designed and 3D-printed attachments that facilitate imaging and fixation of samples, smartphones are capable of achieving high resolution, sensitivity and specificity for the detection of lateral flow immunoassay strips, microfluidic chips or other sample carriers [132, 133].
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4.1.
Colorimetric assay
Among the studies on smart devices for colorimetric detection, it could be found that the most easily and widely used sensing element is
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the image sensor of smart devices. On the one hand, the device is able
to serve as a camera to merely capture the pictures of ROI and then
transmit it to a computer or other instrument for further analysis. On the
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other hand, the detailed information could be analyzed and processed by
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the central processing unit. Then, the results are displayed visually or sent to a destination via a specific communication protocol for a further analysis and consultation.
A typical example of an intelligent wearable device to realize the
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immunochromatographic diagnostic test was demonstrated by Feng et al. [134], who developed a Google Glass-based POCT platform (Fig.
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6B), that was able to qualitatively and quantitatively detect diverse lateral flow immunoassay strips. An assorted custom-designed
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application was written in Google Glass to successively identify the quick response (QR) code on the test strip, control the camera unit to capture images of the strip, transmit image information to a server for data processing and receive the results of quantification analysis. The central server was not only the core of image analysis and processing, but a repository for storing the QR code, strip images and location information on detection. The detection results and other relevant
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information can be accessed through an Internet browser. The performance was demonstrated by the qualitative detection of HIV and the quantitative detection of PSA. The hands-free and wearable
epidemics, mobile medical and telemedicine.
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detection system provides a promising diagnostic platform for
In addition to the detection through wearable smart devices, there are
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plenty of examples about colorimetric detection by smart phones. To
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realize rapid diagnostic tests through LFTSs on a cellphone, Mudanyali et al. developed a compact and cost-effective reader platform which was attached to a smartphone (Fig. 6A) [135]. Three arrays of LEDs were integrated in the attachment to illuminate the LFTS tray for reflection
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on the front side and for transmission on the posterior side. In association with a smartphone camera module and a customized smart
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application, the platform was capable of capturing and digitally processing raw images of LFTSs, displaying the diagnostic results,
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transmitting the data to a central server and marking the detection position on a world map. Users can browse the e-map on the Internet and the cellphone App. The protocol was successfully demonstrated both on Android-based smartphones and an iPhone using assays for malaria, tuberculosis and HIV, and showed the potential of this protocol in assisting professional healthcare personnel, and for epidemic tracking and preparedness.
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Moreover,
Li
et
al.
also
developed
an
integrated
smartphone-app-chip system to detect and quantify aflatoxin B1 (AFB1) [136], which is a food toxin found in moldy corn samples. The
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hardware device is illustrated in Fig. 6C. The optical attachment includes 16 white LEDs to provide ambient lighting, and a chip slot to
fix the microfluidic plastic assay strip. The microfluidic assay strip
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contains several channels for samples. In association with a
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custom-designed Android smartphone App known as AFB1DET to analyze the colorimetric signals of samples in the strip channels, the detection system achieved a LOD of 3±1 parts-per-billion(ppb). Besides the instances foregoing, numerous research papers have reported
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sensing systems in which smartphone camera was used as the imaging unit to capture samples information [136-138]. Companying with outer optical component, Lee and Yang et al. developed a smartphone-based
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chip-scale microscope without an external 3D-printed accessory [139],
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which also performed well with a resolution of 500 nm for imaging blood smears and aquatic microorganisms. Different from the conventional detection approches of image
sensors, more and more studies have constructed smartphone-based detection systems by using the ambient light sensor. This component practically senses the intensity of ambient light and then automatic adjust the brightness of the screen, which is usually located above the
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front panel of the smart phone. In order to improve the universality of external accessories attached to the smartphone, an ambient light sensor was used to capture the density of light rather than a camera [140]. A
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schematic of this system is shown in Fig. 6D. To detect the concentration of samples immobilized on the test line of lateral flow immunoassay strips, this platform utilizes the smartphone ambient light
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sensor to detect the transmission light density from the test line and
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establishes the relationship between the sample concentration and light density. The prototype showed a LOD of 0.16 ng/mL for cadmium ion (Cd2+), 0.046 ng/mL for clenbuterol and 0.055 epidemic diarrhea virus.
g/mL for porcine
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Similarly, Zhao et al. presented an ambient light-based smartphone detection platform (Fig. 6E) to determine enzymatic inhibition and
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phosphorylation [141]. Butylcholinesterase was used as the analyte. The smartphone ambient light sensor was used to measure colorimetric
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signals transmitted from transparent LFTSs. The detection platform showed excellent linear responses and a low detection limit of 0.028 nM.
To provide a closed and stable optical environment, external accessories are of necessity for smart devices. The external accessories not only need to fit the structure and appearance of the smart phones, but also adapt the analyte reaction carrier such as LFTSs and
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microfluidic chips. The external shell for ambient light assays present high universality for various kinds of smart phones, while with a lower accuracy compared to image detection. Conversely, even if the camera
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can achieve convincing results, the adaptation of accessories for the various camera position is a little powerless. It still requires researchers
to make trade-offs in the POCT research. Therefore, the design of the
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outer accessories takes smart phones into the maximum function, and it
phones. 4.2.
Fluorescence detection
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is also an unneglectable direction for developing POCT on smart
In comparison, the operating environment and conditions of
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fluorescence detection are more demanding than colorimetric testing. During colorimetric detection, the native lighting element of smart
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phones such as flash light is using to provide a light source for testing. However, fluorescence detection is performed on instruments with an
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excitation light source at specific wavelength, which puts higher demands on the external accessory. The enclosure not only offers a stable and closed light environment, but also provides several excitation sources with different specific wavelengths. A lot of research work has managed to do this. Barbosa et al. developed a fluorescent detection system using a smartphone-based detection system known as MCFphone that
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quantitatively detected PSA by colorimetric
and fluorescence
immunoassays [142]. The MCFphone (Fig. 7A) consisted of a smartphone with a magnifying lens, a light source, and a miniaturized
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immunoassay platform named Microcapillary Film (MCF). Due to its properties of transparency and flat geometry of the fluoropolymer MCF, the prototype was able to rapidly quantify PSA in whole blood samples.
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It was shown that the LOD was further improved from 0.4 to 0.08
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ng/mL in the fluorescent detection mode. The MCFphone exhibited excellent recovery, efficiency and high sensitivity, which contributed to the integration of portable microfluidic devices, commercial reagents and smartphone technology.
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Likewise, Yeo et al. has also proposed a fluorescent diagnostic system based on a smartphone to detect highly pathogenic H5N1 viruses [143]. As shown in Fig. 7B, an efficient reflective light
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collection module was integrated. During detection, the fluorescent
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lateral flow strip was fixed to the measurement module and excited by UV light through an excitation filter. Using an emission filter, the fluorescence emission from the strip was collected by the non-imaging reflector, and then captured by the camera. The detection results were transmitted by the smartphone through the short message service and collected in a database for further processing. As demonstrated in this work, the detectability of this system was two-fold higher than a
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bench-top fluorescent reader and was capable of identifying patients and controlling avian influenza infection. Some works have used one single external accessory to realize
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dual-modal imaging. Smartphone could detect color of LFTSs
quantitatively anywhere at any time. The white and ultraviolet light were carried out and could switch according to different strips. As an
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example of a smartphone-based imaging and detecting system, Hou et
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al. developed a dual-modality imaging system to quantitatively detect both coloration and fluorescent immunochromatographic strips for the detection of HCG and CEA [138]. As shown in Fig. 7C, the smartphone matched an external 3D-printed shell. Two UV LEDs were assembled in
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the closed shell to excite the fluorescent probe on the strip. The white light source was provided by the smartphone flash lamp. The
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custom-developed Android App selected the types of strips, chose the target diseases, saved and queried the detection results. The achieved
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LODs were 2.3 mIU/mL and 0.037 ng/mL for HCG and CEA respectively.
In another example, You et al. presented a household reader
platform based on a smartphone to quantitatively detect core−shell upconversion NPs, which specifically bound to heart failure antigens such as suppression of tumorigenicity 2 (ST2) and brain natriuretic peptide (BNP) [144]. A schematic of the platform is shown in Fig. 7D.
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The platform consisted of an assembled portable reader containing a power supply, a 980 nm NIR laser and a particular optical system. By using a nonslip mat on the top cover instead of a phone holder, the
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reader was able to adapt various smartphones and obtain consistent results. In addition, a custom-designed smartphone App was integrated with the platform to capture images of the LFTS test region, analyze the
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image information, and share the results with professional personnel via
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the Internet. It was demonstrated that the platform achieved a LOD of 1 ng/mL and 5 pg/mL for ST2 and BNP, respectively. The platform was confirmed to be reliable in relation to the prognosis of heart failure, and has potential for health care in the POCT.
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Considering examples discussed above, custom accessories play a crucial role in fluorescent detection. Despite of various structures and
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different detection targets, the accessories are assembled with an excitation source to achieve fluorescence detection. Researches based
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on intelligent devices for colorimetric and fluorescence testing have become increasingly mature, while there is a huge challenge to realize the detection of magnetic signals. In general, there are no integrated sensors in smart terminals capable of detecting magnetic signals, except for the geomagnetic sensor in smartphones, which only detects geomagnetism. In addition, sensing components, such as the sensors of MAR, GMR and TMR, used to
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detect near-field magnetism require a large amount of space. It is not necessary for smartphones to develop external accessories for the detection of magnetism. Therefore, there are no examples of intelligent
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detection devices for magnetic sensing. For common colorimetric and fluorescent detection, it is hardly possible to place a high precision and highly sensitive sensor such as
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CCD in a smart phone. It generally extends basing on existing sensing
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components in smart devices for the sake of costs. All of the studies in POCT via smart devices are moderate extensions on the original intelligent applications. Fortunately, there is a development route for smart phone in industry, i.e., modularizing the phones by each functions.
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According to this idea, selected functional modules could be customized according to various requirements in POCT and to be integrated into
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main body of smart terminal.
Majority of smart phone-based reader platforms realize functions
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through transforming and expanding on the basis of the existing types of devices. Conversely, if there was possibility to manufacture specialized smart devices for the POCT, the cost of development would be greatly reduced while the performance of detection would be enhanced dramatically. This might be a decent direction for POCT to implement detection in intelligent technology and smart devices.
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5. Conclusions and outlook The application and development of various detection platforms for
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the POCT, and their compositions, structures, analysis mechanisms,
sensing modalities and performances, were discussed in this review in
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terms of three detection methods: colorimetric assay, luminescent
detection and magnetic signal detection. These platforms enabled the
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transition from qualitative analysis, semi-quantification to quantitative detection in the POCT field, and consequently promoted the study and development of the POCT. Furthermore, whether manufactured commercially or self-developed by research groups, these platforms
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were demonstrated to show desirable performance in the detection of LFTSs or microfluidic chips under specific assay conditions. Despite
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the diversity of detection methods, as well as dimensions, detection speed, analytes of interest and study purposes, all the detection
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platforms provided convincing and rapid test results within the allowable error range. Nevertheless, the excellent performance of the detection instruments including sensitivity, accuracy, resolution, LOD and detection range are expected to improve unceasingly, and immunoassay devices in the POCT are no exception. As far as the colorimetric detection and luminescent assays in POCT,
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image sensing and photoelectric detecting are both significant component during whole progress of the detection. The selection of such element and corresponding physical parameters directly affects the
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results and performance. For example, CCD tends to obtain images with more stability and quality than CMOS, while not advantageous in terms
of cost. Additionally, distinction among the central processing units of
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each reader platforms might differentiate efficiency of analysis results.
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It is noted that light source is also vital for colorimetric and fluorescent detection. In order to eliminate the influence of light source during different assays, a reference area is generally defined and the measurement is repeated a plurality of times to reduce the fluctuation of
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the result data. An enclosure or accessory is used to ensure the testing environment especially for optical detection, as well as enhancing the anti-interference capacity. For the detection of magnetic signals, metal
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materials are generally selected as the outer casing to effectively shield
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the interference of electromagnetic waves outside. Besides the hardware, software and algorithms of the reader
platforms also have immediate concern with the image processing of the POCT, especially in colorimetric and fluorescent analysis. Typical examples are color model of RGB and HSV, image binarization, enhancement, restoration, filtering and edge detection, etc. The most commonly used image reconstruction method is to process the original
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image by using morphological erosion or dilation, and then modify with a variety of filters and denoising methods according to a specific threshold. The method can obtain more ideal image information for
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analysis than that captured by the raw camera. On the whole, hardware and software are combined with detection protocols such as colorimetric testing, luminescent assays and magnetic detection to
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function adequately.
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With regard to commercial bench-top apparatuses, it is necessary to increase the sensitivity of each generation. Versatility is also one of the purposes for upgrading. With regard to handheld instruments and intelligent detection devices, miniature and integrated sensing
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components such as cameras, integrated circuits and light sources may limit sensitivity and accuracy. Embedded technology and operating
EP
systems also determine the performance of these platforms. In addition, external accessories attached to the smartphone not only lack
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universality due to different phone models, but also may weaken the flexibility of the immunoassay process to some extent. With the growing demand for home testing as well as personalized healthcare, an increasing number of studies on intelligent diagnostics and detection devices have been reported. There is a trend for miniaturization, integration and facilitation of detection instruments for the POCT. Portable and small size, or even single handheld devices that provide
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rapid and accurate detection have potential application in the POCT. Thus, it takes a long time for immunoassay detection platforms to technologically transfer, update and industrialize.
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In addition, POCT is the closest branch of traditional laboratory medicine to the Internet. POCT technology is capable of cross-border
integration, which makes the POCT much easier to implement in the
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Internet. Along with the exponential growth of artificial intelligence,
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sensor networks and the Internet of Things, the detection devices for immunoassays in the POCT will accommodate smart healthcare and mobile healthcare, with real-time detection, reliable data and remote
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monitoring and analysis.
Acknowledgments
and
Development
Program
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Research
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We are grateful for the financial support by the National Key of
China
(Grant
No.
2017FYA0205303), the National Natural Science Foundation of China (Grant Nos. 81571835, and 81672247), National Key Basic Research Program (973 Project) (No.2015CB931802), Shanghai Science and Technology Fund (No.15DZ2252000).
Conflicts of interest
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The authors declare no conflicts of interests.
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smartphone: The current state-of-the-art (2017–2018), Biosensors and Bioelectronics 132 (2019) 17-37. [134] S. Feng, R. Caire, B. Cortazar, M. Turan, A. Wong, A. Ozcan, Immunochromatographic diagnostic test analysis using Google Glass, ACS nano 8(3) (2014) 3069-3079. [135] O. Mudanyali, S. Dimitrov, U. Sikora, S. Padmanabhan, I. Navruz, A. Ozcan, Integrated rapid-diagnostic-test reader platform on a cellphone, Lab on a chip 12(15) (2012) 2678-86. [136] X. Li, F. Yang, J.X.H. Wong, H.Z. Yu, Integrated Smartphone-App-Chip System for On-Site Parts-Per-Billion-Level Colorimetric Quantitation of Aflatoxins, Analytical chemistry 89(17) (2017) 8908-8916. [137] I. Navruz, A.F. Coskun, J. Wong, S. Mohammad, D. Tseng, R. Nagi, S. Phillips, A. Ozcan, Smart-phone based computational microscopy using multi-frame contact imaging on a fiber-optic array, Lab on a chip 13(20) (2013) 4015-23. [138] Y. Hou, K. Wang, K. Xiao, W. Qin, W. Lu, W. Tao, D. Cui, Smartphone-Based Dual-Modality Imaging System for Quantitative Detection of Color or Fluorescent Lateral Flow Immunochromatographic Strips, Nanoscale research letters 12(1) (2017) 291. [139] S.A. Lee, C. Yang, A smartphone-based chip-scale microscope using ambient illumination, Lab on a chip 14(16) (2014) 3056-63. [140] W. Xiao, C. Huang, F. Xu, J. Yan, H. Bian, Q. Fu, K. Xie, L. Wang, Y. Tang, A simple and compact smartphone-based device for the quantitative readout of colloidal gold lateral flow immunoassay strips, Sensors and Actuators B: Chemical 266 (2018) 63-70. [141] Y. Zhao, M. Yang, Q. Fu, H. Ouyang, W. Wen, Y. Song, C. Zhu, Y. Lin, D. Du, A Nanozyme- and Ambient Light-Based Smartphone Platform for Simultaneous Detection of Dual Biomarkers from Exposure to Organophosphorus Pesticides, Analytical chemistry 90(12) (2018) 7391-7398. [142] A.I. Barbosa, P. Gehlot, K. Sidapra, A.D. Edwards, N.M. Reis, Portable smartphone quantitation of prostate specific antigen (PSA) in a fluoropolymer microfluidic device, Biosensors & bioelectronics 70 (2015) 5-14. [143] S.J. Yeo, K. Choi, B.T. Cuc, N.N. Hong, D.T. Bao, N.M. Ngoc, M.Q. Le, K. Hang Nle, N.C. Thach, S.K. Mallik, H.S. Kim, C.K. Chong, H.S. Choi, H.W. Sung, K. Yu, H. Park, Smartphone-Based Fluorescent Diagnostic System for Highly Pathogenic H5N1 Viruses, Theranostics 6(2) (2016) 231-42. [144] M. You, M. Lin, Y. Gong, S. Wang, A. Li, L. Ji, H. Zhao, K. Ling, T. Wen, Y. Huang, D. Gao, Q. Ma, T. Wang, A. Ma, X. Li, F. Xu, Household Fluorescent Lateral Flow Strip Platform for Sensitive and Quantitative Prognosis of Heart Failure Using Dual-Color Upconversion Nanoparticles, ACS Nano 11(6) (2017) 6261-62
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Captions Fig. 1 (A) The schematic of the assembled reader. Reproduced with permission from ref. [89]. Copyright 2004 Springer. (B) Photograph of
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the implemented test strip reader. Reproduced with permission from ref.
[90]. Copyright 2011 Institute of Electrical and Electronics Engineers.
(C) Schematic illustration of the developed UPT-based optical reader.
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Electrical and Electronics Engineers.
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Reproduced with permission from ref. [99]. Copyright 2009 Institute of
Fig. 2 (A) The detection instrument and the integrated CCD image sensor. Reproduced with permission from ref. [100]. Copyright 2014 Springer. (B) The photograph of Triage MeterPlus. Reproduced with
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permission from ref. [101]. Copyright 2002 Wolters Kluwer. (C) The ESE-Quant Lateral FlowReader with size of 15 × 20 × 5 cm3.
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Reproduced with permission from ref. [107]. Copyright 2018 QIAGEN. (D) Photograph and schematic illustration of the Deep-UV LED
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fluorescence platform. Reproduced with permission from ref. [110]. Copyright 2018 American Chemical Society. Fig. 3 (A) Schematic illustration of MAR detection mechanism and picture of real product of MAR. Reproduced with permission from ref. [111] Copyright 2018 Magna Biosciences LLC. (B) General view of the GMR system and its zooming detail. Reproduced with permission from
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ref. [120]. Copyright 2012 Elsevier. (C) General view of the TMR prototype. Reproduced with permission from ref. [121]. Copyright 2016 Molecular Diversity Preservation International. (D) Measurement
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configuration with two active sensors S1 and S2. Reproduced with permission from ref. [121]. Copyright 2016 Molecular Diversity Preservation International. (A)
The
handheld
computational
imaging
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Fig. 4
platform.
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Reproduced with permission from ref. [123]. Copyright 2014 Springer Nature. (B) The FluoVisualizer and visualization of test results. Reproduced with permission from ref. [124]. Copyright 2008 Society of Photo-Optical Instrumentation Engineers. (C) Overall view of
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portMD-113. It enables rapid and parallel detection of 113 fluorescent spots of a microarray in the POCT. Reproduced with permission from
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ref. [125]. Copyright 2013 Elsevier. (D) Schematic illustration of Handing. Reproduced with permission from ref. [126]. Copyright 2017
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Elsevier.
Fig. 5 (A) Magnetic handheld reader device and schematic illustration of the measuring head. Reproduced with permission from ref. [127]. Copyright 2015 American Society for Microbiology. (B) Schematic illustration of magnetic detection by MPQ reader. Reproduced with permission from ref. [130]. Copyright 2016 Elsevier. (C) Schematic illustration of multiplex assay setup. Reproduced with permission from
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ref. [131]. Copyright 2016 American Chemical Society. Fig. 6 (A) Views of smart reader prototype. Reproduced with permission from ref. [135]. Copyright 2012 Royal Society of Chemistry.
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(B) Front-profile view and structure of the Google Glass. Reproduced with permission from ref. [134]. Copyright 2014 American Chemical
Society. (C) The operation of chip imaging with the device. Reproduced
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with permission from ref. [136]. Copyright 2017 American Chemical
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Society. (D) Schematic illustration of the smartphone based AuNPs-LFIS reading system. Reproduced with permission from ref. [140]. Copyright 2018 Elsevier. (E) Smartphone-based ambient light sensors. Reproduced with permission from ref. [141]. Copyright 2018
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American Chemical Society.
Fig. 7 (A) Main components of MCFphone. (1) Microcapillary Film
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(MCF) (2) Smartphone (3) Magnifying lens (4) Blue LED (5) UV black light for fluorescence detection, light source for chromogenic detection
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(6) dichroic filter. Reproduced with permission from ref. [142]. Copyright
2015
Elsevier.
(B)
Schematic
description
of
a
smartphone-based fluorescence detector with a reflective light concentrator module. Reproduced with permission from ref. [143]. Copyright 2016 Ivyspring. (C) Back view of testing equipment and the main menu of the software. Reproduced with permission from ref. [138]. Copyright 2017 Springer. (D) Schematic illustration of household
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fluorescent LFTS platform. Reproduced with permission from ref. [144].
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Copyright 2017 American Chemical Society.
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Merits
Rapid, widely Colorimetric assay used, reliable performance,
Reader model Detection Operation Analysis mode time
Demerits
Test strip reader LFTS reader
< 5 min < 5 min
DT1030
< 5 min
Alere™ Reader
< 5 min
UPT Reader
< 5 min
Not portable, acquire, average accuracy
CCD-based system
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Benchtop apparatus
Deep-UV platform
More precise and sensitive, Magnetic signal detect entire detection magnetic signals
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or
Luminescent detection
Not portable, need specific Triage MeterPlus 15-20 min High accuracy excitation source, high and sensitive, auto-fluorescence widely used background, complicate ESE-Quant ~15 min operation
Not portable, need ultrasensitive magnetic sensor, vulnerable to external magnetic interference, costly
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Normal
5-8 min
5-10 min
Cost
Analytes
LOD
Medium Semiquantitative Medium Medium Semiquantitative Medium
HBV 1.25 ng/mL Cocaine 1 ng/mL IgG 0.1 ng/mL Medium Semiquantitative Medium DNA 3.75 fM IgG 10 ng/mL Streptococcus pneumoniae, Medium Semiquantitative High / Influenza A, Respiratory syncytial virus
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Category
Summary of various detection platforms of POCT
Medium Semiquantitative Medium Yersinia pestis F1 antigen
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Table 1
20 pg/mL
[100]
/
[101-106]
Parathyroid hormone-like hormone DNA
1.42 ng/mL
[108]
0.4 fM
[109]
BSA
100 nM
[110]
Medium
Quantitative
Medium B-type natriuretic peptide, cTnI
Medium
Quantitative
Medium
Complicated Quantitative
Medium
MAR
15 min
MIR
< 15min
GMR
10 min
Complicated Quantitative
High
TMR
10 min
Complicated Quantitative
High
Medium
Quantitative
High
Medium
[95-98] [99]
Quantitative
Quantitative
[89] [90] [91] [92] [93]
5 ng/mL
Medium
Medium
High
Ref.
CagA
HCG / Parvalbumin 0.046 µg/mL Listeria monocytogenes 104 CFU/mL Bacillus anthracis spores 6×104 spores/g milk powder 30 pg/ml HIV HCG 0.014 mIU/mL cTnI 0.0089 ng/mL CKMB 0.063 ng/mL Myo 0.05 ng/mL Troponin I 0.01 ng/mL HCG 0.05 mIU/ml HCG 25 mIU/mL
[112] [113] [114] [115] [116] [117] [118] [119] [120] [121]
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Detection methods
Merits
Demerits
Reader model
Portable and Average accuracy, Colorimetric convenient, easy limited by battery life assay to manipulate, and storage cost effectively
Glucometer Handheld plasmonic biosensor
< 8 min
Medium Semiquantitative Medium
<2 min
Simple
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FluoVisualizer Need specific High accuracy, excitation source, high Luminescent sensitive, easy to auto-fluorescence portMD-113 detection manipulate, cost Portable background, effectively and complicate operation Handing handheld devices handheld Portable and Need ultrasensitive magnetic reader convenient, Magnetic magnetic sensor, More precise and signal more vulnerable to sensitive, detection external magnetic detectable entire MPQ reader interference magnetic signals
Detection Operation Analysis mode Cost time < 3 min Simple Semiquantitative Medium
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Category
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Table 1 (continued) LOD
Ref.
Glucose
/
[122]
Protein monolayers
down to ng/mL range
[123]
/
[124]
Qualitative
Low
/
< 3 min
Medium
Quantitative
Medium
IgG
tenfold higher [125]
5 min
Medium
Quantitative
Medium
CEA
0.049 ng/mL
[126]
15 min
Medium
Quantitative
Medium
Grapevine fanleaf virus
0.5 ng/ml
[127]
0.33 ng 25 pg/ml 0.20 ng/mL 0.12 ng/mL 0.35 ng/mL
[129] [130]
High
Magnetic NPs PSA BoNT-A BoNT-B BoNT-E
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Analytes
15 min
Medium
Quantitative
[131]
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Merits
Demerits
Detection methods
Reader model
smartphone-base d reader <5 min platform
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Luminescent detection
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Colorimetric assay smartphone-base d reader <5 min platform
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Intelligent detection devices
Rapid, intelligent Complicated operation system, component, average expandable accuracy, need capability, cost external accessory, effectively, no non-universal need for external accessory, limited by power supply battery life
<5 min
Simple
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Google Glass-based reader platform
Detection Operation Analysis mode time
Cost
Semiquantitative Medium
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Category
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Table 1 (continued)
Simple
Simple
Semiquantitative
Quantitative
Low
Low
Analysts
LOD
HIV
/
PSA
Down to ng/mL
Malaria, Tuberculosis, HIV
/
AFB1 3±1 ppb 0.16 ng/mL Cd2+ 0.046 ng/mL Clenbuterol Porcine epidemic 0.055 µg/mL diarrhea virus Butylcholinesterase 0.028 nM PSA H5N1 HCG CEA ST2 BNP
0.08 ng/mL NM 2.3 mIU/mL 0.037 ng/mL 1 ng/mL 5 pg/mL
Ref.
[134]
[135] [136] [140]
[141] [142] [143] [138] [144]
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The progress of the POCT detection equipment is discussed from three detection mechanisms: white light, fluorescence and magnetism Further, instruments of each mechanism are discussed in the review
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by different degree of integration and advance Along with Internet technology and artificial intelligence, future advances and challenges of detection platforms in the POCT is
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proposed
S0039-9140(19)30443-6
DOI:
https://doi.org/10.1016/j.talanta.2019.04.054
Reference:
TAL 19853
To appear in:
Talanta
Received Date: 14 January 2019 Revised Date:
3 April 2019
Accepted Date: 20 April 2019
Please cite this article as: J. Yang, K. Wang, H. Xu, W. Yan, Q. Jin, D. Cui, Detection platforms for pointof-care testing based on colorimetric, luminescent and magnetic assays: A review, Talanta (2019), doi: https://doi.org/10.1016/j.talanta.2019.04.054. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Detection platforms for point-of-care testing based on colorimetric, luminescent and magnetic assays: A review
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Jinchuan Yang1, Kan Wang1*, Hao Xu2, Wenqiang Yan1, Qinghui Jin3,4 and Daxiang Cui1 *Correspondence: [email protected] 1
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Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai Engineering Research Center for Intelligent diagnosis and treatment instrument, Key Laboratory of Thin Film and Microfabrication (Ministry of Education), Shanghai 200240, China. 2
School of Naval Architecture, Ocean & Civil Engineering, Shanghai Jiao Tong University, Shanghai 200240, China. 3
4
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State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050, P. R. China
Faculty of Electrical Engineering and Computer Science, Ningbo University, Ningbo 315211, P. R. China
Jinchuan Yang, [email protected]
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Co-authors Email:
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Kan Wang, [email protected] Hao Xu, [email protected]
Wenqiang Yang, [email protected] Qinghui Jin, [email protected] Daxiang Cui, [email protected]
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Abstract
Along with the considerable potential and increasing demand of the
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point-of-care testing (POCT), corresponding detection platforms have attracted great interest in both academic and practical fields. The first few generations of conventional detection devices tend to be costly,
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complicated to operate and hard to move on account of early limitations in the level of technological development and relatively high
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requirement of performance. Owing to the requirements for rapidity, simplicity, accuracy and cost controlling in the POCT, reader systems are urgently needed to be developed, upgraded and modified constantly,
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realizing on-site testing and healthcare management without a specific place or cumbersome operation. Accordingly, numerous rapid detection platforms with diverse size and performance have emerged such as
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bench-top apparatuses, handheld devices and intelligent detection
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devices. This review discusses various devices developed mainly for the detection of lateral flow test strips (LFTSs) or microfluidic strips in the POCT and summarizes these devices by size and portability. Furthermore, on the basis of various detection methods and diverse probes usually containing specific nanoparticles composites, three most common aspects of detection rationale in the POCT are selected to elaborate each kind of detection platforms in this paper: colorimetric
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assay, luminescent detection and magnetic signal detection. Herein, we focus on their structures, detection mechanisms and assay results, accompany with discussions and comments on the performances, costs
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and potential application, as well as advantages and limitations of each technique. In addition, perspectives on the future advances of detection platforms and some conclusions are proposed.
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Keywords: Point-of-care testing (POCT); Nanoparticles; Detection
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platforms; Colorimetric; Luminescent; Magnetic
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1. Introduction The point-of-care testing (POCT) is an in vitro detection method that is able to obtain detection results instantly at the sampling site by
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utilizing rapid and convenient analytical instruments as well as
supporting reagents. By collecting and analyzing samples such as whole blood, serum, urine, saliva, viruses, bacteria and other proteins, the
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POCT is capable of performing healthcare, disease management,
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therapy assistance and food safety monitoring in a hospital, clinic, doctor’s office or at home [1-11]. Up to now, this technology can be applied in different areas for various testing purposes, such as food safety (detection of food allergen [12], Listeria monocytogenes [13] and
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nitrite [14]), disease diagnostics (determination of pathogen [15], breast cancer biomarkers [16] and Giardia lamblia cysts [17]), environmental
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monitoring (wastewater treatment [18], Vibrio fischeri assay [19] and K+ quantification [20]), clinical guidance (measurement of non-vitamin
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K antagonist oral anticoagulants [21], therapeutic drugs[22] and addictive drugs [23]). In the studies of POCT technology, lateral flow test strips (LFTSs) [24-36] and microfluidic chips [37-48] are widely used as carriers for the reaction, and for characterization and detection of samples. The first application of the strip assay was the pregnancy test which detected human chorionic gonadotropin (HCG) level [49]. Benefiting from the utilization of a membrane strip as the
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immunosorbent, the macroscopic detection results allowed the analytical platform to perform one-step, rapid and low-cost analysis [50].
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In order to improve the sensitivity and specificity of detection, researchers have investigated a variety of materials serving as immunoprobes [51], where colloidal gold is widely used in the
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colorimetric assay, the most common method. The source of colorimetric
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signals is basically derived from colored immunoreaction labels such as colloidal gold nanoparticles (NPs) [52-56], carbon NPs [57-61], and colloidal selenium NPs [62-65]. The preparation process of such colored NPs has been relatively mature, which provides great convenience for detection.
Besides,
with
the
development
of
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immunolabeling
nanotechnology, luminescent NPs have also been widely utilized in the POCT due to their optical stability and applicability in immunoassays,
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and include quantum dots (QDs) [66-69], dye-doped NPs [70-73] and
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up-converting NPs [74-77]. Fluorescent immunolabeling technology based on fluorescent nanoparticles has made great progress due to its robust photo-stability and high specificity. In addition, magnetic NPs especially superparamagnetic NPs, due to their unique magnetic properties, have also been applied in the POCT [78-81]. In particular, advances in magnetic activated cell sorting (MACS) and microfluidics have led to a successful combination of immunology, cytobiology and
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magnetomechanics. Early research on LFTSs and microfluidic chips using the naked eye only obtained qualitative information in terms of negative or positive
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results. Although qualitative or semi-quantitative detection was performed rapidly and conveniently, accurate values of analyte concentrations and reliable detection results are of great significance in
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the application of the POCT [82]. Accordingly, corresponding diagnostic
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platforms are required for the quantitative detection of analytes of interest in LFTSs or microfluidic chips. These detection systems usually need to meet the following requirements: (a) rapid test process, (b) high accuracy and sensitivity, (c) simple to operate, (d) steady working conditions, and
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(e) automatic analysis and data transmission. Hence, a number of analysis platforms with different measurement mechanisms were developed.
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On the basis of the foregoing, there are far more methods applied in the POCT. For example, electrochemical methods are generally applied in
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various detection devices [83-85], where impedance detection is an effective means for rapid detection [86-88], even considering portability and instrument limitations in the POCT. This paper discusses the progress and work on detection platforms in the POCT over the past few years. We focus on three common types of detection methods colorimetric assay, luminescent detection and magnetic signal detection
for study and
evaluation in detail through discussing and reviewing various devices
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developed for the detection of LFTSs or microfluidic strips. These devices are categorized into three types according to their size and operational complexity: normal or bench-top apparatuses, portable or
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handheld devices, and intelligent detection platforms. Based on different rationales of detection, each size category consists of colorimetric detection, fluorescence intensity assay or magnetic signal measurement. A
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summary of the various detection platforms of the POCT is shown in
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Table 1. 2. Normal or bench-top apparatuses
Normal and commercial bulky apparatuses have been developed and updated for generations through numerous applications and user
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feedback. They are able to achieve high accuracy, desirable sensitivity and reliable results, consequently tend to be standard equipment for
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various detection. On the other hand, in order to obtain effects that were more ideal or to adapt particular contents of a study, custom-developed
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instruments appeared to analyze LFTSs or microfluidic chips. Various apparatuses, both purchased from commercial companies and self-developed by research personnel are discussed below. 2.1.
Colorimetric assay
In numerous studies, the color density information of the test or control lines on the immunochromatographic strips and colorimetric
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signals of the micro-channels in the microfluidic chips is represented by an optical density value or color intensity. Generally, an instrument detecting color signals contains a robust image sensor such as a
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complementary metal oxide semiconductor (CMOS) camera or charge-coupled device (CCD) to capture the images of samples on
LFTSs or microfluidic chips. The established reader software is able to
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identify the accurate position of the test line, control line or
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microchannel, minimize the background noise and calculate image parameters such as gray value, peak value, area integral and line distance. Therefore, the concentration of analyte is calculated and the quantification of samples achieved. In addition, the strip holder of the
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reader can be adjusted according to different dipsticks and cassettes. Generally, light source together with image sensors such as CMOS or CCD is strongly required in the colorimetric assays. For the
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quantification of colorimetric signals of samples on LFTSs, Kim et al.
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developed a test strip reader for the immunochromatographic assay [89]. A schematic of the reader is illustrated in Fig. 1A. A custom-designed optical head and a linear movement mechanism of a standard CD (compact-disk)-ROM (read-only memory) deck were used in assembly of the reader. The optical head contained a light-emitting diode (LED), photodiode and anodized aluminum. A stepping motor was driven by the CD-ROM deck at the full step mode. The reader performance was
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demonstrated by the detection of hepatitis B virus (HBV), with a detection limit of 1.25 ng/mL. Based on an embedded Linux operation system, another LFTS reader (Fig. 1B) was designed by Mei et al. [90].
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A green LED served as the light source and a high-resolution CMOS sensor was used to capture LFTS images. A touch screen on the panel
was included to realize the display function and user control
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simultaneously. A thermal printer was assembled to print detection
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reports. By measuring the concentration of cocaine fluid, the reader achieved an accuracy of 1 ng/mL. In addition, the instrument was able to detect various types of LFTSs.
In order to control the time consumption of researches and obtain
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results fast and accurately, a great deal of research groups turn to commercial apparatuses for testing and characterizing. Yang et al.
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utilized the test strip reader, DT1030 [91] purchased from Shanghai Kinbio Tech Co., Ltd.. DT1030 uses a CMOS sensor as the imaging
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component and a USB interface to transmit data to the PC to compute the gray value of the control and test lines, thereby realizing quantification of the detection results. The system was established to realize the quantitative immunoassay of immunoglobulin G (IgG). Sandwich-type LFTSs were prepared based on gold nanocages (GNCs). Combined with the GNC-based LFTS, the reader completed the assay within 15 min. It was demonstrated that the linear detection range of
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IgG concentration ranged from 0.5 to 50 ng/mL, and the limit of detection (LOD) was 0.1 ng/mL. DT1030 was widely used to detect analytes labeled by colored markers. For example, Mao et al. proposed
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a nucleic acid biosensor based on a LFTS to detect deoxyribonucleic acid (DNA) in plasma [92]. Blue dye-doped latex beads were selected
as the colored label. In association with the strip reader DT1030,
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synthesized DNA detection had a linear range from 0.25 to 50 nM of
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DNA, and a detection limit of 3.75 fM in 50 mL human plasma. In another example, Huang et al. utilized DT1030 to record colorimetric signals of the LFTS [93]. Combined with magnetized carbon nanotubes as labels, the protocol was able to realize the visual detection of proteins
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in whole blood without pretreatment of samples. As a result, the detection limit was 10 ng/mL of proteins and the linear range was 10 to
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200 ng/mL of proteins.
Besides the extensive application of DT1030, a number of
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commercial bench-top detection instruments for the POCT have also emerged. The Alere™ Reader manufactured by Abbott (Chicago, USA) is a typical lateral flow test reader [94]. The reader consists of a built-in camera to capture the strips, a barcode scanner to record the information on the strips, a color touch screen for manipulation, and a standard strip for calibration. The Alere™ Reader can be used in laboratories for research and in the POCT. Combined with specific testing cards, the
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Alere™ Reader was able to detect various diseases such as Legionella pneumophila antigen [95], Streptococcus pneumoniae antigen [95], influenza A and B nucleoprotein antigens [96], respiratory syncytial
The above-mentioned examples
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virus [97] and Streptococcus pyogenes Group A antigen [98]. while not limited as these are
typical bench-top equipment for practical colorimetric assay in the
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POCT. With regard to the normal or bench-top apparatuses, the bulky
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size and complicated operation may prevent their popularity, while their excellent detection performance has promoted their popularity in immunoassays by professional personnel. Luminescent detection
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2.2.
Along with the increasing requirement in detection and the improvement of testing approaches, numerous assays in the POCT
determine
fluorescent
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To
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based on luminescent detection especially fluorescence have emerged.
immunoreaction,
plenty
of
intensity
in
bench-top
the
biochemistry
devices
are
and
developed.
Fluorescence and color detection differ in their requirement for an excitation light source, conversion of the fluorescent density into optical density and recording the optical density signals. The excitation light source at certain wavelengths (usually ultraviolet (UV) rays) enables the invisible fluorescent substance to emit light with a longer wavelength,
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which is in the visible light band, rather than incident light. Instruments are able to detect the optical intensity of fluorescence and analyze the image information, similar to the aforementioned method for color
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signals. Luminescent detection is performed to capture the fluorescent signal from luminescent NPs, as aforementioned in the Introduction part before, such as QDs, dye-doped NPs and up-converting NPs etc.
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For instance, Huang et al. developed an optical reader to capture
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upconverting phosphor particles on LFTSs [99]. The reader protocol was based on upconverting phosphor technology (UPT). Fig. 1C shows a schematic of the reader. The excitation source was a 980 nm laser and was focused on a spot on the LFTSs. The slit can prevent stray light
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from the photomultiplier tube. This detection system was used to measure Yersinia pestis F1 antigen at various concentrations, with a
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sensitivity of 5 ng/mL and dynamic range of 150 ng/mL. For the quantitative measurement of fluorescence intensity from
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QDs on the LFTS, Gui et al. developed a CCD-based reader to detect the concentration of cytotoxin-associated protein (CagA), a typical biomarker of gastric carcinoma [100]. A CCD image sensor (29 × 29 × 29 mm3) and arrays of UV LEDs as the excitation source with a wavelength of 365 nm were assembled inside the integrated reader. The image information on the test strips was captured by the CCD sensor and transmitted to a laptop for analysis and processing using customized
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software. Fig. 2A shows the CCD image sensor and the integrated reader as well as the matched laptop. In this research, an image-processing
algorithm
of
weighted
threshold
histogram
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equalization (WTHE) was used as the core method for data analysis. It was demonstrated that this device was ultrasensitive with a detection limit of 20 pg/mL for CagA detection.
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Not limited to self-built instruments, commercial equipment is also
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widely utilized for fluorescent assays in the POCT. A fluorescent microfluidic chip reader known as Triage MeterPlus (Fig. 2B) has been reported [101]. A silicon photodiode inside the device serves as the detector to measure emission light at a wavelength of 760 nm. The
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standard curve and detection principle of fluorescence, which were stored in the memory unit and the built-in signal processing unit,
EP
respectively, converted fluorescent intensity into electrical signals and then transformed them into sample concentrations. Triage MeterPlus
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was able to identify the microfluidic test strips by reading barcodes printed on the strip case. Furthermore, each diagnostic result was displayed on a liquid crystal display (LCD) screen. The results were printed by a built-in printer, and automatically transmitted to the health care information system. During manipulation of the assay, operating personnel, according to their different requirements, can autonomously change the detection parameters such as the cut-off value, user or
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patient identification and times of repetition. The Triage MeterPlus device due to its robust performance is widely used in the POCT for the detection of various analytes, such as B-type natriuretic peptide
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[102-105] and cardiac troponin I (cTnI) [106]. Another example of a commercial desktop reader is ESE-Quant (Fig. 2C) [107] manufactured by ESEGmbH of Stockach, Germany. This
SC
cost-efficient device contains a simple LED as the light source, a
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miniaturized optoelectronic core and a digital processing unit. With this device, 1,500 data points are acquired per second and one scan only takes several seconds. During detection, the reader automatically identifies the peak value of the control line and up to 16 test lines and
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stores the data in the internal memory. The results are displayed on the screen. As an example of its application, Chamorro-Garcia et al. utilized
EP
the ESE-Quant to quantitatively detect parathyroid hormone-like hormone in cancer cell cultures [108]. In addition, combined with the
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reader, Takalkar et al. detected DNA using a fluorescent carbon NP-based LFTS by measuring the fluorescent intensities of the test zone and control zone [109]. A detection limit of 0.4 fM DNA was achieved. In order to decrease or even eliminate the time spent on the reaction between analytes and labels, Challa et al. developed an intrinsic fluorescence visualization platform to excite and detect the unlabeled protein
molecules
and
protein
complexes
flowing
in
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polydimethylsiloxane (PDMS) channels of the microfluidic chips [110]. A photograph and schematic of the system are shown in Fig. 2D. Ultraviolet excitation light generated by a LED at a wavelength of 280
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nm was transmitted through a series of optical components and finally focused on the microfluidic chip to excite the analytes. Accordingly, the
fluorescence from analytes was collected by an electron multiplying
SC
charge-coupled device (EMCCD) camera through a specific optical path.
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Black carbon NPs were applied before measurement to eliminate the background interference due to autofluorescence from other materials under the 280 nm excitation light. Combined with diffusional sizing on a micron-scale, this apparatus was able to detect the hydrodynamic
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radius of each single protein and the complexes, respectively. On the basis of these representative examples, by detecting
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fluorescent signals from the immunoprobes, quantitative detection results with higher sensitivity and lower detection limits can be obtained
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compared with colorimetric assays. 2.3.
Magnetic signal detection
Conventional optical detection methods may be biased due to the
uneven distribution of NPs and the unstable performance of image sensors. Compared with colored NPs and fluorescent markers, which only detect reflected light or fluorescence within the two-dimensional
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top layer of the capture regions, magnetic NPs are able to represent the entire volume magnetic signal in the test areas. Furthermore, magnetic LFTSs show low magnetic background signals of analytes.
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In general, a specific sensing component is required to realize the detection of magnetic signals. One of the quantitative methods used is
the detection of the magnetic flux generated by magnetic NPs on the
SC
LFTSs and microfluidic chips. As an example, the MAR Assay
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Development System (magnetic assay reader, MAR) [111], which was developed and sold by Magna Biosciences LLC (CA, USA), is widely utilized to quantify magnetic NPs labeled samples such as HCG [112], parvalbumin [113], Listeria monocytogenes [114], Bacillus anthracis
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spores [115] and human immunodeficiency virus (HIV) type 1 p24 antigen [116]. The MAR and a schematic illustration of the detection mechanism are shown in Fig. 3A. A C-shaped electromagnet inside the
EP
MAR generates a magnetic field to excite superparamagnetic NPs. In
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addition, a set of thin film induction coils serve as measurement units for magnetic measurement. The intensity of the measured magnetic signal is proportional to the amount of accumulated magnetic NPs on the test strip and is represented by relative magnetic units (RMU). The improvements in hardware would reach a chock point on the detection performance, which might be effectively addressed by some advanced data processing algorithms. For example, Yan et al. [117]
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presented a machine learning-based magnetic biosensing system named MIR to improve the performance of magnetic immunoassays on LFTSs. The protocol managed to demonstrate the excellent sensitivity by the
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LOD of HCG down to 0.014 mIU/mL. Also, Hong et al. [118] utilized the same magnetic reader platform to simultaneously quantify multiplex cardiac markers including cTnI, creatine kinase isoenzyme MB
SC
(CKMB), and myoglobin (Myo), with the detection limit of 0.0089
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ng/mL, 0.063 ng/mL, and 0.05 ng/mL respectively.
Besides the reader model of MAR and MIR, another detection strategy is to measure magnetization saturation generated by magnetic NPs through magnetic sensors. Of the research articles on magnetic
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biosensor technology for lateral flow immunoassay, the giant magnetoresistance (GMR) sensing method has been widely used in the
EP
quantification of analytes labeled by magnetic NPs. For example, Ryu et al. detected the cardiac marker troponin I using a GMR sensor, with a
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sensitivity of 0.01 ng/mL [119]. Furthermore, Marquina et al. presented a general method for monitoring the magnetoresistive response generated from a spin valve GMR sensor which was placed close to the magnetic NPs on the test strip [120]. The measurement equipment used is shown in Fig. 3B. The GMR sensor measured 9 × 9 mm2, and the outer diameter of the circumjacent Helmholtz coils used to provide the magnetic field for polarization of the spin valve, was 150 mm. The
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lateral flow assay test strip, after the immune reaction, was placed on a plastic wheel that enabled switchable situations: either to maintain a soft contact between the sensor and strip or to allow a 2 mm distance from
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the magnetoresistive sensor in the vertical orientation (z direction). The test line on the strip was moved by a step motor in 1 mm steps on the
tangential orientation of the wheel (x direction). The voltage or
SC
magnetoresistance output signal was generated when the test line
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coincided with the sensor. Furthermore, the stray magnetic field of NPs validated the different sensor resistances in the switchable situations. Meaningful signals produced in the distance interval of 1.5 mm approximately corresponded to the width of the test line. The
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measurement results were obtained within 5 min. In addition, Serrate et al. utilized the GMR protocol to quantitatively detect HCG using highly
EP
sensitive magnetic LFTSs [78].
Another example of magnetic measurement was based on tunneling
AC C
magnetoresistance (TMR) sensing. Lei et al. developed a contactless sensing system to quantitatively detect magnetic NPs bound on the LFTSs [121]. Fig. 3C shows a photograph of the prototype. A C-shaped magnetic core, which contains a cross-section of 16 × 16 mm2 as well as a gap of 8 mm, was applied by a direct current. Two parallel and adjacent TMR components (TMR2705) were added to form a differential structure in the gap region where a perpendicular magnetic
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field (approximately 300Oe) existed generated by the C-shaped magnetic core. This differential structure was sensitive to variation in the stray magnetic field due to magnetic NPs in the x direction. During
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detection, as depicted in Fig. 3D, the LFTS was moved in the x direction by a sliding rail and the TMR sensors then transformed the changes in magnetic signals into voltage information. Combined with
SC
the detection of HCG, the device showed a LOD of 25 mIU/mL and the
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ability to measure a stray magnetic field of 0.247 mOe from the test line of the LFTS, which was invisible to the naked eye.
Of the above-mentioned detection devices, MAR is not able to detect positioning and required manual correction of position. In the
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GMR method, the structure of the test strips may be damaged when placed on the detection wheel. Therefore, this method does meet the
EP
requirements for clinical use. The TMR sensor is bulky and the distance between the two side-by-side sensor chips is about 1 cm; thus, it was
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not capable of detecting multiple test lines simultaneously. In addition, electromagnetic interference from the external environment should be taken into account, which is also a bottleneck restricting the miniaturization of magnetic detection equipment. Overviewing the normal or bench-top apparatuses for colorimetric and luminescent detection, large but accurate image sensing element such as CCD is usually selected to obtain results with more reliability.
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Similar to desktop magnetic detection equipment, larger or even more groups of magnetic sensing components are also preferable to complete the measurement of magnetic signals with high accuracy. Such a setup
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will certainly increase the manufacturing cost of bench-top devices, energy consumption and professional resource devotion. Although this
type of instrument with high stability and repeatability has undergone
SC
numerous technological innovations and modifications, portability and
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flexibility of testing equipment are significant factors to meet the requirements of the POCT, especially in the community clinics, mobile testing, and other fields’ detection. Therefore, analytical devices that are accurate, compact in size and easy to operate come into being in the
examples.
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POCT. Handheld portable detection devices are excellent and competent
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3. Portable and handheld devices
With the development of medical care, clinical diagnostics have
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gradually evolved from large hospitals to community clinics, family doctors and rapid on-site detection. Therefore, the demand for portable detection devices has increased. Compared to bulky and bench-top devices, handheld and portable analysis instruments are more integrated, easy-to-handle and time-saving, without considerable loss of accuracy and sensitivity. Generally, the handheld devices contain integrated sensors and a signal transmission unit. The detection results are stored
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in the memory, or wirelessly transmitted and uploaded to central servers or other terminals via Bluetooth, Wireless Local Area Networks (WLAN) and mobile communication. The above characteristics enable
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these devices to perform rapid, accurate and on-site analysis of LFTSs and microfluidic chips. Colorimetric assay
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3.1.
Handheld devices for colorimetric assays due to their portability and
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uncomplicated operation are somewhat more promising than bench-top apparatus. One of the examples is the widespread application of glucose monitoring. For instance, an early glucometer [122] introduced by Johnson & Johnson is a low-cost and advanced blood glucose analyzer
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that provides rapid, precise, convincing and professional results in real time. There is a matched test strip containing glucose oxidase which
EP
reacts with glucose in blood to cause changes in color. After the time, the blood drop on the strip (1.4 µL usually) was wiped off and then
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placed in the glucometer to obtain the blood glucose level by measuring the chromatogram. The detection results can be displayed after 15 seconds. Although measuring more rapidly and requiring less blood sample compared to biochemical analyzers, glucometers that rely solely on color analysis have been basically eliminated in the market with the introduction of photochemical, electrochemical and chemiluminescent techniques.
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Combining with optoelectronic technology, Cetin and Coskun et al. [123] proposed a handheld on-chip sensing platform (Fig. 4A) realizing computational imaging by an optoelectronic sensor array and a CMOS
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imager chip without any lens. An LED, a battery, a plasmonic chip and a CMOS imager are integrated in the light-weight device. The sensing
platform is capable of detecting protein monolayers with label-free
SC
condition and quantitatively analyzing the binding of protein in various
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biomolecule concentration. Furthermore, an image reconstruction method allows the platform much adaptive in diagnostics in the POCT. In the respect of handheld detection platforms for the POCT, colorimetric or chemical colorimetry seems a good start. And this kind
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of devices draw numerous attention in the market due to the principle and simple operation. Nevertheless, with the growth of detection
EP
requirements and constant exploration of other detection methods, colorimetric detection has been unable to meet the increasing
AC C
requirements and has been gradually overrode by other methods such as electrochemistry, chemiluminescence, bioluminescence and magnetic detection. Additionally, multiple detection might be more excellent than singly colorimetric detection. 3.2.
Luminescent detection
Similar to colorimetric testing, luminescent detection carrying on
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handheld devices requires image component with high performance, small size and high precision. The external natural light or white light generated from the device is usually used for colorimetric detection to
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illuminate the region of interest (ROI), while fluorescence detection requires an excitation light source with a specific wavelength when
analyzing the intensity of fluorescence, which is a crucial feature in
Moreover, handheld devices for luminescent
SC
handheld devices.
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detection have many benefits in relation to accuracy compared to bench-top apparatuses. For example, the FluoVisualizer (Fig. 4B) is a handheld, pocket-size device for lateral flow immunoassays [124]. The device contains an illumination source and a filter. Users can view the
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test results directly by the naked eye. Due to no electronic recording of data and simplicity of design and fluorescent detection, the visualizer is cost-effective and is capable of multiplex detection. During operation,
EP
users insert the strip, turn on the excitation source and can then view the
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luminescent control and test lines. Unfortunately, the FluoVisualizer can only be used for qualitative detection instead of quantitative detection. In order to obtain quantitative results under the POCT condition, a
handheld fluorescent reader named portMD-113 [125] was developed, which achieved comparable LOD against a commercial modern benchtop laser scanner, with agreement of R2 = 0.995. Fig. 4C depicts the overall view of portMD-113. The device is made up from several
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cost-effective, handy and small components. Inside the detection platform, biological sample is spotted onto a cyclic olefin copolymer film waveguide in a grid pattern. A laser diode (λ = 635 nm) together
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with a collimator and a prism generates laser to irradiate the waveguide edge. Through a built-in CCD chip, test results are captured for evaluation by a designed algorithm in MATLAB. The portMD-113
SC
device completes measurement within 20 second and allows physicians
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detecting out of hospitals and laboratories, which meets the needs of the POCT.
A recent study by Qin et al. demonstrated a handheld diagnostic system named Handing [126], to rapidly quantify the QDs-labeled
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tumor marker CEA on lateral flow immunoassay strips (Fig. 4D). Combined with a customized data server, the detection terminal based on embedded technology can realize the following series of functions:
EP
fix test strips, form a closed detection environment, generate UV light
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for fluorescent excitation, manipulate the touch screen, obtain and process images, store data and query results. The detection of clinical samples demonstrated that the platform showed excellent performance with a detection limit of 0.049 ng/mL and an analysis range of 1–100 ng/mL, and the total time for each procedure including sampling, analysis and obtaining the results was no more than 15 min. Although the aforementioned handheld devices can perform
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stand-alone detection and data storage, the test results for most devices still need to be uploaded to the host computer through various transmission methods to manage and share the data. Moreover, the
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limitation of a single excitation light source and cumbersome development of the embedded system, as well as the emergence of
handheld fluorescent detection equipment. Magnetic signal detection
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3.3.
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smartphone-based devices, may foster the slow development of
Attributed to the development of integrating physical sensing components such as magnetic induction coil and electromagnet, magnetic detection on miniaturized handheld devices is also an
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attractive task for researchers in the POCT, resulting the magnetic NPs-based immunoassay with high detection sensitivity more portable
EP
and flexible.
As shown in Fig. 5A, Rettcher et al. designed a handheld magnetic
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reader containing a touch screen and an integrated detection device measuring 10 × 23 × 7 cm [127]. A cluster of four coaxial coils were assembled in the detecting device, two for detection, one for driving with a frequency of 61 Hz and the other for excitation with a frequency of 49 kHz. Based on the magnetic immunoassay detection methodology of frequency mixing [128], the superparamagnetic particles functionally bound with virus in the sample solution are immersed in the mixed
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frequency magnetic field. The driving coil generates a strong low-frequency magnetic field, in which a positive and negative anode drive the magnetic beads at magnetic saturation status. The detection
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coils, containing two neighboring compartments with opposite rotation direction, weaken the direct induction generated by the excitation coil through their differential winding. Furthermore, subsequent steps
SC
include amplifying the voltage induced by the detection coils, and
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demodulation of the hybrid frequency through multiplication and low-pass filtering. The detection performance of the complete system ranges from 6 ng/mL to 20 fanleaf virus concentration.
g/mL for the detection of Grapevine
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In another example of a magnetic detection device, Shipunova et al. utilized a handheld magnetic particle quantification (MPQ) reader to achieve accurate quantification of the interactions between iron oxide
EP
NPs and eukaryotic cells [129]. The portable MPQ reader with
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dimensions of 18 × 10 × 4 cm performed measurements at room temperature and detection was at the sub-nanogram level. It was demonstrated that the MPQ device achieved a sensitivity limit of 0.33 ng of magnetic NPs. In addition, the quantification method associated with the MPQ reader did not require costly and sophisticated measurement apparatus or a professional operator and realized rapid diagnostics in field conditions within several seconds for each
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measurement. Combining
200
nm
magnetic
NPs
as
labels
and
immunochromatography technology, Orlov et al. further utilized the
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MPQ reader to quantify prostate specific antigen (PSA) in human serum [130]. In Fig. 5B, after the immune reaction, the LFTS was placed
across the measuring induction coil of the MPQ reader to read the
SC
quantity of magnetic NPs on the test line and control line. In the
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modified MPQ reader, the excitation magnetic fields were enhanced to 144Oe and 56Oe, respectively, for the low and high frequency components, which resulted in a wider dynamic detection range and high sensitivity and linearity. In this work, the measurement device
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showed a sensitivity limit of 60 zeptomoles of magnetic NPs in a 0.2 mL volume. In addition, the whole detection process registered
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magnetic NPs in a three-dimensional spatial domain rather than a layer plane, which reinforced the capture sensitivity for magnetic nanolabels.
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In order to improve the performance of the MPQ reader and to
fulfill multiplex measurements and assays, Orlov et al. incorporated three measurement inductive coils, which were all read by a single processing unit in the MPQ reader [131]. A schematic of this detection system is shown in Fig. 5C. The three inductive coils in parallel corresponded to the diverse positions of the test line of the three LFTSs, respectively. This particular structure enabled the system to
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simultaneously detect three types (A, B and E) of botulinum neurotoxin (BoNT). As previously mentioned, the magnetic quantification system detected entire magnetic signals of the capture region; thus, ensuring
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high detection accuracy. The developed multiplex biosensing system showed a LOD of 0.20, 0.12, and 0.35 ng/mL for BoNT-A, B, and E, respectively. The multiplex detection system exhibited the expected
SC
performance in the detection of orange and apple juice, and milk.
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Among the examples of magnetic signal detection in miniaturized devices, mini magnetic induction coils or multiple groups of coils are employed to monitor the intensity of magnetic field. Although the handheld devices might not be as excellent as commercial magnetic
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detection instruments and even might be interfered by external electromagnetic fields, they could also collect the weak magnetic
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signals from magnetic NPs. Compared with the colorimetric and fluorescent analysis, handheld magnetic detection could obtain results
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with favorable accuracy and high reliability. In general, electrochemistry and electrochemiluminescence are the
potential alternative for handheld instruments. It seems that handheld magnetic testing devices dominate in terms of innovation and novelty, while cost might increase. Furthermore, with the advent of intelligent devices (especially smart phone) and the rapid development of information technology, the advantages of handheld test terminal might
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be gradually overwhelmed by intelligent diagnostic devices and systems. Nonetheless, it does not mean that there is no worth on exploring handheld test equipment. In the detection of LFTSs or simple structure
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microfluidic chips, handheld detection equipment still exerts the handsome features and advantages of the POCT technology.
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4. Intelligent detection devices and platforms
Compared with most conventional bulky equipment, intelligent
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devices such as smartphones, smart wearable devices and other mobile devices are ideal processing tools in the POCT due to their portability, intelligent interaction, openness of the operating system, abundant sensors and wireless communication. Furthermore, the number of users
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of these intelligent devices has increased dramatically and will continue to do so, which will enable smart device-based biosensor systems to be
EP
robust tools for POCT applications. Notably, compared with other intelligent devices, smartphone drawn tremendous attention due to the
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advanced central processing unit, intuitive human-machine interaction, simplified
operation,
open-source
operating
system,
prevalent
availability and bountiful sensing components. Combined with specially designed and 3D-printed attachments that facilitate imaging and fixation of samples, smartphones are capable of achieving high resolution, sensitivity and specificity for the detection of lateral flow immunoassay strips, microfluidic chips or other sample carriers [132, 133].
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4.1.
Colorimetric assay
Among the studies on smart devices for colorimetric detection, it could be found that the most easily and widely used sensing element is
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the image sensor of smart devices. On the one hand, the device is able
to serve as a camera to merely capture the pictures of ROI and then
transmit it to a computer or other instrument for further analysis. On the
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other hand, the detailed information could be analyzed and processed by
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the central processing unit. Then, the results are displayed visually or sent to a destination via a specific communication protocol for a further analysis and consultation.
A typical example of an intelligent wearable device to realize the
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immunochromatographic diagnostic test was demonstrated by Feng et al. [134], who developed a Google Glass-based POCT platform (Fig.
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6B), that was able to qualitatively and quantitatively detect diverse lateral flow immunoassay strips. An assorted custom-designed
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application was written in Google Glass to successively identify the quick response (QR) code on the test strip, control the camera unit to capture images of the strip, transmit image information to a server for data processing and receive the results of quantification analysis. The central server was not only the core of image analysis and processing, but a repository for storing the QR code, strip images and location information on detection. The detection results and other relevant
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information can be accessed through an Internet browser. The performance was demonstrated by the qualitative detection of HIV and the quantitative detection of PSA. The hands-free and wearable
epidemics, mobile medical and telemedicine.
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detection system provides a promising diagnostic platform for
In addition to the detection through wearable smart devices, there are
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plenty of examples about colorimetric detection by smart phones. To
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realize rapid diagnostic tests through LFTSs on a cellphone, Mudanyali et al. developed a compact and cost-effective reader platform which was attached to a smartphone (Fig. 6A) [135]. Three arrays of LEDs were integrated in the attachment to illuminate the LFTS tray for reflection
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on the front side and for transmission on the posterior side. In association with a smartphone camera module and a customized smart
EP
application, the platform was capable of capturing and digitally processing raw images of LFTSs, displaying the diagnostic results,
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transmitting the data to a central server and marking the detection position on a world map. Users can browse the e-map on the Internet and the cellphone App. The protocol was successfully demonstrated both on Android-based smartphones and an iPhone using assays for malaria, tuberculosis and HIV, and showed the potential of this protocol in assisting professional healthcare personnel, and for epidemic tracking and preparedness.
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Moreover,
Li
et
al.
also
developed
an
integrated
smartphone-app-chip system to detect and quantify aflatoxin B1 (AFB1) [136], which is a food toxin found in moldy corn samples. The
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hardware device is illustrated in Fig. 6C. The optical attachment includes 16 white LEDs to provide ambient lighting, and a chip slot to
fix the microfluidic plastic assay strip. The microfluidic assay strip
SC
contains several channels for samples. In association with a
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custom-designed Android smartphone App known as AFB1DET to analyze the colorimetric signals of samples in the strip channels, the detection system achieved a LOD of 3±1 parts-per-billion(ppb). Besides the instances foregoing, numerous research papers have reported
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sensing systems in which smartphone camera was used as the imaging unit to capture samples information [136-138]. Companying with outer optical component, Lee and Yang et al. developed a smartphone-based
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chip-scale microscope without an external 3D-printed accessory [139],
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which also performed well with a resolution of 500 nm for imaging blood smears and aquatic microorganisms. Different from the conventional detection approches of image
sensors, more and more studies have constructed smartphone-based detection systems by using the ambient light sensor. This component practically senses the intensity of ambient light and then automatic adjust the brightness of the screen, which is usually located above the
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front panel of the smart phone. In order to improve the universality of external accessories attached to the smartphone, an ambient light sensor was used to capture the density of light rather than a camera [140]. A
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schematic of this system is shown in Fig. 6D. To detect the concentration of samples immobilized on the test line of lateral flow immunoassay strips, this platform utilizes the smartphone ambient light
SC
sensor to detect the transmission light density from the test line and
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establishes the relationship between the sample concentration and light density. The prototype showed a LOD of 0.16 ng/mL for cadmium ion (Cd2+), 0.046 ng/mL for clenbuterol and 0.055 epidemic diarrhea virus.
g/mL for porcine
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Similarly, Zhao et al. presented an ambient light-based smartphone detection platform (Fig. 6E) to determine enzymatic inhibition and
EP
phosphorylation [141]. Butylcholinesterase was used as the analyte. The smartphone ambient light sensor was used to measure colorimetric
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signals transmitted from transparent LFTSs. The detection platform showed excellent linear responses and a low detection limit of 0.028 nM.
To provide a closed and stable optical environment, external accessories are of necessity for smart devices. The external accessories not only need to fit the structure and appearance of the smart phones, but also adapt the analyte reaction carrier such as LFTSs and
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microfluidic chips. The external shell for ambient light assays present high universality for various kinds of smart phones, while with a lower accuracy compared to image detection. Conversely, even if the camera
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can achieve convincing results, the adaptation of accessories for the various camera position is a little powerless. It still requires researchers
to make trade-offs in the POCT research. Therefore, the design of the
SC
outer accessories takes smart phones into the maximum function, and it
phones. 4.2.
Fluorescence detection
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is also an unneglectable direction for developing POCT on smart
In comparison, the operating environment and conditions of
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fluorescence detection are more demanding than colorimetric testing. During colorimetric detection, the native lighting element of smart
EP
phones such as flash light is using to provide a light source for testing. However, fluorescence detection is performed on instruments with an
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excitation light source at specific wavelength, which puts higher demands on the external accessory. The enclosure not only offers a stable and closed light environment, but also provides several excitation sources with different specific wavelengths. A lot of research work has managed to do this. Barbosa et al. developed a fluorescent detection system using a smartphone-based detection system known as MCFphone that
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quantitatively detected PSA by colorimetric
and fluorescence
immunoassays [142]. The MCFphone (Fig. 7A) consisted of a smartphone with a magnifying lens, a light source, and a miniaturized
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immunoassay platform named Microcapillary Film (MCF). Due to its properties of transparency and flat geometry of the fluoropolymer MCF, the prototype was able to rapidly quantify PSA in whole blood samples.
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It was shown that the LOD was further improved from 0.4 to 0.08
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ng/mL in the fluorescent detection mode. The MCFphone exhibited excellent recovery, efficiency and high sensitivity, which contributed to the integration of portable microfluidic devices, commercial reagents and smartphone technology.
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Likewise, Yeo et al. has also proposed a fluorescent diagnostic system based on a smartphone to detect highly pathogenic H5N1 viruses [143]. As shown in Fig. 7B, an efficient reflective light
EP
collection module was integrated. During detection, the fluorescent
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lateral flow strip was fixed to the measurement module and excited by UV light through an excitation filter. Using an emission filter, the fluorescence emission from the strip was collected by the non-imaging reflector, and then captured by the camera. The detection results were transmitted by the smartphone through the short message service and collected in a database for further processing. As demonstrated in this work, the detectability of this system was two-fold higher than a
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bench-top fluorescent reader and was capable of identifying patients and controlling avian influenza infection. Some works have used one single external accessory to realize
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dual-modal imaging. Smartphone could detect color of LFTSs
quantitatively anywhere at any time. The white and ultraviolet light were carried out and could switch according to different strips. As an
SC
example of a smartphone-based imaging and detecting system, Hou et
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al. developed a dual-modality imaging system to quantitatively detect both coloration and fluorescent immunochromatographic strips for the detection of HCG and CEA [138]. As shown in Fig. 7C, the smartphone matched an external 3D-printed shell. Two UV LEDs were assembled in
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the closed shell to excite the fluorescent probe on the strip. The white light source was provided by the smartphone flash lamp. The
EP
custom-developed Android App selected the types of strips, chose the target diseases, saved and queried the detection results. The achieved
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LODs were 2.3 mIU/mL and 0.037 ng/mL for HCG and CEA respectively.
In another example, You et al. presented a household reader
platform based on a smartphone to quantitatively detect core−shell upconversion NPs, which specifically bound to heart failure antigens such as suppression of tumorigenicity 2 (ST2) and brain natriuretic peptide (BNP) [144]. A schematic of the platform is shown in Fig. 7D.
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The platform consisted of an assembled portable reader containing a power supply, a 980 nm NIR laser and a particular optical system. By using a nonslip mat on the top cover instead of a phone holder, the
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reader was able to adapt various smartphones and obtain consistent results. In addition, a custom-designed smartphone App was integrated with the platform to capture images of the LFTS test region, analyze the
SC
image information, and share the results with professional personnel via
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the Internet. It was demonstrated that the platform achieved a LOD of 1 ng/mL and 5 pg/mL for ST2 and BNP, respectively. The platform was confirmed to be reliable in relation to the prognosis of heart failure, and has potential for health care in the POCT.
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Considering examples discussed above, custom accessories play a crucial role in fluorescent detection. Despite of various structures and
EP
different detection targets, the accessories are assembled with an excitation source to achieve fluorescence detection. Researches based
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on intelligent devices for colorimetric and fluorescence testing have become increasingly mature, while there is a huge challenge to realize the detection of magnetic signals. In general, there are no integrated sensors in smart terminals capable of detecting magnetic signals, except for the geomagnetic sensor in smartphones, which only detects geomagnetism. In addition, sensing components, such as the sensors of MAR, GMR and TMR, used to
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detect near-field magnetism require a large amount of space. It is not necessary for smartphones to develop external accessories for the detection of magnetism. Therefore, there are no examples of intelligent
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detection devices for magnetic sensing. For common colorimetric and fluorescent detection, it is hardly possible to place a high precision and highly sensitive sensor such as
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CCD in a smart phone. It generally extends basing on existing sensing
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components in smart devices for the sake of costs. All of the studies in POCT via smart devices are moderate extensions on the original intelligent applications. Fortunately, there is a development route for smart phone in industry, i.e., modularizing the phones by each functions.
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According to this idea, selected functional modules could be customized according to various requirements in POCT and to be integrated into
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main body of smart terminal.
Majority of smart phone-based reader platforms realize functions
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through transforming and expanding on the basis of the existing types of devices. Conversely, if there was possibility to manufacture specialized smart devices for the POCT, the cost of development would be greatly reduced while the performance of detection would be enhanced dramatically. This might be a decent direction for POCT to implement detection in intelligent technology and smart devices.
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5. Conclusions and outlook The application and development of various detection platforms for
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the POCT, and their compositions, structures, analysis mechanisms,
sensing modalities and performances, were discussed in this review in
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terms of three detection methods: colorimetric assay, luminescent
detection and magnetic signal detection. These platforms enabled the
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transition from qualitative analysis, semi-quantification to quantitative detection in the POCT field, and consequently promoted the study and development of the POCT. Furthermore, whether manufactured commercially or self-developed by research groups, these platforms
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were demonstrated to show desirable performance in the detection of LFTSs or microfluidic chips under specific assay conditions. Despite
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the diversity of detection methods, as well as dimensions, detection speed, analytes of interest and study purposes, all the detection
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platforms provided convincing and rapid test results within the allowable error range. Nevertheless, the excellent performance of the detection instruments including sensitivity, accuracy, resolution, LOD and detection range are expected to improve unceasingly, and immunoassay devices in the POCT are no exception. As far as the colorimetric detection and luminescent assays in POCT,
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image sensing and photoelectric detecting are both significant component during whole progress of the detection. The selection of such element and corresponding physical parameters directly affects the
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results and performance. For example, CCD tends to obtain images with more stability and quality than CMOS, while not advantageous in terms
of cost. Additionally, distinction among the central processing units of
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each reader platforms might differentiate efficiency of analysis results.
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It is noted that light source is also vital for colorimetric and fluorescent detection. In order to eliminate the influence of light source during different assays, a reference area is generally defined and the measurement is repeated a plurality of times to reduce the fluctuation of
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the result data. An enclosure or accessory is used to ensure the testing environment especially for optical detection, as well as enhancing the anti-interference capacity. For the detection of magnetic signals, metal
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materials are generally selected as the outer casing to effectively shield
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the interference of electromagnetic waves outside. Besides the hardware, software and algorithms of the reader
platforms also have immediate concern with the image processing of the POCT, especially in colorimetric and fluorescent analysis. Typical examples are color model of RGB and HSV, image binarization, enhancement, restoration, filtering and edge detection, etc. The most commonly used image reconstruction method is to process the original
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image by using morphological erosion or dilation, and then modify with a variety of filters and denoising methods according to a specific threshold. The method can obtain more ideal image information for
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analysis than that captured by the raw camera. On the whole, hardware and software are combined with detection protocols such as colorimetric testing, luminescent assays and magnetic detection to
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function adequately.
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With regard to commercial bench-top apparatuses, it is necessary to increase the sensitivity of each generation. Versatility is also one of the purposes for upgrading. With regard to handheld instruments and intelligent detection devices, miniature and integrated sensing
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components such as cameras, integrated circuits and light sources may limit sensitivity and accuracy. Embedded technology and operating
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systems also determine the performance of these platforms. In addition, external accessories attached to the smartphone not only lack
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universality due to different phone models, but also may weaken the flexibility of the immunoassay process to some extent. With the growing demand for home testing as well as personalized healthcare, an increasing number of studies on intelligent diagnostics and detection devices have been reported. There is a trend for miniaturization, integration and facilitation of detection instruments for the POCT. Portable and small size, or even single handheld devices that provide
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rapid and accurate detection have potential application in the POCT. Thus, it takes a long time for immunoassay detection platforms to technologically transfer, update and industrialize.
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In addition, POCT is the closest branch of traditional laboratory medicine to the Internet. POCT technology is capable of cross-border
integration, which makes the POCT much easier to implement in the
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Internet. Along with the exponential growth of artificial intelligence,
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sensor networks and the Internet of Things, the detection devices for immunoassays in the POCT will accommodate smart healthcare and mobile healthcare, with real-time detection, reliable data and remote
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monitoring and analysis.
Acknowledgments
and
Development
Program
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Research
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We are grateful for the financial support by the National Key of
China
(Grant
No.
2017FYA0205303), the National Natural Science Foundation of China (Grant Nos. 81571835, and 81672247), National Key Basic Research Program (973 Project) (No.2015CB931802), Shanghai Science and Technology Fund (No.15DZ2252000).
Conflicts of interest
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The authors declare no conflicts of interests.
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Captions Fig. 1 (A) The schematic of the assembled reader. Reproduced with permission from ref. [89]. Copyright 2004 Springer. (B) Photograph of
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the implemented test strip reader. Reproduced with permission from ref.
[90]. Copyright 2011 Institute of Electrical and Electronics Engineers.
(C) Schematic illustration of the developed UPT-based optical reader.
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Reproduced with permission from ref. [99]. Copyright 2009 Institute of
Fig. 2 (A) The detection instrument and the integrated CCD image sensor. Reproduced with permission from ref. [100]. Copyright 2014 Springer. (B) The photograph of Triage MeterPlus. Reproduced with
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permission from ref. [101]. Copyright 2002 Wolters Kluwer. (C) The ESE-Quant Lateral FlowReader with size of 15 × 20 × 5 cm3.
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Reproduced with permission from ref. [107]. Copyright 2018 QIAGEN. (D) Photograph and schematic illustration of the Deep-UV LED
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fluorescence platform. Reproduced with permission from ref. [110]. Copyright 2018 American Chemical Society. Fig. 3 (A) Schematic illustration of MAR detection mechanism and picture of real product of MAR. Reproduced with permission from ref. [111] Copyright 2018 Magna Biosciences LLC. (B) General view of the GMR system and its zooming detail. Reproduced with permission from
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ref. [120]. Copyright 2012 Elsevier. (C) General view of the TMR prototype. Reproduced with permission from ref. [121]. Copyright 2016 Molecular Diversity Preservation International. (D) Measurement
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configuration with two active sensors S1 and S2. Reproduced with permission from ref. [121]. Copyright 2016 Molecular Diversity Preservation International. (A)
The
handheld
computational
imaging
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Fig. 4
platform.
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Reproduced with permission from ref. [123]. Copyright 2014 Springer Nature. (B) The FluoVisualizer and visualization of test results. Reproduced with permission from ref. [124]. Copyright 2008 Society of Photo-Optical Instrumentation Engineers. (C) Overall view of
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portMD-113. It enables rapid and parallel detection of 113 fluorescent spots of a microarray in the POCT. Reproduced with permission from
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ref. [125]. Copyright 2013 Elsevier. (D) Schematic illustration of Handing. Reproduced with permission from ref. [126]. Copyright 2017
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Elsevier.
Fig. 5 (A) Magnetic handheld reader device and schematic illustration of the measuring head. Reproduced with permission from ref. [127]. Copyright 2015 American Society for Microbiology. (B) Schematic illustration of magnetic detection by MPQ reader. Reproduced with permission from ref. [130]. Copyright 2016 Elsevier. (C) Schematic illustration of multiplex assay setup. Reproduced with permission from
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ref. [131]. Copyright 2016 American Chemical Society. Fig. 6 (A) Views of smart reader prototype. Reproduced with permission from ref. [135]. Copyright 2012 Royal Society of Chemistry.
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(B) Front-profile view and structure of the Google Glass. Reproduced with permission from ref. [134]. Copyright 2014 American Chemical
Society. (C) The operation of chip imaging with the device. Reproduced
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with permission from ref. [136]. Copyright 2017 American Chemical
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Society. (D) Schematic illustration of the smartphone based AuNPs-LFIS reading system. Reproduced with permission from ref. [140]. Copyright 2018 Elsevier. (E) Smartphone-based ambient light sensors. Reproduced with permission from ref. [141]. Copyright 2018
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American Chemical Society.
Fig. 7 (A) Main components of MCFphone. (1) Microcapillary Film
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(MCF) (2) Smartphone (3) Magnifying lens (4) Blue LED (5) UV black light for fluorescence detection, light source for chromogenic detection
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(6) dichroic filter. Reproduced with permission from ref. [142]. Copyright
2015
Elsevier.
(B)
Schematic
description
of
a
smartphone-based fluorescence detector with a reflective light concentrator module. Reproduced with permission from ref. [143]. Copyright 2016 Ivyspring. (C) Back view of testing equipment and the main menu of the software. Reproduced with permission from ref. [138]. Copyright 2017 Springer. (D) Schematic illustration of household
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fluorescent LFTS platform. Reproduced with permission from ref. [144].
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Copyright 2017 American Chemical Society.
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Merits
Rapid, widely Colorimetric assay used, reliable performance,
Reader model Detection Operation Analysis mode time
Demerits
Test strip reader LFTS reader
< 5 min < 5 min
DT1030
< 5 min
Alere™ Reader
< 5 min
UPT Reader
< 5 min
Not portable, acquire, average accuracy
CCD-based system
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Benchtop apparatus
Deep-UV platform
More precise and sensitive, Magnetic signal detect entire detection magnetic signals
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Luminescent detection
Not portable, need specific Triage MeterPlus 15-20 min High accuracy excitation source, high and sensitive, auto-fluorescence widely used background, complicate ESE-Quant ~15 min operation
Not portable, need ultrasensitive magnetic sensor, vulnerable to external magnetic interference, costly
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Normal
5-8 min
5-10 min
Cost
Analytes
LOD
Medium Semiquantitative Medium Medium Semiquantitative Medium
HBV 1.25 ng/mL Cocaine 1 ng/mL IgG 0.1 ng/mL Medium Semiquantitative Medium DNA 3.75 fM IgG 10 ng/mL Streptococcus pneumoniae, Medium Semiquantitative High / Influenza A, Respiratory syncytial virus
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Detection methods
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Summary of various detection platforms of POCT
Medium Semiquantitative Medium Yersinia pestis F1 antigen
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20 pg/mL
[100]
/
[101-106]
Parathyroid hormone-like hormone DNA
1.42 ng/mL
[108]
0.4 fM
[109]
BSA
100 nM
[110]
Medium
Quantitative
Medium B-type natriuretic peptide, cTnI
Medium
Quantitative
Medium
Complicated Quantitative
Medium
MAR
15 min
MIR
< 15min
GMR
10 min
Complicated Quantitative
High
TMR
10 min
Complicated Quantitative
High
Medium
Quantitative
High
Medium
[95-98] [99]
Quantitative
Quantitative
[89] [90] [91] [92] [93]
5 ng/mL
Medium
Medium
High
Ref.
CagA
HCG / Parvalbumin 0.046 µg/mL Listeria monocytogenes 104 CFU/mL Bacillus anthracis spores 6×104 spores/g milk powder 30 pg/ml HIV HCG 0.014 mIU/mL cTnI 0.0089 ng/mL CKMB 0.063 ng/mL Myo 0.05 ng/mL Troponin I 0.01 ng/mL HCG 0.05 mIU/ml HCG 25 mIU/mL
[112] [113] [114] [115] [116] [117] [118] [119] [120] [121]
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Detection methods
Merits
Demerits
Reader model
Portable and Average accuracy, Colorimetric convenient, easy limited by battery life assay to manipulate, and storage cost effectively
Glucometer Handheld plasmonic biosensor
< 8 min
Medium Semiquantitative Medium
<2 min
Simple
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FluoVisualizer Need specific High accuracy, excitation source, high Luminescent sensitive, easy to auto-fluorescence portMD-113 detection manipulate, cost Portable background, effectively and complicate operation Handing handheld devices handheld Portable and Need ultrasensitive magnetic reader convenient, Magnetic magnetic sensor, More precise and signal more vulnerable to sensitive, detection external magnetic detectable entire MPQ reader interference magnetic signals
Detection Operation Analysis mode Cost time < 3 min Simple Semiquantitative Medium
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Table 1 (continued) LOD
Ref.
Glucose
/
[122]
Protein monolayers
down to ng/mL range
[123]
/
[124]
Qualitative
Low
/
< 3 min
Medium
Quantitative
Medium
IgG
tenfold higher [125]
5 min
Medium
Quantitative
Medium
CEA
0.049 ng/mL
[126]
15 min
Medium
Quantitative
Medium
Grapevine fanleaf virus
0.5 ng/ml
[127]
0.33 ng 25 pg/ml 0.20 ng/mL 0.12 ng/mL 0.35 ng/mL
[129] [130]
High
Magnetic NPs PSA BoNT-A BoNT-B BoNT-E
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Analytes
15 min
Medium
Quantitative
[131]
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Merits
Demerits
Detection methods
Reader model
smartphone-base d reader <5 min platform
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Luminescent detection
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Colorimetric assay smartphone-base d reader <5 min platform
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Intelligent detection devices
Rapid, intelligent Complicated operation system, component, average expandable accuracy, need capability, cost external accessory, effectively, no non-universal need for external accessory, limited by power supply battery life
<5 min
Simple
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Detection Operation Analysis mode time
Cost
Semiquantitative Medium
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Category
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Table 1 (continued)
Simple
Simple
Semiquantitative
Quantitative
Low
Low
Analysts
LOD
HIV
/
PSA
Down to ng/mL
Malaria, Tuberculosis, HIV
/
AFB1 3±1 ppb 0.16 ng/mL Cd2+ 0.046 ng/mL Clenbuterol Porcine epidemic 0.055 µg/mL diarrhea virus Butylcholinesterase 0.028 nM PSA H5N1 HCG CEA ST2 BNP
0.08 ng/mL NM 2.3 mIU/mL 0.037 ng/mL 1 ng/mL 5 pg/mL
Ref.
[134]
[135] [136] [140]
[141] [142] [143] [138] [144]
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The progress of the POCT detection equipment is discussed from three detection mechanisms: white light, fluorescence and magnetism Further, instruments of each mechanism are discussed in the review
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by different degree of integration and advance Along with Internet technology and artificial intelligence, future advances and challenges of detection platforms in the POCT is
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proposed