Multiplex Detection of Infectious Diseases on Microfluidic Platforms: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Fumin Chen.

Infectious diseases contribute significantly to the global disease burden. Sensitive and accurate screening methods are some of the most effective means of identifying sources of infection and controlling infectivity. Conventional detecting strategies such as quantitative polymerase chain reaction (qPCR), DNA sequencing, and mass spectrometry typically require bulky equipment and well-trained personnel. Therefore, mass screening of a large population using conventional strategies during pandemic periods often requires additional manpower, resources, and time, which cannot be guaranteed in resource-limited settings. Emerging microfluidic technologies have shown the potential to replace conventional methods in performing point-of-care detection because they are automated, miniaturized, and integrated. By exploiting the spatial separation of detection sites, microfluidic platforms can enable the multiplex detection of infectious diseases to reduce the possibility of misdiagnosis and incomplete diagnosis of infectious diseases with similar symptoms. 

  • microfluidic platforms
  • multiplex detection
  • infectious disease diagnosis
  • immunosensors
  • nucleic acid sensors

1. Introduction

Infectious diseases are caused by pathogens, including viruses, bacteria, and parasites [1]. As one of the greatest threats to human health and global security, infectious diseases contribute the most to the global disease burden [2,3][2][3]. For example, according to the World Health Organization, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had infected 6 billion people and caused 6 million deaths by December, 2022 [4]. Compared to other diseases, infectious diseases are characterized by their high infectivity [1]. Managing their infectivity is crucial for preventing and controlling the pandemics of infectious diseases [5,6,7][5][6][7]. It is reported that timely diagnosis can help control the source of infection by isolating and treating infected individuals. A rapid, sensitive, and accurate diagnostic assay is urgently required to effectively investigate and locate the source of infection and control the spread of infectious diseases [7].
Laboratory tests usually detect infectious diseases with methods such as enzyme-linked immunosorbent assays (ELISA), DNA sequencing, and qPCR [8]. These techniques usually require well-trained operators, professional procedures, and expensive testing equipment [9]. For example, ELISA technology requires a complex labeling procedure and a bulky optical reader [10,11][10][11]. As the other gold standard technology for nucleic acid detection [12], qPCR is limited by its many manual steps and precise equipment such as thermocyclers [13]. Therefore, current laboratory detection technologies are struggling to meet the need for rapid mass screening and surveillance of infectious diseases, especially in resource-limited settings. In addition, in many cases (e.g., to distinguish between the different types of sepsis), clinical evidence based on a single biomarker is insufficient to adequately diagnose a disease or monitor its treatment [14].
Recently, microfluidics has been highlighted and extensively researched due to its outstanding advantages, such as fast operation (less than 1 h), low reagent volume (microliter or even nanoliter), and high integration capability (integration of sample preparation, detection, and analysis into the platform) [17][15]. In addition, the characteristics of microfluidic platforms are well-suited for multiplex detection [14,18][14][16]. The general strategies of multiplex detection include spatial separation of detection sites, discrete regions of a channel network or array, or the detection of different markers in integrated microfluidic chips which can effectively reduce the interference between different reaction systems in the simultaneous detection of a large number of targets [14]. Moreover, because of the relatively independent reaction space on the microfluidic platforms, the sensitivity and specificity of each assay can be ensured in multiplex detection. Therefore, multiplex detection technology based on microfluidic platforms shows great potential for the diagnosis and mass screening of infectious diseases [19,20][17][18].

2. Multiplex Immunosensors on Microfluidic Platforms

The microfluidic immunosensor is a well-developed diagnostic tool for detecting analytes at low concentrations, which use antibodies as the biological recognition element to convert an antibody-antigen binding event into a measurable physical signal [24][19]. In the microfluidic multiplex immunosensor, a series of discriminatory biomarkers are simultaneously recognized by the antibodies with high specificity and sensitivity, generating signals in proportion to the antigen concentration in the samples [16,25,26,27,28,29,30,31,32,33,34,35][20][21][22][23][24][25][26][27][28][29][30][31]. For infectious disease diagnosis, multiplex immunosensors based on microfluidic platforms mainly use spatial multiplexing and barcode multiplexing strategies. According to the principle of fluid propulsion, they can be classified into capillary, pressure-driven, centrifugal, electrokinetic, and acoustic systems [36,37][32][33]. Among them, capillary force-driven microfluidic platforms are widely used because they do not require external energy to enable continuous fluid automation, with lateral flow immunoassay (LFIA) being the most typical representative [36][32]. LFIA has become one of the most successful analytical techniques because it meets the ASSURED (affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free, and delivered) criteria of the WHO [38][34]. The rapidity, simplicity, relative cost-effectiveness, and the ability to be used by unskilled personnel have contributed to the widespread acceptance of LFIA [38,39][34][35]. In fact, the global lateral flow assay market was estimated to be approximately $5.98 billion in 2019 and is expected to reach $10.36 billion by 2027 [39][35]. Simultaneous detection of multiple analytes is mainly realized by arranging multiple test lines (TL) in a single strip, which enables discrimination of different targets by spatial resolution [39,40][35][36]. There are three typical signal readout strategies for LFIA platforms, including colorimetric signal, surface-enhanced Raman scattering (SERS) signal. There are various commercial LFIA products. Such as, ActiveXpress (Edinburgh Genetics Ltd, Edinburgh, UK), Roche (SD Biosensor Inc./Roche Diagnostics, Basel, Switzerland), and Standard-Q (SD Biosensor Inc, Gyeonggi-do, Republic of Korea) [48][37]. Despite the extensive LFIAs research and the availability of several commercial products for detection, some challenges remain. First, the sensitivity should be enhanced by fabrication of high-resolution instrumentation and label materials with high response signal [33][29]. Second, the false positives may be reduced by multi-signal synchronous detection based on multiplexed type and multi-signal type [49][38]. Third, the false negatives caused by mutations are required to decrease through selecting new immune targets in a timely manner [50,51][39][40].

3. Multiplex Nucleic Acid Sensors on Microfluidic Platforms

Nucleic acid is another biomarker that can be used for the diagnosis of infectious diseases, due to its unique and outstanding characteristics (e.g., molecular recognition, biocompatibility, functionalization, and programmability), which endow nucleic acids with potential application as powerful sensing elements and provide key information of specific genes and species [52][41]. PCR is typically considered as the gold standard detection method of nucleic acid-based diagnosis, but involves costly/advanced equipment and skilled personnel, so it cannot be easily combined with microfluidic technology [53][42]. Therefore, isothermal amplification and clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (CRISPR/Cas) system, which have the advantage of low-cost, reliability, and do not require for bulky equipment, can be compatible with the microfluidic platforms for nucleic acid detection [20,54][18][43]. Based on the spatial separation of detection sites on microfluidic platforms, the multiplex detection of different nucleic acids can be realized [14]. Multiplex nucleic acid sensors on microfluidic platforms mainly include polymer-based microfluidic chips, paper-based microfluidic devices, and droplet-based microfluidic devices [55][44]. They are characterized by cost-efficiency, portability, low sample consumption (µL-fL), miniaturization (with dimensions of tens to hundreds of micrometers chambers), simplicity (no training is required), and multiplex detection (providing multiple spatially separated detection channels) [56][45].

3.1. Polymer-Based Microfluidics

Fabrication of microfluidic devices is an important step in integrated automated nucleic acid sensing. In this regard, polymers (e.g., polydimethylsiloxane, PDMS) are one of the most common materials, due to their advantages such as cost-effectiveness, good biocompatibility, and simple fabrication protocol [20][18]. Polymer-based microfluidic chip is highly automated (multistep continuous reactions can be realized via sophisticated microstructures) and integrated, which has been widely used for infectious disease detections [60][46]. Depending on the presence or absence of moving mechanical parts, fluid flow support techniques for polymer-based microfluidic chips are generally divided into mechanical drive (e.g., centrifugal force drive and micropump drive) and nonmechanical drive (e.g., electric drive and capillary force drive) [61,62][47][48]. The mechanical drive chips have the advantages of easy large-scale integration, high drive pressure, wide range of flow rates, and high adaptability. The other key element for multiplex detection of infectious diseases is the design of microfluidic channels. The general processing technology of the polymer-based microfluidic channel includes the hot pressing, injection molding, photolithography, and laser etching [65][49]. For example, Huang et al. used laser cauterization to fabricate a basement layer consisting of two sides: side A contained microstructures for the recombinase polymerase amplification (RPA) reaction, and side B for the loop-mediated isothermal amplification (LAMP) reaction. Thus, the two-step of isothermal amplification could be completed on the chip to achieve a higher detection sensitivity (10 copies/μL) [66][50]. 

3.2. Paper-Based Microfluidics

The paper-based microfluidic device is a miniature laboratory analysis system that utilizes a paper substrate to replace the conventional substrates (e.g., quartz, silicon, and glass) [76][51]. There are several advantages of paper-based microfluidic devices: (1) paper is cheaper than conventional substrates; (2) the paper itself has a capillary effect, which can guide reagent flow without external forces; and (3) the flexibility and elasticity of paper facilitate customization [77,78][52][53]. Therefore, paper-based microfluidic devices, including lateral flow assays (LFA) and microfluidic paper-based analytical devices (μPAD) are widely applied to the multiplex detection of infectious diseases [79][54]. Generally, the LFA consists of a sample pad, a conjugate pad, a nitrocellulose filter membrane, an absorbent pad, and a back card. Each part has varied degrees of overlapping to ensure the continuity of sample flow [80][55]. Simultaneous detection of different targets can be achieved by fixing and modifying multiple identification elements and signal transduction elements on the LFA test strip [58][56]. Zhang’s group reported that SHERLOCKv2 can simultaneously detect dengue and Zika virus single-stranded RNA using a fantastic CRISPR/Cas detection system on the LFA platform [81,82][57][58]. There are several successful commercialized LFAs (e.g., urine dipstick and pregnancy test kit) [88,89][59][60] and μPADs (e.g., Diagnostics For All and INSiGHT) [90,91][61][62]. However, problems remain. Firstly, the LFAs often allows only qualitative/semi-quantitative results, and thus researchers have tried to solve this by introducing smart phone attachments to achieve more accurate result analysis [92][63]. In addition, the insufficient validation on their compatibility with real sample matrices may cause discrepancy between the detection results obtained from real samples and standard samples and can eventually require major modification of the device design [93][64]. Thus, the examination of μPADs using clinical samples in a real environment is deemed to be essential [90][61]. 

3.3. Droplet-Based Microfluidics

A droplet-based microfluidic device is an alternative strategy for large-scale and parallel biological and chemical reactions [95][65]. The key technology is to generate small and mono-dispersed droplets (picoliter to nanoliter level) under high frequency (∼kHz) and precise control. Generally, microdroplets are generated from two incompatible liquids as a continuous phase and discrete phase, respectively, and different size distributions can be formed by controlling the microsphere structure and flow ratio of the two phases (the volume of microdroplets varies greatly from microliters to femtoliters) [96][66]. Meanwhile, the spatial separation of detection sites on the chips can be used as independent bioreactors to effectively distinguish different reactions [95,96][65][66]. Therefore, high-throughput droplet-based microfluidic devices enable the large-scale screening and multiplex detection of infectious diseases [97][67]. Depending on the mode of droplet generation, droplet-based microfluidic devices can be divided into active and passive modes. The passive mode requires additional energy input to generate droplets, while the active mode generates droplets without external propulsion [98][68]. The passive modes, which do not require programmable syringe pumps or other automated instrumentation to control fluid flow, have been designed to construct droplet-based microfluidic devices [99][69].  In contrast, active designs enable on-demand generation of droplets with a short response time and a better control of droplet size, content, and motion [102][70]. Specifically, compared with a few seconds or even minutes in a passive approach, the response time can be reduced to a few milliseconds in an active method. In addition, active methods control droplet size and production rate with higher flexibility and additional handles, and allow on-demand droplet generation, thus greatly promoting practical applications of microfluidic droplets [103][71]. However, in the passive approach, it is almost impossible to control droplet size and generation frequency independently because they are interrelated through mass conservation [99,102][69][70]. To date, the cutting-edge active techniques mainly apply magnetic, electrical, thermal, optical, mechanical, and centrifugal methods, by which magnetic, electrical, and centrifugal forces are introduced, and the viscosity, flow, interfacial tension, fluid density, and channel wettability are varied [104][72]. 

4. Conclusions and Future Prospects

Recent research on multiplex microfluidic detection platforms have demonstrated their potential for developing accurate, convenient, and rapid diagnoses of infectious diseases. LFIA is known as an ideal diagnostic assay characterized by fast, easy operation, durable stability, and low cost. Polymer-based microfluidic chips are a highly automated and integrated microfluidic platform. Paper-based microfluidic devices offer advantages such as ease of processing, control of reagent flow without external forces, and ease of customization. Droplet-based microfluidic devices are an alternative strategy for large-scale and parallel biological and chemical reactions, providing advantages of high throughput, low-cost, and multiplex detection. The industrialization of microfluidic platforms is also still in its infancy, and challenges such as liquid leakage and difficulties in reusability need to be improved by enhancing functional modularity of sample processing and target detection, as well as by automating platform fabrication and finding cost-effective substrate substitutes. Moreover, to improve the sensitivity and specificity of detection, the combination of two or more technologies may enhance the signal output or minimize interference [22][73].  
 

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