Recent advances in lab-on-a-chip technologies for viral diagnosis

Abstract

The global risk of viral disease outbreaks emphasizes the need for rapid, accurate, and sensitive detection techniques to speed up diagnostics allowing early intervention. An emerging field of microfluidics also known as the lab-on-a-chip (LOC) or micro total analysis system includes a wide range of diagnostic devices. This review briefly covers both conventional and microfluidics-based techniques for rapid viral detection. We first describe conventional detection methods such as cell culturing, immunofluorescence or enzyme-linked immunosorbent assay (ELISA), or reverse transcription polymerase chain reaction (RT-PCR). These methods often have limited speed, sensitivity, or specificity and are performed with typically bulky equipment. Here, we discuss some of the LOC technologies that can overcome these demerits, highlighting the latest advances in LOC devices for viral disease diagnosis. We also discuss the fabrication of LOC systems to produce devices for performing either individual steps or virus detection in samples with the sample to answer method. The complete system consists of sample preparation, and ELISA and RT-PCR for viral-antibody and nucleic acid detection, respectively. Finally, we formulate our opinions on these areas for the future development of LOC systems for viral diagnostics.

Keywords: Commercialization; Immunoassays; LOC; Microfluidic; Nucleic acid amplification; Viral detection.

Graphical abstract

Fig. 1

Conventional methods for viral detection. (A) Cytopathic effect of measles virus infection of the human HeLa cell line. (B) Haemadsorption (Al-Shammari et al., 2014). (C) Hemagglutination inhibition test (Hierholzer et al., 1969). (D) Cryo-electro micrograph of vaccinia virus (Cyrklaff et al., 2005). (E) ELISA test principle (Niikura et al., 2001). (F) DNA of the Epstein-Barr virus (in red) within lymphoma cells detected by fluorescent imaging after in-situ hybridization (Leenman et al., 2004). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Fabrication methods for LOC and microfluidic devices for viral detection. (A) An example of permanently sealed microfluidics produced by anodically bonding a silicon wafer to a glass wafer (Temiz et al., 2015). (B) Schematic diagram of a micromolding process involving elastomers such as PDMS (Feldman, 2014). (C) Schematic view of the hot embossing process (Sahli et al., 2013). (D) Schematic of xurography fabrication process (Speller et al., 2019). (E) Examples of commercial rapid paper-based microfluidic devices (Yetisen et al., 2013). (F) Lab-on-PCB integrating active control diluter (Moschou and Tserepi, 2017). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Different approaches for chip-based immunoassay. (A) Digital microfluidic cartridge and ELISA used for measles detection (Ng et al., 2018). (B) 3D bead-based microfluidic chip for infection disease detection (Krejcova et al., 2014). (C) A flow-free magnetic actuation platform for microfluidic ELISA test (Coarsey et al., 2019). (D) Paper-based microfluidic test for ZIKV NS1 and DENV detection (Bedin et al., 2017).

Fig. 4

Microfluidic NA amplification testing in different methods: (A) An integrated real-time PCR device for detection of Ebola virus (Ahrberg et al., 2016b). (B) Detail of a fluorescence image-based RT-PCR for detection of hepatitis C virus (HCV), HIV, ZIKV, and human papilloma virus (HPV) (Powell et al., 2018). (C) An integrating sample pretreatment RT-PCR chip for detection of HIV virus (Chen et al., 2010). (D) A real-time LAMP system for detection of respiratory infection virus (Wang et al., 2018b). (E) Fully integrated RT-LAMP system for detection of ZIKV (Song et al., 2016). (F) A completed recombinase polymerase amplification (RPA) system for detection of human adenovirus (Kunze et al., 2015).

Fig. 5

Technique of NA amplification detection. (A) Optic design of integrated real-time fluorescence detection (Zhu et al., 2020). (B) Digital NASBA chip for endpoint detection by fluorescence imaging (Wang et al., 2018a). (C) A series of reaction tubes showing the color change when running the LAMP of H1N1 virus (Ma et al., 2019). (D) Microchip-based CE for NASBA product detection (Liu et al., 2015). (E) LFS-based NA amplification detection (Choi et al., 2016). (F) Schematic of real-time RT-LAMP detection by electrochemical hydrogen ion sensor (Jogezai and Shabbir, 2018). (G) Integrated paper-based chip for LAMP products detection by electrical conductivity measurement (Safavieh et al., 2017). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 6

Commercial rapid devices for viral detection. (A) Cobas® influenza A/B & RSV assay (Chen et al., 2015), (B) Simplexa flu A/B RSV assay, (C) GeneXpert MTB/RIF machine (Nash et al., 2017). (D) Veredus Laboratories Pte. Ltd. system (Tan et al., 2014).