Microfluidics Technology in SARS-CoV-2 Diagnosis and Beyond: A Systematic Review
Abstract
:1. Introduction
2. Methodology
2.1. Search Strategy
2.2. Eligibility Criteria
2.3. Study Assessment and Inclusion
3. Microfluidics in SARS-CoV-2
3.1. Microfluidics in SARS-CoV-2 Antibody Diagnosis
3.1.1. Fluorescence-Based Detection for Antibody Diagnosis
3.1.2. Spectrometer and Image Analysis-Based Detection
3.1.3. Other Detection Techniques
3.2. Microfluidics in Detection of SARS-CoV-2 Antigen
3.2.1. Electrochemical Based Detection
3.2.2. Fluorescence-Based Detection for Antigen Diagnosis
3.2.3. Spectrometer Based Detection
3.2.4. Other Detection Techniques
3.3. Detection of SARS-CoV-2 Nucleic Acids through Microfluidics
3.3.1. Fluorescence-Based Detection of Nucleic Acids
RT-qPCR Based Amplification
Study ID | Methods | Fluid Manipulation Technique | Material | Immobilized Antigen/Antibody/Gene | Detected Biomolecules | Detector | Sensitivity | Specificity | Sample Size/Donor/Standard | Limit of Detection (LOD) | Detection Time | Advantages |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Lin 2021 [22] | Fluorescence immunoassay | Centrifugal force | Polycarbonate | FMS coated SARS-CoV-2 capture antibody | SAS-CoV-2 antigen | homemade fluorescence detection analyzer | NR | NR | 10 patient and 9 healthy people | NR | ˂15 min | Portable, rapid, easy to use, on-site detection, high sensitivity, and specificity. |
Tan 2020 [30] | Microfluidic chemiluminescent ELISA technique | Capillary force | Polystyrene | Capture antibodies to S1 and N | N and S | NanoDrop™ UV-Vis spectrophotometer | NR | NR | 16 convalescent patients and 3 healthy participants | 4 pg/mL (S) and 62 pg/mL (N) | 40 min | Low time consumption, sensitive, low sample volume requirement, low-detection limit |
Wang 2021 [31] | Space-encoding microfluidic biochip | Pump | PDMS | Capture antibodies to S and N | N and S | GenePix 4400A Microarray Scanner | NR | NR | 60 serum samples | ~0.3 pg/mL to ~4 ng/mL | ˂10 min (qualitative) 40 min (quantitative) | 60 sample per test, fast, sensitive, Ultralow detection limit |
Qi H, 2022 [42] | MEA chip based solid−liquid interface capacitance/ trace N-protein detection by microfluidics-coupled capacitive sensor | DEP force (Pneumatic micropumps) | MEA chip modified with an aptamer | An aptamer for SARS-CoV-2 N protein | SARS-CoV-2 N | Sensor and impedance analyzer | NR | NR | 0.1 mL saliva sample collected from 3 volunteer | 1.26 × 10−6 ng/mL (saliva) 2.16 × 10−6 (plasma) and 1.82 × 10−6 ng/mL, (serum) | 15 s | Wide linear range from 10−5 to 10−2 ng/mL, a real-time, easy-to-operate, label-free, and specific |
Li Y, 2021 [43] | MXene–graphene field-effect transistor (FET) sensor to create an ultra-sensitive VSTM | NR | PDMS | APTES linked Anti-S IgG | SARS-CoV-2 spike protein purchased from SinoBiological | fabricated MXene− graphene FET sensor | NR | NR | recombinant 2019-nCoV spike protein | 1 fg/mL | ∼50 min | Relatively simple to construct, fast-responding, ultrasensitive, and specific sensor |
Ge C, 2022 [53] | Microfluidic chip with femtoliter-sized wells, Biotinylated aptamer and β-Galactosidase affinity | Peristaltic pump | PDMS | Capture-SA-β-Gal-linked anti-N IgG Detection- Biotinylated aptamers | SARS-CoV-2 N | Inverted fluorescent microscope | NR | NR | SARS-CoV-2 N (Suzhou) Biotecnology Co., Ltd.) | 33.28 pg/mL | NR | Simple, cost effective, detection by fluorescence, reusable |
Li J, 2021[64] | Microfluidic chip with an integrated immunosensor that utilizes dually labeled magnetic nanobeads | Electromagnetic micropump | PET film stacked with a PMMA cartridge on top of an SPGE sensor | Dually labelled magnetic nanobeads with HRP and detection antibody | SARS-CoV-2 N | Microfluidic immunosensor chip | NR | NR | SARS-CoV-2 N (Advaite, Inc.) | 100 pg/mL (5× diluted serum) and 230 pg/mL (whole serum) | <1 h | Portable, simple, and highly sensitive immunosensor |
S Kim, 2021 [70] | Airborne droplets are captured on the paper microfluidic chip and detected by fluorescent conjugated antibody | Capillary manipulation | Nitrocellulose paper | Detection antibody conjugated with yellow-green fluorescent carboxylated polystyrene particles | SARS-CoV-2 N | Smartphone-based fluorescence microscopic imaging | NR | NR | SARS-CoV-2 Isolate USA-WA1/2020 | NR | <30 min | Low cost, handheld, foldable paper microfluidic assay, rapid virus detection from air droplets |
Xu J, 2021 [71] | Hydrodynamic filtration with sandwich immunoassay | Syringe pump | PDMS | N-MAb conjugated in white microbead and red nanobead | SARS-CoV-2 N | Naked eye detection | 95.4% | 100% | 93 individuals (48 negatives and 45 positives by qPCR) | <100 copies/ mL | NR | Simple to use, point-of-care, reusable and cost-effective chip, |
Sun M, 2022 [73] | Chitosan-glutaraldehyde cross-linking to coated antibody, and sandwich ELISA for detection | Capillary manipulation | Whatman 3 MM filter paper | Capture-N Specific MAb Detection-HRP-tagged MAb | SARS-CoV-2 N | Camera and ImageJ software | NR | NR | N protein (Guangzhou Qianxun Biotechnology Co., Ltd., Guangzhou, China) | 8 μg/mL | NR | Small-sized chip, simple and easy portable, rapid detection |
RT-LAMP Based Amplification
3.3.2. Other Nucleic Acid Detection Techniques
Study ID | Methods | Fluid Manipulation Technique | Material | Immobilized Antigen/Antibody/Gene | Detected Biomolecules | Detector | Sensitivity | Specificity | Sample Size/Donor/Standard | Limit of Detection (LOD) | Detection Time | Advantages |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Fassy 2021 [81] | Quantitative nanofluidic assay based on qPCR | Manual pipetting | 192.24 IFC | N, E, ORF1ab, S, NSP6 gene and mutants | cDNA | Fluorescence based detection | NR | NR | 20 clinical samples | 7 transcript copies per reaction (for N gene) | <3 h for 192 samples | 192 samples in single run, multiple targets |
Xie 2020 [82] | 3 step microfluidic nano-scale qPCR based on microfluidic chip | Manual pipetting | 192.24 IFC | N gene | cDNA | Fluorescence based detection | NR | NR | 182 NP swab samples from 91 positive and 91 negative participants | ˂1 copy/µL | NR | Increased throughput, high precision |
Francesca Dragoni, 2021 [83] | Microfluidic chip PCR technology | NR | NR | RT-qPCR of ORF1ab and N gene | cDNA | Fluorescence based detection | NR | NR | 20 samples | Ct < 36 | 45 min | Easy, Fast, Quantification of viral RNA is possible, Small amount of reagents needed. |
Ji M, 2020 [84] | Microfluidic disc-direct RT-qPCR assay | Centrifugal force | PMMA | N-gene | cDNA | Fluorescence based detection | NR | NR | 29 SARS-CoV-2, and 1572 negative samples | 2 × 101 copies/reaction | 1.5 h | Fast, High sensitivity, Automation capability, Direct viral detection from sample |
Yang, J; 2021 [85] | Portable MiDAS for SARS-CoV-2 nucleic acids detection | Electrochemical pumping | Polycarbonate | 1-Step RT-qPCR based amplification of N gene | cDNA | Fluorescence based detection | NR | NR | 200μL saliva spiked with SARS-CoV2 RNA and/or γ-irradiation inactivated SARS-CoV-2 virions | 1000 copies/mL | ˂2 h | Rapid, Sensitive, Cheap, Automation capability, Cross-contamination is avoided. |
Kim HS, 2021 [94] | RCA of pathogen specific gene amplification on a mesh having multiple microfluidic pores | Hydrostatic pressure | Nylon | RCA based amplification of SARS-CoV-2 nucleic acids. | DNA | Fluorescence based detection | NR | NR | Nucleic acid sequences (20 nt) for COVID-19 (synthesized by Genotech Daejeon, Korea) | 0.7 aM | ≤5 or 15 min | Easy, Effective, Rapid, Does not require any sophisticated device, simple operating principle, Can operate without accessible electricity. |
Ganguli 2020 [97] | Microfluidic system based on RT-LAMP | NR | NR | ORF1a, ORF8, S and N gene | RNA | Fluorescence based detection | 100% | 100% | 20 clinical samles | 50 copies/μL | 40 min | Does not reuire RNA extraction |
Tian F, 2020 [102] | Automated centrifugal microfluidic system with RT-LAMP-based amplification | Centrifugal force | PMMA | N gene specific RT-LAMP primers | cDNA | Fluorescence based detection | NR | NR | Plasmids containing the N gene | 2 copies/reaction | ≤70 min | Rapid, Sensitive, Specific, Viral contamination of aerosol is avoided |
Xiong H, 2021 [103] | Rotating microfluidic fluorescence System, detection based on RT-LAMP | Centrifugal force | Polycarbonate | ORF1ab and N gene | cDNA | Fluorescence based detection | 91.82% | 100% | 115 | 10 copies/μL | 15 min | Rapid, portable, Highly sensitive, Well precision |
Ramachandran A, 2020 [104] | Isotachophoresis coupled RT-LAMP based amplification and CRISPR–Cas12 based detection. | Isotachophoresis | Glass | E and N gene | cDNA | Fluorescence based detection | NR | NR | Synthetic ssRNA | 10 copies/μL | 35 min | Minimal reagent consumption, rapid detection, simple sample processing |
Huang Q, 2021 [105] | Microfluidic-chip-based system with two-stage isothermal amplification method; RPA in the first stage and fluorescence LAMP in the second stage | Capillary action | PMMA | S gene | cDNA | Fluorescence based detection | 95.83% | 94.12% | Plasmid DNA, 17 clinical nasopharyngeal swab | 10 copies | Around 1 h | Parallel detection of multiple target accurately, Rapid detection with high specificity and sensitivity |
Soares, 2021 [106] | Modular centrifugal microfluidic platform to perform RT-LAMP | Centrifugal force | PMMA, PDMS | ORF1ab gene | cDNA | Fluorescence based detection | 96.6% | 100% | 162 nasopharyngeal swab | 100 RNA copies in 10 μL | 1 h | Scalable, rapid, and sensitive |
Yang 2021 [107] | Ultrasensitive isothermal amplification along with microfluidic POC diagnosis system based on the PTS (MPSP) | Manual pipetting followed by capillary action | NR | M and N genes | cDNA | Naked eye detection | NR | NR | 1 clinical authenticated swab sample from COVID-19 positive patient and 16 negative samples of different viruses | 0.5 copy/μL | <2 h | High-throughput, on-site detection of multiple viruses |
Li 2021 [108] | CRISPR-based recognition of SARS-CoV-2 amplified gene by RPA in a microfluidic chamber and AuNP conjugated lateral-flow system for detection. | Capillary action | Clear resin | N-gene | In-direct detection of cDNA | Naked eye detection | 94.1% | 100% | 24 clinical nasopharyngeal sample | 100 copies RNA/target | NR | Easy to use, portable, low cost, no requirement of electricity, high sensitivity, specificity and accuracy, contamination free. |
Yin 2021 [109] | SMCD based integrated on-chip nucleic acid extraction, two-stage isothermal amplification (RPA and LAMP), and colorimetric detection on a 3D printed microfluidic chip | Syringe pump | Clear methacrylate-based resin | N gene, E gene, and Orf1a gene | cDNA | Naked eye detection | 100 GE/mL | NR | 7 samples | NR | ≤1 h | Portable on site detection, low cost, convenient, rapid detection, higher sensitivity and specificity, smartphone-based visualization |
Zhao H, 2021 [110] | eSIREN | Electrochemical pumping | PDMS, PMMA | In-direct detection of SARS-CoV-2 S-gene | RNA | Miniaturized potentiostat (PalmSens, EmStat3) | 92.3% | 87.5% | 21 samples | 7 copies of target RNA/μL | <20 min | Accurate detectio, Reaction operates at room temperature, in-direct viral RNA detection |
4. Material and Fluid Manipulation Technique
5. Microfluidic Devices beyond SARS-CoV-2 Diagnosis
6. Conclusions and Future Direction
Limitations of This Study
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study ID | Methods | Fluid Manipulation Technique | Material | Immobilized Antigen/ Antibody/ Gene | Detected Biomolecules | Detector | Sensitivity % | Specificity % | Sample Size/ Donor/ Standard | Limit of Detection (LOD) | Detection Time | Advantages |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Heggestad 2021 [21] | Microfluidic DA-D4 point-of-care test (POCT) | Pipette pump | POEGMA | S1, N, RBD | Anti-S1, anti-N, anti-RBD Abs | Fluorescent detector (D4Scope) | 100% (anti-S1 & anti-RBD) 96.3% (anti-N) | 100% | 46 plasma samples from 31 positive patients and 41 negative samples. | NR | ≤60 min | Easy to use, quantitative, high specificity and sensitivity, capable of measuring antibody kinetics and seroconversion directly from unprocessed blood or plasma, capable of detecting IP-10, low sample volume requirement, low cost. |
Lin 2021 [22] | Sandwich/Competitive immune-sensors based on lateral chromatography interface | Capillary force | Polycarbonate | FMS-RBD | nAbs | Microfluidic chip fluorescence analyzer | NR | NR | 182 serum samples from vaccinated participants | 4–400 ng/mL (Sandwich assay) & 2.13–213 ng/mL (Competitive assay) | ≤10 min | Reliable, accurate, and rapid detection of nAbs, low-cost detection. |
Moncayo 2021 [23] | Semi-automated multiplexed microfluidic platform with classic multilayer soft-lithography technique | Valve pump | PDMS | S, S1, RBD, and N | Anti-S/S1/RBD/N IgG/IgM | Inverted fluorescence microscope | 95 | 91 | 66 COVID positive patients | 1.6 ng/mL | 2.6 h | High throughput, easy to use, high sensitivity and specificity, low cost. |
Swank 2020 [24] | Microfluidic nano-immunoassay platform based on MITOMI | Pneumatic valves | PDMS | His-tagged S | Anti-S IgG | Nikon ECLIPSE Ti microscope equipped with a LED Fluorescent Excitation System, a Cy3 filter set & a Hamamatsu ORCA-Flash4.0 camera | 98 | 100 | 289 positive and 134 negative samples | 1 nM IgG | NR | High sensitivity and specificity, 1024 samples per device, negligible reagent consumption, ultra-flow volume blood sampling |
Lee 2021 [25] | Microfluidic serological assay combining nanointerstices and digitized flow control | NI driven flow force | PMMA | N | Anti-N IgG, IgM | Fluorescence reader | 91.67% | 100% | 152 serum samples | NR | 5 min | Rapid, on-site, point-of-care detection, high specificity, low cost |
Funari 2020 [26] | Opto-microfluidic sensing platform with gold nanospikes based on LSRP | Syringe pump | PDMS | S | Anti-S IgG | UV–Vis spectrometer | NR | NR | NR | 0.08 ng/mL | ≤30 min | Easy to use, cheap, fast, promising point-of-care detection. |
Gong 2021 [27] | Pulling force spinning top combined with paper-based microfluidic devices | PCBS valves | Paper | RBD | Anti-RBD IgG/IgM/IgA | Commercial smartphone | 97.1 (IgA), 91.4 (IgM) & 85.7 (IgG) | 100 (IgA), 92.8 (IgM) & 100 (IgG) | 104 serum samples | NR | NR | Portable, high sensitivity, instrument-free, low cost |
González 2021 [28] | Automated ELISA on chip | Pump | Polystyrene | S | Anti-S IgG | Microplate reader or smartphone | NR | NR | 22 serum samples from 7 positive patients, 4 vaccinated and 7 negative participants | NR | NR | Low cost, reliable, rapid on-site detection, smartphone-assisted image analysis. |
Liu 2020 [29] | Reciprocating-flowing immunobinding strategy | Pure water bottle pump | PDMS | N | Anti-N IgG | Commercial smartphone | NR | NR | 13 patients | 4.14 pg/mL | ˂5 min | Rapid and efficient immunobinding capacity, reduced time consumption, low limit of detection with 100% true positive and true negative results. |
Tan 2020 [30] | Microfluidic chemiluminescent ELISA technique | Capillary force | Polystyrene | S1 | Anti-S1 IgG | NanoDrop™ UV-Vis spectrophotometer | NR | NR | 16 convalescent patients and 3 healthy participants | 10 pg/mL (LLOD) | 40 min | Low time consumption, sensitive, low sample volume requirement, low detection limit |
Wang 2021 [31] | Space-encoding microfluidic biochip | Pump | PDMS | N/S | Anti-N/S IgG and IgM | GenePix 4400A Microarray Scanner | NR | NR | 60 serum samples | 0.3 pg/mL | ˂10 min (qualitative) 40 min (quantitative) | 60 sample per test, fast, sensitive, Ultralow detection limit |
Xu 2021 [32] | All-fiber Fresnel reflection microfluidic biosensor (FRMB) | Valve pump | Silica | S | Anti-S IgG, IgM | Photodiode detector (PD-1000) | NR | NR | 6 sera spiked with anti-SARS-CoV-2 IgG/IgM | 0.82 ng/mL (IgG) & 0.45 ng/mL (IgM) | 7 min | Simplified structure, sensitive, label-free, easy to use, point-of-care on-site detection, reduced cost, short detection time. |
Schneider 2021 [33] | Microfluidic antibody affinity profiling platform | RBD | nAbs | Biacore T200 surface plasmon resonance (SPR) system | NR | NR | 42 plasma samples from seropositive individuals | NR | NR | Capable of determining the antibody affinities and concentrations of plasma antibodies | ||
Ko 2021 [34] | Microfluidic separation of capture from detection strategy | Syringe pump | PMMA | S-RBD ligated magnetic beads | Anti-S IgG | PalmSens4 potentiostat | NR | NR | NR | ~7.0 × 10−12 molecules of TMB (LLD) | NR | Capable of discriminating between positive patient plasma and controls, enhanced sensitivity, point-of-care detection |
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Jamiruddin, M.R.; Meghla, B.A.; Islam, D.Z.; Tisha, T.A.; Khandker, S.S.; Khondoker, M.U.; Haq, M.A.; Adnan, N.; Haque, M. Microfluidics Technology in SARS-CoV-2 Diagnosis and Beyond: A Systematic Review. Life 2022, 12, 649. https://doi.org/10.3390/life12050649
Jamiruddin MR, Meghla BA, Islam DZ, Tisha TA, Khandker SS, Khondoker MU, Haq MA, Adnan N, Haque M. Microfluidics Technology in SARS-CoV-2 Diagnosis and Beyond: A Systematic Review. Life. 2022; 12(5):649. https://doi.org/10.3390/life12050649
Chicago/Turabian StyleJamiruddin, Mohd. Raeed, Bushra Ayat Meghla, Dewan Zubaer Islam, Taslima Akter Tisha, Shahad Saif Khandker, Mohib Ullah Khondoker, Md. Ahsanul Haq, Nihad Adnan, and Mainul Haque. 2022. "Microfluidics Technology in SARS-CoV-2 Diagnosis and Beyond: A Systematic Review" Life 12, no. 5: 649. https://doi.org/10.3390/life12050649