Miniaturized nucleic acid amplification systems for rapid and point-of-care diagnostics: a review.

Point-of-care (POC) genetic diagnostics critically depends on miniaturization and integration of sample processing, nucleic acid amplification, and detection systems. Polymerase chain reaction (PCR) assays have extensively applied for the diagnosis of genetic markers of disease. Microfluidic chips for microPCR with different materials and designs have been reported. Temperature cycling systems with varying thermal masses and conductivities, thermal cycling times, flow-rates, and cross-sectional areas, have also been developed to reduce the nucleic acid amplification time. Similarly, isothermal amplification techniques (e.g., loop-mediated isothermal amplification or LAMP), which are still are emerging, have a better potential as an alternative to PCR for POC diagnostics. Isothermal amplification techniques have: (i) moderate incubation temperature leading to simplified heating and low power consumption, (ii) yield high amount of amplification products, which can be detected either visually or by simple detectors, (iii) allow direct genetic amplification from bacterial cells due to the superior tolerance to substances that typically inhibit PCR, (iv) have high specificity, and sensitivity, and (v) result in rapid detection often within 10-20 min. The aim of this review is to provide a better understanding of the advantages and limitations of microPCR and microLAMP systems for rapid and POC diagnostics.

[1]  Chen Wenyuan,et al.  Polydimethylsiloxane (PDMS)-based spiral channel PCR chip , 2005 .

[2]  Andreas Manz,et al.  Latest developments in micro total analysis systems. , 2010, Analytical chemistry.

[3]  Michael G. Roper,et al.  A fully integrated microfluidic genetic analysis system with sample-in–answer-out capability , 2006, Proceedings of the National Academy of Sciences.

[4]  Erdogan Gulari,et al.  Gene-Z: a device for point of care genetic testing using a smartphone. , 2012, Lab on a chip.

[5]  P Belgrader,et al.  Rapid pathogen detection using a microchip PCR array instrument. , 1998, Clinical chemistry.

[6]  Hans Lehrach,et al.  Quantitative PCR based expression analysis on a nanoliter scale using polymer nano-well chips , 2007, Biomedical microdevices.

[7]  Luke P. Lee,et al.  Innovations in optical microfluidic technologies for point-of-care diagnostics. , 2008, Lab on a chip.

[8]  Matthew C. Mowlem,et al.  On-chip real-time nucleic acid sequence-based amplification for RNA detection and amplification , 2011 .

[9]  J. Kutter,et al.  Towards a portable microchip system with integrated thermal control and polymer waveguides for real‐time PCR , 2006, Electrophoresis.

[10]  Tza-Huei Wang,et al.  An all-in-one microfluidic device for parallel DNA extraction and gene analysis , 2010, Biomedical microdevices.

[11]  J. Kong,et al.  Loop-mediated isothermal amplification integrated on microfluidic chips for point-of-care quantitative detection of pathogens. , 2010, Analytical chemistry.

[12]  Bruce K Gale,et al.  Spinning disk platform for microfluidic digital polymerase chain reaction. , 2010, Analytical chemistry.

[13]  Stephen R Quake,et al.  Solving the "world-to-chip" interface problem with a microfluidic matrix. , 2003, Analytical chemistry.

[14]  S. Soper,et al.  Flexible fabrication and applications of polymer nanochannels and nanoslits. , 2011, Chemical Society reviews.

[15]  Monya Baker,et al.  Clever PCR: more genotyping, smaller volumes , 2010, Nature Methods.

[16]  James P. Nataro,et al.  Diarrheagenic Escherichia coli , 1998, Clinical Microbiology Reviews.

[17]  Hui-Wen Chen,et al.  Integrated microfluidic systems for DNA analysis. , 2011, Topics in current chemistry.

[18]  Chen Xiang,et al.  A novel miniaturized PCR multi-reactor array fabricated using flip-chip bonding techniques , 2005 .

[19]  I. Hsing,et al.  DNA-based bioanalytical microsystems for handheld device applications , 2005, Analytica Chimica Acta.

[20]  Gregoire Seyrig,et al.  A CCD-based fluorescence imaging system for real-time loop-mediated isothermal amplification-based rapid and sensitive detection of waterborne pathogens on microchips , 2011, Biomedical microdevices.

[21]  T. Notomi,et al.  Accelerated reaction by loop-mediated isothermal amplification using loop primers. , 2002, Molecular and cellular probes.

[22]  J. Karns,et al.  A handheld real time thermal cycler for bacterial pathogen detection. , 2003, Biosensors & bioelectronics.

[23]  V. Ugaz,et al.  Reactions and fluidics in miniaturized natural convection systems. , 2004, Analytical chemistry.

[24]  T. Notomi,et al.  Loop-mediated isothermal amplification of DNA. , 2000, Nucleic acids research.

[25]  Gwo-Bin Lee,et al.  Miniature RT–PCR system for diagnosis of RNA-based viruses , 2005, Nucleic acids research.

[26]  Tai Hyun Park,et al.  Fabrication and characterization of a PDMS–glass hybrid continuous-flow PCR chip , 2006 .

[27]  Y. Mori,et al.  Loop-mediated isothermal amplification (LAMP): a rapid, accurate, and cost-effective diagnostic method for infectious diseases , 2009, Journal of Infection and Chemotherapy.

[28]  Y. Guan,et al.  Loop-Mediated Isothermal Amplification for Influenza A (H5N1) Virus , 2007, Emerging infectious diseases.

[29]  Ben Hatano,et al.  LAMP using a disposable pocket warmer for anthrax detection, a highly mobile and reliable method for anti-bioterrorism. , 2010, Japanese journal of infectious diseases.

[30]  Kagan Kerman,et al.  Microchamber array based DNA quantification and specific sequence detection from a single copy via PCR in nanoliter volumes. , 2005, Biosensors & bioelectronics.

[31]  Da Xing,et al.  Miniaturized PCR chips for nucleic acid amplification and analysis: latest advances and future trends , 2007, Nucleic acids research.

[32]  Johan Roeraade,et al.  Continuous segmented-flow polymerase chain reaction for high-throughput miniaturized DNA amplification. , 2003, Analytical chemistry.

[33]  Timothy B. Stockwell,et al.  Nanoliter Reactors Improve Multiple Displacement Amplification of Genomes from Single Cells , 2007, PLoS genetics.

[34]  L. Mazutis,et al.  Quantitative and sensitive detection of rare mutations using droplet-based microfluidics. , 2011, Lab on a chip.

[35]  Hiroyuki Fujita,et al.  Loop-mediated isothermal amplification of a single DNA molecule in polyacrylamide gel-based microchamber , 2008, Biomedical microdevices.

[36]  J P Landers,et al.  Noncontact infrared-mediated thermocycling for effective polymerase chain reaction amplification of DNA in nanoliter volumes. , 2000, Analytical chemistry.

[37]  John Greenman,et al.  Development of a real-world direct interface for integrated DNA extraction and amplification in a microfluidic device. , 2011, Lab on a chip.

[38]  Victor M Ugaz,et al.  PCR in a Rayleigh-Bénard convection cell. , 2002, Science.

[39]  Andreas Manz,et al.  Total nucleic acid analysis integrated on microfluidic devices. , 2007, Lab on a chip.

[40]  Collin Tranter,et al.  Glass-composite prototyping for flow PCR with in situ DNA analysis , 2010, Biomedical microdevices.

[41]  Jaephil Do,et al.  An integrated disposable device for DNA extraction and helicase dependent amplification , 2010, Biomedical microdevices.

[42]  Benjamin J Hindson,et al.  On-chip, real-time, single-copy polymerase chain reaction in picoliter droplets. , 2007, Analytical chemistry.

[43]  L J Kricka,et al.  PCR in a silicon microstructure. , 1994, Clinical chemistry.

[44]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[45]  Dong-Chul Han,et al.  PDMS-based micro PCR chip with Parylene coating , 2003 .

[46]  L J Kricka,et al.  Chip PCR. I. Surface passivation of microfabricated silicon-glass chips for PCR. , 1996, Nucleic acids research.

[47]  Andrew Ustianowski,et al.  Tropical infectious diseases: Diagnostics for the developing world , 2004, Nature Reviews Microbiology.

[48]  Miss A.O. Penney (b) , 1974, The New Yale Book of Quotations.

[49]  P. Gill,et al.  Nucleic Acid Isothermal Amplification Technologies—A Review , 2008, Nucleosides, nucleotides & nucleic acids.

[50]  Gwo-Bin Lee,et al.  A magnetic bead-based assay for the rapid detection of methicillin-resistant Staphylococcus aureus by using a microfluidic system with integrated loop-mediated isothermal amplification. , 2011, Lab on a chip.

[51]  Stephen R Quake,et al.  Parallel picoliter rt-PCR assays using microfluidics. , 2006, Analytical chemistry.

[52]  Ming-Yuan Huang,et al.  Simulation and experimental validation of micro polymerase chain reaction chips , 2000 .

[53]  K. Heuner,et al.  Molecular characterization of Legionella pneumophila-induced interleukin-8 expression in T cells , 2010, BMC Microbiology.

[54]  Tasuku Yotoriyama,et al.  Point-of-care testing system enabling 30 min detection of influenza genes. , 2011, Lab on a chip.

[55]  Yan Xu,et al.  Helicase‐dependent isothermal DNA amplification , 2004, EMBO reports.

[56]  Victor M Ugaz,et al.  A pocket-sized convective PCR thermocycler. , 2007, Angewandte Chemie.

[57]  I. Rodríguez,et al.  Practical integration of polymerase chain reaction amplification and electrophoretic analysis in microfluidic devices for genetic analysis , 2003, Electrophoresis.

[58]  Jana Lauzon,et al.  An inexpensive and portable microchip-based platform for integrated RT-PCR and capillary electrophoresis. , 2008, The Analyst.

[59]  N. Nguyen,et al.  Continuous flow polymerase chain reaction using a hybrid PMMA-PC microchip with improved heat tolerance , 2008 .

[60]  T Kitamori,et al.  Photothermal temperature control of a chemical reaction on a microchip using an infrared diode laser. , 2001, Analytical chemistry.

[61]  Richard A Mathies,et al.  Multichannel PCR-CE microdevice for genetic analysis. , 2006, Analytical chemistry.

[62]  Weijia Wen,et al.  Fast detection of genetic information by an optimized PCR in an interchangeable chip , 2012, Biomedical microdevices.

[63]  T. Yamane,et al.  High speed polymerase chain reaction in constant flow. , 1994, Bioscience, biotechnology, and biochemistry.

[64]  C. Klapperich,et al.  Thermoplastic microfluidic device for on-chip purification of nucleic acids for disposable diagnostics. , 2006, Analytical chemistry.

[65]  Haim H Bau,et al.  A large volume, portable, real-time PCR reactor. , 2010, Lab on a chip.

[66]  J P Landers,et al.  Infrared-mediated thermocycling for ultrafast polymerase chain reaction amplification of DNA. , 1998, Analytical chemistry.

[67]  J. Compton,et al.  Nucleic acid sequence-based amplification , 1991, Nature.

[68]  Michael Curt Elwenspoek,et al.  Fabrication and interfacing of nanochannel devices for single-molecule studies , 2009 .

[69]  Christine A. Hara,et al.  Under-three minute PCR: probing the limits of fast amplification. , 2011, The Analyst.

[70]  R. Zengerle,et al.  Microfluidic lab-on-a-chip platforms: requirements, characteristics and applications. , 2010, Chemical Society reviews.

[71]  Daniel J. Sadler,et al.  Thermal management of BioMEMS: temperature control for ceramic-based PCR and DNA detection devices , 2003 .

[72]  Roland Zengerle,et al.  Microfluidic lab-on-a-foil for nucleic acid analysis based on isothermal recombinase polymerase amplification (RPA). , 2010, Lab on a chip.

[73]  Gwo-Bin Lee,et al.  An integrated microfluidic chip for DNA/RNA amplification, electrophoresis separation and on‐line optical detection , 2006, Electrophoresis.

[74]  Lukas Novak,et al.  Rapid detection of viral RNA by a pocket-size real-time PCR system. , 2010, Lab on a chip.

[75]  Wei Jin,et al.  Integrated glass microdevice for nucleic acid purification, loop-mediated isothermal amplification, and online detection. , 2011, Analytical chemistry.

[76]  Phillip I. Tarr,et al.  Loop-Mediated Isothermal Amplification Assay for Rapid Detection of Common Strains of Escherichia coli , 2008, Journal of Clinical Microbiology.

[77]  Hui Chen,et al.  Predicting viruses accurately by a multiplex microfluidic loop-mediated isothermal amplification chip. , 2011, Analytical chemistry.

[78]  Gwo-Bin Lee,et al.  An integrated microfluidic loop-mediated-isothermal-amplification system for rapid sample pre-treatment and detection of viruses. , 2011, Biosensors & bioelectronics.

[79]  Daniel Malamud,et al.  An integrated, self-contained microfluidic cassette for isolation, amplification, and detection of nucleic acids , 2010, Biomedical microdevices.

[80]  Youn Tae Kim,et al.  Bulk-micromachined submicroliter-volume PCR chip with very rapid thermal response and low power consumption. , 2004, Lab on a chip.

[81]  Pin-Chuan Chen,et al.  Rapid PCR in a continuous flow device. , 2004, Lab on a chip.

[82]  Eva Herrmann,et al.  Comparison of transcription mediated amplification (TMA) and reverse transcription polymerase chain reaction (RT-PCR) for detection of hepatitis C virus RNA in liver tissue. , 2005, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[83]  P. Yager,et al.  Point-of-care diagnostics for global health. , 2008, Annual review of biomedical engineering.

[84]  Eivind Hovig,et al.  Real-time nucleic acid sequence-based amplification in nanoliter volumes. , 2004, Analytical chemistry.

[85]  Rustem F Ismagilov,et al.  Digital isothermal quantification of nucleic acids via simultaneous chemical initiation of recombinase polymerase amplification reactions on SlipChip. , 2011, Analytical chemistry.

[86]  Yi Zhang,et al.  Advances in microfluidic PCR for point-of-care infectious disease diagnostics. , 2011, Biotechnology advances.

[87]  H. Bau,et al.  A self-heating cartridge for molecular diagnostics. , 2011, Lab on a chip.

[88]  Hai-Qing Gong,et al.  Rapid distribution of a liquid column into a matrix of nanoliter wells for parallel real-time quantitative PCR , 2009 .

[89]  Zhixin Li,et al.  Droplet-based micro oscillating-flow PCR chip , 2005 .

[90]  Y. K. Cheung,et al.  1 Supplementary Information for : Microfluidics-based diagnostics of infectious diseases in the developing world , 2011 .

[91]  Chunsun Zhang,et al.  PCR microfluidic devices for DNA amplification. , 2006, Biotechnology advances.

[92]  P. Craw,et al.  Isothermal nucleic acid amplification technologies for point-of-care diagnostics: a critical review. , 2012, Lab on a chip.

[93]  K. Goodson,et al.  Transient liquid crystal thermometry of microfabricated PCR vessel arrays , 1998 .

[94]  Eric P. Skaar,et al.  Miniature on-chip detection of unpurified methicillin-resistant Staphylococcus aureus (MRSA) DNA using real-time PCR. , 2010, Journal of biotechnology.

[95]  Jing Cheng,et al.  A microchip-based PCR device using flexible printed circuit technology , 2005 .

[96]  Hiroaki Misawa,et al.  A heater-integrated transparent microchannel chip for continuous-flow PCR , 2002 .

[97]  Paul LaBarre,et al.  A Simple, Inexpensive Device for Nucleic Acid Amplification without Electricity—Toward Instrument-Free Molecular Diagnostics in Low-Resource Settings , 2011, PloS one.

[98]  C. Wittwer,et al.  Automated polymerase chain reaction in capillary tubes with hot air. , 1989, Nucleic acids research.

[99]  P. Grodzinski,et al.  Microfabricated polycarbonate CE devices for DNA analysis. , 2001, Analytical chemistry.

[100]  Bruce Gale,et al.  Continuous-flow thermal gradient PCR , 2008, Biomedical microdevices.

[101]  B. Lin,et al.  A microfluidic device integrated with multichamber polymerase chain reaction and multichannel separation for genetic analysis. , 2010, Analytica chimica acta.

[102]  Paul LaBarre,et al.  Non-instrumented nucleic acid amplification (NINA): Instrument-free molecular malaria diagnostics for low-resource settings , 2010, 2010 Annual International Conference of the IEEE Engineering in Medicine and Biology.

[103]  Steffen Hardt,et al.  Automated chip-based device for simple and fast nucleic acid amplification , 2005, Expert review of molecular diagnostics.

[104]  M. Gheorghe,et al.  Fast and accurate temperature control of a PCR microsystem with a disposable reactor , 2009 .

[105]  J. Köhler,et al.  Miniaturized flow-through PCR with different template types in a silicon chip thermocycler. , 2001, Lab on a chip.

[106]  S. Jacobson,et al.  Integrated system for rapid PCR-based DNA analysis in microfluidic devices. , 2000, Analytical chemistry.

[107]  S. Jacobson,et al.  Multiple sample PCR amplification and electrophoretic analysis on a microchip. , 1998, Analytical chemistry.

[108]  Roland Zengerle,et al.  Microstructuring of polymer films for sensitive genotyping by real-time PCR on a centrifugal microfluidic platform. , 2010, Lab on a chip.

[109]  Fan-Gang Tseng,et al.  Microfluidic Systems for Biosensing , 2010, Sensors.

[110]  Olaf Piepenburg,et al.  DNA Detection Using Recombination Proteins , 2006, PLoS biology.

[111]  Nathaniel C. Cady,et al.  Real-time PCR detection of Listeria monocytogenes using an integrated microfluidics platform , 2005 .

[112]  J P Landers,et al.  Polymerase chain reaction in polymeric microchips: DNA amplification in less than 240 seconds. , 2001, Analytical biochemistry.

[113]  Daniel T Chiu,et al.  Disposable microfluidic devices: fabrication, function, and application. , 2005, BioTechniques.

[114]  Brian N. Johnson,et al.  An integrated microfluidic device for influenza and other genetic analyses. , 2005, Lab on a chip.

[115]  Govind V Kaigala,et al.  Automated screening using microfluidic chip‐based PCR and product detection to assess risk of BK virus‐associated nephropathy in renal transplant recipients , 2006, Electrophoresis.

[116]  Yi Zhang,et al.  Catching bird flu in a droplet , 2007, Nature Medicine.

[117]  Yonghao Zhang,et al.  Microfluidic DNA amplification--a review. , 2009, Analytica chimica acta.

[118]  H. John Crabtree,et al.  Microfabricated device for DNA and RNA amplification by continuous-flow polymerase chain reaction and reverse transcription-polymerase chain reaction with cycle number selection. , 2003, Analytical chemistry.

[119]  Michael G. Mauk,et al.  A disposable, integrated loop-mediated isothermal amplification cassette with thermally actuated valves , 2011, Microfluidics and nanofluidics.

[120]  H. Swerdlow,et al.  Fully automated DNA reaction and analysis in a fluidic capillary instrument. , 1997, Analytical chemistry.

[121]  Peter J. Asiello,et al.  Miniaturized isothermal nucleic acid amplification, a review. , 2011, Lab on a chip.

[122]  Hai-Qing Gong,et al.  Real-time PCR-based microfluidic array chip for simultaneous detection of multiple waterborne pathogens , 2010 .

[123]  N. V. Pavlova,et al.  Recent developments in the optimization of thermostable DNA polymerases for efficient applications. , 2004, Trends in biotechnology.

[124]  J. Crain,et al.  Multiplexed optical pathogen detection with lab‐on‐a‐chip devices , 2009, Journal of biophotonics.

[125]  Da Xing,et al.  Single-molecule DNA amplification and analysis using microfluidics. , 2010, Chemical reviews.

[126]  Angelika Niemz,et al.  Point-of-care nucleic acid testing for infectious diseases. , 2011, Trends in biotechnology.

[127]  Jerome P Ferrance,et al.  A simple, valveless microfluidic sample preparation device for extraction and amplification of DNA from nanoliter-volume samples. , 2006, Analytical chemistry.

[128]  Ali Khademhosseini,et al.  Nano/Microfluidics for diagnosis of infectious diseases in developing countries. , 2010, Advanced drug delivery reviews.

[129]  A Manz,et al.  Chemical amplification: continuous-flow PCR on a chip. , 1998, Science.

[130]  Denise Wilson,et al.  Improvements in LED-based fluorescence analysis systems , 2005 .

[131]  Q. Xiang,et al.  Real Time PCR on Disposable PDMS Chip with a Miniaturized Thermal Cycler , 2005, Biomedical microdevices.

[132]  W. Verboom,et al.  Optical sensing systems for microfluidic devices: a review. , 2007, Analytica chimica acta.

[133]  K. Mullis,et al.  Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. , 1988, Science.

[134]  Suhyeon Kim,et al.  Cylindrical compact thermal-cycling device for continuous-flow polymerase chain reaction. , 2003, Analytical chemistry.

[135]  Francis Barany,et al.  Polymerase chain reaction/ligase detection reaction/hybridization assays using flow-through microfluidic devices for the detection of low-abundant DNA point mutations. , 2006, Biosensors & bioelectronics.

[136]  Jong Rak Choi,et al.  Clinical evaluation of micro-scale chip-based PCR system for rapid detection of hepatitis B virus. , 2006, Biosensors & bioelectronics.

[137]  Y. Mori,et al.  Detection of loop-mediated isothermal amplification reaction by turbidity derived from magnesium pyrophosphate formation. , 2001, Biochemical and biophysical research communications.

[138]  Ren Sun,et al.  Genetic analysis of H1N1 influenza virus from throat swab samples in a microfluidic system for point-of-care diagnostics. , 2011, Journal of the American Chemical Society.

[139]  Yuzuru Takamura,et al.  On-chip nanoliter-volume multiplex TaqMan polymerase chain reaction from a single copy based on counting fluorescence released microchambers. , 2004, Analytical chemistry.

[140]  Robin H. Liu,et al.  Development of Plastic Microfluidic Devices for Sample Preparation , 2001 .

[141]  Yan Tie,et al.  Micro-assembled multi-chamber thermal cycler for low-cost reaction chip thermal multiplexing , 2002 .

[142]  Yongqiang Cheng,et al.  Ultrasensitive detection of microRNAs by exponential isothermal amplification. , 2010, Angewandte Chemie.

[143]  Andre Sharon,et al.  Low cost and manufacturable complete microTAS for detecting bacteria. , 2009, Lab on a chip.

[144]  Yi Guan,et al.  Sensitive and inexpensive molecular test for falciparum malaria: detecting Plasmodium falciparum DNA directly from heat-treated blood by loop-mediated isothermal amplification. , 2006, Clinical chemistry.

[145]  Daniel J. Sadler,et al.  A miniaturized cyclic PCR device - Modeling and experiments , 2002 .

[146]  Hai-Qing Gong,et al.  Microfluidic devices harboring unsealed reactors for real-time isothermal helicase-dependent amplification , 2009, Microfluidics and nanofluidics.

[147]  Katta G. Murty,et al.  On KΔ , 1986, Discret. Appl. Math..

[148]  D. DeVoe,et al.  Bonding of thermoplastic polymer microfluidics , 2009 .

[149]  Yasutaka Morita,et al.  Application of a microchamber array for DNA amplification using a novel dispensing method. , 2002, Archives of histology and cytology.

[150]  R. Mathies,et al.  Fully integrated PCR-capillary electrophoresis microsystem for DNA analysis. , 2001, Lab on a chip.

[151]  P. Neužil,et al.  Ultra fast miniaturized real-time PCR: 40 cycles in less than six minutes , 2006, Nucleic acids research.

[152]  D. Xing,et al.  Micropumps, microvalves, and micromixers within PCR microfluidic chips: Advances and trends. , 2007, Biotechnology advances.

[153]  Anupam Singhal,et al.  Megapixel digital PCR , 2011, Nature Methods.

[154]  Masato Saito,et al.  Rapid detection for primary screening of influenza A virus: microfluidic RT-PCR chip and electrochemical DNA sensor. , 2011, The Analyst.

[155]  Patrick M. Pilarski,et al.  Small volume PCR in PDMS biochips with integrated fluid control and vapour barrier , 2006 .

[156]  Tae Seok Seo,et al.  Integrated capture, concentration, polymerase chain reaction, and capillary electrophoretic analysis of pathogens on a chip. , 2009, Analytical chemistry.