Miniaturization of molecular biological techniques for gene assay.

The rapid diagnosis of various diseases is a critical advantage of many emerging biomedical tools. Due to advances in preventive medicine, tools for the accurate analysis of genetic mutation and associated hereditary diseases have attracted significant interests in recent years. The entire diagnostic process usually involves two critical steps, namely, sample pre-treatment and genetic analysis. The sample pre-treatment processes such as extraction and purification of the target nucleic acids prior to genetic analysis are essential in molecular diagnostics. The genetic analysis process may require specialized apparatus for nucleic acid amplification, sequencing and detection. Traditionally, pre-treatment of clinical biological samples (e.g. the extraction of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)) and the analysis of genetic polymorphisms associated with genetic diseases are typically a lengthy and costly process. These labor-intensive and time-consuming processes usually result in a high-cost per diagnosis and hinder their practical applications. Besides, the accuracy of the diagnosis may be affected owing to potential contamination from manual processing. Alternatively, due to significant advances in micro-electro-mechanical-systems (MEMS) and microfluidic technology, there are numerous miniature systems employed in biomedical applications, especially for the rapid diagnosis of genetic diseases. A number of advantages including automation, compactness, disposability, portability, lower cost, shorter diagnosis time, lower sample and reagent consumption, and lower power consumption can be realized by using these microfluidic-based platforms. As a result, microfluidic-based systems are becoming promising platforms for genetic analysis, molecular biology and for the rapid detection of genetic diseases. In this review paper, microfluidic-based platforms capable of identifying genetic sequences and diagnosis of genetic mutations are surveyed and reviewed. Some critical issues with the use of microfluidic-based systems for diagnosis of genetic diseases are also highlighted.

[1]  Gwo-Bin Lee,et al.  Extraction of genomic DNA and detection of single nucleotide polymorphism genotyping utilizing an integrated magnetic bead-based microfluidic platform , 2009 .

[2]  James P. Landers,et al.  Developments toward a complete micro-total analysis system for Duchenne muscular dystrophy diagnosis , 2003 .

[3]  J. Epplen,et al.  Electrophoresis of DNA in human genetic diagnostics – state‐of‐the‐art, alternatives and future prospects , 2006, Electrophoresis.

[4]  Hanlee P. Ji,et al.  Next-generation DNA sequencing , 2008, Nature Biotechnology.

[5]  A. Caughey,et al.  Preimplantation Genetic Diagnosis: , 2005, Gynecologic and Obstetric Investigation.

[6]  Catherine Situma,et al.  Merging microfluidics with microarray-based bioassays. , 2006, Biomolecular engineering.

[7]  Robin H. Liu,et al.  Acoustic micromixer for enhancement of DNA biochip systems , 2003 .

[8]  K. Mitchelson,et al.  The use of capillary electrophoresis for DNA polymorphism analysis , 2003, Molecular biotechnology.

[9]  Eun Kyu Lee,et al.  Rapid DNA hybridization analysis using a PDMS microfluidic sensor and a molecular beacon. , 2007, Analytical sciences : the international journal of the Japan Society for Analytical Chemistry.

[10]  N. Arnheim,et al.  Using PCR in preimplantation genetic disease diagnosis. , 1991, Human reproduction.

[11]  B. J. Cheek,et al.  Chemiluminescence detection for hybridization assays on the flow-thru chip, a three-dimensional microchannel biochip. , 2001, Analytical chemistry.

[12]  Kemin Wang,et al.  A novel sandwich assay with molecular beacon as report probe for nucleic acids detection on one-dimensional microfluidic beads array. , 2007, Analytica chimica acta.

[13]  D. Pinkel,et al.  Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L. Hunyady,et al.  Genetic screening methods for the detection of mutations responsible for multiple endocrine neoplasia type 1. , 2004, Molecular genetics and metabolism.

[15]  P. Thomas,et al.  Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. A. Northrup,et al.  A miniature analytical instrument for nucleic acids based on micromachined silicon reaction chambers. , 1998, Analytical chemistry.

[17]  P. Jannetto,et al.  Pharmacogenomic genotyping methodologies , 2004, Clinical chemistry and laboratory medicine.

[18]  P. Wilding,et al.  Microchip module for blood sample preparation and nucleic acid amplification reactions. , 2001, Genome research.

[19]  Tak Y. Leung,et al.  Digital PCR for the molecular detection of fetal chromosomal aneuploidy , 2007, Proceedings of the National Academy of Sciences.

[20]  Samuel K Sia,et al.  Lab-on-a-chip devices for global health: past studies and future opportunities. , 2007, Lab on a chip.

[21]  J. Santiago.  Electroosmotic flows in microchannels with finite inertial and pressure forces. , 2001, Analytical chemistry.

[22]  A Paulus,et al.  Rapid, parallel separations of d1S80 alleles in a plastic microchannel chip. , 2000, Journal of chromatography. A.

[23]  Jens Anders Branebjerg,et al.  Microfluidics-a review , 1993 .

[24]  A. Guttman,et al.  Rapid analysis of mitochondrial DNA heteroplasmy in diabetes by gel-microchip electrophoresis. , 2001, Clinical chemistry.

[25]  Yining Shi.  DNA sequencing and multiplex STR analysis on plastic microfluidic devices , 2006, Electrophoresis.

[26]  A. Ricco,et al.  Peer Reviewed: Plastic Advances Microfluidic Devices , 2002 .

[27]  L. Penland,et al.  Use of a cDNA microarray to analyse gene expression patterns in human cancer , 1996, Nature Genetics.

[28]  R. Schasfoort,et al.  TUTORIAL REVIEW , 2001 .

[29]  S. Quake,et al.  Microfluidics: Fluid physics at the nanoliter scale , 2005 .

[30]  Andreas Manz,et al.  Continuous Sample Pretreatment Using a Free-Flow Electrophoresis Device Integrated onto a Silicon Chip , 1994 .

[31]  Vincent J Sieben,et al.  An integrated microfluidic chip for chromosome enumeration using fluorescence in situ hybridization. , 2008, Lab on a chip.

[32]  C. Bartram,et al.  Twenty‐three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families in Southern Germany , 2003, Human mutation.

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

[34]  S. Munné.  Preimplantation genetic diagnosis of numerical and structural chromosome abnormalities. , 2002, Reproductive biomedicine online.

[35]  A. Woolley,et al.  Ultra-high-speed DNA sequencing using capillary electrophoresis chips. , 1995, Analytical chemistry.

[36]  Gwo-Bin Lee,et al.  Integrated microfluidic systems for cell lysis, mixing/pumping and DNA amplification , 2005 .

[37]  Elisabeth Verpoorte,et al.  A microfluidic platform using molecular beacon-based temperature calibration for thermal dehybridization of surface-bound DNA. , 2004, Analytical chemistry.

[38]  Guangshan Li,et al.  Microfluidic devices for fluidic circulation and mixing improve hybridization signal intensity on DNA arrays. , 2003, Lab on a chip.

[39]  Edward S Yeung,et al.  On-line integration of PCR and cycle sequencing in capillaries: from human genomic DNA directly to called bases. , 2003, Nucleic acids research.

[40]  P. Ekstrøm,et al.  Detection of mutations in exon 8 of TP53 by temperature gradient 96-capillary array electrophoresis. , 2002, BioTechniques.

[41]  V. Sheffield,et al.  Identification of a Gene That Causes Primary Open Angle Glaucoma , 1997, Science.

[42]  Kinam Park,et al.  Detection of pathogenic E. coli O157:H7 by a hybrid microfluidic SPR and molecular imaging cytometry device , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[43]  S. Cho,et al.  Creating, transporting, cutting, and merging liquid droplets by electrowetting-based actuation for digital microfluidic circuits , 2003 .

[44]  G. Gordon,et al.  Hybridization enhancement using microfluidic planetary centrifugal mixing. , 2004, Analytical chemistry.

[45]  Ralf Lenigk,et al.  DNA amplification and hybridization assays in integrated plastic monolithic devices. , 2002, Analytical chemistry.

[46]  Xuezhu Liu,et al.  Electrokinetically controlled DNA hybridization microfluidic chip enabling rapid target analysis. , 2004, Analytical chemistry.

[47]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[48]  N. Yamaguchi,et al.  Simple detection of small amounts of Pseudomonas cells in milk by using a microfluidic device , 2006, Letters in applied microbiology.

[49]  Jianing Yang,et al.  High sensitivity PCR assay in plastic micro reactors. , 2002, Lab on a chip.

[50]  Jana Lauzon,et al.  Microfluidic platform for single nucleotide polymorphism genotyping of the thiopurine S-methyltransferase gene to evaluate risk for adverse drug events. , 2007, The Journal of molecular diagnostics : JMD.

[51]  Meng-Hua Yen,et al.  Using a microfluidic device for 1 μl DNA microarray hybridization in 500 s , 2005, Nucleic acids research.

[52]  Jr-Lung Lin,et al.  Integrated polymerase chain reaction chips utilizing digital microfluidics , 2006, Biomedical microdevices.

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

[54]  T. Matsunaga,et al.  Microfluidic device using chemiluminescence and a DNA-arrayed thin film transistor photosensor for single nucleotide polymorphism genotyping of PCR amplicons from whole blood. , 2009, Lab on a chip.

[55]  Peter Braude,et al.  Preimplantation genetic diagnosis , 2002, Nature Reviews Genetics.

[56]  C. DeLisi.  The Human Genome Project , 1988 .

[57]  Robin H. Liu,et al.  Plastic biochannel hybridization devices: a new concept for microfluidic DNA arrays. , 2002, Analytical biochemistry.

[58]  Stephen R Quake,et al.  Correction: Digital PCR provides sensitive and absolute calibration for high throughput sequencing , 2008, BMC Genomics.

[59]  Joseph Wang,et al.  Electrochemical biosensors: towards point-of-care cancer diagnostics. , 2006, Biosensors & bioelectronics.

[60]  M. Boissinot,et al.  Specific magnetic bead based capture of genomic DNA from clinical samples: application to the detection of group B streptococci in vaginal/anal swabs. , 2007, Clinical chemistry.

[61]  Darwin R. Reyes,et al.  Micro total analysis systems. 1. Introduction, theory, and technology. , 2002, Analytical chemistry.

[62]  Pieter Telleman,et al.  Polymer microfluidic chip for online monitoring of microarray hybridizations. , 2004, Lab on a chip.

[63]  G. Ferrero,et al.  Integrated strategy for fast and automated molecular characterization of genes involved in craniosynostosis. , 2007, Clinical chemistry.

[64]  Microfluidic lab-on-a-chip for microbial identification on a DNA microarray , 2007 .

[65]  H Morgan,et al.  Separation of submicron bioparticles by dielectrophoresis. , 1999, Biophysical journal.

[66]  Takehiko Kitamori,et al.  AC electroosmotic micromixer for chemical processing in a microchannel. , 2006, Lab on a chip.

[67]  D. Cooper,et al.  Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment , 1991, Human Genetics.

[68]  Gwo-Bin Lee,et al.  Automatic bio-sampling chips integrated with micro-pumps and micro-valves for disease detection. , 2005, Biosensors & bioelectronics.

[69]  J. Weber,et al.  Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. , 1989, American journal of human genetics.

[70]  D. Ehrlich,et al.  Microchip electrophoresis: a method for high-speed SNP detection. , 2000, Nucleic acids research.

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

[72]  Theodore C Marentis,et al.  Ultrasonic mixing in microfluidic channels using integrated transducers. , 2004, Analytical chemistry.

[73]  High‐resolution single‐stranded DNA analysis on 4.5 cm plastic electrophoretic microchannels , 2003, Electrophoresis.

[74]  Roland Zengerle,et al.  Microfluidic platforms for lab-on-a-chip applications. , 2007, Lab on a chip.

[75]  F. Kramer,et al.  Thermodynamic basis of the enhanced specificity of structured DNA probes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[76]  Nicole Pamme,et al.  Continuous flow separations in microfluidic devices. , 2007, Lab on a chip.

[77]  E. Yeung,et al.  High-throughput detection of unknown mutations by using multiplexed capillary electrophoresis with poly(vinylpyrrolidone) solution. , 2000, Analytical chemistry.

[78]  D. Slamon,et al.  Frozen tumor tissue microarray technology for analysis of tumor RNA, DNA, and proteins. , 2001, The American journal of pathology.

[79]  Robin H. Liu,et al.  Self-contained, fully integrated biochip for sample preparation, polymerase chain reaction amplification, and DNA microarray detection. , 2004, Analytical chemistry.

[80]  R. Mathies,et al.  Integrated affinity capture, purification, and capillary electrophoresis microdevice for quantitative double-stranded DNA analysis. , 2007, Analytical chemistry.

[81]  P. Scheinberg.  Dementia due to vascular disease--a multifactorial disorder. , 1988, Stroke.

[82]  Gwo-Bin Lee,et al.  Micromachined pre-focusedM×Nflow switches for continuous multi-sample injection , 2001 .

[83]  Richard A Mathies,et al.  High throughput DNA sequencing with a microfabricated 96-lane capillary array electrophoresis bioprocessor , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[84]  S. Rechitsky,et al.  Human embryonic stem cell lines with genetic disorders. , 2005, Reproductive biomedicine online.

[85]  M. Vandervorst,et al.  Preimplantation genetic diagnosis and sperm analysis by fluorescence in-situ hybridization for the most common reciprocal translocation t(11;22). , 1999, Molecular human reproduction.

[86]  Richard A Mathies,et al.  Inline injection microdevice for attomole-scale sanger DNA sequencing. , 2007, Analytical chemistry.

[87]  Fook Siong Chau,et al.  Microbial detection in microfluidic devices through dual staining of quantum dots-labeled immunoassay and RNA hybridization. , 2006, Analytica chimica acta.

[88]  David Erickson,et al.  Modeling of DNA hybridization kinetics for spatially resolved biochips. , 2003, Analytical biochemistry.

[89]  U. Zimmermann,et al.  Electric field-induced cell-to-cell fusion , 2005, The Journal of Membrane Biology.

[90]  P Belgrader,et al.  A battery-powered notebook thermal cycler for rapid multiplex real-time PCR analysis. , 2001, Analytical chemistry.

[91]  Gwo-Bin Lee,et al.  Micro capillary electrophoresis chips integrated with buried SU-8/SOG optical waveguides for bio-analytical applications (vol 107, pg 125, 2003) , 2003 .

[92]  Eun Kyu Lee,et al.  Fast and sensitive DNA analysis using changes in the FRET signals of molecular beacons in a PDMS microfluidic channel , 2007, Analytical and bioanalytical chemistry.

[93]  N. Larsson,et al.  Molecular genetic aspects of human mitochondrial disorders. , 1995, Annual review of genetics.

[94]  A. von Eckardstein,et al.  Electrophoretic screening for genetic variation in apolipoprotein C-III: identification of a novel apoC-III variant, apoC-III(Asp45-->Asn), in a Turkish patient. , 1994, Journal of lipid research.

[95]  D J Weatherall,et al.  Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases , 2000, BMJ : British Medical Journal.

[96]  Francis Barany,et al.  Microarrays assembled in microfluidic chips fabricated from poly(methyl methacrylate) for the detection of low-abundant DNA mutations. , 2003, Analytical chemistry.

[97]  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.

[98]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[99]  S. Mangru,et al.  Dynamic DNA hybridization on a chip using paramagnetic beads. , 1999, Analytical chemistry.

[100]  Chih-Ming Ho,et al.  MICRO-ELECTRO-MECHANICAL-SYSTEMS (MEMS) AND FLUID FLOWS , 1998 .

[101]  K. Sermon,et al.  Preimplantation genetic diagnosis , 2003, The Lancet.

[102]  Jin-Woo Choi,et al.  Disposable smart lab on a chip for point-of-care clinical diagnostics , 2004, Proceedings of the IEEE.

[103]  Tze Kin Lau,et al.  Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. , 2008, Clinical chemistry.

[104]  A. Barkovich,et al.  Mitochondrial disorders: analysis of their clinical and imaging characteristics. , 1993, AJNR. American journal of neuroradiology.

[105]  E. Milgrom,et al.  Microsatellites and PCR primers for genetic studies and genomic sequencing of the human ISH receptor gene , 1996, Molecular and Cellular Endocrinology.

[106]  Gwo-Bin Lee,et al.  Microfluidic system for detection of alpha-thalassemia-1 deletion using saliva samples. , 2009, Analytical chemistry.

[107]  Sophia Adamia,et al.  Microfluidic chips for detecting the t(4;14) translocation and monitoring disease during treatment using reverse transcriptase-polymerase chain reaction analysis of IgH-MMSET hybrid transcripts. , 2007, The Journal of molecular diagnostics : JMD.

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

[109]  B. Tutschek,et al.  Detection of fetal cells in transcervical samples and prenatal diagnosis of chromosomal abnormalities , 1995, Prenatal diagnosis.

[110]  A Mulchandani,et al.  Molecular beacons: a real-time polymerase chain reaction assay for detecting Salmonella. , 2000, Analytical biochemistry.

[111]  Gwo-Bin Lee,et al.  Integrated reverse transcription polymerase chain reaction systems for virus detection. , 2007, Biosensors & bioelectronics.

[112]  A. Manz,et al.  Micro total analysis systems. Recent developments. , 2004, Analytical chemistry.

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

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

[115]  M. Metzker.  Emerging technologies in DNA sequencing. , 2005, Genome research.

[116]  Francis Barany,et al.  Capillary and microelectrophoretic separations of ligase detection reaction products produced from low‐abundant point mutations in genomic DNA , 2004, Electrophoresis.

[117]  G. Whitesides.  The origins and the future of microfluidics , 2006, Nature.

[118]  D. Wells,et al.  Preimplantation genetic diagnosis , 2002, Current opinion in obstetrics & gynecology.

[119]  J. Vuust,et al.  Capillary electrophoresis‐based single strand DNA conformation analysis in high‐throughput mutation screening , 2003, Human mutation.

[120]  Gwo-Bin Lee,et al.  Microfluidic systems integrated with two-dimensional surface plasmon resonance phase imaging systems for microarray immunoassay. , 2007, Biosensors & bioelectronics.

[121]  D. J. Harrison,et al.  Micromachining a Miniaturized Capillary Electrophoresis-Based Chemical Analysis System on a Chip , 1993, Science.

[122]  Stephen R. Quake,et al.  Microfluidic Digital PCR Enables Multigene Analysis of Individual Environmental Bacteria , 2006, Science.

[123]  D. Kemp,et al.  Method for detection of specific RNAs in agarose gels by transfer to diazobenzyloxymethyl-paper and hybridization with DNA probes. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[124]  Abraham P. Lee,et al.  Rapid label-free DNA analysis in picoliter microfluidic droplets using FRET probes , 2009 .

[125]  Richard B. Fair,et al.  Digital microfluidics: is a true lab-on-a-chip possible? , 2007 .

[126]  T. Liao,et al.  A cell counting/sorting system incorporated with a microfabricated flow cytometer chip , 2006 .

[127]  James R Cerhan,et al.  Microarray and microfluidic methodology for genotyping cytokine gene polymorphisms. , 2003, Human immunology.

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

[129]  J. Landers,et al.  Evaluation of microchip electrophoresis as a molecular diagnostic method for Duchenne muscular dystrophy. , 2002, Clinical chemistry.

[130]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[131]  E. Yeung,et al.  Genetic typing by capillary electrophoresis with the allelic ladder as an absolute standard. , 1996, Analytical chemistry.

[132]  M C Neale,et al.  Models of comorbidity for multifactorial disorders. , 1995, American journal of human genetics.

[133]  Paul Yager,et al.  Recirculating flow accelerates DNA microarray hybridization in a microfluidic device. , 2006, Lab on a chip.

[134]  Peter Enoksson,et al.  Towards an electrowetting-based digital microfluidic platform for magnetic immunoassays. , 2009, Lab on a chip.

[135]  P. Brown,et al.  Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[136]  Bingcheng Lin,et al.  Genotyping the –6A/G functional polymorphism in the core promoter region of angiotensinogen gene by microchip electrophoresis , 2005, Electrophoresis.

[137]  Tomoyuki Taguchi,et al.  High-efficiency single-cell entrapment and fluorescence in situ hybridization analysis using a poly(dimethylsiloxane) microfluidic device integrated with a black poly(ethylene terephthalate) micromesh. , 2008, Analytical chemistry.

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

[139]  David Bryder,et al.  Transcription factor profiling in individual hematopoietic progenitors by digital RT-PCR , 2006, Proceedings of the National Academy of Sciences.

[140]  A. Scarpa,et al.  Microfluidic deletion/insertion analysis for rapid screening of KIT and PDGFRA mutations in CD117-positive gastrointestinal stromal tumors: diagnostic applications and report of a new KIT mutation. , 2007, The Journal of molecular diagnostics : JMD.

[141]  Bruce Jacob,et al.  MEMS-based embedded sensor virtual components for system-on-a-chip (SoC) , 2004 .

[142]  J. Tucker,et al.  Fluorescence in situ hybridization: A brief review , 1996, Environmental and molecular mutagenesis.

[143]  Kia Peyvan,et al.  Fully integrated miniature device for automated gene expression DNA microarray processing. , 2006, Analytical chemistry.

[144]  Wei-Ming Yeh,et al.  A microfluidic system utilizing molecularly imprinted polymer films for amperometric detection of morphine , 2007 .

[145]  Maria R. Capobianchi,et al.  A molecular beacon, bead-based assay for the detection of nucleic acids by flow cytometry , 2005, Nucleic acids research.

[146]  Vittorio Cristini,et al.  Monodispersed microfluidic droplet generation by shear focusing microfluidic device , 2006 .

[147]  Darwin R. Reyes,et al.  Micro total analysis systems. 2. Analytical standard operations and applications. , 2002, Analytical chemistry.

[148]  Antoon F. M. Moorman,et al.  Sensitive Nonradioactive Detection of mRNA in Tissue Sections: Novel Application of the Whole-mount In Situ Hybridization Protocol , 2001, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[149]  Raymond L. White,et al.  International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Meeting Report No. 2. Approaches to determining mutation rates in human DNA. , 1986, Mutation research.

[150]  Igor L. Medintz,et al.  Microfabricated 384-lane capillary array electrophoresis bioanalyzer for ultrahigh-throughput genetic analysis. , 2002, Analytical chemistry.

[151]  G. Wahl,et al.  Hybridization of nucleic acids immobilized on solid supports. , 1984, Analytical biochemistry.

[152]  M. Eichelbaum,et al.  High-throughput genotyping of thiopurine S-methyltransferase by denaturing HPLC. , 2001, Clinical chemistry.

[153]  James P Landers,et al.  A simple PDMS-based electro-fluidic interface for microchip electrophoretic separations. , 2002, The Analyst.

[154]  D. Walt,et al.  Development of a microfluidic platform with an optical imaging microarray capable of attomolar target DNA detection. , 2005, Analytical chemistry.

[155]  Fred Russell Kramer,et al.  Multicolor molecular beacons for allele discrimination , 1998, Nature Biotechnology.

[156]  A. Sandberg.  Chromosome abnormalities in human cancer and leukemia. , 1991, Mutation research.

[157]  S. J. Lee,et al.  Micro total analysis system (μ-TAS) in biotechnology , 2004, Applied Microbiology and Biotechnology.

[158]  M. Somerville,et al.  Heteroduplex-based genotyping with microchip electrophoresis and dHPLC. , 2003, Genetic testing.

[159]  A. Manz,et al.  Lab-on-a-chip: microfluidics in drug discovery , 2006, Nature Reviews Drug Discovery.

[160]  Peter Ertl,et al.  Capillary electrophoresis chips with a sheath-flow supported electrochemical detection system. , 2004, Analytical chemistry.

[161]  P. Pilarski,et al.  FISH and chips: chromosomal analysis on microfluidic platforms. , 2007, IET nanobiotechnology.

[162]  Don L DeVoe,et al.  DNA mutation detection in a polymer microfluidic network using temperature gradient gel electrophoresis. , 2004, Analytical chemistry.

[163]  D. Figeys,et al.  Lab-on-a-chip: a revolution in biological and medical sciences , 2000, Analytical chemistry.

[164]  Bill W Colston,et al.  A reusable flow-through polymerase chain reaction instrument for the continuous monitoring of infectious biological agents. , 2003, Analytical chemistry.

[165]  P. Keightley,et al.  A Comparison of Models to Infer the Distribution of Fitness Effects of New Mutations , 2013, Genetics.

[166]  R A Mathies,et al.  Turn geometry for minimizing band broadening in microfabricated capillary electrophoresis channels. , 2000, Analytical chemistry.

[167]  Zhangrun Xu,et al.  DNA mutation detection with chip-based temperature gradient capillary electrophoresis using a slantwise radiative heating system. , 2007, Lab on a chip.

[168]  B. Lin,et al.  Spatial temperature gradient capillary electrophoresis for DNA mutation detection , 2001, Electrophoresis.