Quantitative microfluidic biomolecular analysis for systems biology and medicine

In the postgenome era, biology and medicine are rapidly evolving towards quantitative and systems studies of complex biological systems. Emerging breakthroughs in microfluidic technologies and innovative applications are transforming systems biology by offering new capabilities to address the challenges in many areas, such as single-cell genomics, gene regulation networks, and pathology. In this review, we focus on recent progress in microfluidic technology from the perspective of its applications to promoting quantitative and systems biomolecular analysis in biology and medicine.

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

[2]  S. Quake,et al.  De Novo Identification and Biophysical Characterization of Transcription Factor Binding Sites with Microfluidic Affinity Analysis , 2010, Nature Biotechnology.

[3]  Han Wei Hou,et al.  Pinched flow coupled shear-modulated inertial microfluidics for high-throughput rare blood cell separation. , 2011, Lab on a chip.

[4]  Charles N. Baroud,et al.  Rails and anchors: guiding and trapping droplet microreactors in two dimensions. , 2011, Lab on a chip.

[5]  Yusi Fu,et al.  Digital polymerase chain reaction in an array of femtoliter polydimethylsiloxane microreactors. , 2012, Analytical chemistry.

[6]  Bo Lu,et al.  A cancer detection platform which measures telomerase activity from live circulating tumor cells captured on a microfilter. , 2010, Cancer research.

[7]  J. Shuga,et al.  Environmental and Molecular Mutagenesis 51:851^870 (2010) Review Article Selected Technologies for Measuring Acquired Genetic Damage in Humans , 2022 .

[8]  Raymond M. Wang,et al.  Oil-sealed femtoliter fiber-optic arrays for single molecule analysis. , 2012, Lab on a chip.

[9]  K. Isselbacher,et al.  Isolation of circulating tumor cells using a microvortex-generating herringbone-chip , 2010, Proceedings of the National Academy of Sciences.

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

[11]  A. Singh,et al.  Microscale isoelectric fractionation using photopolymerized membranes. , 2011, Analytical chemistry.

[12]  Kelly Karns,et al.  Human tear protein analysis enabled by an alkaline microfluidic homogeneous immunoassay. , 2011, Analytical chemistry.

[13]  F. Bruggeman,et al.  The nature of systems biology. , 2007, Trends in microbiology.

[14]  Minseok S. Kim,et al.  Quantitative proteomic profiling of breast cancers using a multiplexed microfluidic platform for immunohistochemistry and immunocytochemistry. , 2011, Biomaterials.

[15]  Pradeep S Rajendran,et al.  Single-cell dissection of transcriptional heterogeneity in human colon tumors , 2011, Nature Biotechnology.

[16]  V. Moreno,et al.  Nanofluidic digital PCR for KRAS mutation detection and quantification in gastrointestinal cancer. , 2012, Clinical chemistry.

[17]  S. Quake,et al.  Microfluidic Large-Scale Integration , 2002, Science.

[18]  Petra S. Dittrich,et al.  Droplet microfluidics with magnetic beads: a new tool to investigate drug–protein interactions , 2011, Analytical and bioanalytical chemistry.

[19]  R. Mathies,et al.  Integrated microfluidic systems for high-performance genetic analysis. , 2009, Trends in biotechnology.

[20]  Yong Zeng,et al.  Microfluidic self-patterning of large-scale crystalline nanoarrays for high-throughput continuous DNA fractionation. , 2008, Angewandte Chemie.

[21]  Christoph A. Merten,et al.  Functional single-cell hybridoma screening using droplet-based microfluidics , 2012, Proceedings of the National Academy of Sciences.

[22]  R. Fair,et al.  Electrowetting-based actuation of liquid droplets for microfluidic applications , 2000 .

[23]  Hong Wu,et al.  A microfluidic platform for systems pathology: multiparameter single-cell signaling measurements of clinical brain tumor specimens. , 2010, Cancer research.

[24]  William J. Greenleaf,et al.  Fluorogenic DNA Sequencing in PDMS Microreactors , 2011, Nature Methods.

[25]  K. Audus,et al.  Digital microfluidics. , 2012, Annual review of analytical chemistry.

[26]  Stephen R Quake,et al.  An in vitro microfluidic approach to generating protein-interaction networks , 2009, Nature Methods.

[27]  S. Quake,et al.  Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis , 2008, Nature Biotechnology.

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

[29]  A. Lee,et al.  Droplet microfluidics. , 2008, Lab on a chip.

[30]  S. Takeuchi,et al.  Generation of femtoliter reactor arrays within a microfluidic channel for biochemical analysis. , 2012, Analytical chemistry.

[31]  David H Wilson,et al.  Isolation and detection of single molecules on paramagnetic beads using sequential fluid flows in microfabricated polymer array assemblies. , 2012, Lab on a chip.

[32]  A. Abate,et al.  High-throughput injection with microfluidics using picoinjectors , 2010, Proceedings of the National Academy of Sciences.

[33]  Gwo-Bin Lee,et al.  Rapid isolation and detection of cancer cells by utilizing integrated microfluidic systems. , 2010, Lab on a chip.

[34]  Alexandra S. Whale,et al.  Comparison of microfluidic digital PCR and conventional quantitative PCR for measuring copy number variation , 2012, Nucleic acids research.

[35]  Sang‐Hyun Oh,et al.  Real-time full-spectral imaging and affinity measurements from 50 microfluidic channels using nanohole surface plasmon resonance. , 2012, Lab on a chip.

[36]  C. Mastrangelo,et al.  Low noise detection of biomolecular interactions with signal-locking surface plasmon resonance. , 2010, Analytical chemistry.

[37]  Gavin MacBeath,et al.  A quantitative protein interaction network for the ErbB receptors using protein microarrays , 2006, Nature.

[38]  Hiroyuki Fujita,et al.  Microfabricated arrays of femtoliter chambers allow single molecule enzymology , 2005, Nature Biotechnology.

[39]  Rong Fan,et al.  A Clinical Microchip for Evaluation of Single Immune Cells Reveals High Functional Heterogeneity in Phenotypically Similar T Cells Nih Public Access Author Manuscript Design Rationale and Detection Limit of the Scbc Online Methods Microchip Fabrication On-chip Secretion Profiling Supplementary Mater , 2022 .

[40]  R. Garrell,et al.  Fluorinated liquid-enabled protein handling and surfactant-aided crystallization for fully in situ digital microfluidic MALDI-MS analysis. , 2012, Lab on a chip.

[41]  Polly M Fordyce,et al.  Basic leucine zipper transcription factor Hac1 binds DNA in two distinct modes as revealed by microfluidic analyses , 2012, Proceedings of the National Academy of Sciences.

[42]  Steve C. C. Shih,et al.  Dried blood spot analysis by digital microfluidics coupled to nanoelectrospray ionization mass spectrometry. , 2012, Analytical chemistry.

[43]  D. Figeys,et al.  New ammunition for the proteomic reactor: strong anion exchange beads and multiple enzymes enhance protein identification and sequence coverage , 2010, Analytical and bioanalytical chemistry.

[44]  C. Kim,et al.  Electrowetting and electrowetting-on-dielectric for microscale liquid handling , 2002 .

[45]  Samuel Aparicio,et al.  High-throughput microfluidic single-cell RT-qPCR , 2011, Proceedings of the National Academy of Sciences.

[46]  Chaoyong James Yang,et al.  Massively parallel single-molecule and single-cell emulsion reverse transcription polymerase chain reaction using agarose droplet microfluidics. , 2012, Analytical chemistry.

[47]  K. Kinzler,et al.  Digital PCR. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Abraham P Lee,et al.  A Laplace pressure based microfluidic trap for passive droplet trapping and controlled release. , 2012, Biomicrofluidics.

[49]  Andrew D Griffiths,et al.  A completely in vitro ultrahigh-throughput droplet-based microfluidic screening system for protein engineering and directed evolution. , 2012, Lab on a chip.

[50]  Marcel Geertz,et al.  Massively parallel measurements of molecular interaction kinetics on a microfluidic platform , 2012, Proceedings of the National Academy of Sciences.

[51]  Qin Tu,et al.  Dynamic trapping and high-throughput patterning of cells using pneumatic microstructures in an integrated microfluidic device. , 2012, Lab on a chip.

[52]  U. Sauer,et al.  Getting Closer to the Whole Picture , 2007, Science.

[53]  M. Hung,et al.  High speed digital protein interaction analysis using microfluidic single molecule detection system. , 2010, Lab on a chip.

[54]  S. Quake,et al.  Monolithic microfabricated valves and pumps by multilayer soft lithography. , 2000, Science.

[55]  Stephanie Forrest,et al.  Modeling Somatic Evolution in Tumorigenesis , 2006, PLoS Comput. Biol..

[56]  J. Ramsey,et al.  High yield sample preconcentration using a highly ion-conductive charge-selective polymer. , 2010, Analytical chemistry.

[57]  Sindy K. Y. Tang,et al.  Uniform amplification of phage with different growth characteristics in individual compartments consisting of monodisperse droplets. , 2010, Angewandte Chemie.

[58]  Amy E. Herr,et al.  Microfluidic integration for automated targeted proteomic assays , 2012, Proceedings of the National Academy of Sciences.

[59]  Richard Novak,et al.  High-performance single cell genetic analysis using microfluidic emulsion generator arrays. , 2010, Analytical chemistry.

[60]  D A Weitz,et al.  Surface acoustic wave actuated cell sorting (SAWACS). , 2010, Lab on a chip.

[61]  Christopher Lausted,et al.  Parallel microfluidic surface plasmon resonance imaging arrays. , 2010, Lab on a chip.

[62]  Erik C Jensen,et al.  Lifting gate polydimethylsiloxane microvalves and pumps for microfluidic control. , 2012, Analytical chemistry.

[63]  Jungkyu Kim,et al.  Microvalve Enabled Digital Microfluidic Systems for High-Performance Biochemical and Genetic Analysis , 2010, JALA.

[64]  Nancy L Allbritton,et al.  Trapping cells on a stretchable microwell array for single-cell analysis , 2011, Analytical and Bioanalytical Chemistry.

[65]  Benjamin J. Hindson,et al.  Evaluation of a Droplet Digital Polymerase Chain Reaction Format for DNA Copy Number Quantification , 2011, Analytical chemistry.

[66]  R. Garrell,et al.  Integration of protein processing steps on a droplet microfluidics platform for MALDI-MS analysis. , 2010, Analytical chemistry.

[67]  J. Derisi,et al.  Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise , 2006, Nature.

[68]  Han Wei Hou,et al.  Deformability based cell margination--a simple microfluidic design for malaria-infected erythrocyte separation. , 2010, Lab on a chip.

[69]  Sau Yin Chin,et al.  Microfluidic CD4+ T-cell counting device using chemiluminescence-based detection. , 2010, Analytical chemistry.

[70]  D. Weitz,et al.  Droplet microfluidics for high-throughput biological assays. , 2012, Lab on a chip.

[71]  Andrew D Griffiths,et al.  Selective droplet coalescence using microfluidic systems. , 2012, Lab on a chip.

[72]  D. J. Harrison,et al.  Self-assembled colloidal arrays as three-dimensional nanofluidic sieves for separation of biomolecules on microchips. , 2007, Analytical chemistry.

[73]  E. Greisheimer,et al.  The proteins. , 1955, Journal of the American Medical Women's Association.

[74]  Fully automated isotopic dimethyl labeling and phosphopeptide enrichment using a microfluidic HPLC phosphochip , 2012, Analytical and Bioanalytical Chemistry.

[75]  Teodor Veres,et al.  Integration and detection of biochemical assays in digital microfluidic LOC devices. , 2010, Lab on a chip.

[76]  F. Tang,et al.  Development and applications of single-cell transcriptome analysis , 2011, Nature Methods.

[77]  Jason P. Gleghorn,et al.  Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. , 2010, Lab on a chip.

[78]  A. Herr,et al.  Multianalyte on-chip native Western blotting. , 2011, Analytical chemistry.

[79]  Aaron R Wheeler,et al.  A digital microfluidic approach to heterogeneous immunoassays , 2011, Analytical and bioanalytical chemistry.

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

[81]  S. Quake,et al.  Single-cell genomics , 2011, Nature Methods.

[82]  J. Shuga,et al.  Single-cell multiplex gene detection and sequencing with microfluidically generated agarose emulsions. , 2011, Angewandte Chemie.

[83]  David M. Rissin,et al.  Single-Molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations , 2010, Nature Biotechnology.

[84]  Mehmet Toner,et al.  Nanoporous elements in microfluidics for multiscale manipulation of bioparticles. , 2011, Small.

[85]  Mais J. Jebrail,et al.  Digital microfluidics: a versatile tool for applications in chemistry, biology and medicine. , 2012, Lab on a chip.

[86]  S. Digumarthy,et al.  Isolation of rare circulating tumour cells in cancer patients by microchip technology , 2007, Nature.

[87]  Stephen R Quake,et al.  Whole-genome molecular haplotyping of single cells , 2011, Nature Biotechnology.

[88]  Michael P Snyder,et al.  High-throughput sequencing for biology and medicine , 2013, Molecular systems biology.

[89]  Francis Barany,et al.  High-throughput selection, enumeration, electrokinetic manipulation, and molecular profiling of low-abundance circulating tumor cells using a microfluidic system. , 2011, Analytical chemistry.

[90]  Xize Niu,et al.  Building droplet-based microfluidic systems for biological analysis. , 2012, Biochemical Society transactions.

[91]  A. deMello,et al.  A microdroplet dilutor for high-throughput screening. , 2011, Nature chemistry.

[92]  Paraskevi Giannakakou,et al.  Functional Characterization of Circulating Tumor Cells with a Prostate-Cancer-Specific Microfluidic Device , 2012, PloS one.

[93]  Mehmet Toner,et al.  Antibody-functionalized fluid-permeable surfaces for rolling cell capture at high flow rates. , 2012, Biophysical journal.

[94]  Bing Sun,et al.  Multiplexed quantification of nucleic acids with large dynamic range using multivolume digital RT-PCR on a rotational SlipChip tested with HIV and hepatitis C viral load. , 2011, Journal of the American Chemical Society.

[95]  K. C. Chan,et al.  Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. , 2011, Blood.

[96]  Marcel Geertz,et al.  iSLIM: a comprehensive approach to mapping and characterizing gene regulatory networks , 2012, Nucleic acids research.

[97]  Mehmet Toner,et al.  Isolation and Characterization of Circulating Tumor Cells from Patients with Localized and Metastatic Prostate Cancer , 2010, Science Translational Medicine.

[98]  A. Abate,et al.  Ultrahigh-throughput screening in drop-based microfluidics for directed evolution , 2010, Proceedings of the National Academy of Sciences.

[99]  Todd Munson,et al.  Theoretical design and analysis of multivolume digital assays with wide dynamic range validated experimentally with microfluidic digital PCR. , 2011, Analytical chemistry.

[100]  Yong-Ak Song,et al.  Enhancing protease activity assay in droplet-based microfluidics using a biomolecule concentrator. , 2011, Journal of the American Chemical Society.

[101]  James A Glazier,et al.  Microfluidic devices integrating microcavity surface-plasmon-resonance sensors: glucose oxidase binding-activity detection. , 2010, Analytical chemistry.

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

[103]  Andrew C. Oates,et al.  Quantitative approaches in developmental biology , 2009, Nature Reviews Genetics.

[104]  Tanyu Wang,et al.  Programmable active droplet generation enabled by integrated pneumatic micropumps. , 2013, Lab on a chip.

[105]  M. Toner,et al.  Nanoporous micro-element arrays for particle interception in microfluidic cell separation. , 2012, Lab on a chip.

[106]  Miles A. Miller,et al.  Multiplexed protease activity assay for low-volume clinical samples using droplet-based microfluidics and its application to endometriosis. , 2013, Journal of the American Chemical Society.

[107]  D. J. Harrison,et al.  Confinement effects on the morphology of photopatterned porous polymer monoliths for capillary and microchip electrophoresis of proteins , 2008, Electrophoresis.

[108]  Cesar M. Castro,et al.  Ultrasensitive Clinical Enumeration of Rare Cells ex Vivo Using a Micro-Hall Detector , 2012, Science Translational Medicine.

[109]  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.

[110]  Samuel K Sia,et al.  Commercialization of microfluidic point-of-care diagnostic devices. , 2012, Lab on a chip.

[111]  A. Manz,et al.  Miniaturized total chemical analysis systems: A novel concept for chemical sensing , 1990 .

[112]  S. Quake,et al.  A Systems Approach to Measuring the Binding Energy Landscapes of Transcription Factors , 2007, Science.

[113]  Klaus Eyer,et al.  A microchamber array for single cell isolation and analysis of intracellular biomolecules. , 2012, Lab on a chip.

[114]  Mehmet Toner,et al.  Biopolymer system for cell recovery from microfluidic cell capture devices. , 2012, Analytical chemistry.

[115]  Shu-Ling Lin,et al.  Microfluidic chip‐based liquid chromatography coupled to mass spectrometry for determination of small molecules in bioanalytical applications , 2012, Electrophoresis.

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

[117]  J. Ramsey,et al.  Monolithic integration of two-dimensional liquid chromatography-capillary electrophoresis and electrospray ionization on a microfluidic device. , 2011, Analytical chemistry.

[118]  Paul J. Choi,et al.  Quantifying E. coli Proteome and Transcriptome with Single-Molecule Sensitivity in Single Cells , 2010, Science.

[119]  S. J. R. Staton,et al.  Blood cell capture in a sawtooth dielectrophoretic microchannel , 2011, Analytical and bioanalytical chemistry.

[120]  S. Quake,et al.  High-performance binary protein interaction screening in a microfluidic format. , 2012, Analytical chemistry.

[121]  Kangsun Lee,et al.  Parallel synchronization of two trains of droplets using a railroad-like channel network. , 2011, Lab on a chip.

[122]  Jeff Mellen,et al.  High-Throughput Droplet Digital PCR System for Absolute Quantitation of DNA Copy Number , 2011, Analytical chemistry.

[123]  Polyacrylamide gel photopatterning enables automated protein immunoblotting in a two-dimensional microdevice. , 2010, Journal of the American Chemical Society.

[124]  R. Gomez-Sjoberg,et al.  Multinozzle emitter array chips for small-volume proteomics. , 2013, Analytical chemistry.

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

[126]  Zhiqiang Gao,et al.  A microfluidic-assisted microarray for ultrasensitive detection of miRNA under an optical microscope. , 2011, Lab on a chip.

[127]  Amy E Herr,et al.  Membrane-assisted online renaturation for automated microfluidic lectin blotting. , 2011, Journal of the American Chemical Society.

[128]  Ben S. Wittner,et al.  Corrigendum: RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis , 2012, Nature.

[129]  Jim F Huggett,et al.  Evaluation of digital PCR for absolute DNA quantification. , 2011, Analytical chemistry.

[130]  Chang-Yu Chen,et al.  Electrical isolation and characteristics of permanent magnet-actuated valves for PDMS microfluidics. , 2011, Lab on a chip.

[131]  J. Lechner-Scott,et al.  Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome , 2012, PloS one.

[132]  A. van Oudenaarden,et al.  Quantitative time-lapse fluorescence microscopy in single cells. , 2009, Annual review of cell and developmental biology.

[133]  Aaron Wheeler,et al.  Putting Electrowetting to Work , 2008, Science.

[134]  Howard Y. Chang,et al.  Systematic reconstruction of RNA functional motifs with high-throughput microfluidics , 2012, Nature Methods.

[135]  A. Wheeler,et al.  A digital microfluidic method for in situ formation of porous polymer monoliths with application to solid-phase extraction. , 2011, Analytical chemistry.

[136]  Mehmet Toner,et al.  Clinical Microfluidics for Neutrophil Genomics and Proteomics , 2010, Nature Medicine.

[137]  E. Kumacheva,et al.  Digital microfluidic hydrogel microreactors for proteomics , 2012, Proteomics.

[138]  X. D. Hoa,et al.  Development of a multiplexed microfluidic proteomic reactor and its application for studying protein-protein interactions. , 2011, Analytical chemistry.

[139]  Patrick S Doyle,et al.  Rapid microRNA profiling on encoded gel microparticles. , 2011, Angewandte Chemie.

[140]  A. Jemere,et al.  Tunable thick polymer coatings for on-chip electrophoretic protein and peptide separation. , 2012, Journal of chromatography. A.

[141]  Stephen R Quake,et al.  Proteome-wide protein interaction measurements of bacterial proteins of unknown function , 2012, Proceedings of the National Academy of Sciences.

[142]  Ron R Lin,et al.  High-throughput single-molecule optofluidic analysis , 2011, Nature Methods.

[143]  Gyan Bhanot,et al.  Single Cell Profiling of Circulating Tumor Cells: Transcriptional Heterogeneity and Diversity from Breast Cancer Cell Lines , 2012, PloS one.

[144]  Tzu-Chiao Chao,et al.  Microfluidic devices for high‐throughput proteome analyses , 2013, Proteomics.

[145]  William H. Grover,et al.  Monolithic membrane valves and diaphragm pumps for practical large-scale integration into glass microfluidic devices , 2003 .

[146]  Stephen R. Quake,et al.  Genome-wide Single-Cell Analysis of Recombination Activity and De Novo Mutation Rates in Human Sperm , 2012, Cell.

[147]  Shashi K Murthy,et al.  Engineered alginate hydrogels for effective microfluidic capture and release of endothelial progenitor cells from whole blood. , 2011, Langmuir : the ACS journal of surfaces and colloids.

[148]  D. Dressman,et al.  Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[149]  Jean Salamero,et al.  Microfluidic sorting and multimodal typing of cancer cells in self-assembled magnetic arrays , 2010, Proceedings of the National Academy of Sciences.

[150]  Avishay Bransky,et al.  Coalescence-assisted generation of single nanoliter droplets with predefined composition. , 2011, Lab on a chip.