Digital Microfluidics for Manipulation and Analysis of a Single Cell

The basic structural and functional unit of a living organism is a single cell. To understand the variability and to improve the biomedical requirement of a single cell, its analysis has become a key technique in biological and biomedical research. With a physical boundary of microchannels and microstructures, single cells are efficiently captured and analyzed, whereas electric forces sort and position single cells. Various microfluidic techniques have been exploited to manipulate single cells through hydrodynamic and electric forces. Digital microfluidics (DMF), the manipulation of individual droplets holding minute reagents and cells of interest by electric forces, has received more attention recently. Because of ease of fabrication, compactness and prospective automation, DMF has become a powerful approach for biological application. We review recent developments of various microfluidic chips for analysis of a single cell and for efficient genetic screening. In addition, perspectives to develop analysis of single cells based on DMF and emerging functionality with high throughput are discussed.

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

[2]  Oscar Ces,et al.  Addressable droplet microarrays for single cell protein analysis. , 2014, The Analyst.

[3]  Wensyang Hsu,et al.  Droplet-on-a-wristband: chip-to-chip digital microfluidic interfaces between replaceable and flexible electrowetting modules. , 2011, Lab on a chip.

[4]  J. Lammertyn,et al.  A versatile electrowetting-based digital microfluidic platform for quantitative homogeneous and heterogeneous bio-assays , 2011 .

[5]  F. Watt,et al.  Stem cell heterogeneity and plasticity in epithelia. , 2015, Cell stem cell.

[6]  Stephen R Quake,et al.  Digital PCR provides absolute quantitation of viral load for an occult RNA virus. , 2012, Journal of virological methods.

[7]  Helene Andersson-Svahn,et al.  High-Density Microwell Chip for Culture and Analysis of Stem Cells , 2009, PloS one.

[8]  S. Fan,et al.  General digital microfluidic platform manipulating dielectric and conductive droplets by dielectrophoresis and electrowetting. , 2009, Lab on a chip.

[9]  Hongshen Ma,et al.  Microfluidic biomechanical assay for red blood cells parasitized by Plasmodium falciparum. , 2012, Lab on a chip.

[10]  S. Ginsberg,et al.  RNA amplification strategies for small sample populations. , 2005, Methods.

[11]  Alison M Thompson,et al.  Microfluidics for single-cell genetic analysis. , 2014, Lab on a chip.

[12]  M. Hertog,et al.  Digital microfluidic chip technology for water permeability measurements on single isolated plant protoplasts , 2014 .

[13]  R. Jaenisch,et al.  Microfluidic Control of Cell Pairing and Fusion , 2009, Nature Methods.

[14]  Luke P. Lee,et al.  Dynamic single cell culture array. , 2006, Lab on a chip.

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

[16]  J. Harper,et al.  The use of arrays in preimplantation genetic diagnosis and screening. , 2010, Fertility and sterility.

[17]  I Cristiani,et al.  An integrated optofluidic device for single-cell sorting driven by mechanical properties. , 2015, Lab on a chip.

[18]  S. Fan,et al.  Cross-scale electric manipulations of cells and droplets by frequency-modulated dielectrophoresis and electrowetting. , 2008, Lab on a chip.

[19]  Guillaume Mernier,et al.  Characterization of a novel impedance cytometer design and its integration with lateral focusing by dielectrophoresis. , 2012, Lab on a chip.

[20]  Chun-Ping Jen,et al.  Single-Cell Electric Lysis on an Electroosmotic-Driven Microfluidic Chip with Arrays of Microwells , 2012, Sensors.

[21]  J E Swain,et al.  Microfluidics for gametes, embryos, and embryonic stem cells. , 2011, Seminars in reproductive medicine.

[22]  Dino Di Carlo,et al.  Hydrodynamic stretching of single cells for large population mechanical phenotyping , 2012, Proceedings of the National Academy of Sciences.

[23]  Katsuo Kurabayashi,et al.  Recent advancements in optofluidics-based single-cell analysis: optical on-chip cellular manipulation, treatment, and property detection. , 2014, Lab on a chip.

[24]  Peter Dubruel,et al.  Chip-based impedance measurement on single cells for monitoring sub-toxic effects on cell membranes. , 2011, Biosensors & bioelectronics.

[25]  Masahito Hosokawa,et al.  Monitoring of cellular behaviors by microcavity array-based single-cell patterning. , 2014, The Analyst.

[26]  J. Lammertyn,et al.  Biofunctionalization of electrowetting-on-dielectric digital microfluidic chips for miniaturized cell-based applications. , 2011, Lab on a chip.

[27]  D. Marshall,et al.  Microfluidics for single cell analysis. , 2012, Current opinion in biotechnology.

[28]  Falk Wottawah,et al.  Oral cancer diagnosis by mechanical phenotyping. , 2009, Cancer research.

[29]  Eric P. Y. Chiou,et al.  EWOD-driven droplet microfluidic device integrated with optoelectronic tweezers as an automated platform for cellular isolation and analysis. , 2009, Lab on a chip.

[30]  Fanyi Zeng,et al.  Transcript profiling during preimplantation mouse development. , 2004, Developmental biology.

[31]  J. Lammertyn,et al.  Controlling droplet size variability of a digital lab-on-a-chip for improved bio-assay performance , 2011 .

[32]  Stephen R Quake,et al.  Microfluidic single-cell mRNA isolation and analysis. , 2006, Analytical chemistry.

[33]  Daniel A Fletcher,et al.  Analyzing cell mechanics in hematologic diseases with microfluidic biophysical flow cytometry. , 2008, Lab on a chip.

[34]  J E Swain,et al.  Advances in embryo culture platforms: novel approaches to improve preimplantation embryo development through modifications of the microenvironment. , 2011, Human reproduction update.

[35]  K. Niakan,et al.  Human pre-implantation embryo development , 2012, Development.

[36]  Saram Lee,et al.  A label-free DC impedance-based microcytometer for circulating rare cancer cell counting. , 2013, Lab on a chip.

[37]  Ralph Weissleder,et al.  Cancer Cell Profiling by Barcoding Allows Multiplexed Protein Analysis in Fine-Needle Aspirates , 2014, Science Translational Medicine.

[38]  E. Shapiro,et al.  Single-cell sequencing-based technologies will revolutionize whole-organism science , 2013, Nature Reviews Genetics.

[39]  S. Bodovitz,et al.  Single cell analysis: the new frontier in 'omics'. , 2010, Trends in biotechnology.

[40]  J. Rossier,et al.  Integrating whole transcriptome assays on a lab-on-a-chip for single cell gene profiling. , 2008, Lab on a chip.

[41]  Ling-Sheng Jang,et al.  Microfluidic device for cell capture and impedance measurement , 2007, Biomedical microdevices.

[42]  Julian Parkhill,et al.  Single-cell genomics , 2008, Nature Reviews Microbiology.

[43]  Arkadiusz Pierzchalski,et al.  Microfluidic impedance‐based flow cytometry , 2010, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[44]  H. Moon,et al.  On-chip characterization of cryoprotective agent mixtures using an EWOD-based digital microfluidic device. , 2011, Lab on a chip.

[45]  J. Voldman,et al.  A scalable addressable positive-dielectrophoretic cell-sorting array. , 2005, Analytical chemistry.

[46]  Dino Di Carlo,et al.  Reagentless mechanical cell lysis by nanoscale barbs in microchannels for sample preparation. , 2003, Lab on a chip.

[47]  Chang Lu,et al.  Microfluidic electroporative flow cytometry for studying single-cell biomechanics. , 2008, Analytical chemistry.

[48]  T. G. Mitchell,et al.  Multiplexed real-time polymerase chain reaction on a digital microfluidic platform. , 2010, Analytical chemistry.

[49]  A. Manz,et al.  Micro total analysis systems. Latest advancements and trends. , 2006, Analytical chemistry.

[50]  A. B. Frazier,et al.  Microsystems for isolation and electrophysiological analysis of breast cancer cells from blood. , 2006, Biosensors & bioelectronics.

[51]  Liying Yan,et al.  Advances in preimplantation genetic diagnosis/screening , 2014, Science China Life Sciences.

[52]  Dino Di Carlo,et al.  Dynamic single-cell analysis for quantitative biology. , 2006, Analytical chemistry.

[53]  Subra Suresh,et al.  A microfabricated deformability-based flow cytometer with application to malaria. , 2011, Lab on a chip.

[54]  X. Gidrol,et al.  An EWOD-based microfluidic chip for single-cell isolation, mRNA purification and subsequent multiplex qPCR. , 2014, Lab on a chip.

[55]  N. Perrimon,et al.  Droplet microfluidic technology for single-cell high-throughput screening , 2009, Proceedings of the National Academy of Sciences.

[56]  Chengxiao Zhang,et al.  Chip based single cell analysis for nanotoxicity assessment. , 2014, The Analyst.

[57]  Christoph A. Merten,et al.  Drop-based microfluidic devices for encapsulation of single cells. , 2008, Lab on a chip.

[58]  A. E. Eckhardt,et al.  Evaluation of a digital microfluidic real-time PCR platform to detect DNA of Candida albicans in blood , 2012, European Journal of Clinical Microbiology & Infectious Diseases.

[59]  Daniel T. Chiu,et al.  Self-Digitization Microfluidic Chip for Absolute Quantification of mRNA in Single Cells , 2014, Analytical chemistry.

[60]  Chun-Ping Jen,et al.  Single-Cell Chemical Lysis on Microfluidic Chips with Arrays of Microwells , 2011, Sensors.

[61]  Paul H. Bessette,et al.  Marker-specific sorting of rare cells using dielectrophoresis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[62]  Helene Andersson-Svahn,et al.  A microwell array device with integrated microfluidic components for enhanced single‐cell analysis , 2009, Electrophoresis.

[63]  S. Fan,et al.  Transmittance tuning by particle chain polarization in electrowetting-driven droplets. , 2010, Biomicrofluidics.

[64]  S. Lindström,et al.  Miniaturization of biological assays -- overview on microwell devices for single-cell analyses. , 2011, Biochimica et biophysica acta.

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

[66]  Elinore M Mercer,et al.  Microfluidic sorting of mammalian cells by optical force switching , 2005, Nature Biotechnology.

[67]  Nikolai Dechev,et al.  A novel permalloy based magnetic single cell micro array. , 2009, Lab on a chip.

[68]  Dorielle T. Price,et al.  Effect of electrode geometry on the impedance evaluation of tissue and cell culture , 2007 .

[69]  Stefan Schinkinger,et al.  Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. , 2005, Biophysical journal.

[70]  Hywel Morgan,et al.  Continuous differential impedance spectroscopy of single cells , 2009, Microfluidics and nanofluidics.

[71]  Hakho Lee,et al.  Rare cell isolation and profiling on a hybrid magnetic/size-sorting chip. , 2013, Biomicrofluidics.

[72]  M. Bennett,et al.  Microfluidic devices for measuring gene network dynamics in single cells , 2009, Nature Reviews Genetics.

[73]  Orli G. Bahcall.  Single cell resolution in regulation of gene expression , 2005, Molecular systems biology.

[74]  K. Cheung,et al.  Droplet-based microfluidic system for multicellular tumor spheroid formation and anticancer drug testing. , 2010, Lab on a chip.

[75]  Rolf Larsson,et al.  Towards high‐throughput single cell/clone cultivation and analysis , 2008, Electrophoresis.

[76]  S. Horvath,et al.  Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing , 2013, Nature.

[77]  Albert van den Berg,et al.  Single cells as experimentation units in lab-ona-chip devices , 2010 .

[78]  R. Wu,et al.  Systems Mapping for Hematopoietic Progenitor Cell Heterogeneity , 2015, PloS one.

[79]  A. Valero,et al.  Optimization of microfluidic single cell trapping for long-term on-chip culture. , 2010, Lab on a chip.

[80]  Ching-Hsiang Hsu,et al.  Particle chain display--an optofluidic electronic paper. , 2012, Lab on a chip.

[81]  C. Giménez,et al.  Preimplantation genetic screening and human implantation. , 2002, Journal of reproductive immunology.

[82]  Shih-Kang Fan,et al.  Asymmetric electrowetting--moving droplets by a square wave. , 2007, Lab on a chip.

[83]  Shih-Kang Fan,et al.  Reconfigurable liquid pumping in electric-field-defined virtual microchannels by dielectrophoresis. , 2009, Lab on a chip.

[84]  Siyang Zheng,et al.  Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. , 2007, Journal of chromatography. A.

[85]  A. Wheeler,et al.  Digital microfluidics for cell-based assays. , 2008, Lab on a chip.

[86]  Ling-Sheng Jang,et al.  Integration of single-cell trapping and impedance measurement utilizing microwell electrodes. , 2011, Biosensors & bioelectronics.

[87]  Christoph A. Merten,et al.  Droplet-based microfluidic platforms for the encapsulation and screening of Mammalian cells and multicellular organisms. , 2008, Chemistry & biology.

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

[89]  T. Graf,et al.  Heterogeneity of embryonic and adult stem cells. , 2008, Cell stem cell.

[90]  Numrin Thaitrong,et al.  Integrated microfluidic bioprocessor for single-cell gene expression analysis , 2008, Proceedings of the National Academy of Sciences.

[91]  S. Shoji.  Micro Total Analysis Systems , 1999 .

[92]  P. Swain,et al.  Strategies for cellular decision-making , 2009, Molecular systems biology.

[93]  Albert van den Berg,et al.  Single cells or large populations? , 2007, Lab on a chip.

[94]  Xuena Zhu,et al.  Lab-on-chip device for single cell trapping and analysis , 2014, Biomedical microdevices.

[95]  Tae Song Kim,et al.  Single-cell assay on CD-like lab chip using centrifugal massive single-cell trap , 2008 .

[96]  Qingming Luo,et al.  Microfluidic chip: next-generation platform for systems biology. , 2009, Analytica chimica acta.

[97]  Helene Andersson-Svahn,et al.  PCR amplification and genetic analysis in a microwell cell culturing chip. , 2009, Lab on a chip.

[98]  Cheng-Hsien Liu,et al.  Digital Microfluidic Dynamic Culture of Mammalian Embryos on an Electrowetting on Dielectric (EWOD) Chip , 2015, PloS one.

[99]  Aaron R Wheeler,et al.  Digital microfluidics with impedance sensing for integrated cell culture and analysis. , 2013, Biosensors & bioelectronics.

[100]  Philip S Low,et al.  Single-cell electrical lysis of erythrocytes detects deficiencies in the cytoskeletal protein network. , 2011, Lab on a chip.

[101]  Peter C. Y. Chen,et al.  Real-time control of a microfluidic channel for size-independent deformability cytometry , 2012 .

[102]  Steve C. C. Shih,et al.  A droplet-to-digital (D2D) microfluidic device for single cell assays. , 2015, Lab on a chip.