Digital microfluidics: A promising technique for biochemical applications
He WANG1,2, Liguo CHEN1(), Lining SUN1
1. Robotics and Microsystems Center, Soochow University, Soochow 215006, China 2. School of Mechanical Engineering, Henan University of Engineering, Zhengzhou 451191, China
Digital microfluidics (DMF) is a versatile microfluidics technology that has significant application potential in the areas of automation and miniaturization. In DMF, discrete droplets containing samples and reagents are controlled to implement a series of operations via electrowetting-on-dielectric. This process works by applying electrical potentials to an array of electrodes coated with a hydrophobic dielectric layer. Unlike microchannels, DMF facilitates precise control over multiple reaction processes without using complex pump, microvalve, and tubing networks. DMF also presents other distinct features, such as portability, less sample consumption, shorter chemical reaction time, flexibility, and easier combination with other technology types. Due to its unique advantages, DMF has been applied to a broad range of fields (e.g., chemistry, biology, medicine, and environment). This study reviews the basic principles of droplet actuation, configuration design, and fabrication of the DMF device, as well as discusses the latest progress in DMF from the biochemistry perspective.
Terry S C, Jerman J H, Angell J B. A gas chromatographic air analyzer fabricated on a silicon wafer. IEEE Transactions on Electron Devices, 1979, 26(12): 1880–1886 https://doi.org/10.1109/T-ED.1979.19791
2
Reyes D R, Iossifidis D, Auroux P A, et al. Micro total analysis system. 1. Introduction, theory, and technology. Analitical Chemistry, 2002, 74(12): 2623–2636 https://doi.org/ 10.1021/ac0202435
Pollack M G, Shenderov A D, Fair R B. Electrowetting-based actuation of droplets for integrated microfluidics. Lab on a Chip, 2002, 2(2): 96–101 https://doi.org/10.1039/b110474h
5
Washizu M. Electrostatic actuation of liquid droplets for microreactor applications. IEEE Transactions on Industry Applications, 1998, 34(4): 732–737 https://doi.org/10.1109/28.703965
6
Cho S K, Fan S K, Moon H, et al. Towards digital microfluidic circuits: Creating, transporting, cutting and merging liquid droplets by electrowetting-based actuation. In: Proceedings of the Fifteenth IEEE International Conference on Micro Electro Mechanical Systems. Las Vegas: IEEE, 2002, 32–35 https://doi.org/10.1109/MEMSYS.2002.984073
7
Cho S K, Moon H, Kim C J. Creating, transporting, cutting, and merging liquid droplets by electrowetting-based actuation for digital microfluidic circuits. Journal of Microelectromechanical Systems, 2003, 12(1): 70–80 https://doi.org/10.1109/JMEMS.2002.807467
8
Berthier J. Microdrops and Digital Microfluidics. Norwich: William Andrew Inc., 2008
9
Wang W, Jones T B. Moving droplets between closed and open microfluidic systems. Lab on a Chip, 2015, 15(10): 2201–2212 https://doi.org/10.1039/C5LC00014A
Hsieh T H, Fan S K. Dielectric droplet manipulations by electropolarization forces. In: Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems. Piskataway: IEEE, 2008, 641–644
12
Jones T B, Wang K L, Yao D J. Frequency-dependent electromechanics of aqueous liquids: Electrowetting and dielectrophoresis. Langmuir, 2004, 20(7): 2813–2818 https://doi.org/10.1021/la035982a
Gupta R, Sheth D M, Boone T K, et al. Impact of pinning of the triple contact line on electrowetting performance. Langmuir, 2011, 27(24): 14923–14929 https://doi.org/10.1021/la203320g
Kang K H. How electrostatic fields change contact angle in electrowetting. Langmuir, 2002, 18(26): 10318–10322 https://doi.org/10.1021/la0263615
17
Peykov V, Quinn A, Ralston J. Electrowetting: A model for contact-angle saturation. Colloid & Polymer Science, 2000, 278(8): 789–793 https://doi.org/10.1007/s003960000333
18
Darhuber A A, Chen J Z, Davis J M, et al. A study of mixing in thermocapillary flows on micropatterned surfaces. Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences, 2004, 362(1818): 1037–1058 https://doi.org/10.1098/rsta.2003.1361
19
Darhuber A A, Valentino J P, Troian S M. Planar digital nanoliter dispensing system based on thermocapillary actuation. Lab on a Chip, 2010, 10(8): 1061–1071 https://doi.org/10.1039/b921759b
20
Heron S R, Wilson R, Shaffer S A, et al. Surface acoustic wave nebulization of peptides as a microfluidic interface for mass spectrometry. Analytical Chemistry, 2010, 82(10): 3985–3989 https://doi.org/10.1021/ac100372c
21
Jin H, Zhou J, He X, et al. Flexible surface acoustic wave resonators built on disposable plastic film for electronics and lab-on-a-chip applications. Scientific Reports, 2013, 3: 2140 https://doi.org/10.1038/srep02140
22
Pang H, Fu Y, Garcia-Gancedo L, et al. Enhancement of microfluidic efficiency with nanocrystalline diamond interlayer in the ZnO-based surface acoustic wave device. Microfluidics and Nanofluidics, 2013, 15(3): 377–386 https://doi.org/10.1007/s10404-013-1155-3
23
Shilton R J, Mattoli V, Travagliati M, et al. Rapid and controllable digital microfluidic heating by surface acoustic waves. Advanced Functional Materials, 2015, 25(37): 5895–5901 https://doi.org/10.1002/adfm.201501130
Gu H, Duits M H G, Mugele F. Droplets formation and merging in two-phase flow microfluidics. International Journal of Molecular Sciences, 2011, 12(12): 2572–2597 https://doi.org/10.3390/ijms12042572
26
Renaudot R, Agache V, Daunay B, et al. Optimization of liquid dielectrophoresis (LDEP) digital microfluidic transduction for biomedical applications. Micromachines, 2011, 2(4): 258–273 https://doi.org/10.3390/mi2020258
27
Renaudot R, Daunay B, Kumemura M, et al. Optimized micro devices for liquid-dielectrophoresis (LDEP) actuation of conductive solutions. Sensors and Actuators B: Chemical, 2013, 177: 620–626 https://doi.org/10.1016/j.snb.2012.11.049
28
Timonen J V I, Latikka M, Leibler L, et al. Switchable static and dynamic self-assembly of magnetic droplets on superhydrophobic surfaces. Science, 2013, 341(6143): 253–257 https://doi.org/10.1126/science.1233775
29
Ng A H C, Choi K, Luoma R P, et al. Digital microfluidic magnetic separation for particle-based immunoassays. Analytical Chemistry, 2012, 84(20): 8805–8812 https://doi.org/10.1021/ac3020627
30
Witters D, Knez K, Ceyssens F, et al. Digital microfluidics-enabled single-molecule detection by printing and sealing single magnetic beads in femtoliter droplets. Lab on a Chip, 2013, 13(11): 2047–2054 https://doi.org/10.1039/c3lc50119a
31
Shi D, Bi Q, He Y, et al. Experimental investigation on falling ferrofluid droplets in vertical magnetic fields. Experimental Thermal and Fluid Science, 2014, 54: 313–320 https://doi.org/10.1016/j.expthermflusci.2014.01.010
Kumar A, Williams S J, Chuang H S, et al. Hybrid opto-electric manipulation in microfluidics—Opportunities and challenges. Lab on a Chip, 2011, 11(13): 2135–2148 https://doi.org/10.1039/c1lc20208a
34
Takinoue M, Takeuchi S. Droplet microfluidics for the study of artificial cells. Analytical and Bioanalytical Chemistry, 2011, 400(6): 1705–1716 https://doi.org/10.1007/s00216-011-4984-5
35
Vergauwe N, Witters D, Atalay Y T, et al. Controlling droplet size variability of a digital lab-on-a-chip for improved bio-assay performance. Microfluidics and Nanofluidics, 2011, 11(1): 25–34 https://doi.org/10.1007/s10404-011-0769-6
36
Yaddessalage J B. Study of the capabilities of electrowetting on dielectric digital microfluidics (EWOD DMF) towards the high efficient thin-film evaporative cooling platform. Dissertation for the Doctoral Degree. Arlington: The University of Texas at Arlington, 2013
37
Elvira K S, Leatherbarrow R, Edel J, et al. Droplet dispensing in digital microfluidic devices: Assessment of long-term reproducibility. Biomicrofluidics, 2012, 6(2): 022003 https://doi.org/ 10.1063/1.3693592
38
Yafia M, Najjaran H. High precision control of gap height for enhancing principal digital microfluidics operations. Sensors and Actuators B: Chemical, 2013, 186: 343–352 https://doi.org/10.1016/j.snb.2013.06.029
39
Chang J H, Pak J J. Twin-plate electrowetting for efficient digital microfluidics. Sensors and Actuators B: Chemical, 2011, 160(1): 1581–1585 https://doi.org/10.1016/j.snb.2011.09.011
40
Cui W, Zhang M, Zhang D, et al. Island-ground single-plate electro-wetting on dielectric device for digital microfluidic systems. Applied Physics Letters, 2014, 105(1): 013509 https://doi.org/10.1063/1.4889895
41
Ko H, Lee J, Kim Y, et al. Active digital microfluidic paper chips with inkjet-printed patterned electrodes. Advanced Materials, 2014, 26(15): 2335–2340 https://doi.org/10.1002/adma.201305014
42
Fobel R, Kirby A E, Ng A H C, et al. Paper microfluidics goes digital. Advanced Materials, 2014, 26(18): 2838–2843 https://doi.org/10.1002/adma.201305168
43
Fobel R, Kirby A E, Wheeler A R. Paper microfluidics goes digital. In: Proceedings of 17th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS. Freiburg: Chemical and Biological Microsystems Society, 2013, 708–710
44
Dixon C, Kirby A E, Fobel R, et al. Paper digital microfluidics and paper spray ionization mass spectrometry. In: Proceedings of 18th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS. San Antonio: Chemical and Biological Microsystems Society, 2014, 2196–2198
45
Dixon C, Ng A H C, Fobel R, et al. An inkjet printed, roll-coated digital microfluidic device for inexpensive, miniaturized diagnostic assays. Lab on a Chip, 2016, 16(23): 4560–4568 https://doi.org/10.1039/C6LC01064D
46
Yafia M, Shukla S, Najjaran H. Fabrication of digital microfluidic devices on flexible paper-based and rigid substrates via screen printing. Journal of Micromechanics and Microengineering, 2015, 25(5): 057001 https://doi.org/10.1088/0960-1317/25/5/057001
47
Taniguchi T, Torii T, Higuchi T. Chemical reactions in microdroplets by electrostatic manipulation of droplets in liquid media. Lab on a Chip, 2002, 2(1): 19–23 https://doi.org/10.1039/B108739H
48
Ito T, Torii T, Higuchi T. Electrostatic micromanipulation of bubbles for microreactor applications. In: Proceedings of IEEE the Sixteenth Annual International Conference on Micro Electro Mechanical System. Kyoto: IEEE, 2003, 335–338 https://doi.org/10.1109/MEMSYS.2003.1189754
49
Sista R S, Eckhardt A E, Wang T, et al. Digital microfluidic platform for multiplexing enzyme assays: Implications for lysosomal storage disease screening in newborns. Clinical Chemistry, 2011, 57(10): 1444–1451 https://doi.org/10.1373/clinchem.2011.163139
50
Boles D J, Benton J L, Siew G J, et al. Droplet-based pyrosequencing using digital microfluidics. Analytical Chemistry, 2011, 83(22): 8439–8447 https://doi.org/10.1021/ac201416j
51
Choi K, Boyacı E, Kim J, et al. A digital microfluidic interface between solid-phase microextraction and liquid chromatography—Mass spectrometry. Journal of Chromatography A, 2016, 1444: 1–7 https://doi.org/10.1016/j.chroma.2016.03.029
52
Keng P Y, Chen S, Ding H J, et al. Micro-chemical synthesis of molecular probes on an electronic microfluidic device. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(3): 690–695 https://doi.org/ 10.1073/pnas.1117566109
53
Dooraghi A A, Keng P Y, Chen S, et al. Optimization of microfluidic PET tracer synthesis with Cerenkov imaging. Analyst (London), 2013, 138(19): 5654–5664 https://doi.org/10.1039/c3an01113e
54
Witters D, Vergauwe N, Ameloot R, et al. Digital microfluidic high-throughput printing of single metal-organic framework crystals. Advanced Materials, 2012, 24(10): 1316–1320 https://doi.org/10.1002/adma.201104922
55
Shamsi M H, Choi K, Ng A H C, et al. A digital microfluidic electrochemical immunoassay. Lab on a Chip, 2014, 14(3): 547–554 https://doi.org/10.1039/C3LC51063H
56
Ng A H C, Lee M, Choi K, et al. Digital microfluidic platform for the detection of rubella infection and immunity: A proof of concept. Clinical Chemistry, 2015, 61(2): 420–429 https://doi.org/10.1373/clinchem.2014.232181
57
Miller E M, Ng A H C, Uddayasankar U, et al. A digital microfluidic approach to heterogeneous immunoassays. Analytical and Bioanalytical Chemistry, 2011, 399(1): 337–345 https://doi.org/10.1007/s00216-010-4368-2
58
Sista R S, Eckhardt A E, Srinivasan V, et al. Heterogeneous immunoassays using magnetic beads on a digital microfluidic platform. Lab on a Chip, 2008, 8(12): 2188–2196 https://doi.org/10.1039/b807855f
Yoon J Y, Garrell R L. Preventing biomolecular adsorption in electrowetting-based biofluidic chips. Analytical Chemistry, 2003, 75(19): 5097–5102 https://doi.org/10.1021/ac0342673
61
Shah G J, Kim C J. Meniscus-assisted high-efficiency magnetic collection and separation for EWOD droplet microfluidics. Journal of Microelectromechanical Systems, 2009, 18(2): 363–375 https://doi.org/10.1109/JMEMS.2009.2013394
62
Barbulovic-Nad I, Au S H, Wheeler A R. A microfluidic platform for complete mammalian cell culture. Lab on a Chip, 2010, 10(12): 1536–1542 https://doi.org/10.1039/c002147d
63
Choi K, Ng A H C, Fobel R, et al. Automated digital microfluidic platform for magnetic-particle-based immunoassays with optimization by design of experiments. Analytical Chemistry, 2013, 85(20): 9638–9646 https://doi.org/10.1021/ac401847x
64
Huang C Y, Tsai P Y, Lee I C, et al. A highly efficient bead extraction technique with low bead number for digital microfluidic immunoassay. Biomicrofluidics, 2016, 10(1): 011901 https://doi.org/10.1063/1.4939942
65
Au S H, Shih S C C, Wheeler A R. Integrated microbioreactor for culture and analysis of bacteria, algae and yeast. Biomedical Microdevices, 2011, 13(1): 41–50 https://doi.org/10.1007/s10544-010-9469-3
66
Shih S C C, Gach P C, Sustarich J, et al. A droplet-to-digital (D2D) microfluidic device for single cell assays. Lab on a Chip, 2015, 15(1): 225–236 https://doi.org/10.1039/C4LC00794H
67
Eydelnant I A, Uddayasankar U, Li B, et al. Virtual microwells for digital microfluidic reagent dispensing and cell culture. Lab on a Chip, 2012, 12(4): 750–757 https://doi.org/10.1039/C2LC21004E
68
Bogojevic D, Chamberlain M D, Barbulovic-Nad I, et al. A digital microfluidic method for multiplexed cell-based apoptosis assays. Lab on a Chip, 2012, 12(3): 627–634 https://doi.org/10.1039/C2LC20893H
69
Fiddes L K, Luk V N, Au S H, et al. Hydrogel discs for digital microfluidics. Biomicrofluidics, 2012, 6(1): 014112 https://doi.org/10.1063/1.3687381
70
George S M, Moon H. Digital microfluidic three-dimensional cell culture and chemical screening platform using alginate hydrogels. Biomicrofluidics, 2015, 9(2): 024116 https://doi.org/10.1063/1.4918377
71
Au S H, Chamberlain M D, Mahesh S, et al. Hepatic organoids for microfluidic drug screening. Lab on a Chip, 2014, 14(17): 3290–3299 https://doi.org/10.1039/C4LC00531G
72
Nejad H R, Chowdhury O Z, Buat M D, et al. Characterization of the geometry of negative dielectrophoresis traps for particle immobilization in digital microfluidic platforms. Lab on a Chip, 2013, 13(9): 1823–1830 https://doi.org/10.1039/c3lc41292j
73
Valley J K, Ningpei S, Jamshidi A, et al. A unified platform for optoelectrowetting and optoelectronic tweezers. Lab on a Chip, 2011, 11(7): 1292–1297 https://doi.org/10.1039/c0lc00568a
74
Kumar P T, Toffalini F, Witters D, et al. Digital microfluidic chip technology for water permeability measurements on single isolated plant protoplasts. Sensors and Actuators B: Chemical, 2014, 199: 479–487 https://doi.org/10.1016/j.snb.2014.04.018
75
Schell W A, Benton J L, Smith P B, et al. Evaluation of a digital microfluidic real-time PCR platform to detect DNA of Candida albicans in blood. European Journal of Clinical Microbiology & Infectious Diseases, 2012, 31(9): 2237–2245 https://doi.org/10.1007/s10096-012-1561-6
76
Hung P Y, Jiang P S, Lee E F, et al. Genomic DNA extraction from whole blood using a digital microfluidic (DMF) platform with magnetic beads. Microsystem Technologies, 2015, 21: 1–8
77
Yehezkel T B, Rival A, Raz O, et al. Synthesis and cell-free cloning of DNA libraries using programmable microfluidics. Nucleic Acids Research, 2015, 44: 1–12
78
Welch E R F, Lin Y Y, Madison A, et al. Picoliter DNA sequencing chemistry on an electrowetting-based digital microfluidic platform. Biotechnology Journal, 2011, 6(2): 165–176 https://doi.org/10.1002/biot.201000324
79
Kim H, Bartsch M S, Renzi R F, et al. Automated digital microfluidic sample preparation for next-generation DNA sequencing. Journal of Laboratory Automation, 2011, 16(6): 405–414 https://doi.org/10.1016/j.jala.2011.07.001
80
Kim H, Jebrail M J, Sinha A, et al. A microfluidic DNA library preparation platform for next-generation sequencing. PLoS One, 2013, 8(7): e68988 https://doi.org/ 10.1371/journal.pone.0068988
81
Wheeler A R, Moon H, Bird C A, et al. Digital microfluidics with in-line sample purification for proteomics analyses with MALDI-MS. Analytical Chemistry, 2005, 77(2): 534–540 https://doi.org/10.1021/ac048754+
82
Wheeler A R, Moon H, Kim C J, et al. Electrowetting-based microfluidics for analysis of peptides and proteins by matrix-assisted laser desorption/ionization mass spectrometry. Analytical Chemistry, 2004, 76(16): 4833–4838 https://doi.org/10.1021/ac0498112
83
Luk V N, Fiddes L K, Luk V M, et al. Digital microfluidic hydrogel microreactors for proteomics. Proteomics, 2012, 12(9): 1310–1318 https://doi.org/10.1002/pmic.201100608
84
Aijian A P, Chatterjee D, Garrell R L. Fluorinated liquid-enabled protein handling and surfactant-aided crystallization for fully in situ digital microfluidic MALDI-MS analysis. Lab on a Chip, 2012, 12(14): 2552–2559 https://doi.org/10.1039/c2lc21135a