Microfluidic Fabrication of Vesicles

  • Ho Cheung ShumEmail author
  • Julian Thiele
  • Shin-Hyun Kim
Part of the Advances in Transport Phenomena book series (ADVTRANS, volume 3)


Vesicles are compartments enclosed by a thin membrane, which is made up of amphiphilic molecules arranged into ordered layers. Vesicle-like structures are Nature’s choice for encapsulating important biochemical species that enable living processes, and are increasingly important as artificial structures for the encapsulation and release of drugs, biomolecules and other active ingredients for biomedical, pharmaceutical, food and consumer industries. Advances in microfluidic technologies have provided a new set of tools for unraveling the science behind formation of vesicles and fabricating novel vesicles. While traditional approaches for fabricating vesicles rely on self-assembly of amphiphiles, the precise control of flow afforded in microfluidic devices enables directed assembly of the amphiphiles. Thus, techniques such as hydrodynamic flow focusing, controlled emulsion-templating and pulsatile jetting offer unprecedented degree of control over vesicle structures. This creates new opportunities to engineer the structures of vesicles and tailor them for specific applications. In this review, we introduce current understanding behind different kinds of vesicles, survey conventional and microfluidic techniques for their formation, discuss new approaches of encapsulation and release of active ingredients in microfluidic vesicles, and point to future research and development in the area.


Microfluidic Device Encapsulation Efficiency Lower Critical Solution Temperature Diblock Copolymer Double Emulsion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    New, R.R.C.: Liposomes : A Practical Approach. IRL Press, Oxford (1990). (Oxford University Press)Google Scholar
  2. 2.
    Discher, B.M., et al.: Polymersomes: Tough vesicles made from diblock copolymers. Science 284, 1143–1146 (1999)CrossRefGoogle Scholar
  3. 3.
    Zhang, L., Eisenberg, A.: Multiple morphologies of “Crew-Cut” aggregates of polystyrene-b-poly(acrylic acid) block copolymers. Science 268, 1728–1731 (1995)CrossRefGoogle Scholar
  4. 4.
    Munoz, S., et al.: Ultrathin monolayer lipid-membranes from a new family of crown ether-based bolar-amphiphiles. J. Am. Chem. Soc. 115, 1705–1711 (1993)CrossRefGoogle Scholar
  5. 5.
    Schreier, H., Bouwstra, J.: Liposomes and niosomes as topical drug carriers—dermal and transdermal drug-delivery. J. Control. Release 30, 1–15 (1994)CrossRefGoogle Scholar
  6. 6.
    Dinsmore, A.D., et al.: Colloidosomes: selectively permeable capsules composed of colloidal particles. Science 298, 1006–1009 (2002)CrossRefGoogle Scholar
  7. 7.
    Hsu, M.F., et al.: Self-assembled shells composed of colloidal particles: fabrication and characterization. Langmuir 21, 2963–2970 (2005)CrossRefGoogle Scholar
  8. 8.
    Segota, S., Tezak, D.: Spontaneous formation of vesicles. Adv. Colloid Interface Sci. 121, 51–75 (2006)CrossRefGoogle Scholar
  9. 9.
    Antonietti, M., Förster, S.: Vesicles and liposomes: a self-assembly principle beyond lipids. Adv. Mater. 15, 1323–1333 (2003)CrossRefGoogle Scholar
  10. 10.
    Lasic, D.D.: The mechanism of vesicle formation. Biochem. J. 256, 1–11 (1988)Google Scholar
  11. 11.
    Kita-Tokarczyk, K., et al.: Block copolymer vesicles—using concepts from polymer chemistry to mimic biomembranes. Polymer 46, 3540–3563 (2005)CrossRefGoogle Scholar
  12. 12.
    Wang, Z.G.: Curvature instability of diblock copolymer bilayers. Macromolecules 25, 3702–3705 (1992)CrossRefGoogle Scholar
  13. 13.
    Marrink, S.J., Mark, A.E.: Molecular dynamics simulation of the formation, structure, and dynamics of small phospholipid vesicles. J. Am. Chem. Soc. 125, 15233–15242 (2003)CrossRefGoogle Scholar
  14. 14.
    Uneyama, T.: Density functional simulation of spontaneous formation of vesicle in block copolymer solutions. J. Chem. Phys. 126, 114902 (2007)CrossRefGoogle Scholar
  15. 15.
    Yamamoto, S., et al.: Dissipative particle dynamics study of spontaneous vesicle formation of amphiphilic molecules. J. Chem. Phys. 116, 5842–5849 (2002)CrossRefGoogle Scholar
  16. 16.
    Noguchi, H., Takasu, M.: Self-assembly of amphiphiles into vesicles: a Brownian dynamics simulation. Phys. Rev. E 64, 041913 (2001)CrossRefGoogle Scholar
  17. 17.
    Du, J., O’Reilly, R.K.: Advances and challenges in smart and functional polymer vesicles. Soft Matter 5, 3544–3561 (2009)CrossRefGoogle Scholar
  18. 18.
    He, X.H., Schmid, F.: Dynamics of spontaneous vesicle formation in dilute solutions of amphiphilic diblock copolymers. Macromolecules 39, 2654–2662 (2006)CrossRefGoogle Scholar
  19. 19.
    Rank, A., et al.: Preparation of monodisperse block copolymer vesicles via a thermotropic cylinder-vesicle transition. Langmuir 25, 1337–1344 (2009)CrossRefGoogle Scholar
  20. 20.
    Discher, D.E., Ahmed, F.: Polymersomes. Ann. Rev. Biomed. Eng. 8, 323–341 (2006)CrossRefGoogle Scholar
  21. 21.
    Israelachvili, J.N., et al.: Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers. J. Chem. Soc. Faraday Trans. Ii 72, 1525–1568 (1976)CrossRefGoogle Scholar
  22. 22.
    Won, Y.Y., et al.: Cryogenic transmission electron microscopy (cryo-TEM) of micelles and vesicles formed in water by polyethylene oxide)-based block copolymers. J. Phys. Chem. B 106, 3354–3364 (2002)CrossRefGoogle Scholar
  23. 23.
    Hyde, S.T.: Curvature and the global structure of interfaces in surfactant-water systems. J. De Phys. 51, C7209–C7228 (1990)Google Scholar
  24. 24.
    Bates, F.S., Fredrickson, G.H.: Block copolymer thermodynamics—theory and experiment. Ann. Rev. Phys. Chem. 41, 525–557 (1990)CrossRefGoogle Scholar
  25. 25.
    Bates, F.S.: Polymer–polymer phase-behavior. Science 251, 898–905 (1991)CrossRefGoogle Scholar
  26. 26.
    Bermudez, H., et al.: Molecular weight dependence of polymersome membrane structure, elasticity, and stability. Macromolecules 35, 8203–8208 (2002)CrossRefGoogle Scholar
  27. 27.
    Dobereiner, H.G., et al.: Mapping vesicle shapes into the phase diagram: a comparison of experiment and theory. Phys. Rev. E 55, 4458–4474 (1997)CrossRefGoogle Scholar
  28. 28.
    Mui, B.L.S., et al.: Influence of transbilayer area asymmetry on the morphology of large unilamellar vesicles. Biophys. J. 69, 930–941 (1995)CrossRefGoogle Scholar
  29. 29.
    Storm, G., Crommelin, D.J.A.: Liposomes: quo vadis? Pharm. Sci. Technol. Today 1, 19–31 (1998)CrossRefGoogle Scholar
  30. 30.
    Angelova, M.I., Dimitrov, D.S.: Liposome electroformation. Faraday Discuss. Chem. Soc. 81, 303–311 (1986)CrossRefGoogle Scholar
  31. 31.
    Sun, B.Y., Chiu, D.T.: Determination of the encapsulation efficiency of individual vesicles using single-vesicle photolysis and confocal single-molecule detection. Anal. Chem. 77, 2770–2776 (2005)CrossRefGoogle Scholar
  32. 32.
    Howse, J.R., et al.: Templated formation of giant polymer vesicles with controlled size distributions. Nat. Mater. 8, 507–511 (2009)CrossRefGoogle Scholar
  33. 33.
    Taylor, P., et al.: Fabrication of 2D arrays of giant liposomes on solid substrates by microcontact printing. Phys. Chem. Chem. Phys. 5, 4918–4922 (2003)CrossRefGoogle Scholar
  34. 34.
    Evans, E., Needham, D.: Physical properties of surfactant bilayer membranes: thermal transitions, elasticity, rigidity, cohesion and colloidal interactions. J. Phys. Chem. 91, 4219–4228 (1987)CrossRefGoogle Scholar
  35. 35.
    Mui, B., et al.: Extrusion technique to generate liposomes of defined size. Liposomes Pt A 367, 3–14 (2003)CrossRefGoogle Scholar
  36. 36.
    Macdonald, R.C., et al.: Small-volume extrusion apparatus for preparation of large, unilamellar vesicles. Biochim. Biophys. Acta 1061, 297–303 (1991)CrossRefGoogle Scholar
  37. 37.
    Frisken, B.J., et al.: Studies of vesicle extrusion. Langmuir 16, 928–933 (2000)CrossRefGoogle Scholar
  38. 38.
    Pautot, S., et al.: Production of unilamellar vesicles using an inverted emulsion. Langmuir 19, 2870–2879 (2003)CrossRefGoogle Scholar
  39. 39.
    Pautot, S., et al.: Engineering asymmetric vesicles. Proc. Natl. Acad. Sci. USA 100, 10718–10721 (2003)CrossRefGoogle Scholar
  40. 40.
    Shah, R.K., et al.: Designer emulsions using microfluidics. Mater. Today 11, 18–27 (2008)CrossRefGoogle Scholar
  41. 41.
    Squires, T.M., Quake, S.R.: Microfluidics: fluid physics at the nanoliter scale. Rev. Mod. Phys. 77, 977–1026 (2005)CrossRefGoogle Scholar
  42. 42.
    Brody, J.P., et al.: Biotechnology at low Reynolds numbers. Biophys. J. 71, 3430–3441 (1996)CrossRefGoogle Scholar
  43. 43.
    Knight, J.B., et al.: Hydrodynamic focusing on a silicon chip: mixing nanoliters in microseconds. Phys. Rev. Lett. 80, 3863–3866 (1998)CrossRefGoogle Scholar
  44. 44.
    Beebe, D.J., et al.: Physics and applications of microfluidics in biology. Ann. Rev. Biomed. Eng. 4, 261–286 (2002)CrossRefGoogle Scholar
  45. 45.
    Gambin, Y., et al.: Ultrafast microfluidic mixer with three-dimensional flow focusing for studies of biochemical kinetics. Lab Chip 10, 598–609 (2010)CrossRefGoogle Scholar
  46. 46.
    Pollack, L., et al.: Compactness of the denatured state of a fast-folding protein measured by submillisecond small-angle x-ray scattering. Proc. Natl. Acad. Sci. USA 96, 10115–10117 (1999)CrossRefGoogle Scholar
  47. 47.
    Lipman, E.A., et al.: Single-molecule measurement of protein folding kinetics. Science 301, 1233–1235 (2003)CrossRefGoogle Scholar
  48. 48.
    Koester, S., et al.: Visualization of flow-aligned type I collagen self-assembly in tunable pH gradients. Langmuir 23, 357–359 (2007)CrossRefGoogle Scholar
  49. 49.
    Koester, S., et al.: An in situ study of collagen self-assembly processes. Biomacromolecules 9, 199–207 (2008)CrossRefGoogle Scholar
  50. 50.
    Yun, J., et al.: Continuous production of solid lipid nanoparticles by liquid flow-focusing and gas displacing method in microchannels. Chem. Eng. Sci. 64, 4115–4122 (2009)CrossRefGoogle Scholar
  51. 51.
    Jahn, A., et al.: Microfluidic mixing and the formation of nanoscale lipid vesicles. ACS Nano 4, 2077–2087 (2010)CrossRefGoogle Scholar
  52. 52.
    Jahn, A., et al.: Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. J. Am. Chem. Soc. 126, 2674–2675 (2004)CrossRefGoogle Scholar
  53. 53.
    Jahn, A., et al.: Microfluidic directed formation of liposomes of controlled size. Langmuir 23, 6289–6293 (2007)CrossRefGoogle Scholar
  54. 54.
    Massignani, M., et al.: Controlling cellular uptake by surface chemistry, size, and surface topology at the nanoscale. Small 5, 2424–2432 (2009)CrossRefGoogle Scholar
  55. 55.
    Gullotti, E., Yeo, Y.: Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol. Pharm. 6, 1041–1051 (2009)CrossRefGoogle Scholar
  56. 56.
    Hong, J.S., et al.: Microfluidic directed self-assembly of liposome-hydrogel hybrid nanoparticles. Langmuir 26, 11581–11588 (2010)CrossRefGoogle Scholar
  57. 57.
    Seiffert, S., et al.: Smart microgel capsules from macromolecular precursors. J. Am. Chem. Soc. 132, 6606–6609 (2010)CrossRefGoogle Scholar
  58. 58.
    Thiele, J., et al.: Preparation of monodisperse block copolymer vesicles via flow focusing in microfluidics. Langmuir 26, 6860–6863 (2010)CrossRefGoogle Scholar
  59. 59.
    Brown, L., et al.: Polymersome production on a microfluidic platform using pH sensitive block copolymers. Lab Chip 10, 1922–1928 (2010)CrossRefGoogle Scholar
  60. 60.
    Karnik, R., et al.: Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett. 8, 2906–2912 (2008)CrossRefGoogle Scholar
  61. 61.
    Kolishetti, N. et al.: Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy. Proceedings of the National Academy of Sciences of the United States of America, vol. 107, pp. 17939–17944. 19 Oct 2010 (2010)Google Scholar
  62. 62.
    Tan, Y.C., et al.: Controlled microfluidic encapsulation of cells, proteins, and microbeads in lipid vesicles. J. Am. Chem. Soc. 128, 5656–5658 (2006)CrossRefGoogle Scholar
  63. 63.
    Shum, H.C., et al.: Microfluidic fabrication of monodisperse biocompatible and biodegradable polymersomes with controlled permeability. J. Am. Chem. Soc. 130, 9543–9549 (2008)CrossRefGoogle Scholar
  64. 64.
    Shum, H.C., et al.: Double emulsion templated monodisperse phospholipid vesicles. Langmuir 24, 7651–7653 (2008)MathSciNetCrossRefGoogle Scholar
  65. 65.
    Hayward, R.C., et al.: Dewetting Instability during the Formation of polymersomes from block-copolymer-stabilized double emulsions. Langmuir 22, 4457–4461 (2006)CrossRefGoogle Scholar
  66. 66.
    Shum, H.C., et al.: Dewetting-induced membrane formation by adhesion of amphiphile-laden interfaces. J. Am. Chem. Soc. 133, 4420–4426 (2011)CrossRefGoogle Scholar
  67. 67.
    Funakoshi, K., et al.: Formation of giant lipid vesiclelike compartments from a planar lipid membrane by a pulsed jet flow. J. Am. Chem. Soc. 129, 12608 (2007)CrossRefGoogle Scholar
  68. 68.
    Stachowiak, J.C., et al.: Unilamellar vesicle formation and encapsulation by microfluidic jetting. Proc. Natl. Acad. Sci. USA 105, 4697–4702 (2008)CrossRefGoogle Scholar
  69. 69.
    Ota, S., et al.: Microfluidic formation of monodisperse, cell-sized, and unilamellar vesicles. Angew. Chem. Int. Ed. 48, 6533–6537 (2009)CrossRefGoogle Scholar
  70. 70.
    Beales, P.A., et al.: Specific adhesion between DNA-functionalized “Janus’’ vesicles: size-limited clusters. Soft Matter 7, 1747–1755 (2011)CrossRefGoogle Scholar
  71. 71.
    Shum, H.C., et al.: Multicompartment polymersomes from double emulsions. Angew. Chem. Int. Ed. 50, 1648–1651 (2011)CrossRefGoogle Scholar
  72. 72.
    Kisak, E.T., et al.: The vesosome—A multicompartment drug delivery vehicle. Curr. Med. Chem. 11, 199–219 (2004)CrossRefGoogle Scholar
  73. 73.
    Kim, S.H., et al.: Multiple polymersomes for programmed release of multiple components. J. Am. Chem. Soc. 133, 15165–15171 (2011). doi: 10.1021/ja205687k CrossRefGoogle Scholar
  74. 74.
    Onaca, O., et al.: Stimuli-responsive polymersomes as nanocarriers for drug and gene delivery. Macromol. Biosci. 9, 129–139 (2009)CrossRefGoogle Scholar
  75. 75.
    Brochard-Wyart, F., et al.: Transient pores in stretched vesicles: role of leak-out. Physica A 278, 32–51 (2000)CrossRefGoogle Scholar
  76. 76.
    Karatekin, E., et al.: Transient pores in vesicles. Polym. Int. 52, 486–493 (2003)CrossRefGoogle Scholar
  77. 77.
    Karatekin, E., et al.: Cascades of transient pores in giant vesicles: line tension and transport. Biophys. J. 84, 1734–1749 (2003)CrossRefGoogle Scholar
  78. 78.
    Sandre, O., et al.: Dynamics of transient pores in stretched vesicles. Proc. Natl. Acad. Sci. 96, 10591 (1999)CrossRefGoogle Scholar
  79. 79.
    Ahmed, F., Discher, D.E.: Self-porating polymersomes of PEG-PLA and PEG-PCL: hydrolysis-triggered controlled release vesicles. J. Controlled Release 96, 37–53 (2004)CrossRefGoogle Scholar
  80. 80.
    Zhang, Z., et al.: The in vivo and in vitro degradation behavior of poly(trimethylene carbonate). Biomaterials 27, 1741–1748 (2006)CrossRefGoogle Scholar
  81. 81.
    Sanson, C., et al.: Biocompatible and Biodegradable Poly(trimethylene carbonate)-b-Poly (l-glutamic acid) Polymersomes: size control and stability. Langmuir 26, 2751–2760 (2010)CrossRefGoogle Scholar
  82. 82.
    Gallagher, F.A., et al.: Magnetic resonance imaging of pH in vivo using hyperpolarized C-13-labelled bicarbonate. Nature 453, 940–973 (2008)CrossRefGoogle Scholar
  83. 83.
    Gerweck, L.E., Seetharaman, K.: Cellular pH gradient in tumor versus normal tissue: Potential exploitation for the treatment of cancer. Cancer Res. 56, 1194–1198 (1996)Google Scholar
  84. 84.
    Chen, W., et al.: pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: A comparative study with micelles. J. Controlled Release 142, 40–46 (2010)CrossRefGoogle Scholar
  85. 85.
    Agut, W., et al.: pH and temperature responsive polymeric micelles and polymersomes by self-assembly of Poly 2-(dimethylamino)ethyl methacrylate -b-Poly(glutamic acid) double hydrophilic block copolymers. Langmuir 26, 10546–10554 (2010)CrossRefGoogle Scholar
  86. 86.
    Needham, D., Dewhirst, M.W.: The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors. Adv. Drug Deliv. Rev. 53, 285–305 (2001)CrossRefGoogle Scholar
  87. 87.
    Hong, C.Y., et al.: Synthesis and characterization of well-defined diblock and triblock copolymers of poly(N-isopropylacrylamide) and poly(ethylene oxide). J. Polym. Sci. Part A-Polym. Chem. 42, 4873–4881 (2004)CrossRefGoogle Scholar
  88. 88.
    Qin, S., et al.: Temperature-controlled assembly and release from polymer vesicles of poly(ethylene oxide)-block-poly(N-isopropylacrylamide). Adv. Mater. 18, 2905 (2006)CrossRefGoogle Scholar
  89. 89.
    Napoli, A., et al.: Glucose-oxidase based self-destructing polymeric vesicles. Langmuir 20, 3487–3491 (2004)CrossRefGoogle Scholar
  90. 90.
    Cerritelli, S., et al.: PEG-SS-PPS: reduction-sensitive disulfide block copolymer vesicles for intracellular drug delivery. Biomacromolecules 8, 1966–1972 (2007)CrossRefGoogle Scholar
  91. 91.
    Kuai, R., et al.: Efficient delivery of payload into tumor cells in a controlled manner by TAT and thiolytic cleavable PEG Co-modified liposomes. Mol. Pharm. 7, 1816–1826 (2010)CrossRefGoogle Scholar
  92. 92.
    Song, L., et al.: Structure of staphylococcal α-Hemolysin, a heptameric transmembrane pore. Science 274, 1859–1865 (1996)CrossRefGoogle Scholar
  93. 93.
    Nisisako, T., Torii, T.: Microfluidic large-scale integration on a chip for mass production of monodisperse droplets and particles. Lab Chip 8, 287–293 (2008)CrossRefGoogle Scholar
  94. 94.
    Malloggi, F., et al.: Monodisperse colloids synthesized with nanofluidic technology. Langmuir 26, 2369–2373 (2010)CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of Mechanical EngineeringUniversity of Hong KongHong KongPeople’s Republic of China
  2. 2.Radboud University NijmegenInstitute for Molecules and MaterialsNijmegenThe Netherlands
  3. 3.Department of Chemical and Biomolecular EngineeringKorea Advanced Institute of Science and TechnologyDaejeonSouth Korea

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