Skip to main content

Droplet-based dielectrophoresis device for on-chip nanomedicine fabrication and improved gene delivery efficiency

Microfluidics and Nanofluidics volume 19, pages 235–243 (2015)Cite this article

Abstract

In this article, we present the design, fabrication, and experimental verification of a droplet-based microfluidic device for effective on-chip fabrication and separation of polymer-based nanoparticles using dielectrophoresis (DEP) effect. The separated polyplexes nanoparticles were used in cells for improved gene transfection efficiency. By adjusting the flow rate of PEI600-CyD-FA (H1) and DNA plasmids, polyplexes products can be mixed and self-assembled inside droplets within approximately a nanoliter volume. This procedure ensures synthesized particles to have a narrow size distribution. In addition, a new microchannel design was developed to automatically coalesce two moving aqueous droplets and to directly extract aqueous polyplex products from oil. Finally, the H1-DNA polyplexes of ~116 nm diameter were separated via negative DEP force under 8 V peak–peak and 20 MHz conditions by passing three times through a non-uniform electric field. The biological findings demonstrated that the DEP-treated polyplexes still possessed the ability to enter HUVEC cells and that the gene transfection efficiency was raised to 15 %, as opposed to the control group’s 4 % where the polyplexes had no DEP treatment. The quantitative comparison was done by counting the number of cells produced via positive EPFG expression. These hydrodynamic and electrodynamic techniques provide an integrated microfluidic platform for fabricating and screening nanoscale drugs.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Abbreviations

H :

Height of flow channel

W :

Width of flow channel

F random :

Random force

F deterministic :

Deterministic force

H1 :

Polymer vector, designed for drug/gene delivery

L assembling :

Length of assembling channel

Q blue :

Volume flow rate of blue liquid

Q oil :

Volume flow rate of mineral oil

Q red :

Volume flow rate of red liquid

V droplet :

Droplet velocity

V pp :

Peak-to-peak voltage

FA:

Folic acid

CyD:

Cyclodextrins

DEP:

Dielectrophoresis

PEI:

Polyethylenimine

PCR:

Polymerase chain reaction

EGFP:

Enhanced green fluorescent protein

HUVEC:

Human umbilical vein endothelial cell

References

  • Bunnell BA, Morgan RA (1998) Gene therapy for infectious diseases. Clin Microbiol Rev 11(1):42–56

    Google Scholar 

  • Burton EA, Glorioso JC, Fink DJ (2003) Gene therapy progress and prospects: parkinson’s disease. Gene Ther 10(20):1721–1727

    Article  Google Scholar 

  • Çetin B, Li D (2011) Dielectrophoresis in microfluidics technology. Electrophoresis 32(18):2410–2427

    Article  Google Scholar 

  • Chen Z, Wu Z, Tong L, Pan H, Liu Z (2006) Simultaneous dielectrophoretic separation and assembly of single-walled carbon nanotubes on multigap nanoelectrodes and their thermal sensing properties. Anal Chem 78(23):8069–8075

    Article  Google Scholar 

  • Duraiswamy S, Khan SA (2009) Droplet-based microfluidic synthesis of anisotropic metal nanocrystals. Small 5(24):2828–2834

    Article  Google Scholar 

  • Dzau VJ, Beatt K, Pompilio G, Smith K (2003) Current perceptions of cardiovascular gene therapy. Am J Cardiol 92(9):18–23

    Article  Google Scholar 

  • Garstecki P, Fuerstman MJ, Stone HA, Whitesides GM (2006) Formation of droplets and bubbles in a microfluidic T-junction-scaling and mechanism of break-up. Lab Chip 6(3):437–446

    Article  Google Scholar 

  • Green NG, Morgan H (1997) Dielectrophoretic separation of nano-particles. J Phys D Appl Phys 30(11):L41

    Article  Google Scholar 

  • Hung LH, Choi KM, Tseng WY, Tan YC, Shea KJ, Lee AP (2006) Alternating droplet generation and controlled dynamic droplet fusion in microfluidic device for CdS nanoparticle synthesis. Lab Chip 6(2):174–178

    Article  Google Scholar 

  • Kuzyk A (2011) Dielectrophoresis at the nanoscale. Electrophoresis 32(17):2307–2313

    Google Scholar 

  • Lehrman S (1999) Virus treatment questioned after gene therapy death. Nature 401(6753):517–518

    Article  Google Scholar 

  • Liu Q, Muruve DA (2003) Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther 10(11):935–940

    Article  Google Scholar 

  • Liu X, Spencer JL, Kaiser AB, Arnold WM (2006) Selective purification of multiwalled carbon nanotubes by dielectrophoresis within a large array. Curr Appl Phys 6(3):427–431

    Article  Google Scholar 

  • Mark D, Haeberle S, Roth G, von Stetten F, Zengerle R (2010) Microfluidic lab-on-a-chip platforms: requirements, characteristics and applications. Chem Soc Rev 39(3):1153–1182

    Article  Google Scholar 

  • Merdan T, Kopec̆ek J, Kissel T (2002) Prospects for cationic polymers in gene and oligonucleotide therapy against cancer. Adv Drug Deliv Rev 54(5):715–758

    Article  Google Scholar 

  • Midoux P, Breuzard G, Gomez JP, Pichon C (2008) Polymer-based gene delivery: a current review on the uptake and intracellular trafficking of polyplexes. Curr Gene Ther 8(5):335–352

    Article  Google Scholar 

  • Mulligan R (1993) The basic science of gene therapy. Science 260(5110):926–932

    Article  Google Scholar 

  • Pack DW, Hoffman AS, Pun S, Stayton PS (2005) Design and development of polymers for gene delivery. Nat Rev Drug Discov 4(7):581–593

    Article  Google Scholar 

  • Park JI, Saffari A, Kumar S, Günther A, Kumacheva E (2010) Microfluidic synthesis of polymer and inorganic particulate materials. Annu Rev Mater Res 40(1):415–443

    Article  Google Scholar 

  • Pethig R (2010) Review article-dielectrophoresis: status of the theory, technology and applications. Biomicrofluidics 4(2):022811–022835

    Article  Google Scholar 

  • Pommer MS, Zhang Y, Keerthi N, Chen D, Thomson JA, Meinhart CD, Soh HT (2008) Dielectrophoretic separation of platelets from diluted whole blood in microfluidic channels. Electrophoresis 29(6):1213–1218

    Article  Google Scholar 

  • Rubin P, Casarett G (1996) Microcirculation of tumours part I: anatomy, function and necrosis. Clin Radiol 17(3):220–229

    Article  Google Scholar 

  • Seemann R, Brinkmann M, Pfohl T, Herminghaus S (2012) Droplet based microfluidics. Rep Prog Phys 75(1):016601

    Article  Google Scholar 

  • Shubik P (1982) Vascularization of tumours: a review. J Cancer Res Clin Oncol 103(3):211–226

    Article  Google Scholar 

  • Simonato M, Bennett J, Boulis NM, Castro MG, Fink DJ, Goins WF, Glorioso JC (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9(5):277–291

    Article  Google Scholar 

  • Sledge GW, Miller KD (2003) Exploiting the hallmarks of cancer: the future conquest of breast cancer. Eur J Cancer 39(12):1668–1675

    Article  Google Scholar 

  • Song H, Tice JD, Ismagilov RF (2003) A microfluidic system for controlling reaction networks in time. Angew Chem Int Ed 42(7):768–772

    Article  Google Scholar 

  • Song H, Chen DL, Ismagilov RF (2006) Reactions in droplets in microfluidic channels. Angew Chem Int Ed 45(44):7336–7356

    Article  Google Scholar 

  • Srivastava SK, Daggolu PR, Burgess SC, Minerick AR (2008) Dielectrophoretic characterization of erythrocytes: positive ABO blood types. Electrophoresis 29(24):5033–5046

    Article  Google Scholar 

  • Suehiro J, Ikeda N, Ohtsubo A, Imasaka K (2008) Fabrication of bio/nano interfaces between biological cells and carbon nanotubes using dielectrophoresis. Microfluid Nanofluid 5(6):741–747

    Article  Google Scholar 

  • Tang GP, Guo HY, Alexis F, Wang X, Zeng S, Lim TM, Wang S (2006) Low molecular weight polyethylenimines linked by β-cyclodextrin for gene transfer into the nervous system. J Gene Med 8(6):736–744

    Article  Google Scholar 

  • Teh SY, Lin R, Hung LH, Lee AP (2008) Droplet microfluidics. Lab Chip 8(2):198–220

    Article  Google Scholar 

  • Tomkins MR, Wood JA, Docoslis A (2008) Observations and analysis of electrokinetically driven particle trapping in planar microelectrode arrays. Can J Chem Eng 86(4):609–621

    Article  Google Scholar 

  • Vile RG, Russell SJ, Lemoine NR (2000) Cancer gene therapy: hard lessons and new courses. Gene Ther 7(1):2–8

    Article  Google Scholar 

  • Wang JT, Wang J, Han JJ (2011) Fabrication of advanced particles and particle-based materials assisted by droplet-based microfluidics. Small 7(13):1728–1754

    MathSciNet  Article  Google Scholar 

  • Williams PD, Kingston PA (2011) Plasmid-mediated gene therapy for cardiovascular disease. Cardiovasc Res 91(4):565–576

    Article  Google Scholar 

  • Yao H, Ng SS, Tucker WO, Tsang YKT, Man K, Wang XM, Lin MC (2009) The gene transfection efficiency of a folate–PEI600–cyclodextrin nanopolymer. Biomaterials 30(29):5793–5803

    Article  Google Scholar 

  • Zhang D, Cheng J, Chen SC (2013) Multi-depth real-time confocal imaging. In: Proceedings of the international symposium on optomechatronic technologies (ISOT)

Download references

Acknowledgments

This research is supported by project #BME-p3-12 of the Shun Shing Institute of Advanced Engineering, The Chinese University of Hong Kong.

Author information

Author notes

    Authors and Affiliations

    1. Department of Mechanical and Automation Engineering and Shun Hing Institute of Advanced Engineering, The Chinese University of Hong Kong, Shatin, Hong Kong

      Shih-Mo Yang, Hong Yao, Dapeng Zhang & Shih-Chi Chen

    2. Department of Surgery, School of Biomedical Science and Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong

      Hong Yao & Hsiang-Fu Kung

    3. Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Kowloon Tong, Hong Kong

      Wen Jung Li

    4. School of Mechanical and Power Engineering, East China University of Science and Technology, Shanghai, China

      Shih-Mo Yang

    Authors
    1. Shih-Mo Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Hong Yao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Dapeng Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Wen Jung Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Hsiang-Fu Kung
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Shih-Chi Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Shih-Chi Chen.

    Additional information

    Shih-Mo Yang and Hong Yao have contributed equally to this work.

    Rights and permissions

    Reprints and Permissions

    About this article

    Verify currency and authenticity via CrossMark

    Cite this article

    Yang, SM., Yao, H., Zhang, D. et al. Droplet-based dielectrophoresis device for on-chip nanomedicine fabrication and improved gene delivery efficiency. Microfluid Nanofluid 19, 235–243 (2015). https://doi.org/10.1007/s10404-015-1560-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10404-015-1560-x

    Keywords

    • Droplet
    • Dielectrophoresis
    • Polymeric nanoparticle
    • Gene delivery
    • Particle separation
    • Lab-on-chip