Skip to main content
Log in

Magnetic Droplet Manipulation Platforms for Nucleic Acid Detection at the Point of Care

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

This review summarizes recent developments in the use of magnetically actuated droplets in point-of-care molecular diagnostic platforms. We discuss the fundamentals of magnetic droplet manipulation and the various modes of actuation. The balance of forces acting on a droplet during transport and particle extraction, as well as the devices and instrumentation developed to perform these operations will be presented and discussed. Furthermore, we review some of the recent advances on the diagnostic applications of platforms utilizing magnetic manipulation for genetic assessment of biological samples.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11

Similar content being viewed by others

References

  1. Alderton, R. P., L. M. Eccleston, R. P. Howe, C. A. Read, M. A. Reeve, and S. Beck. Magnetic bead purification of M13 DNA sequencing templates. Anal. Biochem. 201:166–169, 1992.

    Article  PubMed  CAS  Google Scholar 

  2. Ali-Cherif, A., S. Begolo, S. Descroix, J. L. Viovy, and L. Malaquin. Programmable magnetic tweezers and droplet microfluidic device for high-throughput nanoliter multi-step assays. Angew. Chem. Int. Ed. 51(43):10765–10769, 2012.

    Article  CAS  Google Scholar 

  3. Angione, S. L., A. Chauhan, and Tripathi. Real-time droplet DNA amplification with a new tablet platform. Anal. Chem. 84(6):2654–2661, 2012.

    Article  PubMed  CAS  Google Scholar 

  4. Athamanolap, P., D. J. Shin, and T. H. Wang. Droplet array platform for high-resolution melt analysis of DNA methylation density. J. Lab. Autom. 19(3):304–312, 2013.

  5. Babady, N. E. The FilmArray® respiratory panel: an automated, broadly multiplexed molecular test for the rapid and accurate detection of respiratory pathogens. Expert Rev. Mol. Diagn. 13(8):779–788, 2013.

    Article  PubMed  CAS  Google Scholar 

  6. Berensmeier, S. Magnetic particles for the separation and purification of nucleic acids. Appl. Microbiol. Biotechnol. 73(3):495–504, 2006.

    Article  PubMed  CAS  Google Scholar 

  7. Berry, S. M., E. T. Alarid, and D. J. Beebe. One-step purification of nucleic acid for gene expression analysis via Immiscible Filtration Assisted by Surface Tension (IFAST). Lab Chip 11(10):1747–1753, 2011.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Boles, D. J., J. L. Benton, G. J. Siew, M. H. Levy, P. K. Thwar, M. A. Sandahl, J. L. Rouse, L. C. Perkins, A. P. Sudarsan, R. Jalili, V. K. Pamula, V. Srinivasan, R. B. Fair, P. G. Griffin, A. E. Eckhardt, and M. G. Pollack. Droplet-based pyrosequencing using digital microfluidics. Anal. Chem. 83(22):8439–8447, 2011.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Burns, M. A., B. N. Johnson, S. N. Brahmasandra, K. Handique, J. R. Webster, M. Krishnan, T. S. Sammarco, P. M. Man, D. Jones, D. Heldsinger, C. H. Mastrangelo, and D. T. Burke. An integrated nanoliter DNA analysis device. Science 282(5388):484–487, 1998.

    Article  PubMed  CAS  Google Scholar 

  10. Caliendo, A. M. Multiplex PCR and emerging technologies for the detection of respiratory pathogens. Clin. Infect. Dis. 52(S4):S326–S330, 2011.

    Article  PubMed  Google Scholar 

  11. Chen, D. F., M. Mauk, X. Qiu, C. Liu, J. Kim, S. Ramprasad, S. Ongagna, W. R. Abrams, D. Malamud, P. L. A. M. Corstjens, and H. H. Bau. An integrated, self-contained microfluidic cassette for isolation, amplification, and detection of nucleic acids. Biomed. Microdev. 12(4):705–719, 2010.

    Article  Google Scholar 

  12. Chiou, P. Y., H. Moon, H. Toshiyoshi, C. J. Kim, and M. C. Wu. Light actuation of liquid by optoelectrowetting. Sens. Actuators A 104(3):222–228, 2003.

    Article  CAS  Google Scholar 

  13. Chiou, C. H., D. J. Shin, Y. Zhang, and T. H. Wang. Topography-assisted electromagnetic platform for blood-to-PCR in a droplet. Biosens. Bioelectron. 50:91–99, 2013.

    Article  PubMed  CAS  Google Scholar 

  14. Dhindsa, M., S. Kuiper, and J. Heikenfeld. Reliable and low-voltage electrowetting on thin parylene films. Thin Solid Films 519:3346–3351, 2011.

    Article  CAS  Google Scholar 

  15. Fan, S. K., T. H. Hsieh, and D. Y. Lin. General digital microfluidic platform manipulating dielectric and conductive droplets by dielectrophoresis and electrowetting. Lab Chip 9(9):1236–1242, 2009.

    Article  PubMed  CAS  Google Scholar 

  16. Gervais, L., M. Hitzbleck, and E. Delamarche. Capillary-driven multiparametric microfluidic chips for one-step immunoassays. Biosens. Bioelectron. 27(1):64–70, 2011.

    Article  PubMed  CAS  Google Scholar 

  17. Hashimoto, M., P. C. Chen, M. W. Mitchell, D. E. Nikitopoulos, S. A. Soper, and M. C. Murphy. Rapid PCR in a continuous flow device. Lab Chip 4:638–645, 2004.

    Article  PubMed  CAS  Google Scholar 

  18. Hong, L., and T. Pan. Photopatternable superhydrophobic nanocomposites for microfabrication. J Microelectromech. Syst. 19(2):246–253, 2010.

    Article  CAS  Google Scholar 

  19. Hosokawa, K., M. Omata, K. Sato, and M. Maeda. Power-free sequential injection for microchip immunoassay toward point-of-care testing. Lab Chip 6:236–241, 2006.

    Article  PubMed  CAS  Google Scholar 

  20. Hua, Z. S., J. L. Rouse, A. E. Eckhardt, V. Srinivasan, V. K. Pamula, W. A. Schell, J. L. Benton, T. G. Mitchell, and M. G. Pollack. Multiplexed real-time polymerase chain reaction on a digital microfluidic platform. Anal. Chem. 82:2310–2316, 2010.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Huhmer, A. F. R., and J. P. Landers. Noncontact infrared-mediated thermocycling for effective polymerase chain reaction amplification of DNA in nanoliter volumes. Anal. Chem. 72:5507–5512, 2000.

    Article  PubMed  CAS  Google Scholar 

  22. Hunt, T. P., D. Issadore, and R. M. Westervelt. Integrated circuit/microfluidic chip to programmably trap and move cells and droplets with dielectrophoresis. Lab Chip 8(1):81–87, 2008.

    Article  PubMed  CAS  Google Scholar 

  23. Inagaki, N., K. Narushim, N. Tuchida, and K. Miyazaki. Surface characterization of plasma-modified poly(ethylene terephthalate) film surfaces. J. Polym. Sci. Part B 42:3727, 2004.

    Article  CAS  Google Scholar 

  24. Issadore, D., K. J. Humphry, K. A. Brown, L. Sandberg, D. A. Weitz, and R. M. Westervelt. Microwave dielectric heating of drops in microfluidic devices. Lab Chip 9:1701–1706, 2009.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Kopp, M. U., A. J. de Mello, and A. Manz. Chemical amplification: continuous-flow PCR on a chip. Science 280(5366):1046–1048, 1998.

    Article  PubMed  CAS  Google Scholar 

  26. Legendre, L. A., J. M. Bienvenue, M. G. Roper, J. P. Ferrance, and J. P. Landers. A simple, valveless microfluidic sample preparation device for extraction and amplification of DNA from nanoliter-volume samples. Anal. Chem. 78(5):1444–1451, 2006.

    Article  PubMed  CAS  Google Scholar 

  27. Lehmann, U., C. Vandevyver, V. K. Parashar, and M. A. M. Gijs. Droplet-based DNA purification in a magnetic Lab-on-a-Chip. Angew. Chem. Int. Ed. 45(19):3062–3067, 2006.

    Article  CAS  Google Scholar 

  28. Liu, J., M. Enzelberger, and S. Quake. A nanoliter rotary device for polymerase chain reaction. Electrophoresis 23:1531–1536, 2002.

    Article  PubMed  CAS  Google Scholar 

  29. Long, Z. C., A. M. Shetty, M. J. Solomon, and R. G. Larson. Fundamentals of magnet-actuated droplet manipulation on an open hydrophobic surface. Lab Chip 9(11):1567–1575, 2009.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Lu, H. W., F. Bottausci, J. D. Fowler, A. L. Bertozzi, C. Meinhart, and C. J. Kim. A study of EWOD-driven droplets by PIV investigation. Lab Chip 8:456–461, 2008.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Nakajima, A. Design of hydrophobic surfaces for liquid droplet control. NPG Asia Mater. 3:49–56, 2011.

    Article  Google Scholar 

  32. Neuzil, P., J. Pipper, and T. M. Hsieh. Disposable real-time microPCR device: lab-on-a-chip at a low cost. Mol. Biosyst. 2(6–7):292–298, 2006.

    Article  PubMed  CAS  Google Scholar 

  33. Novak, L., P. Neuzil, J. Pipper, Y. Zhang, and S. Lee. An integrated fluorescence detection system for lab-on-a-chip applications. Lab Chip 7:27–29, 2007.

    Article  PubMed  CAS  Google Scholar 

  34. Ohashi, T., H. Kuyama, N. Hanafusa, and Y. Togawa. A simple device using magnetic transportation for droplet-based PCR. Biomed. Microdev. 9:695–702, 2007.

    Article  CAS  Google Scholar 

  35. Park, S. Y., S. Kalim, C. Callahan, M. A. Teitell, and P. Y. Chiou. A light-induced dielectrophoretic droplet manipulation platform. Lab Chip 9(22):3228–3235, 2009.

    Article  PubMed  CAS  Google Scholar 

  36. Pipper, J., M. Inoue, L. F. P. Ng, P. Neuzil, Y. Zhang, and L. Novak. Catching bird flu in a droplet. Nat. Med. 13(10):1259–1263, 2007.

    Article  PubMed  CAS  Google Scholar 

  37. Pipper, J., Y. Zhang, P. Neuzil, and T. M. Hsieh. Clockwork PCR including sample preparation. Angew. Chem. Int. Ed. 47(21):3900–3904, 2008.

    Article  CAS  Google Scholar 

  38. Pollack, M. G., V. K. Pamula, V. Srinivasan, and A. E. Eckhardt. Applications of electrowetting-based digital microfluidics in clinical diagnostics. Expert Rev. Mol. Diagn. 11(4):393–407, 2011.

    Article  PubMed  CAS  Google Scholar 

  39. Rida, A., V. Fernandez, and M. A. M. Gijs. Long-range transport of magnetic microbeads using simple planar coils placed in a uniform magnetostatic field. Appl. Phys. Lett. 83(12):2396, 2003.

    Article  CAS  Google Scholar 

  40. Saiki, R. K., C. A. Chang, C. H. Levenson, T. C. Warren, C. D. Boehm, H. H. Kazazian, and H. A. Erlich. Diagnosis of sickle cell anemia and beta-thalassemia with enzymatically amplified DNA and nonradioactive allele-specific oligonucleotide probes. N. Engl. J. Med. 319:537–541, 1988.

    Article  PubMed  CAS  Google Scholar 

  41. Schutzius, T. M., M. Elsharkawy, M. K. Tiwari, and C. M. Megaridis. Surface tension confined (STC) tracks for capillary-driven transport of low surface tension liquids. Lab Chip 12:5237–5242, 2012.

    Article  PubMed  CAS  Google Scholar 

  42. Shevkoplyas, S. S., A. C. Siegel, R. M. Westervelt, M. G. Prentiss, and G. M. Whitesides. The force acting on a superparamagnetic bead due to an applied magnetic field. Lab Chip 7(10):1294–1302, 2007.

    Article  PubMed  CAS  Google Scholar 

  43. Shikida, M., N. Nagao, R. Imai, H. Honda, M. Okochi, H. Ito, and K. Sato. A palmtop-sized rotary-drive-type biochemical analysis system by magnetic bead handling. J. Micromech. Microeng. 18:35034–35041, 2008.

    Article  Google Scholar 

  44. Shikida, M., K. Takayanagi, K. Inouchi, H. Honda, and K. Sato. Using wettability and interfacial tension to handle droplets of magnetic beads in a micro-chemical-analysis system. Sens. Actuators B 113(1):563–569, 2006.

    Article  CAS  Google Scholar 

  45. Shin, D. J., Y. Zhang, T. H. Wang. A droplet microfluidic approach to single-stream nucleic acid isolation and mutation detection. Microfluid Nanofluid. 2014. doi:10.1007/s10404-013-1305-7.

  46. Simpson, R. J. Stabilization of proteins for storage. Cold Spring Harb. Protoc. 5:pdb.top79, 2010.

    Google Scholar 

  47. Sista, R., Z. Hua, A. Sudarsan, V. Srinivasan, A. Eckhardt, M. G. Pollack, and V. K. Pamula. Development of a digital microfluidic platform for point of care testing. Lab Chip 8(12):2091–2104, 2008.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Srinivasan, V., V. K. Pamula, and R. B. Fair. An integrated digital microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids. Lab Chip 4(4):310–315, 2004.

    Article  PubMed  CAS  Google Scholar 

  49. Tang, Y. W., G. W. Procop, and D. H. Persing. Molecular diagnostics of infectious diseases. Clin. Chem. 43(11):2021–2038, 1997.

    PubMed  CAS  Google Scholar 

  50. Thery, J., M. Borella, S. Le Vot, D. Jary, F. Rivera, G. Castellan, A. G. Brachet, M. Plissonnier, Y. Fouillet. SiOC as a hydrophobic layer for electrowetting on dielectric applications. Proceedings of the 11th International Conference on Miniaturized Systems for Chemistry and Life Sciences, Paris, 7–11 October 2007. vol. 1, pp. 349–351.

  51. Tsiatis, A. C., A. Norris-Kirby, R. G. Rich, M. J. Hafez, C. D. Gocke, J. R. Eshleman, and K. M. Murphy. Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J. Mol. Diagn. 12(4):425–432, 2010.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Tsuchiya, H., M. Okochi, N. Nagao, M. Shikida, and H. Honda. On-chip polymerase chain reaction microdevice employing a magnetic droplet-manipulation system. Sens Actuators B 130(2):583–588, 2008.

    Article  CAS  Google Scholar 

  53. Velev, O. D., B. G. Prevo, and K. H. Bhatt. On-chip manipulation of free droplets. Nature 426(6966):515–516, 2003.

    Article  PubMed  CAS  Google Scholar 

  54. Vogelstein, B., and D. Gillespie. Preparative and analytical purification of DNA from agarose. Proc. Natl. Acad. Sci. USA 76:615–619, 1979.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Welch, E. R., Y. Y. Lin, A. Madison, and R. B. Fair. Picoliter DNA sequencing chemistry on an electrowetting-based digital microfluidic platform. Biotechnol. J. 6(2):165–176, 2011.

    Article  PubMed  CAS  Google Scholar 

  56. Wittwer, C. T., G. H. Reed, C. N. Gundry, J. G. Vanderstenn, and R. J. Pryor. High-resolution genotyping by amplicon melting analysis using LCGreen. Clin. Chem. 49(6):853–860, 2003.

    Article  PubMed  CAS  Google Scholar 

  57. Wu, D. Y., L. Ugozzoli, B. K. Pal, and R. B. Wallace. Allele-specific enzymatic amplification of beta-globin genomic DNA for diagnosis of sickle cell anemia. Proc. Natl. Acad. Sci. USA 86(8):2757–2760, 1989.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Xia, Y., and G. M. Whitesides. Soft lithography. Angew. Chem. Int. Ed. 37(5):550–575, 1998.

    Article  CAS  Google Scholar 

  59. Xiang, Q., B. Xu, R. Fu, and D. Li. Real time PCR on disposable PDMS chip with a miniaturized thermal cycler. Biomed. Microdev. 7(4):273–279, 2005.

    Article  CAS  Google Scholar 

  60. Xing, S., R. S. Harake, and T. Pan. Droplet-driven transports on superhydrophobic-patterned surface microfluidics. Lab Chip 11:3642–3648, 2011.

    Article  PubMed  CAS  Google Scholar 

  61. Yetisen, A. K., M. S. Akram, and C. R. Lowe. Paper-based microfluidic point-of-care diagnostic devices. Lab Chip 13:2210–2251, 2013.

    Article  PubMed  CAS  Google Scholar 

  62. Zeka, A. N., S. Tasbakan, and C. Cavusoglu. Evaluation of the GeneXpert MTB/RIF assay for rapid diagnosis of tuberculosis and detection of rifampin resistance in pulmonary and extrapulmonary specimens. J. Clin. Microbiol. 49(12):4138–4141, 2011.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhang, Y., S. Park, K. Liu, J. Tsuan, S. Yang, and T. H. Wang. A surface topography assisted droplet manipulation platform for biomarker detection and pathogen identification. Lab Chip 11(3):398–406, 2011.

    Article  PubMed  CAS  Google Scholar 

  64. Zhang, Y., S. Park, S. Yang, and T. H. Wang. An all-in-one microfluidic device for parallel DNA extraction and gene analysis. Biomed. Microdev. 12(6):1043–1049, 2010.

    Article  CAS  Google Scholar 

  65. Zhang, Y., D. J. Shin, and T. H. Wang. Serial dilution via surface energy trap-assisted magnetic droplet manipulation. Lab Chip 13:4827–4831, 2013.

    Article  PubMed  CAS  Google Scholar 

  66. Zhang, Y., and T. H. Wang. Micro magnetic Gyromixer for speeding up reactions in droplets. Microfluid Nanofluid 12(5):787–794, 2012.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Zhang, Y., and T. H. Wang. Full-range magnetic manipulation of droplets via surface energy traps enables complex bioassays. Adv. Mater. 25:2903–2908, 2013.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the funding support from NIH (R01CA155305, U54CA151838 and R21CA173390) and NSF (1159771 and 0967375).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tza-Huei Wang.

Additional information

Associate Editor Tingrui Pan oversaw the review of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, D.J., Wang, TH. Magnetic Droplet Manipulation Platforms for Nucleic Acid Detection at the Point of Care. Ann Biomed Eng 42, 2289–2302 (2014). https://doi.org/10.1007/s10439-014-1060-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-014-1060-2

Keywords

Navigation