Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm

Nature Nanotechnology volume 11, pages 936–940 (2016)Cite this article

Subjects

Abstract

Deterministic lateral displacement (DLD) pillar arrays are an efficient technology to sort, separate and enrich micrometre-scale particles, which include parasites1, bacteria2, blood cells3 and circulating tumour cells in blood4. However, this technology has not been translated to the true nanoscale, where it could function on biocolloids, such as exosomes. Exosomes, a key target of ‘liquid biopsies’, are secreted by cells and contain nucleic acid and protein information about their originating tissue5. One challenge in the study of exosome biology is to sort exosomes by size and surface markers6,7. We use manufacturable silicon processes to produce nanoscale DLD (nano-DLD) arrays of uniform gap sizes ranging from 25 to 235 nm. We show that at low Péclet (Pe) numbers, at which diffusion and deterministic displacement compete, nano-DLD arrays separate particles between 20 to 110 nm based on size with sharp resolution. Further, we demonstrate the size-based displacement of exosomes, and so open up the potential for on-chip sorting and quantification of these important biocolloids.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Nano-DLD nanoparticle sorting using pillar array chips with G ranging from 25 to 235 nm and θmax = 5.7°.
Figure 2: Separation of polystyrene beads using a hydrodynamically focused jet in a nano-DLD array.
Figure 3: Experimental demonstration of displacement and fractionation of exosomes in nano-DLD arrays.

Similar content being viewed by others

References

  1. Holm, S. H., Beech, J. P., Barrett, M. P. & Tegenfeldt, J. O. Separation of parasites from human blood using deterministic lateral displacement. Lab Chip 11, 1326–1332 (2011).

    Article  CAS  Google Scholar 

  2. Ranjan, S., Zeming, K. K., Jureen, R., Fisher, D. & Zhang, Y. DLD pillar shape design for efficient separation of spherical and non-spherical bioparticles. Lab Chip 14, 4250–4262 (2014).

    Article  CAS  Google Scholar 

  3. Davis, J. A. et al. Deterministic hydrodynamics: taking blood apart. Proc. Natl Acad. Sci. USA 103, 14779–14784 (2006).

    Article  CAS  Google Scholar 

  4. Okano, H. et al. Enrichment of circulating tumor cells in tumor-bearing mouse blood by a deterministic lateral displacement microfluidic device. Biomed. Microdevices 17, 58 (2015).

    Article  Google Scholar 

  5. Balaj, L. et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nature Commun. 2, 180–189 (2011).

    Article  Google Scholar 

  6. Im, H. et al. Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor. Nature Biotechnol. 32, 490–495 (2014).

    Article  CAS  Google Scholar 

  7. Liga, A., Vliegenthart, A. D. B., Oosthuyzen, W., Dear, J. W. & Kersaudy-Kerhoas, M. Exosome isolation: a microfluidic road-map. Lab Chip 15, 2388–2394 (2015).

    Article  CAS  Google Scholar 

  8. Huang, L. R., Cox, E. C., Austin, R. H. & Sturm, J. C. Continuous particle separation through deterministic lateral displacement. Science 304, 987–990 (2004).

    Article  CAS  Google Scholar 

  9. McGrath, J., Jimenez, M. & Bridle, H. Deterministic lateral displacement for particle separation: a review. Lab Chip 14, 4139–4158 (2014).

    Article  CAS  Google Scholar 

  10. Heller, M. & Bruus, H. A theoretical analysis of the resolution due to diffusion and size dispersion of particles in deterministic lateral displacement devices. J. Micromech. Microeng. 18, 075030 (2008).

    Article  Google Scholar 

  11. Long, B. R. et al. Multidirectional sorting modes in deterministic lateral displacement devices. Phys. Rev. E 78, 046304 (2008).

    Article  Google Scholar 

  12. Cerbelli, S. Separation of polydisperse particle mixtures by deterministic lateral displacement. The impact of particle diffusivity on separation efficiency. Asia-Pacific J. Chem. Eng. 7, S356–S371 (2012).

    Article  CAS  Google Scholar 

  13. Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).

    Article  CAS  Google Scholar 

  14. Sharma, S., Gillespie, B. M., Palanisamy, V. & Gimzewski, J. K. Quantitative nanostructural and single-molecule force spectroscopy biomolecular analysis of human-saliva-derived exosomes. Langmuir 27, 14394–14400 (2011).

    Article  CAS  Google Scholar 

  15. Nilsson, J. et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br. J. Cancer 100, 1603–1607 (2009).

    Article  CAS  Google Scholar 

  16. Coleman, B. M., Hanssen, E., Lawson, V. A. & Hill, A. F. Prion-infected cells regulate the release of exosomes with distinct ultrastructural features. FASEB J. 26, 4160–4173 (2012).

    Article  CAS  Google Scholar 

  17. De Toro, J., Herschlik, L., Waldner, C. & Mongini, C. Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front. Immunol. 6, 203 (2015).

    Article  Google Scholar 

  18. Lane, R. E., Korbie, D., Anderson, W., Vaidyanathan, R. & Trau, M. Analysis of exosome purification methods using a model liposome system and tunable-resistive pulse sensing. Sci. Rep. 5, 7639 (2015).

    Article  Google Scholar 

  19. Sokolova, V. et al. Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids Surf. 87, 146–150 (2011).

    Article  CAS  Google Scholar 

  20. Inglis, D. W., Davis, J. A., Austin, R. H. & Sturm, J. C. Critical particle size for fractionation by deterministic lateral displacement. Lab Chip 6, 655–658 (2006).

    Article  CAS  Google Scholar 

  21. Koplik, J. & Drazer, G. Nanoscale simulations of directional locking. Phys. Fluids 22, 052005 (2010).

    Article  Google Scholar 

  22. Risbud, S. R. & Drazer, G. Directional locking in deterministic lateral-displacement microfluidic separation systems. Phys. Rev. E 90, 012302 (2014).

    Article  Google Scholar 

  23. Cerbelli, S., Giona, M. & Garofalo, F. Quantifying dispersion of finite-sized particles in deterministic lateral displacement microflow separators through Brenner's macrotransport paradigm. Microfluid. Nanofluid. 15, 431–449 (2013).

    Article  CAS  Google Scholar 

  24. Vernekar, R. & Krüger, T. Breakdown of deterministic lateral displacement efficiency for non-dilute suspensions: a numerical study. Med. Eng. Phys. 37, 845–854 (2015).

    Article  CAS  Google Scholar 

  25. Maxey, M. R. & Riley, J. J. Equation of motion for a small rigid sphere in a nonuniform flow. Phys. Fluids 26, 883 (1983).

    Article  Google Scholar 

  26. Leach, J. et al. Comparison of Faxén's correction for a microsphere translating or rotating near a surface. Phys. Rev. E 79, 026301 (2009).

    Article  CAS  Google Scholar 

  27. Liu, C., Xue, C., Sun, J. & Hu, G. A generalized formula for inertial lift on a sphere in microchannels. Lab Chip 16, 884–892 (2016).

    Article  CAS  Google Scholar 

  28. Zeming, K. K., Thakor, N. V., Zhang, Y. & Chen, C.-H. Real-time modulated nanoparticle separation with an ultra-large dynamic range. Lab Chip 16, 75–85 (2016).

    Article  CAS  Google Scholar 

  29. Kulrattanarak, T., van der Sman, R. G. M., Schroen, C. G. P. H. & Boom, R. M. Analysis of mixed motion in deterministic ratchets via experiment and particle simulation. Microfluid. Nanofluid. 10, 843–853 (2011).

    Article  CAS  Google Scholar 

  30. Wang, C. et al. Hydrodynamics of diamond-shaped gradient nanopillar arrays for effective DNA translocation into nanochannels. ACS Nano 9, 1206–1218 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Pereira for fabrication of the microfluidic cells that hold and interface with nanofluidic chips, S.-C. Kim for the custom Python script to help analyse displacement data, H. Hu for the SEM imaging of exosome samples and P. Meyer for helpful discussion in the preparation of this manuscript. We also thank D. Williams at the Electron Microscopy Resource Laboratory at the University of Pennsylvania for the cryo-EM imaging of exosomes, and the IBM Microelectronics Research Laboratory staff for their contributions to the fabrication of the nano-DLD arrays.

Author information

Author notes

  1. Chao Wang & Yann Astier

    Present address: Present addresses: School of Electrical, Computer and Energy Engineering, and Biodesign Center for Molecular Design & Biomimetics, Arizona State University, Tempe, Arizona 82587, USA (C.W.); Roche Molecular Systems, Pleasanton, California 94588, USA (Y.A.),

  2. Benjamin H. Wunsch and Joshua T. Smith: These authors contributed equally to the paper

Authors and Affiliations

  1. IBM T.J. Watson Research Center, Yorktown Heights, New York 10598, USA

    Benjamin H. Wunsch, Joshua T. Smith, Stacey M. Gifford, Chao Wang, Markus Brink, Robert L. Bruce, Gustavo Stolovitzky & Yann Astier

  2. Department of Physics, Princeton University, Princeton, New Jersey 08540, USA

    Robert H. Austin

  3. Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA

    Gustavo Stolovitzky

Authors
  1. Benjamin H. Wunsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua T. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stacey M. Gifford
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Markus Brink
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert L. Bruce
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert H. Austin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gustavo Stolovitzky
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yann Astier
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.A. developed the nano-DLD concept for biocolloids, and led the experimental research. J.T.S. designed and led the chip technology development. M.B. and R.L.B. contributed to the microfabrication process development. B.H.W., J.T.S. and S.M.G. performed the experiments. B.H.W. and S.M.G. analysed the data. B.H.W., Y.A., S.M.G., C.W., R.H.A. and G.S. contributed to the theory and interpretation of the results. G.S. managed the research team. B.H.W. and J.T.S. co-wrote the paper. All the authors contributed to the review of the manuscript.

Corresponding authors

Correspondence to Benjamin H. Wunsch, Joshua T. Smith or Gustavo Stolovitzky.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 1303 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wunsch, B., Smith, J., Gifford, S. et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nature Nanotech 11, 936–940 (2016). https://doi.org/10.1038/nnano.2016.134

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2016.134

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing