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A high-throughput label-free nanoparticle analyser

Abstract

Synthetic nanoparticles and genetically modified viruses are used in a range of applications, but high-throughput analytical tools for the physical characterization of these objects are needed. Here we present a microfluidic analyser that detects individual nanoparticles and characterizes complex, unlabelled nanoparticle suspensions. We demonstrate the detection, concentration analysis and sizing of individual synthetic nanoparticles in a multicomponent mixture with sufficient throughput to analyse 500,000 particles per second. We also report the rapid size and titre analysis of unlabelled bacteriophage T7 in both salt solution and mouse blood plasma, using just 1 × 10−6 l of analyte. Unexpectedly, in the native blood plasma we discover a large background of naturally occurring nanoparticles with a power-law size distribution. The high-throughput detection capability, scalable fabrication and simple electronics of this instrument make it well suited for diverse applications.

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Figure 1: Device schematics and detector response.
Figure 2: Controlling particle flow.
Figure 3: Detection bandwidth.
Figure 4: Analysis of a polydisperse nanoparticle mixture.
Figure 5: Size and concentration measurements of unlabelled bacteriophage T7 in salt solution.
Figure 6: Particle size distribution and T7 phage detection in mouse blood.

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References

  1. Nohynek, G. J., Lademann, J., Ribaud, C. & Roberts, M. S. Grey goo on the skin? Nanotechnology, cosmetic and sunscreen safety. Crit. Rev. Toxicol 37, 251–277 (2007).

    Article  CAS  Google Scholar 

  2. Franzman, M. A., Schlenker, C. W., Thompson, M. E. & Brutchey, R. L. Solution-phase synthesis of SnSe nanocrystals for use in solar cells. J. Am. Chem. Soc. 132, 4060–4061 (2010).

    Article  CAS  Google Scholar 

  3. Sugahara, K. N. et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16, 510–520 (2009).

    Article  CAS  Google Scholar 

  4. Michalet, X. et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307, 538–544 (2005).

    Article  CAS  Google Scholar 

  5. Harisinghani, M. G. et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. New Engl. J. Med. 348, 2491–2499 (2003).

    Article  Google Scholar 

  6. VanWijk, M. J., VanBavel, E., Sturk, A. & Nieuwland, R. Microparticles in cardiovascular diseases. Cardiovasc. Res. 59, 277–287 (2003).

    Article  CAS  Google Scholar 

  7. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell. Biol. 9, 654–659 (2007).

    Article  CAS  Google Scholar 

  8. Simons, M. & Raposo, G. Exosomes—vesicular carriers for intercellular communication. Curr. Opin. Cell Biol. 21, 575–581 (2009).

    Article  CAS  Google Scholar 

  9. WHO. World Health Statistics 2010 (WHO, 2010).

  10. Cressey, D. Tiny traits cause big headaches. Nature 467, 264–265 (2010).

    Article  Google Scholar 

  11. Nel, A., Xia, T., Madler, L. & Li, N. Toxic potential of materials at the nanolevel. Science 311, 622–627 (2006).

    Article  CAS  Google Scholar 

  12. Maynard, A. D. et al. Safe handling of nanotechnology. Nature 444, 267–269 (2006).

    Article  CAS  Google Scholar 

  13. Coulter, W. H. Means for counting particles suspended in a fluid. US patent 2,656,508 (1953).

  14. DeBlois, R. W. & Bean, C. P. Counting and sizing of submicron particles by the resistive pulse technique. Rev. Sci. Instrum. 41, 909–916 (1970).

    Article  Google Scholar 

  15. Kasianowicz, J. J., Brandin, E., Branton, D. & Deamer, D. W. Characterization of individual polynucleotide molecules using a membrane channel. Proc. Natl Acad. Sci. USA 93, 13770–13773 (1996).

    Article  CAS  Google Scholar 

  16. Li, J., Gershow, M., Stein, D., Brandin, E. & Golovchenko, J. A. DNA molecules and configurations in a solid-state nanopore microscope. Nature Mater. 2, 611–615 (2003).

    Article  CAS  Google Scholar 

  17. Uram, J. D., Ke, K., Hunt, A. J. & Mayer, M. Label-free affinity assays by rapid detection of immune complexes in submicrometer pores. Angew. Chem. Int. Ed. 45, 2281–2285 (2006).

    Article  CAS  Google Scholar 

  18. Saleh, O. A. & Sohn, L. L. An artificial nanopore for molecular sensing. Nano Lett. 3, 37–38 (2003).

    Article  CAS  Google Scholar 

  19. Sen, Y-H. & Karnik, R. Investigating the translocation of λ-DNA molecules through PDMS nanopores. Anal. Bioanal. Chem. 394, 437–446 (2009).

    Article  CAS  Google Scholar 

  20. Bard, A. J. Electrochemical Methods Fundamentals and Applications 2nd edn (Wiley, 1980).

    Google Scholar 

  21. Sridhar, M. et al. Experimental characterization of a metal-oxide-semiconductor field-effect transistor-based coulter counter. J. Appl. Phys. 103, 104701 (2008).

    Article  Google Scholar 

  22. Uram, J. D., Ke, K., Hunt, A. J. & Mayer, M. Submicrometer pore-based characterization and quantification of antibody–virus interactions. Small 2, 967–972 (2006).

    Article  CAS  Google Scholar 

  23. Saleh, O. A. & Sohn, L. L. Quantitative sensing of nanoscale colloids using a microchip Coulter counter. Rev. Sci. Instrum. 72, 4449–4451 (2001).

    Article  CAS  Google Scholar 

  24. Berne, B. J. Dynamic Light Scattering: With Applications to Chemistry, Biology, and Physics (Wiley, 1976).

    Google Scholar 

  25. Teesalu, T., Sugahara, K. N., Kotamraju, V. R. & Ruoslahti, E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc. Natl Acad. Sci. USA 106, 16157–16162 (2009).

    Article  CAS  Google Scholar 

  26. Wakita, T. et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Med. 11, 791–796 (2005).

    Article  CAS  Google Scholar 

  27. Davison, P. F. & Freifelder, D. The physical properties of T7 bacteriophage. J. Mol. Biol. 5, 635–642, IN2 (1962).

    Article  CAS  Google Scholar 

  28. Ronto, G., Agamalyan, M. M., Drabkin, G. M., Feigin, L. A. & Lvov, Y. M. Structure of bacteriophage-T7—small-angle X-ray and neutron-scattering study. Biophys. J. 43, 309–314 (1983).

    Article  CAS  Google Scholar 

  29. Serwer, P. Buoyant density sedimentation of macromolecules in sodium iothalamate density gradients. J. Mol. Biol. 92, 433–448 (1975).

    Article  CAS  Google Scholar 

  30. Stroud, R. M., Serwer, P. & Ross, M. J. Assembly of bacteriophage-T7—dimensions of the bacteriophage and its capsids. Biophys. J. 36, 743–757 (1981).

    Article  CAS  Google Scholar 

  31. Berg, T. et al. Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology 37, 600–609 (2003).

    Article  CAS  Google Scholar 

  32. Caby, M-P., Lankar, D., Vincendeau-Scherrer, C., Raposo, G. & Bonnerot, C. Exosomal-like vesicles are present in human blood plasma. Int. Immunol. 17, 879–887 (2005).

    Article  CAS  Google Scholar 

  33. Kiser, M. A. et al. Titanium nanomaterial removal and release from wastewater treatment plants. Environ. Sci. Technol. 43, 6757–6763 (2009).

    Article  CAS  Google Scholar 

  34. Gottschalk, F., Sonderer, T., Scholz, R. W. & Nowack, B. Modeled environmental concentrations of engineered nanomaterials (TiO2, ZnO, Ag, CNT, fullerenes) for different regions. Environ. Sci. Technol. 43, 9216–9222 (2009).

    Article  CAS  Google Scholar 

  35. Duffy, D., McDonald, J., Schueller, O. & Whitesides, G. Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal. Chem. 70, 4974–4984 (1998).

    Article  CAS  Google Scholar 

  36. Fraikin, J-L., Requa, M. V. & Cleland, A. N. Probing the Debye layer: capacitance and potential of zero charge measured using a Debye-layer transistor. Phys. Rev. Lett. 102, 156601 (2009).

    Article  Google Scholar 

  37. Wood, D. K., Oh, S-H., Lee, S-H., Soh, H. T. & Cleland, A. N. High-bandwidth radio frequency Coulter counter. Appl. Phys. Lett. 87, 184106 (2005).

    Article  Google Scholar 

  38. Wood, D. K., Requa, M. V. & Cleland, A. N. Microfabricated high-throughput electronic particle detector. Rev. Sci. Instrum. 78, 104301 (2007).

    Article  CAS  Google Scholar 

  39. Wood, D. K. et al. A feasible approach to all-electronic digital labeling and readout for cell identification. Lab Chip 7, 469–474 (2007).

    Article  CAS  Google Scholar 

  40. Kubitscheck, H. E. Counting and Sizing Micro-organisms with the Coulter Counter Vol. 1, Ch. XXVII, 593–610 (Academic, 1969).

    Google Scholar 

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Acknowledgements

This research was supported by a National Institutes of Health Program of Excellence in Nanotechnology grant (U01-HL080718). The authors thank C. Axline for construction of the pressure manifold used to control flow in the microfluidic system, and G. Braun for valuable discussions. The authors also acknowledge use of the UC Santa Barbara Nanofabrication Facility, a part of the NSF-supported National Nanofabrication Infrastructure Network (NNIN).

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Contributions

J.-L.F. fabricated the analyser, performed the experiments and analysed the data. J.-L.F. and A.N.C designed the analyser. J.-L.F., T.T. and A.N.C. designed the experiments with contributions from E.R. J.-L.F. and A.N.C. wrote the manuscript with contributions from T.T. T.T. performed the biological procedures, including phage synthesis. C.M.M. contributed to the fabrication of the fluidic mold.

Corresponding author

Correspondence to Andrew N. Cleland.

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The authors declare no competing financial interests.

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Fraikin, JL., Teesalu, T., McKenney, C. et al. A high-throughput label-free nanoparticle analyser. Nature Nanotech 6, 308–313 (2011). https://doi.org/10.1038/nnano.2011.24

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