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.

Weighing of biomolecules, single cells and single nanoparticles in fluid

Nature volume 446, pages 1066–1069 (2007)Cite this article

Abstract

Nanomechanical resonators enable the measurement of mass with extraordinary sensitivity1,2,3,4,5,6,7. Previously, samples as light as 7 zeptograms (1 zg = 10-21 g) have been weighed in vacuum, and proton-level resolution seems to be within reach8. Resolving small mass changes requires the resonator to be light and to ring at a very pure tone—that is, with a high quality factor9. In solution, viscosity severely degrades both of these characteristics, thus preventing many applications in nanotechnology and the life sciences where fluid is required10. Although the resonant structure can be designed to minimize viscous loss, resolution is still substantially degraded when compared to measurements made in air or vacuum11,12,13,14. An entirely different approach eliminates viscous damping by placing the solution inside a hollow resonator that is surrounded by vacuum15,16. Here we demonstrate that suspended microchannel resonators can weigh single nanoparticles, single bacterial cells and sub-monolayers of adsorbed proteins in water with sub-femtogram resolution (1 Hz bandwidth). Central to these results is our observation that viscous loss due to the fluid is negligible compared to the intrinsic damping of our silicon crystal resonator. The combination of the low resonator mass (100 ng) and high quality factor (15,000) enables an improvement in mass resolution of six orders of magnitude over a high-end commercial quartz crystal microbalance17. This gives access to intriguing applications, such as mass-based flow cytometry, the direct detection of pathogens, or the non-optical sizing and mass density measurement of colloidal particles.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Illustration of two mass measurement modes enabled by a fluid-filled microcantilever.
Figure 2: Micrographs and frequency response of a suspended microchannel resonator.
Figure 3: Resonance frequency shifts caused by accumulation of proteins inside the cantilever.
Figure 4: Histograms of peak frequency shifts caused by particles and bacteria flowing through the resonator.

References

  1. Thundat, T., Wachter, E. A., Sharp, S. L. & Warmack, R. J. Detection of mercury vapor using resonating microcantilevers. Appl. Phys. Lett. 66, 1695–1697 (1995)

    Article  ADS  CAS  Google Scholar 

  2. Lange, D., Hagleitner, C., Hierlemann, A., Brand, O. & Baltes, H. Complementary metal oxide semiconductor cantilever arrays on a single chip: Mass-sensitive detection of volatile organic compounds. Anal. Chem. 74, 3084–3095 (2002)

    Article  CAS  Google Scholar 

  3. Lavrik, N. V. & Datskos, P. G. Femtogram mass detection using photothermally actuated nanomechanical resonators. Appl. Phys. Lett. 82, 2697–2699 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Ono, T., Li, X., Miyashita, H. & Esashi, M. Mass sensing of adsorbed molecules in sub-picogram sample with ultrathin silicon resonator. Rev. Sci. Instrum. 74, 1240–1243 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Gupta, A., Akin, D. & Bashir, R. Single virus particle mass detection using microresonators with nanoscale thickness. Appl. Phys. Lett. 84, 1976–1978 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Ilic, B. et al. Attogram detection using nanoelectromechanical oscillators. J. Appl. Phys. 95, 3694–3703 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Forsen, E. et al. Ultrasensitive mass sensor fully integrated with complementary metal-oxide-semiconductor circuitry. Appl. Phys. Lett. 87, 043507 (2005)

    Article  ADS  Google Scholar 

  8. Yang, Y. T., Callegari, C., Feng, X. L., Ekinci, K. L. & Roukes, M. L. Zeptogram-scale nanomechanical mass sensing. Nano Lett. 6, 583–586 (2006)

    Article  ADS  CAS  Google Scholar 

  9. Ekinci, K. L., Yang, Y. T. & Roukes, M. L. Ultimate limits to inertial mass sensing based upon nanoelectromechanical systems. J. Appl. Phys. 95, 2682–2689 (2004)

    Article  ADS  CAS  Google Scholar 

  10. Lucklum, R. & Hauptmann, P. Acoustic microsensors—the challenge behind microgravimetry. Anal. Bioanal. Chem. 384, 667–682 (2006)

    Article  CAS  Google Scholar 

  11. Weinberg, M. S., Dube, C. E., Petrovich, A. & Zapata, A. M. Fluid damping in resonant flexural plate wave device. J. Microelectromech. Syst. 12, 567–576 (2003)

    Article  Google Scholar 

  12. Zhang, H. & Kim, E. S. Micromachined acoustic resonant mass sensor. J. Microelectromech. Syst. 14, 699–706 (2005)

    Article  CAS  Google Scholar 

  13. Braun, T. et al. Micromechanical mass sensors for biomolecular detection in a physiological environment. Phys. Rev. E 72, 031907 (2005)

    Article  ADS  Google Scholar 

  14. Pang, W. et al. Femtogram mass sensing platform based on lateral extensional mode piezoelectric resonator. Appl. Phys. Lett. 88, 243503 (2006)

    Article  ADS  Google Scholar 

  15. Burg, T. P. & Manalis, S. R. Suspended microchannel resonators for biomolecular detection. Appl. Phys. Lett. 83, 2698–2700 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Burg, T. P. et al. Vacuum-packaged suspended microchannel resonant mass sensor for biomolecular detection. J. Microelectromech. Syst. 15, 1466–1476 (2006)

    Article  Google Scholar 

  17. Q-Sense. Model D3000 specifications. 〈http://www.q-sense.com/viewArticle.asp?ID=31〉.

  18. Enoksson, P., Stemme, G. & Stemme, E. Silicon tube structures for a fluid-density sensor. Sens. Actuators A 54, 558–562 (1996)

    Article  CAS  Google Scholar 

  19. Westberg, D., Paul, O., Andersson, G. & Baltes, H. A CMOS-compatible fluid density sensor. J. Micromech. Microeng. 7, 253–255 (1997)

    Article  ADS  CAS  Google Scholar 

  20. Sarid, D. Scanning Force Microscopy: With Applications to Electric, Magnetic, and Atomic Forces (Oxford Univ. Press, USA, 1994)

    Google Scholar 

  21. Myszka, D. G. Analysis of small-molecule interactions using Biacore S51 technology. Anal. Biochem. 329, 316–323 (2004)

    Article  CAS  Google Scholar 

  22. Angenendt, P., Glokler, J., Sobek, J., Lehrach, H. & Cahill, D. J. Next generation of protein microarray support materials: Evaluation for protein and antibody microarray applications. J. Chromatogr. A 1009, 97–104 (2003)

    Article  CAS  Google Scholar 

  23. Wu, G. H. et al. Bioassay of prostate-specific antigen (PSA) using microcantilevers. Nature Biotechnol. 19, 856–860 (2001)

    Article  CAS  Google Scholar 

  24. Backmann, N. et al. A label-free immunosensor array using single-chain antibody fragments. Proc. Natl Acad. Sci. USA 102, 14587–14592 (2005)

    Article  ADS  CAS  Google Scholar 

  25. Akerlund, T., Nordstrom, K. & Bernander, R. Analysis of cell size and DNA content in exponentially growing and stationary-phase batch cultures of Escherichia coli. J. Bacteriol. 177, 6791–6797 (1995)

    Article  CAS  Google Scholar 

  26. Nam, J. M., Thaxton, C. S. & Mirkin, C. A. Nanoparticle-based bio-bar codes for the ultrasensitive detection of proteins. Science 301, 1884–1886 (2003)

    Article  ADS  CAS  Google Scholar 

  27. Agrawal, A., Zhang, C. Y., Byassee, T., Tripp, R. A. & Nie, S. M. Counting single native biomolecules and intact viruses with color-coded nanoparticles. Anal. Chem. 78, 1061–1070 (2006)

    Article  CAS  Google Scholar 

  28. Thorsen, T., Maerkl, S. J. & Quake, S. R. Microfluidic large-scale integration. Science 298, 580–584 (2002)

    Article  ADS  CAS  Google Scholar 

  29. Whitesides, G. M. The origins and the future of microfluidics. Nature 442, 368–373 (2006)

    Article  ADS  CAS  Google Scholar 

  30. Yager, P. et al. Microfluidic diagnostic technologies for global public health. Nature 442, 412–418 (2006)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank N. Milovic, J. Behr, M.T. Thompson and K. Van Vliet for helpful discussions, A. Mirza for substantial contributions to device fabrication, and A. Ting for a critical review of the manuscript. We also acknowledge financial support from the National Institutes of Health (NIH) Cell Decision Process Center Grant, the Institute for Collaborative Biotechnologies from the US Army Research Office, the Air Force Office of Sponsored Research and a National Science Foundation (NSF) Small Business Innovation Research award. M.G. acknowledges support from the Natural Sciences and Engineering Research Council of Canada (NSERC) through a postdoctoral fellowship.

Author information

Author notes

  1. Thomas P. Burg and Michel Godin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Engineering,,

    Thomas P. Burg, Michel Godin, Scott M. Knudsen & Scott R. Manalis

  2. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Scott R. Manalis

  3. Innovative Micro Technology, Santa Barbara, California 93117, USA,

    Wenjiang Shen, Greg Carlson, John S. Foster & Ken Babcock

  4. Affinity Biosensors, Santa Barbara, California 93117, USA,

    Ken Babcock

Authors
  1. Thomas P. Burg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michel Godin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott M. Knudsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenjiang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Greg Carlson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John S. Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ken Babcock
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Scott R. Manalis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott R. Manalis.

Ethics declarations

Competing interests

Competing interests: S.R.M. and K.B. hold equity in, and are co-founders of, Affinity Biosensors, which will develop commercial instruments for applications described in this paper. W.S., G.C. and J.S.F. are employed by Innovative Micro Technology, which manufactures the devices described in this paper as part of a partnership with Affinity Biosensors.

Supplementary information

Supplementary Information

This file contains Supplementary Methods with additional details regarding device fabrication and experimental procedures, and a Supplementary Discussion comparing the suspended microchannel resonator with other mass sensing methods in fluid. The file includes Supplementary Figures S1 and S2, and Supplementary Table S1. (PDF 254 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Burg, T., Godin, M., Knudsen, S. et al. Weighing of biomolecules, single cells and single nanoparticles in fluid. Nature 446, 1066–1069 (2007). https://doi.org/10.1038/nature05741

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05741

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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