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Towards single-molecule nanomechanical mass spectrometry


Mass spectrometry provides rapid and quantitative identification of protein species with relatively low sample consumption. The trend towards biological analysis at increasingly smaller scales, ultimately down to the volume of an individual cell, continues, and mass spectrometry with a sensitivity of a few to single molecules will be necessary. Nanoelectromechanical systems provide unparalleled mass sensitivity, which is now sufficient for the detection of individual molecular species in real time. Here, we report the first demonstration of mass spectrometry based on single biological molecule detection with a nanoelectromechanical system. In our nanoelectromechanical–mass spectrometry system, nanoparticles and protein species are introduced by electrospray injection from the fluid phase in ambient conditions into vacuum, and are subsequently delivered to the nanoelectromechanical system detector by hexapole ion optics. Precipitous frequency shifts, proportional to the mass, are recorded in real time as analytes adsorb, one by one, onto a phase-locked, ultrahigh-frequency nanoelectromechanical resonator. These first nanoelectromechanical system–mass spectrometry spectra, obtained with modest mass sensitivity from only several hundred mass adsorption events, presage the future capabilities of this approach. We also outline the substantial improvements that are feasible in the near term, some of which are unique to nanoelectromechanical system based-mass spectrometry.

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Figure 1: First-generation NEMS–MS system.
Figure 2: Real-time records of single-molecule adsorption events on a NEMS mass sensor.
Figure 3: NEMS mass spectrometry of a gold nanoparticle dispersion.
Figure 4: NEMS–MS of proteins.


  1. 1

    Roukes, M. L. Nanoelectromechanical systems face the future. Phys. World 14, 25–31 (February 2001).

    CAS  Article  Google Scholar 

  2. 2

    Naik, A. et al. Cooling a nanomechanical resonator with quantum back-action. Nature 443, 193–196 (2006).

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    LaHaye, M. D., Buu, O., Camarota, B. & Schwab, K. C. Approaching the quantum limit of a nanomechanical resonator. Science 304, 74–77 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Thompson, J. D. et al. Strong dispersive coupling of a high-finesse cavity to a micromechanical membrane. Nature 452, 72–75 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Rugar, D., Budakian, R., Mamin, H. J. & Chui, B. W. Single spin detection by magnetic resonance force microscopy. Nature 430, 329–332 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Schwab, K., Henriksen, E. A., Worlock, J. M. & Roukes, M. L. Measurement of the quantum of thermal conductance. Nature 404, 974–977 (2000).

    CAS  Article  Google Scholar 

  8. 8

    Burg, T. P. et al. Weighing of biomolecules, single cells and single nanoparticles in fluid. Nature 446, 1066–1069 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Ilic, B., Yang, Y. & Craighead, H. G. Virus detection using nanoelectromechanical devices. Appl. Phys. Lett. 85, 2604–2606 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Domon, B. & Aebersold, R. Mass spectrometry and protein analysis. Science 312, 212–217 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Aebersold, R. & Mann, M. Mass spectrometry-based proteomics. Nature 422, 198–207 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Yu, J., Xiao, J., Ren, X., Lao, K. & Xie, X. S. Probing gene expression in live cells, one protein molecule at a time. Science 311, 1600–1603 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Cai, L., Friedman, N. & Xie, X. S. Stochastic protein expression in individual cells at the single molecule level. Nature 440, 358–362 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Ekinci, K. L., Huang, X. M. H. & Roukes, M. L. Ultrasensitive nanoelectromechanical mass detection. Appl. Phys. Lett. 84, 4469–4471 (2004).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  Article  Google Scholar 

  16. 16

    Feng, X. L., White, C. J., Hajimiri, A. & Roukes, M. L. A self-sustaining ultrahigh-frequency nanoelectromechanical oscillator. Nature Nanotech. 3, 342–346 (2008).

    CAS  Article  Google Scholar 

  17. 17

    Feng, X. L. Ultra high frequency nanoelectromechanical systems with low noise technologies for single molecule mass sensing. PhD. thesis, California Institute of Technology (2006).

  18. 18

    Roukes, M. L. & Ekinci, K. L. Apparatus and method for ultrasensitive nanoelectromechanical mass detection. US patent 6,722,200 (2004).

  19. 19

    Cleland, A. N. Thermomechanical noise limits on parametric sensing with nanomechanical resonators. New J. Phys. 7, 235 (2005).

    Article  Google Scholar 

  20. 20

    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).

    CAS  Article  Google Scholar 

  21. 21

    Lassagne, B., Garcia-Sanchez, D., Aguasca, A. & Bachtold, A. Ultrasensitive mass sensing with a nanotube electromechanical resonator. Nano Lett. 8, 3735–3738 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Jensen, K., Kim, K. & Zettl, A. An atomic-resolution nanomechanical mass sensor. Nature Nanotech. 3, 533–537 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Chiu, H.-Y., Hung, P., Postma, H. W. C. & Bockrath, M. Atomic-scale mass sensing using carbon nanotube resonators. Nano Lett. 8, 4342–4346 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Blain, M. G. et al. Towards the hand-held mass spectrometer: design considerations, simulation and fabrication of micrometer-scaled cylindrical ion traps. Int. J. Mass Spectrom. 236, 91–104 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Xie, J., Miao, Y., Shih, J., Tai, Y. C. & Lee, T. D. Microfluidic platform for liquid chromatography-tandem mass spectrometry analyses of complex peptide mixtures. Anal. Chem. 77, 6947–6953 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Yamashita, M. & Fenn, J. B. Electrospray ion source. Another variation on the free-jet theme. J. Phys. Chem. 88, 4451–4459 (1984).

    CAS  Article  Google Scholar 

  27. 27

    Fenn, J. B., Mann, M., Meng, C. K., Wong, S. F. & Whitehouse, C. M. Electrospray ionization for mass spectrometry of large biomolecules. Science 246, 64–71 (1989).

    CAS  Article  Google Scholar 

  28. 28

    Dieter, G. Inhomogeneous RF fields: A versatile tool for the study of processes with slow ions, in Advances in Chemical Physics: State-Selected and State-To-State Ion-Molecule Reaction Dynamics (eds Ng, C. Y., Baer, M., Prigogine, I. & Rice, S. A.) 1–176 (Wiley, 2007).

  29. 29

    Heck, A. J. & van den Heuvel, R. H. H. Investigation of intact protein complexes by mass spectrometry. Mass Spectrom. Rev. 23, 368–389 (2004).

    CAS  Article  Google Scholar 

  30. 30

    van Berkel, W. J., van den Heuvel, R. H., Versluis, C. & Heck, A. J. Detection of intact megadalton protein assemblies of vanillyl-alcohol oxidase by mass spectrometry. Protein Sci. 9, 435–439 (2000).

    CAS  Article  Google Scholar 

  31. 31

    Dohn, S., Svendsen, W., Boisen, A. & Hansen, O. Mass and position determination of attached particles on cantilever based mass sensors. Rev. Sci. Instrum. 78, 103303 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Hanay, M. S. & Roukes, M. L. Multimode detection schemes for NEMS-based mass spectrometry. US patent CIT-4423-P (2005).

  33. 33

    El-Faramawy, A., Siu, K. W. M. & Thomson, B. A. Efficiency of nano-electrospray ionization. J. Am. Soc. Mass. Spectrom. 16, 1702–1707 (2005).

    CAS  Article  Google Scholar 

  34. 34

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We acknowledge support from the NIH under grant R21-GM072898 and, indirectly, from DARPA/MTO under DOI/NBCH1050001 (MGA program) and SPAWAR/ N66001-02-1-8914 (CSAC program). The latter has enabled development of critical NEMS technology for this work. We thank S. Stryker for expert technical assistance in constructing the NEMS-MS system, C. A. Zorman and M. Mehregany for custom SiC epilayers used in our NEMS fabrication, V. Semenchenko, D. A. Van Valen and R. Philips for help with gel electrophoresis, and I. Bargatin, J. L. Beauchamp, W. Lee, E. B. Myers and M. Shahgoli for helpful discussions.

Author information




A.K.N. and M.S.H. fabricated devices, performed experiments, analysed results and carried out some simulations. W.K.H. designed and assembled the system and performed the initial experiments. X.L.F. made the devices and did the initial phase-locked loop measurements. M.L.R. conceived the project and provided overall guidance throughout. All authors discussed the results and were involved in the analyses and manuscript preparation.

Corresponding authors

Correspondence to X. L. Feng or M. L. Roukes.

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Naik, A., Hanay, M., Hiebert, W. et al. Towards single-molecule nanomechanical mass spectrometry. Nature Nanotech 4, 445–450 (2009).

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