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Weighing of biomolecules, single cells and single nanoparticles in fluid

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.

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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.

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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.

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Correspondence to Scott R. Manalis.

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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)

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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

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