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Integrated nanopore sensing platform with sub-microsecond temporal resolution

Nature Methods volume 9, pages 487–492 (2012)Cite this article

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Abstract

Nanopore sensors have attracted considerable interest for high-throughput sensing of individual nucleic acids and proteins without the need for chemical labels or complex optics. A prevailing problem in nanopore applications is that the transport kinetics of single biomolecules are often faster than the measurement time resolution. Methods to slow down biomolecular transport can be troublesome and are at odds with the natural goal of high-throughput sensing. Here we introduce a low-noise measurement platform that integrates a complementary metal-oxide semiconductor (CMOS) preamplifier with solid-state nanopores in thin silicon nitride membranes. With this platform we achieved a signal-to-noise ratio exceeding five at a bandwidth of 1 MHz, which to our knowledge is the highest bandwidth nanopore recording to date. We demonstrate transient signals as brief as 1 μs from short DNA molecules as well as current signatures during molecular passage events that shed light on submolecular DNA configurations in small nanopores.

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Figure 1: The CNP.
Figure 2: Electrical modeling of a nanopore measurement.
Figure 3: Noise measurements.
Figure 4: Fast single-molecule events.
Figure 5: Fast nanopore event statistics (50 bp dsDNA and pore B).
Figure 6: Intra-event structure.

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Acknowledgements

We thank K. Venta, M. Puster, K. Healy, V. Ray, C. Dean and L. Paninski for their assistance. K.L.S. acknowledges partial support from the Semiconductor Research Corporation through the Focus Center Research Program, the US National Institutes of Health (R33HG003089) and the Office of Naval Research (N00014-09-1-1117). M.D. acknowledges support from the National Institutes of Health (R21HG004767, American Recovery and Reinvestment Act Supplement to R21HG004767 and R21HG006313).

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Authors and Affiliations

  1. Department of Electrical Engineering, Columbia University, New York, New York, USA

    Jacob K Rosenstein & Kenneth L Shepard

  2. Departments of Physics and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA

    Meni Wanunu

  3. Department of Physics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Meni Wanunu, Christopher A Merchant & Marija Drndic

Authors
  1. Jacob K Rosenstein
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Contributions

J.K.R., K.L.S. and M.D. developed the platform concept. J.K.R. designed the amplifier and measurement system. J.K.R., K.L.S., M.W. and M.D. planned experiments. M.W. and C.A.M. fabricated nanopores. J.K.R. and M.W. performed nanopore experiments and analyzed data. J.K.R. and K.L.S. wrote the manuscript. All authors edited the manuscript.

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Correspondence to Jacob K Rosenstein or Kenneth L Shepard.

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The authors declare no competing financial interests.

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Rosenstein, J., Wanunu, M., Merchant, C. et al. Integrated nanopore sensing platform with sub-microsecond temporal resolution. Nat Methods 9, 487–492 (2012). https://doi.org/10.1038/nmeth.1932

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