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.

  • Letter
  • Published:

Label-free biomarker detection from whole blood

Nature Nanotechnology volume 5, pages 138–142 (2010)Cite this article

Abstract

Label-free nanosensors can detect disease markers to provide point-of-care diagnosis that is low-cost, rapid, specific and sensitive1,2,3,4,5,6,7,8,9,10,11,12,13. However, detecting these biomarkers in physiological fluid samples is difficult because of problems such as biofouling and non-specific binding, and the resulting need to use purified buffers greatly reduces the clinical relevance of these sensors. Here, we overcome this limitation by using distinct components within the sensor to perform purification and detection. A microfluidic purification chip simultaneously captures multiple biomarkers from blood samples and releases them, after washing, into purified buffer for sensing by a silicon nanoribbon detector. This two-stage approach isolates the detector from the complex environment of whole blood, and reduces its minimum required sensitivity by effectively pre-concentrating the biomarkers. We show specific and quantitative detection of two model cancer antigens from a 10 µl sample of whole blood in less than 20 min. This study marks the first use of label-free nanosensors with physiological solutions, positioning this technology for rapid translation to clinical settings.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Schematic of MPC operation.
Figure 2: MPC operation.
Figure 3: Nanosensor electrical characteristics.
Figure 4: Label-free sensing.

Similar content being viewed by others

References

  1. Sander, C. Genomic medicine and the future of health care. Science 287, 1977–1978 (2000).

    Article  CAS  Google Scholar 

  2. Jemal, A. et al. Cancer statistics 2008. CA Cancer J. Clin. 58, 71–96 (2008).

    Article  Google Scholar 

  3. Etzioni, R. et al. The case for early detection. Nature Rev. Cancer 3, 243–252 (2003).

    Article  CAS  Google Scholar 

  4. Liang, S. & Chan, D. W. Enzymes and related proteins as cancer biomarkers: a proteomic approach. Clin. Chim. Acta 381, 93–97 (2007).

    Article  CAS  Google Scholar 

  5. Fan, R. et al. Integrated barcode chips for rapid, multiplexed analysis of proteins in microliter quantities of blood. Nature Biotechnol. 26, 1373–1378 (2008).

    Article  CAS  Google Scholar 

  6. Zheng, G., Patolsky, F., Cui, Y., Wang, W. U. & Lieber, C. M. Multiplexed electrical detection of cancer markers with nanowire sensor arrays. Nature Biotechnol. 23, 1294–1301 (2005).

    Article  CAS  Google Scholar 

  7. Cui, Y., Wei, Q., Park, H. & Lieber, C. M. Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species. Science 293, 1289–1292 (2001).

    Article  CAS  Google Scholar 

  8. Jain, K. K. Nanotechnology in clinical laboratory diagnostics. Clin. Chim. Acta 358, 37–54 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Kim, A. et al. Ultrasensitive, label-free and real-time immunodetection using silicon field-effect transistors. Appl. Phys. Lett. 91, 103901 (2007).

    Article  Google Scholar 

  11. Stern, E. et al. Label-free immunodetection with CMOS-compatible semiconducting nanowires. Nature 445, 519–522 (2007).

    Article  CAS  Google Scholar 

  12. Stern, E., Vacic, A. & Reed, M. A. Semiconducting nanowire field-effect transistor biomolecular sensors. IEEE Trans. Electron. Dev. 55, 3119–3130 (2008).

    Article  CAS  Google Scholar 

  13. Bunimovich, Y. L. et al. Quantitative real-time measurements of DNA hybridization with alkylated nonoxidized silicon nanowires in electrolyte solution. J. Am. Chem. Soc. 128, 16323–16331 (2006).

    Article  CAS  Google Scholar 

  14. Nagrath, S. et al. Isolation of rare circulating tumor cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).

    Article  CAS  Google Scholar 

  15. Gupta, A. K. et al. Anomalous resonance in a nanomechanical biosensor. Proc. Natl Acad. Sci. USA 103, 13362–13367 (2006).

    Article  CAS  Google Scholar 

  16. Stern, E. et al. Importance of the Debye screening length on nanowire field effect transistor sensors. Nano Lett. 7, 3405–3409 (2007).

    Article  CAS  Google Scholar 

  17. Zhou, H., Ranish, J. A., Watts, J. D. & Aebersold, R. Quantitative proteome analysis by solid-phase isotope tagging and mass spectrometry. Nature Biotechnol. 20, 512–515 (2002).

    Article  CAS  Google Scholar 

  18. Templin, M. F., Stoll, D., Bachmann, J. & Joos, T. O. Protein microarrays and multiplexed sandwich immunoassays: what beats the beads? Comb. Chem. High Through. Screen 7, 223–229 (2004).

    Article  CAS  Google Scholar 

  19. Hermanson, G. T. Bioconjugate Techniques (Elsevier, 1996).

    Google Scholar 

  20. Bai, X., Kim, S., Li, Z., Turro, N. J. & Ju, J. Design and synthesis of a photocleavable biotinylated nucleotide for DNA analysis by mass spectrometry. Nucleic Acids Res. 32, 535–541 (2004).

    Article  CAS  Google Scholar 

  21. Handwerger, R. G. & Diamond, S. L. Biotinylated photocleavable polyethylenimine: capture and triggered release of nucleic acids from solid supports. Bioconjug. Chem. 18, 717–723 (2007).

    Article  CAS  Google Scholar 

  22. Senter, P. D. et al. Novel photocleavable protein crosslinking reagents and their use in the preparation of antibody–toxin conjugates. Photochem. Photobiol. 42, 231–237 (1985).

    Article  CAS  Google Scholar 

  23. Olejnik, J. et al. Photocleavable biotin derivatives—a versatile approach for the isolation of biomolecules. Proc. Natl Acad. Sci. USA 92, 7590–7594 (1995).

    Article  CAS  Google Scholar 

  24. Vickers, A. J., Savage, C., O'Brien, M. F. & Lilja, H. Systematic review of pretreatment prostate-specific antigen velocity and doubling time as predictors for prostate cancer. J. Clin. Oncol. 27, 398–403 (2009).

    Article  Google Scholar 

  25. Shariat, S. F., Scardino, P. T. & Lilja, H. Screening for prostate cancer: an update. Can. J. Urol. 15, 4363–4374 (2008).

    Google Scholar 

  26. Rubach, M., Szymendera, J. J., Kaminska, J. & Kowalska, M. Serum CA 15.3, CEA and ESR patterns in breast cancer. Int. J. Biol. Markers 12, 168–173 (1997).

    Article  CAS  Google Scholar 

  27. Uehara, M. et al. Long-term prognostic study of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in breast cancer. Int. J. Clin. Oncol. 13, 447–451 (2008).

    Article  CAS  Google Scholar 

  28. Elfstrom, N., Karlstrom, A. E. & Linnros, J. Silicon nanoribbons for electrical detection of biomolecules. Nano Lett. 8, 945–949 (2008).

    Article  Google Scholar 

  29. Cantor, C. R. & Schimmel, P. R. Biophysical Chemistry: Part III: The Behavior of Biological Macromolecules (Freeman, 1980).

    Google Scholar 

  30. Homola, J. Present and future of surface plasmon resonance biosensors. Anal. Bioanal. Chem. 377, 528–539 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank J. Straight for many helpful discussions, M. Look and J. Bertram for blood samples, M. Power for device processing assistance, M. Saltzman for departmental support, and D. Stern and K. Milnamow for critical reading of the manuscript. The work was supported in part by the National Institute of Health (NIH) through grant no. R01EB008260 (M.A.R. and T.M.F.), Canadian Institute for Advanced Research (CIfAR), and Army Research Office (ARO) (W911NF-08-1-0365). This work was performed in part at the Cornell Nanoscale Science and Technology Facility, a member of the National Nanotechnology Infrastructure Network that is supported by the National Science Foundation (NSF), and at the Yale Institute for Nanoscience and Quantum Engineering. This paper is dedicated to the memory of Alan R. Stern.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, 06511, Connecticut, USA

    Eric Stern, Jason M. Criscione, Jason Park & Tarek M. Fahmy

  2. Department of Electrical Engineering, School of Engineering and Applied Science, Yale University, New Haven, 06511, Connecticut, USA

    Aleksandar Vacic, Nitin K. Rajan & Mark A. Reed

  3. Cornell Nanofabrication Facility, Cornell University, Ithaca, 14853, New York, USA

    Bojan R. Ilic

  4. Department of Bioengineering, School of Engineering and Applied Science, Harvard University, Cambridge, 02138, Massachusetts, USA

    David J. Mooney

  5. Department of Applied Physics, School of Engineering and Applied Science, Yale University, New Haven, 06511, Connecticut, USA

    Mark A. Reed

  6. Department of Chemical Engineering, School of Engineering and Applied Science, Yale University, New Haven, 06511, Connecticut, USA

    Tarek M. Fahmy

Authors
  1. Eric Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aleksandar Vacic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nitin K. Rajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jason M. Criscione
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jason Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bojan R. Ilic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David J. Mooney
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark A. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tarek M. Fahmy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.S. designed the MPC and performed all MPC experiments. E.S. and B.R.I. designed the MPC fabrication and performed MPC processing. E.S., A.V. and M.A.R. designed the nanosensor fabrication process and E.S., A.V. and B.R.I. performed nanosensor processing. D.J.M. assisted with MPC and nanosensor experimental design, and data analysis. E.S., A.V., N.K.R. and J.M.C. performed the sensing measurements. E.S., J.M.C. and J.P. prepared and analysed the protein samples. E.S., M.A.R. and T.M.F. wrote the manuscript and edited it, with contributions from all authors.

Corresponding authors

Correspondence to Mark A. Reed or Tarek M. Fahmy.

Supplementary information

Supplementary information

Supplementary information (PDF 2005 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stern, E., Vacic, A., Rajan, N. et al. Label-free biomarker detection from whole blood. Nature Nanotech 5, 138–142 (2010). https://doi.org/10.1038/nnano.2009.353

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2009.353

This article is cited by

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