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Chip–NMR biosensor for detection and molecular analysis of cells

Nature Medicine volume 14, pages 869–874 (2008)Cite this article

Abstract

Rapid and accurate measurement of biomarkers in tissue and fluid samples is a major challenge in medicine. Here we report the development of a new, miniaturized diagnostic magnetic resonance (DMR) system for multiplexed, quantitative and rapid analysis. By using magnetic particles as a proximity sensor to amplify molecular interactions, the handheld DMR system can perform measurements on unprocessed biological samples. We show the capability of the DMR system by using it to detect bacteria with high sensitivity, identify small numbers of cells and analyze them on a molecular level in real time, and measure a series of protein biomarkers in parallel. The DMR technology shows promise as a robust and portable diagnostic device.

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Figure 1: Principle of the assay and structure of the DMR system.
Figure 2: Accuracy and sensitivity of the DMR system.
Figure 3: Sensitive detection of bacteria.
Figure 4: Profiling of mammalian cells.

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References

  1. Cheng, M.M.-C. et al. Nanotechnologies for biomolecular detection and medical diagnostics. Curr. Opin. Chem. Biol. 10, 11–19 (2006).

    Article  CAS  Google Scholar 

  2. Wulfkuhle, J.D., Liotta, L.A. & Petricoin, E.F. Proteomic applications for the early detection of cancer. Nat. Rev. Cancer 3, 267–275 (2003).

    Article  CAS  Google Scholar 

  3. Hood, L., Heath, J.R., Phelps, M.E. & Lin, B. Systems biology and new technologies enable predictive and preventative medicine. Science 306, 640–643 (2004).

    Article  CAS  Google Scholar 

  4. Schroder, L., Lowery, T., Hilty, C., Wemmer, D. & Pines, A. Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor. Science 314, 446–449 (2006).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Aslan, K., Lakowicz, J.R. & Geddes, C.D. Plasmon light scattering in biology and medicine: new sensing approaches, visions and perspectives. Curr. Opin. Chem. Biol. 9, 538–544 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Sidransky, D. Emerging molecular markers of cancer. Nat. Rev. Cancer 2, 210–219 (2002).

    Article  CAS  Google Scholar 

  10. Perez, J.M., Josephson, L., O'Loughlin, T., Hogemann, D. & Weissleder, R. Magnetic relaxation switches capable of sensing molecular interactions. Nat. Biotechnol. 20, 816–820 (2002).

    Article  CAS  Google Scholar 

  11. Nair, P.R. & Alam, M.A. Performance limits of nanobiosensors. Appl. Phys. Lett. 88, 233120–233123 (2006).

    Article  Google Scholar 

  12. Peck, T.L., Magin, R.L. & Lauterbur, P.C. Design and analysis of microcoils for NMR microscopy. J. Magn. Reson. B. 108, 114–124 (1995).

    Article  CAS  Google Scholar 

  13. Massin, C. et al. Planar microcoil-based microfluidic NMR probes. J. Magn. Reson. 164, 242–255 (2003).

    Article  CAS  Google Scholar 

  14. Trumbull, J.D., Glasgow, I.K., Beebe, D.J. & Magin, R.L. Integrating microfabricated fluidic systems and NMR spectroscopy. IEEE Trans. Biomed. Eng. 47, 3–7 (2000).

    Article  CAS  Google Scholar 

  15. Lee, H., Liu, Y., Westervelt, R.M. & Ham, D. IC/microfluidic hybrid system for magnetic manipulation of biological cells. IEEE J. Solid-State Circuits 41, 1471–1480 (2006).

    Article  Google Scholar 

  16. Xia, H.M., Wan, S.Y.M., Shu, C. & Chew, Y.T. Chaotic micromixers using two-layer crossing channels to exhibit fast mixing at low Reynolds numbers. Lab Chip 5, 748–755 (2005).

    Article  CAS  Google Scholar 

  17. Koh, I., Hong, R., Weissleder, R. & Josephson, L. Sensitive NMR sensors detect antibodies to influenza. Angew. Chem. Int. Ed. Engl. 47, 4119–4121 (2008).

    Article  CAS  Google Scholar 

  18. Olson, D.L., Peck, T.L., Webb, A.G., Magin, R.L. & Sweedler, J.V. High-resolution microcoil 1H-NMR for mass-limited, nanoliter-volume samples. Science 270, 1967–1970 (1995).

    Article  CAS  Google Scholar 

  19. Boero, G., de Raad Iseli, C., Besse, P.A. & Popovic, R.S. An NMR magnetometer with planar microcoils and integrated electronics for signal detection and amplification. Sens. Actuators A 67, 18–23 (1998).

    Article  CAS  Google Scholar 

  20. Lee, J.H. et al. Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging. Nat. Med. 13, 95–99 (2007).

    Article  CAS  Google Scholar 

  21. Halbach, K. Design of permanent multipole magnets with oriented rare earth cobalt material. Nucl. Instrum. Methods 169, 1–10 (1980).

    Article  CAS  Google Scholar 

  22. Perlo, J., Casanova, F. & Blumich, B. Ex situ NMR in highly homogeneous fields: 1H spectroscopy. Science 315, 1110–1112 (2007).

    Article  CAS  Google Scholar 

  23. Dittrich, P.S. & Manz, A. Lab-on-a-chip: microfluidics in drug discovery. Nat. Rev. Drug Discov. 5, 210–218 (2006).

    Article  CAS  Google Scholar 

  24. Urdea, M. et al. Requirements for high impact diagnostics in the developing world. Nature 444 (suppl. 1), 73–79 (2006).

    Article  Google Scholar 

  25. Barna, J.C. & Williams, D.H. The structure and mode of action of glycopeptide antibiotics of the vancomycin group. Annu. Rev. Microbiol. 38, 339–357 (1984).

    Article  CAS  Google Scholar 

  26. Keeler, E. et al. Reducing the global burden of tuberculosis: the contribution of improved diagnostics. Nature 444 (suppl. 1), 49–57 (2006).

    Article  Google Scholar 

  27. Ricci, K.A. et al. Reducing stunting among children: the potential contribution of diagnostics. Nature 444 (suppl. 1), 29–38 (2006).

    Article  Google Scholar 

  28. Lim, Y.W. et al. Reducing the global burden of acute lower respiratory infections in children: the contribution of new diagnostics. Nature 444 (suppl. 1), 9–18 (2006).

    Article  Google Scholar 

  29. Cristofanilli, M. et al. Circulating tumor cells, disease progression and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004).

    Article  CAS  Google Scholar 

  30. Liu, Y., Sun, N., Lee, H., Weissleder, R. & Ham, D. CMOS mini nuclear magnetic resonance system and its application for biomolecular sensing. ISSCC Dig. Tech. Papers 1, 140–141 (2008).

    Google Scholar 

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Acknowledgements

The authors gratefully acknowledge N. Sergeyev for synthesizing CLIO, K. Kelly, K. Kristof and S. Thomas for cell culture and I. Koh for help in magnetic microparticle–based assay. We especially thank L. Josephson, J. Bradner and M. Cima for many helpful suggestions, R.M. Westervelt for generous support in device fabrication and D.S. Yun and A. Belcher for assistance in imaging bacteria with a transmission electron microscope.

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Authors and Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Hakho Lee, Eric Sun & Ralph Weissleder

  2. School of Engineering and Applied Sciences, Harvard University, 29 Oxford Street, Cambridge, 02138, Massachusetts, USA

    Donhee Ham

Authors
  1. Hakho Lee
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  2. Eric Sun
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  3. Donhee Ham
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  4. Ralph Weissleder
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Contributions

H.L. designed the device, built the DMR prototype, obtained measurements, analyzed data and wrote the manuscript. E.S. performed all chemical modifications of magnetic nanoparticles and assisted in measurements and data analysis. D.H. collaborated in the development of the NMR electronics of discrete components. R.W. conceived the project, provided overall guidance, designed experiments and targeted nanoparticles, analyzed the data and wrote the manuscript with contributions from all authors.

Corresponding author

Correspondence to Ralph Weissleder.

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Competing interests

R.W. is a shareholder of T2 Biosystems. H.L., D.H. and R.W. are listed on a patent application to the US Patent Office filed by Harvard University and Massachusetts General Hospital.

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Supplementary Figs. 1–5, Supplementary Tables 1–5 and Supplementary Methods (PDF 3354 kb)

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Lee, H., Sun, E., Ham, D. et al. Chip–NMR biosensor for detection and molecular analysis of cells. Nat Med 14, 869–874 (2008). https://doi.org/10.1038/nm.1711

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