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Matrix-insensitive protein assays push the limits of biosensors in medicine

Nature Medicine volume 15, pages 1327–1332 (2009)Cite this article

Abstract

Advances in biosensor technologies for in vitro diagnostics have the potential to transform the practice of medicine. Despite considerable work in the biosensor field, there is still no general sensing platform that can be ubiquitously applied to detect the constellation of biomolecules in diverse clinical samples (for example, serum, urine, cell lysates or saliva) with high sensitivity and large linear dynamic range. A major limitation confounding other technologies is signal distortion that occurs in various matrices due to heterogeneity in ionic strength, pH, temperature and autofluorescence. Here we present a magnetic nanosensor technology that is matrix insensitive yet still capable of rapid, multiplex protein detection with resolution down to attomolar concentrations and extensive linear dynamic range. The matrix insensitivity of our platform to various media demonstrates that our magnetic nanosensor technology can be directly applied to a variety of settings such as molecular biology, clinical diagnostics and biodefense.

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Figure 1: Sensor architecture and assay.
Figure 2: Sensitivity and linear dynamic range (on a log-log plot) of magneto-nanosensors and ELISA.
Figure 3: Magnetonanosensors exhibit matrix-insensitive detection.
Figure 4: Multiplex protein detection in a diversity of media.
Figure 5: Femtomolar-level multiplex tumor marker profiling in xenograft mice.

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References

  1. Srinivas, P.R. et al. Proteomics in early detection of cancer. Clin. Chem. 47, 1901–1911 (2001).

    CAS  PubMed  Google Scholar 

  2. Lopez, M.F. et al. A novel, high-throughput workflow for discovery and identification of serum carrier protein-bound peptide biomarker candidates in ovarian cancer samples. Clin. Chem. 53, 1067–1074 (2007).

    Article  CAS  Google Scholar 

  3. Gorelik, E. et al. Multiplexed immunobead-based cytokine profiling for early detection of ovarian cancer. Cancer Epidemiol. Biomarkers Prev. 14, 981–987 (2005).

    Article  CAS  Google Scholar 

  4. Zheng, Y. et al. A multiparametric panel for ovarian cancer diagnosis, prognosis, and response to chemotherapy. Clin. Cancer Res. 13, 6984–6992 (2007).

    Article  CAS  Google Scholar 

  5. Heath, J.R. & Davis, M.E. Nanotechnology and cancer. Annu. Rev. Med. 59, 251–265 (2008).

    Article  CAS  Google Scholar 

  6. Mitchell, P. A perspective on protein microarrays. Nat. Biotechnol. 20, 225–229 (2002).

    Article  CAS  Google Scholar 

  7. Chan, S.M. et al. Protein microarrays for multiplex analysis of signal transduction pathways. Nat. Med. 10, 1390–1396 (2004).

    Article  CAS  Google Scholar 

  8. Shingyoji, M. et al. Quantum dots–based reverse phase protein microarray. Talanta 67, 472–478 (2005).

    Article  CAS  Google Scholar 

  9. Zheng, G. et al. Multiplexed electrical detection of cancer markers with nanowire sensor arrays. Nat. Biotechnol. 23, 1294–1301 (2005).

    Article  CAS  Google Scholar 

  10. Ji, H. et al. Microcantilever biosensors based on conformational change of proteins. Analyst 133, 434–443 (2008).

    Article  CAS  Google Scholar 

  11. Ghosh, S., Sood, A.K. & Kumar, N. Carbon nanotube flow sensors. Science 299, 1042–1044 (2003).

    Article  CAS  Google Scholar 

  12. Drummond, T.G., Hill, M.G. & Barton, J.K. Electrochemical DNA sensors. Nat. Biotechnol. 21, 1192–1199 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Barnas, J. et al. Novel magnetoresistance effect in layered magnetic structures: Theory and experiment. Phys. Rev. B Condens. Matter 42, 8110–8120 (1990).

    Article  CAS  Google Scholar 

  15. Prinz, G.A. Magnetoelectronics. Science 282, 1660–1663 (1998).

    Article  CAS  Google Scholar 

  16. Wolf, S.A. et al. Spintronics: A spin-based electronics vision for the future. Science 294, 1488–1495 (2001).

    Article  CAS  Google Scholar 

  17. Baselt, D.R. et al. A biosensor based on magnetoresistance technology. Biosens. Bioelectron. 13, 731–739 (1998).

    Article  CAS  Google Scholar 

  18. Li, G. et al. Detection of single micron-sized magnetic bead and magnetic nanoparticles using spin valve sensors for biological applications. J. Appl. Phys. 93, 7557–7559 (2003).

    Article  CAS  Google Scholar 

  19. Graham, D.L. et al. Single magnetic microsphere placement and detection on-chip using current line designs with integrated spin valve sensors: biotechnological applications. J. Appl. Phys. 91, 7786–7788 (2002).

    Article  CAS  Google Scholar 

  20. Schotter, J. et al. Comparison of a prototype magnetoresistive biosensor to standard fluorescent DNA detection. Biosens. Bioelectron. 19, 1149–1156 (2004).

    Article  CAS  Google Scholar 

  21. Millen, R.L. et al. Giant magnetoresistive sensors and superparamagnetic nanoparticles: a chip-scale detection strategy for immunosorbent assays. Anal. Chem. 77, 6581–6587 (2005).

    Article  CAS  Google Scholar 

  22. Li, G. et al. Spin valve sensors for ultrasensitive detection of superparamagnetic nanoparticles for biological applications. Sens. Actuators A Phys. 126, 98–106 (2006).

    Article  CAS  Google Scholar 

  23. Xu, L. et al. Giant magnetoresistive biochip for DNA detection and HPV genotyping. Biosens. Bioelectron. 24, 99–103 (2008).

    Article  CAS  Google Scholar 

  24. Osterfeld, S.J. et al. Multiplex protein assays based on real-time magnetic nanotag sensing. Proc. Natl. Acad. Sci. USA 105, 20637–20640 (2008).

    Article  CAS  Google Scholar 

  25. Arao, S. et al. Measurement of urinary lactoferrin as a marker of urinary tract infection. J. Clin. Microbiol. 37, 553–557 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Georganopoulou, D.G. et al. Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proc. Natl. Acad. Sci. USA 102, 2273–2276 (2005).

    Article  CAS  Google Scholar 

  28. Wu, G. et al. Bioassay of prostate-specific antigen (PSA) using microcantilevers. Nat. Biotechnol. 19, 856–860 (2001).

    Article  CAS  Google Scholar 

  29. Zimmerman, R., Wahren, B. & Edsmyr, F. Assessment of serial CEA determinations in urine of patients with bladder carcinoma. Cancer 46, 1802–1809 (1980).

    Article  CAS  Google Scholar 

  30. Mukherjee, S. et al. A longitudinal study of unsaturated iron-binding capacity and lactoferrin in unstimulated parotid saliva. Biol. Trace Elem. Res. 57, 1–8 (1997).

    Article  CAS  Google Scholar 

  31. Chen, Z. et al. Protein microarrays with carbon nanotubes as multicolor Raman labels. Nat. Biotechnol. 26, 1285–1292 (2008).

    Article  CAS  Google Scholar 

  32. Cui, Y. et al. Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species. Science 293, 1289–1292 (2001).

    Article  CAS  Google Scholar 

  33. Tom, B.H. et al. Human colonic adenocarcinoma cells. I. Establishment and description of a new line. In Vitro 12, 180–191 (1976).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by US National Cancer Institute grants 1U54CA119367 and N44CM–2009-00011, US National Science Foundation grant ECCS-0801385-000, US Defense Threat Reduction Agency grant HDTRA1-07-1-0030-P00005, the US Defense Advanced Research Projects Agency/Navy Grant N00014–02-1–0807, NCI ICMIC P50 CA114747, the US Department of Veterans Affairs Merit Review B4872, the Canary Foundation and The National Semiconductor Corporation. R.S.G. acknowledges financial support from Stanford Medical School Medical Scientist Training Program and a National Science Foundation graduate research fellowship. C.H.N. acknowledges financial support from the Denmark-American Foundation and the Lundbeck Foundation.

Author information

Author notes

  1. Richard S Gaster and Drew A Hall: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Bioengineering, Stanford University, Stanford, California, USA

    Richard S Gaster & Sanjiv S Gambhir

  2. Medical Scientist Training Program, Stanford University, Stanford, California, USA

    Richard S Gaster

  3. Department of Electrical Engineering, Stanford University, Stanford, California, USA

    Drew A Hall, Boris Murmann & Shan X Wang

  4. Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, California, USA

    Carsten H Nielsen & Sanjiv S Gambhir

  5. Cluster for Molecular Imaging and Department of Clinical Physiology, Nuclear Medicine and Positron Emission Tomography, Rigshospitalet & University of Copenhagen, Denmark

    Carsten H Nielsen

  6. Department of Electrical Engineering, Section for Biomedical Engineering, Technical University of Denmark, Kgs. Lyngby, Denmark

    Carsten H Nielsen

  7. Department of Materials Science and Engineering, Stanford University, Stanford, California, USA

    Sebastian J Osterfeld, Robert J Wilson & Shan X Wang

  8. MagArray, Inc., Sunnyvale, California, USA

    Sebastian J Osterfeld & Heng Yu

  9. Department of Urology, Stanford University, Stanford, California, USA

    Kathleen E Mach & Joseph C Liao

  10. Bio-X Program, Stanford University, Stanford, California, USA

    Joseph C Liao, Sanjiv S Gambhir & Shan X Wang

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  1. Richard S Gaster
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Contributions

R.S.G., D.A.H., S.S.G. and S.X.W designed research; R.S.G., D.A.H., C.H.N. and K.E.M. performed research; R.S.G., D.A.H., C.H.N., S.J.O., H.Y., K.E.M., R.J.W., B.M., J.C.L., S.S.G. and S.X.W contributed new reagents and/or analytical tools; R.S.G., D.A.H. and S.X.W analyzed data; S.J.O. and S.X.W. designed the magnetic sensors; R.S.G. and H.Y. developed the biochemistry; and R.S.G., S.S.G. and S.X.W. wrote the paper.

Corresponding authors

Correspondence to Sanjiv S Gambhir or Shan X Wang.

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Competing interests

Stanford University has licensed part of the magnetic bioassay chip technology contained in this publication to MagArray Inc., an early-stage startup company in Silicon Valley, California. S.X.W., S.S.G., H.Y. and S.J.O. hold financial interests in MagArray in the form of stock options.

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Gaster, R., Hall, D., Nielsen, C. et al. Matrix-insensitive protein assays push the limits of biosensors in medicine. Nat Med 15, 1327–1332 (2009). https://doi.org/10.1038/nm.2032

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