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Whispering-gallery-mode biosensing: label-free detection down to single molecules

Abstract

Optical label-free detectors, such as the venerable surface plasmon resonance (SPR) sensor, are generally favored for their ability to obtain quantitative data on intermolecular binding. However, before the recent introduction of resonant microcavities that use whispering gallery mode (WGM) recirculation, sensitivity to single binding events had not materialized. Here we describe the enhancement mechanisms responsible for the extreme sensitivity of the WGM biosensor, review its current implementations and applications, and discuss its future possibilities.

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Figure 1: Concept of the WGM biosensor.
Figure 2: Model for estimating WGM biosensor layer sensitivity.
Figure 3: WGM resonator geometries.
Figure 4

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References

  1. Cooper, M.A. Label-free screening of bio-molecular interactions. Anal. Bioanal. Chem. 377, 834–842 (2003).

    Article  CAS  Google Scholar 

  2. Nakatani, K., Sando, S. & Saito, I. Scanning of guanine-guanine mismatches in DNA by synthetic ligands using surface plasmon resonance. Nat. Biotechnol. 19, 51–55 (2001).

    Article  CAS  Google Scholar 

  3. Vollmer, F. et al. Protein detection by optical shift of a resonant microcavity. Appl. Phys. Lett. 80, 4057–4059 (2002).

    Article  CAS  Google Scholar 

  4. Arnold, S., Khoshsima, M., Teraoka, I., Holler, S. & Vollmer, F. Shift of whispering gallery modes in microspheres by protein adsorption. Opt. Lett. 28, 272–274 (2003).

    Article  CAS  Google Scholar 

  5. Armani, A.M., Kulkarni, R.P., Fraser, S.E., Flagan, R.C. & Vahala, K.J. Label-free, single-molecule detection with optical microcavities. Science 317, 783–787 (2007).

    Article  CAS  Google Scholar 

  6. Serpengüzel, A., Arnold, S. & Griffel, G. Excitation of resonances of a microsphere on an optical fiber. Opt. Lett. 20, 654–656 (1995).

    Article  Google Scholar 

  7. Knight, J.C. & Cheung, G., Jacques, F. & Birks, T.A. Phase-matched excitation of whispering-gallery-mode resonances by a fiber taper. Opt. Lett. 22, 1129–1131 (1997).

    Article  CAS  Google Scholar 

  8. Griffel, G. et al. Morphology-dependent resonances of a microsphere-optical fiber system. Opt. Lett. 21, 695–697 (1996).

    Article  CAS  Google Scholar 

  9. Vollmer, F., Arnold, S., Braun, D., Teraoka, I. & Libchaber, A. Multiplexed DNA quantification by spectroscopic shift of two microsphere cavities. Biophys. J. 85, 1974–1979 (2003).

    Article  CAS  Google Scholar 

  10. Arnold, S., Ramjit, R., Keng, D., Kolchenko, V. & Teraoka, I. Microparticle photophysics illuminates viral biosensing. Faraday Discuss. 137, 65–83 (2008).

    Article  CAS  Google Scholar 

  11. Chao, C.Y. & Guo, L.J. Polymer microring resonators for biochemical sensing applications. IEEE J. Selected Topics Quantum Electron. 12, 134–142 (2006).

    Article  CAS  Google Scholar 

  12. Zhu, H.Y., White, I.M., Suter, J.D., Suter, P.S. & Fan, X.D. Analysis of biomolecule detection with optofluidic ring resonator sensors. Opt. Express 15, 9129–9146 (2007).

    Article  Google Scholar 

  13. De Vos, K., Bartolozzi, I., Schacht, E., Bienstman, P. & Baets, R. Silicon-on-insulator microring resonator for sensitive and label-free biosensing. Opt. Express 15, 7610–7615 (2007).

    Article  Google Scholar 

  14. Yalcin, A. et al. Optical sensing of biomolecules using microring resonators. IEEE Journal of Selected Topics in Quantum Electronics 12, 148–155 (2006).

    Article  CAS  Google Scholar 

  15. Rabiei, P., Steier, W.H., Zhang, C. & Dalton, L.R. Polymer micro-ring filters and modulators. J. Lightwave Technol. 20, 1968–1974 (2002).

    Article  Google Scholar 

  16. McDonald, J.C. et al. Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis 21, 27–40 (2000).

    Article  CAS  Google Scholar 

  17. Keng, D., McAnanama, S.R., Teraoka, I. & Arnold, S. Resonance fluctuations of a whispering gallery mode biosensor by particles undergoing Brownian motion. Appl. Phys. Lett. 91, 103902 (2007).

    Article  Google Scholar 

  18. White, I.M., Oveys, H., Fan, X., Smith, T.L. & Zhang, J. Integrated multiplexed biosensors based on liquid core optical ring resonators and anti-resonant reflecting optical waveguide. Appl. Phys. Lett. 89, 191106 (2006).

    Article  Google Scholar 

  19. Teraoka, I., Arnold, S. & Vollmer, F. Perturbation approach to shift of whispering-gallery modes in microspheres by protein adsorption. J. Opt. Soc. Am. B 20, 1937–1946 (2003).

    Article  CAS  Google Scholar 

  20. Quan, H.Y. & Guo, Z.X. Simulation of whispering-gallery-mode resonance shifts for optical miniature biosensors. J. Quant. Spectrosc. Radiat. Transf. 93, 231–243 (2005).

    Article  CAS  Google Scholar 

  21. Boyd, R.W. & Heebner, J.E. Sensitive disk resonator photonic biosensor. Appl. Opt. 40, 5742–5747 (2001).

    Article  CAS  Google Scholar 

  22. Noto, M., Keng, D., Teraoka, I. & Arnold, S. Detection of protein orientation on the silica microsphere surface using transverse electric/transverse magnetic whispering gallery modes. Biophys. J. 92, 4466–4472 (2007).

    Article  CAS  Google Scholar 

  23. Topolancik, J. & Vollmer, F. Photoinduced transformations in bacteriorhodopsin membrane monitored with optical microcavities. Biophys. J. 92, 2223–2229 (2007).

    Article  CAS  Google Scholar 

  24. Hoffmann, C., Zuern, A., Buenemann, M. & Lohse, M.J. Conformational changes in G-protein-coupled receptors the quest for functionally selective conformations is open. Br. J. Pharmacol. 153, S358–S366 (2008).

    Article  CAS  Google Scholar 

  25. Gust, D., Moore, T.A. & Moore, A.L. Mimicking photosynthetic solar energy transduction. Acc. Chem. Res. 34, 40–48 (2001).

    Article  CAS  Google Scholar 

  26. Ren, H.-C., Vollmer, F., Arnold, S. & Libchaber, A. High-Q microsphere biosensor analysis for adsorption of rodlike bacteria. Opt. Express 25, 17410–17423 (2007).

    Article  Google Scholar 

  27. Armani, A.M., Srinivasan, A. & Vahala, K.J. Soft lithographic fabrication of high Q polymer microcavity arrays. Nano Lett. 7, 1823–1826 (2007).

    Article  CAS  Google Scholar 

  28. Boyd, R.W. et al. Nanofabrication of optical structures and devices for photonics and biophotonics. J. Mod. Opt. 50, 2543–2550 (2003).

    Article  CAS  Google Scholar 

  29. Lee, M. & Fauchet, P.M. Two-dimensional silicon photonic crystal based biosensing platform for protein detection. Opt. Express 15, 4530–4535 (2007).

    Article  CAS  Google Scholar 

  30. Skivesen, N. et al. Photonic-crystal waveguide biosensor. Opt. Express 15, 3169–3176 (2007).

    Article  CAS  Google Scholar 

  31. Poon, A.W., Chang, R.K. & Chowdhury, D.Q. Measurement of fiber-cladding diameter uniformity by use of whispering-gallery modes: nanometer resolution in diameter variations along millimeter to centimeter lengths. Opt. Lett. 26, 1867–1869 (2001).

    Article  CAS  Google Scholar 

  32. White, I.M., Gohring, J. & Fan, X. SERS-based detection in an optofluidic ring resonator platform. Opt. Express 25, 17433–17442 (2007).

    Article  Google Scholar 

  33. Fang, Y., Ferrie, A., Fontaine, N. & Yuen, P. Characteristics of dynamic mass redistribution of EGF receptor signaling in living cells measured with label-free optical biosensors. Anal. Chem. 77, 5720–5725 (2005).

    Article  CAS  Google Scholar 

  34. Fang, Y., Ferrie, A., Fontaine, N., Mauro, J. & Balakrishnan, J. Resonant waveguide grating biosensor for living cell sensing. Biophys. J. 91, 1925–1940 (2006).

    Article  CAS  Google Scholar 

  35. Arnold, S. Microspheres, photonic atoms, and the physics of nothing. Am. Sci. 89, 414–421 (2001).

    Article  Google Scholar 

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Acknowledgements

S.A. was supported by the US National Science Foundation grant BES-0522668, and F.V. was supported by a Rowland Junior Fellowship.

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Correspondence to Stephen Arnold.

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Vollmer, F., Arnold, S. Whispering-gallery-mode biosensing: label-free detection down to single molecules. Nat Methods 5, 591–596 (2008). https://doi.org/10.1038/nmeth.1221

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