Annals of Biomedical Engineering

, Volume 37, Issue 10, pp 1974–1983 | Cite as

Whispering Gallery Mode Biosensors Consisting of Quantum Dot-Embedded Microspheres

  • Hope T. Beier
  • Gerard L. Coté
  • Kenith E. Meissner


New methods of biological analyte sensing are needed for development of miniature biosensors that are highly sensitive and require minimal sample preparation. One technique employs optical resonances, known as whispering gallery modes (WGMs), in spherical or cylindrical microstructures. The spectral positions of these resonant modes are very sensitive to the local refractive index and spectral shifts may be used to sense changes in the index. To excite these WGMs and enable remote excitation, quantum dots are embedded in polystyrene microspheres to serve as local light sources. Using a simple continuous wave excitation optical system, these sensors are demonstrated by monitoring the wavelength shift of multiple resonant modes as bulk index of refraction is changed in ethanol–water mixtures. The potential for targeted biosensing is explored through addition of a protein that adsorbs to the microsphere surface, thrombin, and one that does not, bovine serum albumin (BSA). The thrombin produced a spectral shift that was much larger than that due to the bulk index change. The BSA produced a significantly smaller shift that was slightly larger than the expected shift due to bulk index change. Most likely due to the thin, high index layer of quantum dots, microsensor response in all cases demonstrated increased sensitivity over theoretical predictions.


Whispering gallery modes Quantum dots Biosensor Evanescent field Refractive index 


  1. 1.
    Arnold, S., S. Holler, N. L. Goddard and G. Griffel. Cavity-mode selection in spontaneous emission from oriented molecules in a microparticle. Opt. Lett. 22:1452-1454, 1997. doi:10.1364/OL.22.001452 CrossRefPubMedGoogle Scholar
  2. 2.
    Arnold, S., M. Khoshsima, I. Teraoka, S. Holler and F. Vollmer. Shift of whispering-gallery modes in microspheres by protein adsorption. Opt. Lett. 28:272-274, 2003. doi:10.1364/OL.28.000272 CrossRefPubMedGoogle Scholar
  3. 3.
    Bohren, C. F., and D. R. Huffman. Absorption and Scattering of Light by Small Particles. New York: Wiley, xiv, 530 p., 1998.Google Scholar
  4. 4.
    Born, M. and E. Wolf. Principles of Optics. New York: Pergamon, 1980.Google Scholar
  5. 5.
    Chan, W. C. W. and S. M. Nie. Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science. 281:2016–2018, 1998. doi:10.1126/science.281.5385.2016 CrossRefPubMedGoogle Scholar
  6. 6.
    Cheng, M. M. C., G. Cuda, Y. L. Bunimovich, M. Gaspari, J. R. Heath, H. D. Hill, C. A. Mirkin, A. J. Nijdam, R. Terracciano, T. Thundat and M. Ferrari. Nanotechnologies for biomolecular detection and medical diagnostics. Curr. Opin. Chem. Biol. 10:11-19, 2006. doi:10.1016/j.cbpa.2006.01.006 CrossRefPubMedGoogle Scholar
  7. 7.
    Chylek, P., J. T. Kiehl and M. K. W. Ko. Narrow resonance structure in mie scattering characteristics. Appl. Opt. 17:3019-3021, 1978. doi:10.1364/AO.17.003019 CrossRefPubMedGoogle Scholar
  8. 8.
    Erickson, D., S. Mandal, A. H. J. Yang and B. Cordovez. Nanobiosensors: Optofluidic, electrical and mechanical approaches to biomolecular detection at the nanoscale. Microfluid. Nanofluid. 4:33-52, 2008. doi:10.1007/s10404-007-0198-8 CrossRefPubMedGoogle Scholar
  9. 9.
    Fan, X., P. Palinginis, S. Lacey, H. Wang and M. C. Lonergan. Coupling semiconductor nanocrystals to a fused-silica microsphere: a quantum-dot microcavity with extremely high q factors. Opt. Lett. 25:1600-1602, 2000. doi:10.1364/OL.25.001600 CrossRefPubMedGoogle Scholar
  10. 10.
    Francois, A., and M. Himmelhaus. Optical biosensor based on whispering gallery mode excitations in clusters of microparticles. Appl. Phys. Lett. 92:141107, 2008.CrossRefGoogle Scholar
  11. 11.
    Francois, A., and M. Himmelhaus. Whispering gallery mode biosensor operated in the stimulated emission regime. Appl. Phys. Lett. 94:031101, 2009.CrossRefGoogle Scholar
  12. 12.
    Gomez, D. E., I. Pastoriza-Santos and P. Mulvaney. Tunable whispering gallery mode emission from quantum-dot-doped microspheres. Small. 1:238-241, 2005. doi:10.1002/smll.200400019 CrossRefPubMedGoogle Scholar
  13. 13.
    Hanumegowda, N. M., C. J. Stica, B. C. Patel, I. White, and X. Fan. Refractometric sensors based on microsphere resonators. Appl. Phys. Lett. 87:201107, 2005.CrossRefGoogle Scholar
  14. 14.
    Hanumegowda, N. M., I. M. White and X. D. Fan. Aqueous mercuric ion detection with microsphere optical ring resonator sensors. Sens. Actuators B Chem. 120:207-212, 2006. doi:10.1016/j.snb.2006.02.011 CrossRefGoogle Scholar
  15. 15.
    Hanumegowda, N. M., I. M. White, H. Oveys and X. Fan. Label-free protease sensors based on optical microsphere resonators. Sensor Lett. 3:1-5, 2005. doi:10.1166/sl.2005.044 CrossRefGoogle Scholar
  16. 16.
    Hood, L., J. R. Heath, M. E. Phelps and B. Y. Lin. Systems biology and new technologies enable predictive and preventative medicine. Science. 306:640-643, 2004. doi:10.1126/science.1104635 CrossRefPubMedGoogle Scholar
  17. 17.
    Jain, K. K. The role of nanobiotechnology in drug discovery. Drug Discov. Today 10:1435-1442, 2005. doi:10.1016/S1359-6446(05)03573-7 CrossRefPubMedGoogle Scholar
  18. 18.
    Johnson, B. R. Theory of morphology-dependent resonances—shape resonances and width formulas. J. Opt. Soc. Am. A 10:343-352, 1993.CrossRefGoogle Scholar
  19. 19.
    Lam, C. C., P. T. Leung and K. Young. Explicit asymptotic formulas for the positions, widths, and strengths of resonances in mie scattering. J. Opt. Soc. Am. B 9:1585-1592, 1992. doi:10.1364/JOSAB.9.001585 CrossRefGoogle Scholar
  20. 20.
    Mie, G. Beitrage zur optik truber medien speziell kolloidaler metallosungen. Ann. Phys. 25:377-445, 1908. doi:10.1002/andp.19083300302 CrossRefGoogle Scholar
  21. 21.
    Moller, B., U. Woggon and M. V. Artemyev. Photons in coupled microsphere resonators. J. Opt. A 8:S113-S121, 2006. doi:10.1088/1464-4258/8/4/S10 Google Scholar
  22. 22.
    Morrish, D., X. S. Gan and M. Gu. Morphology-dependent resonance induced by two-photon excitation in a micro-sphere trapped by a femtosecond pulsed laser. Opt. Express 12:4198-4202, 2004. doi:10.1364/OPEX.12.004198 CrossRefPubMedGoogle Scholar
  23. 23.
    Noto, M., D. Keng, I. Teraoka and S. Arnold. Detection of protein orientation on the silica microsphere surface using transverse electric/transverse magnetic whispering gallery modes. Biophys. J. 92:4466-4472, 2007. doi:10.1529/biophysj.106.103200 CrossRefPubMedGoogle Scholar
  24. 24.
    Nuhiji, E. and P. Mulvaney. Detection of unlabeled oligonucleotide targets using whispering gallery modes in single, fluorescent microspheres. Small. 3:1408-1414, 2007. doi:10.1002/smll.200600676 CrossRefPubMedGoogle Scholar
  25. 25.
    Pang, S., R. E. Beckham, and K. E. Meissner. Quantum dot-embedded microspheres for remote refractive index sensing. Appl. Phys. Lett. 92:221108, 2008.CrossRefPubMedGoogle Scholar
  26. 26.
    Peng, Z. A. and X. G. Peng. Formation of high-quality cdte, cdse, and cds nanocrystals using cdo as precursor. J. Am. Chem. Soc. 123:183-184, 2001. doi:10.1021/ja003633m CrossRefPubMedGoogle Scholar
  27. 27.
    Rayleigh, L. The problem of the whispering gallery. Philos. Mag. 20:1001-1004, 1910.Google Scholar
  28. 28.
    Teraoka, I. and S. Arnold. Enhancing the sensitivity of a whispering-gallery mode microsphere sensor by a high-refractive-index surface layer. J. Opt. Soc. Am. B. 23:1434-1441, 2006. doi:10.1364/JOSAB.23.001434 CrossRefGoogle Scholar
  29. 29.
    Teraoka, I. and S. Arnold. Theory of resonance shifts in te and tm whispering gallery modes by nonradial perturbations for sensing applications. J. Opt. Soc. Am. B. 23:1381-1389, 2006. doi:10.1364/JOSAB.23.001381 CrossRefGoogle Scholar
  30. 30.
    Teraoka, I. and S. Arnold. Whispering-gallery modes in a microsphere coated with a high-refractive index layer: Polarization-dependent sensitivity enhancement of the resonance-shift and te-tm resonance matching. J. Opt. Soc. Am. B 24:653-659, 2007. doi:10.1364/JOSAB.24.000653 CrossRefGoogle Scholar
  31. 31.
    Teraoka, I., S. Arnold and F. Vollmer. Perturbation approach to resonance shifts of whispering-gallery modes in a dielectric microsphere as a probe of a surrounding medium. J. Opt. Soc. Am. B 20:1937-1946, 2003. doi:10.1364/JOSAB.20.001937 CrossRefGoogle Scholar
  32. 32.
    Topolancik, J. and F. Vollmer. Photoinduced transformations in bacteriorhodopsin membrane monitored with optical microcavities. Biophys. J. 92:2223-2229, 2007. doi:10.1529/biophysj.106.098806 CrossRefPubMedGoogle Scholar
  33. 33.
    van de Hulst, H. C. Light Scattering by Small Particles. New York: Wiley, 1981.Google Scholar
  34. 34.
    Vollmer, F., S. Arnold, D. Braun, I. Teroka and A. Libchaber. Multiplexed DNA quantification by spectroscopic shift of two microsphere cavities. Biophys. J. 85:1974-1979, 2003. doi:10.1016/S0006-3495(03)74625-6 CrossRefPubMedGoogle Scholar
  35. 35.
    Vollmer, F., D. Braun, A. Libchaber, M. Khoshsima, I. Teraoka and S. Arnold. Protein detection by optical shift of a resonant microcavity. Appl. Phys. Lett. 80:4057-4059, 2002. doi:10.1063/1.1482797 CrossRefGoogle Scholar
  36. 36.
    Wang, J. Electrochemical biosensors: Towards point-of-care cancer diagnostics. Biosens. Bioelectron. 21:1887-1892, 2006. doi:10.1016/j.bios.2005.10.027 CrossRefPubMedGoogle Scholar
  37. 37.
    Weller, A., F. C. Liu, R. Dahint and M. Himmelhaus. Whispering gallery mode biosensors in the low-q limit. Appl. Phys. B 90:561-567, 2008. doi:10.1007/s00340-007-2893-2 CrossRefGoogle Scholar
  38. 38.
    White, I. M., N. M. Hanumegowda and X. Fan. Subfemtomole detection of small molecules with microsphere sensors. Opt. Lett. 30:3189-3191, 2005. doi:10.1364/OL.30.003189 CrossRefPubMedGoogle Scholar
  39. 39.
    Zhang, L. M., Y. X. Wang, F. J. Zhang and R. O. Claus. Observation of whispering-gallery and directional resonant laser emission in ellipsoidal microcavities. J. Opt. Soc. Am. B 23:1793-1800, 2006. doi:10.1364/JOSAB.23.001793 CrossRefGoogle Scholar
  40. 40.
    Zhu, H. Y., J. D. Suter, I. M. White and X. D. Fan. Aptamer based microsphere biosensor for thrombin detection. Sensors. 6:785-795, 2006. doi:10.3390/s6080785 CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2009

Authors and Affiliations

  • Hope T. Beier
    • 1
  • Gerard L. Coté
    • 1
  • Kenith E. Meissner
    • 1
  1. 1.Department of Biomedical EngineeringTexas A&M University, 337 Zachry Engineering CenterCollege StationUSA

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