1. Highly sensitive optical biosensing in whispering gallery microcavities Yun-Feng Xiao ( 肖云峰 ) Peking University, Beijing 100871, P. R. China Email: yfxiao@pku.edu.cnyfxiao@pku.edu.cn Tel: (86)10-62765512 http://www.phy.pku.edu.cn/~yfxiao/

2. Collaborators Bei-Bei Li Yong-Chun Liu Xu Yi Qiu-Shu Chen Lan Yang, Jiangang Zhu, and Lina He @ WUSTL Microcavity Photonics and Quantum Optics Group @ PKU

3. Optical biosensors are a powerful detection and analysis tool that has vast applications in Healthcare Homeland security Environmental monitoring Biomedical research Optical biosensors

4. Fan et al., Analytica chimica acta 620, 8-26 (2008) Two general detection protocols of optical biosensors 1.Fluorescence-based detection 2.Label-free detection Intensity of the fluorescence: the number of target molecules Extremely sensitive, down to a single molecule detection (1) Suffers from laborious labeling processes, that may also interfere with the function of a biomolecule; (2) Quantitative analysis is challenging due to the fluorescence signal bias, as the fluorophores number on each molecule cannot be precisely controlled (1)Allow for quantitative and kinetic measurement of molecular interaction; (2)Detection signal does not scale down with the sample volume, which is particularly attractive when ultrasmall (femtoliter to nanoliter) detection volume is involved. Molecules are not labeled/altered, detected in their natural forms. Relatively easy and cheap to perform

5. Surface plasmon resonance based biosensors Interferometer-based biosensors Optical waveguide based biosensors Optical resonator based biosensors Optical fiber based biosensors Photonic crystal based sensors Label-free optical detections

6. Optical sensors fundamentally require interaction between light and the target molecules. Increase interaction Increase sensitivity In a waveguide or optical fiber sensor, light interacts with target molecule only once. In a resonator, light circulates in the resonator multiple times. Number of round trip  Finesse (F), Q WHY resonator based biosensors?

7. Advantages of microcavities Cavity power build-up factor: Q ~1×10 8, D ~ 50  m, V m ~ 600  m 3  B ~ 10 5 Cavity photon lifetime: WHY ultra-high-Q whispering gallery resonator? P in = 1 mW  P cav ~ 100 W, I cav ~ 2.5 GW/cm 2,  ~ 100 ns, # of round trip ~ 2  10 5. Experimental data in our group 1 mW > 100 W

8. Detection mechanism of WGM resonator-based biosensor Li et al., unpublished

9. Detection methods of resonator-based sensor 1, Resonant wavelength shift detection High concentration detection Limited by the wavelength resolution! Low concentration detection Limited by the detector noise! 2, Intensity detection at a single wavelength

10. Optical biosensing with whispering gallery microcavities SOI ring resonator Polymer ring resonator Silica microtoroid Glass ring resonator array Capillary-based ring resonator Silica microsphere For a review, e.g., See Fan et al., Analytica chimica acta 620, 8-26 (2008)

11. Temperature drift: including thermal expansion, thermal refraction Nonlinear optical effect; Surround stress; Optical pressure induced by the probe field. Though the high sensitivity, the detection limit is strongly degraded Optical biosensing with whispering gallery microcavities The sensing is dependent on monitoring the resonance shift Dominantly confined in the high-refraction-index dielectric material, i.e., the inside of the cavity. The few energy is stored in the form of weak exterior evanescent field with a characteristic length of ~ 100 nm. Detection sensitivity is limited.

12. Outline  Coupled resonators --- sensitivity enhancement  Compensating thermal-refraction noise with a cavity surface function --- detection limit improved  Biosensing with mode splitting --- new detection mechanism  Summary

13. From symmetric to asymmetric lineshape Resonance of a single cavity: symmetric Lorenzian lineshape S. Fan, Appl. Phys. Lett. 80, 908-910 (2002). C.-Y. Chao and L. J. Guo, Appl. Phys. Lett. 83, 1527-1529 (2003). W. M. N. Passaro and F. D. Leonardis, IEEE J. Sel. Top. Quantum Electron. 12, 124-133 (2006). Coupled-cavity configuration: asymmetric lineshape, a larger transmission slope  improved sensitivity in sensing Fano Resonance

14. Sensitivity-enhanced method: coupled resonators two microresonators are coupled through a waveguide. EIT-like Sensitivity one order of magnitude enhancement in detection sensitivity. Propagting phase, k*L

15. EIT/Fano resonance in a single microcavity Control Probe Li, Xiao* et al., Appl. Phys. Lett. 96, 251109 (2010) Coupling decreasing Fano EIT Xiao et al, Appl. Phy. Lett. 94, 231115 (2009) Both: over coupled High-Q: over coupled Low-Q: under coupled

16. Fano resonance in two controllable coupled microcavities transmission of individual microdisk transmission of individual microtoroid transmission of coupled disk/toroid Fano resonance Fano resonance takes place only when the cavity surface roughness can strongly scatter light to the counter-propagating mode (high-Q) A microdisk free from its silicon pillar is indirectly coupled with a microtoroid through a fiber taper. Li, Xiao* et al., APL (2012)

17. Compensating thermal refraction noise Han and Wang, Opt. Lett., 2007 Silica: positive thermal-optic effect Polymer: negative thermal-optic effect

18. Complete Compensation Stable cavity modes! The coated microtoroids can be used in bio- sensing to improve the measurement precision, and also hold potential applications in nonlinear optics. PDMS coating Lina He et al., APL 93, 201102 (2008) Compensating thermal refraction noise 1.Thermal expansion noise is still difficult to be compensated. 2.Monitoring the small mode shift is a challenging.

19. Ultrastable single-nanoparticle detection - Physics Polarizability: CW CCW 1, 2, WGM: traveling mode scattering back (counter-propagating mode) scattering to the vacuum modes Zhu et al., Nature Photonics 4, 46 (2010)

20. Ultrastable single-nanoparticle detection - Physics Superposition of CW and CCW modes: Standing Wave modes (CW+CCW)/2 (symmetric) (CW-CCW)/2 (anti-symmetric) symmetricanti-symmetric Shift and dampingNot affected 1.It is independent of the particle position r; 2.It is independent of the temperature drift.

21. Ultrastable single-nanoparticle detection - Experiment Zhu et al., Nature Photonics 4, 46 (2010)

22. Detection of R=100 nm PS nanospheres Ultrastable single-nanoparticle detection - Result Zhu et al., Nature Photonics 4, 46 (2010)

23. 23 Ultrastable single-nanoparticle detection with WGM 670 nm band1450 nm band Zhu et al., Nature Photonics 4, 46 (2010)

24. Ultrastable single-particle detection – nonspherical particle TE TM Case 1: a nanosphere in TE or TM mode field Case 2: a standing cylinder in TM mode field Case 3: a standing cylinder in TE mode field, or a lying cylinder in TM mode field S strongly depends on the orientation of particle on the cavity surface and the choice of the detection mode, TE or TM polarized mode. Mode-splitting method in detecting non- spherical nanoparticle Yi, Xiao* et al., Appl. Phys. Lett., 97, 203705 (2010)

25. Ultrastable single-particle detection – nonspherical particle This polarization-dependent effect allows for studying the orientation of single biomolecule, molecule-molecule interaction on the microcavity surface, and possibly distinguishing inner configuration of similar biomolecules. Combing TE and TM mode detection Yi, Xiao* et al., Appl. Phys. Lett., 97, 203705 (2010)

26. Multiple-Rayleigh-scatterer-induced mode splitting Yi, Xiao * et al., Phys. Rev. A 83, 023803 (2011) In real optical biosensing, many molecules may interact with the cavity mode simultaneously. By involving the phase factors of propagating WGMs, we extend to the multi-nanoparticle-induced mode splitting situation. Resonance shifts and linewidth broadenings: increase linearly with N (N>>N 1/2 ) Resonance splitting and linewidth difference: increase linearly with N 1/2. Mode shifts Linewidth broadings Considering the random nature of scatterer adsorption, we use Monte Carlo simulation and obtain  =0.87 Mode splitting Linewidth difference

27. Multiple-Rayleigh-scatterer-induced mode splitting Yi, Xiao * et al., Phys. Rev. A 83, 023803 (2011) Small nanoparticle, r = 20 nmLarge nanoparticle, r = 100 nm The splitting tends to be more resolvable with larger number N The splitting tends to dissolve with larger number N

28. Detection ability with multiple-nanoparticle scattering With various nanoparticles, the size of nanoparticles that can be detected is extended down to ten nanometers (small biomolecules). Yi, Xiao * et al., Phys. Rev. A 83, 023803 (2011) Detection limit? Mode splitting can be resolved only if the frequency splitting is larger than the half of the resonant linewidth of new modes, composing of the original linewidth and the additional broadenings. Nanoparticle sizing merely relevant to the inherent property of the nanoparticle; immune to thermal noises and particle positions.

29. Detection ability with multiple-nanoparticle scattering Experimental realization

30. The impact of the biorecognition IgG antibody 8nm 3nm The label-free nature originates from that the biorecognitions are pre-covered on microresonators. For the mode shift mechanism, by resetting the zero point of the signal, the detection of the biological targets can be realized. However, for the mode-splitting mechanism, the pre-covering also produces Rayleigh scattering. Moreover, the magnitude of frequency splitting does not monotonously increase (in some cases, it may even decrease) with more and more nanoparticles binding on microcavity, and this cannot be removed by simply setting the zero point of the detection signal.

31. The impact of the biorecognition The impact of the biorecognition can be removed by resetting the zero point of the signal. Furthermore, the total linewidth broadening is immune to the thermal fluctuation of the environment. Nevertheless, the linewidth broadening still depends on the binding positions of the targets. When N is large enough, Monte Carlo treatment can be utilized, f(theta)  f

32. aquatic Splitting in aquatic environment Li, Xiao * et al., unpublished From air to aquatic environment Observable splitting: splitting > linewidth

33. Splitting in aquatic environment Li, Xiao * et al., unpublished

34. Thank you for your attention! For more information: www.phy.pku.edu.cn/~yfxiao/index.html Summary To enhance the sensitivity of WGM-based biosensing, we studied Fano resonance linewidth in coupled resonators, and experimentally demonstrate Fano resonances in a single or coupled WG microcavities. To suppress the thermal-noise, we coated the silica microcavity with a negative thermal-optic-coefficient PDMS. The thermal-optic noise can be nearly compensated. We investigated the mode splitting mechanism in detail, and demonstrated single-nanoparticle response ability. We further found that the multi-nanoparticle-induced splitting help to improve the detection limit. By considering the presence of the biomarkers, we demonstrate the mode splitting mechanism is also feasible in truly biosensing.