Label-free detection with high-Q microcavities: a review of biosensing mechanisms for integrated devices

Abstract

Optical microcavities that confine light in high-Q resonance promise all of the capabilities required for a successful next-generation microsystem biodetection technology. Label-free detection down to single molecules as well as operation in aqueous environments can be integrated cost-effectively on microchips, together with other photonic components, as well as electronic ones. We provide a comprehensive review of the sensing mechanisms utilized in this emerging field, their physics, engineering and material science aspects, and their application to nanoparticle analysis and biomolecular detection. We survey the most recent developments such as the use of mode splitting for self-referenced measurements, plasmonic nanoantennas for signal enhancements, the use of optical force for nanoparticle manipulation as well as the design of active devices for ultra-sensitive detection. Furthermore, we provide an outlook on the exciting capabilities of functionalized high-Q microcavities in the life sciences.

Keywords: biosensing; integrated photonics; microlasers; nanoparticle detection; optical microcavities; optical resonator; optical trapping; plasmonics.

Figure 1

Prominent microsystem biosensing technologies developed for label-free detection down to single molecules. From left to right: optical resonator, plasmon resonance biosensor, nanomechanical resonator and nanowire sensor. Reproduced with permission from [–5].

Figure 2

Left: total internal reflection of a whispering-gallery-mode (WGM) in a glass microsphere. Right: corresponding wave optics.

Figure 3

Probing high Q resonances of different optical resonators in biosensor applications. (A–D) Reproduced with permission from [13, 24, 30, 42]. (reprinted with permission from [23]. Copyright (2002), American Institute of Physics. Reprinted from [42]. Copyright (2010), with permission from Elsevier.).

Figure 4

(A) Illustration of a Whispering Gallery Mode (WGM) optical resonance in a glass microsphere. The binding of a protein to the microsphere surface increases the WGM path length by Δl, which is detected as a resonance frequency shift Δω. (B) The reactive sensing principle. A molecule binding to the microsphere surface is polarized within the evanescent field (yellow ring) of a WGM. The energy that is needed to polarize the molecule causes the resonance frequency to shift.

Figure 5

Mode splitting in a WGM resonator. Left: WGM resonators supports degenerate counter-propagating modes: clockwise (CW) and counterclockwise (CCW). Light scattering from a scattering center introduces additional damping to the optical modes and couples the initially degenerate CW and CCW modes, lifting the mode degeneracy. Right: Experimentally obtained mode-splitting transmission spectrum (blue) after the deposition of a single nanoparticle in the mode volume of a microtoroid WGM resonator and the fitted curve (red) adapted from [30].

Figure 6

Examples of biorecognition schemes utilized in microresonator biosensing applications: (A) antibody-based detection of a cancer biomarker carcinoembryonic antigen (CEA) with silicon rings in serum (adapted with permission from [85], copyright (2009) American Chemical Society), (B) detection of DNA oligonucleotides by hybridization to dextran-functionalized microspheres (reprinted from [57], copyright (2003), with permission from Elsevier), (C) breast cancer biomarker HER2 detection in LCORRs functionalized with antibody (reprinted from [42], copyright (2010), with permission from Elsevier), (D) silane-based bioconjugation techniques that have been explored for achieving high surface densities in DNA detection [86].

Figure 7

Equatorial WGM. The green ring, which traces the trajectory of the fundamental equatorial WGM, is due to the luminescence of the erbium ions with which the microsphere is doped image taken from [151].

Figure 8

The binding of molecules on the surface of a resonator shifts the resonant frequency. (A) For a passive resonator (resonator without gain medium), too much overlap with the original resonant mode makes it difficult to distinguish the shifted resonance since the resonant frequency shift induced by the attached molecule is smaller than the linewidth. (B) For an active resonator (resonator gain medium), the resonant shift is clearly resolved due to large separation of the shifted resonance from its original position in the spectrum. The narrow linewidth due to the optical gain (g) improves the sensor resolution by reducing the smallest detectable shift in the resonance.

Figure 9

Optical gain to enhance the sensing performance of optical resonators. (A) Typical transmission spectra of an active resonator (resonator doped with optical gain medium) when the excitation pump for the gain medium is off (left: a broad resonance) and on (right: two distinct narrow resonance [70]). (B) Detection of nanoparticles using mode-splitting in a microcavity laser. A beatnote is generated by photo-mixing the split lasing modes in a photoreceiver. The changes in beat frequency with time reflect the scatterer induced frequency splitting in the microlaser which indicates a scatterer entering the laser mode volume. If a multimode microlaser is used, each lasing mode undergoes splitting with the splitting amount depending on the overlap of the scatterer with the volume of the lasing mode. Using a multimode laser reduces the possibility of missing a binding scatterer since one splitting signal could capture a binding event that might have been missed by the other one (lower right panel) adapted from [66].

Figure 10

Plasmonic nanoantennas coupled to microcavities enhance sensitivity in biodetection. (A) A molecule binding to a plasmonic nanoantenna coupled to a WGM microcavity experiences field strengths that are enhanced in proportion to E²/E₀², boosting the frequency shift upon binding [147]. (B) Up to three orders of sensitivity enhancement has been predicted for protein detection with a nanorod coupled to a toroidal cavity, reprinted with permission from [58], copyright (2011), American Institute of Physics.

Figure 11

Trapping nanoparticles using gradient force stemming from highly localized field intensities in optical resonators. (A) A nanoparticle is trapped and propelled along the equatorial plane of a fiber taper coupled microsphere, where the fundamental WGM resides, adapted from [32]. (B) A waveguide coupled optofluidic ring resonator is used to manipulate, transport and trap nanoparticles; the particles either pass through the resonator (indicated by particles in green) under off-resonant condition or get trapped on the ring resonator under resonant condition (indicated by particles in red), with permission from [29], reproduced by permission of The Royal Society of Chemistry.