Biosensors based on the shift of whispering-gallery modes in microspheres accompanying protein adsorption are described by use of a perturbation theory. For random spatial adsorption, theory predicts that the shift should be inversely proportional to microsphere radius $R$ and proportional to protein surface density and excess polarizability. Measurements are found to be consistent with the theory, and the correspondence enables the average surface area occupied by a single protein to be estimated. These results are consistent with crystallographic data for bovine serum albumin. The theoretical shift for adsorption of a single protein is found to be extremely sensitive to the target region, with adsorption in the most sensitive region varying as $1/R^{5/2}$. Specific parameters for single protein or virus particle detection are predicted.

Individual nanoparticles in aqueous solution are observed to be attracted to and orbit within the evanescent sensing ring of a Whispering Gallery Mode micro-sensor with only microwatts of driving power. This Carousel trap, caused by attractive optical gradient forces, interfacial interactions, and the circulating momentum flux, considerably enhances the rate of transport to the sensing region, thereby overcoming limitations posed by diffusion on such small area detectors. Resonance frequency fluctuations, caused by the radial Brownian motion of the nanoparticle, reveal the radial trapping potential and the nanoparticle size. Since the attractive forces draw particles to the highest evanescent intensity at the surface, binding steps are found to be uniform.

We describe and demonstrate a physical mechanism that substantially enhances the label-free sensitivity of a whispering-gallery-mode biosensor for the detection of individual nanoparticles in aqueous solution. It involves the interaction of dielectric nanoparticle in an equatorial carousel orbit with a plasmonic nanoparticle bound at the microparticle’s equator. As the dielectric particle parks to hot spots on the plasmonic particle we observe frequency shifts that are enhanced by a factor of 4, consistent with a simple reactive model. Once optimized the enhancement by this mechanism should exceed several orders of magnitude, putting individual protein within reach.

We report the label-free detection and sizing by a microcavity of the smallest individual RNA virus, MS2, with a mass only ∼1% of InfluenzaA (6 vs. 512 ag). Although detection of such a small bio-nano-particle has been beyond the reach of a bare spherical microcavity, it was accomplished with ease (S/N = 8, Q = 4 × 10⁵) using a single dipole stimulated plasmonic-nanoshell as a microcavity wavelength shift enhancer, providing an enhancement of ∼70×, in agreement with theory. Unique wavelength shift statistics are recorded consistent with an ultra-uniform genetically programmed substance that is drawn to the plasmonic hot spots by light-forces.

Thermo-optic and reactive mechanisms for label-free sensing of bio-particles are compared theoretically for Whispering Gallery Mode (WGM) resonators (sphere, toroid) formed from silica and stimulated into a first order equatorial mode. Although it has been expected that a thermo-optic mechanism should “greatly enhance” wavelength shift signals [A.M. Armani et al, Science 317, 783-787 (2007)] accompanying protein binding on a silica WGM cavity having high Q (10⁸), for a combination of wavelength (680 nm), drive power (1 mW), and cavity size (43 μm radius), our calculations find no such enhancement. The possible reasons for this disparity are discussed.