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The Q-factor of WGM resonators can be very high (up to 1010 has been reported177 and is often only limited by the surface roughness of the ring or sphere. This makes the WGM approach well suited for microfluidics as liquid droplets containing a dissolved gain medium form spherical WGM resonators with extremely smooth surfaces. (A liquid-air or a liquid-liquid interface is generally atomically flat due to surface tension effects.) This approach was used in a microfluidic dropmaker, where alternating droplets of different laser dye solutions were produced. By optically exciting each droplet, a laser with alternating or switchable wavelength was obtained.178 Recently, emulsions of dye-doped microdroplets and an

immiscible host liquid were also used as WGM lasers. This idea was combined with optical trapping which enabled fixing of the lasing droplets at a certain position and also facilitate translation throughout a sample chamber.179 In addition, droplet lasers were used to study FRET between two rhodamine laser dyes which established the dominance of non-radiative FRET over cavity-assisted radiative energy transfer.180

In order to enable stable operation of microdroplet WGM lasers in air rather than in a host liquid, fluorescent dyes were mixed into slowly evaporating solvents. On superhydrophobic surfaces these solvents from stable microdroplets, which acted as WGM resonators. However, for Rhodamine B-doped glycerol/water microdroplets, the reported threshold fluences were extremely high (750 J/cm2) even though the absolute pulse energies used were apparently below 40 µJ/pulse. In other work, a similar WGM lasers were realized that were based entirely on biomaterials that are listed by the FDA as GRAS (‘Generally-Recognized-As-Safe’) materials. Gain was provided by a flavin mononucleotide, a biomolecule produced from vitamin B2. Flavin containing microdroplets of glycerol with diameters of 10 to 40 µm were formed by spraying onto pre-patterned super-hydrophobic poly-L-lactic acid films. Lasing was observed at 15 nJ/pulse, corresponding to about 1 mJ/cm2.88 More recently, glycerol-water droplets containing a fluorescent protein or a suspension of E.coli bacteria producing a fluorescent protein were used as WGM lasers. Although threshold fluences remained high (46 mJ/cm2), the concentration of fluorescent protein required for lasing was very low (49 µM). In situations where the gain material is produced by cells in situ and lasers are used predominantly for bio-sensing, the ability to achieve lasing at low concentrations of organic gain material may be more important than low threshold fluences.

As an alternative to superhydrophobic surfaces, airborne glycerol-water droplets were used and these were kept in position using optical trapping.181

Spherical WGM resonators can also be fabricated from solid gain materials, e.g. if dye doped polymer microspheres are used. For instance, WGM lasers based on Nile-Red doped polystyrene nanoparticles

were used to follow adsorption kinetics of bovine serum albumin. When operated above threshold, the signal-to-noise ratio was improved eightfold relative to conventional sub-threshold fluorescence. In addition, the spectral linewidth of emission narrowed above the lasing threshold, thus rendering WGM lasers interesting for sensing applications.182 (Spectral shifts of the modes of WGM resonators are already widely used in bio-sensing already. However, the resonator is normally not emissive so that the mode structure needs to be probed using light from external light source, e.g. a spectrally tunable laser that is coupled to the resonator.) In further work, the dimensions of polymer WGM microsphere lasers were optimized to increase their sensitivity in the lasing regime.183

Very recently, it was shown that spherical WGM resonators can be introduced into live cells to achieve intracellular lasing (Figure 9). This demonstration was based on dye-doped polystyrene microspheres with a refractive index of 1.6. The average refractive index inside cells is typically 1.37-1.4 and the resulting index contrast was sufficient to achieve efficient trapping of light within the microsphere and thus obtain large Q-factors even for spheres with diameters well below 15 µm. A number of different cells types were found to be capable of internalizing the polystyrene microspheres. Thresholds for lasing were typically around 1 nJ/pulse, well below the onset of cellular damage. It was demonstrated that the strong dependence of the lasing spectrum on the microsphere size can be exploited for cell tagging. Once a given cell internalized a laser, the laser spectrum of this cell provided a unique optical barcode that allowed re-identification of this cell amongst a large number of other tagged cells.184 Related work looked at lasing from cells without solid WGM resonators. In particular adipocytes, which are fat cells that naturally contain a large lipid vesicle (typically diameter 40 to 50 µm), were investigated. When the adipocyte vesicle was stained with a lipophilic fluorescent dye, lasing from these cells was achieved without the need to introduce an artificial resonator structure.185

Figure 9: Whispering gallery mode resonators allow lasing within individual living cells. (a) Schematic of cell with WGM resonator and path for optical pumping and detection.184 (b) Confocal microscopy images showing a green fluorescing polystyrene bead internalized by a macrophage cell. Cell cytoplasm stained in red, cell nucleus in blue. Maximum intensity projection (top) and cross section along dashed line (bottom). Scale bar, 20 µm.184 (c) Laser spectra from six representative cells, recorded over the cause of 19 h, illustrate that each cell has a unique laser spectrum (left). Bright-field microscopy images of cells (right). 185 (d) Confocal image of an adipocyte containing a fluorescently stained lipid droplet. Scale bar, 20 µm. (e) Emission spectrum of an adipocyte above lasing threshold. Inset shows fluorescence image of the lasing cell.185 Reproduced from [184]. Copyright 2015 American Chemical Society. Reprinted by permission from Macmillan Publishers Ltd: Nature Photonics [185], copyright 2015.