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Review of Biosensing with Whispering-Gallery Mode Lasers Nikita Toropov 1, Gema Cabello 1, Mariana P

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Review of Biosensing with Whispering-Gallery Mode Lasers Nikita Toropov 1, Gema Cabello 1, Mariana P Toropov et al. Light: Science & Applications (2021) 10:42 Official journal of the CIOMP 2047-7538 https://doi.org/10.1038/s41377-021-00471-3 www.nature.com/lsa REVIEW ARTICLE Open Access Review of biosensing with whispering-gallery mode lasers Nikita Toropov 1, Gema Cabello 1, Mariana P. Serrano 2, Rithvik R. Gutha1,MatíasRafti 2 and Frank Vollmer1 Abstract Lasers are the pillars of modern optics and sensing. Microlasers based on whispering-gallery modes (WGMs) are miniature in size and have excellent lasing characteristics suitable for biosensing. WGM lasers have been used for label- free detection of single virus particles, detection of molecular electrostatic changes at biointerfaces, and barcode-type live-cell tagging and tracking. The most recent advances in biosensing with WGM microlasers are described in this review. We cover the basic concepts of WGM resonators, the integration of gain media into various active WGM sensors and devices, and the cutting-edge advances in photonic devices for micro- and nanoprobing of biological samples that can be integrated with WGM lasers. Introduction introduced as a fluid into the core of a thin-walled glass Lasers have played a crucial role in optics since Theo- capillary, thereby providing good sensitivity for the dore Maiman first reported on Stimulated Optical detection of health biomarkers such as DNA and protein Radiation in Ruby 60 years ago1. Experiments with lasers molecules10,11. 2 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; have enabled the development of quantum optics theory , Many optical platforms are potentially useful for label- as well as many different applications, for example, in free sensing in biology and chemistry. Examples include manufacturing, imaging, spectroscopy, metrology and optical sensors that make use of plasmonic nanos- sensing3. During the last few years, the application of tructures and nanoparticles, photonic crystals, tapered microlasers, especially whispering-gallery mode (WGM) optical fibres, zero-mode waveguides and passive WGM – microlasers, in chemical and biological sensing has resonators12 18. These micro- and nanoscale optical increased due to advances made in reducing the gap platforms have already been used for some of the most between laboratory experiments and their real-world demanding biosensing tasks such as detection of single application. A number of exciting applications of WGM molecules17,19 and detection of single influenza A virus lasers in biosensing have been reported, such as lasing particles and other nanoparticles20,21. The use of WGM within living cells4, monitoring contractility in cardiac microlasers for chemical and biological sensing can offer tissue5, detection of molecular electrostatic changes at sensing modalities that are often not easily accessed on biointerfaces6, label-free detection of single virus parti- other optical sensor platforms. For example, in vivo sen- cles7 and advancement of in vivo sensing4,8,9. WGM sing with WGM microlasers is facilitated by detection of microlasers with a liquid-core optical ring resonator the emission of relatively bright laser light at frequencies (LCORR) can probe the properties of a gain medium that are spectrally well separated from the frequency of the free-space excitation beam. Furthermore, WGM microlasers may offer a potentially very high detection Correspondence: Nikita Toropov ([email protected])or sensitivity for molecules due to the narrow linewidth of Frank Vollmer ([email protected]) the laser lines, which could enable detection of the fre- 1 Department of Physics and Astronomy, Living Systems Institute, University of quency shifts induced by single molecules. Herein, we aim Exeter, Exeter EX4 4QD, UK 2Departamento de Química, Instituto de Investigaciones Fisicoquímicas to provide a comprehensive review of the emerging field Teóricas y Aplicadas, Universidad Nacional de La Plata, La Plata 1900, Argentina © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Toropov et al. Light: Science & Applications (2021) 10:42 Page 2 of 19 of biological and biochemical sensing with WGM dome of St Paul’s Cathedral23; whispering-gallery wave or microlasers. Our review is structured as follows. In the mode is now used to describe the effect of any wave travel- first section, we review the building blocks of WGM ling around a concave surface. Comparable to this effect, microlaser devices, their biosensing applications and their light in a WGM microlaser is confined through near-total sensing mechanisms. In the second and third sections, we internal reflection and circumnavigates a typically spherical focus on the use of WGM microdroplet resonators in cavity, such as a glass microbead24; the interference of the biosensing and the most recent advances made in the light results in WGM optical resonances. WGMs may be integration of WGM microdroplet resonators with gain confined in cavity geometries such as disks25,toroids26,or media. In the fourth section, we review state-of-the-art deformed hexagonal resonators27. The unique characteristics techniques for micro- and nanoprobing of biological of WGM microcavities, such as the long lifetime of the samples that can be combined with WGM microlasers. intracavity photons and the small volume of the modes, We close with a discussion of the prospects of using make them excellent candidates for constructing WGM emerging WGM microlasers in biological and chemical microlasers with low lasing thresholds that exhibit narrow sensing applications and as an emerging research tool for spectral linewidths. To the best of our knowledge, the first single-molecule biosensing. WGM laser was made from a highly polished crystalline calcium fluoride (CaF2)sphereof1–2 mm diameter. The + WGM microlasers in biosensing rare-earth ion samarium (Sm2 ) was used as the optical gain Building blocks dopant28. Since then, lasing has been demonstrated in many Similar to conventional lasers, WGM microlasers consist different spherical WGM cavity geometries8,28,29 and others, of three principal building blocks: the gain medium, the such as triangular nanoplatelets30 and ZnO hexagonal and pump source, and the optical resonator—here the WGM dodecagonal microrods and nanonails31.Achievingalow resonator. The gain medium defines most of the spectral, lasing threshold is especially important in biosensing appli- temporal and power characteristics of the laser light emis- cations where the photodamage of biological samples must sion. Usually, an optical pump source supplies the energy be avoided. The light intensities of WGMs range from − − needed to maintain population inversion of the active par- MWcm 2 to GWcm 2 and are comparable to those in ticles in the gain medium, i.e., fluorophore molecules, for microscopy32. For example22,foraWGMresonatorof40µm light amplification by stimulated emission of radiation. The diameter and finesse 3 × 105, when the input power is 16 µW, various gain media that have already found use in WGM the built‐up circulating optical power is as high as 800 mW, − microlaser-based sensors are reviewed in sections ‘Micro- and the circulating optical intensity is 20 MWcm 2.WGM droplet resonators as active cavities in biosensing’ and lasing thresholds at µW pump power levels and below have – ‘Review of gain media in WGM microlasers for sensing’. been demonstrated33 35. Lasing thresholds of nJ have been The performance of a WGM microlaser can be further shown for spatially and temporally incoherent optical − characterised by the quality factor (Q-factor) of the pumping36. WGM thresholds of µJ cm 2 have been optical resonator, which is a measure of the damping of demonstrated for pumping with a pulsed laser37.Apartfrom the resonator modes. The Q-factor is defined as the ratio optical pumping with a pulsed laser, the ability to realize free- of the stored energy to the energy dissipated per radian of space continuous-wave optical pumping38 is advantageous the oscillation. Various important laser parameters because it allows for a wider selection of wavelengths, a depend on the Q-factor of the cavity such as (i) the laser smaller laser linewidth and thus a potentially higher sensi- linewidth, a measure of the spectral coherence of the laser tivity in biosensing applications. emission and its monochromaticity; (ii) the photon life- time, the time it takes for the energy in the resonator Sensing mechanisms cavity to decay to 1/e of the original value; and (iii) the In Table 1, we list WGM microlasers that have been lasing threshold, the lowest optical pump power at which used in some of the most exciting and most recent sensing stimulated emission is observed. Several optical waves and biosensing applications. In this section, we review (modes)
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