Towards next-generation label-free biosensors: recent advances in whispering gallery mode sensors.

Whispering gallery mode biosensors have been widely exploited over the past decade to study molecular interactions by virtue of their high sensitivity and applicability in real-time kinetic analysis without the requirement to label. There have been immense research efforts made for advancing the instrumentation as well as the design of detection assays, with the common goal of progressing towards real-world sensing applications. We therefore review a set of recent developments made in this field and discuss the requirements that whispering gallery mode label-free sensors need to fulfill for making a real world impact outside of the laboratory. These requirements are directly related to the challenges that these sensors face, and the methods proposed to overcome them are discussed. Moving forward, we provide the future prospects and the potential impact of this technology.

[1]  K. Crozier,et al.  Trapping-assisted sensing of particles and proteins using on-chip optical microcavities. , 2013, ACS nano.

[2]  T. Kippenberg,et al.  Cavity Optomechanics: Back-Action at the Mesoscale , 2008, Science.

[3]  Anatolii N Oraevsky,et al.  Whispering-gallery waves , 2002 .

[4]  John L. Hall,et al.  Laser phase and frequency stabilization using an optical resonator , 1983 .

[5]  Dhabih V. Chulhai,et al.  The origin of relative intensity fluctuations in single-molecule tip-enhanced Raman spectroscopy. , 2013, Journal of the American Chemical Society.

[6]  Mario La Notte,et al.  Ultra high sensitivity chemical photonic sensing by Mach–Zehnder interferometer enhanced Vernier-effect , 2013 .

[7]  Michal Lipson,et al.  High confinement micron-scale silicon nitride high Q ring resonator. , 2009, Optics express.

[8]  Wei Shi,et al.  Silicon photonic micro-disk resonators for label-free biosensing. , 2013, Optics express.

[9]  R. Dunn,et al.  Scanning Resonator Microscopy: Integrating Whispering Gallery Mode Sensing with Atomic Force Microscopy , 2015 .

[10]  Ryan C Bailey,et al.  High-Q optical sensors for chemical and biological analysis. , 2012, Analytical chemistry.

[11]  Robert J. Thompson,et al.  Frequency stability of a dual-mode whispering gallery mode optical reference cavity. , 2012, Optics express.

[12]  Anbo Wang,et al.  Temperature compensation of optical microresonators using a surface layer with negative thermo-optic coefficient. , 2007, Optics letters.

[13]  T. Kippenberg,et al.  Dual-mode temperature compensation technique for laser stabilization to a crystalline whispering gallery mode resonator. , 2012, Optics express.

[14]  M. Foreman,et al.  Thermal characterisation of (bio)polymers with a temperature-stabilised whispering gallery mode microsensor , 2015 .

[15]  Dmitry Strekalov,et al.  Temperature measurement and stabilization in a birefringent whispering gallery mode resonator. , 2011, Optics express.

[16]  Laura M. Lechuga,et al.  Integrated optical devices for lab‐on‐a‐chip biosensing applications , 2012 .

[17]  S. Berneschi,et al.  Fluorescence biosensing in selectively photo–activated microbubble resonators , 2017 .

[18]  Abraham J. Qavi,et al.  Multiplexed detection and label-free quantitation of microRNAs using arrays of silicon photonic microring resonators. , 2010, Angewandte Chemie.

[19]  S. Arnold,et al.  Shift of whispering-gallery modes in microspheres by protein adsorption. , 2003, Optics letters.

[20]  Byoungho Lee,et al.  Review of the present status of optical fiber sensors , 2003 .

[21]  Mani Hossein-Zadeh,et al.  Fiber-taper coupling to Whispering-Gallery modes of fluidic resonators embedded in a liquid medium. , 2006, Optics express.

[22]  Frank Vollmer,et al.  Ultrasensitive detection of a protein by optical trapping in a photonic-plasmonic microcavity. , 2012, Journal of biophotonics.

[23]  Yongfeng Mei,et al.  Whispering-gallery nanocavity plasmon-enhanced Raman spectroscopy , 2015, Scientific Reports.

[24]  Andrea M Armani,et al.  Silica microtoroid resonator sensor with monolithically integrated waveguides. , 2013, Optics express.

[25]  M. Orrit,et al.  Optical detection of single non-absorbing molecules using the surface plasmon resonance of a gold nanorod. , 2012, Nature nanotechnology.

[26]  Wenlei Yang,et al.  Packaged Optical Add-Drop Filter Based on an Optical Microfiber Coupler and a Microsphere , 2016, IEEE Photonics Technology Letters.

[27]  Silicon slot waveguide ring resonators: Can we target high Q factors? , 2015, 2015 17th International Conference on Transparent Optical Networks (ICTON).

[28]  C Koos,et al.  All-polymer photonic sensing platform based on whispering-gallery mode microgoblet lasers. , 2015, Lab on a chip.

[29]  Tal Carmon,et al.  Water-walled microfluidics for high-optical finesse cavities , 2016, Nature Communications.

[30]  Andreas Henkel,et al.  Single unlabeled protein detection on individual plasmonic nanoparticles. , 2012, Nano letters.

[31]  Ting Lei,et al.  Silicon coupled-resonator optical-waveguide-based biosensors using light-scattering pattern recognition with pixelized mode-field-intensity distributions , 2014, Scientific Reports.

[32]  Matthew R Foreman,et al.  Single-molecule nucleic acid interactions monitored on a label-free microcavity biosensor platform. , 2014, Nature nanotechnology.

[33]  Vanessa Zamora,et al.  Investigation of cascaded SiN microring resonators at 1.3 µm and 1.5 µm. , 2013, Optics express.

[34]  L. Razzari,et al.  Engineering the Absorption and Field Enhancement Properties of Au-TiO2 Nanohybrids via Whispering Gallery Mode Resonances for Photocatalytic Water Splitting. , 2016, ACS nano.

[35]  Rui Chen,et al.  Tuning Whispering Gallery Mode Lasing from Self-Assembled Polymer Droplets , 2013, Scientific Reports.

[36]  Florian Sedlmeir,et al.  High-Q MgF₂ whispering gallery mode resonators for refractometric sensing in aqueous environment. , 2014, Optics express.

[37]  B Tiribilli,et al.  High-Q polymer-coated microspheres for immunosensing applications. , 2009, Optics express.

[38]  Abraham J. Qavi,et al.  Isothermal discrimination of single-nucleotide polymorphisms via real-time kinetic desorption and label-free detection of DNA using silicon photonic microring resonator arrays. , 2011, Analytical chemistry.

[39]  T. Krauss,et al.  The electrophotonic silicon biosensor , 2016, Nature Communications.

[40]  K. Vahala,et al.  Compensation of thermal nonlinearity effect in optical resonators. , 2011, Optics express.

[41]  Yves-Alain Peter,et al.  Real-Time Detection of Staphylococcus Aureus Using Whispering Gallery Mode Optical Microdisks , 2016, Biosensors.

[42]  S. Arnold,et al.  PAPER www.rsc.org/faraday_d | Faraday Discussions MicroParticle photophysics illuminates viral bio-sensing , 2007 .

[43]  Zachary S. Ballard,et al.  Stand-Off Biodetection with Free-Space Coupled Asymmetric Microsphere Cavities , 2015, Sensors.

[44]  Hans-Peter Loock,et al.  Direct Sensing in Liquids Using Whispering‐Gallery‐Mode Droplet Resonators , 2014 .

[45]  Ozan Aktas,et al.  Label-Free Biosensing with High Selectivity in Complex Media using Microtoroidal Optical Resonators , 2015, Scientific Reports.

[46]  Jun Tang,et al.  Compensation of thermal nonlinear effect in hybrid microsphere resonators , 2014 .

[47]  Melik C. Demirel,et al.  Nanoparticle-based protein detection by optical shift of a resonant microcavity , 2002, 1108.2337.

[48]  Alper Kiraz,et al.  In vitro and in vivo biolasing of fluorescent proteins suspended in liquid microdroplet cavities. , 2014, Lab on a chip.

[49]  Zeev Valy Vardeny,et al.  RING MICROLASERS FROM CONDUCTING POLYMERS , 1997 .

[50]  J. Klucken,et al.  Tracking micro-optical resonances for identifying and sensing novel procaspase-3 protein marker released from cell cultures in response to toxins , 2016, Nanotechnology.

[51]  R. Goldsmith,et al.  Chip‐Scale Fabrication of High‐Q All‐Glass Toroidal Microresonators for Single‐Particle Label‐Free Imaging , 2016, Advanced materials.

[52]  P. Bienstman,et al.  Label-Free Biosensing With a Slot-Waveguide-Based Ring Resonator in Silicon on Insulator , 2009, IEEE Photonics Journal.

[53]  Jian-Jun He,et al.  High-sensitivity optical biosensor based on cascaded Mach-Zehnder interferometer and ring resonator using Vernier effect. , 2014, Optics letters.

[54]  So-Hyun Lee,et al.  Multiplexed cancer biomarker detection using chip-integrated silicon photonic sensor arrays. , 2016, The Analyst.

[55]  Matthew R. Foreman,et al.  Optimizing detection limits in whispering gallery mode biosensing. , 2014, Optics express.

[56]  Rajan P Kulkarni,et al.  Label-Free, Single-Molecule Detection with Optical Microcavities , 2007, Science.

[57]  Hongying Zhu,et al.  Thermal characterization of liquid core optical ring resonator sensors. , 2007, Applied optics.

[58]  Lan Yang,et al.  Phone-sized whispering-gallery microresonator sensing system. , 2016, Optics express.

[59]  Yan Li,et al.  On chip, high-sensitivity thermal sensor based on high-Q polydimethylsiloxane-coated microresonator , 2010 .

[60]  Lan Yang,et al.  Compensation of thermal refraction effect in high-Q toroidal microresonator by polydimethylsiloxane coating , 2008 .

[61]  Daoxin Dai,et al.  Cascaded-Ring Optical Sensor With Enhanced Sensitivity by Using Suspended Si-Nanowires , 2011, IEEE Photonics Technology Letters.

[62]  Peng Yin,et al.  Ultraspecific and highly sensitive nucleic acid detection by integrating a DNA catalytic network with a label-free microcavity. , 2014, Small.

[63]  Zheng-Fu Han,et al.  Fabrication of high-Q polydimethylsiloxane optical microspheres for thermal sensing , 2009 .

[64]  K. Vahala,et al.  Dynamical thermal behavior and thermal self-stability of microcavities , 2004, (CLEO). Conference on Lasers and Electro-Optics, 2005..

[65]  Vanessa Zamora,et al.  A Highly Sensitive Refractometric Sensor Based on Cascaded SiN Microring Resonators , 2013, Sensors.

[66]  Serge Rosenblum,et al.  Cavity ring-up spectroscopy for ultrafast sensing with optical microresonators , 2015, Nature Communications.

[67]  J Johansson,et al.  Levitated droplet dye laser. , 2006, Optics express.

[68]  Shuren Hu,et al.  Porous silicon ring resonator for compact, high sensitivity biosensing applications. , 2015, Optics express.

[69]  B. Lewis,et al.  Refractometric sensing of Li salt with visible-light Si3N4 microdisk resonators , 2014, 1412.7167.

[70]  Wei Wang,et al.  Detection of Single Nanoparticles and Lentiviruses Using Microcavity Resonance Broadening , 2013, Advanced materials.

[71]  Shizhuo Yin,et al.  High-temperature sensing using whispering gallery mode resonance in bent optical fibers , 2005 .

[72]  Tao Ling,et al.  Fabrication and characterization of High Q polymer micro-ring resonator and its application as a sensitive ultrasonic detector , 2011, Optics express.

[73]  N. Billington,et al.  Label-Free, All-Optical Detection, Imaging, and Tracking of a Single Protein , 2014, Nano letters.

[74]  Yuqiang Wu,et al.  Integrating a DNA Strand Displacement Reaction with a Whispering Gallery Mode Sensor for Label-Free Mercury (II) Ion Detection , 2016, Sensors.

[75]  Tao Zhang,et al.  DNA origami based assembly of gold nanoparticle dimers for surface-enhanced Raman scattering , 2014, Nature Communications.

[76]  Matthew A. Cooper,et al.  Optical biosensors in drug discovery , 2002, Nature Reviews Drug Discovery.

[77]  G. Zumofen,et al.  Controlled coupling of counterpropagating whispering-gallery modes by a single Rayleigh scatterer: a classical problem in a quantum optical light. , 2007, Physical review letters.

[78]  I. Teraoka,et al.  Whispering Gallery Mode Dip Sensor for Aqueous Sensing. , 2015, Analytical chemistry.

[79]  K. Crozier,et al.  Planar silicon microrings as wavelength-multiplexed optical traps for storing and sensing particles. , 2011, Lab on a chip.

[80]  Vittorio M. N. Passaro,et al.  Guided-Wave Optical Biosensors , 2007, Sensors (Basel, Switzerland).

[81]  Samuel K Sia,et al.  Commercialization of microfluidic point-of-care diagnostic devices. , 2012, Lab on a chip.

[82]  Stephen Holler,et al.  Plasmonic enhancement of a whispering-gallery-mode biosensor for single nanoparticle detection , 2011 .

[83]  Leopoldo L. Martin,et al.  Tweezers controlled resonator. , 2015, Optics express.

[84]  Frank Vollmer,et al.  Optical observation of single atomic ions interacting with plasmonic nanorods in aqueous solution , 2016, Nature Photonics.

[85]  S. Grant,et al.  Integrating Nanostructured Artificial Receptors with Whispering Gallery Mode Optical Microresonators via Inorganic Molecular Imprinting Techniques , 2016, Biosensors.

[86]  J. Homola.  Present and future of surface plasmon resonance biosensors , 2003, Analytical and bioanalytical chemistry.

[87]  Vahid Sandoghdar,et al.  Direct optical sensing of single unlabelled proteins and super-resolution imaging of their binding sites. , 2014, Nature communications.

[88]  Ivan Favero,et al.  Optical instability and self-pulsing in silicon nitride whispering gallery resonators. , 2012, Optics express.

[89]  Anatoliy A. Savchenkov,et al.  Optical resonant sensors: a method to reduce the effect of thermal drift. , 2009, Applied optics.

[90]  Alper Kiraz,et al.  Probing of ultrahigh optical Q-factors of individual liquid microdroplets on superhydrophobic surfaces using tapered optical fiber waveguides , 2012 .

[91]  Guo-Qiang Lo,et al.  Label-free aptamer sensor based on silicon microring resonators , 2013 .

[92]  S. Ozdemir,et al.  Detecting single viruses and nanoparticles using whispering gallery microlasers. , 2011, Nature nanotechnology.

[93]  Menno W J Prins,et al.  Stochastic protein interactions monitored by hundreds of single-molecule plasmonic biosensors. , 2015, Nano letters.

[94]  G. Stemme,et al.  A packaged optical slot-waveguide ring resonator sensor array for multiplex label-free assays in labs-on-chips. , 2010, Lab on a chip.

[95]  Ş. Özdemir,et al.  Optothermal spectroscopy of whispering gallery microresonators , 2011 .

[96]  Xiu-Min Lin,et al.  Ringing phenomenon based whispering-gallery-mode sensing , 2016, Scientific Reports.

[97]  A. Meldrum,et al.  Tuning a microsphere whispering-gallery-mode sensor for extreme thermal stability , 2014 .

[98]  Lan Yang,et al.  Encapsulation of a Fiber Taper Coupled Microtoroid Resonator in a Polymer Matrix , 2013, IEEE Photonics Technology Letters.

[99]  Yun-Feng Xiao,et al.  Enhanced Raman scattering of single nanoparticles in a high- Q whispering-gallery microresonator , 2015 .

[100]  Lan Yang,et al.  On-chip single nanoparticle detection and sizing by mode splitting in an ultrahigh- Q microresonator , 2010 .

[101]  Paul Mulvaney,et al.  Detection of unlabeled oligonucleotide targets using whispering gallery modes in single, fluorescent microspheres. , 2007, Small.

[102]  Stephen Holler,et al.  Label-free detection of single protein using a nanoplasmonic-photonic hybrid microcavity. , 2013, Nano letters.

[103]  Hans-Peter Loock,et al.  Enhanced nanoparticle detection with liquid droplet resonators , 2014 .

[104]  Lan Yang,et al.  Highly sensitive detection of nanoparticles with a self-referenced and self-heterodyned whispering-gallery Raman microlaser , 2014, Proceedings of the National Academy of Sciences.

[105]  Wei C. Jiang,et al.  Cavity optomechanical spring sensing of single molecules , 2015, Nature Communications.

[106]  Kerry Vahala,et al.  Cavity opto-mechanics. , 2007, Optics express.

[107]  A. Kiraz,et al.  Observation of whispering gallery modes in elastic light scattering from microdroplets optically trapped in a microfluidic channel , 2016 .

[108]  NaCl ion detection using a silica toroid microcavity. , 2015, Applied optics.

[109]  Kebin Shi,et al.  Single nanoparticle detection using split-mode microcavity Raman lasers , 2014, Proceedings of the National Academy of Sciences.

[110]  F. Vollmer,et al.  In Situ Observation of Single‐Molecule Surface Reactions from Low to High Affinities , 2016, Advanced materials.

[111]  Erik H. Horak,et al.  Optical microresonators as single-particle absorption spectrometers , 2016, Nature Photonics.

[112]  George C Schatz,et al.  Whispering-gallery mode resonators: Surface enhanced Raman scattering without plasmons. , 2008, The Journal of chemical physics.

[113]  Donghyun Kim,et al.  Detection of Single Nanoparticles Using the Dissipative Interaction in a High-Q Microcavity , 2016, 1604.02249.

[114]  Guang-Can Guo,et al.  Transient microcavity sensor. , 2015, Optics express.

[115]  Q. Gong,et al.  Light confinement in a low-refraction-index microcavity bonded on a silicon substrate , 2016 .