Optical Whispering-Gallery-Mode Microbubble Sensors

Whispering-gallery-mode (WGM) microbubble resonators are ideal optical sensors due to their high quality factor, small mode volume, high optical energy density, and geometry/design/structure (i.e., hollow microfluidic channels). When used in combination with microfluidic technologies, WGM microbubble resonators can be applied in chemical and biological sensing due to strong light–matter interactions. The detection of ultra-low concentrations over a large dynamic range is possible due to their high sensitivity, which has significance for environmental monitoring and applications in life-science. Furthermore, WGM microbubble resonators have also been widely used for physical sensing, such as to detect changes in temperature, stress, pressure, flow rate, magnetic field and ultrasound. In this article, we systematically review and summarize the sensing mechanisms, fabrication and packing methods, and various applications of optofluidic WGM microbubble resonators. The challenges of rapid production and practical applications of WGM microbubble resonators are also discussed.


Introduction
The invention of lasers in the 1960s promoted the rapid development of different types of optical sensors. Optical sensors have had a significant impact based on their ability to directly convert detected changes into the information of the light intensity, wavelength, polarization and phase with a high sensitivity and a fast response time. Various types of optical sensors, such as surface plasmon resonance (SPR) [1,2], planar waveguides [3,4], optical fiber sensors [5,6], optical interferometers [7,8] and optical microcavities [9,10] have been studied. Optical microcavities are miniature optical resonators at the micrometer or sub-micrometer scale, which confine the photons to a small space through the reflection or diffraction effects and are flexible for the integration in lab-on-chip systems.

Optical Characteristics
The optical characteristics of a microbubble resonator are typically described according to their Q-factor, photon lifetime (τ), FSR and mode volume [88]. The Q-factor is related to the energy attenuation or the ability to constrain energy in the microcavity, which can be calculated as follows: where ω 0 is the central frequency of a resonance mode, U is the energy inside the microcavity, −dU/dt is the energy attenuation per unit of time, ∆ω is the spectral linewidth for frequency, λ 0 is the central wavelength of a resonance mode, and ∆λ is the spectral linewidth for wavelength, which can be written as follows: where c is the speed of light in vacuum. The photon lifetime is defined as the time scale when the light intensity decays to 1/e of its initial value, which is caused by a depletion in the cavity. The photon lifetime can be written as follows: The photon lifetime increases with the increasing of Q-factor, which indicates a stronger interaction between the light and the analytes. The FSR is defined as the wavelength interval between two adjacent resonance modes, which can be written as follows: where n eff is the effective refractive index (RI), and R is the radius of the microbubble. The mode volume is the spatial distribution of a resonance mode in the cavity, which can be written as follows: where ε(r) is the spatial dielectric constant, E(r) is the spatial electric field strength, and V is the volume of the microcavity. The energy density increases as the mode volume decreases. Therefore, a smaller mode volume can lead to a stronger interaction between the light and the analytes.

Sensing Mechanism
Due to the extension of WGM fields into the surrounding analytes, any changes occurring around the evanescent field can lead to the changes of the resonance mode. Therefore, the sensing mechanism of WGM microbubble resonators are divided into the wavelength shift [89,90], mode-broadening [91,92], and mode-splitting [46,55,64].

Wavelength Shift
WGM microbubble resonators are constituted of an inner air core and an outer spherical shell, which provides a fluidic channel for analyte delivery. Due to the total internal reflection, the light propagates along the azimuth of the microbubble wall, and it will Micromachines 2022, 13, 592 4 of 23 resonate stably when it meets the constructive interference. The resonance wavelength λ can be written as follows [84]: where m and q represents the azimuth quantum number and axial quantum number, respectively, and ∆k is the microbubble curvature parameter, which increases with the increases in the microbubble radius (∆k = 2 [84,88], as shown in Figure 3. For a zero-order axial mode that propagates along the microbubble equator (q = 0), due to m 2 m∆kR, the resonance wavelength can be approximated as follows: where m and q represents the azimuth quantum number and axial quan spectively, and ∆k is the microbubble curvature parameter, which incre creases in the microbubble radius (Δ 1) [84,88], as shown i zero-order axial mode that propagates along the microbubble equator (q mΔkR, the resonance wavelength can be approximated as follows: The resonance wavelength is related to the effective RI and the mic and it increases when either the effective RI or the microbubble radius inc it is possible to monitor the environmental disturbances by converting it of the RI and microbubble radius, such as concentration, temperatur stress. The effective RI changes with the changing of the surrounding med a wavelength shift. For different concentrations of the surrounding m nance wavelengths will also differ. Generally, the resonance wavelengt the increasing of the medium concentration, as shown in Figure 4a. Ho tivity of the microbubble resonator is low due to most of the mode fie inside the microbubble wall. To achieve a higher sensitivity, the microb corroded with hydrofluoric acid (HF), or a higher order radial mode is ch [89,90,93]. Furthermore, the effective RI changes with the changing of [94,95] and magnetic field [96,97] due to the thermo-optical effect and effect, respectively. Changing of geometric shapes can also lead to a wav example, the microbubble size is easily changed by the pressure, flow rat and thermal expansion [98][99][100][101]. By monitoring the wavelength shift, th external physical parameters are easily determined, as shown in Figure  wall thickness of a microbubble resonator is dependent on its practical ap wall is always chosen for the detection of media inside the microbubble, w is chosen for physical sensing, such as the temperature. The resonance wavelength is related to the effective RI and the microbubble radius, and it increases when either the effective RI or the microbubble radius increase. Therefore, it is possible to monitor the environmental disturbances by converting it into the changes of the RI and microbubble radius, such as concentration, temperature, pressure, and stress.
The effective RI changes with the changing of the surrounding medium, resulting in a wavelength shift. For different concentrations of the surrounding medium, the resonance wavelengths will also differ. Generally, the resonance wavelength red shifts with the increasing of the medium concentration, as shown in Figure 4a. However, the sensitivity of the microbubble resonator is low due to most of the mode field is constrained inside the microbubble wall. To achieve a higher sensitivity, the microbubble is usually corroded with hydrofluoric acid (HF), or a higher order radial mode is chosen for sensing [89,90,93]. Furthermore, the effective RI changes with the changing of the temperature [94,95] and magnetic field [96,97] due to the thermo-optical effect and magneto-optical effect, respectively. Changing of geometric shapes can also lead to a wavelength shift. For example, the microbubble size is easily changed by the pressure, flow rate, stress, tension, and thermal expansion [98][99][100][101]. By monitoring the wavelength shift, the changes in the external physical parameters are easily determined, as shown in Figure 4b. Note that the wall thickness of a microbubble resonator is dependent on its practical applications: a thin wall is always chosen for the detection of media inside the microbubble, while a thick wall is chosen for physical sensing, such as the temperature.

Mode-Broadening
The spectral linewidth of a resonance mode is related to the Q-factor, a Equation (1). Variations in the optical loss will result in different values of th Generally, the total Q-factor of a microbubble resonator can be written as follo Material Scattering where 1⁄QMaterial is the absorption loss of the material; 1⁄QScattering is the scattering by the surface roughness and other artificially introduced scattering points; 1⁄Q unclean surface loss; 1⁄QRadiation is the radiation loss due to the evanescent field le the microbubble wall; and 1⁄QExternal is the coupling loss due to the coupling b cavity and the external coupling device. The spectral linewidth increases with the cavity loss, such as the scattering loss and radiation loss [91,92], as show 4c. Different from the wavelength shift, mode-broadening is not affected by tions in external environment due to its self-referenced sensing mechanism. T has smaller detection limits for the small molecules and single nanoparticles the additional loss of the surrounding medium can significantly damage the m surface and preclude its reuse.

Mode-Splitting
WGM microcavity has a degenerate state between clockwise-and counte propagating resonance modes [23]. When a small molecule or nanoparticle en tical evanescent field, coupling between the counterpropagating modes is intro to the node and antinode of each mode at the molecules or nanoparticles locat

Mode-Broadening
The spectral linewidth of a resonance mode is related to the Q-factor, as shown in Equation (1). Variations in the optical loss will result in different values of the Q-factor. Generally, the total Q-factor of a microbubble resonator can be written as follows [88]: where 1⁄Q Material is the absorption loss of the material; 1⁄Q Scattering is the scattering loss caused by the surface roughness and other artificially introduced scattering points; 1⁄Q Surface is the unclean surface loss; 1⁄Q Radiation is the radiation loss due to the evanescent field leaks outside the microbubble wall; and 1⁄Q External is the coupling loss due to the coupling between the cavity and the external coupling device. The spectral linewidth increases with increasing the cavity loss, such as the scattering loss and radiation loss [91,92], as shown in Figure 4c. Different from the wavelength shift, mode-broadening is not affected by the disruptions in external environment due to its self-referenced sensing mechanism. Therefore, it has smaller detection limits for the small molecules and single nanoparticles. However, the additional loss of the surrounding medium can significantly damage the microbubble surface and preclude its reuse.

Mode-Splitting
WGM microcavity has a degenerate state between clockwise-and counterclockwisepropagating resonance modes [23]. When a small molecule or nanoparticle enters the optical evanescent field, coupling between the counterpropagating modes is introduced due to the node and antinode of each mode at the molecules or nanoparticles location. Therefore, the eigenstates are transformed into two orthogonal standing waves in the cavity, as shown in Figure 4d. The size and number of scatters, such as the nanoparticles, can be determined by measuring the frequency-splitting [46,55,64]. Note that the two modes experience the same thermal noise. Therefore, disturbances in the surrounding environment and thermal fluctuations are eliminated by the self-referencing of the two modes. Compared with the mode-broadening, a cavity of the ultra-high Q-factor is required to differentiate the two modes in the splitting spectrum.

Fabrication Methods of a Microbubble Resonator
The fabrication of microbubbles is based on the fuse-and-blow method [86,[102][103][104][105]. For melting of the silica microcapillaries, different methods, such as the electrode-discharge heating [102,103], oxyhydrogen-flame heating [104,105], and carbon dioxide laser heating [106], have been proposed. Differently from the carbon dioxide laser heating and oxyhydrogen-flame heating, the electrode-discharge heating is accomplished using a portable, low-cost fiber fusion splicer. A microbubble is fabricated through the following four steps: (I) sealing one end of the silica microcapillary via a high temperature while the other is left open to allow air to be pushed into the microcapillary, as shown in Figure 5(a2); (II) removing the outer polymer coating of the silica microcapillary at the intended location and then cleaning it until there is no residue, as shown in Figure 5(a3); (III) heating the position where the coating has been removed and pressing air into the silica microcapillary at the same time, as shown in Figure 5(a4); (IV) repeating the process of step (III) until a symmetrical and high-optical-quality microbubble has been fabricated, as shown in Figure 5(a5),(a6),b.

Fabrication Methods of a Microbubble Resonator
The fabrication of microbubbles is based on the fuse-and-blow method [86,[102][103][104][105] For melting of the silica microcapillaries, different methods, such as the electrode-dis charge heating [102,103], oxyhydrogen-flame heating [104,105], and carbon dioxide lase heating [106], have been proposed. Differently from the carbon dioxide laser heating an oxyhydrogen-flame heating, the electrode-discharge heating is accomplished using portable, low-cost fiber fusion splicer. A microbubble is fabricated through the followin four steps: (Ⅰ) sealing one end of the silica microcapillary via a high temperature while th other is left open to allow air to be pushed into the microcapillary, as shown in Figur 5(a2); (Ⅱ) removing the outer polymer coating of the silica microcapillary at the intende location and then cleaning it until there is no residue, as shown in Figure 5(a3); (Ⅲ) heatin the position where the coating has been removed and pressing air into the silica microca pillary at the same time, as shown in Figure 5(a4); (Ⅳ) repeating the process of step (Ⅲ until a symmetrical and high-optical-quality microbubble has been fabricated, as show in Figure 5  To reduce the wall thickness of the microbubble to meet special experimental require ments, different methods have been proposed. One method involves corroding a silic microcapillary with HF solution before fabrication [89]. The wall thickness of a silica m crocapillary can be controlled via the corrosion time. However, the internal surfac smoothness of the microbubble may be reduced due to the uneven corrosion. Therefore a new method by melting and tapering the silica microcapillary was proposed. The wa thickness of the silica microcapillary and its outer diameter were controlled by the taper ing time [105].
In addition to the microbubble fabrication with a silica microcapillary, other new ma To reduce the wall thickness of the microbubble to meet special experimental requirements, different methods have been proposed. One method involves corroding a silica microcapillary with HF solution before fabrication [89]. The wall thickness of a silica microcapillary can be controlled via the corrosion time. However, the internal surface smoothness of the microbubble may be reduced due to the uneven corrosion. Therefore, a new method by melting and tapering the silica microcapillary was proposed. The wall thickness of the silica microcapillary and its outer diameter were controlled by the tapering time [105].
In addition to the microbubble fabrication with a silica microcapillary, other new materials have also been used. For example, a gas microbubble was generated by locally heating a fiber tip, where a gold nanofilm had been coated [107]. To further improve the sensitivity, additional materials have been used for the microbubble fabrication, such as polymethylmethacrylate (PMMA)-based optical microbubbles for temperature sensing [108] and lead-silicate-based optical microbubbles for nonlinear optical effects [109], etc. [110][111][112].

Packaging Process of a Microbubble Resonator
The optical coupling between a microbubble resonator and the tapered fiber is easily affected by surrounding perturbations, such as the mechanical vibration and airflow. Therefore, noise levels limit its practical application as well as result in the poor detection of weak signals. To improve the stability while maintaining a high Q-factor for a long working period, specific packing schemes have been proposed [89][90][91]93]. As shown in Figure 6a, a glass scaffold was fabricated for a coupling system. Firstly, the tapered fiber was fixed on the glass scaffold, and two ports were further fixed with a low-RI polymer (e.g., MY 133) to reduce the vibration of the tapered fiber, as shown in Figure 6b,c. Then, the gap between the tapered fiber and the microbubble resonator was precisely controlled by 5D stages until the optimal coupling condition was realized, which was monitored through the transmission spectrum. Thirdly, the two ports of the microbubble were also fixed to the glass scaffold to reduce the coupling position change between the tapered fiber and the microbubble resonator, as shown in Figure 6d. Finally, the optical coupling region was wrapped with a low-RI polymer via the UV exposure, which further improved the stability of the coupling system, as shown in Figure 6e. A coverslip was placed on the glass scaffold to insulate the low-RI polymer from oxygen and accelerate its solidification, as shown in Figure 6f. Various coupling methods, such as the waveguide coupling, prism coupling, and fiber-tip coupling have been proposed for the WGM microcavity. However, the tapered fiber has typically been used for the microbubble resonators due to its high efficiency and ease of integration [113][114][115][116]. heating a fiber tip, where a gold nanofilm had been coated [107]. To further improve the sensitivity, additional materials have been used for the microbubble fabrication, such as polymethylmethacrylate (PMMA)-based optical microbubbles for temperature sensing [108] and lead-silicate-based optical microbubbles for nonlinear optical effects [109], etc. [110][111][112].

Packaging Process of a Microbubble Resonator
The optical coupling between a microbubble resonator and the tapered fiber is easily affected by surrounding perturbations, such as the mechanical vibration and airflow. Therefore, noise levels limit its practical application as well as result in the poor detection of weak signals. To improve the stability while maintaining a high Q-factor for a long working period, specific packing schemes have been proposed [89][90][91]93]. As shown in Figure 6a, a glass scaffold was fabricated for a coupling system. Firstly, the tapered fiber was fixed on the glass scaffold, and two ports were further fixed with a low-RI polymer (e.g., MY 133) to reduce the vibration of the tapered fiber, as shown in Figure 6b,c. Then, the gap between the tapered fiber and the microbubble resonator was precisely controlled by 5D stages until the optimal coupling condition was realized, which was monitored through the transmission spectrum. Thirdly, the two ports of the microbubble were also fixed to the glass scaffold to reduce the coupling position change between the tapered fiber and the microbubble resonator, as shown in Figure 6d. Finally, the optical coupling region was wrapped with a low-RI polymer via the UV exposure, which further improved the stability of the coupling system, as shown in Figure 6e. A coverslip was placed on the glass scaffold to insulate the low-RI polymer from oxygen and accelerate its solidification, as shown in Figure 6f. Various coupling methods, such as the waveguide coupling, prism coupling, and fiber-tip coupling have been proposed for the WGM microcavity. However, the tapered fiber has typically been used for the microbubble resonators due to its high efficiency and ease of integration [113][114][115][116].   Due to the thermo-optical effect and thermal expansion, the RI and geometric shape are easily affected by temperature. Furthermore, the optical characteristics of a high Qfactor and a small mode volume imply a high sensitivity for the temperature sensing [94]. The thermal drift of two different cores of the microbubble, such as water and ethanol, were measured by Ward et al. in 2013 [95]. They found that the liquid core with a negative thermo-optical coefficient material can realize a high sensitivity of 100 GHz/K while effectively reducing the thermal drift. Furthermore, microbubbles based on polymethyl methacrylate (PMMA) material were proposed by He et al. in 2018 [108], as shown in Figure 7a. Different microbubble sizes were fabricated using a volume-controllable pipette, and a sensitivity of 39 pm/ • C for a temperature range of 25 • C to 80 • C was obtained.
To address the issues of the microbubble structure fragility and solution evaporation, a stable and encapsulated quasi-droplet microbubble was used for temperature sensing by Chen et al. in 2018 [117]. A high sensitivity of 205.3 pm/ • C was experimentally achieved, as shown in Figure 7b. Optical WGM barcode technology based on the simultaneous measurement of multiple WGM modes was proposed by Liao et al. in 2021 [118] for temperature sensing, as shown in Figure 8a,b. Compared with monitoring the relative wavelength drift of a specific mode, the dynamic detection range was further increased, and the temperature was directly derived by searching the spectrum in the database. This method achieved a detection limit of 0.002 • C. Compared with other optical temperature sensors, the thermal drift can be reduced by introducing materials with negative thermooptic coefficients inside the WGM microbubble resonators. Therefore, a high sensitivity and large dynamic detection ranges for the temperature sensing can be realized using WGM microbubble resonators. Due to the thermo-optical effect and thermal expansion, the RI and geometric shape are easily affected by temperature. Furthermore, the optical characteristics of a high Qfactor and a small mode volume imply a high sensitivity for the temperature sensing [94]. The thermal drift of two different cores of the microbubble, such as water and ethanol, were measured by Ward et al. in 2013 [95]. They found that the liquid core with a negative thermo-optical coefficient material can realize a high sensitivity of 100 GHz/K while effectively reducing the thermal drift. Furthermore, microbubbles based on polymethyl methacrylate (PMMA) material were proposed by He et al. in 2018 [108], as shown in Figure  7a. Different microbubble sizes were fabricated using a volume-controllable pipette, and a sensitivity of 39 pm/°C for a temperature range of 25 °C to 80 °C was obtained. To address the issues of the microbubble structure fragility and solution evaporation, a stable and encapsulated quasi-droplet microbubble was used for temperature sensing by Chen et al. in 2018 [117]. A high sensitivity of 205.3 pm/°C was experimentally achieved, as shown in Figure 7b. Optical WGM barcode technology based on the simultaneous measurement of multiple WGM modes was proposed by Liao et al. in 2021 [118] for temperature sensing, as shown in Figure 8a,b. Compared with monitoring the relative wavelength drift of a specific mode, the dynamic detection range was further increased, and the temperature was directly derived by searching the spectrum in the database. This method achieved a detection limit of 0.002 °C. Compared with other optical temperature sensors, the thermal drift can be reduced by introducing materials with negative thermo-optic coefficients inside the WGM microbubble resonators. Therefore, a high sensitivity and large dynamic detection ranges for the temperature sensing can be realized using WGM microbubble resonators.

Bulk RI and Liquid-Concentration Sensing
As the distribution of an evanescent field penetrates to the microbubble core, the changing of RI and concentrations can result in wavelength shifts. Therefore, bulk RI and liquid-concentration sensing can be accomplished through a combination of microfluidic technologies. Lab-on-fiber sensing technology based on gas microbubbles was proposed by Zhang et al. in 2018 [107], in which they locally heated a fiber tip with a gold nanomembrane, as shown in Figure 9a. The growth rate of the air microbubbles is dependent on the surrounding solution. For the evaporation of a solution, the growth rate of a microbubble decreases as the concentration increases due to the increase in boiling point. In addition, chemical decomposition can also lead to the generation of air microbubbles. The growth rate usually increases when the concentration increases, which is due to the increasing of decomposition rate. The dynamic detection range of the sucrose solutions from 0.5% to 50% and five orders of the magnitude (10 −5~1 M) for hydrogen peroxide were realized. Such air microbubbles can also be repeatedly reused. However, they are easily affected by surrounding mechanical disturbances. To reduce the effect of environmental perturbance, a packaged microbubble tapered-fiber coupling system was proposed by Tang et al. in 2016 [89], as shown in Figure 9b. A type of low-RI polymer was used as the cladding layer. They found such a sensing system maintained a high Q-factor for a significant length of time and had a high signal-to-noise ratio. Furthermore, bulk-RI sensitivity of 18.8 nm/RIU and a detection limit of 5.4 × 10 −5 RIU were experimentally achieved, as shown in Figure 9c. In 2018, this same research group proposed a new packaged microbubble tapered-fiber coupling system. The signal-to-noise ratio and stability were further increased, and the detection of a low concentrations of small molecules was realized [90]. The microfluidic channel in microbubble resonators provides advantages when used for RI-based and liquid-concentration-based sensing. In addition, ultra-low detection limits can be realized due to the high Q-factor. However, only a small part of the WGM field extends into the surrounding analytes, resulting in a low sensitivity of the RI sensing.

Pressure and Flow Rate Sensing
Due to the hollow microfluidic channel, an accurate measurement of the pressure and flow rate can be realized through a combination with microfluidic technologies. For different pressures inside the microbubble, the geometric shape is different [119]. By changing the pressure inside a microbubble, the resonance mode was tuned over hundreds of GHz [98]. To further improve the sensitivity, an ultra-thin microbubble wall (500 nm) was used for aerostatic pressure sensing by Yang et al. in 2016 [106], as shown in Figure 9d. A high sensitivity of 19 GHz/bar at 1.55 μm, 38 GHz/bar at 0.78 μm and a resolution of 0.17 mbar were realized. In addition, the microbubble wall thickness was precisely measured with a combination of pressure sensing by Lu et al. in 2016 [99]. The minimum measurement uncertainty of the microbubble wall thickness was approximately 0.02 μm. The advantages of such pressure sensors are their simple structures and their low detection limits. However, the sensitivity is limited due to the large Young's modulus of the silica material. Therefore, new materials are needed for the fabrication of microbub-

Pressure and Flow Rate Sensing
Due to the hollow microfluidic channel, an accurate measurement of the pressure and flow rate can be realized through a combination with microfluidic technologies. For different pressures inside the microbubble, the geometric shape is different [119]. By changing the pressure inside a microbubble, the resonance mode was tuned over hundreds of GHz [98]. To further improve the sensitivity, an ultra-thin microbubble wall (500 nm) was used for aerostatic pressure sensing by Yang et al. in 2016 [106], as shown in Figure 9d. The advantages of such pressure sensors are their simple structures and their low detection limits. However, the sensitivity is limited due to the large Young's modulus of the silica material. Therefore, new materials are needed for the fabrication of microbubble resonators aimed at pressure or flow rate sensing.
The pressure inside the microbubble decreases with increasing of velocity. Therefore, a microbubble resonator can also be used for the flow rate sensing. As shown in Figure 10a, a flow rate sensor whereby detection is based on the Bernoulli effect was proposed and experimentally proven by Chen et al. in 2019 [100]. By combination with a packaged microbubble resonator, a dynamic detection range of 10 µL/min to 200 µL/min and sensitivity of 0.0196 pm/(µL/min) were realized. To further improve the sensitivity, a higher order radial mode and a thinner microbubble wall were applied for the flow rate sensing by Wang et al. in 2021 [101]. A high sensitivity of 0.079 pm/(µL/min) and a dynamic detection range of 0 µL/min to 200 µL/min were realized. Moreover, the microbubble resonators were also used for air-coupled ultrasound sensing [120]. By the combination with an optical frequency comb, a femtometer resolution of the resonance wavelength shift and sub-microsecond response time were realized to trace the ultrasound pressure, as shown in Figure 10b. The noise equivalent pressure was 4.4 mPa/ √ Hz. Compared with other flow rate sensors, microbubble resonators provide a simple and flexible structure while maintaining a high sensitivity.
Micromachines 2022, 13, 592 12 of 24 sensitivity of 0.0196 pm/(μL/min) were realized. To further improve the sensitivity, a higher order radial mode and a thinner microbubble wall were applied for the flow rate sensing by Wang et al. in 2021 [101]. A high sensitivity of 0.079 pm/(μL/min) and a dynamic detection range of 0 μL/min to 200 μL/min were realized. Moreover, the microbubble resonators were also used for air-coupled ultrasound sensing [120]. By the combination with an optical frequency comb, a femtometer resolution of the resonance wavelength shift and sub-microsecond response time were realized to trace the ultrasound pressure, as shown in Figure 10b. The noise equivalent pressure was 4.4 mPa/√Hz. Compared with other flow rate sensors, microbubble resonators provide a simple and flexible structure while maintaining a high sensitivity.

Magnetic-Field Sensing
By coating with magnetic material, the microbubble resonators have been used for magnetic field sensing due to the magneto-optical effect [121]. Terfenol-D with a high magnetostriction coefficient was fixed to one side of the microbubble resonator [96]. When

Magnetic-Field Sensing
By coating with magnetic material, the microbubble resonators have been used for magnetic field sensing due to the magneto-optical effect [121]. Terfenol-D with a high magnetostriction coefficient was fixed to one side of the microbubble resonator [96]. When the strength of the surrounding magnetic field was altered, the longitudinal length and RI of microbubble were changed. A sensitivity of 0.081 pm/mT and a dynamic detection range of 0.41 mT to 21.8 mT were realized. To further increase the sensitivity, magnetic-fluid-filled microbubble resonators were proposed by Liu et al. in 2021 [97], as shown in Figure 10c. A high sensitivity of 25.21 pm/mT was realized. Due to their high Q-factor, small mode volume, and high optical energy density, microbubble resonators can provide the high sensitivity required to sense the magnetic-fields. Compared with other magnetic-field sensors, the microbubble resonators have the advantages of its small size and having high accuracy for magnetic-filed sensing.

Gas Sensing
By modifying the inner surface of the microbubble with special materials, the detection of low concentrations of chemical gases becomes possible, especially for harmful gases. Due to the high Q-factor and the hollow microfluidic channel of the microbubble resonator, real-time and high sensitivity gas sensors were realized. As shown in Figure 11a, an approach that extended electron-photon interaction to electron-phonon-photon interaction in a graphene-deposited microbubble was proposed by Yao et al. in 2017 [122]. Ultrasensitive and rapid detection of ammonia gas was realized with a noise equivalent limit of 1 ppb and a dynamic detection range of more than five orders of magnitude, as shown in Figure 11b. In addition, a carbon dioxide (CO 2 ) gas sensor developed by coating polyhexamethylenebiguanide (PHMB) inside the microbubble surface was proposed by Li et al. in 2019 [123], as shown in Figure 11c. When the CO 2 gas is delivered into the microbubble resonator, it interacts with the PHMB molecular layers, resulting in a blue shift in resonance wavelength. A sensitivity of 0.46 pm/ppm and a detection limit of 50 ppm in a range of 200 ppm to 700 ppm with a good selectivity was realized. Furthermore, a self-assembled polydimethylsiloxane (PDMS) microbubble was proposed for the detection of ethanol gas [111]. When the ethanol gas concentrations changes, the volume and RI of PDMS change accordingly, resulting in a resonance wavelength shift, as shown in Figure 11d. A sensitivity of 36.24 pm/ppm and a dynamic range of 4.19 ppm to 272.35 ppm were realized. However, those gas sensors were dependent on the internal surface coating and can only detect one medium.
To overcome the difficulty of surface coating and allow the detection of different gases at the same time, a method based on pressure-induced geometric deformation and gas-molecules-induced heat dissipation in the microbubble resonator was proposed by Peng et al. in 2020 [124]. When the flow rate increases, the resonance frequency redshifts while the thermal effect decreases due to the heat dissipation. The different thermal conductivities of He, N 2 , and CO 2 gases allowed them to be simultaneously distinguished. Using a combination of microbubble resonators, different chemical gases were detected with high sensitivity and low detection limits. In addition, the sensor size was further decreased. However, the complicated coating process has limited its practical application.

Ion and pH Sensing
The ultra-sensitive and real-time specificity detection of lead ions was proposed by Fu et al. in 2020 [125], as shown in Figure 12a. Preprocessing with the piranha solution and poly-L-lysine solutions results in the inner surface of the microbubbles being positively charged. The GR-5 DNAzyme and substrate strands were then successfully modified by electrostatic adsorption. When the lead ions solutions are delivered into the microbubble, they cleave the substrate strands, resulting in blue shifts of the resonance modes, as shown in Figure 12b. A detection limit of 15 fM and a dynamic detection range of 0.1 pM to 100 pM were realized. In addition, a pH-sensitive polymer, N-isopropylacrylamide (polyNIPA), was coated onto the inner surface for pH sensing by Stoian et al. in 2019 [126], as shown in Figure 12c,d. When changing the pH inside the microbubble, the polymer particles changed from a shrunken to a swollen state, resulting in a change in the RI. A response time of 10~15 s and a resolution of 0.06 pH were realized. The drawback of such a method is the large size of the polyNIPA particles, and it was not adapted to the thin-film-related theoretical models. Figure 11. Gas sensing with microbubble resonators: (a,b) a graphene-deposited microbubb the ammonia gas sensing (reprinted with permission from [122], © ACS Publications); (c) a P deposited microbubble for the CO2 gas sensing (reprinted with permission from [123], © O formerly the Optical Society of America); (d) a PDMS-deposited microbubble for the ethan sensing (reprinted with permission from [111], © Elsevier).

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To overcome the difficulty of surface coating and allow the detection of diff gases at the same time, a method based on pressure-induced geometric deformation gas-molecules-induced heat dissipation in the microbubble resonator was propose Peng et al. in 2020 [124]. When the flow rate increases, the resonance frequency red- Figure 11. Gas sensing with microbubble resonators: (a,b) a graphene-deposited microbubble for the ammonia gas sensing (reprinted with permission from [122], © ACS Publications); (c) a PHMBdeposited microbubble for the CO 2 gas sensing (reprinted with permission from [123], © Optica, formerly the Optical Society of America); (d) a PDMS-deposited microbubble for the ethanol gas sensing (reprinted with permission from [111], © Elsevier). drawback of such a method is the large size of the polyNIPA particles, and it wa adapted to the thin-film-related theoretical models.

Hydrogel Phase Sensing
Real-time monitoring of the internal structural changes of hydrogel was propose Yang et al. in 2020 [91,92,127]. The phase transition from hydrophilic to hydrophobic changing of temperatures was studied, as shown in Figure 13a. By simultaneously m toring the resonance wavelength shift, spectral linewidth broadening and microscop aging, RI increase and light scattering enhancement were observed during the trans from hydrophilic to hydrophobic, as shown in Figure 13b. Compared with other meth rapid and real-time monitoring of the phase transition dynamics of certain materials achieved via the microbubble resonators. In addition, the cost was further decreased

Hydrogel Phase Sensing
Real-time monitoring of the internal structural changes of hydrogel was proposed by Yang et al. in 2020 [91,92,127]. The phase transition from hydrophilic to hydrophobic with changing of temperatures was studied, as shown in Figure 13a. By simultaneously monitoring the resonance wavelength shift, spectral linewidth broadening and microscope imaging, RI increase and light scattering enhancement were observed during the transition from hydrophilic to hydrophobic, as shown in Figure 13b. Compared with other methods, rapid and real-time monitoring of the phase transition dynamics of certain materials was achieved via the microbubble resonators. In addition, the cost was further decreased. Figure 13. Sensing of the hydrogel phase transition between hydrophob printed with permission from [92], © The Chinese Laser Press): (a) schematic system with a microbubble resonator; (b) resonance wavelength shift, spec ing, and scattering enhancement from hydrophilic to hydrophobic.

Biosensing
Due to their favorable optical characteristics and microfluidic c resonators have been used for the biosensing, such as biotin and pr referencing optofluidic microbubble resonator was studied and use (BSA) detection [64]. The noise was further suppressed to 0.029 pm Figure 13. Sensing of the hydrogel phase transition between hydrophobic and hydrophilic (reprinted with permission from [92], © The Chinese Laser Press): (a) schematic of the hydrogel sensing system with a microbubble resonator; (b) resonance wavelength shift, spectral linewidth broadening, and scattering enhancement from hydrophilic to hydrophobic.

Biosensing
Due to their favorable optical characteristics and microfluidic channel, microbubble resonators have been used for the biosensing, such as biotin and protein. In 2013, a selfreferencing optofluidic microbubble resonator was studied and used for bovine albumin (BSA) detection [64]. The noise was further suppressed to 0.029 pm by monitoring two splitting modes. A detection limit of 0.5 pg/mL was realized. Furthermore, a method of theoretical analysis for the sensitivity and the detection limit of biosensing was proposed by Barucci et al. in 2016 [128]. By decreasing the microbubble wall thickness or choosing a higher order radial mode, the sensitivity and detection limit for biosensing were further increased. As shown in Figure 14a,c, D-biotins of different concentrations could be detected with the microbubble resonators [90]. A detection limit of 0.41 pM was realized. However, the noise limited its further measurement of ultra-low concentrations of biomolecules. To further reduce the noise, an external referencing microbubble resonator was proposed by Guo et al. in 2019 [93]. An ultra-low concentration of 1 fg/mL for BSA and D-biotin were reported, as shown in Figure 14b,d. The drawback of this method is its complicated referencing systems.  [129], as shown in Figure 14e, The orientation of the LC molecules changed with the increasing of biomolecule concen trations, resulting in the amplification of the wavelength shift. Different biomolecule were detected at the concentrations of 2 fM. In addition, a single DNA molecule with kDa was detected by the plasmonic-enhanced interface mode in the microbubble resona tors [130]. However, the above methods can only detect one specific biomolecule. To rea Furthermore, ultrasensitive biomolecule detection employing the amplification of liquid crystals (LC) was proposed by Wang et al. in 2021 [129], as shown in Figure 14e,f. The orientation of the LC molecules changed with the increasing of biomolecule concentrations, resulting in the amplification of the wavelength shift. Different biomolecules were detected at the concentrations of 2 fM. In addition, a single DNA molecule with 8 kDa was detected by the plasmonic-enhanced interface mode in the microbubble resonators [130]. However, the above methods can only detect one specific biomolecule. To realize the simultaneous detection of multiple biomolecules, a method based on selectively immobilizing antibodies on a specific microbubble was proposed by Berneschi et al. in 2016 [131]. As shown in Figure 15a,b, by the combination with the photochemical activation method, multiple antibodies were modified on different microbubbles for parallel antigen detection. Using a combination of microbubble resonators, an ultra-low detection limit of biosensing was realized with a miniature sensor system. However, the internal surface modification had low efficiency, which would need to be further improved for practical application.

Summary and Outlook
Here, we summarize the recent developments in the use of WGM microbubble resonators, including the sensing principles, fabrication methods, as well as various physical, chemical, and biological sensing applications, as shown in Table 1. Due to their high Qfactor, small mode volume, high optical energy density and hollow microfluidic channel, microbubble resonators possess advantages for the sensing of small changes. Miniaturized sensors have been fabricated using a combination of microfluidic technologies and can be used for the detection of temperature, stress, strain, pressure, flow rate, RI, ultrasound, gas, ions, and biomolecules, as shown in Figure 16. The different types of microbubble sensors used indicate their broad potential research value and future practical applications.

Summary and Outlook
Here, we summarize the recent developments in the use of WGM microbubble resonators, including the sensing principles, fabrication methods, as well as various physical, chemical, and biological sensing applications, as shown in Table 1. Due to their high Q-factor, small mode volume, high optical energy density and hollow microfluidic channel, microbubble resonators possess advantages for the sensing of small changes. Miniaturized sensors have been fabricated using a combination of microfluidic technologies and can be used for the detection of temperature, stress, strain, pressure, flow rate, RI, ultrasound, gas, ions, and biomolecules, as shown in Figure 16. The different types of microbubble sensors used indicate their broad potential research value and future practical applications.

Summary and Outlook
Here, we summarize the recent developments in the use of WGM microbubble resonators, including the sensing principles, fabrication methods, as well as various physical, chemical, and biological sensing applications, as shown in Table 1. Due to their high Qfactor, small mode volume, high optical energy density and hollow microfluidic channel, microbubble resonators possess advantages for the sensing of small changes. Miniaturized sensors have been fabricated using a combination of microfluidic technologies and can be used for the detection of temperature, stress, strain, pressure, flow rate, RI, ultrasound, gas, ions, and biomolecules, as shown in Figure 16. The different types of microbubble sensors used indicate their broad potential research value and future practical applications.   However, there remain technical challenges to overcome regarding their production and practical application. Firstly, microbubble resonators with three-dimensional structures are difficult to prepare quickly and in batches using the conventional semiconductor processing technology. Therefore, it is possible to further optimize the fabrication method based on an automated process. Secondly, it can be difficult to miniaturize a tunable laser while maintaining a high stability. The large size of a tunable laser is not flexible for integration and commercialization. Thirdly, it is important to maintain the same performance of the sensor outside the laboratory environment for applicability in realworld measurements. Therefore, it will be necessary to further improve the stability and signal-to-noise ratio of microbubble sensors. In addition, new data processing and analysis techniques are required to fully utilize the multiple WGMs formed. The level of sensitivity and the dynamic measurement range of the sensor will also require further improvement. Among the potential analysis methods developed for WGM microbubble sensors thus far, the barcode technology may be a feasible solution.