Optical manipulation in optofluidic microbubble resonators

An optical manipulation system based on optofluidic microbubble resonators(MBR) is proposed. As the high-Q whispering gallery modes(WGMs) are excited in an MBR, the buildup of the field intensity inside the resonator is large enough to trap nanoscale particles. The optical gradient forces generated by the WGMs with different radial orders are investigated numerically. The negative effect of the resonance detuning induced by the particles is taken into account to investigate the optical gradient forces exerting on the particles. By the stability analysis, the WGMs with high radial orders show a better trapping stability under Brownian motion since most of the optical fields reside within the water core.     

多层膜磁性微泡的非线性声振动特性

超顺磁性氧化铁纳米粒子与造影剂微泡结合形成磁性微泡,用于产生多模态造影剂,以增强医学超声和磁共振成像.将装载有纳米磁性颗粒的微泡包膜层看作由磁流体膜与磷脂膜组合而成的双层膜结构,同时考虑磁性纳米颗粒体积分数a对膜密度及黏度的影响,从气泡动力学基本理论出发,构建多层膜结构磁性微泡非线性动力学方程.数值分析了驱动声压和频率等声场参数、颗粒体积分数、膜层厚度以及表面张力等膜壳参数对微泡声动力学行为的影响.结果表明,当磁性颗粒体积分数较小且a≤0.1时,磁性微泡声响应特性与普通包膜微泡相似,微泡的声频响应与其初始尺寸和驱动压有关;当驱动声场频率f为磁性微泡共振频率f0的2倍(f=2f0)时,微泡振动失稳临界声压最低;磁性颗粒的存在抑制了泡的膨胀和收缩但抑制效果非常有限;磁性微泡外膜层材料的表面张力参数K及膜层厚度d也会影响微泡的振动,当表面张力参数及膜厚取值分别为0.2—0.4 N/m及50—150 nm时,可观察到气泡存在不稳定振动响应区.     

Sonochemical reaction with microbubbles generated by hollow ultrasonic horn

A microbubble generator with a cylindrical hollow ultrasonic horn (HUSH), gas flow path, and an orifice inside it can produce high ultrasonic pressure around the generated microbubbles. We used this microbubble generator with a HUSH as a sonochemical reactor for the degradation of indigo carmine and evaluated the sonochemical reaction by simply inserting the horn end into a liquid. The experimental results revealed that the ultrasonic irradiation around ultrasonically generated microbubbles effectively degraded indigo carmine in water. In addition, degradation experiments performed by varying the ultrasonic power and gas flow rates indicated that a continuous gas supply and ultrasonic pressure were required for generating the microbubbles, without the generation of millimeter-scale bubbles, to enhance the sonochemical reaction in water.     

Single-input spherical microbubble resonator

A single-input whispering gallery optical microbubble resonator is presented. Spherical microbubbles with diameters less than 100 μm, micrometer-sized wall thicknesses, and a single opening or input were fabricated by heating the tapered tip of a pressurized glass capillary using a CO(2) laser. Optical whispering gallery modes with Q factors of ～10(5) were obtained. The bubbles were filled with water and mode shifts of ～20 GHz were observed. Fano-type resonances were detected when the coupling optical fiber diameter was less than 1 μm, causing the microresonator to switch from being a band-stop filter to a bandpass filter. Larger bubbles with submicrometer wall thickness were also fabricated.     

Difference-frequency ultrasound generation from microbubbles under dual-frequency excitation

The difference-frequency (DF) ultrasound generated by using parametric effect promises to improve detection depth owing to its low attenuation, which is beneficial for deep tissue imaging. With ultrasound contrast agents infusion, the harmonic components scattered from the microbubbles, including DF, can be generated due to the nonlinear vibration. A theoretical study on the DF generation from microbubbles under the dual-frequency excitation is proposed in formula based on the solution of the RPNNP equation. The optimisation of the DF generation is discussed associated with the applied acoustic pressure, frequency, and the microbubble size. Experiments are performed to validate the theoretical predictions by using a dual-frequency signal to excite microbubbles. Both the numerical and experimental results demonstrate that the optimised DF ultrasound can be achieved as the difference frequency is close to the resonance frequency of the microbubble and improve the contrast-to-tissue ratio in imaging.     

Direct observations of ultrasound microbubble contrast agent interaction with the microvessel wall

Many thousands of contrast ultrasound studies have been conducted in clinics around the world. In addition, the microbubbles employed in these examinations are being widely investigated to deliver drugs and genes. Here, for the first time, the oscillation of these microbubbles in small vessels is directly observed and shown to be substantially different than that predicted by previous models and imaged within large fluid volumes. Using pulsed ultrasound with a center frequency of 1 MHz and peak rarefactional pressure of 0.8 or 2.0 MPa, microbubble expansion was significantly reduced when microbubbles were constrained within small vessels in the rat cecum (p<0.05). A model for microbubble oscillation within compliant vessels is presented that accurately predicts oscillation and vessel displacement within small vessels. As a result of the decreased oscillation in small vessels, a large resting microbubble diameter resulting from agent fusion or a high mechanical index was required to bring the agent shell into contact with the endothelium. Also, contact with the endothelium was observed during asymmetrical collapse, not during expansion. These results will be used to improve the design of drug delivery techniques using microbubbles.     

Fast mode-hop-free acousto-optically tuned laser with a simple laser diode

A mode-hop-free tunable external-cavity Littrow diode laser with intracavity acousto-optic modulators (AOMs) has been built. The modes of the red laser diode without a special antireflection coating are shifted by varying the injection current. The external resonator modes and the grating selectivity are independently electrically alterable by two AOMs. Thus, a tuning of the external resonator over up to 1900 GHz is possible. A precise computer control of laser diode and AOMs allowed a single-mode tuning of the whole laser with a tuning range of 225 GHz in 250 s. Additionally, we demonstrated fast tuning over 90 GHz in 190 micros and a repetition rate of 2.5 kHz.     

Harmonic responses and cavitation activity of encapsulated microbubbles coupled with magnetic nanoparticles

Encapsulated microbubbles coupled with magnetic nanoparticles, one kind of hybrid agents that can integrate both ultrasound and magnetic resonance imaging/therapy functions, have attracted increasing interests in both research and clinic communities. However, there is a lack of comprehensive understanding of their dynamic behaviors generated in diagnostic and therapeutic applications. In the present work, a hybrid agent was synthesized by integrating superparamagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles (named as SPIO-albumin microbubbles). Then, both the stable and inertial cavitation thresholds of this hybrid agent were measured at varied SPIO concentrations and ultrasound parameters (e.g., frequency, pressure amplitude, and pulse length). The results show that, at a fixed acoustic driving frequency, both the stable and inertial cavitation thresholds of SPIO-albumin microbubble should decrease with the increasing SPIO concentration and acoustic driving pulse length. The inertial cavitation threshold of SPIO-albumin microbubbles also decreases with the raised driving frequency, while the minimum sub- and ultra-harmonic thresholds appear at twice and two thirds resonance frequency, respectively. It is also noticed that both the stable and inertial cavitation thresholds of SonoVue microbubbles are similar to those measured for hybrid microbubbles with a SPIO concentration of 114.7 μg/ml. The current work could provide better understanding on the impact of the integrated SPIOs on the dynamic responses (especially the cavitation activities) of hybrid microbubbles, and suggest the shell composition of hybrid agents should be appropriately designed to improve their clinical diagnostic and therapeutic performances of hybrid microbubble agents.     

Ultrasonic bubbles in medicine: influence of the shell

Ultrasound contrast agents consist of microscopically small bubbles encapsulated by an elastic shell. These microbubbles oscillate upon ultrasound insonification, and demonstrate highly nonlinear behavior, ameliorating their detectability. (Potential) medical applications involving the ultrasonic disruption of contrast agent microbubble shells include release-burst imaging, localized drug delivery, and noninvasive blood pressure measurement. To develop and enhance these techniques, predicting the cracking behavior of ultrasound-insonified encapsulated microbubbles has been of importance. In this paper, we explore microbubble behavior in an ultrasound field, with special attention to the influence of the bubble shell. A bubble in a sound field can be considered a forced damped harmonic oscillator. For encapsulated microbubbles, the presence of a shell has to be taken into account. In models, an extra damping parameter and a shell stiffness parameter have been included, assuming that Hooke's Law holds for the bubble shell. At high acoustic amplitudes, disruptive phenomena have been observed, such as microbubble fragmentation and ultrasonic cracking. We analyzed the occurrence of ultrasound contrast agent fragmentation, by simulating the oscillating behavior of encapsulated microbubbles with various sizes in a harmonic acoustic field. Fragmentation occurs exclusively during the collapse phase and occurs if the kinetic energy of the collapsing microbubble is greater than the instantaneous bubble surface energy, provided that surface instabilities have grown big enough to allow for break-up. From our simulations it follows that the Blake critical radius is not a good approximation for a fragmentation threshold. We demonstrated how the phase angle differences between a damped radially oscillating bubble and an incident sound field depend on shell parameters.     

Effect of coupled oscillations on microbubble behavior

Ultrasound contrast agents are encapsulated microbubbles whose nonlinear acoustic scattering signatures have been the foundation of their use in diagnostic imaging. The coupled oscillations of microbubbles along their lines of center are investigated theoretically using radial equations in the monopole approximation and an energy balance, which is obtained for the system. Coupled microbubble pairs of different initial radii are investigated numerically relative to the normal modes for the linearized system. For microbubble pairs of different size bubbles driven below the mode of the smaller bubble and above the mode of the larger bubble, it is shown that oscillations of the smaller agent are affected substantially more by the coupling than those of the larger one. For separation distances of 10 and 500 microns, a difference of approximately 10 dB occurs in the second harmonic output of a 1.0-micron radius agent coupled with a 2.2-micron radius agent forced at 2.0 MHz and 0.3 MPa. The subharmonic spectral peak is shown to decrease approximately 19 dB for the coupling of 1.5- and 2.2-micron radius agents at 10- and 500-micron distances under the same acoustic forcing conditions. These coupling effects on the radiated pressure and its spectral power are highlighted for contrast agent imaging applications.     

Modeling photothermal and acoustical induced microbubble generation and growth

Previous experimental studies showed that powerful heating of nanoparticles by a laser pulse using energy density greater than 100 mJ/cm², could induce vaporization and generate microbubbles. When ultrasound is introduced at the same time as the laser pulse, much less laser power is required. For therapeutic applications, generation of microbubbles on demand at target locations, e.g. cells or bacteria can be used to induce hyperthermia or to facilitate drug delivery. The objective of this work is to develop a method capable of predicting photothermal and acoustic parameters in terms of laser power and acoustic pressure amplitude that are needed to produce stable microbubbles; and investigate the influence of bubble coalescence on the thresholds when the microbubbles are generated around nanoparticles that appear in clusters.

We develop and solve here a combined problem of momentum, heat and mass transfer which is associated with generation and growth of a microbubble, filled with a mixture of non-vaporized gas (air) and water vapor. The microbubble’s size and gas content vary as a result of three mechanisms: gas expansion or compression, evaporation or condensation on the bubble boundary, and diffusion of dissolved air in the surrounding water. The simulations predict that when ultrasound is applied relatively low threshold values of laser and ultrasound power are required to obtain a stable microbubble from a single nanoparticle. Even lower power is required when microbubbles are formed by coalescence around a cluster of 10 nanoparticles. Laser pulse energy density of 21 mJ/cm² is predicted for instance together with acoustic pressure of 0.1 MPa for a cluster of 10 or 62 mJ/cm² for a single nanoparticle. Those values are well within the safety limits, and as such are most appealing for targeted therapeutic purposes.     

Mode coupling between first- and second-order whispering-gallery modes in coupled microdisks

The mode characteristics for two coupled microdisks are investigated by the finite-difference time-domain technique. In the two coupled micodisks, mode coupling between the same order whispering-gallery modes (WGMs) results in coupled WGMs with split mode wavelengths. The numerical results show that the split mode wavelengths of the coupled first- and second-order WGMs can have a crossing point in some cases, which can induce anticrossing mode coupling between them and greatly reduce the mode Q factor of the coupled first-order WGMs. The time variation of mode field pattern shows the transformation between the coupled first- and second-order WGMs.     

Controlled observation of nondegenerate cavity modes in a microdroplet on a superhydrophobic surface

We demonstrate controlled lifting of the azimuthal degeneracy of the whispering gallery modes (WGMs) of single glycerol-water microdroplets standing on a superhydrophobic surface by using a uniform electric field. A good agreement is observed between the measured spectral positions of the nondegenerate WGMs and predictions made for a prolate spheroid. Our results reveal fewer azimuthal modes than expected from an ideal spherical microdroplet due to the truncation by the surface. We use this difference to estimate the contact angles of the microdroplets.     

Easily coupled whispering gallery plasmons in dielectric nanospheres embedded in gold films

A new self-aligned robust method for coupling to whispering gallery modes (WGMs) of submicron microspheres utilizes their periodic arrangement without relying on nanopositioned external coupling devices. The microspheres are embedded in a nanostructured gold surface supporting delocalized plasmonic crystal modes that mediate the coupling, and can be tuned by the geometry. Detailed measurements of the angle- and orientation-dependent reflectivity reveal localized plasmonic WGMs whose energies scale with sphere diameter and agree closely with Mie calculations. Coupling between these plasmonic WGMs leads to mode splitting and the formation of plasmonic minibands of a controllable bandwidth.     

调频超声脉冲驱动微气泡运动偏移的研究

提出调频超声辐射力技术驱动微泡群,以加强微泡的吸附效率.基于改进的RP方程及粒子轨迹方程研究了微泡群整体的运动位移与调频信号的中心频率、调频范围、信号声压,以及微泡半径分布关系.研究结果表明调频信号在驱动半径具有宽泛分布的气泡群,以及半径分布远离谐振半径的气泡群时,作用效果好于传统正弦波信号.例如中心频率1 MHz、调频范围0.75 MHz的调频脉冲作用高斯分布（平均半径3.5 μm、均方差为1）的微泡群200 μs,可比同等声压的正弦波多约12%的微气泡产生位移30 μm. 关键词： 超声辐射力 调频波 高斯分布     

超声造影剂微气泡的包膜黏弹特性的定量表征研究

包膜黏弹特性显著影响微气泡超声造影剂的诊断及治疗应用效果. 本文结合原子力显微镜技术及声衰减特性测量提出了一种对微气泡造影剂包膜黏弹特性定量表征的新方法. 首先采用原子力显微镜技术进行机械特性分析得到包膜微气泡的有效硬度及体弹性模量; 然后测量声衰减特性, 基于微气泡动力学理论, 计算包膜微气泡的体黏度系数. 为验证方法的有效性, 实验制备了直径为1-5 μm的白蛋白包膜微气泡造影剂, 原子力显微镜测量的有效硬度和体弹性模量分别为0.149±0.012 N/m和8.31±0.667 MPa, 并与粒径无关. 声衰减特性测量和动力学理论拟合的包膜微气泡的体黏度系数为0.374±0.003 Pa·s. 该方法可推广至其他种类包膜微气泡的黏弹特性表征, 对超声造影剂的制备及其诊断和治疗应用有积极意义.     

Resonance behaviors of encapsulated microbubbles oscillating nonlinearly with ultrasonic excitation

The resonance behaviors of a few lipid-coated microbubbles acoustically activated in viscoelastic media were comprehensively examined via radius response analysis. The size polydispersity and random spatial distribution of the interacting microbubbles, the rheological properties of the lipid shell and the viscoelasticity of the surrounding medium were considered simultaneously. The obtained radius response curves present a successive occurrence of linear resonances, nonlinear harmonic and sub-harmonic resonances with the acoustic pressure increasing. The microbubble resonance is radius-, pressure- and frequency-dependent. Specifically, the maximum bubble expansion ratio at the main resonance peak increases but the resonant radius decreases as the ultrasound pressure increases, while both of them decrease with the ultrasound frequency increasing. Moreover, compared to an isolated microbubble case, it is found that large microbubbles in close proximity prominently suppress the resonant oscillations while slightly increase the resonant radii for both harmonic and subharmonic resonances, even leading to the disappearance of the subharmonic resonance with the influences increasing to a certain degree. In addition, the results also suggest that both the encapsulating shell and surrounding medium can substantially dampen the harmonic and subharmonic resonances while increase the resonant radii, which seem to be affected by the medium viscoelasticity to a greater degree rather than the shell properties. This work offers valuable insights into the resonance behaviors of microbubbles oscillating in viscoelastic biological media, greatly contributing to further optimizing their biomedical applications.     

Resonance frequency of microbubbles: effect of viscosity

The transmitted frequency at which a gas bubble of millimeter or submillimeter size oscillates resonantly in a low-viscosity liquid is approximately equal to the undamped natural frequency (referred to as the Minnaert frequency if surface tension effects are disregarded). Based on a theoretical analysis of bubble oscillation, this paper shows that such an approximation cannot be validated for microbubbles used in contrast-enhanced ultrasound imaging. The contrast-agent microbubbles represent either encapsulated bubbles of size less than 10 microm or free (nonencapsulated) bubbles of submicron size. The resonance frequency of the microbubbles deviates significantly from the undamped natural frequency over the whole range of microbubble sizes due to the increased viscous damping coefficient. The difference between these two frequencies is shown to have a tremendous impact on the resonant backscatter by the microbubbles. In particular, the first and second harmonics of the backscattered signal from the microbubbles are characterized by their own resonance frequencies, equal to neither the microbubble resonance frequency nor the undamped natural frequency.     

Fiber taper coupled high-quality-factor planar microdisk

A fiber taper can evanescently couple to whispering gallery modes (WGMs) in a planar silica microdisk for observing the optical properties of the microdisk cavity. It is revealed that WGMs have very high quality (Q) factors by controlling the air gap between the taper and the microdisk. The best coupling efficiency from the taper to the microdisk is as high as 98%, and can be continuously adjusted from the under-coupling, critical-coupling to over-coupling regimes. The influence of the laboratory circumstance such as surface contamination on the microdisk is also discussed. It is experimentally shown that the high-Q-factor (105) modes can be kept for a long period in a general laboratory circumstance.     

Radionuclide tumour therapy with ultrasound contrast microbubbles

Radionuclides have shown to be effective in tumour therapy. However, the side effects determine the maximum deliverable dose. Recently, it has been demonstrated that cells can be permeabilised through sonoporation using ultrasound and contrast microbubbles. The use of sonoporation in treatment of tumours may increase the anti-tumour efficacy of radionuclide treatment. The mechanisms as well as the effects sonoporation in tumour treatment strategies are still not understood. The purpose of this study is to determine the effects of ultrasound and contrast microbubbles on the internalisation of the radionuclide (111)In-DOTA-Tyr(3)-octreotate in tumour cells. To optimize ultrasound settings for ultrasound adjunctive tumour therapy we incubated rat pancreatic CA20948 tumour cells with two dyes (MW 40 and 70 kDa). The uptake levels were compared with cells treated with ultrasound and contrast microbubbles for different ultrasound settings. The highest molecular uptake was found with addition of contrast microbubbles (ratio of 10 bubbles to 1 cell) and with the ultrasound setting: duty cycle 0.013%, mechanical index (MI) 0.42, and treatment times of 30 and 60 min. These settings were used to enhance the internalisation of (111)In-DOTA-Tyr(3)-octreotate. We found a 160% higher internalisation of (111)In-DOTA-Tyr(3)-octreotate by tumour cells adjunctively treated with ultrasound and contrast microbubbles compared to untreated cells. These results show that adjunctive tumour treatment with the radionuclide (111)In-DOTA-Tyr(3)-octreotate and ultrasound contrast microbubbles may be feasible. When using adjunctive ultrasound contrast microbubble treatment, a lower radionuclide doses are required to reach the same anti-tumour effect.