Session A4: Bubbles: Biomedical

Research of surface modified microbubbles generated by microchannel for selective adsorption

Microbubbles have been already used as ultrasound contrast agents to visualize microcirculation system. They are also expected to be used as drag delivery agents. For these bubbles, one of the important requirements is functionality of adsorption to the targeted area. In order to qualify this requirement, it is expected to modify microbubbles with ligand which has ability of specific adsorption to receptor. Biotin as ligand has very high affinity to avidin as receptor, therefore using these materials is supposed to be proper for the first experimental model to satisfy the requirement. In the present study, microbubbles are generated using T-junction type microchannel, because this system has the advantages to control the size and its monodispersity with the wide variety of choice in both liquid phase and gas phase and the capability of surface coating. Polystyrene-dish is confirmed to be coated with avidin. Furthermore, to confirm microbubbles' selective adsorption, microbubbles generated with liquid containing biotinylated lipids are tried being put on avidin-coated polystyrene-dish. The results will be discussed in the presentation.   

Deformation of a soft interface by an oscillating microbubble

Acoustically driven oscillating bubbles are used in biomedical applications, for instance to promote pore formation in cell membranes and enhance gene transfection, or to transiently open the blood-brain barrier, which is otherwise impermeable to drugs. However, control over the stresses generated by oscillating bubbles on cells and tissues is still lacking. We use high-speed video microscopy to observe the deformation of a soft interface (agarose gel, a hydrogel that is commonly used as tissue phantom) by the oscillations of a bubble. The mechanical properties of the hydrogel can be tuned to mimic different tissues. The deformation is measured by tracking the displacement of tracer particles embedded in the gel. The results show that the deformation is due to the ``push and pull'' motion of the bubble against the soft surface. The phase of the deformation varies with the distance to the bubble, which can be explained by the viscoelastic properties of the gel.   

Shockwave-Gas bubble Interaction in Complex Configurations

Shockwave-gas bubble interaction is relevant in biomedical applications such as shock wave lithotripsy and histotripsy where cell rupture needs to be avoided or is advantageous, as well as in the mining industry for microbubble aerated explosive gels. Here we demonstrate an experimental technique to study this interaction in a well-controlled manner utilizing microfluidics and high-speed photography of up to 2 million frames per second. Micron-size gas bubbles are generated with a continuous wave laser beam modulated with a digital hologram, whereas the shockwave and an expanding cavitation bubble are created with a pulsed laser. Gas bubbles are known to generate fast jets when impacted by shockwaves and we observe jets of 125 m/s and more. Complex interactions are reported for geometric arrangements of up to 6 gas bubbles: cascaded and simultaneous collapse of gas bubbles, back reaction of the gas bubbles on the cavitation bubble, and the deflection of jets for neighbouring bubbles. Besides, we find secondary cavitation within the liquid film below the expanding cavitation bubble, which is likely due to trapped gas exposed to low pressures and high shear, i.e. a regime relevant for cavitation in lubricating films.   

Acoustic Droplet Vaporization in Microchannels

Gas embolotherapy is a proposed cancer therapy where gas bubbles acting as embolic agents are selectively generated near the tumor site to block blood supply, resulting to tumor necrosis. The gas bubbles are generated by using focused ultrasound to selective vaporize intravenously injected microdroplets. In this study, albumin encapsulated dodecafluorocarbon microdroplets were isolated in 25 to 100 micron diameter polydimethylsiloxane microchannels. The droplets were vaporized at 37 $^{\circ}$C using a single pulse from a 7.5 MHz single element focused transducer with 8-32 cycles at 2.2 to 5.6 MPa peak negative pressure. The vaporization process was recorded using an ultra-high speed camera attached to an inverted microscope. A theoretical Rayleigh-Plesset like model was derived to describe the both the expansion of small spherical bubbles as well as cylindrical bubbles in a long microchannel. The gas phase was described as an ideal gas and the liquid DDFP and bulk fluid were viscous Newtonian fluids. Additionally, surface tension, viscous losses from the channel, and the phase change process were included in the model. The theoretical model matched very well to experiments with channel diameters or 50 micron or less. This work was supported by NIH grant R01EB006476.   

Pinched flow fractionation of microbubbles for ultrasound contrast agent enrichment

An ultrasound contrast agent (UCA) suspension contains a wide size distribution of encapsulated microbubbles (typically 1-10 $\mu $m in diameter) that resonate to the driving ultrasound field by the intrinsic relationship between bubble size and ultrasound frequency. Medical transducers, however, operate in a narrow frequency range, which severely limits the number of bubbles that contribute to the echo signal. Thus, the sensitivity can be improved by narrowing down the size distribution of the bubble suspension. Here, we present a novel, low-cost, lab-on-a-chip method for the sorting of contrast microbubbles by size, based on a microfluidic separation technique known as pinched flow fractionation (PFF). We show by experimental and numerical investigation that the inclusion of particle rotation is essential for an accurate physical description of the sorting behavior of the larger bubbles. Successful sorting of a bubble suspension with a narrow size distribution (3.0$\pm $ 0.6 $\mu $m) has been achieved with a PFF microdevice. This sorting technique can be easily parallelized, and may lead to a significant improvement in the sensitivity of contrast-enhanced medical ultrasound.   

The effect of relaxation on cavitation dynamics in viscoelastic media

Cavitation plays an important role in diagnostic and therapeutic ultrasound. In certain applications, cavitation bubbles are produced directly in soft tissue, a viscoelastic medium. Although bubble dynamics research in water has received significant attention, the behavior of bubbles in tissue-like media is much less well understood, as the dynamics are strongly affected by the viscoelastic properties of the surroundings, including viscosity, elasticity and relaxation. In the present work, we numerically investigate the role of stress relaxation on spherical bubble dynamics. We simulate bubble dynamics in viscoelastic media with linear and nonlinear relaxation under different types of forcing. Results indicate that the presence of relaxation causes faster growth rates and permits bubble rebound driven purely by residual stresses in the surroundings, a phenomenon not observed in Newtonian media. Differences between nonlinear models become important only following a strong collapse (in which high stresses are generated), thus requiring a robust numerical approach.   

Numerical Modeling of 3-D Dynamics of Ultrasound Contrast Agent Microbubbles Using the Boundary Integral Method

Ultrasound contrast agents (UCAs) are microbubbles stabilized with a shell typically of lipid, polymer, or protein and are emerging as a unique tool for noninvasive therapies ranging from gene delivery to tumor ablation. The nonspherical dynamics of contrast agents are thought to play an important role in both diagnostic and therapeutic applications, for example, causing the emission of subharmonic frequency components and enhancing the uptake of therapeutic agents across cell membranes and tissue interfaces. A three-dimensional model for nonspherical contrast agent dynamics based on the boundary integral method is presented. The effects of the encapsulating shell are approximated by adapting Hoff's model for thin-shell, spherical contrast agents to the nonspherical case. A high-quality mesh of the bubble surface is maintained by implementing a hybrid approach of the Lagrangian method and elastic mesh technique. Numerical analyses for the dynamics of UCAs in an infinite liquid and near a rigid wall are performed in parameter regimes of clinical relevance. The results show that the presence of a coating significantly reduces the oscillation amplitude and period, increases the ultrasound pressure amplitude required to incite jetting, and reduces the jet width and velocity.   

Selective breakup of lipid vesicles under acoustic microstreaming flow

The dynamics of lipid vesicles under small deformation in simple shear flow is well characterized: complex behaviors such as tumbling, breathing, and tank-treading are observed depending on the viscosity contrast between inner and outer fluid, vesicle excess area, membrane viscosity, and bending modulus. In contrast, phenomena upon large deformation are still poorly understood, in particular vesicle breakup. Simple shear flow geometries do not allow to reach the large stresses necessary to cause vesicle breakup. We use the acoustic microstreaming flow generated by an oscillating microbubble to study the large deformation and breakup of giant unilamellar vesicles. The deformation is governed by a capillary number based on the membrane elasticity $K$: $Ca = \eta\dot{\gamma}a/K$ where $\eta$ is the viscosity of the outer fluid, $a$ the vesicle radius, and $\dot{\gamma}$ the shear rate. We explore the effect of the mechanical properties of the membrane, and demonstrated selective breakup of vesicles based on the difference in membrane elasticity. The results reveal the influence of membrane mechanical properties in shear-induced vesicle breakup and the possibility to control in a quantitative way the selectivity of the process, with potential applications in biomedical technologies.