Multi-time scale characterization of acoustic droplet vaporization and payload release of phase-shift emulsions using high-speed microscopy

Acoustic droplet vaporization (ADV) is the phase-transitioning of perfluorocarbon emulsions, termed phase-shift emulsions, into bubbles using focused ultrasound. ADV has been utilized in many biomedical applications. For localized drug release, phase-shift emulsions with a bioactive payload can be incorporated within a hydrogel to yield an acoustically-responsive scaffold (ARS). The dynamics of ADV and associated drug release within hydrogels are not well understood. Additionally, emulsions used in ARSs often contain high molecular weight perfluorocarbons, which is unique relative to other ADV applications. In this study, we used ultra-high-speed brightfield and fluorescence microscopy, at frame rates up to 30 million and 0.5 million frames per second, respectively, to elucidate ADV dynamics and payload release kinetics in fibrin-based ARSs containing phase-shift emulsions with three different perfluorocarbons: perfluoropentane (PFP), perfluorohexane (PFH), and perfluorooctane (PFO). At an ultrasound excitation frequency of 2.5 MHz, the maximum expansion ratio, defined as the maximum bubble diameter during ADV normalized by the initial emulsion diameter, was 4.3 ± 0.8, 4.1 ± 0.6, and 3.6 ± 0.4, for PFP, PFH, PFO emulsions, respectively. ADV yielded stable bubble formation in PFP and PFH emulsions, though the bubble growth rate post-ADV was three orders of magnitudes slower in the latter emulsion. Comparatively, ADV generated bubbles in PFO emulsions underwent repeated vaporization/recondensation or fragmentation. Different ADV-generated bubble dynamics resulted in distinct release kinetics in phase-shift emulsions carrying fluorescently-labeled payloads. The results provide physical insight enabling the modulation of bubble dynamics with ADV and hence release kinetics, which can be used for both diagnostic and therapeutic applications of ultrasound.     

Standing wave-assisted acoustic droplet vaporization for single and dual payload release in acoustically-responsive scaffolds

An ultrasound standing wave field (SWF) has been utilized in many biomedical applications. Here, we demonstrate how a SWF can enhance drug release using acoustic droplet vaporization (ADV) in an acoustically-responsive scaffold (ARS). ARSs are composite fibrin hydrogels containing payload-carrying, monodispersed perfluorocarbon (PFC) emulsions and have been used to stimulate regenerative processes such as angiogenesis. Elevated amplitudes in the SWF significantly enhanced payload release from ARSs containing dextran-loaded emulsions (nominal diameter: 6 μm) compared to the -SWF condition, both at sub- and suprathreshold excitation pressures. At 2.5 MHz and 4 MPa peak rarefactional pressure, the cumulative percentage of payload released from ARSs reached 84.1 ± 5.4% and 66.1 ± 4.4% under + SWF and -SWF conditions, respectively, on day 10. A strategy for generating a SWF for an in situ ARS is also presented. For dual-payload release studies, bi-layer ARSs containing a different payload within each layer were exposed to temporally staggered ADV at 3.25 MHz (day 0) and 8.6 MHz (day 4). Sequential payload release was demonstrated using dextran payloads as well as two growth factors relevant to angiogenesis: basic fibroblast growth factor (bFGF) and platelet-derived growth factor BB (PDGF-BB). In addition, bubble growth and fibrin degradation were characterized in the ARSs under +SWF and -SWF conditions. These results highlight the utility of a SWF for modulating single and dual payload release from an ARS and can be used in future therapeutic studies.     

Predicting initial nucleation events occurred in a metastable nanodroplet during acoustic droplet vaporization

Acoustic droplet vaporization (ADV) capable of converting liquid perfluorocarbon (PFC) micro/nanodroplets into gaseous microbubbles has gained much attention due to its medical potentials. However, its physical mechanisms for nanodroplets have not been well understood due to the disappeared superharmonic focusing effect and the prominent Laplace pressure compared to microdroplets, especially for the initial ADV nucleation occurring in a metastable PFC nanodroplet. The classical nucleation theory (CNT) was modified to describe the ADV nucleation via combining the phase-change thermodynamics of perfluoropentane (PFP) and the Laplace pressure effect on PFP nanodroplets. The thermodynamics was exactly predicted by the Redlich–Kwong equation of state (EoS) rather than the van der Waals EoS, based on which the surface tension of the vapor nucleus as a crucial parameter in the CNT was successfully obtained to modify the CNT. Compared to the CNT, the modified CNT eliminated the intrinsic limitations of the CNT, and it predicted a larger nucleation rate and a lower ADV nucleation threshold, which agree much better with experimental results. Furthermore, it indicated that the nanodroplet properties exert very strong influences on the nucleation threshold instead of the acoustic parameters, providing a potential strategy with an appropriate droplet design to reduce the ADV nucleation threshold. This study may contribute to further understanding the ADV mechanism for PFC nanodroplets and promoting its potential theranostic applications in clinical practice.     

Bubble size distribution in acoustic droplet vaporization via dissolution using an ultrasound wide-beam method

Performance and efficiency of numerous cavitation enhanced applications in a wide range of areas depend on the cavitation bubble size distribution. Therefore, cavitation bubble size estimation would be beneficial for biological and industrial applications that rely on cavitation. In this study, an acoustic method using a wide beam with low pressure is proposed to acquire the time intensity curve of the dissolution process for the cavitation bubble population and then determine the bubble size distribution. Dissolution of the cavitation bubbles in saline and in phase-shift nanodroplet emulsion diluted with undegassed or degassed saline was obtained to quantify the effects of pulse duration (PD) and acoustic power (AP) or peak negative pressure (PNP) of focused ultrasound on the size distribution of induced cavitation bubbles. It was found that an increase of PD will induce large bubbles while AP had only a little effect on the mean bubble size in saline. It was also recognized that longer PD and higher PNP increases the proportions of large and small bubbles, respectively, in suspensions of phase-shift nanodroplet emulsions. Moreover, degassing of the suspension tended to bring about smaller mean bubble size than the undegassed suspension. In addition, condensation of cavitation bubble produced in diluted suspension of phase-shift nanodroplet emulsion was involved in the calculation to discuss the effect of bubble condensation in the bubble size estimation in acoustic droplet vaporization. It was shown that calculation without considering the condensation might underestimate the mean bubble size and the calculation with considering the condensation might have more influence over the size distribution of small bubbles, but less effect on that of large bubbles. Without or with considering bubble condensation, the accessible minimum bubble radius was 0.4 or 1.7 μm and the step size was 0.3 μm. This acoustic technique provides an approach to estimate the size distribution of cavitation bubble population in opaque media and might be a promising tool for applications where it is desirable to tune the ultrasound parameters to control the size distribution of cavitation bubbles.     

Enhanced photoacoustic imaging in tissue-mimicking phantoms using polydopamine-shelled perfluorocarbon emulsion droplets

The current work features process parameters for the ultrasound (25 kHz)-assisted fabrication of polydopamine-shelled perfluorocarbon (PDA/PFC) emulsion droplets with bimodal (modes at 100–600 nm and 1–6 µm) and unimodal (200–600 nm) size distributions. Initial screening of these materials revealed that only PDA/PFC emulsion droplets with bimodal distributions showed photoacoustic signal enhancement due to large size of their optically absorbing PDA shells. Performance of this particular type of emulsion droplets as photoacoustic agents were evaluated in Intralipid®–India ink media, mimicking the optical scattering and absorbance of various tissue types. From these measurements, it was observed that PDA/PFC droplets with bimodal size distributions can enhance the photoacoustic signal of blood-mimicking phantom by up to five folds in various tissue-mimicking phantoms with absorption coefficients from 0.1 to 1.0 cm⁻¹. Furthermore, using the information from enhanced photoacoustic images at 750 nm, the ultimate imaging depth was explored for polydopamine-shelled, perfluorohexane (PDA/PFH) emulsion droplets by photon trajectory simulations in 3D using a Monte Carlo approach. Based on these simulations, maximal tissue imaging depths for PDA/PFH emulsion droplets range from 10 to 40 mm, depending on the tissue type. These results demonstrate for the first time that ultrasonically fabricated PDA/PFC emulsion droplets have great potential as photoacoustic imaging agents that can be complemented with other reported characteristics of PDA/PFC emulsion droplets for extended applications in theranostics and other imaging modalities.     

On-demand regulation and enhancement of the nucleation in acoustic droplet vaporization using dual-frequency focused ultrasound

Acoustic droplet vaporization (ADV) plays an important role in focused ultrasound theranostics. Better understanding of the relationship between the ultrasound parameters and the ADV nucleation could provide an on-demand regulation and enhancement of ADV for improved treatment outcome. In this work, ADV nucleation was performed in a dual-frequency focused ultrasound configuration that consisted of a continuous low-frequency ultrasound and a short high-frequency pulse. The combination was modelled to investigate the effects of the driving frequency and acoustic power on the nucleation rate, efficiency, onset time, and dimensions of the nucleation region. The results showed that the inclusion of short pulsed high-frequency ultrasound significantly increased the nucleation rate with less energy, reduced the nucleation onset time, and changed the length–width ratio of the nucleation region, indicating the dual-frequency ultrasound mode yields an efficient enhancement of the ADV nucleation, compared to a single-frequency ultrasound mode. Furthermore, the acoustic and temperature fields varied independently with the dual-frequency ultrasound parameters. This facilitated the spatial and temporal control over the ADV nucleation, and opens the door to the possibility to realize on-demand regulation of the ADV occurrence in ultrasound theranostics. In addition, the improved energy efficacy that is obtained with the dual-frequency configuration lowered the requirements on hardware system, increasing its flexibility and could facilitate its implementation in practical applications.     

Phase transitions of nanoemulsions using ultrasound: experimental observations

The ultrasound-induced transformation of perfluorocarbon liquids to gases is of interest in the area of drug and gene delivery. In this study, three independent parameters (temperature, size, and perfluorocarbon species) were selected to investigate the effects of 476-kHz and 20-kHz ultrasound on nanoemulsion phase transition. Two levels of each factor (low and high) were considered at each frequency. The acoustic intensities at gas bubble formation and at the onset of inertial cavitation were recorded and subsequently correlated with the acoustic parameters. Experimental data showed that low frequencies are more effective in forming and collapsing a bubble. Additionally, as the size of the emulsion droplet increased, the intensity required for bubble formation decreased. As expected, perfluorohexane emulsions require greater intensity to form cavitating bubbles than perfluoropentane emulsions.     

High-speed imaging of ultrasound driven cavitation bubbles in blind and through holes

The interest in application of ultrasonic cavitation for cleaning and surface treatment processes has increased greatly in the last decades. However, not much is known about the behavior of cavitation bubbles inside the microstructural features of the solid substrates. Here we report on an experimental study on dynamics of acoustically driven (38.5 kHz) cavitation bubbles inside the blind and through holes of PMMA plates by using high-speed imaging. Various diameters of blind (150, 200, 250 and 1000 µm) and through holes (200 and 1000 µm) were investigated. Gas bubbles are usually trapped in the holes during substrate immersion in the liquid thus preventing their complete wetting. We demonstrate that trapped gas can be successfully removed from the holes under ultrasound agitation. Besides the primary Bjerknes force and acoustic streaming, the shape oscillations of the trapped gas bubble seem to be a driving force for bubble removal out of the holes. We further discuss the bubble dynamics inside microholes for water and Cu²⁺ salt solution. It is found that the hole diameter and partly the type of liquid media influences the number, size and dynamics of the cavitation bubbles. The experiments also showed that a large amount of the liquid volume inside the holes can be displaced within one acoustic cycle by the expansion of the cavitation bubbles. This confirmed that ultrasound is a very effective tool to intensify liquid exchange processes, and it might significantly improve micro mixing in small structures. The investigation of the effect of ultrasound power on the bubble density distribution revealed the possibility to control the cavitation bubble distribution inside the microholes. At a high ultrasound power (31.5 W) we observed the highest bubble density at the hole entrances, while reducing the ultrasound power by a factor of ten shifted the bubble locations to the inner end of the blind holes or to the middle of the through holes.     

过冷沸腾中的局域气泡和射流的动态行为

本文以10 mm直径加热钢管为研究对象,通过大量可视化的实验研究,对核态过冷沸腾中的气泡动力学行为以及射流现象进行了描述和分析。在实验中我们观察到泡顶射流和核态射流的竞争,双射流,“液洞”现象等一些特殊的沸腾现象。射流的泵吸作用、汽泡表面相变换热、Marangoni效应等是导致射流和气泡结构演化的根本原因。     

Vortex nucleation by collapsing bubbles in Bose-Einstein condensates

Nucleation of vortex rings accompanies the collapse of ultrasound bubbles in superfluids. Using the Gross-Pitaevskii equation for a uniform condensate we elucidate the various stages of the collapse of a stationary spherically symmetric bubble and establish conditions necessary for vortex nucleation. The minimum radius of the stationary bubble, whose collapse leads to vortex nucleation, was found to be 28+/-1 healing lengths. The time after which the nucleation becomes possible is determined as a function of the bubble's radius. We show that vortex nucleation takes place in moving bubbles of even smaller radius if the motion makes them sufficiently oblate.     

New insights into the mechanisms of ultrasonic emulsification in the oil–water system and the role of gas bubbles

Ultrasonic emulsification (USE) assisted by cavitation is an effective method to produce emulsion droplets. However, the role of gas bubbles in the USE process still remains unclear. Hence, in the present paper, high-speed camera observations of bubble evolution and emulsion droplets formation in oil and water were used to capture in real-time the emulsification process, while experiments with different gas concentrations were carried out to investigate the effect of gas bubbles on droplet size. The results show that at the interface of oil and water, gas bubbles with a radius larger than the resonance radius collapse and sink into the water phase, inducing (oil–water) blended liquid jets across bubbles to generate oil-in-water-in-oil (O/W/O) and water-in-oil (W/O) droplets in the oil phase and oil-in-water (O/W) droplets in the water phase, respectively. Gas bubbles with a radius smaller than the resonance radius at the interface always move towards the oil phase, accompanied with the generation of water droplets in the oil phase. In the oil phase, gas bubbles, which can attract bubbles nearby the interface, migrate to the interface of oil and water due to acoustic streaming, and generate numerous droplets. As for the gas bubbles in the water phase, those can break neighboring droplets into numerous finer ones during bubble oscillation. With the increase in gas content, more bubbles undergo chaotic oscillation, leading to smaller and more stable emulsion droplets, which explains the beneficial role of gas bubbles in USE. Violently oscillating microbubbles are, therefore, found to be the governing cavitation regime for emulsification process. These results provide new insights to the mechanisms of gas bubbles in oil–water emulsions, which may be useful towards the optimization of USE process in industry.     

Numerical study of the effect of liquid compressibility on acoustic droplet vaporization

In acoustic droplet vaporization (ADV), a cavitated bubble grows and collapses depending on the pressure amplitude of the acoustic pulse. During the bubble collapse, the surrounding liquid is compressed to high pressure, and liquid compressibility can have a significant impact on bubble behavior and ADV threshold. In this work, a one-dimensional numerical model considering liquid compressibility is presented for ADV of a volatile microdroplet, extending our previous Rayleigh-Plesset based model [Ultrason. Chem. 71 (2021) 105361]. The numerical results for bubble motion and liquid energy change in ADV show that the liquid compressibility highly inhibits bubble growth during bubble collapse and rebound, especially under high acoustic frequency conditions. The liquid compressibility effect on the ADV threshold is quantified with varying acoustic frequencies and amplitudes.     

Spatial-temporal dynamics of cavitation bubble clouds in 1.2 MHz focused ultrasound field

Cavitation bubbles have been recognized as being essential to many applications of ultrasound. Temporal evolution and spatial distribution of cavitation bubble clouds induced by a focused ultrasound transducer of 1.2 MHz center frequency are investigated by high-speed photography. It is revealed that at a total acoustic power of 72 W the cavitation bubble cloud first emerges in the focal region where cavitation bubbles are observed to generate, grow, merge and collapse during the initial 600 μs. The bubble cloud then grows upward to the post-focal region, and finally becomes visible in the pre-focal region. The structure of the final bubble cloud is characterized by regional distribution of cavitation bubbles in the ultrasound field. The cavitation bubble cloud structure remains stable when the acoustic power is increased from 25 W to 107 W, but it changes to a more violent form when the acoustic power is further increased to 175 W.     

Numerical investigation of acoustic vaporization threshold of microdroplets

A numerical model is presented for the acoustic vaporization threshold of a dodecafluoropentane (or perfluoropentane) microdroplet. The model is based on the Rayleigh-Plesset equation and is improved by properly treating the supercritical state that occurs when a bubble collapses rapidly and by employing the van der Waals equation of state to consider the supercritical state. The present computations demonstrate that the microdroplet vaporization behavior depends intricately on bubble compressibility, liquid inertia and phase-change heat transfer under acoustic excitation conditions. We present acoustic pressure-frequency diagrams for bubble growth regimes and the ADV threshold conditions. The effects of acoustic parameters, fluid properties and the droplet radius on the ADV threshold are investigated.     

Impact of bubble coalescence in the determination of bubble sizes using a pulsed US technique: Part 2 – Effect of the nature of saturating gas

Knowledge on cavitation bubble size distribution, ambient radius of bubbles is of interest for many applications that include therapeutic and diagnostic medicine. It however becomes a hard quest when increasing the ultrasonic frequency, when direct observation of bubble dynamics is no longer possible. An indirect method based on the estimation of the bubble dissolution time under pulsed ultrasound (362 kHz) is used here under optimized conditions to derive ambient radii of cavitation bubbles in water saturated with He, Ar, Xe, O₂, N₂ and air: 3.0 µm for Ar, 1.2 µm for He, 3.1 µm for Xe, 2.8 µm for O₂, around 1 µm for N₂ and air. If the pulse on-time is increased, bubble coalescence occurs, the extent of which is rather limited for Ar but extremely high for He or N₂.     

A study on the primary and secondary nucleation of ice by power ultrasound

Several different investigations have been carried out to study the primary and secondary nucleation of ice by sonocrystallisation. Firstly, the primary nucleation of discrete ice crystals in a supercooled sucrose solution has been observed. For increasing concentrations of sucrose solutions from 0 to 45 wt%, the nucleation temperature consistently occurs at a higher nucleation temperature in the presence of ultrasound. The nucleation temperature also increases as the power output and duty cycle of a commercial ultrasonic horn are increased. Snap shot images of the bubble clouds obtained from the ultrasonic horn also show that the number of bubbles appears to increase as the ultrasonic output is increased. This suggests that the nucleation of ice is related to the power output and number of cavitation bubbles. The effect of a single bubble on the sonocrystallisation of ice is discussed. High-speed movies (1120 fps) have shown that the crystallisation appears to occur in the immediate vicinity of the single bubble. In most cases, many crystals are observed and it is not known whether a single ice crystal is being fragmented by the bubble or whether many crystals are being initiated. The bubble appears to undergo a dancing regime, frequently splitting and rejoining and also emitting some small microbubbles. A study on the secondary nucleation of ice in sucrose solutions has been carried out using a unique ultrasonic cold stage device. Images taken using a microscope system show that the pre-existing ice dendrite crystals can be broken up into smaller fragments by an ultrasonic field. Cavitation bubbles appear to be important during the fragmentation process, possibly melting any ice crystals in their path. Flow patterns around cavitation bubbles have also been observed, and these may be responsible for the fragmentation of ice crystals.     

Experimental study of bubble departure characteristics in forced convective subcooled nucleate boiling

Visualization experiments in upward forced convective nucleate boiling flows were carried out. The bubble growth and collapse have been measured using high-speed photography technique with distilled water under atmospheric pressure. The experiments show that the bubbles depart from nucleating sites shortly after nucleation and slide along the heater surface. The bubbles grow while sliding, attain a maximum size, then lift from the surface sometime during condensation, and quickly vanish in the bulk liquid. Parametric studies show that bubble diameter and departure frequency increases with an increase in heat flux, a decrease in subcooling, and a decrease in mass flux.     

State-dependent diffusion coefficients and free energies for nucleation processes from Bayesian trajectory analysis

ABSTRACT

The rate of nucleation processes such as the freezing of a supercooled liquid or the condensation of supersaturated vapour is mainly determined by the height of the nucleation barrier and the diffusion coefficient for the motion across it. Here, we use a Bayesian inference algorithm for Markovian dynamics to extract simultaneously the free energy profile and the diffusion coefficient in the nucleation barrier region from short molecular dynamics trajectories. The specific example we study is the nucleation of vapour bubbles in liquid water under strongly negative pressures, for which we use the volume of the largest bubble as a reaction coordinate. Particular attention is paid to the effects of discretisation, the implementation of appropriate boundary conditions and the optimal selection of parameters. We find that the diffusivity is a linear function of the bubble volume over wide ranges of volumes and pressures, and is mainly determined by the viscosity of the liquid, as expected from the Rayleigh–Plesset theory for macroscopic bubble dynamics. The method is generally applicable to nucleation processes and yields important quantities for the estimation of nucleation rates in classical nucleation theory.     

Peculiarities of boiling of emulsions with a low-boiling dispersed phase

The results of an investigation of heat transfer from thin wires to emulsions whose dispersed phase is low-boiling in comparison with its dispersion medium are presented. A peculiarity of heat transfer with such emulsions is observed in the bubble boiling regime when only droplets of the emulsion dispersed phase are boiling. Theoretical and experimental investigations of the activation mechanism of boiling centers have been performed. The critical volume V ₀ of the emulsion, with chain nucleation taking place when this volume is exceeded, has been determined. A model of chain activation of low-temperature boiling centers has been developed. The model has been qualitatively confirmed by the experimental data obtained.