Stable and transient bubble formation in acoustically-responsive scaffolds by acoustic droplet vaporization: theory and application in sequential release

Acoustically-responsive scaffolds (ARSs), which are fibrin hydrogels containing monodispersed perfluorocarbon (PFC) emulsions, respond to ultrasound in an on-demand, spatiotemporally-controlled manner via a mechanism termed acoustic droplet vaporization (ADV). Previously, ADV has been used to control the release of bioactive payloads from ARSs to stimulate regenerative processes. In this study, we used classical nucleation theory (CNT) to predict the nucleation pressure in emulsions of different PFC cores as well as the corresponding condensation pressure of the ADV-generated bubbles. According to CNT, the threshold bubble radii above which ADV-generated bubbles remain stable against condensation were 0.4 µm and 5.2 µm for perfluoropentane (PFP) and perfluorohexane (PFH) bubbles, respectively, while ADV-generated bubbles of any size in perfluorooctane (PFO) condense back to liquid at ambient condition. Additionally, consistent with the CNT findings, stable bubble formation from PFH emulsion was experimentally observed using confocal imaging while PFO emulsion likely underwent repeated vaporization and recondensation during ultrasound pulses. In further experimental studies, we utilized this unique feature of ADV in generating stable or transient bubbles, through tailoring the PFC core and ultrasound parameters (excitation frequency and pulse duration), for sequential delivery of two payloads from PFC emulsions in ARSs. ADV-generated stable bubbles from PFH correlated with complete release of the payload while transient ADV resulted in partial release, where the amount of payload release increased with the number of ultrasound exposure. Overall, these results can be used in developing drug delivery strategies using ARSs.     

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.     

Scavenging dissolved oxygen via acoustic droplet vaporization

Acoustic droplet vaporization (ADV) of perfluorocarbon emulsions has been explored for diagnostic and therapeutic applications. Previous studies have demonstrated that vaporization of a liquid droplet results in a gas microbubble with a diameter 5–6 times larger than the initial droplet diameter. The expansion factor can increase to a factor of 10 in gassy fluids as a result of air diffusing from the surrounding fluid into the microbubble. This study investigates the potential of this process to serve as an ultrasound-mediated gas scavenging technology. Perfluoropentane droplets diluted in phosphate-buffered saline (PBS) were insonified by a 2 MHz transducer at peak rarefactional pressures lower than and greater than the ADV pressure amplitude threshold in an in vitro flow phantom. The change in dissolved oxygen (DO) of the PBS before and after ADV was measured. A numerical model of gas scavenging, based on conservation of mass and equal partial pressures of gases at equilibrium, was developed. At insonation pressures exceeding the ADV threshold, the DO of air-saturated PBS decreased with increasing insonation pressures, dropping as low as 25% of air saturation within 20 s. The decrease in DO of the PBS during ADV was dependent on the volumetric size distribution of the droplets and the fraction of droplets transitioned during ultrasound exposure. Numerically predicted changes in DO from the model agreed with the experimentally measured DO, indicating that concentration gradients can explain this phenomenon. Using computationally modified droplet size distributions that would be suitable for in vivo applications, the DO of the PBS was found to decrease with increasing concentrations. This study demonstrates that ADV can significantly decrease the DO in an aqueous fluid, which may have direct therapeutic applications and should be considered for ADV-based diagnostic or therapeutic applications.     

Characterising the chemical and physical properties of phase-change nanodroplets

Phase-change nanodroplets have attracted increasing interest in recent years as ultrasound theranostic nanoparticles. They are smaller compared to microbubbles and they may distribute better in tissues (e.g. in tumours). They are composed of a stabilising shell and a perfluorocarbon core. Nanodroplets can vaporise into echogenic microbubbles forming cavitation nuclei when exposed to ultrasound. Their perfluorocarbon core phase-change is responsible for the acoustic droplet vaporisation. However, methods to quantify the perfluorocarbon core in nanodroplets are lacking. This is an important feature that can help explain nanodroplet phase change characteristics. In this study, we fabricated nanodroplets using lipids shell and perfluorocarbons. To assess the amount of perfluorocarbon in the core we used two methods, ¹⁹F NMR and FTIR. To assess the cavitation after vaporisation we used an ultrasound transducer (1.1 MHz) and a high-speed camera. The ¹⁹F NMR based method showed that the fluorine signal correlated accurately with the perfluorocarbon concentration. Using this correlation, we were able to quantify the perfluorocarbon core of nanodroplets. This method was used to assess the content of the perfluorocarbon of the nanodroplets in solutions over time. It was found that perfluoropentane nanodroplets lost their content faster and at higher ratio compared to perfluorohexane nanodroplets. The high-speed imaging indicates that the nanodroplets generate cavitation comparable to that from commercial contrast agent microbubbles. Nanodroplet characterisation should include perfluorocarbon concentration assessment as critical information for their development.     

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.     

Nitrogen nanobubbles and butane nanodroplets at Si(1 0 0)

Nanobubbles and nanodroplets were spontaneously formed at Si(1 0 0) in contact with nitrogen and butane saturated water, respectively. The topographic images obtained by tapping mode AFM were similar truncated nanospheres, but the phase images suggested that the nanobubbles were harder than the nanodroplets. The tip–sphere interactions showed the nanodroplets were much viscoelastic than the nanobubbles. The surface and three-phase contact line energies were estimated by analysis of the topographic images. The nanodroplet was stable, but the nanobubble was unstable in spite of the experimental long life. The two-dimensional spatial distribution indicated an attractive interaction between the nanodroplets, but no interaction was observed between the nanobubbles.     

Surface active agents stabilize nanodroplets and enhance haze formation

Although many organic molecules found commonly in the atmosphere are known to be surface-active in aqueous solutions, their effects on the mechanisms underlying haze formation remain unclear. In this paper, based on a simple thermodynamic analysis, we report that the adsorption of amphiphilic organics alone not only lowers the surface tension,but also unexpectedly stabilizes nanodroplets of specific size under water vapor supersaturation. Then we determine how various factors, including relative humidity, water activity effect due to dissolution of inorganic components as well as surface tension effect due to surface adsorption of organic components, cooperatively induce the stability of nanodroplets.The nanodroplet stability behaviors not captured in the current theory would change the formation mechanism of haze droplets, from the hygroscopic growth pathway to a nonclassical two-step nucleation pathway.     

Overrun effects in nuclear fusion within a single Coulomb exploding nanodroplet

We present a theoretical-computational study of intra-nanodroplet (INTRA) collisions, and of dd and dt nuclear fusion driven by nonuniform Coulomb explosion (CE) induced by overrun effects in (D₂)_n and (DT)_n nanodroplets. We explored two systems where distinct overrun effects induce INTRA nuclear reactions: (1) double-pulse ultraintense laser irradiation of homonuclear (D₂)_n nanodroplets, which attain a transient inhomogeneous density profile that serves as a target for the realization of nonuniform CE. Overrun effects between nuclei originating from different spatial regions of the exploding nanodroplet drive INTRA dd fusion; (2) single-pulse ultraintense laser irradiation of heteonuclear (DT)_n nanodroplets, which results in kinematic overrun effects driving INTRA dt fusion. We utilized scaled electron and ion dynamics simulations to explore the inner and outer ionization electron dynamics, the time dependent deuteron and triton density profiles, the velocities of nuclei and the INTRA fusion yields in the two systems. In system (1) we identify the formation of a localized “overrun shell” at the periphery of the exploding nanodroplet, which is characterized by a narrow spatial range of the fusion generation function, by maxima in the local density and in the spatially averaged local velocity, as well as in the bifurcation of the local velocities, which manifests overrun effects. In system (2) we identify a marked local density enhancement with dt fusion occurring within most of the entire volume of the exploding nanodroplet without shell formation. The four-orders-of-magnitude increase of the dt fusion yield in the one-pulse irradiated (DT)_n nanodroplet, as compared with the two-pulse irradiated (D₂)_n nanodroplet, originates from cumulative effects of density and cross section enhancement.     

Electron spin pumping of Rb atoms on He nanodroplets via nondestructive optical excitation

We measured laser-induced-fluorescence (LIF) and beam-depletion (BD) spectra of rubidium atoms (5S-5P transition) on the surface of superfluid helium nanodroplets (M-He_{N} with M=Rb). It is known that when M is a lighter alkali atom electronic excitation always leads to detachment of the excited atom (M;{*}). The dissociation energy, few tens cm;{-1}, comes either as photon excess energy or from the barrierless formation of a M;{*}-He exciplex. We observe that this picture does not hold when M=Rb and the photon excess energy is small: we are able to excite atoms without detaching them from the droplet, thanks to a barrier preventing formation of the exciplex. This system is ideally suited for optical spin pumping in a He nanodroplet, whose achievement we explicitly demonstrate in a pump-probe magnetic circular dichroism experiment.     

Nucleation and metastability in three-dimensional Ising models

We present Monte Carlo experiments on nucleation theory in the nearest-neighbor three-dimensional Ising model and in Ising models with long-range interactions. For the nearest-neighbor model, our results are compatible with the classical nucleation theory (CNT) for low temperatures, while for the long-range model a breakdown of the CNT was observed near the mean-field spinodal. A new droplet model and a zeroth-order theory of droplet growth are also presented.Supported in part by grants from ARO, ONR, and NSF.     

dt nuclear fusion within a single Coulomb exploding composite nanodroplet

We present a computational study of dt fusion driven by Coulomb explosion within a single, large, heteronuclear two-component D₂/T₂nanodroplet, originating from kinematic overrun effects between deuterons and tritons. Scaled electron and ion dynamics simulations have been used to explore the size dependence and the isotopic composition dependence of the intra-nanodroplet (INTRA) dt fusion yield in a composite D_2n-2kT_2k nanodroplet, initially consisting of an inner sphere of D₂ molecules surrounded by an outer sphere of T₂ molecules (n = 1.4×10⁸–2.0×10⁹, k/n = 0.10–0.60, and initial radii R₀= 1100–2700 Å) driven by a single, ultraintense, near-infrared, Gaussian laser pulse (peak intensity 10²⁰ W?cm^-2, pulse length 25 fs). INTRA dt fusion in D_2n-2kT_2k nanodroplets with neutron yields of 30–90 (per nanodroplet, per laser pulse) were attained in the size domain R₀ = 2000–2700 Å with the optimal composition in the range of k/n = 0.2–0.4. INTRA yields in D_2n-2kT_2k nanodroplets are similar (within 20–40%) to those in initially homogeneous (DT)_n nanodroplets of the same size. These INTRA yields are sufficiently large to warrant experimental observation in a single nanodroplet. The INTRA dt fusion can be distinguished from the inter-nanodroplet dt fusion reaction, which occurs inside and outside the macroscopic plasma filament, by the nanodroplet size dependence of the yield and by the different energies of the neutrons produced in these two channels.     

Growth of crystalline/amorphous biphase Sm-Fe-Ta-N magnetic nanodroplets

Thin films of biphase (amorphous/crystalline) magnetic Sm-Fe-Ta-N nanodroplets were fabricated at room temperature with 157 nm pulse laser deposition in nitrogen from a Sm_13.8Fe_82.2Ta_4.0 target. The 50-100 nm biphase spherical nanodroplets consist of a 5-10 nm internal crystal portion surrounded by the external amorphous phase. Nitrogen fixation in the nanodroplets occurred in the plume. The films exhibit a ferromagnetic response of 2.5 kOe coercivity at room temperature. With further annealing and thermal treatment in nitrogen, the coercivity was increased to 5.0 kOe. The surrounding amorphous layer prevents post-ablation oxidization of the crystalline magnetic nucleus of the nanodroplet.     

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 and temporal observation of phase-shift nano-emulsions assisted cavitation and ablation during focused ultrasound exposure

Background: Phase-shift nano-emulsions (PSNEs) with a small initial diameter in nanoscale have the potential to leak out of the blood vessels and to accumulate at the target point of tissue. At desired location, PSNEs can undergo acoustic droplet vaporization (ADV) process, change into gas bubbles and enhance focused ultrasound efficiency. The threshold of droplet vaporization and influence of acoustic parameters have always been research hotspots in order to spatially control the potential of bioeffects and optimize experimental conditions. However, when the pressure is much higher than PSNEs’ vaporization threshold, there were little reports on their cavitation and thermal effects.Object: In this study, PSNEs induced cavitation and ablation effects during pulsed high-intensity focused ultrasound (HIFU) exposure were investigated, including the spatial and temporal information and the influence of acoustic parameters.Methods: Two kinds of tissue-mimicking phantoms with uniform PSNEs were prepared because of their optical transparency. The Sonoluminescence (SL) method was employed to visualize the cavitation activities. And the ablation process was observed as the heat deposition could produce white lesion.Results: Precisely controlled HIFU cavitation and ablation can be realized at a relatively low input power. But when the input power was high, PSNEs can accelerate cavitation and ablation in pre-focal region. The cavitation happened layer by layer advancing the transducer. While the lesion appeared to be separated into two parts, one in pre-focal region stemmed from one point and grew quickly, the other in focal region grew much more slowly. The influence of duty cycle has also been examined. Longer pulse off time would cause heat transfer to the surrounding media, and generate smaller lesion. On the other hand, this would give outer layer bubbles enough time to dissolve, and inner bubbles can undergo violent collapse and emit bright light.     

Nucleation barriers for the liquid-to-crystal transition in simple metals: Experiment vs. simulation

Crystal nucleation in the one-component metals Ni and Au is investigated using a combination of differential thermal analysis (DTA) experiments and Monte Carlo (MC) simulations. A novel experimental methodology allows to measure nucleation rates J over a range of 8 orders of magnitude. Evidence is given that these rates correspond to homogeneous nucleation. From the nucleation rates, free energy nucleation barriers ΔG ^? are extracted using an ansatz obtained in the framework of classical nucleation theory (CNT). The latter ansatz is rationalized by MC simulations that directly yield estimates for the temperature dependence of ΔG ^?. The values of ΔG ^?, as determined from the simulation, are in very good agreement with those extracted from the experiments. The simulations indicate that in the range where experiments are available the corrections to CNT are relatively small, thus justifying the application of CNT. We also discuss how the conditions for heterogeneous nucleation on a flat or structured wall can be obtained from computer simulations.     

表面能梯度驱动下纳米水滴在不同微结构表面上的运动

近年来, 微观尺度下水滴在能量梯度表面上的运动情况受到了广泛关注, 然而通过实验进行研究尚存在困难. 本文利用分子动力学方法研究了不同微结构表面上纳米水滴在表面能梯度驱动下的运动情况. 结果表明: 槽状和柱状微结构可以明显提升纳米水滴在微结构表面上的运动效率, 钉状微结构会降低纳米水滴的运动效率, 尽管它具有稳定的疏水性; 结合槽状和钉状结构的混合状微结构兼具二者的优点, 不但可以有效地提高纳米水滴在粗糙表面上的运动效率, 而且具有比较高的疏水稳定性. 此外, 表面能的微小改变会明显影响水滴的运动效率.     

Area effect of patterned carbon nanotube bundle on field electron emission characteristics

Patterned carbon nanotube (CNT) bundles were fabricated using thermal chemical vapor deposition (CVD) method. Patterns of different diameters and distances were defined on Si(100) substrates using photolithography. CNT bundle height was controlled using different acetylene (C₂H₂) flow times. The inter-bundle distance of CNTs to CNT bundle height ratio was maintained at approximately 2, a number predicted to have a maximum field emission for CNT, and left the patterned CNT bundle area as a variable parameter. The relationship between CNT bundle area and the field electron emission characteristics was studied. The lowest threshold electric field (E_th) of 0.7 V/μm was obtained when the total area of patterned CNT bundles was approximately 46%. The result shows that there is an optimal CNT bundle area for electron field emission.     

Thermodynamic surface characteristics of liquid-metal nanodroplets at the vapor boundary

New relationships for the size-dependent surface tension σ(r), surface energy ū(r), the temperature T(r) of equilibrium between a liquid droplet and the surrounding vapor, and derivatives dσ/dT and dT/dr, which define spherical nanodroplets of liquid metals at the vapor boundary, are derived under the assumption that the two-phase (liquid nanodroplet-vapor) and three-phase (liquid nanodroplet-vapor-solid phase) equilibrium conditions are fulfilled. Consistent calculations of the aforementioned quantities are performed. The revealed dependences between the surface characteristics of nanodroplets of several metals and the calculation results are discussed.     

Molecular dynamics study of nanodroplet diffusion on smooth solid surfaces

We perform molecular dynamics simulations of Lennard–Jones particles in a canonical ensemble to study the diffusion of nanodroplets on smooth solid surfaces. Using the droplet-surface interaction to realize a hydrophilic or hydrophobic surface and calculating the mean square displacement of the center-of-mass of the nanodroplets, the random motion of nanodroplets could be characterized by shorttime subdiffusion, intermediate-time superdiffusion, and long-time normal diffusion. The short-time subdiffusive exponent increases and almost reaches unity (normal diffusion) with decreasing droplet size or enhancing hydrophobicity. The diffusion coefficient of the droplet on hydrophobic surfaces is larger than that on hydrophilic surfaces.     

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.