Bubble nucleation and dynamics in acoustic droplet vaporization: a review of concepts, applications, and new directions.

The development of phase-shift droplets has broadened the scope of ultrasound-based biomedical applications. When subjected to sufficient acoustic pressures, the perfluorocarbon phase in phase-shift droplets undergoes a phase-transition to a gaseous state. This phenomenon, termed acoustic droplet vaporization (ADV), has been the subject of substantial research over the last two decades with great progress made in design of phase-shift droplets, fundamental physics of bubble nucleation and dynamics, and applications. Here, we review experimental approaches, carried out via high-speed microscopy, as well as theoretical models that have been proposed to study the fundamental physics of ADV including vapor nucleation and ADV-induced bubble dynamics. In addition, we highlight new developments of ADV in tissue regeneration, which is a relatively recently exploited application. We conclude this review with future opportunities of ADV for advanced applications such as in situ microrheology and pressure estimation.

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.

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.

The 5:1 rule overestimates the needed tunnel length during ureteral reimplantation.

AIMS: Paquin asserts that in order for ureterovesical junctions (UVJs) to prevent reflux, the ureteral tunnel length-to-diameter ratio needs to be 5:1. We hypothesize that the surgical implementation of this observation results in an overestimation of the needed length-to-diameter ratio to prevent vesicoureteral reflux. METHODS: With finite elements, we model the urine storage phase of the bladder under nonlinear conditions. In the reference state, the bladder is assumed to be a sphere with an oblique straight elliptical hole as the UVJ. Broad parametric studies on different length-to-diameter ratios are performed as the bladder volume increases from 10% to 110% capacity. RESULTS: The capability of the UVJ to prevent reflux during storage depends on its length-to-diameter ratio. UVJs with larger length-to-diameter ratios lengthen and narrow as the bladder volume increases, causing the closure of the UVJ and rise in its flow resistance. Our model shows that the UVJ length-to-diameter ratio decreases as the bladder volume increases. The 5:1 ratio implemented at 80% capacity-approximate volume or bladder wall stretch during ureteroneocystostomy (UNC)-corresponds to 7:1 at the reference state-used by Paquin. The 5:1 ratio implemented at the reference state corresponds to 3:1 at 80% capacity. CONCLUSIONS: Our modeling results are consistent with Paquin's original observation on the significance of the UVJ length-to-diameter ratio in preventing reflux. They, however, indicate that the surgical implementation of this rule during UNC results in an overestimation of the requisite tunnel length-to-diameter ratio to prevent reflux. They also suggest that the UVJ closure is due to the bladder wall deformation rather than the pressure.

Partial Volume Effect and Correction for 3-D Color Flow Acquisition of Volumetric Blood Flow.

Blood volume flow (VF) estimation is becoming an integral part of quantitative medical imaging. Three-dimensional color flow can be used to measure volumetric flow, but partial volume correction (PVC) is essential due to finite beamwidths and lumen diameters. Color flow power was previously assumed to be directly proportional to the perfused fractional color flow beam area (voxel). We investigate the relationship between color flow power and fractionally perfused voxels. We simulate 3-D color flow imaging using Field II based on a 3.75-MHz mechanically swept linear array. A 16-mm-diameter tube with laminar flow was embedded into soft tissue. We investigated two study scenarios where soft tissue backscatter is 1) 40 dB higher and 2) 40 dB lower, relative to blood. Velocity and power were computed from color flow packets ( n = 16 ) using autocorrelation. Study 1 employed a convolution-based wall filter. Study 2 did not employ a wall filter. VF was computed from the resulting color flow data, as published previously. Partial volume voxels in Study 1 show lesser power than those in Study 2, likely due to wall filter effects. An "S"-shaped relationship was found between color flow power and fractionally perfused voxel area in Study 2, which could be due to an asymmetric lateral-elevational point spread function. Flow computation is biased low by 7.3% and 7.9% in Study 1 and Study 2, respectively. Uncorrected simulation estimates are biased high by 41.5% and 12.5% in Study 1 and Study 2, respectively. Our findings show that PVC improves 3-D VF estimation and that wall filter processing alters the proportionality between color flow power and fractionally perfused voxel area.

Numerical Study of Bubble Area Evolution During Acoustic Droplet Vaporization-Enhanced HIFU Treatment.

Acoustic droplet vaporization has the potential to shorten treatment time of high-intensity focused ultrasound (HIFU) while minimizing the possible effects of microbubbles along the propagation path. Distribution of the bubbles formed from the droplets during the treatment is the major factor shaping the therapeutic region. A numerical model was proposed to simulate the bubble area evolution during this treatment. Using a linear acoustic equation to describe the ultrasound field, a threshold range was defined that determines the amount of bubbles vaporized in the treated area. Acoustic parameters, such as sound speed, acoustic attenuation coefficient, and density, were treated as a function of the bubble size distribution and the gas void fraction, which were related to the vaporized bubbles in the medium. An effective pressure factor was proposed to account for the influence of the existing bubbles on the vaporization of the nearby droplets. The factor was obtained by fitting one experimental result and was then used to calculate bubble clouds in other experimental cases. Comparing the simulation results to these other experiments validated the model. The dynamic change of the pressure and the bubble distribution after exposure to over 20 pulses of HIFU are obtained. It is found that the bubble area grows from a grainlike shape to a "tadpole," with comparable dimensions and shape to those observed in experiments. The process was highly dynamic with the shape of the bubble area changing with successive HIFU pulses and the focal pressure. The model was further used to predict the shape of the bubble region triggered by HIFU when a bubble wall pre-exists. The results showed that the bubble wall helps prevent droplet vaporization on the distal side of the wall and forms a particularly shaped region with bubbles. This simulation model has predictive potential that could be beneficial in applications, such as cancer treatment, by parametrically studying conditions associated with these treatments and designing treatment protocols.

Initial nucleation site formation due to acoustic droplet vaporization.

Acoustic droplet vaporization (ADV) is the selective vaporization of liquid microdroplets using ultrasound, resulting in gas bubbles. The ADV process has been proposed as a tool in biomedical applications such as gas embolotherapy, drug delivery, and phase-change contrast agents. Using a 7.5 MHz focused transducer, the initial gas nucleus formed in perfluorocarbon microdroplets was directly visualized using ultra-high speed imaging. The experimental results of initial nucleation site location were compared to a 2D axisymmetric linear acoustic model investigating the focal spot of the acoustic wave within the microdroplets. Results suggest a wavelength to droplet diameter dependence on nucleation site formation.

Formation of toroidal bubbles from acoustic droplet vaporization.

Acoustic droplet vaporization (ADV) is the selective vaporization of liquid microdroplets using ultrasound to produce stable gas bubbles. ADV is the primary mechanism in an ultrasound based cancer therapy, called gas embolotherapy, where the resulting bubbles are used to create localized occlusions leading to tumor necrosis. In this investigation, early time scale events including phase change are directly visualized using ultra-high speed imaging. Modulating elevated acoustic pressure or pulse length resulted in toroidal bubbles. For sufficiently short pulses (4 cycles at 7.5 MHz), toroidal bubble formation could be avoided, regardless of acoustic pressures tested.

Photoacoustic tomography of joints aided by an Etanercept-conjugated gold nanoparticle contrast agent-an ex vivo preliminary rat study.

Monitoring of anti-rheumatic drug delivery in experimental models and in human diseases would undoubtedly be very helpful for both basic research and clinical management of inflammatory diseases. In this study, we have investigated the potential of an emerging hybrid imaging technology-photoacoustic tomography-in noninvasive monitoring of anti-TNF drug delivery. After the contrast agent composed of gold nanorods conjugated with Etanercept molecules was produced, ELISA experiments were performed to prove the conjugation and to show that the conjugated anti-TNF-α drug was biologically active. PAT of ex vivo rat tail joints with the joint connective tissue enhanced by intra-articularly injected contrast agent was conducted to examine the performance of PAT in visualizing the distribution of the gold-nanorod-conjugated drug in articular tissues. By using the described system, gold nanorods with a concentration down to 1 pM in phantoms or 10 pM in biological tissues can be imaged with good signal-to-noise ratio and high spatial resolution. This study demonstrates the feasibility of conjugating TNF antagonist pharmaceutical preparations with gold nanorods, preservation of the mechanism of action of TNF antagonist along with preliminary evaluation of novel PAT technology in imaging optical contrast agents conjugated with anti-rheumatic drugs. Further in vivo studies on animals are warranted to test the specific binding between such conjugates and targeted antigen in joint tissues affected by inflammation.