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Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High-Speed Imaging and Cavitation Detection.

ABSTRACT: Ultrasound (US)-microbubble (MB)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. On the presumption that MBs do not persist during long US exposure under high acoustic pressures, most schemes use short US pulses when a high US pressure is employed. However, we recently observed an enhanced thrombolytic effect using long US pulses at high acoustic pressures. Therefore, we explored the fate of MBs during long tone-burst exposures (5 ms) at various acoustic pressures and MB concentrations via direct high-speed optical observation and passive cavitation detection. MBs first underwent stable or inertial cavitation depending on the acoustic pressure and then formed gas-filled clusters that continued to oscillate, break up and form new clusters. Cavitation detection confirmed continued, albeit diminishing, acoustic activity throughout the 5-ms US excitation. These data suggest that persisting cavitation activity during long tone bursts may confer additional therapeutic effects.

SUBMITTER: Chen X

PROVIDER: S-EPMC4698009 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High-Speed Imaging and Cavitation Detection.

Chen Xucai X Wang Jianjun J Pacella John J JJ Villanueva Flordeliza S FS

Ultrasound in medicine & biology 20151118 2

Ultrasound (US)-microbubble (MB)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. On the presumption that MBs do not persist during long US exposure under high acoustic pressures, most schemes use short US pulses when a high US pressure is employed. However, we recently observed an enhanced thrombolytic effect using long US pulses at high acoustic pressures. Therefore, we explored the fate of MBs during long tone-burst exposures (5 ms) at various acoustic p ...[more]

PMID: 26603628

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Project description:Acoustic behavior of lipid-coated microbubbles has been widely studied, which has led to several numerical microbubble dynamics models that incorporate lipid coating behavior, such as buckling and rupture. In this study we investigated the relationship between microbubble acoustic and lipid coating behavior on a nanosecond scale by using fluorescently labeled lipids. It is hypothesized that a local increased concentration of lipids, appearing as a focal area of increased fluorescence intensity (hot spot) in the fluorescence image, is related to buckling and folding of the lipid layer thereby highly influencing the microbubble acoustic behavior. To test this hypothesis, the lipid microbubble coating was fluorescently labeled. The vibration of the microbubble (n = 177; 2.3-10.3 ?m in diameter) upon insonification at an ultrasound frequency of 0.5 or 1 MHz at 25 or 50 kPa acoustic pressure was recorded with the UPMC Cam, an ultra-high-speed fluorescence camera, operated at ~4-5 million frames per second. During short tone-burst excitation, hot spots on the microbubble coating occurred at relative vibration amplitudes > 0.3 irrespective of frequency and acoustic pressure. Around resonance, the majority of the microbubbles formed hot spots. When the microbubble also deflated acoustically, hot spot formation was likely irreversible. Although compression-only behavior (defined as substantially more microbubble compression than expansion) and subharmonic responses were observed in those microbubbles that formed hot spots, both phenomena were also found in microbubbles that did not form hot spots during insonification. In conclusion, this study reveals hot spot formation of the lipid monolayer in the microbubble's compression phase. However, our experimental results show that there is no direct relationship between hot spot formation of the lipid coating and microbubble acoustic behaviors such as compression-only and the generation of a subharmonic response. Hence, our hypothesis that hot spots are related to acoustic buckling could not be verified.

Project description:ObjectivesUltrasound-mediated gene delivery can be amplified by acoustic disruption of microbubble carriers that undergo cavitation. We hypothesized that endothelial targeting of microbubbles bearing cDNA is feasible and, through optimizing proximity to the vessel wall, increases the efficacy of gene transfection.BackgroundContrast ultrasound-mediated gene delivery is a promising approach for site-specific gene therapy, although there are concerns with the reproducibility of this technique and the safety when using high-power ultrasound.MethodsCationic lipid-shelled decafluorobutane microbubbles bearing a targeting moiety were prepared and compared with nontargeted microbubbles. Microbubble targeting efficiency to endothelial adhesion molecules (P-selectin or intercellular adhesion molecule [ICAM]-1) was tested using in vitro flow chamber studies, intravital microscopy of tumor necrosis factor-alpha (TNF-α)-stimulated murine cremaster muscle, and targeted contrast ultrasound imaging of P-selectin in a model of murine limb ischemia. Ultrasound-mediated transfection of luciferase reporter plasmid charge coupled to microbubbles in the post-ischemic hindlimb muscle was assessed by in vivo optical imaging.ResultsCharge coupling of cDNA to the microbubble surface was not influenced by the presence of targeting ligand, and did not alter the cavitation properties of cationic microbubbles. In flow chamber studies, surface conjugation of cDNA did not affect attachment of targeted microbubbles at microvascular shear stresses (0.6 and 1.5 dyne/cm(2)). Attachment in vivo was also not affected by cDNA according to intravital microscopy observations of venular adhesion of ICAM-1-targeted microbubbles and by ultrasound molecular imaging of P-selectin-targeted microbubbles in the post-ischemic hindlimb in mice. Transfection at the site of high acoustic pressures (1.0 and 1.8 MPa) was similar for control and P-selectin-targeted microbubbles but was associated with vascular rupture and hemorrhage. At 0.6 MPa, there were no adverse bioeffects, and transfection was 5-fold greater with P-selectin-targeted microbubbles.ConclusionsWe conclude that ultrasound-mediated transfection at safe acoustic pressures can be markedly augmented by endothelial juxtaposition.

Project description:Therapeutic focused ultrasound in combination with encapsulated microbubbles is being widely investigated for its ability to elicit bioeffects in the microvasculature, such as transient permeabilization for drug delivery or at higher pressures to achieve 'antivascular' effects. While it is well established that the behaviors of microbubbles are altered when they are situated within sufficiently small vessels, there is a paucity of data examining how the bubble population dynamics and emissions change as a function of channel (vessel) diameter over a size range relevant to therapeutic ultrasound, particularly at pressures relevant to antivascular ultrasound. Here we use acoustic emissions detection and high-speed microscopy (10 kframes/s) to examine the behavior of a polydisperse clinically employed agent (Definity®) in wall-less channels as their diameters are scaled from 1200 to 15 µm. Pressures are varied from 0.1 to 3 MPa using either a 5 ms pulse or a sequence of 0.1 ms pulses spaced at 1 ms, both of which have been previously employed in an in vivo context. With increasing pressure, the 1200 µm channel - on the order of small arteries and veins - exhibited inertial cavitation, 1/2 subharmonics and 3/2 ultraharmonics, consistent with numerous previous reports. The 200 and 100 µm channels - in the size range of larger microvessels less affected by therapeutic focused ultrasound - exhibited a distinctly different behavior, having muted development of 1/2 subharmonics and 3/2 ultraharmonics and reduced persistence. These were associated with radiation forces displacing bubbles to the distal wall and inducing clusters that then rapidly dissipated along with emissions. As the diameter transitioned to 50 and then 15 µm - a size regime that is most relevant to therapeutic focused ultrasound - there was a higher threshold for the onset of inertial cavitation as well as subharmonics and ultraharmonics, which importantly had more complex orders that are not normally reported. Clusters also occurred in these channels (e.g. at 3 MPa, the mean lateral and axial sizes were 23 and 72 µm in the 15 µm channel; 50 and 90 µm in the 50 µm channel), however in this case they occupied the entire lumens and displaced the wall boundaries. Damage to the 15 µm channel was observed for both pulse types, but at a lower pressure for the long pulse. Experiments conducted with a 'nanobubble' (<0.45 µm) subpopulation of Definity followed broadly similar features to 'native' Definity, albeit at a higher pressure threshold for inertial cavitation. These results provide new insights into the behavior of microbubbles in small vessels at higher pressures and have implications for therapeutic focused ultrasound cavitation monitoring and control.

Project description:BackgroundUltrasound-mediated cavitation of microbubble contrast agents produces high intravascular shear. We hypothesized that microbubble cavitation increases myocardial microvascular perfusion through shear-dependent purinergic pathways downstream from ATP release that is immediate and sustained through cellular ATP channels such as Pannexin-1.MethodsQuantitative myocardial contrast echocardiography perfusion imaging and in vivo optical imaging of ATP was performed in wild-type and Pannexin-1-deficient (Panx1-/-) mice before and 5 and 30 minutes after 10 minutes of ultrasound-mediated (1.3 MHz, mechanical index 1.3) myocardial microbubble cavitation. Flow augmentation in a preclinical model closer to humans was evaluated in rhesus macaques undergoing myocardial contrast echocardiography perfusion imaging after high-power cavitation in the apical four-chamber plane for 10 minutes.ResultsMicrobubble cavitation in wild-type mice (n = 7) increased myocardial perfusion by 64% ± 25% at 5 minutes and 95% ± 55% at 30 minutes compared with baseline (P < .05). In Panx1-/- mice (n = 5), perfusion increased by 28% ± 26% at 5 minutes (P = .04) but returned to baseline at 30 minutes. Myocardial ATP signal in wild-type (n = 7) mice undergoing cavitation compared with sham-treated controls (n = 3) was 450-fold higher at 5 minutes and 90-fold higher at 30 minutes after cavitation (P < .001). The ATP signal in Panx1-/- mice (n = 4) was consistently 10-fold lower than that in wild-type mice and was similar to sham controls at 30 minutes. In macaques (n = 8), myocardial perfusion increased twofold in the cavitation-exposed four-chamber plane, similar in degree to that produced by adenosine, but did not increase in the control two-chamber plane.ConclusionsCavitation of microbubbles in the myocardial microcirculation produces an immediate release of ATP, likely from cell microporation, as well as sustained release, which is channel dependent and responsible for persistent flow augmentation. These findings provide mechanistic insight by which cavitation improves perfusion and reduces infarct size in patients with myocardial infarction.

Dataset Information

Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High-Speed Imaging and Cavitation Detection.

Publications

Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High-Speed Imaging and Cavitation Detection.

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