Ultrasound contrast agents are valuable in diagnostic ultrasound imaging, and they increasingly show potential for drug delivery. This review focuses on the acoustic behavior of flexible-coated ...microbubbles and rigid-coated microcapsules and their contribution to enhanced drug delivery. Phenomena relevant to drug delivery, such as non-spherical oscillations, shear stress, microstreaming, and jetting will be reviewed from both a theoretical and experimental perspective. Further, the two systems for drug delivery, co-administration and the microbubble as drug carrier system, are reviewed in relation to the microbubble behavior. Finally, future prospects are discussed that need to be addressed for ultrasound contrast agents to move from a pre-clinical tool into a clinical setting.
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An ultrasound contrast agent (UCA) suspension contains encapsulated microbubbles with a wide size distribution, with radii ranging from 1 to 10 μm. Medical transducers typically operate at a single ...frequency, therefore only a small selection of bubbles will resonate to the driving ultrasound pulse. Thus, the sensitivity can be improved by narrowing down the size distribution. Here, we present a simple lab-on-a-chip method to sort the population of microbubbles on-chip using a traveling ultrasound wave. First, we explore the physical parameter space of acoustic bubble sorting using well-defined bubble sizes formed in a flow-focusing device, then we demonstrate successful acoustic sorting of a commercial UCA. This novel sorting strategy may lead to an overall improvement of the sensitivity of contrast ultrasound by more than 10 dB.
Resonant microbubbles are sorted from a polydisperse ultrasound contrast agent suspension in an acoustic bubble sorting chip.
In the last couple of decades, ultrasound-driven microbubbles have proven excellent candidates for local drug delivery applications. Besides being useful drug carriers, microbubbles have demonstrated ...the ability to enhance cell and tissue permeability and, as a consequence, drug uptake herein. Notwithstanding the large amount of evidence for their therapeutic efficacy, open issues remain. Because of the vast number of ultrasound- and microbubble-related parameters that can be altered and the variability in different models, the translation from basic research to (pre)clinical studies has been hindered. This review aims at connecting the knowledge gained from fundamental microbubble studies to the therapeutic efficacy seen in in vitro and in vivo studies, with an emphasis on a better understanding of the response of a microbubble upon exposure to ultrasound and its interaction with cells and tissues. More specifically, we address the acoustic settings and microbubble-related parameters (i.e., bubble size and physicochemistry of the bubble shell) that play a key role in microbubble–cell interactions and in the associated therapeutic outcome. Additionally, new techniques that may provide additional control over the treatment, such as monodisperse microbubble formulations, tunable ultrasound scanners, and cavitation detection techniques, are discussed. An in-depth understanding of the aspects presented in this work could eventually lead the way to more efficient and tailored microbubble-assisted ultrasound therapy in the future.
Evaporating droplets on oil-wetted surfaces Li, Yaxing; Diddens, Christian; Segers, Tim ...
Proceedings of the National Academy of Sciences - PNAS,
07/2020, Letnik:
117, Številka:
29
Journal Article
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The evaporation of suspension droplets is the underlying mechanism in many surface-coating and surface-patterning applications. However, the uniformity of the final deposit suffers from the ...coffee-stain effect caused by contact line pinning. Here, we show that control over particle deposition can be achieved through droplet evaporation on oil-wetted hydrophilic surfaces. We demonstrate by flow visualization, theory, and numerics that the final deposit of the particles is governed by the coupling of the flow field in the evaporating droplet, the movement of its contact line, and the wetting state of the thin film surrounding the droplet. We show that the dynamics of the contact line can be tuned through the addition of a surfactant, thereby controlling the surface energies, which then leads to control over the final particle deposit. We also obtain an analytical expression for the radial velocity profile which reflects the hindering of the evaporation at the rim of the droplet by the nonvolatile oil meniscus, preventing flow toward the contact line, thus suppressing the coffee-stain effect. Finally, we confirm our physical interpretation by numerical simulations that are in qualitative agreement with the experiment.
The Greek aperitif Ouzo is not only famous for its specific anise-flavoured taste, but also for its ability to turn from a transparent miscible liquid to a milky-white coloured emulsion when water is ...added. Recently, it has been shown that this so-called Ouzo effect, i.e. the spontaneous emulsification of oil microdroplets, can also be triggered by the preferential evaporation of ethanol in an evaporating sessile Ouzo drop, leading to an amazingly rich drying process with multiple phase transitions (Tan et al., Proc. Natl Acad. Sci. USA, vol. 113 (31), 2016, pp. 8642–8647). Due to the enhanced evaporation near the contact line, the nucleation of oil droplets starts at the rim which results in an oil ring encircling the drop. Furthermore, the oil droplets are advected through the Ouzo drop by a fast solutal Marangoni flow. In this article, we investigate the evaporation of mixture droplets in more detail, by successively increasing the mixture complexity from pure water over a binary water–ethanol mixture to the ternary Ouzo mixture (water, ethanol and anise oil). In particular, axisymmetric and full three-dimensional finite element method simulations have been performed on these droplets to discuss thermal effects and the complicated flow in the droplet driven by an interplay of preferential evaporation, evaporative cooling and solutal and thermal Marangoni flow. By using image analysis techniques and micro-particle-image-velocimetry measurements, we are able to compare the numerically predicted volume evolutions and velocity fields with experimental data. The Ouzo droplet is furthermore investigated by confocal microscopy. It is shown that the oil ring predominantly emerges due to coalescence.
Acoustically sensitive emulsion droplets composed of a liquid perfluorocarbon have the potential to be a highly efficient system for local drug delivery, embolotherapy, or for tumor imaging. The ...physical mechanisms underlying the acoustic activation of these phase-change emulsions into a bubbly dispersion, termed acoustic droplet vaporization, have not been well understood. The droplets have a very high activation threshold; its frequency dependence does not comply with homogeneous nucleation theory and localized nucleation spots have been observed. Here we show that acoustic droplet vaporization is initiated by a combination of two phenomena: highly nonlinear distortion of the acoustic wave before it hits the droplet and focusing of the distorted wave by the droplet itself. At high excitation pressures, nonlinear distortion causes significant superharmonics with wavelengths of the order of the droplet size. These superharmonics strongly contribute to the focusing effect; therefore, the proposed mechanism also explains the observed pressure thresholding effect. Our interpretation is validated with experimental data captured with an ultrahigh-speed camera on the positions of the nucleation spots, where we find excellent agreement with the theoretical prediction. Moreover, the presented mechanism explains the hitherto counterintuitive dependence of the nucleation threshold on the ultrasound frequency. The physical insight allows for the optimization of acoustic droplet vaporization for therapeutic applications, in particular with respect to the acoustic pressures required for activation, thereby minimizing the negative bioeffects associated with the use of high-intensity ultrasound.
Abstract In the last years, research on ultrasound mediated drug delivery using microbubbles is vastly expanding. While some groups simply mix drugs and microbubbles (co-administration), other ...researchers have a major interest in the potential of drug-loaded microbubbles. However, today, little is known on the pros and cons of these two strategies. In this study we evaluated the delivery of nanoparticles (polystyrene nanospheres and mRNA-lipoplexes) to cells in vitro , in case the nanoparticles were mixed with unloaded microbubbles versus loaded onto the microbubbles. Flow cytometry experiments demonstrated that unloaded microbubbles did not enhance the cellular delivery of the nanospheres and mRNA-lipoplexes. However, upon loading the nanoparticles onto the microbubbles, their delivery to cells substantially improved. Real-time swept field confocal microscopy imaging of the microbubbles and cells during ultrasound radiation revealed that nanoparticle-loaded microbubbles directly deposited the nanoparticles in patches onto the cell membrane, a process that we termed ‘sonoprinting’. This phenomenon resulted in the delivery of large amounts of nanoparticles to the cells and is suggested to be different from the creation of cell membrane pores and enhanced endocytosis, which have been reported before as mechanisms behind the improved delivery of drugs to cells by ultrasound.
Buckling of lipidic ultrasound contrast agents under quasi-static load Chabouh, Georges; van Elburg, Benjamin; Versluis, Michel ...
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
04/2023, Letnik:
381, Številka:
2244
Journal Article
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Collapse of lipidic ultrasound contrast agents under high-frequency compressive load has been historically interpreted by the vanishing of surface tension. By contrast, buckling of elastic shells is ...known to occur when costly compressible stress is released through bending. Through quasi-static compression experiments on lipidic shells, we analyse the buckling events in the framework of classical elastic buckling theory and deduce the mechanical characteristics of these shells. They are then compared with that obtained through acoustic characterization. This article is part of the theme issue 'Probing and dynamics of shock sensitive shells'.
In this paper we study both experimentally and theoretically the dynamics of an ultrasound-driven vapor bubble of perfluoropentane (PFP) inside a droplet of the same liquid, immersed in a water ...medium superheated with respect to the PFP boiling point. We determine the temporal evolution of the bubble radius with ultra-high speed imaging at 20 million frames per second. In addition, we model the vapor-gas bubble dynamics, based on a Rayleigh-Plesset-type equation, including thermal and gas diffusion inside the liquid. We compare the numerical results with the experimental data and find good agreement. We underline the fundamental role of gas diffusion in order to prevent total recondensation of the bubble at collapse.
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