Properties Of Microbubbles Research Articles

What Is the Magical Cavitation Bubble: A Holistic Perspective to Trigger Advanced Bubbles, Nano-Sonocatalysts, and Cellular Sonosensitizers

Sonodynamic therapy (SDT) has emerged as a novel and highly researched advancement in the medical field. Traditional ultrasound contrast agents and novel bubble-shaped agents are used to stimulate cavitation and enhance SDT efficiency. However, the impact of artificially modified shell structures on the acoustic properties of microbubbles remains to be explored. Alternatively, in the absence of bubble-shaped agents, some clinically available organic sonosensitizers and advanced inorganic materials are also used to enhance the efficacy of SDT. Diagnostic and therapeutic ultrasound can also activate cavitation bubbles, which supply energy to sonosensitive agents, leading to the production of cytotoxic free radicals to achieve therapeutic effects. While inorganic materials often spark controversy in clinical applications, their relatively simple structure enables researchers to gain insight into the mechanism by which SDT produces various free radicals. Some organic–inorganic hybrid sonosensitive systems have also been reported, combining the benefits of inorganic and organic sonosensitive agents. Alternatively, by employing cell surface modification engineering to enable cells to perform functions such as immune escape, drug loading, gas loading, and sonosensitivity, cellular sonosensitizers have also been developed. However, further exploration is needed on the acoustic properties, ability to generate reactive oxygen species (ROS), and potential clinical application of this cellular sonosensitizer. This review offers a comprehensive analysis of vesical microbubbles and nanoscale sonocatalysts, including organic, inorganic, combined organic–inorganic sonosensitizers, and cellular sonosensitizers. This analysis will enhance our understanding of SDT and demonstrate its important potential in transforming medical applications.

Hybrid (Bovine Serum Albumin)/Poly(N-vinyl-2-pyrrolidone-co-acrylic acid)-Shelled Microbubbles as Advanced Ultrasound Contrast Agents.

Microbubbles are routinely used ultrasound contrast agents in the clinic. While a soft protein shell is commercially preferable for imaging purposes, a rigid polymer shell demonstrates prolonged agent stability. Hence, combining polymers and proteins in one shell composition can advance microbubble properties. We formulated the hybrid "protein-copolymer" microbubble shell with a complex of bovine serum albumin and an amphiphilic copolymer of N-vinyl-2-pyrrolidone and acrylic acid. The resulting microbubbles demonstrated advanced physicochemical and acoustic properties, preserving in vitro biocompatibility. Adjusting the mass ratio between protein and copolymer allowed fine tuning of the microbubble properties of concentration (by two orders, up to 1010 MBs/mL), mean size (from 0.8 to 5 μm), and shell thickness (from 28 to 50 nm). In addition, the minimum air-liquid surface tension for the "protein-copolymer" solution enabled the highest bubble concentration. At the same time, a higher copolymer amount in the bubble shell increased the bubble size and tuned duration and intensity of the contrast during an ultrasound procedure. Demonstrated results exemplify the potential of the hybrid "protein-polymer" microbubble shell, allowing tailoring of microbubble properties for image-guided applications, combining advances of each material involved in the formulation.

An analytical model to calculate the primary and secondary acoustic forces acting on microbubbles due to a short pulsed laser excitation

This work presents a comprehensive analytical approach to describe photoacoustic waves resulting from a pulsed laser excitation. The spatial part of the laser is modeled by a zeroth-order Bessel function of the first kind, which has a wide range of applications in optics and medical physics, such as optical trapping and nonlinear effects resulting from the interaction of a pulsed laser with tissue in photoacoustic imaging. The temporal part of the laser is described by a Gaussian function, which is a pretty realistic approximation since the interaction of the laser with the medium is instantaneous. The photoacoustic wave equation is solved analytically using the Fourier transform and the Greens’ function methods. The solution of the photoacoustic wave equation depends explicitly on position, time, pulse duration, and beam-width of the pulsed laser. The effects of these dependencies on the photoacoustic wave are investigated. Later, the primary and secondary radiation forces acting on microbubbles Albunex and Quantison are calculated using the magnitude of the photoacoustic pressure wave. The primary and secondary radiation forces decrease considerably with the distance from the photoacoustic absorber. These forces increase as the beam-width increases while they decrease as the pulse duration gets longer. The primary radiation forces on the microbubbles are on the order of nanonewtons. The force at this scale can be used to manipulate microbubbles. The secondary radiation force between identical microbubbles is in the range of piconewtons. Hence, this force can be used to determine the viscoelastic properties of microbubbles even though it is very small compared to the primary radiation force. The radiation forces determined by this work are also compared with those calculated by another study describing the laser’s spatial profile with a Gaussian function. The forces obtained by this work are larger than the forces determined by the Gaussian function approximation at the positions near the source. The forces obtained by the two approaches show similar behaviors, and they decrease remarkably with the distance from the source. Thus, the model presented in this work can be used to study the nonlinear mechanism in photoacoustics, such as enhancing image contrast and determining the tissue temperature. It can also be helpful for the applications of microbubbles in medical imaging and drug delivery as carriers.

Impact of fluorescent dyes on the physicochemical parameters of microbubbles stabilized by albumin-dye complex

Gas-filled microbubbles are routinely used as ultrasound contrast agents in the clinic. Recently, microbubbles attracted attention as agents for multimodal imaging and image-guided drug delivery. Hence, we prepared microbubbles based on albumin-dye complexes to achieve optimal bimodal (fluorescent/ultrasound) imaging properties. The fluorescent dyes used for in vitro/in vivo/medical imaging (Fluorescein, and Rhodamine B, Cyanine 5.5, and Cyanine 7, Indocyanine Green) were introduced into the albumin-dye complex structure. Interconnections between dyes parameters (chemical structure, molecular weight, and hydrophobicity), properties of albumin-dye complexes (type of bond and ratio between protein and dye, solution surface tension), and bimodal agent properties (concentration, mean size, storage stability) were evaluated. Bimodal imaging of "colored" microbubbles was assessed using ultrasound with 33, 50 MHz frequencies and fluorescence tomography. We observed that the ratio between the protein molecules and the protein-dye complex in the microbubble shell was approximately equal, highlighting the impact of dye chemical structure on albumin-dye complex properties and resulting microbubble properties in characterization and imaging. These findings shed light on correlations between microbubble interface stabilization with albumin, microbubble structure formed by albumin-dye complexes, physicochemical properties and applications of bimodal (fluorescent/ultrasound) contrast agents.

Characterization of microbubble-enhanced molecular delivery to cells in acoustofluidic channels

Cell therapies are rapidly emerging as a promising approach for treatment of many diseases, such as cancer and cardiovascular diseases. Non-viral methods for molecular delivery are currently in development to increase safety and reduce varability during manufacturing of cell therapies. Ultrasound-mediated microbubble cavitation has been utilized as an effective approach for non-viral molecular delivery via sonoporation or other mechanisms. However, prior ultrasound studies have primarily utilized static sample chambers, which have limited throughput and are generally not practical for cell therapy manufacturing processes. To address these limitations, we are developing novel acoustofluidic platforms to enable intracellular delivery of biomolecules as cells continuously pass through an ultrasound field in a flow chamber. We have investigated a range of fundamental parameters that influence acoustofluidic-mediated molecular delivery to human cells, including microbubble properties, channel geometry, and ultrasound parameters. In addition, we investigated biological factors that influence acoustofluidic-mediated molecular delivery to cells, including cellular properties and extracellular metabolite levels. The results of these studies will be presented to provide new insights into the key parameters and mechanisms that affect the efficiency of molecular delivery to human cells in acoustofluidic channels. Further development of acoustofluidic platforms may enable improved processes for manufacturing of cell therapies.

Engineering Responsive Ultrasound Contrast Agents Through Crosslinked Networks on Lipid-Shelled Microbubbles.

Ultrasound imaging with contrast agents, especially with lipid-shelled microbubbles, has become a vital tool in clinical diagnostics. Efforts to adapt these agents for molecular imaging have typically focused on targeted binding. More recently, crosslinking the lipid shell to alter its mechanical properties, followed by decrosslinking upon exposure to a stimulus, has been shown as a promising approach for imaging soluble molecular targets. Nevertheless, a systematic study of the influence of crosslinker concentration and structure on the mechanical properties of microbubbles has not been undertaken. An improved understanding of the role of these parameters is necessary to more effectively design contrast agents that detect proteases, an informative class of soluble disease markers. Here, the influence of crosslinker parameters on the acoustic properties of microbubbles, developing a model of crosslinker network formation on microbubble shells that explains the experimental observations, are studied. By incorporating cleavable elements that respond to UV light or proteolysis, kinetically resolved acoustic detection of these stimuli and the relevance of crosslinker design are demonstrated. The framework established in this study can be readily adapted to other protease-cleavable units and provides a basis for the future development of responsive ultrasound contrast agents for molecular imaging of proteolytic activity.

Contrast-Enhanced Ultrasonography: Review and Applications.

Contrast-enhanced ultrasound (CEUS) has revolutionized ultrasound imaging adding enhanced diagnostic imaging and therapeutic applications to its repertoire. CEUS involves the use of microbubbles which are lauded for their benefit of enhanced imaging without the limitations of radiation exposure or risk of nephrotoxicity seen with other contrast agents. In addition, many innovative uses of microbubbles in diagnosis and treatment stages have been discovered. This article summarizes the composition and resonance properties of microbubbles as the contrast agents for ultrasound, as well as their advanced uses in medicine. The basic role of CEUS is in enhancing the imaging of vessels on a macro and micro level to better classify pathological lesions like atherosclerosis. CEUS is also used in identifying tumor lesions by observing for angiogenesis and monitoring tumors post treatment for remission and relapses. Recent research on using microbubbles for focused drug delivery is very promising. Microbubbles can be used for thrombolysis and targeted delivery of chemotherapeutics in an efficient targeted manner while limiting systemic side effects. CEUS can also be used with therapeutic and diagnostic agents to penetrate into the brain allowing better assessment and management of neurodegenerative disorders. In conclusion, the use of microbubbles opens new frontiers in diagnosis and treatment and will likely be a key technique in medicine in the near future.

Enhancement of CO2 dissolution and sweep efficiency in saline aquifer by micro bubble CO2 injection

Due to the favorable physical properties of micro bubbles (MBs), MB CO2 injection into saline aquifers was proposed as a novel, economic, and leak-free underground injection method in the purpose of sequestration. In this study, supercritical CO2 injection into a Berea sandstone sample at 0.05 mL/min under reservoir conditions was investigated using X-ray CT. Experiments with micro bubble (MB) and normal bubble (NB) CO2 injection were conducted. The dependence of CO2 migration on pore space shows macroscopic bypassing via preferential flow paths, as the distribution and saturation of CO2 were largely influenced by the heterogeneous pore structure. Most CO2 migrated forwards via three flow paths that formed along the bedding layers with high porosity. The CO2 distribution was discontinuous, and isolated CO2 clusters appeared due to the heterogeneity of the pore structure and tortuosity of the flow paths. MB CO2 migrated into the areas adjacent to major flow paths, forming irregular channels, while NB CO2 migrated through smooth channels. MB CO2 breakthrough occurred at 0.18 pore volume (PV), which was larger than NB CO2. A long breakthrough time reflects high pore space utilization. A significant differences of MB and NB CO2 in the existing duration of flow paths in the whole displacement period was observed, which reflected higher stability of MB CO2 in the sample. Additionally, little MB CO2 was observed near the inlet, suggesting that MBs accelerated dissolution in the early stage of injection (0.02 PV). Smaller saturation and larger volume differences were observed for MB CO2 compared to NB CO2 in the early stage because of dissolution. The enhanced dissolution efficiency of MB CO2 reached 18.7% at 0.02 PV. Moreover, pore space utilization improved because MB CO2 permeated into regions of low porosity and low flow ability. The improvement in the utilization efficiency reached 4.9% in low-porosity regions. And the storage efficiency was increased up to 23.6%.The results of this study suggest that MB CO2 injection has higher dissolution and improved pore space utilization, making it an efficient method of CO2 sequestration in low-porosity regions.

Ultrasound mediates iRGD targeted liposome-microbubble complex for thrombolytic therapy in vitro

Objective To fabricate iRGD targeted liposome-microbubble complex containing uPA (iRGD-LMC), and to improve the thrombolytic efficiency and reduce the risk of thrombolysis by iRGD-LMC combining with ultrasound targeted microbubbles destruction (UTMD) to release drug into the thrombus site with the help of microbubble cavitation effect. Methods Biotinylated iRGD-MBs were fabricated by thin-film rehydration method.Biotinylated liposomes containing uPA were fabricated by freeze-thaw method and were conjugated to the biotinylated iRGD-MBs surface through biotin-avidin linkage. The iRGD-LMC was subjected to confocal microscopy to determine the particle morphology. The concentration, average diameter and size distribution were determined by particle sizing instrument. The uPA loading efficiency was measured by BCA Protein Assay Kit. Ultrasound imaging was performed using a Vevo 2100 ultrasound imaging system. The iRGD-LMC was irradiated by different ultrasound time and intensity to release drug. Thrombolytic effect in vitro of iRGD-LMC combined with UTMD was observed on the thrombosis model which was extracted from mouse blood. Results iRGD-LMC was successfully prepared. iRGD-LMC was exhibited a well-defined spherical morphology and homogeneous distribution, like ordinary microbubbles. The concentration of iRGD-LMC was (0.51±0.03)×109/ml and average diameter was (2.62±0.12) μm. Drugs loading efficiency was (3 878.5±97.8) μg uPA per 108 microbubbles. iRGD-LMC could achieve contrast-enhanced ultrasound imaging in vitro. The thrombolytic effect of iRGD-LMC+ US group (87.66±1.69)% was the best in vitro, and had significant difference with others groups (P<0.05), followed by iRGD-LMC group (53.32±4.86)% and uPA group (51.09±9.01)%, Compared with PBS group, US group (23.56±9.46)% had thrombolytic effect. Conclusions iRGD-LMC is successfully prepared, which has the advantages of high drug loading of liposomes and good acoustic properties of microbubbles. iRGD-LMC combined with UTMD achieves a significant thrombolytic effect in vitro. Key words: Ultrasound targeted microbubble destruction; Urinary plasminogen activator; Thrombolytic therapy; iRGD-LMC

Fundamental Properties of Microbubble in Semiconductor Cleaning Technology

Fundamental Properties of Microbubble in Semiconductor Cleaning Technology

The effect of properties of microbubbles on drag reduction

The effect of properties of microbubbles on drag reduction

State-of-the-art of microbubble-assisted blood-brain barrier disruption.

Focused ultrasound with microbubbles promises unprecedented advantages for blood-brain barrier disruption over existing intracranial drug delivery methods, as well as a significant number of tunable parameters that affect its safety and efficacy. This review provides an engineering perspective on the state-of-the-art of the technology, considering the mechanism of action, effects of microbubble properties, ultrasound parameters and physiological variables, as well as safety and potential therapeutic applications. Emphasis is placed on the use of unified parameters, such as microbubble volume dose (MVD) and ultrasound mechanical index, to optimize the procedure and establish safety limits. It is concluded that, while efficacy has been demonstrated in several animal models with a wide range of payloads, acceptable measures of safety should be adopted to accelerate collaboration and improve understanding and clinical relevance.

Efficient Control of Microbubble Properties by Alcohol Shear Flows in Ceramic Membrane Channels

AbstractEfficient control of microbubbles is achieved by alcohol shear flows in ceramic membrane channels. The dependence of hydrodynamic and mass transfer properties of microbubbles on liquid viscosity was investigated in a bubble column. The multichannel ceramic membrane worked as the gas sparger, and the shear flow on the membrane surface controlled the microbubble generation. Oxygen gas and glycerin solutions with different viscosities served as gas phase and liquid phase, respectively. The microbubbles were massively generated at different liquid viscosities. With increasing viscosity, the bubble size first decreased and then increased. The dual effect of viscosity on bubble size was related to bubble coalescence. However, an impact of viscosity on gas holdup was not observed for microbubbles.

人工海水中のマイクロバブルの収縮特性

人工海水中のマイクロバブルの収縮特性

Coating microbubbles with nanoparticles for medical imaging and drug delivery.

Coating microbubbles with nanoparticles for medical imaging and drug delivery.

Bubbles versus biofilms: a novel method for the removal of marine biofilms attached on antifouling coatings using an ultrasonically activated water stream

The accumulation of marine organisms on a range of manmade surfaces, termed biofouling, has proven to be the Achilles’ heel of the shipping industry. Current antifouling coatings, such as foul release coatings (FRCs), only partially inhibit biofouling, since biofilms remain a major issue. Mechanical ship hull cleaning is commonly employed to remove biofilms, but these methods tend to damage the antifouling coating and often do not result in full removal. Here, we report the effectiveness of biofilm removal from FRCs through a novel cleaning device that uses an ultrasonically activated stream (UAS). In this device, ultrasound enhances the cleaning properties of microbubbles in a freely flowing stream of water. The UAS was applied on two types of commercial FRCs which were covered with biofilm growth following twelve days immersion in the marine environment. Biofilm removal was quantified in terms of reduction in biovolume and surface roughness, both measured using an optical profilometer, which were then compared with similar measurements after cleaning with a non-ultrasonically activated water stream. It was found that the UAS significantly improves the cleaning capabilities of a water flow, up to the point where no detectable biofilm remained on the coating surfaces. Overall biofilm surface coverage was significantly lower on the FRC coatings cleaned with the UAS system when compared to the coatings cleaned with water or not cleaned at all. When biofilm biomass removal was investigated, the UAS system resulted in significantly lower biovolume values even when compared to the water cleaning treatment with biovolume values close to zero. Remarkably, the surface roughness of the coatings after cleaning with the UAS was found to be comparable to that of the blank, non-immersed coatings, illustrating that the UAS did not damage the coatings in the process.The data supporting this study are openly available from the University of Southampton repository at http://dx.doi.org/10.5258/SOTON/399420.

Mineral beneficiation by ionic microbubble in continuous plant prototype: Efficiency and its analysis by kinetic model

Microbubbles are miniature gas bubbles of less than 100μm diameter in liquid. The performance of ionic microbubble for fine particle separation is investigated and reported in the paper. The effects of different operating variables and physicochemical properties of liquid on the separation characteristics of ionic microbubble are enunciated. A phenomenological kinetic model based on collision, attachment and detachment mechanisms of fine particle is developed to analyze the flotation characteristics of the ionic microbubbles. Generalized correlations for flotation rate constant and induction time are also developed based on the physicochemical properties of microbubble–particle mixture. It is concluded that ionic microbubble is highly efficient for removal of fine particles of opposite charge. The findings from this research may be helpful to understand and explain the process better and possibly can be used to modify and improve the microbubble aided flotation process.

Technique for the Characterization of Phospholipid Microbubbles Coatings by Transmission Electron Microscopy

Gas microbubbles stabilized by a surfactant or polymer coating are of considerable clinical interest because of their imaging and drug delivery potential under ultrasound exposure. The utility of microbubbles for a given application is intrinsically linked to their structure and stability. These in turn are highly sensitive to coating composition and fabrication techniques. Various methods including fluorescence and atomic force microscopy have been applied to characterize microbubble properties, but direct observation of coating structure at the nanoscale still poses a considerable challenge. Here we describe a transmission electron microscopy (TEM) technique to observe the surface of microbubbles. Images from a series of phospholipid-coated microbubble systems, including those decorated with nanoparticles, are presented. They indicate that the technique enables visualization of the coating structure, in particular lipid discontinuities and nanoparticle distribution. This information can be used to better understand how microbubble surface structure relates to formulation and/or processing technique and ultimately to functionality.

Non-linear Response and Viscoelastic Properties of Lipid-Coated Microbubbles: DSPC versus DPPC

For successful in vivo contrast-enhanced ultrasound imaging (CEUS) and ultrasound molecular imaging, detailed knowledge of stability and acoustical properties of the microbubbles is essential. Here, we compare these aspects of lipid-coated microbubbles that have either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) as their main lipid; the other components were identical. The microbubbles were investigated in vitro over the frequency range 1–4 MHz at pressures between 10 and 100 kPa, and their response to the applied ultrasound was recorded using ultrahigh-speed imaging (15 Mfps). Relative to DPPC-coated microbubbles, DSPC-coated microbubbles had (i) higher acoustical stability; (ii) higher shell elasticity as derived using the Marmottant model (DSPC: 0.26 ± 0.13 N/m, DPPC: 0.06 ± 0.06 N/m); (iii) pressure amplitudes twice as high at the second harmonic frequency; and (iv) a smaller amount of microbubbles that responded at the subharmonic frequency. Because of their higher acoustical stability and higher non-linear response, DSPC-coated microbubbles may be more suitable for contrast-enhanced ultrasound.

Encapsulated microbubbles and echogenic liposomes for contrast ultrasound imaging and targeted drug delivery.

Micron- to nanometer-sized ultrasound agents, like encapsulated microbubbles and echogenic liposomes, are being developed for diagnostic imaging and ultrasound mediated drug/gene delivery. This review provides an overview of the current state of the art of the mathematical models of the acoustic behavior of ultrasound contrast microbubbles. We also present a review of the in vitro experimental characterization of the acoustic properties of microbubble based contrast agents undertaken in our laboratory. The hierarchical two-pronged approach of modeling contrast agents we developed is demonstrated for a lipid coated (Sonazoid™) and a polymer shelled (poly D-L-lactic acid) contrast microbubbles. The acoustic and drug release properties of the newly developed echogenic liposomes are discussed for their use as simultaneous imaging and drug/gene delivery agents. Although echogenicity is conclusively demonstrated in experiments, its physical mechanisms remain uncertain. Addressing questions raised here will accelerate further development and eventual clinical approval of these novel technologies.