Microbubble Suspension Research Articles

Microbubbling by co-axial electrohydrodynamic atomization

The preparation of microbubble suspensions is an important feature of medical engineering research. Recently, co-axial electrohydrodynamic atomization was used in our laboratory for the first time to prepare microbubble suspensions. In this paper, using a model glycerol-air system, we investigate in detail the characteristics of this microbubbling process. Modes of microbubbling are elucidated with respect to applied voltage and liquid and air flow rates. Thus, a parametric plot is constructed to identify a liquid and gas flow rate regime, which allows continuous microbubbling. This map provides a basis for the selection of a suitable combination of liquid and gas flow rates particularly in relation to yield and bubble size. The mechanism of microbubbling in microfluidic systems is compared with that of microbubbling by co-axial electrohydrodynamic atomization to identify the advantages and the limiting factors of the latter. Stability of microbubbles prepared by this method in terms of variation of diameter as a function of time is compared with previous literature on the dissolution of microbubbles with an air core and suggests the need for further work to stabilize the bubbles.

Contrast-enhanced ultrasonography (CEUS) in retroperitoneal liposarcomas

20514 Background: CEUS with second-generation contrast agents has been proposed to monitor tumor response to imatinib in patients with metastatic GIST. There are no data in patients with other sarcomas. Our aim was to assess the value of CEUS as a marker of tumor response in retroperitoneal liposarcoma, in addition to its ability to render the baseline malignancy grade of the disease. Methods: CEUS was performed after a SonoVue injection (Bracco, Milano, Italia). SonoVue is a suspension of microbubbles of exafluoride sulphure gas (average diameter 3 μm) with a phospholipidic shell. A low mechanical index (MI<0.09) was used in order to minimize microbubbles rupture. Ultrasound device systems (Philips ATL HDI 5000, Bothel, Washington) with a broandband probe (2–5 Mhz) and specific contrast agent algorithms (Pulse Inversion Harmonic Imaging) were used. The use of this algorithm allowed a real time imaging of all vascular phases (arterial, portal and late). All patients underwent CT scan, PET tomography and routine blood examinations. Ten patients with retroperitoneal liposarcomas were enrolled in this study (5 high grade, 3 intermediate grade, 2 low grade). Results: Five males and five females with metastatic or relapsed disease were enrolled. Median age was 57 years (range 40–70). All underwent chemotherapy with Ifosfamide and Doxorubicin. In all patients there was a clear correlation between contrast enhancement and grading: in low-grade patients there was no contrast enhancement, while the highest level of enhancement was seen in undifferentiated sarcomas. With regard to tumor response to chemotherapy, only 4 patients were evaluable. One patient had a PR and 3 patients had PD. In the 3 patients with PD CEUS showed contrast enhancement, PET was uptaking, but CT scan did not detect any change. In the patient with a PR, strong decrease of tumor perfusion on CEUS and uptaking on PET was seen, again with no change on CT scan. Conclusions: These preliminary observations suggest that CEUS may be more useful than CT scan on assessing tumor response in retroperitoneal sarcomas, and may predict the baseline malignancy grade. Data on a larger number of patients will be presented. No significant financial relationships to disclose.

Detection of ultrasonic cavitation based on low-frequency analysis of acoustic signal

AbstractThe acoustic cavitation phenomenon constitutes a potential hazard in ultrasound diagnostics and therapy so that early and effective detection of cavitation is of great interest. However, cavitation might even bring a higher risk especially when an echocontrast agent based on microbubbles is used. The major goal of the present work was to develop a cavitation detection method based on increased level of cavitation noise in the range of low frequencies (about 1 Hz). This method was applied in vitro using a model of body fluid containing a model echocontrast agent, such as 5% solution of lyophilized egg albumin, which was sonicated by ultrasound disintegrator. Ultrasound signal evokes cavitation in microbubble suspension accompanied by a certain level of cavitation acoustic noise. The level of noise voltage increased in the frequency range of 0.1 to 2 Hz in the presence of cavitation. Hence, this method makes it possible to determine the value of cavitation threshold. In addition, we examined how the cavitation threshold is affected by temperature and viscosity. It was found that the cavitation threshold decreased with growing temperature while it increased with growing viscosity.

Finite-bandwidth Kramers-Kronig relations for acoustic group velocity and attenuation derivative applied to encapsulated microbubble suspensions

Kramers-Kronig (KK) analyses of experimental data are complicated by the conflict between the inherently bandlimited data and the requirement of KK integrals for a complete infinite spectrum of input information. For data exhibiting localized extrema, KK relations can provide accurate transforms over finite bandwidths due to the local-weighting properties of the KK kernel. Recently, acoustic KK relations have been derived for the determination of the group velocity (cg) and the derivative of the attenuation coefficient (alpha') (components of the derivative of the acoustic complex wave number). These relations are applicable to bandlimited data exhibiting resonant features without extrapolation or unmeasured parameters. In contrast to twice-subtracted finite-bandwidth KK predictions for phase velocity and attenuation coefficient (components of the undifferentiated wave number), these more recently derived relations for cg and alpha' provide stricter tests of causal consistency because the resulting shapes are invariant with respect to subtraction constants. The integrals in these relations can be formulated so that they only require the phase velocity and attenuation coefficient data without differentiation. Using experimental data from suspensions of encapsulated microbubbles, the finite-bandwidth KK predictions for cg and alpha' are found to provide an accurate mapping of the primary wave number quantities onto their derivatives.

Ultrasound contrast agents and methods of making and using them

Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain surfactants and, optionally, hydrophilic stabilizers. The surfactants can be in the form of liposomes. The suspensions are obtained by exposing the surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003. Contrast agents with particular mixtures of gases are also disclosed that have advantageous properties.

Nonlinear propagation of ultrasound through microbubble contrast agents and implications for imaging

Microbubble contrast agents produce nonlinear echoes under ultrasound insonation, and current imaging techniques detect these nonlinear echoes to generate contrast agent images accordingly. For these techniques, there is a potential problem in that bubbles along the ultrasound transmission path between transducer and target can alter the ultrasound transmission nonlinearly and contribute to the nonlinear echoes. This can lead to imaging artefacts, especially in regions at depth. In this paper we provide insight, through both simulation and experimental measurement, into the nonlinear propagation caused by microbubbles and the implications for current imaging techniques. A series of investigations at frequencies below, at, and above the resonance frequency of microbubbles were performed. Three specific effects on the pulse propagation (i.e., amplitude attenuation, phase changes, and harmonic generation) were studied. It was found that all these effects are dependent on the initial pulse amplitude, and their dependence on the initial phase of the pulse is shown to be insignificant. Two types of imaging errors are shown to result from this nonlinear propagation: first, that tissue can be misclassified as microbubbles; second, the concentration of microbubbles in the image can be misrepresented. It is found that these imaging errors are significant for all three pulse frequencies when the pulses transmit through a microbubble suspension of 6 cm in path length. It also is found that the first type of error is larger at the bubble resonance frequency.

Preparation of microbubble suspensions by co-axial electrohydrodynamic atomization

In this paper we report a novel method, based on co-axial electrohydrodynamic jetting, for the preparation of microbubble suspensions containing bubbles <10 μm in size and having a narrow size distribution. No selective filtration is necessary and the suspensions are produced directly by the process. To demonstrate the method, glycerol was used as the liquid medium, flowing in the outer needle of the co-axial twin needle arrangement and undergoing electrohydrodynamic atomization in the stable cone-jet mode while air flowed through the inner needle at the same time. At zero applied voltage a hollow stream of liquid flowed from the outer needle. When the applied voltage was increased, eventually the hollow stream became a stable cone-jet and emitted a microthread of bubbles, which were collected in a container of glycerol to obtain microbubble suspensions. The size of the microbubbles was measured via optical microscopy and laser diffractometry. Several microbubble suspensions were prepared and characterised and the size distribution was found to be critically dependent on the ratio ( n) of flow rates of liquid/air and, in particular the flow rate of the air. At n = 1.5, with the flow rate of air set at ∼1.7 μl/s, a microbubble suspension containing bubbles in the size range 2–8 μm was obtained.

Contrast-Enhanced Breast Ultrasonography Reveals an Unusual Breast Tumor in a Male Patient With Gynecomastia

Pseudoangiomatous stromal hyperplasia (PASH), first described in 1986, is a benign breast lesion consisting of complex, anastomosing, slitlike pseudovascular spaces, which are either acellular or lined by slender, spindle-shaped cells. 1,2 The exact etiology of PASH is unknown. It usually presents as a breast mass, affecting women in their reproductive years. Pseudoangiomatous stromal hyperplasia has been reported in at least 25% of cases of gynecomastia. 2 Although PASH is a benign lesion, it has a propensity for growth over time and local recurrence after excision.3 Several small-scale studies already described the mammographic and gray scale ultrasonographic findings of PASH. 3,4,5 To our knowledge, the appearance of PASH on contrast-enhanced ultrasonography (CEUS) of the breast has never been described before. In past years, CEUS has been used increasingly in clinical practice to characterize indeterminate breast lesions. 6-14 In CEUS, a contrast agent consisting of a suspension of microbubbles is used to increase the blood echogenicity and to improve detection of slow and low-volume blood flow in microvessels (<5 μm). Because malignant breast tumors display neoangiogenesis that can be depicted by the contrast agent, it is believed that CEUS can be used to characterize breast masses and distinguish benign from malignant lesions. In this report, we describe the case of an elderly male patient with gynecomastia in whom conventional mammography and gray scale ultrasonography revealed a solid tumor in the left breast that was suggestive of malignancy. Additional workup of the lesion included CEUS of the breast with SonoVue (Bracco SpA, Milan, Italy) microbubbles to analyze tumor vascularization. On the basis of the CEUS findings, the lesion was down-staged to a benign breast lesion, probably a PASH. 6-13 After ultrasonographically guided biopsy of the lesion, histologic examination of the tissue confirmed the diagnosis. We describe the imaging characteristics of PASH on CEUS and provide an in-depth review of the literature.

Quantification of phosphatidylserine, phosphatidic acid and free fatty acids in an ultrasound contrast agent by normal-phase high-performance liquid chromatography with evaporative light scattering detection

Sonazoid™ is a new contrast agent for ultrasound imaging. The product is an aqueous suspension of perfluorobutane microbubbles coated with phospholipids obtained from hydrogenated egg phosphatidylserine (H-EPS). A normal-phase high-performance liquid chromatographic (HPLC) method with evaporative light scattering detection was developed for quantification of free fatty acids, phosphatidylserine and phosphatidic acid in H-EPS and Sonazoid™. Separation of the lipids was carried out on an HPLC diol column and a gradient of chloroform and methanol with 0.2% formic acid titrated to pH 7.5 with ammonia. The calibration standards contained stearic acid, distearoyl-phosphatidic acid (DSPA) and distearoyl-phosphatidylserine (DSPS) in the concentration range of 0.016–1.0 mg/ml (0.4–25 μg injected). The method was validated with a limit of quantification of the three lipids set to 0.4 μg (approximately 20–60 μM). The best fit of the three calibration curves were obtained when the logarithmic transformed theoretical lipid concentration was plotted against the logarithmic transformed area under the peak and fitted to a second order polynomial equation. Stearic acid, DSPA and DSPS were analysed with an intermediate precision ranging from 4.4% to 5.3% R.S.D. and they were extracted from an aqueous suspension with a recovery ranging from 103.3% to 113.3%. The sum of total phospholipid concentration determined in H-EPS ranged from 96.4% to 103.2% of the theoretical values. The lipids in the ultrasound product were quantitated with a repeatability ranging from 6.2% to 11.7% R.S.D.

Ultrasound attenuation in encapsulated microbubble suspensions: The multiple scattering effects

The phenomenon of image distortions caused by the multiple scattering (MS) effects of encapsulated microbubbles in ultrasoniqc imaging was experimentally found in previous studies (Soetanto and Chan 2000a), but its mechanism has not been fully understood. To study the MS effects of microbubbles in contrast imaging, two approaches are employed in this article--the effective medium approach initialized by Kargl (2002), which includes all the high-order rescattering of free bubbles, and the classic lowest-order approximation approach of Commander and Prosperetti (1989), which ignores the higher-order rescattering between bubbles. In this work, they are modified to model encapsulated microbubble suspensions, and the discrepancies in attenuation coefficients calculated by these two approaches, i.e., the higher-order rescattering of bubbles are defined as the measure of the MS effects of microbubbles. The intrinsic relations between the MS effects of microbubbles in suspensions and physical properties of the microbubbles, such as the bubble concentrations, sizes, and the shell thicknesses etc., are simulated and discussed. It is found that in suspensions for identical microbubbles >12 microm in size, the MS effects come to be significant when the bubble concentrations exceed 1 x 10(5) bubbles/mL. The MS effects of microbubbles with broad size spectrums are examined by simulating Soetanto and Chan's experiments. Also, the MS effects of UCAs in current ultrasonic imaging practice are discussed. The STARs and extinction cross-sections of different-sized individual encapsulated microbubbles are calculated for further investigations on the mechanism of the MS effects of UCAs.

Investigating the significance of multiple scattering in ultrasound contrast agent particle populations

The majority of the existing models describing the behavior of microbubble ultrasound contrast agents consider single, isolated microbubbles suspended in infinite media. The behavior of a microbubble population is predicted by summing the results for single microbubbles and ignoring multiple scattering effects. The aim of this investigation is to determine the significance of multiple scattering in microbubble populations and establish whether an alternative approach is required. In the first part of the work, linear models are derived to identify approximately the conditions under which multiple scattering may be expected. A nonlinear model for sound propagation in a microbubble suspension then is developed and used to examine multiple scattering at higher insonation pressures. Broadband attenuation measurements are described for two different types of microbubble suspension (albumin encapsulated octofluropropane and copolymer encapsulated isobutane) to ascertain whether or not multiple scattering may be observed experimentally. The results from the simulation work indicate that multiple scattering effects would be discernible at moderate concentrations (10(6) microbubbles/ml) such as may be present in vivo. The effect upon attenuation in the suspension would be pronounced, however, only if the population contained a sufficient proportion of relatively large (> 4 microm radius) microbubbles excited at their resonance frequency. This also is found to be the case experimentally. These findings may have important implications for the characterization of ultrasound contrast agents and their use in quantitative diagnostic techniques.

Preparation and evaluation of poly(L‐lactide‐co‐glycolide) (PLGA) microbubbles as a contrast agent for myocardial contrast echocardiography

A kind of absorbable PLGA microbubble-based contrast agent (PLGA microspheres with porous or hollow inner structure) was fabricated by an improved double emulsion-solvent evaporation method. The contrast efficiency was evaluated and proved both in vitro and in vivo. By adjusting the polymer concentration and volume of the inner aqueous phase during the fabrication of microbubbles, the inner structure of the microbubbles could be controlled. Both air-filled and perfluoropropane-filled microbubbles can opacify the left ventricle. However, when compared with air-filled microbubbles, perfluoropropane-filled microbubbles can produce significantly longer enhancement in left ventricle in the dog model due to the lower diffusivity and lower solubility of perfluoropropane in blood. A suspension of perfluoropropane-filled PLGA microbubbles (1.8 microm average microbubbles size, 2 x 10(8) microbubbles/mL concentration) has successfully and safely achieved myocardial opacification in closed-chest dogs. A perfusion defect was observed in both of the two dogs with acute myocardial infarction with Power Contrast Imaging (PCI) triggered technology. In the examination of contrast in both ventricular and myocardial opacification, the high mechanical index (MI) was found to have superior contrast sensitivity over the low MI for PLGA-based contrast agents.

Imaging the destruction of individual ultrasound contrast microbubbles with diagnostic ultrasound

Ultrasound imaging of ultrasound contrast agent fragmentation in a water bath was performed with the color Doppler mode of the HDI 5000 (Phillips Ultrasound). A highly diluted suspension of ultrasound contrast microbubbles (Optison®) was injected into the water bath such that individual microbubbles passed through the image plane every few seconds. Decorrelation of the signal, along with the appearance of multiple signals, suggests that single microbubble fragmentation was observed, with daughter bubbles being formed from the original microbubbles, depending on the applied acoustic pressure.

Detection of individual microbubbles of ultrasound contrast agents: imaging of free-floating and targeted bubbles.

During echo examinations with microbubble contrast, individual "dots" of ultrasound reflection can be visualized. To address the question whether these signals represent individual microbubbles, very dilute suspensions of ultrasound contrast agents or individual microbubbles attached to Petri dishes were prepared and studied by ultrasound imaging. Microbubble suspensions were diluted in saline and evaluated by a clinical ultrasound imaging system. Microbubble concentration was verified by Coulter counter. Single microbubble preparation on a Petri dish was established by streptavidin-biotin interaction under microscopy control and subjected to ultrasound imaging. Ultrasound of dilute microbubble dispersions demonstrated distinct white foci; concentration of these sites was consistent with signals from individual microbubbles as determined by Coulter. Individual microbubbles immobilized on polystyrene were also visualized by ultrasound. Ultrasound medical systems can resolve backscatter signals from individual microbubbles of ultrasound contrast, both in solution and in the targeted immobilized state, implying picogram sensitivity.

Sentinel Node Detection Using Contrast-Enhanced Power Doppler Ultrasound Lymphography

To establish the feasibility of using contrast-enhanced interstitial ultrasound (US) lymphography as an alternative to current sentinel node detection methods. Aqueous US contrast microbubble suspensions of varying diameter were evaluated in vitro to characterize response to insonation. Contrast media were then injected subcutaneously into the distal extremities of 11 normal dogs to target the cervical and popliteal lymph nodes (nodes, n = 40). First-order (sentinel) lymph nodes and second-order sublumbar nodes were imaged intermittently from 0 to at least 120 minutes following contrast injection using continuous power Doppler mode. Lymphoscintigraphy studies were performed on 4 dogs to verify lymphatic drainage patterns and sentinel lymph nodes. Contrast enhancement occurred in 34/40 (85%) sentinel nodes overall and in 30/32 (94%) nodes when submicron or near-micron diameter bubble formulations were used. In many instances, enhancement persisted throughout the imaging period. Contrast response was most pronounced using a high mechanical index and tissue artifact was reduced or eliminated when using a high pulse repetition frequency. Contrast-enhanced interstitial US lymphography could serve as an alternative to current sentinel node detection methods. Preliminary findings suggest that submicron or near-micron-diameter bubbles may be suitable for lymphatic imaging applications.

The behaviour of individual contrast agent microbubbles

In recent years, our knowledge of the behaviour of ultrasonic microbubble contrast agents has improved substantially through in vitro experiments. However, there has been a tendency to use high concentrations of contrast agents in suspension, so that ultrasonic backscatter data are generated by a cloud of microbubbles. Such experiments involve a variety of assumptions with validity that is open to question. In addition, high concentrations of microbubbles cannot be used to understand the behaviour of individual microbubble scatterers. This paper proposes a technique that minimises the number of assumptions that need to be made to interpret in vitro experimental data. The basis of the technique is a dilute suspension of microbubbles that makes single scattering events distinguishable. A commercial scanner was used to collect radio frequency (RF) data from suspensions of two different contrast agents, Quantison™ and Definity. Backscatter data were collected over a range of acoustic pressures. It was found that Definity provided a constant number of scattering events per unit volume of suspension for almost all applied acoustic pressures. Quantison™ demonstrated an increasing number of scattering events per unit volume with increasing acoustic pressure. Below 0.6 MPa, Quantison™ scatterers were not individually detectable and provided levels of backscatter similar to those of a blood-mimicking fluid, which suggests that Quantison™ microbubbles had almost linear scattering behaviour. At acoustic pressures greater than 0.6 MPa, both agents appeared to provide echoes from free bubbles. The change in the number of scatterers per unit volume with acoustic pressure cannot be demonstrated using high concentrations of contrast agent. (E-mail: Vassilis.Sboros@ed.ac.uk)

Amphiphilic Lipopeptide Microparticles as Contrast Agents for Medical Ultrasound Imaging

AbstractIn this study we investigated the utility of complementary amphiphilic lipopeptides as a new membrane formulation suitable for the preparation of gas‐filled microbubbles. Through primarily ion pairing and hydrophobic interactions we rationalized that the stacking of synthetic lipopeptides into the surface of microbubbles would make bubble suspensions useful as ultrasound contrast agents. By mixing charged lipopeptides in propylene glycol/glycerol solutions in the presence of a perfluorocarbon gas followed by vigorous shaking, microbubble suspensions were formed in good yield with a size distribution spanning the range 1–7 × 10−6 m. The microbubbles were studied in an in vivo model and provided imaging efficacy comparable with conventional ultrasound contrast agents. Crude sample (before flotation) of Formulation A analyzed at ×40 magnification. The solid bar indicates 10 × 10−6 m.magnified imageCrude sample (before flotation) of Formulation A analyzed at ×40 magnification. The solid bar indicates 10 × 10−6 m.

Safety of the Galactose–Based Ultrasound Contrast Agent Levovist

The introduction of microbubble suspensions represents a new class of contrast agents for enhancement of vascular imaging in ultrasound. The effective ingredients of this class of contrast agents are acoustically active and produce micrometer-sized inhomogeneities in the blood pool. The microbubbles interact with the sound field either by scattering the incident sound beam or by oscillations that produce resonance, which at higher acoustic power can lead to the destruction of the microbubbles. Different processing of the various microbubble echo responses led to a number of new imaging modes that exhibit varying sensitivity and specificity for microbubble detection, of which the nonlinear scatter during destruction (“stimulated acoustic emission”) is the most sensitive, enabling the detection of a single microbubble in a capillary bed. With these techniques, the visualization of organ perfusion with ultrasound became possible. These agents are characterized not only by their physicochemical uniqueness but also by their unique pharmaceutical properties. All microbubble contrast agents can be considered to be “particulates,” which, by nature of their size, remain in the blood pool until the gas is dissolved or until they are sequestered by the reticulendothelial system (RES). Their character as blood pool agents makes them ideally suited for enhancing vascular imaging. The galactose–based agent Levovist (Schering AG, Berlin, Germany) was the first microbubble agent to enter the market with sufficient stability to provide enhancement of the total body blood pool following intravenous (IV) injection. Due to the particulate character, the risk profile of this new class of agents differs from contrast agents for x-ray or magnetic resonance imaging (MRI). The theoretical risks are generated by the tolerance of the tracer medium, its osmolality, the microbubble shell material, and the microbubble particles themselves. Gas bubbles may grow either by coalescence or by inward diffusion of gases, potentially occluding small vessels in the lung and periphery. In addition, microbubbles provide a theoretical nidus for cavitation. The purpose of this article is to report the broader experience in clinical routine as regards the safety of this new class of contrast agents.

MR perfusion imaging using encapsulated laser-polarized 3He.

In this work, the use of a new carrier agent for intravascular laser-polarized 3He imaging is reported. Lipid-based helium microbubbles were investigated. Their average diameter of 3 microm, which is smaller than that of the capillaries, makes it possible to conduct in vivo studies. The NMR relaxation parameters T1, T2, and T2* of a microbubble suspension were measured as 90 s, 300 ms, and 4.5 ms, respectively, and in vivo images of encapsulated 3He with signal-to-noise ratios (SNRs) larger than 30 were acquired. Dynamic cardiac images and vascular images of encapsulated 3He were obtained in rats using intravenous injections of microbubble suspensions. Excellent preservation of 3He polarization through the lung capillaries and heart cavities was observed. The first images of 3He microbubble distributions in the lungs were obtained. Additionally, the potential of this technique for lung perfusion assessment was validated through an experimental embolism model with the visualization of perfusion defects.

Generation of stable microbubbles and their transport through porous media

Laboratory experiments were conducted to generate stable microbubbles and to measure their transport properties in porous media in order to evaluate their possible use in subsurface remediation. A mathematic model was developed as a special case of filtration theory for predicting microbubble transport in porous media. Several physical‐chemical parameters were tested, including surfactant type, surfactant concentration, generation method, and pressure. A combination of an anionic surfactant and a hydrophobic nonionic surfactant was found to yield the highest concentrations of stable microbubbles (3 × 109 bubbles mL−1) in the size range of 0.7 to 20 μm. The specific surface areas of the microbubble suspensions were in the range of 50 cm2 mL−1, and specific air volumes were &gt;0.07 mL mL−1. For 1 pore volume of injected bubble suspension, effluent recoveries of 100, 80, and 30% were achieved from columns of coarse (415–500 μm), medium (150–212 μm), and fine (53–106 μm) sands, respectively. Effluent recovery in the fine sand column increased to 63% following a 3 pore volume injection. Microbubble generation and injection under pressure were shown to minimize microbubble loss due to gas dissolution. Results from the modeling suggest that retention of microbubbles could be adequately described by filtration theory.