Ultrasound Contrast Agent Microbubbles Research Articles

Endothelial vascular cell adhesion molecule 1 is a marker for high-risk carotid plaques and target for ultrasound molecular imaging

BackgroundMolecular imaging of carotid plaque vulnerability to atheroembolic events is likely to lead to improvements in selection of patients for carotid endarterectomy (CEA). The aims of this study were to assess the relative value of endothelial inflammatory markers for this application and to develop molecular ultrasound contrast agents for their imaging. MethodsHuman CEA specimens were obtained prospectively from asymptomatic (30) and symptomatic (30) patients. Plaques were assessed by semiquantitative immunohistochemistry for vascular cell adhesion molecule 1 (VCAM-1), lectin-like oxidized low-density lipoprotein receptor 1, P-selectin, and von Willebrand factor. Established small peptide ligands to each of these targets were then synthesized and covalently conjugated to the surface of lipid-shelled microbubble ultrasound contrast agents, which were then evaluated in a flow chamber for binding kinetics to activated human aortic endothelial cells under variable shear conditions. ResultsExpression of VCAM-1 on the endothelium of CEA specimens from symptomatic patients was 2.4-fold greater than that from asymptomatic patients (P < .01). Expression was not significantly different between groups for P-selectin (P = .43), von Willebrand factor (P = .59), or lectin-like oxidized low-density lipoprotein receptor 1 (P = .99). Although most plaques from asymptomatic patients displayed low VCAM-1 expression, approximately one in five expressed high VCAM-1 similar to plaques from symptomatic patients. In vitro flow chamber experiments demonstrated that VCAM-1-targeted microbubbles bind cells that express VCAM-1, even under high-shear conditions that approximate those found in human carotid arteries, whereas binding efficiency was lower for the other agents. ConclusionsVCAM-1 displays significantly higher expression on high-risk (symptomatic) vs low-risk (asymptomatic) carotid plaques. Ultrasound contrast agents bearing ligands for VCAM-1 can sustain high-shear attachment and may be useful for identifying patients in whom more aggressive treatment is warranted.

Effects of a microbubble ultrasound contrast agent on high-intensity focused ultrasound for uterine fibroids: a randomised controlled trial

Objective: To investigate the effects of a microbubble ultrasound contrast agent on high-intensity focused ultrasound (HIFU) treatment of uterine fibroids.Methods: A total of 120 patients with solitary uterine fibroid were randomly assigned into Groups A, B, C and D. Patients in Groups A and B received 1.5 ml of SonoVue, Groups C and D received 1.5 ml of saline before HIFU ablation. HIFU sonication started at 6 min after administration of SonoVue or saline in Groups A and C, whereas it started at 10 min in Groups B and D. On day 1 after HIFU, magnetic resonance imaging was performed. Patients were followed up via phone or clinic visit during the first week after HIFU.Results: No significant difference was observed in terms of age, fibroid location, diameter of fibroids, signal intensity on T2-weighted imaging, or tumour volume among the four groups (p > 0.05). The use of SonoVue significantly shortened the treatment time and sonication time. The sonication start time of 6 min, relative to 10 min, had significant effects on the treatment time and sonication time. The use of intravenous SonoVue followed by HIFU ablation 6 min later significantly increased the rate of significant grey-scale changes (55.9%) and the non-perfused volume ratio (94.2% ± 10.6%). No significant differences were observed in the incidence of intra-procedure and post-HIFU adverse effects among the four groups (p > 0.05).Conclusions: SonoVue could be safely used to enhance the ablation effects of HIFU treatment of uterine fibroids.

Acoustic Characterization and Enhanced Ultrasound Imaging of Long-Circulating Lipid-Coated Microbubbles.

A long-circulating lipid-coated ultrasound (US) contrast agent was fabricated to achieve a longer wash-out time and gain more resistance against higher-mechanical index sonication. Systemic physical, acoustic, and in vivo imaging experiments were performed to better understand the underlying mechanism enabling the improvement of contrast agent performance by adjusting the physical and acoustic properties of contrast agent microbubbles. By simply altering the gas core, a kind of US contrast agent microbubble was synthesized with a similar lipid-coating shell as SonoVue microbubbles (Bracco SpA, Milan, Italy) to achieve a longer wash-out time and higher inertial cavitation threshold. To bridge the structure-performance relationship of the synthesized microbubbles, the imaging performance of the microbubbles was assessed in vivo with SonoVue as a control group. The size distribution and inertial cavitation threshold of the synthesized microbubbles were characterized, and the shell parameters of the microbubbles were determined by acoustic attenuation measurements. All of the measurements were compared with SonoVue microbubbles. The synthesized microbubbles had a spherical shape, a smooth, consistent membrane, and a uniform distribution, with an average diameter of 1.484 μm. According to the measured attenuation curve, the synthesized microbubbles resonated at around 2.8 MHz. Although the bubble's shell elasticity (0.2 ± 0.09 N/m) was comparable with SonoVue, it had relatively greater viscosity and inertial cavitation because of the different gas core. Imaging studies showed that the synthesized microbubbles had a longer circulation time and a better chance of fighting against rapid collapse than SonoVue. Nano/micrometer long-circulating lipid-coated microbubbles could be fabricated by simply altering the core composition of SonoVue microbubbles with a higher-molecular weight gas. The smaller diameter and higher inertial cavitation threshold of the synthesized microbubbles might make it easier to access deep-seated organs and give prolonged imaging enhancement in the liver.

Targeting property and toxicity of a novel ultrasound contrast agent microbubble carrying the targeting and drug-loaded complex FA-CNTs-PTX on MCF7 cells

The application of ultrasound contrast agents not only is confined to the enhancement of ultrasound imaging but also has started to be used as a drug system for diagnosis and treatment. In this paper, Span60 and PEG1500 were used as membrane materials, and a new targeting and drug-loading multifunctional ultrasound contrast agent microbubble enveloping the FA-CNTs-PTX complex was successfully prepared by acoustic cavitation. With the breast cancer cell line MCF7 as the research target, the effects of the microbubble with FA-CNTs-PTX on the proliferation and toxicity of MCF7 cells were studied using a CCK-8 and AO/EB double-staining method. The influences of the microbubbles with FA-CNTs-PTX on the cellular morphology and apoptosis period of the MCF7 cells were detected using an inverted fluorescence microscope. The apoptosis of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was investigated with flow cytometry and an annexin and PI double staining fluorescence quantitative analysis. The results indicated that the ultrasound contrast agent microbubble with FA-CNTs-PTX remarkably inhibited the proliferation of MCF7 cells, which was mainly controlled by the drug loading rate and the nanometer size of the microbubbles. Moreover, the proliferative inhibition rate of the microbubbles with FA-CNTs-PTX was related to the cell apoptosis period of MCF7 cells. Its inhibition degree on the proliferation of MCF7 cells was higher than that of the hepatoma HepG2 cells. The apoptosis rate of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was higher than that of normal human umbilical vein endothelial cells (HUVECs), and the microbubbles with FA-CNTs-PTX could target the MCF7 cells.

Anti-microRNA-21/221 and microRNA-199a transfected by ultrasound microbubbles induces the apoptosis of human hepatoma HepG2 cells.

Gene therapy, particularly microRNA (miRNA), is a promising candidate in the treatment of cancer; however, it is challenging to develop gene delivery systems. Ultrasound microbubbles have been used for gene delivery with excellent results. The present study aimed to investigate the transfection efficiency of HepG2 cells using ultrasound microbubbles. The effects of three miRNAs (miR-21, miR-221 and miR-199a) on HepG2 cells were also determined by performing ultrasound microbubble-mediated gene transfection. Three recombinant plasmids containing anti-miR-21, anti-miR-221 and miR-199a were fused with enhanced green fluorescent protein. For the transfection of genes, the type of contrast agent, the concentration of microbubble contrast agent and the exposure intensity of ultrasound were optimized. The expression of miRNAs was detected using reverse transcription-polymerase chain reaction. To determine the effect of anti-miR-21, anti-miR-221 and miR-199a on HepG2 cells, MTT, cell cycle analysis and Annexin V-PE/7-ADD apoptosis assays were performed. The optimal condition was 10% sulfur hexafluoride microbubbles at an ultrasound frequency of 2.0 MHz and mechanical index of 0.28. When cells were transfected with three recombinant plasmids using ultrasound microbubbles, there was significant downregulation of miR-21 and miR-221 and upregulation of miR-199a (P<0.05). All three treatments inhibited cell proliferation and promoted the apoptosis of cells. The present data indicated that the delivery of anti-miR-21, anti-miR-221 and miR-199a may be mediated by ultrasound microbubble contrast agents. With this approach, cell proliferation may be effectively inhibited and cell apoptosis may be induced. These are novel cancer therapy targets.

Time-resolved measurement of bubble cavitation by using power Doppler ultrasound image

In this study, a novel measurement method for a secondary ultrasound wave irradiated by microbubble cavitation is proposed. High-intensity ultrasound (h-US, 1.0–1.5 MPa), which produces bubble cavitation, is irradiated with a fixed time delay after introducing imaging US, whose frequency is different from that of the h-US. The bubble cavitation signal (BCS) is detected by the signal-processing unit of an ultrasound power Doppler imaging instrument. By this method, both a spatially resolved bubble image (S-image) and the temporal transition of the BCS (T-image) are monitored simultaneously. A feature of the method is that the BCS is observed in situ with sub-µs time resolution. The accuracy of the method is evaluated and it is found that the maximum deviation of the amplitude of the simulated BCS is 4.80%. This method is applied to measure the BCS of ultrasound contrast agent microbubbles. As a result, the dependence of the inherent temporal transition of the BCS on the sound pressure of the h-US (0.6–1.2 MPa) is observed.

Ultrasound Microbubble Contrast Agents Promote Transdermal Drug Delivery

This report discusses a new development in the use of ultrasound (US) microbubble contrast agents on transdermal drug delivery. In clinical applications, microbubbles serve as imaging agents to enhance the contrast of ultrasound images via intravenous injection. Different degrees of microbubble oscillation due to distinct acoustic fields can elicit various degrees of cavitation. Inertial cavitation can enhance the permeability in the surrounding tissues, increase vessel wall permeability, and promote drug entry from blood into cytosol or matrix, whereas stable cavitation can slightly increase tissue permeability without causing any harm. At present, most ultrasound contrast agents are designed for injection into blood vessels, nevertheless, microbubbles with different condition parameters are highly correlated with efficiency in transdermal permeation. As for applications in a transdermal drug delivery, we also used microbubbles at a given concentration in combination with ultrasound to widen intercellular spaces, thereby successfully enhancing the in vivo delivery of arbutin across the skin. In order for liquid-phase microbubbles to be conveniently applied to skin surface, our team modified the medium surrounding the microbubbles at the optimum concentration from liquid to gel. Moreover, it is found that under the same ultrasound power density, microbubbles of larger particle sizes can extend the penetration depths of dye at the phantom surface. Recently, US-mediated drug-coated microbubble cavitation for enhancing hair growth, the treatment of inflammatory skin diseases, and wound healing both in vitro and in vivo have been investigated by our group.

Combined optical sizing and acoustical characterization of single freely-floating microbubbles

In this study we present a combined optical sizing and acoustical characterization technique for the study of the dynamics of single freely-floating ultrasound contrast agent microbubbles exposed to long burst ultrasound excitations up to the milliseconds range. A co-axial flow device was used to position individual microbubbles on a streamline within the confocal region of three ultrasound transducers and a high-resolution microscope objective. Bright-field images of microbubbles passing through the confocal region were captured using a high-speed camera synchronized to the acoustical data acquisition to assess the microbubble response to a 1-MHz ultrasound burst. Nonlinear bubble vibrations were identified at a driving pressure as low as 50 kPa. The results demonstrate good agreement with numerical simulations based on the shell-buckling model proposed by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499–3505 (2005)]. The system demonstrates the potential for a high-throughput in vitro characterization of individual microbubbles.

Nonlinear response of ultrasound contrast agent microbubbles: From fundamentals to applications**Projects supported by the National Natural Science Foundation of China (Grant Nos. 81127901, 81227004, 11374155, 11274170, 11274176, 11474001, 11474161, 11474166, and 11674173), the National High-Technology Research and Development Program, China (Grant No. 2012AA022702), and Qing Lan Project of Jiangsu Province, China.

Modelling and biomedical applications of ultrasound contrast agent (UCA) microbubbles have attracted a great deal of attention. In this review, we summarize a series of researches done in our group, including (i) the development of an all-in-one solution of characterizing coated bubble parameters based on the light scattering technique and flow cytometry; (ii) a novel bubble dynamic model that takes into consideration both nonlinear shell elasticity and viscosity to eliminate the dependences of bubble shell parameters on bubble size; (iii) the evaluation of UCA inertial cavitation threshold and its relationship with shell parameters; and (iv) the investigations of transfection efficiency and the reduction of cytotoxicity in gene delivery facilitated by UCAs excited by ultrasound exposures.

The effect of particle density on ultrasound-mediated transport of nanoparticles

A significant barrier to successful drug delivery is the limited penetration of nanoscale therapeutics beyond the vasculature. Building on recent in vivo findings in the context of cancer drug delivery, the current study investigates whether modification of nanoparticle drug-carriers to increase their density can be used to enhance their penetration into viscoelastic materials under ultrasound exposure. A computational model is first presented to predict the transport of identically sized nanoparticles of different densities in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming and microstreaming. Experiments are then described in which near monodisperse (polydispersity index <0.2) nanoparticles of approximate mean diameter 200 nm and densities ranging from 1.01 g cm−3 to 5.58 g cm−3 were fabricated and delivered to a tissue-mimicking material in the presence or absence of a microbubble ultrasound contrast agent, at ultrasound frequencies of 0.5 MHz and 1.6 MHz and a peak negative pressure of 1 MPa. Both the theoretical and experimental results confirm that denser particles exhibit significantly greater ultrasound-mediated transport than their lower density counterparts, indicating that density is a key consideration in the design of nanoscale therapeutics.

Nonlinear Imaging of Microbubble Contrast Agent Using the Volterra Filter: In Vivo Results.

A nonlinear filtering approach to imaging the dynamics of microbubble ultrasound contrast agents (UCAs) in microvessels is presented. The approach is based on the adaptive third-order Volterra filter (TVF), which separates the linear, quadratic, and cubic components from beamformed pulse-echo ultrasound data. The TVF captures polynomial nonlinearities utilizing the full spectral components of the echo data and not from prespecified bands, e.g., second or third harmonics. This allows for imaging using broadband pulse transmission to preserve the axial resolution and the SNR. In this paper, we present the results from imaging the UCA activity in a 200- [Formula: see text] cellulose tube embedded in a tissue-mimicking phantom using a linear array diagnostic probe. The contrast enhancement was quantified by computing the contrast-to-tissue ratio (CTR) for the different imaging components, i.e., B-mode, pulse inversion (PI), and the TVF components. The temporal mean and standard deviation of the CTR values were computed for all frames in a given data set. Quadratic and cubic images, referred to as QB-mode and CB-mode, produced higher mean CTR values than B-mode, which showed improved sensitivity. Compared with PI, they produced similar or higher mean CTR values with greater spatial specificity. We also report in vivo results from imaging UCA activity in an implanted LNCaP tumor with heterogeneous perfusion. The temporal means and standard deviations of the echogenicity were evaluated in small regions with different perfusion levels in the presence and absence of UCA. The in vivo measurements behaved consistently with the corresponding calculations obtained under microflow conditions in vitro. Specifically, the nonlinear VF components produced larger increases in the temporal mean and standard deviation values compared with B-mode in regions with low to relatively high perfusion. These results showed that polynomial filters such as the TVF can provide an important tool for imaging UCA activity in regions with heterogeneous perfusion as is the case in some tumors and ischemic tissues.

Effect of pulse repetition frequency of high-intensity focused ultrasound on in vitro thrombolysis

Vascular occlusion by the thrombi is the main reason for ischemic stroke and deep vein thrombosis. High-intensity focused ultrasound (HIFU) and histotripsy or microtripsy pulses can effectively dissolve the blood clot with no use of thrombolytic agent and ultrasound contrast agent (microbubbles). In this study, HIFU bursts at the same duty cycle (2%) but varied pulse repetition frequency (PRF) from 1Hz to 1000Hz were delivered to in vitro porcine blood clot for 30s. Thrombolysis efficiency initially increases slightly with the PRF, 86.4±10.3%, 89.9±11.9, and 92.9±12.8% at the PRF of 1Hz, 10Hz, and 100Hz, respectively, without significant difference (p>0.05), but then drops dramatically to 37.9±6.9% at the PRF of 1000Hz (p<0.05). The particle size in the supernatant of dissolution is 547.1±129.5nm, which suggests the disruption of thrombi into the subcellular level. Thrombi motion during HIFU exposure shows violent motion and significant curling at the low PRF, rotation about its axis with occasional curling at the moderate PRF, and localized vibration at the high PRF due to the generation of acoustic radiation force and streaming. Quantitative analysis of recorded motion shows the axial displacement decreases with the PRF of delivered HIFU bursts, from 3.9±1.5mm at 1Hz to 0.7±0.4mm at 1000Hz. Bubble cavitation during HIFU exposure to the blood clot was also monitored. The increase of PRF led to the increase of inertial cavitation but the decrease of stable cavitation. In summary, the PRF of delivered HIFU bursts at the same output energy has a significant effect on the thrombi motion, bubble cavitation activities, and subsequently thrombolysis efficiencies.

Ultrasound in Biomedical Engineering: Ultrasound Microbubble Contrast Agents Promote Transdermal Permeation of Drugs

This report discusses a new development in the use of ultrasound microbubble contrast agents on transdermal drug delivery. The medium surrounding the microbubbles at the optimum concentration from liquid to gel can be modified and it can still achieve the same enhancement for transdermal drug permeation as liquid medium. It was also found that under the same ultrasound power density, microbubbles of larger particle sizes can extend the penetration depths of dye at the phantom surface.

Development and validation of a quantitative measurement of the biomechanical marker of arterial disease, wall shear stress, using contrast enhanced high-frame rate plane-wave Doppler ultrasound

The development of arterial disease in the renal arteries is of clinical interest as it is associated with increased risk of conditions such as heart failure, hypertension, diabetes mellitus and cerebrovascular disease (Ganz and Hsue, 2013) [1] . A biomechanical marker of this damage is Wall Shear Stress (WSS), which plays a significant role in maintaining proper arterial functioning, and is linked to arterial wall stiffening and the formation of atherosclerotic plaques, and also contributes to the initiation and possibly the progression of atherosclerotic disease (Ganz and Hsue, 2013) [1] , (Zalunardo and Tuttle, 2004) [2] and (Chien et al., 1998) [3] . The effect of WSS on haemodynamic flow, is hence of considerable scientific and clinical interest. This poster will firstly, present an overview of wall shear stress and then critically review the different attempts which have been made to measure WSS, namely, magnetic resonance imaging and conventional pulsed-wave Doppler ultrasound techniques. The main limitations associated with both of these techniques are their inability to detect low blood velocity and also their poor velocity resolution, both of which are critical for accurate WSS measurements (Katritsis et al., 2007) [4] and (Torii et al., 2009) [5] . One approach which can be potentially implemented to improve the SNR and velocity resolution of pulsed-wave Doppler ultrasound is ultrasound microbubble contrast agents. However, ultrasound contrast agents have been used with limited success to improve the quality of the velocity information from blood and the main results from these studies will be discussed in this poster. Finally, the concluding aspect of this review will be a discussion of whether the determination of wall shear stress can be achieved using commercially available ultrasound systems.

Contrast-Enhanced Ultrasound: Practical Review for the Assessment of Hepatic and Renal Lesions.

The use of microbubble contrast greatly enhances the ability of ultrasound to delineate structures and therefore aid in diagnosis. Ultrasound microbubble contrast agents are composed of low-solubility gas encapsulated in a biomaterial shell. These agents use the physics of ultrasound imaging to effectively identify and characterize focal hepatic and renal lesions. Not only can contrast agents be used to evaluate multiple phases of lesion contrast enhancement, but ultrasound also allows for real-time study of enhancement patterns. The short half-life and intravascular location of the microbubbles allows for multiple, sequential administrations of contrast to observe enhancement of lesions in different sites. Furthermore, the ability to perform imaging without ionizing radiation and the lack of nephrotoxicity make contrast-enhanced ultrasound an ideal evaluation method for patients who need serial surveillance or in whom imaging options are severely limited because of renal insufficiency. These techniques are widely used in many countries for diagnostic radiological purposes; however, the lack of both Food and Drug Administration approval and reimbursement for noncardiac hospital-based imaging has delayed widespread use in the United States. Despite these limitations, continued research and innovations in ultrasound contrast make it essential to have a working knowledge of the typical enhancement patterns of frequently seen hepatic and renal lesions as these techniques offer an alternative option for contrast imaging.

Correlation study of biological characteristics of non-small cell lung cancer A549 cells after transfecting plasmid by microbubble ultrasound contrast agent.

To explore the role of the abnormal expression of miRNAs in the development process of non-small cell lung cancer and the feasibility of ultrasound microbubble-mediated gene therapy after transfecting antisense miRNA-224 and miRNA-122a plasmids into non-small cell lung cancer A549 cells. Antisense miRNA-224 and miRNA-122a plasmids were transfected into non-small cell lung cancer A549 cells on the optimal ultrasound microbubble-mediated condition. We set up a control group. The cell proliferation activity, apoptosis, invasion ability were detected by MTT assay, Annexin V-PE, Transwell invasion experiment and colony formation assay, respectively. The expression of miRNA-224 decreased and the expression of miRNA-122a rose after the plasmids of target genes were transfected into non-small cell lung cancer A549 cells, and there were significant differences when compared with those of the control group (P<0.05). After the plasmids of target genes were transfected into A549 cells, the growth of antisense miRNA-224 and miRNA-122a were inhibited, and the differences were significant as compared with the control group (P<0.05). Besides, the inhibition of miRNA-122a group was the most significant and there was statistically significant difference as compared with miRNA-224 group (t=-4.694, P=0.009). After the plasmids of target genes were transfected into A549 cells, the proportion of apoptotic cells increased, the invasive cells were decreased and the clone ability reduced, and also there was a significant difference as compared with those of the control group (P<0.05). What's more, the apoptotic peak appeared in miRNA-122a group. Its invasion ability decreased most obviously (40.25±3.97/visual field), the number of clone ability was 104.93±4.87 and the inhibitory effect was the most obviously. There was statistically significant difference as compared with other groups (P<0.05). A549 cells transfected by ultrasound microbubble-mediated antisense miRNA-224 and miRNA-122a plasmids possessed good transfection efficiency. The cell growth, invasion and colony-forming abilities of transfected A549 cells were suppressed, which laid a solid foundation for the gene therapy of non-small cell lung cancer.

Stability of Monodisperse Phospholipid-Coated Microbubbles Formed by Flow-Focusing at High Production Rates.

Monodisperse microbubble ultrasound contrast agents may dramatically increase the sensitivity and efficiency in ultrasound imaging and therapy. They can be produced directly in a microfluidic flow-focusing device, but questions remain as to the interfacial chemistry, such as the formation and development of the phospholipid monolayer coating over time. Here, we demonstrate the synthesis of monodisperse bubbles with radii of 2-10 μm at production rates ranging from 10(4) to 10(6) bubbles/s. All bubbles were found to dissolve to a stable final radius 2.55 times smaller than their initial radius, independent of the nozzle size and shear rate, indicating that the monolayer self-assembles prior to leaving the nozzle. The corresponding decrease in surface area by a factor 6.6 reveals that lipid molecules are adsorbed to the gas-liquid interface in the disordered expanded state, and they become mechanically compressed by Laplace pressure-driven bubble dissolution to a more ordered condensed state with near zero surface tension. Acoustic characterization of the stabilized microbubbles revealed that their shell stiffness gradually increased from 0.8 to 2.5 N/m with increasing number of insonations through the selective loss of the more soluble lipopolymer molecules. This work therefore demonstrates high-throughput production of clinically relevant monodisperse contrast microbubbles with excellent control over phospholipid monolayer elasticity and microbubble resonance.

Shape mode stability of lipid-coated ultrasound contrast agent microbubbles

Ultrasound contrast agents (UCAs) are shell encapsulated microbubbles developed originally for ultrasound imaging enhancement. More recently, UCAs are being exploited for therapeutic applications such as drug and gene delivery. Ultrasound transducer pulses can induce spherical (radial) UCA oscillations, translation, and nonspherical shape oscillations, the latter of which can lead to breakup. Breakup can facilitate drug or gene delivery, but should be minimized for imaging purposes to increase residence time and maximize diagnostic effect. Therefore, an understanding of the interplay between the acoustic driving and shape mode stability of UCAs is important for both diagnostic and therapeutic applications. The present work couples a radial model of a lipid-coated microbubble with a model for bubble translation and nonspherical shape oscillation to predict shape mode stability for ultrasound driving frequencies and pressure amplitudes of clinical interest. In addition, calculations of the stability of individual shape modes, residence time, maximum radius, and translation are provided with respect to acoustic driving parameters and compared to an unshelled bubble. The effects of shell elasticity, shell viscosity, and initial radius on stability are investigated. The results show greater stability at higher values of shell elasticity and viscosity and at smaller radius, and provide guidance for optimizing shell design and ultrasound driving parameters with respect to shape stability.

Ultrasound-mediated transport of nanoparticles and the influence of particle density

A significant barrier to successful drug delivery in cancer therapy is the limited penetration of nanoscale therapeutics deep into tumors. Ultrasound mediated cavitation has been shown to promote nanoparticle transport, but achieving tumor wide distribution still represents a considerable challenge. The current study investigates the way in which nanoparticle drug-carriers may be designed to enhance penetration under ultrasound exposure. A computational model has been developed to predict the transport of a nanoparticle in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming, and microstreaming. Experimental investigations were also performed in a tissue-mimicking phantom to study the transport of different types of particle, in the presence or absence of a microbubble ultrasound contrast agent, at ultrasound frequencies of 0.5 MHz and 1.6 MHz with peak pressures in the range of 0–2.0 MPa. Micro- and nanoparticles with contrasting density cores ranging from 1.0 g/cm3 to 19.3 g/cm3 were used for the study. Both the theoretical and experimental results showed that the denser particles exhibit significantly greater ultrasound-mediated transport than their lower density counterparts, indicating that this is a key consideration in the design of nanoscale therapeutics.

A novel technology: microfluidic devices for microbubble ultrasound contrast agent generation.

Microbubbles are used as ultrasound contrast agents, which enhance ultrasound imaging techniques. In addition, microbubbles currently show promise in disease therapeutics. Microfluidic devices have increased the ability to produce microbubbles with precise size, and high monodispersity compared to microbubbles created using traditional methods. This paper will review several variations in microfluidic device structures used to produce microbubbles as ultrasound contrast agents. Microfluidic device structures include T-junction, and axisymmetric and asymmetric flow-focusing. These devices have made it possible to produce microbubbles that can enter the vascular space; these microbubbles must be less than 10μm in diameter and have high monodispersity. For different demands of microbubbles production rate, asymmetric flow-focusing devices were divided into individual and integrated devices. In addition, asymmetric flow-focusing devices can produce double layer and multilayer microbubbles loaded with drug or biological components. Details on the mechanisms of both bubble formation and device structures are provided. Finally, microfluidically produced microbubble acoustic responses, microbubble stability, and microbubble use in ultrasound imaging are discussed.