The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Alexander L Klibanov - One of the best experts on this subject based on the ideXlab platform.
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ultrasound mediated vascular gene transfection by cavitation of endothelial targeted cationic Microbubbles
Jacc-cardiovascular Imaging, 2012Co-Authors: Aris Xie, Alexander L Klibanov, Todd Belcik, Terry Morgan, Shivam A Champaneri, Sarah Taylor, Brian P Davidson, Yan Zhao, Michael A Kuliszewski, Howard LeongpoiAbstract:Objectives Ultrasound-mediated gene delivery can be amplified by acoustic disruption of Microbubble carriers that undergo cavitation. We hypothesized that endothelial targeting of Microbubbles bearing cDNA is feasible and, through optimizing proximity to the vessel wall, increases the efficacy of gene transfection. Background Contrast ultrasound-mediated gene delivery is a promising approach for site-specific gene therapy, although there are concerns with the reproducibility of this technique and the safety when using high-power ultrasound. Methods Cationic lipid-shelled decafluorobutane Microbubbles bearing a targeting moiety were prepared and compared with nontargeted Microbubbles. Microbubble targeting efficiency to endothelial adhesion molecules (P-selectin or intercellular adhesion molecule [ICAM]-1) was tested using in vitro flow chamber studies, intravital microscopy of tumor necrosis factor-alpha (TNF-α)–stimulated murine cremaster muscle, and targeted contrast ultrasound imaging of P-selectin in a model of murine limb ischemia. Ultrasound-mediated transfection of luciferase reporter plasmid charge coupled to Microbubbles in the post-ischemic hindlimb muscle was assessed by in vivo optical imaging. Results Charge coupling of cDNA to the Microbubble surface was not influenced by the presence of targeting ligand, and did not alter the cavitation properties of cationic Microbubbles. In flow chamber studies, surface conjugation of cDNA did not affect attachment of targeted Microbubbles at microvascular shear stresses (0.6 and 1.5 dyne/cm 2 ). Attachment in vivo was also not affected by cDNA according to intravital microscopy observations of venular adhesion of ICAM-1–targeted Microbubbles and by ultrasound molecular imaging of P-selectin–targeted Microbubbles in the post-ischemic hindlimb in mice. Transfection at the site of high acoustic pressures (1.0 and 1.8 MPa) was similar for control and P-selectin–targeted Microbubbles but was associated with vascular rupture and hemorrhage. At 0.6 MPa, there were no adverse bioeffects, and transfection was 5-fold greater with P-selectin–targeted Microbubbles. Conclusions We conclude that ultrasound-mediated transfection at safe acoustic pressures can be markedly augmented by endothelial juxtaposition.
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Microbubbles as ultrasound contrast agents for molecular imaging preparation and application
American Journal of Roentgenology, 2012Co-Authors: Sunil Unnikrishnan, Alexander L KlibanovAbstract:OBJECTIVE. The purpose of this review is to describe trends in Microbubble application in molecular imaging. CONCLUSION. Microbubbles are used for contrast ultrasound imaging as blood-pool agents in cardiology and radiology. Their promise as targeted agents for molecular imaging is now being recognized. Microbubbles can be functionalized with ligand molecules that bind to molecular markers of disease. Potential clinical applications of molecular imaging with Microbubble-based ultrasound contrast agents are in the monitoring of the biomarker status of vascular endothelium, visualizing tumor vasculature, and imaging inflammation and ischemia-reperfusion injury zones and thrombi.
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intravascular ultrasound catheter to enhance Microbubble based drug delivery via acoustic radiation force
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control, 2012Co-Authors: Joseph P Kilroy, Alexander L Klibanov, Brian R Wamhoff, John A. HossackAbstract:Previous research has demonstrated that acoustic radiation force enhances intravascular Microbubble adhesion to blood vessels in the presence of flow for molecular-targeted ultrasound imaging and drug delivery. A prototype acoustic radiation force intravascular ultrasound (ARFIVUS) catheter was designed and fabricated to displace a Microbubble contrast agent in flow representative of conditions encountered in the human carotid artery. The prototype ARFIVUS transducer was designed to match the resonance frequency of 1.4- to 2.6-μm-diameter Microbubbles modeled by an experimentally verified 1-D Microbubble acoustic radiation force translation model. The transducer element was an elongated Navy Type I (hard) lead zirconate titanate (PZT) ceramic designed to operate at 3 MHz. Fabricated devices operated with center frequencies of 3.3 and 3.6 MHz with -6-dB fractional bandwidths of 55% and 50%, respectively. Microbubble translation velocities as high as 0.86 m/s were measured using a high-speed streak camera when insonating with the ARFIVUS transducer. Finally, the prototype was used to displace Microbubbles in a flow phantom while imaging with a commercial 45-MHz imaging IVUS transducer. A sustained increase of 31 dB in average video intensity was measured following insonation with the ARFIVUS, indicating Microbubble accumulation resulting from the application of acoustic radiation force.
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ultrasound triggered release of materials entrapped in Microbubble liposome constructs a tool for targeted drug delivery
Journal of Controlled Release, 2010Co-Authors: Alexander L Klibanov, Talent I Shevchenko, Balasundar Iyyavu Raju, Ralf Seip, Chien Ting ChinAbstract:Abstract We investigated the preparation of ultrasound-triggered drug delivery system, based on a pendant complex of Microbubble coated with liposomes. Biotinylated decafluorobutane Microbubbles were coated with biotinylated liposomes via a streptavidin linker. Liposomes were prepared incorporating calcein and thrombin. Based on initial concentration of calcein, over 1 um3 payload volume per each Microbubble–liposome particle was achieved, when 100 nm liposomes were used. Insonation of Microbubble–liposome pendants in vitro resulted in the complete destruction of Microbubbles and triggered release of a significant fraction of the entrapped material. Treatment with 1 MHz ultrasound (5 pulses, 100 ms, 7 MPa peak negative acoustic pressure) resulted in the release of ~ 30% of entrapped calcein, as estimated by the fluorescence quenching assay. Thrombin release from liposomes complexed with Microbubbles (11% of entrapped material) due to ultrasound treatment was estimated by a chromogenic substrate study. Prior to insonation, substrate hydrolysis was at background level. Ultrasound-triggered release of thrombin from the pendant complexes caused an acceleration of blood clotting.
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dual targeting improves Microbubble contrast agent adhesion to vcam 1 and p selectin under flow
Journal of Controlled Release, 2009Co-Authors: Elisa A Ferrante, Alexander L Klibanov, Joshua J Rychak, J E Pickard, Klaus LeyAbstract:Abstract To improve ultrasound contrast agents targeted to the adhesion molecules P-selectin and VCAM-1 for the purpose of molecular imaging of atherosclerotic plaques, perfluorocarbon-filled phospholipid Microbubble contrast agents were coupled by a polyethylene glycol–biotin–streptavidin bridge with mAb MVCAM.A(429), a sialyl Lewis x polymer (PAA-sLe x ), or both (dual). Approximately three hundred thousand antibody molecules were coupled to the surface of each Microbubble. Recombinant mouse P-selectin and/or VCAM-1 coated on flow chambers showed saturation of binding at approximately 15 ng/μl, resulting in 800 and 1200 molecules/µm 2 for P-selectin and VCAM-1, respectively. Dual substrates coated with equal concentrations of P-selectin and VCAM-1 had site densities between 50 and 60% of single substrates. When Microbubbles were perfused through flow chambers at 5 × 10 6 Microbubbles/ml (wall shear stress from 1.5 to 6 dyn/cm 2 ) dual-targeted Microbubbles adhered almost twice as efficiently as single-targeted Microbubbles at 6 dyn/cm 2 . The present study suggests that dual-targeted contrast agents may be useful for atherosclerotic plaque detection at physiologically relevant shear stresses.
Mark A Borden - One of the best experts on this subject based on the ideXlab platform.
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Lipid monolayer collapse and Microbubble stability
Advances in Colloid and Interface Science, 2012Co-Authors: James J Kwan, Mark A BordenAbstract:Abstract Microbubbles are micrometer-size gaseous particles suspended in water, and they are often stabilized by a lipid monolayer shell. Natural Microbubbles are found in freshwater and saltwater systems, and engineered Microbubbles have a variety of applications in food sciences, biotechnology and medicine. Lipid-coated Microbubbles are found to have remarkable stability and mechanical behavior owing to the resistance of the lipid monolayer encapsulation to collapse. The purpose of this review is to tie in recent observations of lipid-coated Microbubble dissolution and gas exchange with current literature on the physics of lipid monolayer collapse in the context of lung surfactant. Based on this analysis, we conclude that Microbubble shells collapse through the nucleation of microscopic folds, which then catalyze the formation and aggregation of new folds, leading to macroscopic folding events. This process results in a cyclic behavior of crumple-to-smooth transitions, which can be modulated through lipid composition. Eventually, the Microbubbles stabilize at 1–2 μm diameter, regardless of initial size or lipid composition, and various mechanisms for this stabilization are postulated. Our ultimate goal is to inspire the reader to consider lipid monolayer collapse as the main long-term stabilizing mechanism for lipid-coated Microbubbles, and to stimulate the use of Microbubbles as a platform for studying monolayer collapse phenomena.
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lipid monolayer dilatational mechanics during Microbubble gas exchange
Soft Matter, 2012Co-Authors: James J Kwan, Mark A BordenAbstract:Lipid-coated Microbubbles are being developed for a variety of biomedical applications in imaging and therapy. In order to better understand Microbubble stability and in vivo fate, it is important to elucidate the mechanical properties of the phospholipid monolayer shell. Here, a gas exchange method was used to probe the monolayer dilatational properties of individual Microbubbles. The Microbubbles were observed to grow and then dissolve back to the initial diameter in a manner that depended on both Microbubble size and lipid composition. The experimental diameter–time curves were analyzed with a gas transport model employing the energy barrier theory for monolayer permeation to account for gas species, acyl-chain length and variable surface pressure. Model analysis allowed computation of apparent surface tension as a function of area, which exhibited a characteristic “flag-shaped” curve comprising three regimes: (i) linear elastic expansion, (ii) nonlinear relaxation during expansion and (iii) linear elastic compression. A comparison of fitted model parameters suggested a molecular mechanism involving expansion, rupture and lipid lateral diffusion in the monolayer shell during growth and lipid domain growth and packing during dissolution. Overall, these results provide new physical insights into lipid monolayer behavior that are relevant to understanding Microbubble stability and medical performance.
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polyplex Microbubble hybrids for ultrasound guided plasmid dna delivery to solid tumors
Journal of Controlled Release, 2012Co-Authors: Shashank R Sirsi, Shunichi Homma, Sonia L Hernandez, Lukasz Zielinski, Henning Blomback, Adel Koubaa, Milo Synder, Jessica J Kandel, Darrell J Yamashiro, Mark A BordenAbstract:Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-Microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated Microbubbles. The PEI-Microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-Microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent Microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-Microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-Microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-Microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-Microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection.
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advances in ultrasound mediated gene therapy using Microbubble contrast agents
Theranostics, 2012Co-Authors: Shashank R Sirsi, Mark A BordenAbstract:Microbubble ultrasound contrast agents have the potential to dramatically improve gene therapy treatments by enhancing the delivery of therapeutic DNA to malignant tissue. The physical response of Microbubbles in an ultrasound field can mechanically perturb blood vessel walls and cell membranes, enhancing drug permeability into malignant tissue. In this review, we discuss literature that provided evidence of specific mechanisms that enhance in vivo gene delivery utilizing Microbubble contrast agents, namely their ability to 1) improving cell membrane permeability, 2) modulate vascular permeability, and 3) enhance endocytotic uptake in cells. Additionally, we review novel Microbubble vectors that are being developed in order to exploit these mechanisms and deliver higher gene payloads with greater target specificity. Finally, we discuss some future considerations that should be addressed in the development of next-generation Microbubbles in order to improve in vivo Microbubble gene delivery. Overall, Microbubbles are rapidly gaining popularity as efficient gene carriers, and combined with their functionality as imaging contrast agents, they represent powerful theranostic tools for image guided gene therapy applications.
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effect of Microbubble size on fundamental mode high frequency ultrasound imaging in mice
Ultrasound in Medicine and Biology, 2010Co-Authors: Shashank R Sirsi, Jameel A Feshitan, James J Kwan, Shunichi Homma, Mark A BordenAbstract:Abstract High-frequency ultrasound imaging using Microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse Microbubble suspensions, which may provide a complex and varied acoustic response. To study the effect of individual Microbubble size populations, Microbubbles of 1–2 μm, 4–5 μm and 6–8 μm diameter were isolated using the technique of differential centrifugation. Size-selected Microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system (Visualsonics, Toronto, Ontario, Canada) with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on Microbubble size and concentration. Large Microbubbles (4–5 and 6–8 μm) strongly enhanced the ultrasound image with positive contrast, while 1–2 μm Microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6–8 μm diameter Microbubbles at 5 × 10 7 MB/bolus compared with 4–5 μm Microbubbles at the same concentration. Interestingly, 1–2 μm diameter Microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger Microbubbles were more persistent in circulation. However, when volume matched, all Microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that Microbubbles can be tailored for optimal contrast enhancement in fundamental mode imaging. (E-mail: mb2910@columbia.edu )
Shashank R Sirsi - One of the best experts on this subject based on the ideXlab platform.
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polyplex Microbubble hybrids for ultrasound guided plasmid dna delivery to solid tumors
Journal of Controlled Release, 2012Co-Authors: Shashank R Sirsi, Shunichi Homma, Sonia L Hernandez, Lukasz Zielinski, Henning Blomback, Adel Koubaa, Milo Synder, Jessica J Kandel, Darrell J Yamashiro, Mark A BordenAbstract:Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-Microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated Microbubbles. The PEI-Microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-Microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent Microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-Microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-Microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-Microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-Microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection.
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advances in ultrasound mediated gene therapy using Microbubble contrast agents
Theranostics, 2012Co-Authors: Shashank R Sirsi, Mark A BordenAbstract:Microbubble ultrasound contrast agents have the potential to dramatically improve gene therapy treatments by enhancing the delivery of therapeutic DNA to malignant tissue. The physical response of Microbubbles in an ultrasound field can mechanically perturb blood vessel walls and cell membranes, enhancing drug permeability into malignant tissue. In this review, we discuss literature that provided evidence of specific mechanisms that enhance in vivo gene delivery utilizing Microbubble contrast agents, namely their ability to 1) improving cell membrane permeability, 2) modulate vascular permeability, and 3) enhance endocytotic uptake in cells. Additionally, we review novel Microbubble vectors that are being developed in order to exploit these mechanisms and deliver higher gene payloads with greater target specificity. Finally, we discuss some future considerations that should be addressed in the development of next-generation Microbubbles in order to improve in vivo Microbubble gene delivery. Overall, Microbubbles are rapidly gaining popularity as efficient gene carriers, and combined with their functionality as imaging contrast agents, they represent powerful theranostic tools for image guided gene therapy applications.
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effect of Microbubble size on fundamental mode high frequency ultrasound imaging in mice
Ultrasound in Medicine and Biology, 2010Co-Authors: Shashank R Sirsi, Jameel A Feshitan, James J Kwan, Shunichi Homma, Mark A BordenAbstract:Abstract High-frequency ultrasound imaging using Microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse Microbubble suspensions, which may provide a complex and varied acoustic response. To study the effect of individual Microbubble size populations, Microbubbles of 1–2 μm, 4–5 μm and 6–8 μm diameter were isolated using the technique of differential centrifugation. Size-selected Microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system (Visualsonics, Toronto, Ontario, Canada) with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on Microbubble size and concentration. Large Microbubbles (4–5 and 6–8 μm) strongly enhanced the ultrasound image with positive contrast, while 1–2 μm Microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6–8 μm diameter Microbubbles at 5 × 10 7 MB/bolus compared with 4–5 μm Microbubbles at the same concentration. Interestingly, 1–2 μm diameter Microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger Microbubbles were more persistent in circulation. However, when volume matched, all Microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that Microbubbles can be tailored for optimal contrast enhancement in fundamental mode imaging. (E-mail: mb2910@columbia.edu )
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effect of Microbubble size on fundamental mode high frequency ultrasound imaging in mice
Ultrasound in Medicine and Biology, 2010Co-Authors: Shashank R Sirsi, Jameel A Feshitan, James J Kwan, Shunichi Homma, Mark A BordenAbstract:High-frequency ultrasound imaging using Microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse Microbubble suspensions, which may provide a complex and varied acoustic response. To study the effect of individual Microbubble size populations, Microbubbles of 1-2 microm, 4-5 microm and 6-8 microm diameter were isolated using the technique of differential centrifugation. Size-selected Microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system (Visualsonics, Toronto, Ontario, Canada) with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on Microbubble size and concentration. Large Microbubbles (4-5 and 6-8 microm) strongly enhanced the ultrasound image with positive contrast, while 1-2 microm Microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6-8 microm diameter Microbubbles at 5 x 10(7) MB/bolus compared with 4-5 microm Microbubbles at the same concentration. Interestingly, 1-2 microm diameter Microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger Microbubbles were more persistent in circulation. However, when volume matched, all Microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that Microbubbles can be tailored for optimal contrast enhancement in fundamental mode imaging.
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Microbubble compositions properties and biomedical applications
Bubble Science Engineering & Technology, 2009Co-Authors: Shashank R Sirsi, Mark A BordenAbstract:Over the last decade, there has been significant progress towards the development of Microbubbles as theranostics for a wide variety of biomedical applications. The unique ability of Microbubbles to respond to ultrasound makes them useful agents for contrast ultrasound imaging, molecular imaging, and targeted drug and gene delivery. The general composition of a Microbubble is a gas core stabilized by a shell comprised of proteins, lipids or polymers. Each type of Microbubble has its own unique advantages and can be tailored for specialized functions. In this review, different Microbubbles compositions and physiochemical properties are discussed in the context of current progress towards developing novel constructs for biomedical applications, with specific emphasis on molecular imaging and targeted drug/gene delivery.
James J Kwan - One of the best experts on this subject based on the ideXlab platform.
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Lipid monolayer collapse and Microbubble stability
Advances in Colloid and Interface Science, 2012Co-Authors: James J Kwan, Mark A BordenAbstract:Abstract Microbubbles are micrometer-size gaseous particles suspended in water, and they are often stabilized by a lipid monolayer shell. Natural Microbubbles are found in freshwater and saltwater systems, and engineered Microbubbles have a variety of applications in food sciences, biotechnology and medicine. Lipid-coated Microbubbles are found to have remarkable stability and mechanical behavior owing to the resistance of the lipid monolayer encapsulation to collapse. The purpose of this review is to tie in recent observations of lipid-coated Microbubble dissolution and gas exchange with current literature on the physics of lipid monolayer collapse in the context of lung surfactant. Based on this analysis, we conclude that Microbubble shells collapse through the nucleation of microscopic folds, which then catalyze the formation and aggregation of new folds, leading to macroscopic folding events. This process results in a cyclic behavior of crumple-to-smooth transitions, which can be modulated through lipid composition. Eventually, the Microbubbles stabilize at 1–2 μm diameter, regardless of initial size or lipid composition, and various mechanisms for this stabilization are postulated. Our ultimate goal is to inspire the reader to consider lipid monolayer collapse as the main long-term stabilizing mechanism for lipid-coated Microbubbles, and to stimulate the use of Microbubbles as a platform for studying monolayer collapse phenomena.
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lipid monolayer dilatational mechanics during Microbubble gas exchange
Soft Matter, 2012Co-Authors: James J Kwan, Mark A BordenAbstract:Lipid-coated Microbubbles are being developed for a variety of biomedical applications in imaging and therapy. In order to better understand Microbubble stability and in vivo fate, it is important to elucidate the mechanical properties of the phospholipid monolayer shell. Here, a gas exchange method was used to probe the monolayer dilatational properties of individual Microbubbles. The Microbubbles were observed to grow and then dissolve back to the initial diameter in a manner that depended on both Microbubble size and lipid composition. The experimental diameter–time curves were analyzed with a gas transport model employing the energy barrier theory for monolayer permeation to account for gas species, acyl-chain length and variable surface pressure. Model analysis allowed computation of apparent surface tension as a function of area, which exhibited a characteristic “flag-shaped” curve comprising three regimes: (i) linear elastic expansion, (ii) nonlinear relaxation during expansion and (iii) linear elastic compression. A comparison of fitted model parameters suggested a molecular mechanism involving expansion, rupture and lipid lateral diffusion in the monolayer shell during growth and lipid domain growth and packing during dissolution. Overall, these results provide new physical insights into lipid monolayer behavior that are relevant to understanding Microbubble stability and medical performance.
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effect of Microbubble size on fundamental mode high frequency ultrasound imaging in mice
Ultrasound in Medicine and Biology, 2010Co-Authors: Shashank R Sirsi, Jameel A Feshitan, James J Kwan, Shunichi Homma, Mark A BordenAbstract:Abstract High-frequency ultrasound imaging using Microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse Microbubble suspensions, which may provide a complex and varied acoustic response. To study the effect of individual Microbubble size populations, Microbubbles of 1–2 μm, 4–5 μm and 6–8 μm diameter were isolated using the technique of differential centrifugation. Size-selected Microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system (Visualsonics, Toronto, Ontario, Canada) with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on Microbubble size and concentration. Large Microbubbles (4–5 and 6–8 μm) strongly enhanced the ultrasound image with positive contrast, while 1–2 μm Microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6–8 μm diameter Microbubbles at 5 × 10 7 MB/bolus compared with 4–5 μm Microbubbles at the same concentration. Interestingly, 1–2 μm diameter Microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger Microbubbles were more persistent in circulation. However, when volume matched, all Microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that Microbubbles can be tailored for optimal contrast enhancement in fundamental mode imaging. (E-mail: mb2910@columbia.edu )
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effect of Microbubble size on fundamental mode high frequency ultrasound imaging in mice
Ultrasound in Medicine and Biology, 2010Co-Authors: Shashank R Sirsi, Jameel A Feshitan, James J Kwan, Shunichi Homma, Mark A BordenAbstract:High-frequency ultrasound imaging using Microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse Microbubble suspensions, which may provide a complex and varied acoustic response. To study the effect of individual Microbubble size populations, Microbubbles of 1-2 microm, 4-5 microm and 6-8 microm diameter were isolated using the technique of differential centrifugation. Size-selected Microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system (Visualsonics, Toronto, Ontario, Canada) with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on Microbubble size and concentration. Large Microbubbles (4-5 and 6-8 microm) strongly enhanced the ultrasound image with positive contrast, while 1-2 microm Microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6-8 microm diameter Microbubbles at 5 x 10(7) MB/bolus compared with 4-5 microm Microbubbles at the same concentration. Interestingly, 1-2 microm diameter Microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger Microbubbles were more persistent in circulation. However, when volume matched, all Microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that Microbubbles can be tailored for optimal contrast enhancement in fundamental mode imaging.
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Microbubble Dissolution in a Multigas Environment
Langmuir, 2010Co-Authors: James J Kwan, Mark A BordenAbstract:Microbubbles occur naturally in the oceans and are used in many industrial and biomedical applications. Here, a theoretical and experimental study was undertaken to determine the fate of a Microbubble suddenly suspended in a medium with several gas species as in, for example, the injection of an ultrasound contrast agent into the bloodstream. The model expands on Epstein and Plesset’s analysis to include any number of gases. An experimental system was developed which isolates the Microbubble in a permeable hollow fiber submerged in a perfusion chamber, allowing rapid exchange of the external aqueous medium. Experimental verification of the model was performed with individual sulfur hexafluoride (SF6) Microbubbles coated with the soluble surfactant, sodium dodecyl sulfate (SDS). SDS-coated Microbubbles suddenly placed in an air-saturated medium initially grew with the influx of O2 and N2 and then dissolved under Laplace pressure. SF6-filled Microbubbles coated with the highly insoluble lipid, dibehenoylpho...
Nico De Jong - One of the best experts on this subject based on the ideXlab platform.
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dspc or dppc as main shell component influences ligand distribution and binding area of lipid coated targeted Microbubbles
European Journal of Lipid Science and Technology, 2014Co-Authors: Klazina Kooiman, Tom J. A. Kokhuis, Antonius F.w. Van Der Steen, Tom Van Rooij, Ilya Skachkov, Alex L Nigg, J G Bosch, Wiggert A Van Cappellen, Nico De JongAbstract:Ultrasound contrast agents (UCA) consist of gas-filled coated Microbubbles with diameters of 1–10 µm. Targeted UCA can bind to biomarkers associated with disease through coating-incorporated ligands, making ultrasound molecular imaging possible. The aim of our research was to compare the ligand distribution, binding area, and bound Microbubble shape of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) based and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) based lipid-coated Microbubbles using super-resolution microscopy. Ligand distribution was studied by conjugating the fluorescent streptavidin Oregon Green 488 to the biotinylated Microbubbles. An inhomogeneous streptavidin distribution was found when DSPC was the main coating lipid. When DSPC was replaced by DPPC, a more homogeneous streptavidin distribution was observed. Binding area of targeted Microbubbles was studied using biotinylated Microbubbles bound to a streptavidin-coated surface. DSPC Microbubbles had a significantly smaller binding area than DPPC Microbubbles. Whereas the bound DSPC Microbubbles remained spherical, the DPPC Microbubbles were dome-shaped. This study reveals that lipid-coated Microbubbles differ in ligand distribution, binding area, and bound Microbubble shape solely on the basis of their main lipid component. Practical applications: A homogeneous ligand distribution, larger binding area and domed shape upon binding could be advantageous for binding of targeted Microbubbles, thereby favoring DPPC over DSPC as main lipid for UCA for ultrasound molecular imaging. The findings of the present study can be used for the design of targeted Microbubbles with improved binding capabilities and for the ongoing research to acoustically distinguish bound from unbound Microbubbles. Targeted biotinylated DSPC and DPPC-based Microbubbles bound to streptavidin-coated surface. Left graph: binding area; right panels: Microbubbles (red fluorescent) bound to streptavidin-coated surface (green fluorescent).
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the onset of Microbubble vibration
Ultrasound in Medicine and Biology, 2007Co-Authors: M Emmer, Nico De Jong, Annemieke Van Wamel, David E GoertzAbstract:A linear relationship between the relative expansion of an off-resonance ultrasound contrast Microbubble and low acoustic pressures is expected. In this study, high-speed optical recordings of individual phospholipid-coated Microbubbles were used to investigate this relationship for Microbubbles ranging from 2 to 11 μm and for acoustic pressures ranging from 20 to 250 kPa at a driving frequency of 1.7 MHz. For Microbubbles larger than 5 μm, the relative expansion (ΔD/D0) increased linearly with applied acoustic pressure, starting at the origin. The response of smaller Microbubbles (<5 μm) also increased linearly with the applied acoustic pressure. However, linearity started at an acoustic pressure threshold value of 30 to 120 kPa for the different individual Microbubbles. Below these pressure values, little or no oscillation was observed. The results may be explained by size-dependent mechanical properties of the phospholipid shells. An imaging technique such as power modulation imaging could profit from the presence of an acoustic pressure threshold in the Microbubble response.
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micromanipulation of endothelial cells ultrasound Microbubble cell interaction
Ultrasound in Medicine and Biology, 2004Co-Authors: Nico De Jong, Annemieke Van Wamel, Ayache Bouakaz, Michel VersluisAbstract:Ultrasound (US) in combination with contrast Microbubbles has been shown to alter the permeability of cell membranes without affecting cell viability. This permeabilisation feature is used to design new drug delivery systems using US and contrast agents. The underlying mechanisms are still unknown. One hypothesis is that oscillating Microbubbles cause cell deformation resulting in enhanced cell membrane permeability. This technical note reveals the interaction between oscillating Microbubbles and endothelial cells under a microscope recorded with a fast framing camera at 10 million frames per second. A Microbubble expansion of 100% resulted a 2.3-m displacement of the cell membrane. During the insonification, changes of approximately 15% in the cross-sectional distance of the endothelial cells were observed due to Microbubble vibrations. In conclusion, the use of such a camera makes it possible to reveal the mechanisms of interactions between ultrasound, Microbubbles and cells.