Asymmetric oscillation of adherent targeted ultrasound contrast agents

Abstract

With a lipid shell containing biotin, micron-sized bubbles bound to avidin on a porous and flexible cellulose boundary were insonified by ultrasound. The oscillation of these targeted microbubbles was observed by high-speed photography and compared to the oscillation of free-floating microbubbles. Adherent microbubbles were observed to oscillate asymmetrically in the plane normal to the boundary, and nearly symmetrically in the plane parallel to the boundary, with a significantly smaller maximum expansion in each dimension for bound than free bubbles. With sufficient transmitted pressure, a jet was produced traveling toward the boundary.There is a great interest in developing molecularly targeted ultrasound contrast agents due to the potential medical applications. [1][2][3][4] The agents are gas bubbles with a diameter on the order of a few microns and a shell of albumin, lipid, or polymer. After intravenous injection, peptides or antibodies attached to the shells link the agents to a receptor on endothelial cells. Because of their high echogencity, these targeted agents can be detected by an ultrasound system with high sensitivity, and therefore can provide important information such as the spatial distribution and extent of tumor angiogenesis, 5,6 inflammatory response, 7,8 or thrombus. 9 Current contrast imaging schemes are not yet optimized for imaging these targeted agents because the microbubbles retained in tissue are limited in number, 5,9 and the signal from adherent microbubbles can be masked by the signal from freely circulating microbubbles. Strategies for imaging these agents currently require waiting for clearance of free-floating microbubbles or employing image averaging and subtraction techniques. Neither of these techniques is optimal since they require either a time delay, or multiple frames, which impede real-time imaging. Hence, there is a need for the development of a new selective and sensitive method for detecting adherent microbubbles, which will depend on our understanding of the acoustic behavior of a targeted microbubble after it binds to a targeting site.Mathematical simulations have been developed for modeling microbubble radial oscillation with different assumptions and simplifications. [10][11][12] High-speed micrography has been used to study microbubble radial oscillation, 13 translation, 14 and fragmentation. 15 In these studies, a microbubble is assumed to remain spherical and in an infinite medium. Asymmetrical oscillation of a cavitation bubble and formation of a jet have been studied both theoretically and experimentally by a number of research groups, [16][17][18] although previous experimental studies have involved unencapsulated bubbles of a diameter larger than micron-sized contrast agents, and have not used ultrasound as an excitation source. The behavior of a targeted microbubble after it binds to a vessel wall and is insonified by an ultrasound pulse has not been reported previously. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn...

Ultrasound contrast agents : dynamics of coated bubbles

“…Finally, asymmetric oscillations may arise in the vicinity of the wall. The eccentricity of bubbles in the vicinity of a capillary wall and driven at comparable pressures has been indeed reported to be close to 0.7 [95], although these observations were made on adherent bubbles. In our experiments, the possible adhesion to the wall was excluded by verifying with the optical tweezers whether bubbles were indeed non-adherent, yet in contact with the wall.…”

“…the non-invasive detection of a specific disease at a molecular level, it will be crucial to develop methods for selectively detecting adherent UCA microbubbles that have bound to specific molecular targets from freely flowing ones, primarily based on a change in their acoustic response. Considerable differences in the amplitude of oscillations [95,96] and in the spectral response [97] were reported recently. In general, the studies on UCA microbubble dynamics suffer from the lack of control on bubble position, however, and they are therefore based on ensemble averaging and statistical observations of many different bubbles.…”

Geometrical effects on the tuning of Chinese and Korean stone chimes

“…16 Third, Zhao et al observed previously that microbubbles adherent to a vessel wall oscillate asymmetrically in the plane normal to the boundary, in contrast to free microbubbles which oscillate symmetrically. 5 Further, for a low transmission pressure, the volume oscillation was observed to decrease in comparison with free agents. Asymmetrical oscillation of a cavitation bubble and formation of a jet near a boundary or within a vessel have been studied both theoretically and experimentally by number of research groups.…”

“…Thus, tethers on the order of nanometers in length connect these small bubbles to endothelial cells and bring them in close contact with a boundary. The oscillation of these adherent microbubbles was observed to be asymmetrical by high-speed photography 5 but their acoustic response has not been reported previously. Optimal detection of bound agents would require differentiating their echoes from those produced by freely circulating agents and the surrounding tissue.…”

A non-linear three-dimensional model for quantifying microbubble dynamics

“…2(d)]. Similar experimental parameters were used in works published by Garbin et al, 13 Zhao et al, 14 and Vos et al 15 In the adherent microbubble model, the vessel wall was simulated using the mechanical properties of a stiff arterial wall 8 with the stiffness of ͑E = 1 MPa͒ and the density of 1000 kg/ m 3 . The arterial wall was assumed to be incompressible.…”