Medical bubbles


  • Thesis Supervisors: Professor Nico de Jong (University of Twente), Professor Ton van der Steen (Erasmus University Rotterdam) Ph.D. conferred: September, 2004


Ultrasound contrast agents consist of gas bubbles with equilibrium radii to 5μm. These medical bubbles are small enough to be transported intravascularly and to pass through capillary vessels. Because their resonance frequencies coincide with those applied in ultrasonic imaging, they are suitable markers for the detection of perfused areas. Most of the ultrasound contrast agents that have been developed for clinical diagnostics contain slowly diffusing gas microbubbles encapsulated by highly elastic shells, to prevent them from dissolving too quickly during application. After intravascular injection of an agent into the circulation, microbubbles will pass the site of interest which is insonified by the clinician. Upon insonification, the microbubbles will generate a characteristic response, which is detected by the ultrasound scanner used. The resulting echographic image can then be interpreted by the clinician. Most studies on microbubble behavior have been based on the acoustic response from an ensemble of bubbles. With high-speed photography fast enough to surpass the bubble resonance periods, the observation of individual microbubble behavior has become possible. In this thesis, we made use of fast-framing camera systems operating at three million frames per second and higher, to observe dynamic behavior of individual microbubbles subjected to ultrasound. Multiple frames were captured during a single ultrasonic cycle. To account for the presence of a shell encapsulating the gas microbubble, the physical properties shell stiffness and shell friction have been accounted for in models describing microbubble oscillation. These properties have been measured for ensembles of ultrasound contrast agent microbubbles. From our results, however, it is suggested that the shell properties may differ between individual bubbles, because optically identical bubbles reveal different oscillating behavior. The presence of a shell appears to be less of interest for ultrasound contrast agent microbubble phenomena observed at high acoustic pressures: The physical mechanisms of microbubble coalescence, fragmentation, translation, and jetting (microsyringing) are comparable to those of free gas bubbles in the millimeter range. Because of the fast-framing, we are the first to notice repeated coalescence and fragmentation. Irregular shapes of insonified bubbles were previously interpreted and published in literature as modes of shape instability of a single bubble. However, these shapes may also be accounted for by coalescence of bubbles or bubble fragments. We investigated the influence of the lipid shell on the coalescence by computing the film drainage for immobile bubble surfaces resulting in a laminar flow, and for mobile bubbles surfaces resulting in a plug flow. The coalescence of lipid-encapsulated microbubbles appeared to be unimpeded by shells. Previously, release of gas from encapsulated microbubbles had been assumed from acoustical measurements. We demonstrated such release from encapsulated microbubbles with a rigid albumin shell during insonification. After this so-called “sonic cracking,” the free gas dissolves in the surrounding fluid. The release of gas from encapsulations may find an application in noninvasive pressure measurements. Medical bubbles will continue to play an important role in ultrasonic imaging, but they have potential therapeutic applications, too. The experiments have been performed at the Department of Experimental Echocardiography, Erasmus MC, Rotterdam, The Netherlands. The Ph.D. defense was held at the University of Twente, Enschede, The Netherlands, on 17 September, 2004. The project has been supported by the Technology Foundation STW (RKG.5104) and the Interuniversity Cardiology Institute of the Netherlands.