In Vitro Evaluation and Theoretical Modeling of the Dissolution Behavior of a Microbubble Contrast Agent for Ultrasound Imaging

Recent literature has reported increasing interest in using contrast agents for ultrasound imaging, in the form of shelled gas microbubbles, for innovative advanced purposes such as noninvasive targeted imaging and drug delivery. Effectiveness of such agents is time-dependent and is determined by microbubble dissolution behavior, a complex phenomenon whose knowledge is still limited. In the present study, we monitored the microbubbles of an experimental phospholipid-shelled perfluorobutane contrast agent through time-scheduled size distribution measurements. The diameter-time curve we obtained for shelled perfluorobutane microbubbles showed a rapid diameter increment up to about 1.4 times the initial value, followed by a slow decrement towards bubble disappearance. This behavior is qualitatively similar to the one theoretically predicted by Kabalnov's model for unshelled bubbles, with an extended lifetime due to shell effect. Kabalnov's model, devised for spontaneous dissolution of unshelled microbubbles, was consequently modified in order to get a proper prediction of experimental results also in the case of encapsulated bubbles. A theoretical diameter-time curve was then derived from this new model and fitted to our experimental data points, to estimate microbubble surface tension and to determine the value of an empirical parameter accounting for the shell effect. The proposed model has the potential to predict the dissolution behavior of all kinds of microbubble contrast agents for ultrasound imaging and the adopted experimental methodology represents a new and simple way to estimate microbubble surface tension, essential also for predicting microbubble oscillation performance.