IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICS, AND FREQUENCY CONTROL, . 59, . 12, DECEMBER 2012 2818 0885–3010/$25.00 © 2012 IEEE Abstract—Phospholipid-coated ultrasound contrast agents may deflate or even collapse because of stress resulting from ultrasound-induced oscillations. In this work, we investigate the behavior of isolated contrast agent microbubbles during prolonged ultrasound excitation. Isolated microbubbles placed in a thin capillary tube were excited with hundreds of ultra- sound pulses at a low mechanical index, and their oscillations were recorded using the Brandaris-128 ultra-high-speed cam- era. Results show that microbubbles undergo an irreversible, non-destructive deflation process. Such deflation seems to oc- cur in discrete steps rather than as a continuous process; fur- thermore, the dynamics of the bubble change during deflation: radial oscillations, both symmetric and asymmetric around the resting radius of the bubble, occur at various stages of the deflation process. Strongly asymmetric oscillations, such as compression-only and expansion-only behavior, were also observed: notably, expansion-only behavior is associated with a rapid size reduction, whereas compression-only behavior most- ly occurs without a noticeable change of the bubble radius. We hypothesize that bubble deflation results from at least two distinct phenomena, namely diffusive gas loss and lipid mate- rial shedding from the encapsulating shell. I. I U  contrast agents (UCAs) are made of a suspension of micrometer-sized gas bubbles, which are coated by a thin flexible shell. The microbubbles os- cillate when hit by an ultrasound (US) pressure pulse, thereby generating an echo that can be detected in the far field. In medical US imaging, UCAs are used to increase the contrast between the echoes backscattered from the blood pool and those backscattered from tissue [1]–[4]. The optimal strategy for contrast detection should take into account both the specific application scenario and the UCA physical characteristics; for example, when imaging regions with a very low blood velocity, such as in the capil- lary bed of organs, microbubbles might be exposed to sev- eral hundreds of US pulses. Such prolonged excitation is expected to drive the microbubbles toward dissolution [5], [6]. Dissolution of the bubbles may result from different physical phenomena. In phospholipid-coated bubbles, dis- solution occurs mostly as direct gas loss from the bubble through the release of smaller bubbles [7], or through gas diffusion from the bubble core into the surrounding fluid [8], [9]. The former process is a fast phenomenon, often occurring after violent oscillations, whereas the latter pro- cess is relatively slow, because it is driven by capillary pressure and gas concentration. Because these dissolution phenomena are expected to alter the bubble response in a significant way, accurate characterization of UCAs should also attempt to track bubble transformations in time dur- ing multiple exposures to ultrasound, because changes in the bubble response may alter the performance of the im- aging strategy. In this work, we investigated experimentally how single phospholipid-coated microbubbles respond to prolonged US excitation. A custom setup was built to position a single, isolated bubble in the optical focus of an immer- sion microscope and in the acoustical focus of an US transducer. The latter repeatedly excited the bubble with low-pressure pulses, to stress the bubble while avoiding its rapid destruction. Bubble oscillations were recorded at different stages of the deflation process using ultrafast optical imaging. This approach offered insight into the physical process leading to deflation, and two different phenomena are highlighted from the recorded dynamics. II. M  M A. Setup A schematic representation of the setup is shown in Fig. 1. The Brandaris-128 camera [10] was connected to an immersion microscope focused on a thin cellulose capillary (outer diameter 200 μm; wall thickness 20 μm) stretched across a cylindrical water tank. Flow inside the capillary was controlled manually using a syringe connect- ed to a fine-pitch micrometer screw. Definity (Lantheus Medical Imaging Inc., N. Billerica, MA) contrast agent bubbles were used. The bubble oscillations were recorded at approximately 13 million frames/s, with an optical 70× magnification factor, yielding a final image resolution of 0.135 μm per pixel. US pulses were transmitted by a wide- band transducer (PA076 PVDF, Precision Acoustics Ltd., Dorchester, UK) driven by the bubble behavior testing (BBT) board, a two-channel custom programmable ultra- sound system developed in-house [11]. B. Experiments A highly diluted suspension of Definity was injected in the capillary, then flushed until a single, isolated bubble was in the optical focus of the microscope objective, which was co-aligned with the acoustical focus of the US trans- Nonlinear Oscillations of Deflating Bubbles Jacopo Viti, Riccardo Mori, Francesco Guidi, Michel Versluis, Nico de Jong, and Piero Tortoli Correspondence Manuscript received April 24, 2012; accepted September 3, 2012. J. Viti, R. Mori, F. Guidi, and P. Tortoli are with the Department of Electronics and Telecommunications, University of Florence, Florence, Italy (e-mail: jacopo.viti@unifi.it). J. Viti and N. de Jong are with the Department of Biomedical Engi- neering, Erasmus Medical Center, Rotterdam, The Netherlands. M. Versluis is with the Physics of Fluids, Faculty of Science and Tech- nology, Universiteit Twente, Enschede, The Netherlands. DOI http://dx.doi.org/10.1109/TUFFC.2012.2524