Abstract
Acoustic behavior of lipid-coated microbubbles has been widely studied, which has led to several numerical microbubble dynamics models that incorporate lipid coating behavior, such as buckling and rupture. In this study we investigated the relationship between microbubble acoustic and lipid coating behavior on a nanosecond scale by using fluorescently labeled lipids. It is hypothesized that a local increased concentration of lipids, appearing as a focal area of increased fluorescence intensity (hot spot) in the fluorescence image, is related to buckling and folding of the lipid layer thereby highly influencing the microbubble acoustic behavior. To test this hypothesis, the lipid microbubble coating was fluorescently labeled. The vibration of the microbubble (n = 177; 2.3–10.3 μm in diameter) upon insonification at an ultrasound frequency of 0.5 or 1 MHz at 25 or 50 kPa acoustic pressure was recorded with the UPMC Cam, an ultra-high-speed fluorescence camera, operated at ~4–5 million frames per second. During short tone-burst excitation, hot spots on the microbubble coating occurred at relative vibration amplitudes > 0.3 irrespective of frequency and acoustic pressure. Around resonance, the majority of the microbubbles formed hot spots. When the microbubble also deflated acoustically, hot spot formation was likely irreversible. Although compression-only behavior (defined as substantially more microbubble compression than expansion) and subharmonic responses were observed in those microbubbles that formed hot spots, both phenomena were also found in microbubbles that did not form hot spots during insonification. In conclusion, this study reveals hot spot formation of the lipid monolayer in the microbubble’s compression phase. However, our experimental results show that there is no direct relationship between hot spot formation of the lipid coating and microbubble acoustic behaviors such as compression-only and the generation of a subharmonic response. Hence, our hypothesis that hot spots are related to acoustic buckling could not be verified.
Highlights
Ultrasound contrast agents (UCAs) consist of coated gas microbubbles (1–10 μm in diameter) dispersed in an aqueous suspension
In clinically used UCAs, the microbubble coating consists of albumin or lipids; the most prevalent coating consists of lipids [12]
Observations of ultrasound-induced hot spot formation on the microbubble coating were made in earlier work by others [24, 30], our new ultra-high-speed recordings show that these hot spots form on a nanosecond time scale
Summary
Ultrasound contrast agents (UCAs) consist of coated gas microbubbles (1–10 μm in diameter) dispersed in an aqueous suspension. These blood pool agents aid in the diagnosis of for example liver [1] and kidney lesions [2] and in left ventricular visualization [3]. Lipid-coated microbubbles can show various vibration regimes in an ultrasound field, which are characterized by the volumetric vibration dynamics and shape oscillations of the microbubble These vibrations vary from gentle for imaging and drug uptake applications to violent for drug uptake and cell killing applications [5, 9]
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