Subharmonic behavior of phospholipid-coated ultrasound contrast agent microbubbles

Abstract

Coated microbubbles, unlike tissue are able to scatter sound subharmonically. Therefore, the subharmonic behavior of coated microbubbles can be used to enhance the contrast in ultrasound contrast imaging. Theoretically, a threshold amplitude of the driving pressure can be calculated above which subharmonic oscillations of microbubbles are initiated. Interestingly, earlier experimental studies on coated microbubbles demonstrated that the threshold for these bubbles is much lower than predicted by the traditional linear viscoelastic shell models. This paper presents an experimental study on the subharmonic behavior of differently sized individual phospholipid coated microbubbles. The radial subharmonic response of the microbubbles was recorded with the Brandaris ultra high-speed camera as a function of both the amplitude and the frequency of the driving pulse. Threshold pressures for subharmonic generation as low as 5 kPa were found near a driving frequency equal to twice the resonance frequency of the bubble. An explanation for this low threshold pressure is provided by the shell buckling model proposed by Marmottant et al. [ J. Acoust. Soc. Am. 118, 3499-3505 (2005)]. It is shown that the change in the elasticity of the bubble shell as a function of bubble radius as proposed in this model, enhances the subharmonic behavior of the microbubbles. Coated microbubbles, unlike tissue are able to scatter sound subharmonically. Therefore, the subharmonic behavior of coated microbubbles can be used to enhance the contrast in ultrasound contrast imaging. Theoretically, a threshold amplitude of the driving pressure can be calculated above which subharmonic oscillations of microbubbles are initiated. Interestingly, earlier experimental studies on coated microbubbles demonstrated that the threshold for these bubbles is much lower than predicted by the traditional linear viscoelastic shell models. This paper presents an experimental study on the subharmonic behavior of differently sized individual phospholipid coated microbubbles. The radial subharmonic response of the microbubbles was recorded with the Brandaris ultra high-speed camera as a function of both the amplitude and the frequency of the driving pulse. Threshold pressures for subharmonic generation as low as 5 kPa were found near a driving frequency equal to twice the resonance frequency of the bubble. An explanation for this low threshold pressure is provided by the shell buckling model proposed by Marmottant et al. ͓J. Acoust. Soc. Am. 118, 3499-3505 ͑2005͔͒. It is shown that the change in the elasticity of the bubble shell as a function of bubble radius as proposed in this model, enhances the subharmonic behavior of the microbubbles.

Nonlinear response to ultrasound of encapsulated microbubbles

“…However, it has some limitations because the harmonics generated may be reflected by the surrounding tissue with the subsequent reduction of resolution. To overcome these restrictions the use of harmonics of higher order [37], or subharmonic ultrasound signals has been proposed [38,39]. Consequently, the analysis given here could be extended in order to determine the range of governing parameters where subharmonic and superharmonic imaging are optimized.…”

Monodisperse bubbles and droplets for medical applications

“…A possible downside of sorting bubbles by size using pinched flow fractionation with the aim of increasing ultrasound sensitivity, is that the phospholipid packing density in the shell may vary slightly from bubble to bubble. This means that two bubbles of identical size need not necessarily show identical acoustical behavior 109 . This problem is inherent to all sorting methods aimed at sorting by size, and can only be lessened by improving the initial production.…”

“…It was also shown that the shell surfactant concentration had a major impact on the generation of the harmonic response, i.e. even for bubbles of the same size a very different acoustic response can be observed 40,109 . The bubbles can oscillate in an elastic regime with a low concentration of phospholipids and finite surface tension, or they can oscillate in a buckled regime owing to the high concentration of phospholipids with virtually no surface tension 41 .…”

“…The acoustic sorting method outlined by Segers et al 85 is employed here to sort a perfluorobutane-based ultrasound contrast agent (Bracco BR-14, Bracco Research Geneva) containing bubbles coated with a DSPC and DPPG phospholipid mixture 109 . The sorting chip used here is differerent from that reported by Segers et al 85 in that it comprises two outlet channels to separate the resonant from the non-resonant bubbles.…”

“…A well-controlled microfluidic size-sorting technique for contrast bubbles was recently reported and it was based on a pinched flow fractionation technique 88 . On the other hand, it was shown recently that the shell surfactant concentration of phospholipid coated bubbles can be very different from bubble to bubble, even for bubbles of the same size 40,109 . The reason is that the encapsulation of the bubble, typically consisting of a phospholipid monolayer, dramatically changes the resonance behaviour of the bubbles.…”