Ultrasound contrast agents : dynamics of coated bubbles

Abstract

Contrast-enhanced ultrasound imaging relies on the nonlinear scattering of microbubbles suspended in an ultrasound contrast agent. The bubble dynamics is described by a Rayleigh-Plesset-type equation, and the success of harmonic imaging using contrast agents has always been attributed to the nonlinear behavior predicted by this equation. Contrast agent microbubbles are stabilized by a coating of a surfactant layer of phospholipids. The coating reduces the capillary pressure and inhibits gas diffusion into the blood. Several extensions to the Rayleigh-Plesset equation were made to include the effect of the coating on the bubble dynamics. Most models incorporate a thin elastic shell, including shell viscous damping. It has always been assumed that the visco-elastic properties of the shell lead to a reduction of the nonlinear response of the bubbles. Here we show that the coating material in fact leads to an increased nonlinear bubble response even at low acoustic pressures where the traditional models for coated as well as uncoated bubbles would only predict linear behavior. From acoustical and high-speed optical observations it was found that a distinct class of bubbles show a decrease of the frequency of maximum response with increasing acoustic pressures, leading to a pronounced skewness of the resonance curve. We show this to be the origin of the ‘threshold’ behavior, where it appears as if the smaller bubbles of the population are activated only at elevated pressures. For the other bubbles the frequency of maximum response was found to lie just above the resonance frequency of an uncoated bubble, and to be independent of the applied acoustic pressure. These bubbles also show a so-called ‘compression-only’ behavior, where the bubbles were observed to efficiently compress, while their expansion was highly reduced. Moreover, the majority of these bubbles display a very strong subharmonic response when driven at twice their resonance frequency, which is highly beneficial for nonlinear imaging in ultrasound. The shell-buckling model by Marmottant et al., which accounts for buckling and rupture of the shell, captures all of the above cases for a unique set of the shell parameters, the relevant parameter being the phospholipid concentration at the bubble interface.