Characterization of stability and shell elasticity of monodisperse microbubbles with different pegylated-lipid content using pressure-dependent attenuation spectra.

Abstract

The stability and acoustic-induced oscillation of microbubbles strongly depend on their shell properties. Determining the relationships between the shell composition and bubble stability and shell elasticity is crucial for improving microbubble-based ultrasound imaging and therapy. We used a flow-focusing microfluidic to fabricate monodisperse microbubbles with a primary lipid and pegylated-lipid at different molar ratios. The lipid density on the shell was regulated via the ambient pressure. The measured pressure-dependent resonance-frequency curve was used to characterize bubble states (i.e., elasticity, rupture, buckling, elastic-rupture transition, and elastic-buckling transition). Further, by tracking pressure-dependent resonance-frequency curves over time during dissolution, the rate of bubble dissolution (i.e., stability) was quantified. The surface-area-dependent elasticity was obtained by fitting the bubble oscillation model to the measured pressure-dependent attenuation spectra. With decreasing molar fraction of pegylated-lipid, the evolution rate of microbubbles from the elasticity to elastic-buckling regimes gradually increased, corresponding to a decrease in stability of microbubbles. Upon bubble expansion, the elasticity first peaked, then decreased to the elasticity-rupture transition point, followed by a quick decrease to the rupture regime. Upon bubble compression, the elasticity plateaued until the elastic-buckling transition point, and then rapidly declined to the buckling regime. Significantly lower elasticity was found in microbubbles with 5 %-10 % pegylated-lipid than those with 1 % and 2 %; above and below 5 %, the molar fraction did not affect the elasticity. This work represents a reliable and accurate approach to understand the bubble stability and shell viscoelastic mechanisms, and to tailor phospholipids for microbubble-based medical applications. STATEMENT OF SIGNIFICANCE: Determining the relationships between shell composition, bubble stability and shell elasticity is critical for designing state-of-art microbubbles and improving ultrasound-based imaging and therapy. The pressure-dependent resonance-frequency curves over time was used to characterize monodisperse microbubble states (i.e., elasticity, rupture, buckling, elastic-rupture transition, and elastic-buckling transition) and to quantify the bubble dissolution rate (i.e., stability). With decreasing pegylated-lipid content on the shell, the bubble dissolution rate increased while stability decreased. Additionally, the pressure-dependent attenuation spectra were used to characterize nonlinear surface-area-dependent elasticity. The chain configurations (e.g., mushroom or brush) of pegylated-lipid dominated shell elasticity. This work deepens the understanding of viscoelastic mechanisms of bubble shell, and provides a systematic approach to tailor shell compositions for optimized microbubble-based medical applications.