Tuning the Shell Elasticity of Phospholipid-Coated Microbubbles via Palmitic Acid Doping

Phospholipid-coated microbubbles have been developed as blood pool agents for contrast-enhanced ultrasound imaging. Tuning their acoustic response is key to expanding their use beyond contrast imaging alone. Here, we demonstrate that the shell elasticity of coated microbubbles can be controlled over 1 order of magnitude, from 0.5 N/m up to 4.5 N/m, by doping the native shell with palmitic acid. Characterization of shell elasticity as a function of bubble surface area via ambient pressure-controlled acoustic attenuation measurements revealed that the increased shell elasticity is confined to a narrow region around the equilibrium bubble surface area. Upon expansion of just 1-2% in bubble surface area, the surface elasticity rapidly drops to levels observed in non-PA-doped bubbles. The results further demonstrated that shell viscosity also varies with bubble surface area, which may further enhance nonlinear bubble dynamics. Dilatational surface tension curves, obtained by numerically integrating the elasticity curves, were used as input to a nonlinear bubble dynamics model based on a Rayleigh-Plesset-type equation. The results demonstrate that the controlled shell elasticity offered by this work allows microbubbles to be tuned in nonlinear acoustic response, significantly enhancing the sensitivity of their subharmonic response for a range of applications, including noninvasive pressure sensing.