Time-dependent nanobubble stability: Correlating bubble size and concentration with ultrasound performance

Abstract

Lipid shell-stabilized nanobubbles (NB, <500 nm) are widely explored as next-generation contrast agents for diagnostic ultrasound (US) imaging and drug delivery. For a successful clinical translation, it is important to understand the factors which contribute to the stability and rate of signal decay from the NB over time. The small size and fragile nature of NB have limited the characterization of their stability to correlations with their loss of signal over time under US. Bubble oscillations in the acoustic field, however, can accelerate their dissolution process. In this study, the passive, non-acoustically driven dissolution of lipid-shelled, C3F8 NB, and the relationship between bubble size/concentration and US signal intensity were assessed. The change in the acoustic activity of NB over time was correlated with the changes in size and concentration of the buoyant (bubbles) and non-buoyant particle population, measured using a novel resonant mass measurement technique. Clinical US was used to measure signal enhancement at different time points in a tissue phantom (f = 12.0 MHz, MI: 0.29, 1 fp/s). Results demonstrate a clear nonlinear relationship between the rate of ultrasound signal decay and concentration. While US signal decayed significantly over time (from 0 to 5 h), bubble concentration did not change significantly. A statistically significant decrease in the NB diameter was observed 1 h after the NBs were prepared and isolated while no change in the size was observed between 1 and 5 h.