Controlling the stability of monodisperse lipid-coated microbubbles by tuning their buckling pressure

Through recent years, major hurdles associated with the microfluidic production of phospholipid-coated monodisperse microbubble have been overcome which has granted them a long shelf life. This has heaved the hope of using their unique properties in vivo for improved contrast, controlled therapy, or noninvasive pressure measurement. However, these bubbles are also very sensitive to small changes in ambient pressure which compromises their clinical translation: upon intravenous injection, physiological pressures will cause bubble dissolution, degrading their uniformity. Here, we demonstrate the direct relation between shell buckling and bubble dissolution by acoustically measuring the buckling pressure and the response of bubbles to controlled pressure changes. We show that the concentration of PEGylated lipid, necessary for microfluidic operation, can be used to tune the buckling pressure, and thereby increase bubble stability. We show that this concentration can be changed either directly during bubble production or, more conveniently, by heating the microbubbles after production. The proposed heating step exploits the phase-change of the phospholipids within the shell to selectively expel the PEGylated lipids. Doing so, the bubble buckling pressure can be increased from 0 kPa to 27 kPa which is above physiological pressures.