HYPOTHESIS: Monodisperse phospholipid-coated microbubbles, with a size and resonance frequency tuned to the ultrasound driving frequency, have strong potential to enhance sensitivity, efficiency, and control in emerging diagnostic and therapeutic applications involving bubbles and ultrasound. A key requirement is that they retain their gas volume and shell material during physiologic pressure changes and withstand the overpressure during intravenous injection. The shell typically comprises a mixture of a phospholipid (e.g., DSPC) mixed with a PEGylated phospholipid (e.g., DPPE-PEG5000). We hypothesize that (i) lipid-coated microbubbles destabilize when shell buckling occurs under pressurization, (ii) the overpressure at which buckling occurs (buckling pressure) is linked to the molar fraction of PEGylated lipid in the shell, and (iii) PEGylated lipid can be selectively expelled from the shell by fluidizing it at elevated temperatures. EXPERIMENTS: The buckling pressure was measured using ultrasound attenuation spectroscopy while the ambient pressure was varied. When the ambient pressure increased, the microbubble resonance frequency dropped sharply due to shell buckling and the associated loss of elasticity. The buckling pressure P FINDINGS: Quasi-static compression of a microbubble above its buckling pressure leads to its destabilization. Lowering the PEG molar fraction from 10 to 1.5% increased the buckling pressure from 3 kPa to 27 kPa. Similarly, heating the 10 mol% bubble suspension at 60