Tuning Coalescence Stability and Acoustic Properties of High-Production-Rate Fabricated DSPC-Based Monodisperse Microbubbles Using Surfactant Tween 20

Monodisperse microbubbles (MDMBs) fabricated by microfluidics exhibit a narrow size distribution and uniform acoustic response, making them promising for ultrasound imaging and therapy. However, significantly high lipid concentrations were inevitably required to inhibit bubble coalescence during high-production-rate fabrication of lipid-coated MDMBs with a low polydispersity index (PDI), leading to substantial waste and poor cost-effectiveness. Therefore, under low lipid concentrations, minimizing bubble coalescence during high-production-rate MDMB fabrication and enabling fine-tuning of acoustic properties are crucial for advancing medical applications of MDMBs. We used a flow-focusing microfluidic chip to fabricate MDMBs under varied lipid concentrations, surfactant Tween 20 concentrations, and production rates. The coalescence rate of initially formed bubbles at the chip's orifice and outlet was statistically analyzed from high-speed photographic images. Tween 20 effectively prevented bubble coalescence under low lipid concentrations during high-production-rate MDMB fabrication, yielding a low PDI. An increased contraction ratio of MDMBs at a higher Tween-20-to-lipid ratio indicated that the incorporation of Tween 20's alkyl chains into the lipid monolayer enhanced steric repulsion, thereby preventing bubble proximity and coalescence. After a 2-day stabilization of the freshly collected MDMBs, the acoustic attenuation spectra and cavitation dynamics were accurately characterized. Statistical results revealed that both shell elasticity and cavitation stability of MDMBs significantly increased with higher Tween 20 concentration, but significantly decreased with elevated lipid concentration, thereby enabling their precise tuning via the Tween-20-to-lipid ratio. These findings establish a feasible approach for fabricating, under low lipid concentrations, high-production-rate lipid-coated MDMBs with low PDI and tunable acoustic properties, thus advancing ultrasound-based medical applications.