Foam-free monodisperse lipid-coated ultrasound contrast agent synthesis by flow-focusing through multi-gas-component microbubble stabilization

Monodisperse lipid-coated microbubbles are a promising avenue to unlock the full potential of ultrasound contrast agents for medical diagnosis and therapy. However, their formation by microfluidic flow-focusing is non-trivial. The lipid monolayer shell around the freshly formed bubbles is initially loosely packed, resulting in gas exchange between bubbles through Ostwald ripening, eventually leading to the formation of large, potentially thrombogenic, foam bubbles. Here, we show that by formulating a gas mixture of a low- and a high-aqueous solubility gas, a microbubble suspension can be formed that is not only monodisperse and highly stable, but it can also be synthesized without foam bubble formation at clinically relevant concentrations. The optimal gas volume fraction and resulting gas composition of the stable bubbles are modeled and were found to be in excellent agreement with the experimental data. This physics approach to an interfacial chemistry problem therefore opens a route to bedside production of stable, safe, and readily injectable monodisperse bubbles for medical applications.