To use microbubbles both as ultrasound contrast agents and as a therapeutic agent, it is important to guarantee consistent acoustic behaviors between the bubbles. This requires avoiding the formation of foam, which can block capillary blood vessels, and ensuring the bubbles are of the same size. Though this can be achieved by filtering and sorting the bubbles, Segers et al. demonstrate uniform bubbles can be produced directly at a production rate of 400,000 bubbles per second.

“For an acoustically uniform bubble suspension, all bubbles oscillate with the same radial amplitude of oscillation, which is important for improved imaging sensitivity and for more controlled and possibly efficient therapy using microbubbles and ultrasound,” said author Tim Segers.

Using a custom-made microfluidic flow-focusing device, the researchers created microbubbles filled with a mixture of water-soluble and water-insoluble gases and coated with a biocompatible lipid layer. Because the bubbles are suspended in an aqueous solution, the water-soluble gas rapidly dissolves, decreasing the surface tension and stabilizing the microbubbles.

By properly tuning the volume ratios of the two gases, the microbubbles can be formed at medically relevant concentrations and quickly reach their stable size while avoiding the creation of a foam layer in the collection vial. The method, which can increase ultrasound imaging sensitivity by over an order of magnitude, was developed within a pharmaceutical company and is currently being tested for clinical use.

“It is really exciting that such a relatively simple physics approach can solve an interfacial chemistry problem,” Segers said. “This now opens up a route to the mass production of readily injectable monodisperse ultrasound contrast agents.”

Source: “Foam-free monodisperse lipid-coated ultrasound contrast agent synthesis by flow-focusing through multi-gas-component microbubble stabilization,” by Tim Segers, Emmanuel Gaud, Gilles Casqueiro, Anne Lassus, Michel Versluis, and Peter Frinking, Applied Physics Letters (2020). The article can be accessed at