Scaleable production of microbubbles using an ultrasound-modulated microfluidic device

Surfactant-coated gas microbubbles are widely used as contrast agents in ultrasound imaging and increasingly in therapeutic applications. The response of microbubbles to ultrasound can be strongly influenced by their size and coating properties, and hence the production method. Ultrasonic emulsification (sonication) is the most commonly employed method and can generate high concentrations of microbubbles rapidly, but with a broad size distribution, and there is a risk of contamination and/or degradation of sensitive components. Microfluidic devices provide excellent control over microbubble size, but are often challenging or costly to manufacture, offer low production rates (<106s−1), and are prone to clogging. In this study, a hybrid sonication-microfluidic or “sonofluidic” device was developed. Bubbles of ∼180  μm diameter were produced rapidly in a T-junction and subsequently exposed to ultrasound (71–73 kHz) within a microchannel, generating microbubbles (mean diameter: 1–2  μm) at a rate of >108s−1 using a single device. Microbubbles were prepared using either the sonofluidic device or conventional sonication, and their size, concentration, and stability were comparable. The mean diameter, concentration, and stability were found to be comparable between techniques, but the microbubbles produced by the sonofluidic device were all <5  μm in diameter and thus did not require any post-production fractionation.