High-throughput production of microbubble contrast agents using a sonofluidic device

The response of microbubbles to a given sound field is determined by their size and coating. These, in turn, depend on their chemical formulation and the production technique. Sonication is the most commonly employed method and can generate high concentrations of microbubbles rapidly but with a broad size distribution and poor reproducibility. Microfluidic devices provide excellent control over size, but the small-scale architectures required are often challenging to manufacture, offer low production rates, and are prone to clogging. Microbubbles may also have inferior surface characteristics and stability compared to those produced by sonication. In this study we investigate a hybrid technique in which monodisperse microbubbles of ~200μm diameter are produced at high flow rates in a simple T-junction and then undergo controlled fragmentation by exposure to ultrasound via an integrated transducer operating between 71-73kHz. Microbubbles were prepared using the device or a standard sonication protocol and compared in terms of their size, size distribution, concentration, stability, acoustic response, and surface molecular concentration using quantitative fluorescence microscopy. The characteristics of the microbubbles produced by the device were found to be equivalent in terms of production rate, stability and acoustic response but with a narrower size distribution and tunable mean size.