Engineering Theranostic Microbubbles Using Microfluidics for Ultrasound Imaging and Therapy: A Review

Microbubbles interact with ultrasound in various ways to enable their applications in ultrasound imaging and diagnosis. To generate high contrast and maximize therapeutic efficacy, microbubbles of high uniformity are required. Microfluidic technology, which enables precise control of small volumes of fluid at the sub-millimeter scale, has provided a versatile platform on which to produce highly uniform microbubbles for potential applications in ultrasound imaging and diagnosis. Here, we describe fundamental microfluidic principles and the most common types of microfluidic devices used to produce sub-10 μm microbubbles, appropriate for biomedical ultrasound. Bubbles can be engineered for specific applications by tailoring the bubble size, inner gas and shell composition and by functionalizing for additional imaging modalities, therapeutics or targeting ligands. To translate the laboratory-scale discoveries to widespread clinical use of these microfluidic-based microbubbles, increased bubble production is needed. We present various strategies recently developed to improve scale-up. We conclude this review by describing some outstanding problems in the field and presenting areas for future use of microfluidics in ultrasound.