Combined flow-focus and self-assembly routes for the formation of lipid stabilized oil-shelled microbubbles

Lipid and polymer stabilized microbubbles are used in medicine as contrast agents for ultrasound imaging and are being developed for the delivery of water soluble drugs to diseased areas of the body. However, many new therapeutics exhibit poor water solubility or stability, which has led to the requirement for the development of effective hydrophobic drug delivery systems. This study presents a new method to produce microbubbles coated with an oil layer capable of encapsulating hydrophobic drugs and suitable for targeted, triggered drug release. This new method utilizes highly controllable flow-focusing microfluidics with lipid oil nanodroplets self-assembling and spreading at gas–aqueous interfaces. Oil layer inside microbubbles were produced with diameters of 2.4 ± 0.3 μm (s.d., 1.6 μm) and at concentrations up to 10⁶ bubbles per milliliter. The mechanism of oil layer inside microbubble assembly and stability were characterized using methods including contact angle measurements, quartz crystal microbalance with dissipation monitoring and fluorescence resonance energy transfer imaging.