Combining Ultrasound and Capillary-Embedded T-Junction Microfluidic Devices to Scale Up the Production of Narrow-Sized Microbubbles through Acoustic Fragmentation

Microbubbles are tiny gas-filled bubbles that have a variety of applications in ultrasound imaging and therapeutic drug delivery. Microbubbles can be synthesized using a number of techniques including sonication, amalgamation, and saline shaking. These approaches can produce highly concentrated microbubble suspensions but offer minimal control over the size and polydispersity of the microbubbles. One of the simplest and effective methods for producing monodisperse microbubbles is capillary-embedded T-junction microfluidic devices, which offer great control over the microbubble size. However, lower production rates (similar to 200 bubbles/s) and large microbubble sizes (similar to 300 mu m) limit the applicability of such devices for biomedical applications. To overcome the limitations of these technologies, we demonstrate in this work an alternative approach to combine a capillary-embedded T-junction device with ultrasound to enhance the generation of narrow-sized microbubbles in aqueous suspensions. Two T-junction microfluidic devices were connected in parallel and combined with an ultrasonic horn to produce lipid-coated SF6 core microbubbles in the size range of 1-8 mu m. The rate of microbubble production was found to increase from 180 microbubbles/s in the absence of ultrasound to (6.5 +/- 1.2) x 106 bubble/s in the presence of ultrasound (100% ultrasound amplitude). When stored in a closed environment, the microbubbles were observed to be stable for up to 30 days, with the concentration of the microbubble suspension decreasing from similar to 2.81 x 109/mL to similar to 2.3 x 106/mL and the size changing from 1.73 +/- 0.2 to 1.45 +/- 0.3 mu m at the end of 30 days. The acoustic response of these microbubbles was examined using broadband attenuation spectroscopy, and flow phantom imaging was performed to determine the ability of these microbubble suspensions to enhance the contrast relative to the surrounding tissue. Overall, this approach of coupling ultrasound with microfluidic parallelization enabled the continuous production of stable microbubbles at high production rates and low polydispersity using simple T-junction devices.