Liquid Flooded Flow-Focusing Microfluidic Device for in situ Generation of Monodisperse Microbubbles

Current microbubble-based ultrasound contrast agents are administered intravenously resulting in large losses of contrast agent, systemic distribution, and strict requirements for microbubble longevity and diameter size. Instead we propose in situ production of microbubbles directly within the vasculature to avoid these limitations. Flow focusing microfluidic devices (FFMDs) are a promising technology for enabling in situ production as they can produce microbubbles with precisely controlled diameters in real-time. While the microfluidic chips are small, the addition of inlets and interconnects to supply the gas and liquid phase greatly increases the footprint of these devices preventing the miniaturization of FFMDs to sizes compatible with medium and small vessels. To overcome this challenge, we introduce a new method for supplying the liquid (shell) phase to an FFMD that eliminates bulky interconnects. A pressurized liquid-filled chamber is coupled to the liquid inlets of an FFMD, which we term a flooded FFMD. The microbubble diameter and production rate of flooded FFMDs were measured optically over a range of gas pressures and liquid flow rates. The smallest FFMD manufactured measured 14.5 × 2.8 × 2.3 mm. A minimum microbubble diameter of 8.1 ± 0.3 μm was achieved at a production rate of 450,000 microbubbles/s (MB/s). This represents a significant improvement with respect to any previously reported result. The flooded design also simplifies parallelization and production rates of up to 670,000 MB/s were achieved using a parallelized version of the flooded FFMD. In addition, an intravascular ultrasound (IVUS) catheter was coupled to the flooded FFMD to produce an integrated ultrasound contrast imaging device. B-mode and IVUS images of microbubbles produced from a flooded FFMD in a gelatin phantom vessel were acquired to demonstrate the potential of in situ microbubble production and real-time imaging. Microbubble production rates of 222,000 MB/s from a flooded FFMD within the vessel lumen provided a 23 dB increase in B-mode contrast. Overall, the flooded design is a critical contribution towards the long- term goal of utilizing in situ produced microbubbles for contrast enhanced ultrasound imaging of, and drug delivery to, the vasculature.