Development and Characterization of a Microfluidic Method for Real-Time Generation of Transiently Stable Biocompatible Microbubbles In Situ for Image-Guided Therapy

Microbubbles are ultrasound contrast and therapeutic agents with a gas core encapsulated by a shell. Conventional methods of production (i.e. agitation and sonication) result in a polydisperse distribution that must be size-sorted before administration. With systemic administration by IV or bolus injection, microbubbles experience changes in diameter, distribution, and concentration during transit in the vasculature, resulting in unknown microbubble characteristics at the site of interest. We report a microfluidic method of generating monodisperse microbubbles in situ, to eliminate the uncertainty in microbubble characteristics in vivo. We introduce a novel method of supplying the shell and gas material to a flow-focusing microfluidic device (FFMD), enabling FFMDs to be potentially scaled down to vascular dimensions. By producing microbubbles in real-time in situ, novel microbubble compositions are possible, such as larger microbubbles for increased contrast and bioeffects. Additionally, microbubbles with semi-stable shells can be utilized to facilitate rapid dissolution downstream the site of interest, reducing the risk of gas entrapment in small vessels. We demonstrate that real-time production of transiently stable microbubbles upstream can improve image contrast and delivery of a model drug under flow. Lastly, we show that a completely biocompatible microbubble can be generated with a microfluidic device from whole blood. This demonstrates the potential for a lab-on-a-chip method of generating an image-guided therapeutic agent at the point-of-care using a patient’s own blood as the medium.