Scaled-up production of monodisperse, dual layer microbubbles using multi-array microfluidic module for medical imaging and drug delivery

Abstract

The production of uniform-sized and multilayer microbubbles enables promising medical applications that combine ultrasound contrast and targeted delivery of therapeutics, with improvements in the consistency of acoustic response and drug loading relative to non-uniform populations of microbubbles. Microfluidics has shown utility in the generation of such small multi-phase systems, however low production rates from individual devices limit the potential for clinical translation. We present scaled-up production of monodisperse dual-layered microbubbles in a novel multi-array microfluidic module containing four or eight hydrodynamic flow-focusing orifices. Production reached 1.34 × 105 Hz in the 8-channel configuration, and microbubble diameters in the high-speed regime (> 5 × 104 Hz) ranged between 18.6–22.3 μm with a mean pooled polydispersity index under 9 percent. Results demonstrate that microfluidic scale-up for high-output production of multilayer bubbles is possible while maintaining consistency in size production, suggesting that this method may be appropriate for future clinical applications.

A novel technology: microfluidic devices for microbubble ultrasound contrast agent generation

“…Based on these findings, Kaya et al [46] investigated Fig. 13 Geometry of an eightchannel multiarray microfluidic module for three-layer microbubble production; a schematic view, and b image of the hydrodynamic flow-focusing region [47] echo responses of monodisperse lipid microbubbles made by flow-focusing devices [39] in an attempt to establish a relationship between scattered echo, microbubble diameter, and excitation frequency. Both the simulations and the experimental acoustic results demonstrate that the monodisperse microbubble acoustic response increased as the microbubble diameter increased.…”

“…Therefore, microfluidic devices are ideal for the production of microbubbles that are used in both contrast enhancement and drug delivery. The main problem with microfluidic technology is low microbubble production, which can be remedied by performing parallel connections and using multiple devices [1,22,35,42,47,53,66].…”

Parallel generation of uniform fine droplets at hundreds of kilohertz in a flow-focusing module

“…25 To instead produce droplets and to accommodate the elevated flow rates and pressures required of dripping, the current module consists of two levels of PDMS on a glass substrate and occupies a reduced footprint. Continuous lipid and dispersed perfluoropentane phases are infused in the bottom level, shown in Figure 1, in order to maximize bond strength at the inlets (as the strength of bonding between PDMS and glass far exceeds that between PDMS and PDMS).…”

Quantitative Ultrasound Molecular Imaging in Large Blood Vessel Environments

“…This distortion might lead to a build-up in liquid pressure, which again could overcome gas pressure leading to the cessation of MB production. However, by massively parallelizing MB production [191], [197], [225], [226] -either through FFMDs with multiple nozzles or multiple…”