Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications

Abstract

Ultrasound imaging often calls for the injection of contrast agents, micron-sized bubbles which echo strongly in blood and help distinguish vascularized tissue. Such microbubbles are also being augmented for targeted drug delivery and gene therapy, by the addition of surface receptors and therapeutic payloads. Unfortunately, conventional production methods yield a polydisperse population, whose nonuniform resonance and drug-loading are less than ideal. An alternative technique, microfluidic flow-focusing, is able to produce highly monodisperse microbubbles with stabilizing lipid membranes and drug-carrying oil layers. However, the published 1 kHz production rate for these uniform drug bubbles is very low compared to conventional methods, and must be improved before clinical use can be practical. In this study, flow-focusing production of oil-layered lipid microbubbles was tested up to 300 kHz, with coalescence suppressed by high lipid concentrations or inclusion of Pluronic F68 surfactant in the lipid solution. The transition between geometry-controlled and dripping production regimes was analysed, and production scaling was found to be continuous, with a power trend of exponent ~5/12 similar to literature. Unlike prior studies with this trend, however, scaling curves here were found to be pressure-dependent, particularly at lower pressure-flow equilibria (e.g. <15 psi). Adjustments in oil flow rate were observed to have a similar effect, akin to a pressure change of 1–3 psi. This analysis and characterization of high-speed dual-layer bubble generation will enable more-predictive production control, at rates practical for in vivo or clinical use.

Interfacial tension based on-chip extraction of microparticles confined in microfluidic Stokes flows

“…[1][2][3][4] In two-phase microfluidics, an aqueous solution is dispersed into droplets in carrier oil (or vice versa) under Plateau-Rayleigh instability. 4,5 The aqueous droplets can be physically or chemically crosslinked into hydrogel microparticles.…”

“…[1][2][3][4] In two-phase microfluidics, an aqueous solution is dispersed into droplets in carrier oil (or vice versa) under Plateau-Rayleigh instability. 4,5 The aqueous droplets can be physically or chemically crosslinked into hydrogel microparticles. 6 Due to the small dimension of microfluidic channel and high viscosity of oil, the two-phase microfluidic flow is typically in the regimen of Stokes laminar flows where the viscous force dominates inertia force.…”

Monodisperse bubbles and droplets for medical applications

“…to remove solvents. Flow focusing techniques have also shown to be able to produce concentric bubbles with an outer oil layer facilitating drug loading 64 . A challenging aspect of this approach is to understand how the monodisperse bubbles can be encapsulated with a biocompatible coating to stabilize them [65][66][67] , to investigate how to maintain the monodispersity of bubbles produced at high production rates over time 64 , and to investigate the dynamics of different coating materials for in-vivo and clinical use 68 .…”

“…Recent advances into the production of monodisperse UCA are promising, such as the use of flow-focusing devices to produce highly monodisperse bubble populations as reported by Hettiarachchi et al 65 . These methods are capable of producing highly monodisperse bubble populations at significant rates 64 , however, challenges remain in maintaining the monodispersity for extended periods of time 66,118 . Mechanical filtration is a widely used technique, where the microbubble sus- pension is forced through a filter 87 , acting as a low-pass filter.…”

“…In a flow-focusing geometry a gas thread is focused in between two external liquid flows through a constriction, where the gas is pinched off to form monodisperse bubbles 62,63 . One challenging aspect of this approach is to investigate how the monodisperse bubbles could be encapsulated with a biocompatible coating to stabilize them [65][66][67] , to investigate how to maintain the monodispersity of bubbles produced at high production rates over time 64 , and to investigate the dynamics of different coating materials for in-vivo and clinical use 68 . Enriching commercially available UCAs can be done by means of mechanical filtration 79 .…”