On-chip generation of microbubbles as a practical technology for manufacturing contrast agents for ultrasonic imaging

TLDR

The study introduces a microfluidic flow‑focusing method that produces monodisperse lipid‑shell perfluorocarbon microbubbles with a polydispersity index below 2%. PDMS devices with an expanding nozzle and a 7 µm orifice, operated for hours, were used to tune bubble size by adjusting channel geometry, liquid flow rate, and gas pressure, as characterized by high‑speed imaging. Optimizing geometry, flow, and pressure yielded microbubbles averaging <5 µm, demonstrating that microfluidics can reliably generate contrast agents with precise size, varied gas, and shell materials for targeted imaging and therapy.

Abstract

This paper presents a new manufacturing method to generate monodisperse microbubble contrast agents with polydispersity index (σ) values of <2% through microfluidic flow-focusing. Micron-sized lipid shell-based perfluorocarbon (PFC) gas microbubbles for use as ultrasound contrast agents were produced using this method. The poly(dimethylsiloxane) (PDMS)-based devices feature expanding nozzle geometry with a 7 μm orifice width, and are robust enough for consistent production of microbubbles with runtimes lasting several hours. With high-speed imaging, we characterized relationships between channel geometry, liquid flow rate Q, and gas pressure P in controlling bubble sizes. By a simple optimization of the channel geometry and Q and P, bubbles with a mean diameter of <5 μm can be obtained, ideal for various ultrasonic imaging applications. This method demonstrates the potential of microfluidics as an efficient means for custom-designing ultrasound contrast agents with precise size distributions, different gas compositions and new shell materials for stabilization, and for future targeted imaging and therapeutic applications.