High throughput synthesis of liposomes using vibrating sharp-tip mixing

Abstract

Lipid nanoparticles (LNPs) have emerged as a promising drug delivery system due to their biocompatibility, biodegradability, and ability to deliver a wide range of therapeutic agents. While conventional bulk synthesis of LNPs results in batch-to-batch variability in particle physiochemical properties, microfluidic-based synthesis enables highly controllable outcomes. In recent years, acoustics have emerged as a powerful tool for LNP synthesis due to its flexibility and contactless operation. However, implementing acoustic-based methods in microfluidic devices usually requires precise microstructure fabrication within the channels, limiting scalability for large-scale synthesis. To overcome these challenges, we present a 3D-printed microfluidic device equipped with an acoustically driven, vibrating sharp-tip glass capillary, engineered to accommodate a wide range of flow rates and enable the scalable production of phosphatidylcholine (POPC) liposomes. Additionally, the impact of crucial parameters including total flow rates and flow rate ratios on the final product was assessed. To validate the results obtained from the sharp-tip mixing method, we compared the device with two widely used microfluidic devices for synthesizing liposomes: the NanoAssembler™ Ignite™ NxGen mixing device and the commercial herringbone mixing device. The mixing characterization results demonstrated that the sharp-tip mixer microfluidic device achieved optimal mixing across a broad range of total flow rates, from 30 µL/min to 3500 µL/min. Size distribution characterization of the final products showed that the sharp-tip mixer device produces homogeneous POPC liposomes with tunable sizes ranging from 60 to 150 nm.