High‐Throughput Continuous Flow Production of Nanoscale Liposomes by Microfluidic Vertical Flow Focusing

Abstract

Liposomes represent a leading class of nanoparticles for drug delivery. While a variety of techniques for liposome synthesis have been reported that take advantage of microfluidic flow elements to achieve precise control over the size and polydispersity of nanoscale liposomes, with important implications for nanomedicine applications, these methods suffer from extremely limited throughput, making them impractical for large-scale nanoparticle synthesis. High aspect ratio microfluidic vertical flow focusing is investigated here as a new approach to overcoming the throughput limits of established microfluidic nanoparticle synthesis techniques. Here the vertical flow focusing technique is utilized to generate populations of small, unilamellar, and nearly monodisperse liposomal nanoparticles with exceptionally high production rates and remarkable sample homogeneity. By leveraging this platform, liposomes with modal diameters ranging from 80 to 200 nm are prepared at production rates as high as 1.6 mg min(-1) in a simple flow-through process.

Microfluidic synthesis of multifunctional liposomes for tumour targeting

“…Hood et al recently reported the high throughput production of liposomes using a high aspect ratio HFF device. The production rate was as high as 95 mg h -1 , which was approximately 1000 times higher than using the original HFF device [15]. Furthermore, the production throughput can be increased through parallelization [16].…”

Microfluidic hydrodynamic focusing for synthesis of nanomaterials

“…In a recent study, Liu et al utilized a coaxial glass reactor and controlled micromixing to achieve polymeric NP synthesis of about 240 grams per day [72]. Similar approaches have also been tried for increasing throughput of other diverse microfluidic synthesis devices with promising results [16,73–78], which shows potential for commercialization and adaptation of microfluidic HF based devices. Noting that, there is still room for improvement in terms of device simplicity and dexterity that can aid in mass production and applicability for different size NPs.…”

Multiphase microfluidic synthesis of micro- and nanostructures for pharmaceutical applications

“…A number of microfluidic methods became available, including pulsed jetting (Funakoshi et al, 2007), droplet-based microfluidics (Kong et al, 2015;Ryan et al, 2012), microfluidic hydrodynamic focusing (MHF) (Jahn et al, 2004) and vertical flow focusing (VFF) (Hood and DeVoe, 2015). The pulsed jetting and droplet-based microfluidics are mainly designed for producing micrometer-sized lipid vesicles, and the MHF and VFF methods are widely used for making nanoscale liposomes.…”

“…Because of the fast mixing in the MHF, liposomes with high reproducibility and controllable size were fabricated (Belliveau et al, 2012;Hood et al, 2014;Jahn et al, 2004) (Jahn et al, 2013;Jahn et al, 2010;Mijajlovic et al, 2013;Phapal and Sunthar, 2013). Furthermore, a VFF approach using a large microchannel aspect ratio (channel depth to channel width), up to 100:1, was developed for producing liposomes at a throughput of nearly 100 mg/h (Hood and DeVoe, 2015), which makes the microfluidic technology promising for fabricating liposomes for practical applications. Liposomes have been developed as nanocarriers by loading various functional cargoes for pharmaceutical applications, including drugs (Hood et al, 2014;Kastner et al, 2015) and genes (Balbino et al, 2013;Belliveau et al, 2012;Chen et al, 2012).…”