Abstract
Continuous-flow production of liposomes using microfluidic reactors has demonstrated advantages compared to batch methods, including greater control over liposome size and size distribution and reduced reliance on post-production processing steps. However, the use of microfluidic technology for the production of nanoscale vesicular systems (such as liposomes) has not been fully translated to industrial scale yet. This may be due to limitations of microfluidic-based reactors, such as low production rates, limited lifetimes, and high manufacturing costs. In this study, we investigated the potential of millimeter-scale flow reactors (or millireactors) with a serpentine-like architecture, as a scalable and cost-effective route to the production of nanoscale liposomes. The effects on liposome size of varying inlet flow rates, lipid type and concentration, storage conditions, and temperature were investigated. Liposome size (i.e., mean diameter) and size dispersity were characterised by dynamic light scattering (DLS); z-potential measurements and TEM imaging were also carried out on selected liposome batches. It was found that the lipid type and concentration, together with the inlet flow settings, had significant effects on the properties of the resultant liposome dispersion. Notably, the millifluidic reactor was able to generate liposomes with size and dispersity ranging from 54 to 272 nm, and from 0.04 to 0.52 respectively, at operating flow rates between 1 and 10 mL/min. Moreover, when compared to a batch ethanol-injection method, the millireactor generated liposomes with a more therapeutically relevant size and size dispersity.
Highlights
Liposomes are polymolecular aggregates of certain amphipathic molecules, formed in aqueous solutions. They typically each consist of an aqueous core enclosed within one or more bilayers of natural or synthetic amphipathic molecules [1,2]. Their unique architecture provides a useful platform for incorporating hydrophilic and/or hydrophobic molecules within the core and/or the bilayer, which has opened the way for the usage of liposomes as nanocarrier systems in pharmaceutical, cosmetic, and nutraceutical applications [3]
The produced liposomes were imaged by transmission electron microscopy (TEM); 5 μL of the sample was placed on a carbon-coated grid and allowed to adsorb for 30 s, and any excess amount was removed with a filter paper (Whatman)
This design feature was introduced to ensure that the inlet flow streams could meet parallel to each other, and differs from conventional microfluidic hydrodynamic focusing architectures where the inlet channels typically meet at an angle in the range of 30–90◦
Summary
Liposomes are polymolecular aggregates (i.e., polymolecular assemblies) of certain amphipathic molecules, formed in aqueous solutions. The batch methods most commonly employed for liposome production involve a series of steps, which often include (i) lipid dissolution in organic solvents; (ii) solvent evaporation; and (iii) hydration of the formed dry lipid film Such production methods may suffer from significant drawbacks, including limited control over process parameters to produce nanoscale vesicles with desired features, requiring additional post-production steps to achieve suitable particle dimensional properties [18,21]. The stability of the produced liposomes was evaluated and production performance was compared with a commonly used batch “ethanol-injection” method
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