Controlled liposome production using micromixers based on Dean flow dynamics

Liposomes are multipurpose delivery carriers capable of targeting specific organs, tissues, and cells. This specificity is controlled by their physicochemical properties, which determine their interactions with biological systems. Therefore, controlling liposome properties is crucial for their effective implementation. Liposomes must be produced on an industrial scale in a reproducible way to be effectively deployed as nanomedicines. Conventional bulk production methods have inadequate control over liposome properties and require multiple homogenization and drug encapsulating steps adding to reproducibility problems. By contrast, liposome production using microfluidic devices such as micromixers enables continuous-flow liposome synthesis with enhanced control over liposomes properties such as size and size distribution. Previously proposed micromixers suffer from low liposome productivity, fabrication problems, clogging, agglomeration, and harmful organic solvent residues. Most of the time, these devices were tailored to chemical reactions and not specifically to liposome production. Liposome self-assembly requires a mixing process that is fast to produce small liposomes, but to a certain extent, it should be uniform, so liposome formation conditions are similar for all the particles and thus result in homogenous size populations. Dean flow dynamics-based micromixers, which are used in this work, offer an alternative to earlier microfluidic devices, with the potential of producing uniform controllable nanosized liposomes, at a high production rate. Also, their fabrication is simplified because they do not require complicated three-dimensional structures to create flow perturbations. In this dissertation, numerical modeling and confocal imaging were used to investigate the mixing process. As a result, a novel micromixer was proposed. Liposome production factors using the proposed microfluidic device were identified and modeled using statistical tools. Size-controlled liposomes as small as 27 nm, at a production rate as high as 41 mg/mL were produced. Additionally, liposomes showed to be stable for up to 6 months. Other molecular related factors were investigated to better understand their effects in liposome physicochemical properties. Likewise, the polarity change rate influence over liposome size was demonstrated using both conventional organic solvents and Transcutol®. The latter has the potential to avoid filtration steps due to its reduced toxicity. Th