Abstract
We describe the manufacture of low-cost microfluidic systems to produce nanoscale liposomes with highly uniform size distributions (i.e., low polydispersity indexes (PDI)) and acceptable colloidal stability. This was achieved by exploiting a Y-junction device followed by a serpentine micromixer geometry to facilitate the diffusion between the mixing phases (i.e., continuous and dispersed) via advective processes. Two different geometries were studied. In the first one, the microchannels were engraved with a laser cutting machine on a polymethyl methacrylate (PMMA) sheet and covered with another PMMA sheet to form a two-layer device. In the second one, microchannels were not engraved but through-hole cut on a PMMA sheet and encased by a top and a bottom PMMA sheet to form a three-layer device. The devices were tested out by putting in contact lipids dissolved in alcohol as the dispersed phase and water as the continuous phase to self-assemble the liposomes. By fixing the total flow rate (TFR) and varying the flow rate ratio (FRR), we obtained most liposomes with average hydrodynamic diameters ranging from 188 ± 61 to 1312 ± 373 nm and 0.30 ± 0.09 PDI values. Such liposomes were obtained by changing the FRR from 5:1 to 2:1. Our results approached those obtained by conventional bulk synthesis methods such as a thin hydration bilayer and freeze-thaw, which produced liposomes with diameters ranging from 200 ± 38 to 250 ± 38 nm and 0.30 ± 0.05 PDI values. The produced liposomes might find several potential applications in the biomedical field, particularly in encapsulation and drug delivery.
Highlights
Microfluidic systems have gained considerable attention over the past decade due to their considerable potential for basic and applied scientific research in several fields, including organic synthesis, catalysis, fluid mechanics, thermodynamics, biotechnology, and medicine [1]
Even though no clear tendencies were identified for zeta potentials as a function of flow rate ratio (FRR) in either of the two configurations, the obtained values varied between −4 mV and −16 mV, which are comparable with the results reported for distearoylphosphatidylethanolamine-poly(ethyleneglycol)(DSPE-PEGF) liposomes where the zeta potential ranged from −8 mV to −13 mV [32]
Despite the low-cost, the manufactured devices offer a robust platform for the reproducible and high-throughput production of nanoscale liposomes with acceptable physical properties, which are even comparable with those obtained by bulk methods and more expensive manufacturing cleanroom techniques
Summary
Microfluidic systems have gained considerable attention over the past decade due to their considerable potential for basic and applied scientific research in several fields, including organic synthesis, catalysis, fluid mechanics, thermodynamics, biotechnology, and medicine [1]. Depending on the manufacturing technique, they may be produced at low costs [2] Despite these benefits, most microfluidic experiments are conducted at low Reynolds numbers, where processes such as mixing are significantly limited due to the prevalence of the viscous forces [3]. An alternative route is provided by microfluidic devices where the laminar flow conditions allow the controlled chemical synthesis or physical assembly of nanoscale objects [5,6]. In this regard, recent reports have demonstrated the efficient production of oxide nanoparticles, vesicles, polymeric capsules, and liposomes with highly uniform morphologies and size distributions [5]. Despite the growing interest in microfluidics, as evidenced by the increasing number of applications and types of devices, standardized protocols for manufacturing and characterization of nanoscale objects with the aid of these devices are rather scarce [5]
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