Herringbone-Patterned 3D-Printed Devices as Alternatives to Microfluidics for Reproducible Production of Lipid Polymer Hybrid Nanoparticles

Abstract

Major barriers to the implementation of nanotechnology include reproducible synthesis and scalability. Batch solution phase methods do not appear to have the potential to overcome these barriers. Microfluidic methods have been investigated as a means to enable controllable and reproducible synthesis; however, the most popular constituent of microfluidics, polydimethylsiloxane, is ill-suited for mass production. Multi-inlet vortex mixers (MIVMs) have been proposed as a method for scalable nanoparticle production; however, the control and reproducibility of the nanoparticle is wanting. Here, we investigate the ability to improve the control and reproducibility of nanoparticles produced by using 3D printed MIVMs with herringbone patterns in the flow channels. We compare three methods, viz., microfluidic, MIVM, and herringbone-patterned MIVM methods, for the synthesis of lipid–polymer hybrid nanoparticles (LPHNPs). The 3D printed herringbone-patterned MIVM method resulted in the smallest LPHNPs with the most uniform size distribution and shows more reproducible results as compared to the other two methods. To elucidate the mechanism underlying these results, concentration slices and vorticity streamlines of mixing chambers have been analyzed for 3D printed herringbone-patterned MIVM devices. The results bode well for LPHNPs, a formulation widely investigated for its improved therapeutic efficacy and biocompatibility. The herringbone-patterned device also has the potential to be broadly applied to many solution phase processes that take advantage of efficient mixing. The methods discussed here have broad implications for reproducible production of nanoparticles with constituents such as siRNA, proteins, quantum dots, and inorganic materials.

Microfluidics for Production of Particles: Mechanism, Methodology, and Applications

“…More importantly, for the first time it was reported liposomes size tuning at 10 nm intervals in the size range from 20 to 100 nm (Figure f) . Not only by designing the geometry of the mixing chamber, Bokare et al reported that even by simply change the geometry pattern of the inlet channel for the fluids, the mixing efficiency can also be affected, as by integrating the herringbone‐pattern with the inlet channel of a microcortex mixer (Figure g), the size of produced PLGA/lipid nanohybrids reduced from 199 to 74.5 nm …”

“…Copyright 2018, American Chemical Society. (g) Reproduced with permission . Copyright 2019, American Chemical Society.…”

“…[54] Not only by designing the geometry of the mixing chamber, Bokare et al reported that even by simply change the geometry pattern of the inlet channel for the fluids, the mixing efficiency can also be affected, as by integrating the herringbone-pattern with the inlet channel of a microcortex mixer (Figure 4g), the size of produced PLGA/lipid nanohybrids reduced from 199 to 74.5 nm. [55] Besides of influencing the size and morphology of NPs, as the altered geometry of microfluidic chips may impact on the mixing efficiency and shear force of the fluids, [56] thus the geometry of microfluidic chips may also dictate the internal crystallinities of the NPs. Moffitt and co-workers investigated the size, morphologies and crystallinities of polycaprolactoneblock-poly(ethylene oxide) (PCL-b-PEO) NPs produced by singlephase staggered herringbone (SHB) mixer (featured with high mixing rate, but low shear force) or two-phase gas-liquid segmented mixer (featured with low mixing rate, but high shear force).…”

“…(g) Reproduced with permission. [55] Copyright 2019, American Chemical Society. (h) Reproduced with permission.…”

Flow‐based reactor design for the continuous production of polymeric nanoparticles

“…On larger scales, confined impinging jet mixers, multiple inlet vortex mixers, coaxial turbulent jet mixers, and glass capillary devices have been developed for continuous production of polymeric NPs at high throughput . The coaxial turbulent jet mixer was particularly attractive on account of its broad solvent compatibility, process robustness, and ease of fabrication .…”