Three-dimensional flash flow microreactor for scale-up production of monodisperse PEG–PLGA nanoparticles

Min, Kyoung‐Ik; Im, Do Jin; Lee, Hyune-Jea; Kim, Dong‐Pyo

doi:10.1039/c4lc00700j

Cited by 48 publications

(32 citation statements)

References 27 publications

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“…15 However, those systems require sophisticated fabrication procedures, and the lack of robustness at high flow rates turns these designs unappropriated for long-term use. Recently, a glass flow focusing reactor 16 and 3D hydrodynamic flow focusing microfluidic reactor fabricated in polyimide, 18 a more durable material, enhanced the productivity of polymeric PLGA NPs achieving production rates of ∼10 g/h. New millifluidic reactors based on coaxial turbulent jet mixers have also arisen to address the insufficient production of NPs, achieving a throughput as high as 126 g/h.…”

Section: Introductionmentioning

confidence: 99%

Continuous synthesis of drug-loaded nanoparticles using microchannel emulsification and numerical modeling: effect of passive mixing

Solorzano¹,

Usón²,

Larrea³

et al. 2016

IJN

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By using interdigital microfluidic reactors, monodisperse poly( d , l lactic-co-glycolic acid) nanoparticles (NPs) can be produced in a continuous manner and at a large scale (~10 g/h). An optimized synthesis protocol was obtained by selecting the appropriated passive mixer and fluid flow conditions to produce monodisperse NPs. A reduced NP polydispersity was obtained when using the microfluidic platform compared with the one obtained with NPs produced in a conventional discontinuous batch reactor. Cyclosporin, an immunosuppressant drug, was used as a model to validate the efficiency of the microfluidic platform to produce drug-loaded monodisperse poly( d , l lactic-co-glycolic acid) NPs. The influence of the mixer geometries and temperatures were analyzed, and the experimental results were corroborated by using computational fluid dynamic three-dimensional simulations. Flow patterns, mixing times, and mixing efficiencies were calculated, and the model supported with experimental results. The progress of mixing in the interdigital mixer was quantified by using the volume fractions of the organic and aqueous phases used during the emulsification–evaporation process. The developed model and methods were applied to determine the required time for achieving a complete mixing in each microreactor at different fluid flow conditions, temperatures, and mixing rates.

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Section: Introductionmentioning

confidence: 99%

Continuous synthesis of drug-loaded nanoparticles using microchannel emulsification and numerical modeling: effect of passive mixing

Solorzano¹,

Usón²,

Larrea³

et al. 2016

IJN

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show abstract

“…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.…”

Section: Scale-up For Mass Productionmentioning

confidence: 99%

Microfluidic hydrodynamic focusing for synthesis of nanomaterials

et al. 2016

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Microfluidics expands the synthetic space such as heat transfer, mass transport, and reagent consumption to conditions not easily achievable in conventional batch processes. Hydrodynamic focusing in particular enables the generation and study of complex engineered nanostructures and new materials systems. In this review, we present an overview of recent progress in the synthesis of nanostructures and microfibers using microfluidic hydrodynamic focusing techniques. Emphasis is placed on distinct designs of flow focusing methods and their associated mechanisms, as well as their applications in material synthesis, determination of reaction kinetics, and study of synthetic mechanisms.

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“…This 3D HFF method was also demonstrated to continuously produce micelles over a long period without channel fouling, therefore parallelization of this 3D HFF device can expand to clinically relevant production scales. In contrast to multilayer 3D HFF systems that require high‐level expertise for fabrication, Rhee designed a simple 3D HFF enabled by three sequential inlets and a conventional cross junction in a monolithic single layer (Figure B). Various polymeric micelles with monodispersity were synthesized by this 3D HFF device, some of which, such as monodisperse PLGA‐ b ‐PEG micelles obtained from polymers with a PLGA block of high molecular weight (>45 kDa), proved to be significantly difficult to assemble in 2D HFF synthesis, due to their aggregation on the channel wall .…”

Section: Microfluidics For Fabrication Of Sddss With Well‐controlled mentioning

confidence: 99%

Microfluidics for Cancer Nanomedicine: From Fabrication to Evaluation

Zhang

Zhu

Shen

2018

Small

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Self-assembled drug delivery systems (sDDSs), made from nanocarriers and drugs, are one of the major types of nanomedicines, many of which are in clinical use, under preclinical investigation, or in clinical trials. One of the hurdles of this type of nanomedicine in real applications is the inherent complexity of their fabrication processes, which generally lack precise control over the sDDS structures and the batch-to-batch reproducibility. Furthermore, the classic 2D in vitro cell model, monolayer cell culture, has been used to evaluate sDDSs. However, 2D cell culture cannot adequately replicate in vivo tissue-level structures and their highly complex dynamic 3D environments, nor can it simulate their functions. Thus, evaluations using 2D cell culture often cannot correctly correlate with sDDS behaviors and effects in humans. Microfluidic technology offers novel solutions to overcome these problems and facilitates studying the structure-performance relationships for sDDS developments. In this Review, recent advances in microfluidics for 1) fabrication of sDDSs with well-defined physicochemical properties, such as size, shape, rigidity, and drug-loading efficiency, and 2) fabrication of 3D-cell cultures as "tissue/organ-on-a-chip" platforms for evaluations of sDDS biological performance are in focus.

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Three-dimensional flash flow microreactor for scale-up production of monodisperse PEG–PLGA nanoparticles

Abstract: We present a pressure-tolerant 3D parallel polyimide (PI) film microreactor operating at up to ~160 bars with direct 3D flow focusing geometry for mass production of PEG-PLGA nanoparticles in a ~10(1) gram-scale (g h(-1)).

Cited by 48 publications

References 27 publications

Continuous synthesis of drug-loaded nanoparticles using microchannel emulsification and numerical modeling: effect of passive mixing

Continuous synthesis of drug-loaded nanoparticles using microchannel emulsification and numerical modeling: effect of passive mixing

Microfluidic hydrodynamic focusing for synthesis of nanomaterials

Microfluidics for Cancer Nanomedicine: From Fabrication to Evaluation

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