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Horseshoe lamination mixer (HLM) sets new standards in the production of monodisperse lipid nanoparticles
Lab on a Chip ( IF 6.1 ) Pub Date : 2022-07-06 , DOI: 10.1039/d2lc00240j
Peer Erfle 1, 2 , Juliane Riewe 2, 3 , Songtao Cai 1 , Heike Bunjes 2, 3 , Andreas Dietzel 1, 2
Affiliation  

Microfluidic mixers promise unique conditions for the controlled and continuous preparation of nanoparticles by antisolvent precipitation. Nanoparticles may enable encapsulation of drug or mRNA molecules in the form of carrier nanoparticles or can provide higher bioavailability in the form of drug nanoparticles. The ultimate goal in microfluidic approaches is the production of nanoparticles with narrow size distributions while avoiding contaminations and achieving sufficiently high throughput. To achieve this, a novel microfluidic precipitation device was developed and realized by two-photon polymerization: mixing elements were designed in such a way that the liquids undergo a repeated Smale horseshoe transformation resulting in an increased interfacial area and mixing times of less than 10 ms. These elements and an additional 3D flow focusing ensure that no organic phase is exposed to the channel walls. The integration of a fluidic shield layer in the flow focusing proved to be useful to delay the precipitation process until reaching a sufficient distance to the injection nozzle. Lipid nanoparticle preparation with different concentrations of castor oil or the hard fat Softisan® 100 were performed at different flow rates and mixing ratios with and without a shield layer. Flow rates of up to 800 μl min−1 and organic phase mixing ratios of up to 20% resulted in particle sizes ranging from 42 nm to 166 nm with polydispersity indices from 0.04 to 0.11, indicating very narrowly distributed, and in most cases even monodisperse, nanoparticles. The occurrence of fouling can be completely suppressed with this new type of mixing elements, as long as Dean vortices are prevented. Moreover, this parameter range in the horseshoe lamination mixer provided a stable and continuous process, which enables a scalable production.

中文翻译:

马蹄形层压混合器 (HLM) 为单分散脂质纳米粒子的生产设立了新标准

微流体混合器为通过反溶剂沉淀控制和连续制备纳米粒子提供了独特的条件。纳米颗粒可以以载体纳米颗粒的形式封装药物或mRNA分子,或者可以以药物纳米颗粒的形式提供更高的生物利用度。微流体方法的最终目标是生产具有窄尺寸分布的纳米颗粒,同时避免污染并实现足够高的通量。为了实现这一目标,开发了一种新型微流体沉淀装置,并通过双光子聚合实现:混合元件的设计方式使液体经历重复的 Smale 马蹄形转变,从而增加了界面面积,混合时间小于 10 毫秒. 这些元件和额外的 3D 流动聚焦确保没有有机相暴露于通道壁。事实证明,在流动聚焦中集成流体屏蔽层有助于延迟沉淀过程,直到达到与喷射喷嘴的足够距离。用不同浓度的蓖麻油或硬脂 Softisan® 100 制备脂质纳米颗粒,在有和没有屏蔽层的情况下以不同的流速和混合比进行。流速高达 800 μl min 用不同浓度的蓖麻油或硬脂 Softisan® 100 制备脂质纳米颗粒,在有和没有屏蔽层的情况下以不同的流速和混合比进行。流速高达 800 μl min 用不同浓度的蓖麻油或硬脂 Softisan® 100 制备脂质纳米颗粒,在有和没有屏蔽层的情况下以不同的流速和混合比进行。流速高达 800 μl min-1和高达 20% 的有机相混合比导致粒径范围为 42 nm 至 166 nm,多分散指数为 0.04 至 0.11,表明纳米粒子分布非常窄,在大多数情况下甚至是单分散的。只要防止迪恩涡流,这种新型混合元件就可以完全抑制结垢的发生。此外,马蹄形层压混合机中的这个参数范围提供了稳定和连续的工艺,从而实现了可扩展的生产。
更新日期:2022-07-06
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