Preparation of nanoliposomes by microfluidic mixing in herring-bone channel and the role of membrane fluidity in liposomes formation

Kotouček, Jan; Hubatka, František; Mašek, Josef; Kulich, Pavel; Velínská, Kamila; Bezděková, Jaroslava; Fojtíková, Martina; Bartheldyová, Eliška; Tomečková, Andrea; Stráská, Jana; Hrebik, D.; Macaulay, S. Lance; Kratochvílová, Irena; Raška, Milan; Tuřánek, Jaroslav

doi:10.1038/s41598-020-62500-2

Cited by 71 publications

(60 citation statements)

References 32 publications

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“…The difference in size between the two formulations may have been due to the superior fluidity of the unsaturated fatty acids in the PC double layer. It has been previously reported that an increase in fluidity results in a decrease in liposome size [ 65 ]. Moreover, it has been shown that lipids with shorter chains lead to the formation of larger liposomes [ 66 , 67 ], which may be due to the reduced thickness of the bilayer when a shorter chain length lipid is employed, e.g., the alkyl chain lengths of DPPC (16:0) vs. PC (18:2/16:0), leading to reduced membrane bending modulus [ 68 ] and lower line tension [ 69 ].…”

Section: Resultsmentioning

confidence: 99%

Continuous-Flow Production of Liposomes with a Millireactor under Varying Fluidic Conditions

et al. 2020

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Continuous-flow production of liposomes using microfluidic reactors has demonstrated advantages compared to batch methods, including greater control over liposome size and size distribution and reduced reliance on post-production processing steps. However, the use of microfluidic technology for the production of nanoscale vesicular systems (such as liposomes) has not been fully translated to industrial scale yet. This may be due to limitations of microfluidic-based reactors, such as low production rates, limited lifetimes, and high manufacturing costs. In this study, we investigated the potential of millimeter-scale flow reactors (or millireactors) with a serpentine-like architecture, as a scalable and cost-effective route to the production of nanoscale liposomes. The effects on liposome size of varying inlet flow rates, lipid type and concentration, storage conditions, and temperature were investigated. Liposome size (i.e., mean diameter) and size dispersity were characterised by dynamic light scattering (DLS); z-potential measurements and TEM imaging were also carried out on selected liposome batches. It was found that the lipid type and concentration, together with the inlet flow settings, had significant effects on the properties of the resultant liposome dispersion. Notably, the millifluidic reactor was able to generate liposomes with size and dispersity ranging from 54 to 272 nm, and from 0.04 to 0.52 respectively, at operating flow rates between 1 and 10 mL/min. Moreover, when compared to a batch ethanol-injection method, the millireactor generated liposomes with a more therapeutically relevant size and size dispersity.

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Section: Resultsmentioning

confidence: 99%

Continuous-Flow Production of Liposomes with a Millireactor under Varying Fluidic Conditions

et al. 2020

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“…Fibrin targeted contrasting MRI imaging has already been used in various models [ 8 ], including a rabbit model [ 34 , 35 ]. In the present study, however, a novel fibrin binding system using protein binders and liposomal carriers [ 31 ] with gadolinium-labelled contrast agent was applied [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Thrombus Imaging Using 3D Printed Middle Cerebral Artery Model and Preclinical Imaging Techniques: Application to Thrombus Targeting and Thrombolytic Studies

et al. 2020

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Diseases with the highest burden for society such as stroke, myocardial infarction, pulmonary embolism, and others are due to blood clots. Preclinical and clinical techniques to study blood clots are important tools for translational research of new diagnostic and therapeutic modalities that target blood clots. In this study, we employed a three-dimensional (3D) printed middle cerebral artery model to image clots under flow conditions using preclinical imaging techniques including fluorescent whole-body imaging, magnetic resonance imaging (MRI), and computed X-ray microtomography (microCT). Both liposome-based, fibrin-targeted, and non-targeted contrast agents were proven to provide a sufficient signal for clot imaging within the model under flow conditions. The application of the model for clot targeting studies and thrombolytic studies using preclinical imaging techniques is shown here. For the first time, a novel method of thrombus labeling utilizing barium sulphate (Micropaque®) is presented here as an example of successfully employed contrast agents for in vitro experiments evaluating the time-course of thrombolysis and thus the efficacy of a thrombolytic drug, recombinant tissue plasminogen activator (rtPA). Finally, the proof-of-concept of in vivo clot imaging in a middle cerebral artery occlusion (MCAO) rat model using barium sulphate-labelled clots is presented, confirming the great potential of such an approach to make experiments comparable between in vitro and in vivo models, finally leading to a reduction in animals needed.

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“…It is out of the scope of this Review to report on the mathematical details of the model; the interested reader can refer to the paper from Kotouček et al [151] for further information. Researchers have further optimized microfluidic mixing devices based on hydrodynamic focusing in which a central fluid flow of an organic phase containing lipids is interfaced by two streams of aqueous buffer, [152] or also vertical flow focusing in which high aspect ratio mixing channels allow for an enhancement of the size of the lipid/water interface.…”

Section: Microfluidics and Printing Approachesmentioning

confidence: 99%

“…However, further engineering of the AVs production is necessary to reach the nanometer scale, adequate for intracellular delivery. This can be achieved by microfluidic mixing [151] of an organic water-miscible solvent phase (typically ethanol) containing lipids with an aqueous phase containing molecules to encapsulate ( Figure 4D). Such set-up (based on the NanoAssemblr microfluidic platform) allows for the assembly of liposomes with diameters on the 100 nm scale and can be integrated with gadolinium lipid complexes for applications as MRI contrast agents ( Figure 4E).…”

Section: Microfluidics and Printing Approachesmentioning

confidence: 99%

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Mastering the Tools: Natural versus Artificial Vesicles in Nanomedicine

Leggio

Arrabito

Ferrara

et al. 2020

Adv Healthcare Materials

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Naturally occurring extracellular vesicles and artificially made vesicles represent important tools in nanomedicine for the efficient delivery of biomolecules and drugs. Since its first appearance in the literature 50 years ago, the research on vesicles is progressing at a fast pace, with the main goal of developing carriers able to protect cargoes from degradation, as well as to deliver them in a time‐ and space‐controlled fashion. While natural occurring vesicles have the advantage of being fully compatible with their host, artificial vesicles can be easily synthetized and functionalized according to the target to reach. Research is striving to merge the advantages of natural and artificial vesicles, in order to provide a new generation of highly performing vesicles, which would improve the therapeutic index of transported molecules. This progress report summarizes current manufacturing techniques used to produce both natural and artificial vesicles, exploring the promises and pitfalls of the different production processes. Finally, pros and cons of natural versus artificial vesicles are discussed and compared, with special regard toward the current applications of both kinds of vesicles in the healthcare field.

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Preparation of nanoliposomes by microfluidic mixing in herring-bone channel and the role of membrane fluidity in liposomes formation

Cited by 71 publications

References 32 publications

Continuous-Flow Production of Liposomes with a Millireactor under Varying Fluidic Conditions

Continuous-Flow Production of Liposomes with a Millireactor under Varying Fluidic Conditions

Thrombus Imaging Using 3D Printed Middle Cerebral Artery Model and Preclinical Imaging Techniques: Application to Thrombus Targeting and Thrombolytic Studies

Mastering the Tools: Natural versus Artificial Vesicles in Nanomedicine

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