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Microfluidic step-emulsification in axisymmetric geometry
Laboratoire Biophysique et Evolution - Chakraborty, J. Ricouvier, P. Yazhgur, P. Tabelingb and A. M. Leshansky
Lab. Chip - 17 3609-3620 - DOI: 10.1039/C7LC00755H - 2017
Biphasic step-emulsification (Z. Li et al., Lab Chip, 2015, 15, 1023) is a promising microfluidic technique for high-throughput production of μm and sub-μm highly monodisperse droplets. The step-emulsifier consists of a shallow (Hele-Shaw) microchannel operating with two co-flowing immiscible liquids and an abrupt expansion (i.e., step) to a deep and wide reservoir. Under certain conditions the confined stream of the disperse phase, engulfed by the co-flowing continuous phase, breaks into small highly monodisperse droplets at the step. Theoretical investigation of the corresponding hydrodynamics is complicated due to the complex geometry of the planar device, calling for numerical approaches. However, direct numerical simulations of the three dimensional surface-tension-dominated biphasic flows in confined geometries are computationally expensive. In the present paper we study a model problem of axisymmetric step-emulsification. This setup consists of a stable core-annular biphasic flow in a cylindrical capillary tube connected co-axially to a reservoir tube of a larger diameter through a sudden expansion mimicking the edge of the planar step-emulsifier. We demonstrate that the axisymmetric setup exhibits similar regimes of droplet generation to the planar device. A detailed parametric study of the underlying hydrodynamics is feasible via inexpensive (two dimensional) simulations owing to the axial symmetry. The phase diagram quantifying the different regimes of droplet generation in terms of governing dimensionless parameters is presented. We show that in qualitative agreement with experiments in planar devices, the size of the droplets generated in the step-emulsification regime is independent of the capillary number and almost insensitive to the viscosity ratio. These findings confirm that the step-emulsification regime is solely controlled by surface tension. The numerical predictions are in excellent agreement with in-house experiments with the axisymmetric step-emulsifier.
Paper Microfluidics for Nucleic Acids Amplification Testing (NAAT) of Infectious Diseases
Laboratoire Biophysique et Evolution - Magro L1, Escadafal C, Garneret P, Jacquelin B, Kwasiborski A, Manuguerra JC, Monti F, Sakuntabhai A, Vanhomwegen J, Lafaye P, Tabeling P.
Lab. Chip - 17(14) 2347-2371 - doi: 10.1039/c7lc00013h. - 2017
The diagnosis of infectious diseases is entering a new and interesting phase. Technologies based on paper microfluidics, coupled to developments in isothermal amplification of Nucleic Acids (NAs) raise opportunities for bringing the methods of molecular biology in the field, in a low setting environment. A lot of work has been performed in the domain over the last few years and the landscape of contributions is rich and diverse. Most often, the level of sample preparation differs, along with the sample nature, the amplification and detection methods, and the design of the device, among other features. In this review, we attempt to offer a structured description of the state of the art. The domain is not mature and there exist bottlenecks that hamper the realization of Nucleic Acid Amplification Tests (NAATs) complying with the constraints of the field in low and middle income countries. In this domain however, the pace of progress is impressively fast. This review is written for a broad Lab on a Chip audience.
Information-theoretic analysis of the directional influence between cellular processes
Laboratoire Biophysique et Evolution - Sourabh Lahiri, Philippe Nghe, Sander J. Tans, Martin Luc Rosinberg, David Lacoste
- 12(11) - - 2017
Inferring the directionality of interactions between cellular processes is a major challenge in systems biology. Time-lagged correlations allow to discriminate between alternative models, but they still rely on assumed underlying interactions. Here, we use the transfer entropy (TE), an information-theoretic quantity that quantifies the directional influence between fluctuating variables in a model-free way. We present a theoretical approach to compute the transfer entropy, even when the noise has an extrinsic component or in the presence of feedback. We re-analyze the experimental data from Kiviet et al. (2014) where fluctuations in gene expression of metabolic enzymes and growth rate have been measured in single cells of E. coli. We confirm the formerly detected modes between growth and gene expression, while prescribing more stringent conditions on the structure of noise sources. We furthermore point out practical requirements in terms of length of time series and sampling time which must be satisfied in order to infer optimally transfer entropy from times series of fluctuations.
Topological and thermodynamic factors that influence the evolution of small networks of catalytic RNA species.
Laboratoire Biophysique et Evolution - Yeates JAM, Nghe P, Lehman N.
RNA. - 23(7) 1088-1096 - doi: 10.1261/rna.061093.117 - 2017
An RNA-directed recombination reaction can result in a network of interacting RNA species. It is now becoming increasingly apparent that such networks could have been an important feature of the RNA world during the nascent evolution of life on the Earth. However, the means by which such small RNA networks assimilate other available genotypes in the environment to grow and evolve into the more complex networks that are thought to have existed in the prebiotic milieu are not known. Here, we used the ability of fragments of the Azoarcus group I intron ribozyme to covalently self-assemble via genotype-selfish and genotype-cooperative interactions into full-length ribozymes to investigate the dynamics of small (three- and four-membered) networks. We focused on the influence of a three-membered core network on the incorporation of additional nodes, and on the degree and direction of connectivity as single new nodes are added to this core. We confirmed experimentally the predictions that additional links to a core should enhance overall network growth rates, but that the directionality of the link (a "giver" or a "receiver") impacts the growth of the core itself. Additionally, we used a simple mathematical model based on the first-order effects of lower-level interactions to predict the growth of more complex networks, and find that such a model can, to a first approximation, predict the ordinal rankings of nodes once a steady-state distribution has been reached.
Laplace pressure based disjoining pressure isotherm in non symmetric conditions
Laboratoire Biophysique et Evolution - Huerre, A., Valignat, M. P., Maggs, A. C., Theodoly, O., & Jullien, M. C.
Applied Physics Letters - 111(22) 221601 - - 2017
Single-cell deep phenotyping of IgG-secreting cells for high-resolution immune monitoring.
Laboratoire Colloïdes et Matériaux Divisés - Eyer K, Doineau RCL,Castrillon C, Briseño-Roa L, Menrath V, Mottet G, England P, Godina A, Brient-Litzler E, Nizak C, Jensen A, Griffiths AD, Bibette J, Bruhns P, Baudry J.
Nat Biotechnol. - 35(10) 977-982 - doi: 10.1038/nbt.3964. - 2017
Studies of the dynamics of the antibody-mediated immune response have been hampered by the absence of quantitative, high-throughput systems to analyze individual antibody-secreting cells. Here we describe a simple microfluidic system, DropMap, in which single cells are compartmentalized in tens of thousands of 40-pL droplets and analyzed in two-dimensional droplet arrays using a fluorescence relocation-based immunoassay. Using DropMap, we characterized antibody-secreting cells in mice immunized with tetanus toxoid (TT) over a 7-week protocol, simultaneously analyzing the secretion rate and affinity of IgG from over 0.5 million individual cells enriched from spleen and bone marrow. Immunization resulted in dramatic increases in the range of both single-cell secretion rates and affinities, which spanned at maximum 3 and 4 logs, respectively. We observed differences over time in dynamics of secretion rate and affinity within and between anatomical compartments. This system will not only enable immune monitoring and optimization of immunization and vaccination protocols but also potentiate antibody screening.
Interparticle Capillary Forces at a Fluid − Fluid Interface with Strong Polymer-Induced Aging
Laboratoire Colloïdes et Matériaux Divisés - Stefano Cappelli, Arthur M. de Jon, Jean Baudry, and Menno W. J. Prins
Langmuir - 33 (3) 696–705 - DOI: 10.1021/acs.langmuir.6b03910 - 2017
We report on a measurement of forces between particles adsorbed at a water–oil interface in the presence of an oil-soluble polymer. The cationic polymer interacts electrostatically with the negatively charged particles, thereby modulating the particle contact angle and the magnitude of capillary attraction between the particles. However, polymer adsorption to the interface also generates an increase in the apparent interfacial viscosity over several orders of magnitude in a time span of a few hours. We have designed an experiment in which repeated motion trajectories are measured on pairs of particles. The experiment gives an independent quantification of the interfacial drag coefficient (10–7–10–4 Ns/m) and of the interparticle capillary forces (0.1–10 pN). We observed that the attractive capillary force depends on the amount of polymer in the oil phase and on the particle pair. However, the attraction appears to be independent of the surface rheology, with changes over a wide range of apparent viscosity values due to aging. Given the direction (attraction), the range (∼μm), and the distance dependence (∼1/S5) of the observed interparticle force, we interpret the force as being caused by quadrupolar deformations of the fluid–fluid interface induced by particle surface roughness. The results suggest that capillary forces are equilibrated in the early stages of interface aging and thereafter do not change anymore, even though strong changes in surface rheology still occur. The described experimental approach is powerful for studying dissipative as well as conservative forces of micro- and nanoparticles at fluid–fluid interfaces for systems out of equilibrium.
Controlled production of sub-millimeter liquid core hydrogel capsules for parallelized 3D cell culture
Laboratoire Colloïdes et Matériaux Divisés - Hugo Doméjean, Mathieu de la Motte Saint Pierre, Anette Funfak, Nicolas Atrux-Tallau, Kevin Alessandri, Pierre Nassoy, Jérôme Bibette and Nicolas Bremond
Lab. Chip - 17 110-119 - DOI: 10.1039/C6LC00848H - 2017
Liquid core capsules having a hydrogel membrane are becoming a versatile tool for three-dimensional culture of micro-organisms and mammalian cells. Making sub-millimeter capsules at a high rate, via the breakup of a compound jet in air, opens the way to high-throughput screening applications. However, control of the capsule size monodispersity, especially required for quantitative bioassays, was still lacking. Here, we report how the understanding of the underlying hydrodynamic instabilities that occur during the process can lead to calibrated core–shell bioreactors. The requirements are: i) damping the shear layer instability that develops inside the injector arising from the co-annular flow configuration of liquid phases having contrasting viscoelastic properties; ii) controlling the capillary instability of the compound jet by superposing a harmonic perturbation onto the shell flow; iii) avoiding coalescence of drops during jet fragmentation as well as during drop flight towards the gelling bath; iv) ensuring proper engulfment of the compound drops into the gelling bath for building a closed hydrogel shell. We end up with the creation of numerous identical compartments in which cells are able to form multicellular aggregates, namely spheroids. In addition, we implement an intermediate composite hydrogel layer, composed of alginate and collagen, allowing cell adhesion and thus the formation of epithelia or monolayers of cells.
High throughput micropatterning of interspersed cell arrays using capillary assembly
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - Delapierre, Francois-Damien, Mottet, Guillaume ; Taniga, Velan ; Boisselier, Julie ; Viovy, Jean-Louis ; Malaquin, Laurent
BIOFABRICATION - 9 (1) 015015 - 10.1088/1758-5090/aa5852 - 2017
Geometrical determinants of neuronal actin waves
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - Tomba, C., Braïni, C., Bugnicourt, G., Cohen, F., Friedrich, B., Gov, N. S., & Villard, C.
Frontiers in Cellular Neuroscience - 11 86 - - 2017
Chromatin immunoprecipitation in microfluidic droplets: towards fast and cheap analyses
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - Teste, Bruno, Champ, Jerome ; Londono-Vallejo, Arturo, Descroix, Stephanie, Malaquin, Laurent, Viovy, Jean-Louis, Draskovic, Irena, Mottet, Guillaume
Lab. Chip - 17, 3: 530-537 - DOI: 10.1039/c6lc01535b - 2017
Genetic organization is governed by the interaction of DNA with histone proteins, and differential modifications of these proteins is a fundamental mechanism of gene regulation. Histone modifications are primarily studied through chromatin immunoprecipitation (ChIP) assays, however conventional ChIP procedures are time consuming, laborious and require a large number of cells. Here we report for the first time the development of ChIP in droplets based on a microfluidic platform combining nanoliter droplets, magnetic beads (MB) and magnetic tweezers (MT). The droplet approach enabled compartmentalization and improved mixing, while reducing the consumption of samples and reagents in an integrated workflow. Anti-histone antibodies grafted to MB were used as a solid support to capture and transfer the target chromatin from droplets to droplets in order to perform chromatin immunoprecipitation, washing, elution and purification of DNA. We designed a new ChIP protocol to investigate four different types of modified histones with known roles in gene activation or repression. We evaluated the performances of this new ChIP in droplet assay in comparison with conventional methods. The proposed technology dramatically reduces analytical time from a few days to 7 hours, simplifies the ChIP protocol and decreases the number of cells required by 100 fold while maintaining a high degree of sensitivity and specificity. Therefore this droplet-based ChIP assay represents a new, highly advantageous and convenient approach to epigenetic analyses.
Magnetic fluidized bed for solid phase extraction in microfluidic systems
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - Pereiro, Iago ; Tabnaoui, Sanae ; Fermigier, Marc ; du Roure, Olivia ; Descroix, Stephanie ; Viovy, Jean-Louis ; Malaquin, Laurent
Lab. Chip - 17, 9 1603-1615 - DOI: 10.1039/C7LC00063D - 2017
Fluidization, a process in which a granular solid phase behaves like a fluid under the influence of an imposed upward fluid flow, is routinely used in many chemical and biological engineering applications. It brings, to applications involving fluid–solid exchanges, advantages such as high surface to volume ratio, constant mixing, low flow resistance, continuous operation and high heat transfer. We present here the physics of a new miniaturized, microfluidic fluidized bed, in which gravity is replaced by a magnetic field created by an external permanent magnet, and the solid phase is composed of magnetic microbeads with diameters ranging from 1 to 5 μm. These beads can be functionalized with different ligands, catalysts or enzymes, in order to use the fluidized bed as a continuous purification column or bioreactor. It allows flow-through operations at flow rates ranging from 100 nL min−1 up to 5 μL min−1 at low driving pressures (<100 mbar) with intimate liquid/solid contact and a continuous recirculation of beads for enhanced target capture efficiencies. The physics of the system presents significant differences as compared to conventional fluidized beds, which are studied here. The effects of magnetic field profile, flow chamber shape and magnetic bead dipolar interactions on flow regimes are investigated, and the different regimes of operation are described. Qualitative rules to obtain optimal operation are deduced. Finally, an exemplary use as a platform for immunocapture is provided, presenting a limit of detection of 0.2 ng mL−1 for 200 μL volume samples.
FISH-in-CHIPS: A Microfluidic Platform for Molecular Typing of Cancer Cells
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - Serra, M ; Pereiro, I; Yamada, A; Viovy, J. –L.; Descroix, S. Ferraro
Methods Mol Biol. - 1547 211-220 - doi: 10.1007/978-1-4939-6734-6_16 - 2017
The sealing of microfluidic devices remains a complex and time-consuming process requiring specific equipment and protocols: a universal method is thus highly desirable. We propose here the use of a commercially available sealing tape as a robust, versatile, reversible solution, compatible with cell and molecular biology protocols, and requiring only the application of manually achievable pressures. The performance of the seal was tested with regards to the most commonly used chip materials. For most materials, the bonding resisted 5 bars at room temperature and 1 bar at 95 °C. This method should find numerous uses, ranging from fast prototyping in the laboratory to implementation in low technology environments or industrial production.
A simple and low-cost chip bonding solution for high pressure, high temperature and biological applications Serra
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - Serra, M ; Pereiro, I; Yamada, A; Viovy, J. –L.; Descroix, S. Ferraro
Lab. Chip - 17: 4 629-634 - doi: 10.1039/c6lc01319h - 2017
The sealing of microfluidic devices remains a complex and time-consuming process requiring specific equipment and protocols: a universal method is thus highly desirable. We propose here the use of a commercially available sealing tape as a robust, versatile, reversible solution, compatible with cell and molecular biology protocols, and requiring only the application of manually achievable pressures. The performance of the seal was tested with regards to the most commonly used chip materials. For most materials, the bonding resisted 5 bars at room temperature and 1 bar at 95 °C. This method should find numerous uses, ranging from fast prototyping in the laboratory to implementation in low technology environments or industrial production.
Droplet Microfluidic and Magnetic Particles Platform for Cancer Typing
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - Ferraro D, Champ J, Teste B, Serra M, Malaquin L, Descroix S, de Cremoux P, Viovy JL.
Lab. Chip - 1547 113-121 - doi: 10.1007/978-1-4939-6734-6_9. - 2017
Analyses of nucleic acids are routinely performed in hospital laboratories to detect gene alterations for cancer diagnosis and treatment decision. Among the different possible investigations, mRNA analysis provides information on abnormal levels of genes expression. Standard laboratory methods are still not adapted to the isolation and quantitation of low mRNA amounts and new techniques needs to be developed in particular for rare subsets analysis. By reducing the volume involved, time process, and the contamination risks, droplet microfluidics provide numerous advantages to perform analysis down to the single cell level.We report on a droplet microfluidic platform based on the manipulation of magnetic particles that allows the clinical analysis of tumor tissues. In particular, it allows the extraction of mRNA from the total-RNA sample, Reverse Transcription, and cDNA amplification, all in droplets.
The power of solid supports in multiphase and droplet-based microfluidics: towards clinical applications
Laboratoire Macromolécules et Microsystèmes en Biologie et Médecine - M. Serra, D. Ferraro, I. Pereiro, J.-L. Viovyabc and S. Descroix
Lab. Chip - 17 3979-3999 - - 2017
Multiphase and droplet microfluidic systems are growing in relevance in bioanalytical-related fields, especially due to the increased sensitivity, faster reaction times and lower sample/reagent consumption of many of its derived bioassays. Often applied to homogeneous (liquid/liquid) reactions, innovative strategies for the implementation of heterogeneous (typically solid/liquid) processes have recently been proposed. These involve, for example, the extraction and purification of target analytes from complex matrices or the implementation of multi-step protocols requiring efficient washing steps. To achieve this, solid supports such as functionalized particles (micro or nanometric) presenting different physical properties (e.g. magnetic, optical or others) are used for the binding of specific entities. The manipulation of such supports with different microfluidic principles has both led to the miniaturization of existing biomedical protocols and the development of completely new strategies for diagnostics and research. In this review, multiphase and droplet-based microfluidic systems using solid suspensions are presented and discussed with a particular focus on: i) working principles and technological developments of the manipulation strategies and ii) applications, critically discussing the level of maturity of these systems, which can range from initial proofs of concept to real clinical validations.
Nanoscale capillary freezing of ionic liquids confined between metallic interfaces and the role of electronic screening
Laboratoire Micromégas - J. Comtet, A. Niguès, V. Kaiser, B. Coasne, L. Bocquet and A. Siria, Nature Materials
Nature Materials - 16 634‐639 - doi: 10.1038/nmat4880 - 2017
Room-temperature ionic liquids (RTILs) are new materials with fundamental importance for energy storage and active lubrication. They are unusual liquids, which challenge the classical frameworks of electrolytes, whose behaviour at electrified interfaces remains elusive, with exotic responses relevant to their electrochemical activity. Using tuning-fork-based atomic force microscope nanorheological measurements, we explore here the properties of confined RTILs, unveiling a dramatic change of the RTIL towards a solid-like phase below a threshold thickness, pointing to capillary freezing in confinement. This threshold is related to the metallic nature of the confining materials, with more metallic surfaces facilitating freezing. This behaviour is interpreted in terms of the shift of the freezing transition, taking into account the influence of the electronic screening on RTIL wetting of the confining surfaces. Our findings provide fresh views on the properties of confined RTIL with implications for their properties inside nanoporous metallic structures, and suggests applications to tune nanoscale lubrication with phase-changing RTILs, by varying the nature and patterning of the substrate, and application of active polarization.
Pairwise frictional profile between particles determines discontinuous shear thickening transition in non‐colloidal suspensions
Laboratoire Micromégas - J. Comtet, G. Chatté, A. Niguès, L. Bocquet, A. Siria, and A. Colin
Nat Commun - 8 15633 - DOI: 10.1038/ncomms15633 - 2017
The process by which sheared suspensions go through a dramatic change in viscosity is known as discontinuous shear thickening. Although well-characterized on the macroscale, the microscopic mechanisms at play in this transition are still poorly understood. Here, by developing new experimental procedures based on quartz-tuning fork atomic force microscopy, we measure the pairwise frictional profile between approaching pairs of polyvinyl chloride and cornstarch particles in solvent. We report a clear transition from a low-friction regime, where pairs of particles support a finite normal load, while interacting purely hydrodynamically, to a high-friction regime characterized by hard repulsive contact between the particles and sliding friction. Critically, we show that the normal stress needed to enter the frictional regime at nanoscale matches the critical stress at which shear thickening occurs for macroscopic suspensions. Our experiments bridge nano and macroscales and provide long needed demonstration of the role of frictional forces in discontinuous shear thickening.
Contact dependence and velocity crossover in friction between microscopic solid/solid contacts
Laboratoire Micromégas - McGraw, A. Niguès, A. Chennevière, A. Siria
Nano Lett. - 17 (10) 6335–6339 - DOI: 10.1021/acs.nanolett.7b03076 - 2017
Friction at the nanoscale differs markedly from that between surfaces of macroscopic extent. Characteristically, the velocity dependence of friction between apparent solid/solid contacts can strongly deviate from the classically assumed velocity independence. Here, we show that a nondestructive friction between solid tips with radius on the scale of hundreds of nanometers and solid hydrophobic self-assembled monolayers has a strong velocity dependence. Specifically, using laterally oscillating quartz tuning forks, we observe a linear scaling in the velocity at the lowest accessed velocities, typically hundreds of micrometers per second, crossing over into a logarithmic velocity dependence. This crossover is consistent with a general multicontact friction model that includes thermally activated breaking of the contacts at subnanometric elongation. We find as well a strong dependence of the friction on the dimensions of the frictional probe.
New avenues for the large-scale harvesting of blue energy
Laboratoire Micromégas - Alessandro Siria, Marie-Laure Bocquet & Lydéric Bocquet
Nature Reviews Chemistry - 91 - doi:10.1038/s41570-017-0091 - 2017
Salinity gradients have been identified as promising clean, renewable and non-intermittent sources of energy — so-called blue energy. However, the low efficiency of current harvesting technologies is a major limitation for large-scale viability and is mostly due to the low performances of the membrane processes currently in use. Advances in materials fabrication with dedicated chemical properties can resolve this bottleneck and lead to a new class of membranes for blue-energy conversion. In this Perspective, we briefly present current technologies for the conversion of blue energy, describe their performances and note their limitations. We then discuss new avenues for the development of a new class of membranes, combining considerations in nanoscale fluid dynamics and surface chemistry. Finally, we discuss how new functionalities originating from the exotic behaviour of fluids in the nanoscale regime can further boost energy conversion, making osmotic energy a tangible, clean alternative.


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