Degas-Driven Deterministic Lateral Displacement in Poly(dimethylsiloxane) Microfluidic Devices.

In this work, degas-driven microfluidic deterministic lateral displacement devices were fabricated from poly(dimethylsiloxane). Two device configurations were considered: one with a single input for the enrichment of particles and the other one with sheath inputs for the separation of particles based on their sizes. Using the single-input device, the characteristics of the degas-driven fluid through micropillars were investigated, and then selective enrichment of fluorescent polymer particles with diameters of around 13 µm mixed with similar 7 µm particles was demonstrated. Using the sheath-input device, the separation of 13 and 7 µm beads was achieved (the corresponding purities exceeded 92.62% and 99.98%, respectively). In addition, clusters composed of 7 µm beads (including doublets, triplets, and quadruplets) were fractionated based on their equivalent sizes. Finally, white blood cells could be separated from red blood cells at a relatively high capture efficiency (95.57%) and purity (86.97%).

Capillary-assisted fabrication of biconcave polymeric microlenses from microfluidic ternary emulsion droplets.

In this study, a simple capillary-based approach for producing biconcave polymeric microlenses with uniform size and shape from ternary emulsion droplets is presented. Monodisperse ternary emulsion droplets (0.6-4.0 nL) are produced which contain a photocurable segment of an acrylate monomer and two non-curable segments of silicone oil (SO) by using a microfluidic sheath-flowing droplet generator on a glass chip. The curvature radius of the interfaces separating the droplet segments, as well as the droplet size, and production rate can be flexibly varied by changing the flow conditions of the organic and aqueous phases. Subsequently, off-chip suspension photopolymerization yields non-spherical polymeric microparticles with two spherical concave surfaces templated by two SO segments at random positions. By ultraviolet light irradiation of ternary droplets with two SO segments trapped by the interior wall of a cylindrical microcapillary (internal diameter: 130 µm), biconcave microlenses can be produced with two spherical concave surfaces with a common lens axis. The produced lenses are suitable for use as optical diverging lenses.

Microfluidic passive permeability assay using nanoliter droplet interface lipid bilayers.

Membrane permeability assays play an important role in assessing drug transport activities across biological membranes. However, in conventional parallel artificial membrane permeability assays (PAMPA), the membrane model used is dissimilar to biological membranes physically and chemically. Here, we describe a microfluidic passive permeability assay using droplet interface bilayers (DIBs). In a microfluidic network, nanoliter-sized donor and acceptor aqueous droplets are alternately formed in cross-flowing oil containing phospholipids. Subsequently, selective removal of oil through hydrophobic pseudo-porous sidewalls induces the contact of the lipid monolayers, creating arrayed planar DIBs between the donor and acceptor droplets. Permeation of fluorescein from the donor to the acceptor droplets was fluorometrically measured. From the measured data and a simple diffusion model we calculated the effective permeabilities of 5.1 × 10(-6) cm s(-1), 60.0 × 10(-6) cm s(-1), and 87.6 × 10(-6) cm s(-1) with donor droplets at pH values of 7.5, 6.4 and 5.4, respectively. The intrinsic permeabilities of specific monoanionic and neutral fluorescein species were obtained similarly. We also measured the permeation of caffeine in 10 min using UV microspectroscopy, obtaining a permeability of 20.8 × 10(-6) cm s(-1). With the small solution volumes, short measurement time, and ability to measure a wide range of compounds, this device has considerable potential as a platform for high-throughput drug permeability assays.

Tunable deterministic lateral displacement of particles flowing through thermo-responsive hydrogel micropillar arrays.

Deterministic lateral displacement (DLD) is a promising technology that allows for the continuous and the size-based separation of suspended particles at a high resolution through periodically arrayed micropillars. In conventional DLD, the critical diameter (Dc), which determines the migration mode of a particle of a particular size, is fixed by the device geometry. Here, we propose a novel DLD that uses the pillars of a thermo-responsive hydrogel, poly(N-isopropylacrylamide) (PNIPAM) to flexibly tune the Dc value. Upon heating and cooling, the PNIPAM pillars in the aqueous solution shrink and swell because of their hydrophobic-hydrophilic phase transitions as the temperature varies. Using the PNIPAM pillars confined in a poly(dimethylsiloxane) microchannel, we demonstrate continuous switching of particle (7-µm beads) trajectories (displacement or zigzag mode) by adjusting the Dc through temperature control of the device on a Peltier element. Further, we perform on/off operation of the particle separation (7-µm and 2-µm beads) by adjusting the Dc values.

Microfluidic Coupling of Step Emulsification and Deterministic Lateral Displacement for Producing Satellite-Free Droplets and Particles.

Step emulsification, which uses a geometry-dependent mechanism for generating uniformly sized droplets, has recently gained considerable attention because of its robustness against flow fluctuations. However, like shear-based droplet generation, step emulsification is susceptible to impurities caused by satellite droplets. Herein, we demonstrate the integration of deterministic lateral displacement (DLD) to separate the main and satellite droplets produced during step emulsification. Step-emulsification nozzles (16 µm deep) in the upstream region of the proposed device were arrayed on the sidewalls of the main channel (91 µm deep). In the downstream region, the DLD micropillars were arrayed periodically with a critical diameter (cut-off value for size-based separation) of 37 µm. When an acrylate monomer and aqueous polyvinyl alcohol solution were infused as the dispersed and continuous phases, respectively, the nozzles produced monodisperse main droplets in the dripping regime, with an average diameter of ~60 µm, coefficient of variation (CV) value below 3%, and satellite droplets of ~3 µm. Upon entering the DLD region near the sidewall, these main and satellite droplets were gradually separated through the pillars based on their sizes. Finally, off-chip photopolymerization yielded monodisperse polymeric microspheres with an average diameter of 55 µm and a CV value of 2.9% (n = 202).

Understanding droplet breakup in a post-array device with sheath-flow configuration.

Microfluidic post-array devices have the potential to generate quasi-monodisperse emulsion droplets with high throughput and dispersed phase fractions by splitting droplets with regularly arranged posts. However, the lack of understanding of post-array devices makes it challenging to predict droplet size and quantitatively evaluate the influence of post geometry, hindering their widespread application. Therefore, we investigated the characteristics of droplet breakup through a post array using a series of devices with sheath-flow configurations, in which the dispersed and continuous flow rates could be flexibly tuned. Using a poly(dimethylsiloxane)-glass device fabricated via soft lithography, we found that the volume ratio of the dispersed phase to the continuous phase significantly affects the droplet size, even when the viscosity ratio is close to one. For the first time, we demonstrated that the effective capillary number calculated from the emulsion viscosity and effect of the dispersed phase fraction consistently describes various experimental results. Furthermore, our flow observations and droplet diameter measurement showed two breakup modes: the size-constant obstruction and shear-induced modes with a power-law correlation similar to droplet splitting in a T-junction. Thus, the power-law correlation in microfluidic droplet splitting successfully expresses the droplet generation characteristics in post-array devices. A combination of effective viscosity correction and curve fitting allowed us to evaluate the influence of the material and post-geometry on droplet generation characteristics. This study contributes to the understanding of droplet breakup in post-array devices and extends their unique droplet generation properties to include high-throughput, high-fraction, robust, and continuous emulsification processes.

Editorial for the Special Issue on Particles Separation in Microfluidic Devices, Volume II.

Particle separation in the nano- to microscale range is a significant step for biological, chemical, and medical analyses [...].

Microfluidic generation of monodispersed Janus alginate hydrogel microparticles using water-in-oil emulsion reactant.

Microparticles with uniform anisotropic structures are widely used in physical, chemical, and biological fields owing to their ability to combine multiple functions on a micro-scale. Here, a microfluidic emulsion-based external gelation method was demonstrated for the first time to produce monodisperse Janus calcium alginate (Ca-alginate) hydrogel microparticles consisting of two compartments. This approach provided a fast reaction condition under which we could prepare magnetic Janus Ca-alginate microparticles with diameters ranging from 148 to 179 µm and a coefficient of variation (CV) less than 4%. Moreover, the boundaries between the two compartments were clear. In addition, the volume fraction of each compartment could be adjusted by varying the flow rate ratio between two dispersed phases. Next, we produced fluorescent Janus beads and magnetic-fluorescent Janus beads with an average diameter of ∼150 µm (CV < 4.0%). The magnetic Janus hydrogel microparticles we produced could be manipulated by applying a magnetic field to achieve self-assembly, rotation, and accumulation. Magnetic Janus hydrogel microparticles are also capable of mammalian cell encapsulation with good cell viability. This article presents a simple and stable approach for producing monodisperse bi-compartmental Janus hydrogel microparticles that could have great potential for application in physical, biochemical, and biomedical fields.

Generation and Characterization of a Library of Novel Biologically Active Functional Surfactants (Surfmers) Using Combined High-Throughput Methods.

We report the first successful combination of three distinct high-throughput techniques to deliver the accelerated design, synthesis, and property screening of a library of novel, bio-instructive, polymeric, comb-graft surfactants. These three-dimensional, surface-active materials were successfully used to control the surface properties of particles by forming a unimolecular deep layer on the surface of the particles via microfluidic processing. This strategy deliberately utilizes the surfactant to both create the stable particles and deliver a desired cell-instructive behavior. Therefore, these specifically designed, highly functional surfactants are critical to promoting a desired cell response. This library contained surfactants constructed from 20 molecularly distinct (meth)acrylic monomers, which had been pre-identified by HT screening to exhibit specific, varied, and desirable bacterial biofilm inhibitory responses. The surfactant's self-assembly properties in water were assessed by developing a novel, fully automated, HT method to determine the critical aggregation concentration. These values were used as the input data to a computational-based evaluation of the key molecular descriptors that dictated aggregation behavior. Thus, this combination of HT techniques facilitated the rapid design, generation, and evaluation of further novel, highly functional, cell-instructive surfaces by application of designed surfactants possessing complex molecular architectures.

Microfluidic Encapsulation of Hydrophobic Antifouling Biocides in Calcium Alginate Hydrogels for Controllable Release.

Microencapsulation of biocides is used in long-life antifouling coating paints for marine applications and building materials. Here, we report the microfluidic production of calcium alginate (Ca-alginate) hydrogel particles to modulate the release of the encapsulated drug Irgarol (N-cyclopropyl-N'-(1,1-dimethylethyl)-6-(methylthio)-1,3,5-triazine-2,4-diamine), which is a hydrophobic and specifically phytotoxic antifoulant that inhibits photosystem II in aquatic plant species. We first encapsulated the drug inside the highly spherical Ca-alginate hydrogels of an average diameter ∼160 µm with a coefficient of variation of less than 4% and an average roundness of more than 0.96. The release speeds of the encapsulated and nonencapsulated drugs in pure water were measured separately by ultraviolet-visible spectroscopy. A stable and controllable release rate of the loaded drug was achieved by hydrophilic encapsulation. In addition, cellulose fibers were incorporated to enhance the mechanical strength of the hydrogels. Finally, the antifouling effect of the encapsulated drug was demonstrated using water grass (Bacopa monnieri).

Surfactant-Laden Janus Droplets with Tunable Morphologies and Enhanced Stability for Fabricating Lens-Shaped Polymeric Microparticles.

Janus droplets can function as excellent templates for fabricating physically and chemically anisotropic particles. Here, we report new surfactant-laden Janus droplets with curvature controllability and enhanced stability against coalescence, suitable for fabricating shape-anisotropic polymer microparticles. Using a microfluidic flow-focusing device on a glass chip, nanoliter-sized biphasic droplets, comprising an acrylate monomer segment and a silicone-oil (SO) segment containing a surfactant, were produced in a co-flowing aqueous polyvinyl alcohol (PVA) solution. At equilibrium, the droplets formed a Janus geometry based on the minimization of interfacial energy, and each of the two Janus segments were uniform in size with coefficient-of-variation values below 3%. By varying the concentration of the surfactant in the SO phase, the curvature of the interface between the two lobes could be shifted among concave, planar, and convex shapes. In addition, the Janus droplets exhibited significantly improved stability against coalescence compared with previously reported Janus droplets carrying no surfactant that coalesced rapidly. Finally, via off-chip photopolymerization, concave-convex, planar-convex, and biconvex lens-shaped particles were fabricated.

Polymer Capsules with Tunable Shell Thickness Synthesized via Janus-to-core shell Transition of Biphasic Droplets Produced in a Microfluidic Flow-Focusing Device.

Droplet microfluidics has enabled the synthesis of polymeric particles with controlled sizes, shell thickness, and morphologies. Here, we report the Janus to core-shell structural evolution of biphasic droplets formed in a microfluidic flow-focusing device (MFFD) for the synthesis of polymer microcapsules with oil core/thickness-tunable shell via off-chip photo- and thermally induced polymerization. First, nanoliter-sized biphasic Janus droplets comprising an acrylate monomer and silicone oil were generated in a co-flowing aqueous polyvinyl alcohol (PVA) solution in an MFFD on a glass chip. Immediately following their break-off, the produced Janus droplets started to change their geometry from Janus to core-shell structure comprising a single silicone-oil core and an acrylate-monomer shell by the minimization of interfacial energy. Thus, we could produce monodisperse core-shell drops with average diameters of 105-325 µm, coefficient of variation (CV) values of 1.0-4.5%, and shell thickness of 1-67 µm. Subsequently, these drops were synthesized to fabricate polymeric microcapsules with tunable shell thickness via photo- and thermally induced polymerization. By increasing the concentration of the photo- and thermal initiator, we successfully produced thinner and ultra-thin shell (800 nm thickness) microcapsules. The surface structure of resulting particles was smooth in photopolymerization and porous in thermal polymerization.

Particle/cell separation using sheath-free deterministic lateral displacement arrays with inertially focused single straight input.

This paper proposes microfluidic particle separation by sheath-free deterministic lateral displacement (DLD) with inertial focusing in a single straight input channel. Unlike conventional DLD devices for size-based particle separation, in which sheath streams are used to focus the particles before the solution containing them reaches the DLD arrays, the proposed method uses inertial focusing to align the particles along the middle or the sidewalls of the straight rectangular input channel. The two-stage model of inertial focusing is applied to reduce the length of the side-focusing channel. The proposed method is demonstrated by using it to separate fluorescent polymer particles of diameters 13 and 7 µm, in the process of which the effect of the particle focusing regime on the separation performance is also investigated. Through middle focusing, the method is further used to separate MCF-7 cells (a model of circulating tumor cells (CTCs)) and blood cells, with ∼99.0% capture efficiency achieved.

Editorial for the Special Issue on Particles Separation in Microfluidic Devices.

The separation and sorting of micro- and nano-sized particles is an important step in chemical, biological, and medical analyses [...].

Microfluidic large-scale integration on a chip for mass production of monodisperse droplets and particles.

In this study, we report the mass production of monodisperse emulsion droplets and particles using microfluidic large-scale integration on a chip. The production module comprises a glass microfluidic chip with planar microfabricated 16-256 droplet-formation units (DFUs) and a palm-sized stainless steel holder having several layers for supplying liquids into the inlets of the mounted chip. By using a module having 128 cross-junctions (i.e., 256 DFUs) arranged circularly on a 4 cm x 4 cm chip, we could produce droplets of photopolymerizable acrylate monomer at a throughput of 320.0 mL h(-1). The product was monodisperse, having a mean diameter of 96.4 microm, with a coefficient of variation (CV) of 1.3%. Subsequent UV polymerization off the module yielded monodisperse acrylic microspheres at a throughput of approximately 0.3 kg h(-1). Another module having 128 co-flow geometries could produce biphasic Janus droplets of black and white segments at 128.0 mL h(-1). The product had a mean diameter of 142.3 microm, with a CV of 3.3%. This co-flow module could also be applied in the mass production of homogeneous monomer droplets.

Effect of surfactant on Pseudomonas aeruginosa colonization of polymer microparticles and flat films.

Micro- and nanoparticles are of great interest because of their potential for trafficking into the body for applications such as low-fouling coatings on medical devices, drug delivery in pharmaceutics and cell carriers in regenerative medicine strategies. Particle production often relies on the use of surfactants to promote stable droplet formation. However, the presence of residual surfactant has been shown to complicate the surface chemistry and resultant properties. When forming particles from polymerizable monomer droplets, these polymeric surfactant chains can become physically entangled in the particle surface. Due to the key role of the outermost layers of the surface in biomaterial interactions, the surface chemistry and its influence on cells needs to be characterized. This is the first study to assess surfactant retention on microfluidic produced particles and its effect on bacterial attachment; surfactant contaminated microparticles are compared with flat films which are surfactant-free. Polymeric microparticles with an average diameter of 76 ± 1.7 µm were produced by using a T-junction microfluidic system to form monomer droplets which were subsequently photopolymerized. Acrylate based monomer solutions were found to require 2 wt% PVA to stabilize droplet formation. ToF-SIMS was employed to assess the surface chemistry revealing the presence of PVA in a discontinuous layer on the surface of microparticles which was reduced but not removed by solvent washing. The effect of PVA on bacterial (Pseudomonas aeruginosa) attachment was quantified and showed reduction as a function of the amount of PVA retained at the surface. The insights gained in this study help define the structure-function relationships of the particulate biomaterial architecture, supporting materials design with biofilm control.

Correction: Effect of surfactant on Pseudomonas aeruginosa colonization of polymer microparticles and flat films.

[This corrects the article DOI: 10.1039/C8RA01491D.].

Controlled formulation of monodisperse double emulsions in a multiple-phase microfluidic system.

This paper gives an overview of our recent work on the use of microfluidic devices to formulate double emulsions. Key issues in the controlled encapsulation of highly monodisperse drops include: (a) regular periodicity in the formation of micro droplets due to the interplay between viscous shearing and interfacial tension in low Reynolds number streams; (b) serially connected hydrophobic and hydrophilic microchannels to form aqueous and organic drops consecutively. Water-in-oil-in-water emulsions and oil-in-water-in-oil emulsions can both be produced by reversing the order of hydrophobic and hydrophilic junctions. Alternating formation of aqueous droplets at a cross junction has enabled the production of organic droplets that encase two aqueous droplets of differing compositions.

Droplet formation in a microchannel network.

A method is given for generating droplets in a microchannel network. With oil as the continuous phase and water as the dispersed phase, pico/nanoliter-sized water droplets can be generated in a continuous phase flow at a -junction. The channel for the dispersed phase is 100 microm wide and 100 microm deep, whereas the channel for the continuous phase is 500 microm wide and 100 microm deep. For given experimental parameters, regular-sized droplets are reproducibly formed at a uniform speed. The diameter of these droplets is controllable in the range from 100-380 microm as the flow velocity of the continuous phase is varied from 0.01 m s(-1) to 0.15 m s(-1).

High-volume production of single and compound emulsions in a microfluidic parallelization arrangement coupled with coaxial annular world-to-chip interfaces.

This study describes a microfluidic platform with coaxial annular world-to-chip interfaces for high-throughput production of single and compound emulsion droplets, having controlled sizes and internal compositions. The production module consists of two distinct elements: a planar square chip on which many copies of a microfluidic droplet generator (MFDG) are arranged circularly, and a cubic supporting module with coaxial annular channels for supplying fluids evenly to the inlets of the mounted chip, assembled from blocks with cylinders and holes. Three-dimensional flow was simulated to evaluate the distribution of flow velocity in the coaxial multiple annular channels. By coupling a 1.5 cm × 1.5 cm microfluidic chip with parallelized 144 MFDGs and a supporting module with two annular channels, for example, we could produce simple oil-in-water (O/W) emulsion droplets having a mean diameter of 90.7 µm and a coefficient of variation (CV) of 2.2% at a throughput of 180.0 mL h(-1). Furthermore, we successfully demonstrated high-throughput production of Janus droplets, double emulsions and triple emulsions, by coupling 1.5 cm × 1.5 cm - 4.5 cm × 4.5 cm microfluidic chips with parallelized 32-128 MFDGs of various geometries and supporting modules with 3-4 annular channels.