Symmetrically pulsating bubbles swim in an anisotropic fluid by nematodynamics.

Swimming in low-Reynolds-number fluids requires the breaking of time-reversal symmetry and centrosymmetry. Microswimmers, often with asymmetric shapes, exhibit nonreciprocal motions or exploit nonequilibrium processes to propel. The role of the surrounding fluid has also attracted attention because viscoelastic, non-Newtonian, and anisotropic properties of fluids matter in propulsion efficiency and navigation. Here, we experimentally demonstrate that anisotropic fluids, nematic liquid crystals (NLC), can make a pulsating spherical bubble swim despite its centrosymmetric shape and time-symmetric motion. The NLC breaks the centrosymmetry by a deformed nematic director field with a topological defect accompanying the bubble. The nematodynamics renders the nonreciprocity in the pulsation-induced fluid flow. We also report speed enhancement by confinement and the propulsion of another symmetry-broken bubble dressed by a bent disclination. Our experiments and theory propose another possible mechanism of moving bodies in complex fluids by spatiotemporal symmetry breaking.

Enhanced Diamagnetic Repulsion of Blood Cells Enables Versatile Plasma Separation for Biomarker Analysis in Blood.

A hemolysis-free and highly efficient plasma separation platform enabled by enhanced diamagnetic repulsion of blood cells in undiluted whole blood is reported. Complete removal of blood cells from blood plasma is achieved by supplementing blood with superparamagnetic iron oxide nanoparticles (SPIONs), which turns the blood plasma into a paramagnetic condition, and thus, all blood cells are repelled by magnets. The blood plasma is successfully collected from 4 mL of blood at flow rates up to 100 µL min-1 without losing plasma proteins, platelets, or exosomes with 83.3±1.64% of plasma volume recovery, which is superior over the conventional microfluidic methods. The theoretical model elucidates the diamagnetic repulsion of blood cells considering hematocrit-dependent viscosity, which allows to determine a range of optimal flow rates to harvest platelet-rich plasma and platelet-free plasma. For clinical validations, it is demonstrated that the method enables the greater recovery of bacterial DNA from the infected blood than centrifugation and the immunoassay in whole blood without prior plasma separation.

Spontaneous Wrinkle Formation on Hydrogel Surfaces Using Photoinitiator Diffusion from Oil-Water Interface.

Patterning wrinkles on three-dimensional curved or enclosed surfaces can be challenging due to difficulties in application of uniform films and stresses on such structures. In this study, we demonstrate a simple one-step wrinkle-formation method on various hydrogel structures utilizing the oil-water interfaces. By diffusion of the photoinitiator from the oil phase to the prepolymer solution in water through the interface, a characteristic cross-linking gradient is set up in the hydrogel. Then, after photopolymerization, we observe diverse patterns of wrinkles upon changing the concentration of the hydrogel or photoinitiator. As the wrinkle formation via photoinitiator diffusion through the interface requires only UV exposure for polymerization, while taking advantage of the oil-water interfacial tension, wrinkles can be developed easily on various curved structures. In addition, we illustrate the formation of wrinkles on surfaces underneath another layer of polymer or on completely enclosed surfaces, which is difficult with conventional methods. We expect that our results will lead to production of novel microstructures and provide a platform for studying the morphogenesis of wrinkles found in nature such as in curved substrates and multilayers.

Phase synchronization of fluid-fluid interfaces as hydrodynamically coupled oscillators.

Hydrodynamic interactions play a role in synchronized motions of coupled oscillators in fluids, and understanding the mechanism will facilitate development of applications in fluid mechanics. For example, synchronization phenomenon in two-phase flow will benefit the design of future microfluidic devices, allowing spatiotemporal control of microdroplet generation without additional integration of control elements. In this work, utilizing a characteristic oscillation of adjacent interfaces between two immiscible fluids in a microfluidic platform, we discover that the system can act as a coupled oscillator, notably showing spontaneous in-phase synchronization of droplet breakup. With this observation of in-phase synchronization, the coupled droplet generator exhibits a complete set of modes of coupled oscillators, including out-of-phase synchronization and nonsynchronous modes. We present a theoretical model to elucidate how a negative feedback mechanism, tied to the distance between the interfaces, induces the in-phase synchronization. We also identify the criterion for the transition from in-phase to out-of-phase oscillations.

Correction: Immature dendritic cells navigate microscopic mazes to find tumor cells.

Correction for 'Immature dendritic cells navigate microscopic mazes to find tumor cells' by Eujin Um et al., Lab Chip, 2019, 19, 1665-1675.

Immature dendritic cells navigate microscopic mazes to find tumor cells.

Dendritic cells (DCs) are potent antigen-presenting cells with high sentinel ability to scan their neighborhood and to initiate an adaptive immune response. Whereas chemotactic migration of mature DCs (mDCs) towards lymph nodes is relatively well documented, the migratory behavior of immature DCs (imDCs) in tumor microenvironments is still poorly understood. Here, microfluidic systems of various geometries, including mazes, are used to investigate how the physical and chemical microenvironment influences the migration pattern of imDCs. Under proper degree of confinement, the imDCs are preferentially recruited towards cancer vs. normal cells, accompanied by increased cell speed and persistence. Furthermore, a systematic screen of cytokines, reveals that Gas6 is a major chemokine responsible for the chemotactic preference. These results and the accompanying theoretical model suggest that imDC migration in complex tissue environments is tuned by a proper balance between the strength of the chemical gradients and the degree of spatial confinement.

Advection Flows-Enhanced Magnetic Separation for High-Throughput Bacteria Separation from Undiluted Whole Blood.

A major challenge to scale up a microfluidic magnetic separator for extracorporeal blood cleansing applications is to overcome low magnetic drag velocity caused by viscous blood components interfering with magnetophoresis. Therefore, there is an unmet need to develop an effective method to position magnetic particles to the area of augmented magnetic flux density gradients while retaining clinically applicable throughput. Here, a magnetophoretic cell separation device, integrated with slanted ridge-arrays in a microfluidic channel, is reported. The slanted ridges patterned in the microfluidic channels generate spiral flows along the microfluidic channel. The cells bound with magnetic particles follow trajectories of the spiral streamlines and are repeatedly transferred in a transverse direction toward the area adjacent to a ferromagnetic nickel structure, where they are exposed to a highly augmented magnetic force of 7.68 µN that is much greater than the force (0.35 pN) at the side of the channel furthest from the nickel structure. With this approach, 91.68% ± 2.18% of Escherichia coli (E. coli) bound with magnetic nanoparticles are successfully separated from undiluted whole blood at a flow rate of 0.6 mL h-1 in a single microfluidic channel, whereas only 23.98% ± 6.59% of E. coli are depleted in the conventional microfluidic device.

Cell migration in microengineered tumor environments.

Recent advances in microengineered cell migration platforms are discussed critically with a focus on how cell migration is influenced by engineered tumor microenvironments, the medical relevance being to understand how tumor microenvironments may promote or suppress the progression of cancer. We first introduce key findings in cancer cell migration under the influence of the physical environment, which is systematically controlled by microengineering technology, followed by multi-cues of physico-chemical factors, which represent the complexity of the tumor environment. Recognizing that cancer cells constantly communicate not only with each other but also with tumor-associated cells such as vascular, fibroblast, and immune cells, and also with non-cellular components, it follows that cell motility in tumor microenvironments, especially metastasis via the invasion of cancer cells into the extracellular matrix and other tissues, is closely related to the malignancy of cancer-related mortality. Medical relevance of forefront research realized in microfabricated devices, such as single cell sorting based on the analysis of cell migration behavior, may assist personalized theragnostics based on the cell migration phenotype. Furthermore, we urge development of theory and numerical understanding of single or collective cell migration in microengineered platforms to gain new insights in cancer metastasis and in therapeutic strategies.

Controlled Uniform Coating from the Interplay of Marangoni Flows and Surface-Adsorbed Macromolecules.

Surface coatings and patterning technologies are essential for various physicochemical applications. In this Letter, we describe key parameters to achieve uniform particle coatings from binary solutions. First, multiple sequential Marangoni flows, set by solute and surfactant simultaneously, prevent nonuniform particle distributions and continuously mix suspended materials during droplet evaporation. Second, we show the importance of particle-surface interactions that can be established by surface-adsorbed macromolecules. To achieve a uniform deposit in a binary mixture, a small concentration of surfactant and surface-adsorbed polymer (0.05 wt% each) is sufficient, which offers a new physicochemical avenue for control of coatings.

On-chip generation of monodisperse giant unilamellar lipid vesicles containing quantum dots.

Monodispersed lipid vesicles have been used as a drug delivery vehicle and a biochemical reactor. To generate monodispersed lipid vesicles in the nano- to micrometer size range, an extrusion step should be included in conventional hand-shaking method of lipid vesicle synthesis. In addition, lipid vesicles as a drug carrier still need to be improved to effectively encapsulate concentrated biomolecules such as cells, proteins, and target drugs. To overcome these limitations, this paper reports a new microfluidic platform for continuous synthesis of small-sized (∼10 µm) giant unilamellar vesicles (GUVs) containing quantum dots (QDs) as a nanosized model drug. To generate GUVs, we introduced an additional cross-flow to break vesicles into small size. 1,2 - dimyristoyl-sn-glycero - 3 - phosphocholine (DMPC) in an octanol-chloroform mixture was used in the construction of self-assembled membrane. Consequently, we have successfully demonstrated the fabrication of monodispersed GUVs with 7-12 µm diameter containing QDs. The proposed synthesis method of cell-sized GUVs would be highly desirable for applications such as multipurpose drug encapsulation and delivery.

Size-dependent control of colloid transport via solute gradients in dead-end channels.

Transport of colloids in dead-end channels is involved in widespread applications including drug delivery and underground oil and gas recovery. In such geometries, Brownian motion may be considered as the sole mechanism that enables transport of colloidal particles into or out of the channels, but it is, unfortunately, an extremely inefficient transport mechanism for microscale particles. Here, we explore the possibility of diffusiophoresis as a means to control the colloid transport in dead-end channels by introducing a solute gradient. We demonstrate that the transport of colloidal particles into the dead-end channels can be either enhanced or completely prevented via diffusiophoresis. In addition, we show that size-dependent diffusiophoretic transport of particles can be achieved by considering a finite Debye layer thickness effect, which is commonly ignored. A combination of diffusiophoresis and Brownian motion leads to a strong size-dependent focusing effect such that the larger particles tend to concentrate more and reside deeper in the channel. Our findings have implications for all manners of controlled release processes, especially for site-specific delivery systems where localized targeting of particles with minimal dispersion to the nontarget area is essential.

Optimization of Pathogen Capture in Flowing Fluids with Magnetic Nanoparticles.

Magnetic nanoparticles have been employed to capture pathogens for many biological applications; however, optimal particle sizes have been determined empirically in specific capturing protocols. Here, a theoretical model that simulates capture of bacteria is described and used to calculate bacterial collision frequencies and magnetophoretic properties for a range of particle sizes. The model predicts that particles with a diameter of 460 nm should produce optimal separation of bacteria in buffer flowing at 1 L h(-1) . Validating the predictive power of the model, Staphylococcus aureus is separated from buffer and blood flowing through magnetic capture devices using six different sizes of magnetic particles. Experimental magnetic separation in buffer conditions confirms that particles with a diameter closest to the predicted optimal particle size provide the most effective capture. Modeling the capturing process in plasma and blood by introducing empirical constants (ce ), which integrate the interfering effects of biological components on the binding kinetics of magnetic beads to bacteria, smaller beads with 50 nm diameters are predicted that exhibit maximum magnetic separation of bacteria from blood and experimentally validated this trend. The predictive power of the model suggests its utility for the future design of magnetic separation for diagnostic and therapeutic applications.

Multicompartment microfibers: fabrication and selective dissolution of composite droplet-in-fiber structures.

We present a microfluidic method to continuously produce multicompartment microfibers, where embedded single or double emulsion droplets are regularly spaced along the length of the fiber. Both hydrophobic and hydrophilic compounds can be encapsulated in different microcompartments of the fiber for storage, selective dissolution, and delivery applications, as well as to provide multifunctionality.

Combinatorial generation of droplets by controlled assembly and coalescence.

We describe a microfluidic system for generating a sequence of liquid droplets of multiple concentrations in a single experimental condition. The series of final droplets has the combination of the compositions varying periodically, with polydispersity of the size less than 8%. By utilizing the design of the microchannel geometry and the passive control of three immiscible fluids (oil, water, and air) including generation, breakup, separation and coalescence of droplets, we can change the system to generate diverse sets of combination of materials. The device can be used for testing different concentration of materials in picoliter volumes and developing a new way to deliver dynamic signals of chemicals with microfluidics.

Mesh-integrated microdroplet array for simultaneous merging and storage of single-cell droplets.

We constructed a mesh-grid integrated microwell array which enables easy trapping and consistent addition of droplets. The grid acts as a microchannel structure to guide droplets into the microwells underneath, and also provides open access for additional manipulation in a high-throughput manner. Each droplet in the array forms a stable environment of pico-litre volume to implement a single-cell-based assay.

Microbridge structures for uniform interval control of flowing droplets in microfluidic networks.

Precise temporal control of microfluidic droplets such as synchronization and combinatorial pairing of droplets is required to achieve a variety range of chemical and biochemical reactions inside microfluidic networks. Here, we present a facile and robust microfluidic platform enabling uniform interval control of flowing droplets for the precise temporal synchronization and pairing of picoliter droplets with a reagent. By incorporating microbridge structures interconnecting the droplet-carrying channel and the flow control channel, a fluidic pressure drop was derived between the two fluidic channels via the microbridge structures, reordering flowing droplets with a defined uniform interval. Through the adjustment of the control oil flow rate, the droplet intervals were flexibly and precisely adjustable. With this mechanism of droplet spacing, the gelation of the alginate droplets as well as control of the droplet interval was simultaneously achieved by additional control oil flow including calcified oleic acid. In addition, by parallel linking identical microfluidic modules with distinct sample inlet, controlled synchronization and pairing of two distinct droplets were demonstrated. This method is applicable to facilitate and develop many droplet-based microfluidic applications, including biological assay, combinatorial synthesis, and high-throughput screening.

A microfluidic abacus channel for controlling the addition of droplets.

This paper reports the first use of the abacus-groove structure to handle droplets in a wide microchannel, with no external forces integrated to the system other than the pumps. Microfluidic abacus channels are demonstrated for the sequential addition of droplets at the desired location. A control channel which is analogous to biasing in electronics can also be used to precisely determine the number of added droplets, when all other experimental conditions are fixed including the size of the droplets and the frequency of droplet-generation. The device allows programmable and autonomous operations of complex two-phase microfluidics as well as new applications for the method of analysis and computations in lab-on-a-chip devices.

Microfluidic self-assembly of insulin monomers into amyloid fibrils on a solid surface.

We report the self-assembly of insulin monomers into amyloid fibrils within microchannels. To demonstrate the microfluidic amyloid formation and fibril growth on a solid surface, we seeded the internal surfaces of the microchannels with insulin monomers via N-hydroxysuccinimide ester activation and continuously flushed a fresh insulin solution through the microchannels. According to our analysis using optical and fluorescence microscopy, insulin amyloid preferentially formed in the center of the microchannels and, after reaching a certain density, spread to the side walls of the microchannels. By using ex situ atomic force microscopy, we observed the growth of amyloid fibrils inside the microchannels, which occurred at a much higher rate than that in bulk systems. After 12 h of incubation, insulin formed amyloid spherulites having "Maltese cross" extinction patterns within the microchannels according to the polarized microscopic analysis. Microfluidic amyloid formation enabled low consumption of reagents, reduction of incubation time, and simultaneous observation of amyloid formation under different conditions. This work will contribute to the rapid analysis of amyloid formation associated with many protein misfolding diseases.