Formation of Pickering emulsions stabilized via interaction between nanoparticles dispersed in aqueous phase and polymer end groups dissolved in oil phase

The influence of end groups of a polymer dissolved in an oil phase on the formation of a Pickering-type hydroxyapatite (HAp) nanoparticle-stabilized emulsion and on the morphology of HAp nanoparticle-coated microspheres prepared by evaporating solvent from the emulsion was investigated. Polystyrene (PS) molecules with varying end groups and molecular weights were used as model polymers. Although HAp nanoparticles alone could not function as a particulate emulsifier for stabilizing dichloromethane (oil) droplets, oil droplets could be stabilized with the aid of carboxyl end groups of the polymers dissolved in the oil phase. Lower-molecular-weight PS molecules containing carboxyl end groups formed small droplets and deflated microspheres, due to the higher concentration of carboxyl groups on the droplet/microsphere surface and hence stronger adsorption of the nanoparticles at the water/oil interface. In addition, Pickering-type suspension polymerization of styrene droplets stabilized by PS molecules containing carboxyl end groups successfully led to the formation of spherical HAp-coated microspheres.     

Synthesis of titania-silica core-shell microspheres via a controlled interface reaction in a microfluidic device

In this work, we describe a novel, simple microfluidic method for fabricating titania-silica core-shell microspheres. Uniform droplets of silica sol were dispersed into an oil phase containing tetrabutyl titanate via a coaxial microfluidic device. The titanium alkoxide hydrolyzed at the water-oil interface after the formation of the aqueous droplets. A gel shell containing the titanium hydroxide formed around the droplets, and the titania-silica core-shell microspheres were obtained after calcinations. The X-ray diffraction results show that titania coatings crystallized into a pure anatase structure. The scanning electron microscopy and energy-dispersive spectrometry characterization shows that the microspheres are monodispersed with uniform titania coating on the surface. The dispersity and size of the microspheres could easily be controlled by changing the microfluidic flow parameters. The titania content on the surface could be adjusted in the large range of 1.0-98.0 mol % by varying the continuous phase composition and the reaction time, and the structures of the core-shell microshperes could also be controlled.     

Microfluidic fabrication of SERS-active microspheres for molecular detection

In this paper, we demonstrated a microfluidic system for fabricating microspheres with hierarchical surface nanopatterns for molecular detection based on surface-enhanced Raman scattering (SERS). Briefly, a photocurable silica suspension was emulsified into monodisperse droplets using a microfluidic device composed of two coaxial glass capillaries. The silica particles in each droplet protruded through the interface and spontaneously formed a hexagonal array. After polymerization of the droplets, we selectively decorated the exposed areas of the silica particles with silver nanoparticles through electroless deposition. The resulting hierarchically-structured microspheres showed high sensitivity and fast binding kinetics in molecular detection based on SERS, owing to the dense array of hot spots on each microsphere and high mobility of the microspheres, respectively. Notably, the SERS signals from molecules adsorbed on the microspheres could be detected in both the dried and suspension states. In addition, we demonstrated that the SERS-active microspheres can be functionalized into structural colored or magnetoresponsive microspheres for advanced applications.     

Sizing nanoparticle-covered droplets by extrusion through track-etch membranes

Interfacial segregation of nanoparticles on droplets, such as water droplets in oil, is achieved by mixing or shaking organic solutions of the nanoparticles with water. This typically results in the formation of droplets with a large distribution of sizes, ranging from 10 microm to greater than 200 microm in diameter. Here we describe the application of track-etch membranes to control the size of these nanoparticle-coated droplets. Passing nanoparticle-coated droplets through the membranes substantially reduces their size by breaking up the droplets during the extrusion process and reforming droplets of comparable size to the membrane pore diameter. When the nanoparticles used in these sizing procedures are covered with functional ligands, stabilization of the post-extrusion diameter is achieved by polymerization/cross-linking of the ligand periphery.     

Manipulating the generation of Ca-alginate microspheres using microfluidic channels as a carrier of gold nanoparticles

In this paper the manipulation of Ca-alginate microspheres, using a microfluidic chip, for the encapsulation of gold nanoparticles is presented. Our strategy is based on hydrodynamic-focusing on the forming of a series of self-assembling sphere structures, the so-called water-in-oil (w/o) emulsions, in the cross-junction microchannel. These fine emulsions, consisting of aqueous Na-alginates, are then dripped into a solution of 20% calcium salt to accomplish Ca-alginate microspheres in an efficient manner. Experimental data show that microspheres with diameters ranging from 50 microm to 2000 microm with a variation less than 5% were precisely generated. The size and gap of the droplets are tunable by adjusting the relative sheath/sample flow rate ratio. Furthermore, we applied them to encapsulated gold nanoparticles, and this one shot operation performs the 'Lab on a Chip'.     

流动聚焦型微流控体系中的液滴的图案化排列和转变模式

流体在微流通道中形成剪切流场（低雷诺数）．不同于宏观体系,由于剪切力和表面张力的竞争作用,产生的液滴在微尺度下的微流通道中形成特殊的排列现象---周期性类似“晶格”排列现象．设计了新型流动聚焦型微流控芯片,分析研究在微流体系中液滴周期性图案化排列和转变机理性,液滴排列模式受两方面因素影响：水油两相的流速比值和微通道尺寸．当微通道宽度为250或300 μm时,液滴形成单层分散,双层和单层挤压排列．当微通道宽度为350 μm 时,液滴会形成单层分散到三层排列到双层挤压最后到单层挤压排列．当出口通道宽度增加到400 μm时,甚至出现了液滴四层排列的现象．同时研究了各个液滴排列模式的“转变点”.     

Preparation of Poly(vinyl alcohol) Microspheres Based on Droplet Microfluidic Technology

A new method for preparing poly (vinyl alcohol) (PVA) microspheres was developed by using droplet microfluidic technology. In the microfluidic chip, a large number of uniform, monodispersed PVA droplets were prepared quickly and continuously by using droplet formation technology, and the droplet preparation speed reached 7 per second. The size of the PVA droplets could be controlled by changing the injection flow rate of the two-phase fluid and the width of microfluidic channel. Then the PVA microspheres were formed by physical crosslinking. This method has high preparation efficiency and good monodispersity of the obtained microspheres. Moreover, the process does not require the incorporation of chemical crosslinking agents, avoiding interference with the inclusion material, and is well suited for applications such as drug carrier.     

Biopolymer microparticle and nanoparticle formation within a microfluidic device

This paper reports a novel microfluidic method for the production of cross-linked alginate microparticles and nanoparticles. We describe a continuous process relying on both thermodynamic and hydrodynamic factors to form microdroplets. A rapid cross-linking reaction thereafter allows solidification of the polymer droplets either within the microfluidic device or "off-chip" to form alginate micro- and nanoparticles. Monodisperse droplets are generated by extruding an aqueous alginate solution using an axisymmetric flow-focusing design. As they flow downstream in the channel, due to water and the continuous phase being partially miscible, the water diffuses very slowly out of the polymeric droplets into the transport fluid, which causes the shrinkage of the drops and the condensation of the polymer phase. The resulting size of the solid particles depends on the polymer concentration and the ensuing balance between the kinetics of the cross-linking reaction and the volume loss due to solvent diffusion. This work details both a single-step microfluidic technique for the formation of alginate microparticles of sizes ranging from 1 to 50 microm via near-equilibrium solvent diffusion within a microfluidic device and thereafter a two-step method, which was shown to generate biopolymer nanoparticles of sizes ranging from 10 to 300 nm. These novel methodologies are extremely flexible and can be extended to the preparation of micro- and nanoparticles from a wide range of single or mixed synthetic and biologically derived polymers.     

The influence of chitosan on in vitro properties of Eudragit RS microspheres

Eudragit RS microspheres containing chitosan hydrochloride were prepared by the solvent evaporation method using acetone/liquid paraffin solvent system and their properties were compared with Eudragit RS microspheres without chitosan, prepared in our previous study. Different stirring rates were applied (400-1200 rpm) and drug content, Higuchi dissolution rate constant, surface and structure characteristics of the microspheres were determined for each size fraction. An increase in average particle size with a reduction of stirring rate appeared in limited interval in both series. The average particle size of microspheres without chitosan, prepared at the same stirring rate, was smaller. Pipemidic acid content increased with increasing fraction particle size, but not with increasing stirring rate as it was observed for microspheres without chitosan. We presume that high pipemidic acid content in larger microspheres is a consequence of cumulation of undissolved pipemidic acid particles in larger droplets during microspheres preparation procedure. Pipemidic acid release was faster from microspheres with chitosan and no correlation between Higuchi dissolution rate constant and stirring rate or fraction particle size was found, though it existed in the system without chitosan. Structure and surface characteristics of microspheres observed by scanning electron microscope (SEM) were not changed significantly by incorporation of chitosan. But in contrast with microspheres without chitosan, the surface of chitosan microspheres was more porous after three hours of dissolution. It is supposed that the influence of particle size fraction and stirring rate on release characteristics is expressed to a great extent through porosity and indirectly through total effective surface area, but the incorporation of highly soluble component i.e. chitosan salt hides these effects on drug release. In conclusion, changes in biopharmaceutical properties due to varying stirring rate and fraction particle size exhibited the same direction as those reported for the microspheres without chitosan, although they are less expressed because of increased experimental variability, likely caused by chitosan.     

Controlled synthesis of fluorescent silica nanoparticles inside microfluidic droplets

We study the droplet-based synthesis of fluorescent silica nanoparticles (50-350 nm size) in a microfluidic chip. Fluorescein-isothiocyanate (FITC) dye is first chemically linked to aminopropyl triethoxysilane (APTES) in ethanol and this reaction product is subsequently mixed with tetraethyl orthosilicate (TEOS) to yield a fluorescent silicon alkoxide precursor solution. The latter reacts with an aqueous ethanol-ammonia hydrolysing mixture inside droplets, forming fluorescent silica nanoparticles. The droplets are obtained by pinching-off side-by-side flowing streams of alkoxide solution/hydrolysing mixture on a microfluidic chip using a Fluorinert oil continuous phase flow. Synthesis in droplets leads to a faster reaction and allows drastically improved nanoparticle size uniformity (down to 3% relative standard deviation for 350 nm size particles) when compared to conventional bulk synthesis methods, thanks to the precise control of reagent concentrations and reaction times offered by the microfluidic format. Incorporating FITC inside silica nanoparticles using our method leads to reduced dye leakage and increases the dye's stability, as evidenced by a reduced photochemical bleaching compared to a pure FITC solution.     

Alternating droplet generation and controlled dynamic droplet fusion in microfluidic device for CdS nanoparticle synthesis

A multifunctional and high-efficiency microfluidic device for droplet generation and fusion is presented. Through unique design of the micro-channels, the device is able to alternately generate droplets, generating droplet ratios ranging from 1 ratio 5 to 5 ratio 1, and fuse droplets, enabling precise chemical reactions in several picoliters on a single chip. The controlled fusion is managed by passive control based on the channel geometry and liquid phase flow. The synthesis of CdS nanoparticles utilizing each fused droplet as a microreactor for rapid and efficient mixing of reagents is demonstrated in this paper. Following alternating droplet generation, the channel geometry allows the exclusive fusion of alternate droplets with concomitant rapid mixing and produces supersaturated solution of Cd2+ and S2- ions to form CdS nanoparticles in each fused droplet. The spectroscopic properties of the CdS nanoparticles produced by this method are compared with CdS prepared by bulk mixing.     

Novel one-pot route to monodisperse thermosensitive hollow microcapsules in a microfluidic system

We present a simple one-pot synthetic approach for the preparation of monodisperse thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) microcapsules in a microfluidic system. Based on the mechanism of shear force-driven break-off, aqueous droplets of monomer solution are continuously generated in an immiscible continuous phase containing photoinitiators. Under UV irradiation, activated initiators are diffused into the interface between the continuous phase and the aqueous droplets, which trigger polymerization of NIPAM monomers. The PNIPAM microcapsules produced are hollow microcapsules with a thin shell membrane, high monodispersity, and fast response to environmental temperature. In addition, the size of microcapsules produced can be manipulated by the flow rate of the continuous phase or aqueous phase and different concentrations of surfactant to control interfacial tension between continuous phase and aqueous phase. Furthermore, the versatility of this approach enables the preparation of monodisperse microcapsules having the capability to encapsulate various materials such as proteins and nanoparticles under mild conditions. The in situ microfluidic synthetic method provides a novel approach for the preparation of monodisperse hollow microcapsules via a one-pot route.     

Surface fabrication of hollow microspheres from N-methylated chitosan cross-linked with glutaraldehyde

We have successfully prepared biocompatible and biodegradable hollow microspheres with sizes between 2 and 5 mum using cyclohexane droplets as a template and the N-methylated chitosan (NMC) cross-linked with glutaraldehyde (GA) as the shell. The structure, morphology, and formation process of the hollow microspheres were characterized by FT-IR, (1)H and (13)C NMR, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The results revealed that the microspheres exhibited a very smooth and hollow structure. This work confirmed that the hollow microspheres were accomplished by fabricating on the basis of chemical cross-linking on the surface of the emulsion droplets and by removing cyclohexane as core. The results from SEM and TEM indicated that the emulsion droplets covered with cross-linked NMC in the oil-in-water system aggregated together to form a precipitate of microspheres by coagulating with acetone. Moreover, the cross-linked NMC on the surface of the microspheres continuously cured to form the tight shell, whereas the inner area became a cavity with increase of the aging time, leading to the hollow microspheres. In addition, an anti-infective drug, ofloxacin (Floxin), encapsulated in the microspheres more rapidly released to reach 90 wt % at pH 7.4 within 8 h than at pH 1.2.     

Controllable gas/liquid/liquid double emulsions in a dual-coaxial microfluidic device

This article presents a simple and novel approach to prepare monodispersed gas-in-oil-in-water (G/O/W) and gas-in-water-in-oil (G/W/O) double-emulsions in the same dual-coaxial microfluidic device. The effects of three phase flow rates on the sizes of microbubbles and droplets and the number of the encapsulated microbubbles were systematically studied. We successfully synthesized two different types of gas/liquid/liquid (G/L/L) double emulsions with different inner structures in the same geometry by adjusting the flow rates sequentially. Mathematical models were developed to predict the size and structures of the double emulsions. This simple approach gives a new idea for preparing hollow and porous microspheres with microbubbles as the direct core/pores templates.     

Preparation of uniform-sized pH-sensitive quaternized chitosan microsphere by combining membrane emulsification technique and thermal-gelation method

In this study, uniform-sized pH-sensitive quaternized chitosan microsphere was prepared by combining Shirasu porous glass (SPG) membrane emulsification technique and a novel thermal-gelation method. In this preparation process, the mixture of quaternized chitosan solution and alpha-beta-glycerophosphate (alpha-beta-GP) was used as water phase and dispersed in oil phase to form uniform W/O emulsion by SPG membrane emulsification technique. The droplets solidified into microspheres at 37 degrees C by thermal-gelation method. The whole process was simple and mild. The influence of process conditions on the property of prepared microspheres was investigated and the optimized preparation condition was obtained. As a result, the coefficient of variation (C.V.) of obtained microspheres diameters was below 15%. The obtained microsphere had porous structure and showed apparent pH-sensitivity. It dissolved rapidly in acid solution (pH 5) and kept stable in neutral solution (pH 7.4). The pH-sensitivity of microspheres also affected its drug release behavior. Bovine serum albumin (BSA) as a model drug was encapsulated in microspheres, and it was released rapidly in acid solution and slowly in neutral medium. The novel quaternized chitosan microspheres with pH-sensitivity can be used as drug delivery system in the biomedical field, such as tumor-targeted drug carrier.     

Pillar-induced droplet merging in microfluidic circuits

A novel method is presented for controllably merging aqueous microdroplets within segmented flow microfluidic devices. Our approach involves exploiting the difference in hydrodynamic resistance of the continuous phase and the surface tension of the discrete phase through the use of passive structures contained within a microfluidic channel. Rows of pillars separated by distances smaller than the representative droplet dimension are installed within the fluidic network and define passive merging elements or chambers. Initial experiments demonstrate that such a merging element can controllably adjust the distance between adjacent droplets. In a typical scenario, a droplet will enter the chamber, slow down and stop. It will wait and then merge with the succeeding droplets until the surface tension is overwhelmed by the hydraulic pressure. We show that such a merging process is independent of the inter-droplet separation but rather dependent on the droplet size. Moreover, the number of droplets that can be merged at any time is also dependent on the mass flow rate and volume ratio between the droplets and the merging chamber. Finally, we note that the merging of droplet interfaces occurs within both compressing and the decompressing regimes.     

Multi-step synthesis of nanoparticles performed on millisecond time scale in a microfluidic droplet-based system

This paper reports a plug-based, microfluidic method for performing multi-step chemical reactions with millisecond time-control. It builds upon a previously reported method where aqueous reagents were injected into a flow of immiscible fluid (fluorocarbons)(H. Song et al., Angew. Chem. Int. Ed., 2003, 42, 768). The aqueous reagents formed plugs--droplets surrounded and transported by the immiscible fluid. Winding channels rapidly mixed the reagents in droplets. This paper shows that further stages of the reaction could be initiated by flowing additional reagent streams directly into the droplets of initial reaction mixture. The conditions necessary for an aqueous stream to merge with aqueous droplets were characterized. The Capillary number could be used to predict the behavior of the two-phase flow at the merging junction. By transporting solid reaction products in droplets, the products were kept from aggregating on the walls of the microchannels. To demonstrate the utility of this microfluidic method it was used to synthesize colloidal CdS and CdS/CdSe core-shell nanoparticles.     

Molecularly imprinted polymeric shell coated monodisperse‐porous silica microspheres as a stationary phase for microfluidic boronate affinity chromatography

Molecular imprinting of cis‐diol functionalized agents via boronate affinity interaction has been usually performed using nanoparticles as a support which cannot be utilized as a stationary phase in continuous microcolumn applications. In this study, monodisperse‐porous, spherical silica particles in the micron‐size range, with bimodal pore diameter distribution were selected as a new support for the synthesis of a molecularly imprinted boronate affinity sorbent, using a cis‐diol functionalized agent as the template. A specific surface area of 158 m²/g was achieved with the imprinted sorbent by using monodisperse‐porous silica microspheres containing both mesoporous and macroporous compartments as the support. High porosity originating from the macroporous compartment and sufficiently high particle size provided good column permeability to the imprinted sorbent in microcolumn applications. The mesoporous compartment provided a large surface area for the parking of imprinted molecules while the macroporous compartment facilitated the intraparticular diffusion of imprinted target within the microsphere interior. A microfluidic boronate affinity system was first constructed by using molecularly imprinted polymeric shell coated monodisperse‐porous silica microspheres as a stationary phase. The synthetic route for the imprinting process, the reversible adsorption/ desorption behavior of selected target and the selectivity of imprinted sorbent in both batch and microfluidic boronate affinity chromatography systems are reported.     

通过调控表面活性剂的HLB值制备具有拓扑结构的磁性聚合物微球

具有不同形貌的聚合物微球在生物和材料等领域应用广泛。目前,越来越多的研究选择以微流控技术为平台来制备聚合物微球。在这里,本文介绍了一种基于微流控技术,通过调节表面活性剂的HLB值从而制备具有拓扑结构磁性聚合物微球的方法。结果表明,不同表面活性剂的HLB值能够调控液滴的演变行为和目标微球的形貌特征。同时,该方法具备一定的普适性。这可作为制备聚合物微球的有效补充工具。     

Highly productive droplet formation by anisotropic elongation of a thread flow in a microchannel

We developed a microfluidic device to form monodisperse droplets with high productivity by anisotropic elongation of a thread flow, defined as a threadlike flow of a dispersed liquid phase in a flow of an immiscible, continuous liquid phase. The thread flow was anisotropically elongated in the depth direction in a straight microchannel with a step, where the microchannel depth changed. Consequently, the elongated thread flow was given capillary instability (Rayleigh-Plateau instability) and was continuously transformed into monodisperse droplets at the downstream area of the step in the microchannel. We examined the effects of the flow rates of the dispersed phase and the continuous phase on the droplet formation behavior, including the droplet diameter and droplet formation frequency. The droplet diameter increased as the fraction of the dispersed-phase flow rate relative to the total flow rate increased and was independent of the total flow rate. The droplet formation frequency proportionally increased with the total flow rate at a constant dispersed-phase flow rate fraction. These results are explained in terms of a mechanism similar to that of droplet formation from a cylindrical liquid thread flow by Rayleigh-Plateau instability. The microfluidic device described was capable of forming monodisperse droplets with a 160-microm average diameter and 3-microm standard deviation at a droplet formation frequency of 350 droplets per second from a single thread flow. The highest total flow rate achieved was 6 mL/h using the present device composed of a straight microchannel with a step. We also demonstrated parallel droplet formation by anisotropic elongation of multiple thread flows; the process was applied to form W/O and O/W droplets. The highly productive droplet formation process presented in this study is expected to be useful for future industrial applications.