Xiao-Jie Ju

Nano-structured smart hydrogels with rapid response and high elasticity

Smart hydrogels, or stimuli-responsive hydrogels, are three-dimensional networks composed of crosslinked hydrophilic polymer chains that are able to dramatically change their volume and other properties in response to environmental stimuli such as temperature, pH and certain chemicals. Rapid and significant response to environmental stimuli and high elasticity are critical for the versatility of such smart hydrogels. Here we report the synthesis of smart hydrogels which are rapidly responsive, highly swellable and stretchable, by constructing a nano-structured architecture with activated nanogels as nano-crosslinkers. The nano-structured smart hydrogels show very significant and rapid stimuli-responsive characteristics, as well as highly elastic properties to sustain high compressions, resist slicing and withstand high level of deformation, such as bending, twisting and extensive stretching. Because of the concurrent rapid and significant stimuli-response and high elasticity, these nano-structured smart hydrogels may expand the scope of hydrogel applications, and provide enhanced performance in their applications.

Controllable microfluidic production of multicomponent multiple emulsions

A hierarchical and scalable microfluidic device constructed from a combination of three building blocks enables highly controlled generation of multicomponent multiple emulsions. The number, ratio and size of droplets, each with distinct contents being independently co-encapsulated in the same level, can be precisely controlled. The building blocks are a drop maker, a connector and a liquid extractor; combinations of these enable the scale-up of the device to create higher-order multicomponent multiple emulsions with exceptionally diverse structures. These multicomponent multiple emulsions offer a versatile and promising platform for precise encapsulation of incompatible actives or chemicals, for synergistic delivery and biochemical and chemical reactions, and for engineering multicompartment materials with controlled internal phases.

Monodisperse core-shell chitosan microcapsules for pH-responsive burst release of hydrophobic drugs

Monodisperse core-shell microcapsules based on crosslinked chitosan membrane with acid-triggered burst release properties are successfully developed. The microcapsules are fabricated from double emulsion precursors that are prepared with a microfluidic approach. In neutral medium (pH 7.1), the microcapsules maintain a good spherical shape and structural integrity; while, in acidic medium (pH 1.5 ∼ 4.7), the microcapsules decompose rapidly and release the encapsulated contents completely in short periods varying from 39 s to 22 min. The acid-triggered burst release pattern from the proposed chitosan microcapsules may make them capable for stomach-specific drug delivery systems with quick and complete release characteristics in a controllable pH-responsive manner.

Smart thermo-triggered squirting capsules for nanoparticle delivery

A squirting capsule is designed to deliver nanoparticles inspired by the squirting cucumber ejecting its seeds. The capsule has a thermo-sensitive hydrogel shell, and encapsulates nanoparticles by emulsifying the nanoparticle aqueous suspension in the water-in-oil emulsion core. The squirting capsule can completely squirt out the encapsulated nanoparticles with a high momentum, just like a nanoparticle bomb, by the dramatic shrinkage and sudden rupture of the capsule membrane upon heating.

Hole–Shell Microparticles from Controllably Evolved Double Emulsions

Polymeric core–shell microparticles with hollow interiors have great potential for use as microencapsulation systems for controlled load/release, active protection, and confined microreaction. Core–shell structures with solid shells provide effective encapsulation; however, transport of the encapsulated molecule through the shell is more difficult. Addition of holes to the shell can provide more versatility for the microparticles by facilitating mass transport through the shell based on the size or functional selectivity of the holes; this produces microparticles with porous shells for a myriad of uses including controlled capture of particles, controlled release of active molecules and small particles, and removal of pollutants. Additional uses for these microparticles can be achieved through finer control of the holes in the shell: for example, a single, defined hole can provide a very versatile structure for selectively capturing particles for classification and separation, or capturing cells for confined culture. Even more versatility can be obtained through control of the shape of the hollow core: for example, microparticles with a dimple-shaped core are useful for sizeselective capture of colloidal particles, whereas microparticles with a fishbowl-shaped core are more useful for loading objects such as cells and confining a microreaction. Finally, to make these structures fully functional, it is also desirable to control the interfacial properties of the core to enable precise interactions between encapsulated molecules and the solid shell. Colloidal-scale core–shell microparticles with a single hole in the shell are typically made with particle or emulsiontemplate methods: polymerization-induced buckling of silicon drops, freeze-drying solvent-swollen polymeric particles, self-assembly of phase-separated polymers, diffusion-induced escape of monomers or solvents from the microparticles during fabrication, selective polymerization of phase-separated drops, and other means to control the phase behavior of the templates. These microparticles provide excellent performance when sizes less than a few microns are required. By contrast, larger microparticles provide additional versatility when the size requirements are not constrained to very small particles. These microparticles are typically formed using emulsion drops as templates and have sizes of tens of micrometers or larger. Even finer control over the monodispersity of the microparticles is achieved using microfluidic techniques to produce the emulsion templates. The microparticle structure strongly depends on the configuration between the coredrop and shell-drop in the emulsion templates. With the shelldrop partially wetted on the core-drop, organic-biphasic Janus drops produce truncated-sphere-shaped microparticles. With completely wetted core–shell configurations, aqueousbiphasic drops and water-in-oil-in-water (W/O/W) double emulsions respectively produce bowl-shaped and fishbowlshaped microparticles. Surface modification of these microparticles was recently achieved by introducing functional nanoparticles such as SiO2 nanoparticles into the organic phase of the emulsion templates. Complete versatility of the microparticles requires accurate and independent control of the shape and size of both the single-hole and the hollow-core, as well as the functionality of the core surface; this requires precise control of the configurations and interfacial properties of the emulsion templates. However, techniques to achieve this sort of fine control do not exist. Herein, we report a versatile strategy for fabrication of highly controlled hole–shell microparticles with a hollow core and a single, precisely determined hole, and with simultaneous, independent control of the properties of the core interface. W/O/W double emulsions from capillary microfluidics were used as the initial templates for the microparticles. By controlling the composition of the organic middle phase, we varied the adhesion energy DF between the inner drop and outer phase to control the evolution of the emulsions from initial core-shell to the desired acorn-shaped configuration; this produces versatile emulsion templates for controllable fabrication of monodisperse hole-shell microparticles with advanced shapes. Further adjustment of the hole–shell structures can be achieved by changing the size and [*] Dr. W. Wang, M.-J. Zhang, Dr. R. Xie, Dr. X.-J. Ju, C. Yang, C.-L. Mou, Prof. L.-Y. Chu School of Chemical Engineering, Sichuan University Chengdu, Sichuan, 610065 (China) E-mail: chuly@scu.edu.cn Homepage: http://teacher.scu.edu.cn/ftp_teacher0/cly/

Preparation of monodisperse calcium alginate microcapsules via internal gelation in microfluidic-generated double emulsions

Monodisperse hollow and core-shell calcium alginate microcapsules are successfully prepared via internal gelation in microfluidic-generated double emulsions. Microfluidic emulsification is introduced to generate monodisperse oil-in-water-in-oil (O/W/O) double emulsion templates, which contain Na-alginate, CaCO3 nanoparticles, and photoacid generator in the middle aqueous phase, for synthesizing Ca-alginate microcapsules. The internal gelation of the aqueous middle layer of O/W/O double emulsions is induced by crosslinking alginate polymers with Ca(2+) ions that are released from CaCO3 nanoparticles upon UV exposure of the photoacid generator. The as-prepared hollow and core-shell calcium alginate microcapsules are highly monodisperse and spherical in water. Model proteins Bovine serum albumin (BSA) molecules can be encapsulated into the Ca-alginate microcapsules after the capsule preparation, which demonstrates an alternative route for loading active drugs or chemicals into carriers to avoid the inactivation during the carrier preparation. The proposed technique in this study provides an efficient approach for synthesis of monodisperse hollow or core-shell calcium alginate microcapsules with large cavity or encapsulated lipophilic drugs, chemicals, and nutrients.

Monodisperse alginate microcapsules with oil core generated from a microfluidic device.

A microfluidic approach is developed to fabricate monodisperse alginate microcapsules with oil cores, which have the potential to be a brand-new type of vehicles for encapsulating, storing and/or transferring lipophilic drugs or active ingredients/chemicals. The alginate microcapsules with oil cores are generated in a microcapillary microfluidic device using monodisperse oil-in-water-in-oil (O/W/O) double emulsions as templates. All the as-prepared alginate microcapsules and the encapsulated oil droplets are satisfactorily spherical. Both the alginate microcapsule size and the thickness of alginate membrane can be easily controlled by modulating the dimensions of microfluidic device and the flow rates of solutions, because the outer diameter of the O/W/O double emulsion templates and the size of their inner oil cores can be controlled independently by adjusting the inner diameters of emulsification tubes and the flow rates of different solutions. The as-fabricated monodisperse micro-egg-like core-shell alginate microcapsules with oil cores may open new possibilities for engineering novel functional materials.

A Novel Thermo‐Induced Self‐Bursting Microcapsule with Magnetic‐Targeting Property

In recent years, considerable efforts have been devoted to the design and fabrication of multifunctional microcapsules due to their potential applications in numerous fields, including controlled release of various substances, 2] protection of active species, 4] and creation of microreactors for confined chemical reaction, 6] etc. In the biomedical field, microcapsules are widely investigated as effective drug delivery carriers for the treatment of deadly diseases such as cancer. Because most anticancer drugs have harmful side effects to the normal tissues, the most ideal delivery carriers should be able to transport and release the anticancer drugs specifically to the targeted tumor site without drug leakage during the transport process. Up to now, numerous studies have been conducted on using external magnetic field for targeted drug delivery by incorporating magnetic nanoparticles into drug delivery carriers. Some stimuli-responsive carriers such as core/shell microparticles and microcapsules functionalized with magnetic nanoparticles have been designed for magnetic-guided drug delivery and subsequent controlled drug release by an external trigger such as temperature, 8] pH, 10] ultrasonic, and high frequency magnetic field. 13] Most of the carriers mentioned above were designed for hydrophilic drugs. However, it is worth noting that, currently available anticancer drugs such as paclitaxel and carmustine are usually lipophilic molecules. Therefore, design of carriers for lipophilic drugs is of great importance and necessity. Here we report on a novel type of monodisperse thermo-induced self-bursting microcapsules with oil cores for encapsulating lipophilic substances. The thermo-responsive polymeric shell embedded with superparamagnetic Fe3O4 nanoparticles enables not only magnetic-guided targeting but also thermoinduced rapid and complete burst-release of encapsulated lipophilic chemicals, and there is no leakage of encapsulated susbtances at all before the thermo-triggering. Figure 1 schematically illustrates the concept of the as-proposed thermo-induced self-bursting microcapsule with magnetic-targeting property and its fabrication procedure. The proposed microcapsules are monodisperse and each of them has a core/shell structure comprising an oil core and a thermo-responsive shell composed of poly(N-isopropylacrylamide) (PNIPAM) and homogeneously embedded superparamagnetic Fe3O4 nanoparticles (Figure 1 a). The expected oil-core/polymer-shell structure and monodispersity can be achieved by using microfluidic fabrication technique. 16] The oil core can be used to encapsulate lipophilic drug molecules. In the shell, the embedded Fe3O4 nanoparticles contribute magnetic-response property to the microcapsule and the PNIPAM network makes the shell thermo-responsive. As a result, the Fe3O4/PNIPAM shell enables the microcapsule to undergo magnetic-guided targeting delivery, have no unintended drug leakage during microcapsule transport, and exhibit thermo-triggered drug release. To better illustrate this design concept, here we present a more detailed description on the transportrelease process of the as-proposed microcapsules. Thermo-responsive behavior of PNIPAM network is characterized by its lower critical solution temperature (LCST). Specifically, PNIPAM shell is in the swollen and hydrophilic state when environmental temperature is lower than the LCST, while it dramatically shrinks when the temperature is higher than the LCST. Because the microcapsules are fabricated at temperatures below the LCST, the as-prepared microcapsules are initially in the swollen and hydrophilic state. Because the encapsulated oil phase and loaded lipophilic chemicals inside the microcapsule are immiscible with or insoluble in aqueous solutions, there is no way for them to pass through the hydrophilic PNIPAM shell via solution/diffusion when the temperature is below the LCST, although the concentration gradient exists between inside and outside of the microcapsule. Therefore, when the microcapsules are stored, transported, or delivered at temperatures below the LCST, there is no leakage of encapsulated lipophilic substances from the microcapsules. After the microcapsules reach the desired site via magnetic guide, burst release of their encapsulated lipophilic substances can be triggered by an external thermal stimulus, for example, local heating. When the environmental temperature is increased from one below the LCST to another one above the LCST, the PNIPAM shell shrinks rapidly. During the shell shrinkage process, internal pressure in the oil core gradually increases because the oil phase is incompressible. When the internal pressure reaches a certain critical value, the PNIPAM shell ruptures due to its limited mechanical strength. Such dramatic shrinkage and final rupture of the PNIPAM shell squeeze the oil core out from the microcapsule with a strong boost to the environment. In such a release process, the loaded lipophilic drug molecules are released together with the burst ejecting of encapsulated oil phase from the microcapsule, which leads to not only rapid release but also complete release. The fabrication procedure of our microcapsules consists of three major steps (see Experimental Section for details). Briefly, [a] W. Wang, L. Liu, Dr. X.-J. Ju, Dr. R. Xie, Dr. L. Yang, Prof. L.-Y. Chu School of Chemical Engineering Sichuan University, Chengdu, Sichuan 610065 (China) Fax: (+ 86) 28-8540-4976 E-mail : chuly@scu.edu.cn [b] Dr. D. Zerrouki Department of Chemical Engineering University of Ouargla, BP 511 Ouargla, 30000 (Algeria) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cphc.200900450.

A Novel Thermoresponsive Hydrogel with Ion-Recognition Property through Supramolecular Host−Guest Complexation

A novel thermoresponsive hydrogel with ion-recognition property was prepared via free-radical cross-linking copolymerization of N-isopropylacrylamide (NIPAM) with benzo-18-crown-6-acrylamide (BCAm) as host receptor. Both chemical structures and stimuli-sensitive properties of the prepared poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide) P(NIPAM-co-BCAm) hydrogel were characterized. The smart hydrogel could respond to both temperature and ion stimuli. When the crown ether units captured Ba2+ and formed stable BCAm/Ba2+ host-guest complexes, the lower critical solution temperature (LCST) of the hydrogel increased due to the repulsion among charged BCAm/Ba2+ complex groups and osmotic pressure within the hydrogel. Whereas crown ethers captured Cs+, the LCST shifted to a lower temperature because of the formation of 2:1 sandwich complexes. Unexpectedly, the LCST of the cross-linked P(NIPAM-co-BCAm) hydrogel in K+ solution did not shift to a higher temperature, which was definitely different from the previously reported linear P(NIPAM-co-BCAm) copolymer in K+ solution. The results of this work provide valuable information for development of dual thermo- and ion-responsive hydrogels which have potential applications in drug controlled-release systems or biomedical fields.

Microfluidic preparation of monodisperse ethyl cellulose hollow microcapsules with non-toxic solvent.

Monodisperse ethyl cellulose (EC) hollow microcapsules are successfully prepared by using a simple and novel method which combines microfluidic double emulsification and solvent diffusion. To dissolve EC, we use a non-toxic solvent ethyl acetate (EA), instead of methylene chloride which is commonly used but carcinogenic. By introducing chitosan (CS) into outer fluid, we can increase the viscosity of outer fluid and obtain smaller microcapsules which are desired. On the other hand, introducing CS only into outer fluid could lead to osmotic pressure gradient between the inner and outer fluids which could cause the undesired collapse of microcapsules. To avoid the collapse phenomena, we try adding iso-osmotic NaCl into inner aqueous fluid but failed in achieving osmotic pressure balance possibly because the small Na(+) and Cl(-) ions could penetrate the EC matrix during solidification. However, success is achieved when we introduce CS into both inner and outer fluids because CS polymer is too big to permeate through the EC matrix and thus could maintain iso-osmotic state. The microcapsules prepared under iso-osmotic state show perfect spherical shape and no collapse. The method developed in this work provides a novel and versatile route for fabricating monodisperse biocompatible microcapsules composed of water insoluble polymers.