Anisotropic microparticles created by phase separation of polymers confined in emulsion drops

Abstract

“Microparticles” is the term which includes isotropic and anisotropic particles with diameters in the micrometer range. Isotropic microparticles have been synthesized by emulsion or dispersion polymerization with a high controllability over their size and properties and utilized for applications such as chemicals, cosmetics, pharmaceuticals, and electronics industries. Due to their unique morphologies, anisotropic microparticles have served as new class of colloidal models such as Janus, core-shell, dumbbell, and ellipsoidal shapes, and furthermore, functional anisotropic microparticles can be prepared by adding functional additives over polymerization step. Although the methods such as post-processing of isotropic microparticles, lithography using photo mask, micro-molding technique have been used to produce the dumbbell-shaped, ellipsoidal, and oblate microparticles, all the methods use materials which have fixed shape and size. So, it is still difficult to produce anisotropic particles with highly controlled sizes and shapes. Here, I demonstrate the anisotropic microparticles by polymer phase separation confined in emulsion drops. Polymer phase separation, which is phenomenon that depends on molecular parameter and thermodynamic parameters, enables that preparation of anisotropic microparticles through homogeneous emulsion drops which involve two distinct polymer blends. To achieve functional anisotropic microparticles, fabrication of anisotropic microparticles should be prepared first. In chapter 2, I report the microfluidic fabrication of monodisperse anisotropic microparticles created by phase separation of polymer blends. Two different polymers are dissolved uniformly at low concentrations in organic solvents, which is emulsified to oil-in-water emulsion drops by microfluidic device. As the organic solvent diffuses, small domains are formed in the emulsion droplet, and then only the merged two regions are formed. After the droplets are completely solidified, uniform anisotropic microparticles with two compartments are produced. The form of the obtained microparticles is determined by a combination of the kind of the polymer and the surfactant. Spherical microparticles with eccentric core and incomplete shell are prepared by consolidation of polystyrene (PS) and poly(lactic acid) (PLA), and microparticles with single crater are formed by consolidation of PS and poly(methyl methacrylate) (PMMA). Both emulsions are stabilized with polyvinyl alcohol (PVA). By using a triblock copolymer surfactant to stabilize the emulsion containing PS and PLA, acorn-shaped Janus particles are obtained. This microfluidic production of anisotropic microparticles can be further extended to any combination of polymers and surfactants to provide various structural and chemical anisotropies. Among these microparticles, Janus microparticles, which are composed of two compartments that have different properties such as chemical and physical, can be used as materials for active display pigment. In chapter 3, I report the simple method to create bicolored Janus microparticles using polymer phase separation with dye molecules. Monodisperse emulsion drops containing two immiscible polymers and dye molecules are generated in the continuous water phase in microfluidic device. As the organic solvent is depleted by evaporation, the drops evolve to Janus microparticles with two compartments. One of the compartments is selectively stained by spontaneous migration of the dye molecules, thereby providing optical anisotropy. In addition, the Janus microparticles can be further rendered to be magneto-responsive by embedding aligned magnetic nanoparticles in the polymer matrix. Furthermore, the configuration of Janus microparticles is exclusively selected from the core-incomplete shell, dumbbell, and acorn, according to the surfactant in the continuous phase. Microparticles, which are composed of two distinct biocompatible and biodegradable polymers, can be used as microcarriers for drug delivery system. In chapter 4, I report the microcarriers which are engineered using polymer phase separation to have multiple compartments to release distinct drugs in a more controlled fashion. The capillary microfluidic device prepares monodisperse emulsion drops containing two immiscible biocompatible polymers, one of which is biodegradable and the other is pH responsive. The emulsion droplets eventually form a uniform microcarrier with separate compartments. During phase separation and solidification, two model drugs with different hydrophobicity in the droplets are spontaneously concentrated in their compartments with higher affinity. The shape of the microcarriers is selected in five structures depending on the pH of the continuous phase and the organic solvent of the emulsion droplets. The microcarriers in each configuration provide their own release behavior of the model drug. They are potentially useful for selecting the release profile of various drugs suitable for a particular disease. Combination chemotherapy administering multiple chemo-agents is widely exploited for the treatment of various cancers in the clinic. Specially for hepatocellular carcinoma (HCC), one of the most common malignancies, a co-administration of combinational cytostatic multi-kinase inhibitors and cytotoxic chemo-agents has been suggested as a potential curative approach. In chapter 5, I report the Janus microparticles developed for the controlled local combination chemotherapy of HCC. The Janus microparticles are composed of polycaprolactone (PCL) compartment and magnetic nanoparticles-loaded poly(lactide-co-glycolic acid) (PLGA) compartment which contain hydrophobic regorafenib and hydrophilic doxorubicin, respectively. Exploiting the magnetic anisotropy, rotational motion of the Janus microparticles is controlled with magnetic field, which enables the active co-release of dual chemo-agents. Furthermore, Janus microparticles exhibit magnetic resonance (MR) contrast effect, supporting the successful transcatheter intra-arterial delivery of the combination chemo-agents loaded the microcarriers to the targeted tumor. This Janus microparticles potentially serve as a general combinational chemo-therapeutic platform for the co-delivery of various combinations of multi-chemo-agents.