Characteristics and release properties of drug loaded microparticles depend upon material used and choice of production method. Conversely to most of the conventional ones, microfluidic methods give an edge by improving the control over droplet generation, size and size distribution. Capillary-based microfluidic devices were successfully used to obtain monodisperse drug(s) loaded microbeads, janus, core-shell and trojan particles using UV initiated free radical polymerization while keeping activity of active loaded molecules. These devices can be assembled in a short period of time and a slight change in design gives completely different microparticles morphologies. These particles were developed with the aim to address different issues experienced in oral drug delivery. For instance microbeads can be used to deliver NASIDs in a sustained release manner while janus particles can release two APIs with completely different properties (solubility, compatibility) also in a sustained release manner. Core-shell particles were designed to target colonic region of human intestine for dual drug delivery. Trojan particles were synthesized in a new semi-continuous microfluidic process, thus improving nanoparticles safety handling and release in simulated gastric fluid. Each system was fully characterized to insure batch to batch consistency and reproducibility. In general, the release of active ingredients was controlled by tuning the operating and material parameters like phases flow rates, nature and concentration of drug, (co)monomers, surfactant and crosslinker, pH of release media with the result of different particle morphologies, sizes and shapes or matrix crosslinking density.

This dissertation, "Drug Delivery Devices Fabricated by Microfluidic Method and Their Applications in Long-term Antimicrobial Therapy" by Jun, Wu, 吴隽, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Controlled drug delivery devices provide numerous advantages such as reduced side effects, higher therapeutic efficiency and improved patient compliance. Biodegradable polymer has become the most important material for controlled drug delivery device because of the excellent biocompatibility and tunable physicochemical properties. Biodegradable polymeric drug delivery devices are usually processed into various types of micro-particles due to the ease of fabrication and administration. However, controlling the drug release kinetics of these microparticles is still a challenge. One important reason is that drug release kinetics is significantly influenced by the microstructure of drug delivery devices, which is difficult to control. Microfluidic method is a group of technologies involved in the manipulation of fluids using channels in the scale of micrometers. Microfluidic method is particularly useful in controlling the structure of micro-droplets and generating homogeneous droplets. Therefore, microfluidics suggests great potential in controlling microstructures of drug delivery devices and drug release kinetics. In this study, biodegradable polymer based controlled drug delivery devices were fabricated using microfluidic method. Various types of microstructures were developed such as microspheres, core-shell microspheres, hollow microspheres and hydrogel microspheres. The results showed that microstructures were well controlled by fluid flow rates and geometries of capillary microfluidic devices. Both hydrophobic and hydrophilic drugs could be delivered by choosing drug delivery devices with suitable microstructures. Drug release kinetics of biodegradable polymeric microspheres has been studies a lot, yet complete understanding is still to be achieved. The diameter is an important factor which contributes to the drug release kinetics. However, the influence of diameter has not been systemically studied because monodisperse microspheres are difficult to obtain. Using microfluidic method, monodisperse PLGA microspheres with different diameters were fabricated to study the influence of diameter on drug release kinetics. It was found that diameter only influence the duration of the first phase (lag phase) in drug release process and smaller microspheres exhibited shorter lag phase. The relatively faster expansion of smaller microspheres was found to be responsible for the size effect by monitoring physicochemical changes during drug release. Rifampicin, a broad-spectrum antibiotic, was encapsulated by PLGA microspheres and PLGA-alginate core-shell microspheres. The long-term antimicrobial effects of drug loaded microspheres were investigated by drug release test and antimicrobial test against Staphylococcus aureus. The results showed that drug delivery devices could provide antimicrobial effect for more than one month. These drug delivery devices show potential in applications of controlled drug delivery and long-term antimicrobial therapy. In conclusion, drug delivery devices with different microstructures were fabricated using microfluidic method. The diameter of PLGA microspheres only influence the first phase of drug release profile (lag phase) and smaller microspheres exhibited shorter lag phase. The size effect is due to the relatively faster expansion rate of smaller microspheres. Rifampicin loaded PLGA microspheres and PLGA-alg

This dissertation, "Microfluidic Fabrication of Polymer-based Microparticles for Biomedical Applications" by Tiantian, Kong, 孔湉湉, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Delivery vehicles that can encapsulate and release active ingredients of pre-determined volumes at the target site on-demand present a challenge in biomedical field. Due to their tunable physiochemical properties and degradation rate, polymeric particles are one of the most extensively employed delivery vehicles. Generally they are fabricated from emulsion templates. Conventional bulk emulsification technique provides little control over the characteristics of droplets generated. Thus the properties of the subsequent particles cannot be controlled. The advance of droplet microfluidics enables the generation and manipulation of designer single, double or higher-order emulsion droplets with customizable structure. These droplets are powerful and versatile templates for fabricating polymeric delivery vehicles with pre-determined properties. Due to the monodispersity of droplet templates by microfluidics, the relationship between size, size distribution, shape, architecture, elastic responses and release kinetics can be systematically studied. These understandings are of key importance for the design and fabrication of the next generation polymeric delivery vehicles with custom-made functions for specific applications. In the present work, we engineer the droplet templates generated from microfluidics to fabricate designer polymeric microparticles as delivery vehicles. We investigate and obtain the relationship between the particle size, size distribution, structure of microparticles and their release kinetics. Moreover, we also identify an innovative route to tune the particle shape that enables the investigation of the relationship between particle shape and release kinetics. We take advantage of the dewetting phenomena driving by interfacial tensions of different liquid phases to vary the droplet shape. We find that the phase-separation-induced shape variation of polymeric composite particles can be engineered by manipulating the kinetic barriers during droplet shape evolution. To predict the performance of our advanced polymer particles in practical applications, for instance, in narrow blood vessels in vivo, we also develop a novel capillary micromechanics technique to characterize the linear and non-linear elastic response of our polymer particles on single particle level. The knowledge of the mechanical properties enables the prediction as well as the design of the mechanical aspects of polymer particles in different applications. The ability to control and design the physical, chemical, mechanical properties of the delivery vehicles, and the understanding between these properties and the biological functionalities of delivery vehicles, such as the release kinetics, lead towards tailor-designed delivery vehicles with finely-designed functionalities for various biomedical applications. Our proposed electro-microfluidic platform potentially enables generation of submicron droplet templates with a narrow size distribution and nanoscaled delivery vehicles with well-controlled properties, leading to a next generation of intracellular delivery vehicles. Microfluidic-based technique has the potential to be scaled up by parallel operation. Therefore, we are well-equipped for the massive production of custom-made droplet templates of both micron-size and nanosized, and we can design the physiochemical properties and biological functionalities of the delivery vehicle

The use of nanotechnology to engineer drug delivery vehicles comprised of controlled release polymers with targeting molecules has the potential to revolutionize cancer therapy, among other diseases. Although a myriad of nanotherapeutics have been developed at the bench side, many of them stay at the research stage due to their complexity and difficulty in their optimization. A key challenge for optimization of nanoparticles (NPs) for drug delivery is the ability to systematically and combinatorially create and screen libraries of NPs with distinct physicochemical properties, from which promising formulations can be moved forward to preclinical and clinical studies. In this work, the development of a controlled method to synthesize libraries of NPs with distinct properties is described. The procedure uses a microfluidic platform that rapidly mixes reagents and provides homogeneous reaction environments, resulting in the reproducible, single-step synthesis of NPs with well-defined properties and narrow size distributions. The microfluidic system is composed of a mixing unit and a NP assembly unit. The mixing unit consists of a multi-inlet, 2-layer mixer where different precursors such as polymers of different MW and charge, ligand- and drug-conjugated polymers, free drugs, and solvents are mixed at different ratios into a homogenous solution. In the assembly unit, the precursor solution is quickly mixed with an anti-solvent (i.e. water) using 3D hydrodynamic flow focusing where NPs self-assemble after complete mixing. With the microfluidic platform, a library of 100 NPs with different sizes (15-200nm), charge (-30 to +30mV), surface chemistry (i.e. PEG coverage), surface ligand density (0-2.5105 ligands/[mu]m2), and drug loading (0-5 w/w%) was producedd in a high-throughput manner by simply varying the flow ratios of precursors entering the system. This library was implemented for (i) screening for formulations (in vitro and in vivo) with optimal clinical properties for cancer treatment and (ii) deepening the understanding of how NP properties affect their biological behavior. The platform developed in this work would likely lead to better understanding of the design parameters for polymeric NPs and their smoother transition to the clinic.

Polymer nanoparticles (PNPs) that exhibit selective stimuli-responsive degradation and drug release at tumor sites are promising candidates in the development of smart nanomedicines. In this thesis, we demonstrate a microfluidic approach to manufacturing biological stimuli-responsive PNPs with flow-tunable physicochemical and pharmacological properties. The investigated PNPs contain cleavable disulfide linkages in two different locations (core and interface, DualM PNPs) exhibiting responsivity to elevated levels of glutathione (GSH), such as those found within cancerous cells. First, we conduct a mechanistic study on the microfluidic formation of DualM PNPs without encapsulated drug. We show that physicochemical properties, including size, morphology, and internal structure, of DualM PNPs are tunable with manufacturing flow rate. Microfluidic formation of DualM PNPs is explained by the interplay of shear-induced coalescence, shear-induced breakup, and intraparticle chain rearrangements. In addition, we demonstrate that rates of GSH-triggered changes in size and internal structure are linearly correlated with initial PNP sizes and internal structures, respectively. Next, we expand our study to focus on microfluidic control of pharmacological properties of DualM PNPs containing either an anticancer drug (paclitaxel, PAX-PNPs) or a fluorescent drug surrogate (DiI-PNPs). Microfluidic PAX-PNPs and DiI-PNPs show similar sizes and morphologies with their non-drug-loaded counterparts under the same flow conditions. We then show that pharmacological properties of DualM PNPs, including encapsulation efficiency, GSH-triggered release rate, cell uptake, cytotoxicity against MCF-7 (cancerous) and HaCaT (healthy), and relative difference in MCF-7 and HaCaT cytotoxicity, all increase linearly as flow-directed PNP size decreases, providing remarkably simple process-structure-property relationships. In addition, we show that microfluidic manufacturing improves encapsulation homogeneities within PNPs relative to bulk nanoprecipitation. These results highlight the potential of flow-directed shear processing in microfluidics for providing controlled manufacturing routes to biological stimuli-responsive nanomedicines optimized for specific therapeutic applications. Finally, we summarize various design strategies of biological stimuli-responsive PNPs. We show that the location and density of disulfide linkages within PNPs determines stimulus-triggered degradation mechanism and kinetics. In addition, we show various bottom-up approaches to tune PNP responsivities that involves chemical processing, including formulation chemistry and intramolecular forces. Along with the top-down microfluidic approach that we demonstrate experimentally, this chapter provides a more comprehensive understanding of process-structure-property relations opening up vast possibilities for manufacturing smarter nanomedicines.