Droplet-based microfluidics for synthesis of functional microparticles

This thesis describes the Droplet-based microfluidic for synthesis of monodisperse functional microparticles and various applications. Functional microparticles have been widely used in biological applications, biochemistry and chemistry research. Conventional manufacturing processes have a high production rate and volume but lack control over size and monodispersity. In contrast, droplet based microfluidics provides precise control of multiphase flow dynamics in confined micro-channels, and thus enables the formation of micro-droplets with controlled size, composition, and morphology. However, the low production rate of microfluidic devices has remained a hurdle to bring the promising yet laboratory-scale functional materials synthesized by microfluidics to the commercial-scale for industrial applications. Therefore, further improvement is desired to make the microfluidic droplet platform more controllable and facile in operation. In this thesis, I developed two types of microdroplet generators that enable synthesis of highly uniform microspheres with excellent stability, precise control over droplet volume and composition. Firstly, a high-throughput droplet generator by parallelization of high aspect ratio rectangular structures was presented. It enables facile and scalable generation of uniform droplets without the need to precisely control external flow conditions. A multilayer device is formed by stacking layer-by-layer of the polydimethylsiloxane (PDMS) replica patterned with parallelized generators. By feeding the sample fluid into the device immersed in the carrying fluid, we used the multilayer device with 1200 parallelized generators to generate monodisperse droplets (~45 μm in diameter with a coefficient of variation <3%) at a frequency of 25 kHz. We demonstrate this approach is versatile for a wide range of materials by synthesis of polyacrylamide hydrogel and Poly (l-lactide-co-glycolide) (PLGA) through water-in-oil (W/O) and oil-in-water (O/W) emulsion templates, respectively. The combined scalability and robustness of such droplet emulsion technology is promising for production of monodisperse functional materials for large‐scale applications. Secondly, a droplet generator that incorporates mixing of two fluids was developed to allow for synthesis of co-polymer microparticles. Typical biocompatible materials, including Polyethylene glycol (PEG), Dextran (Dex), Chitosan (CQA), and Sodium hyaluronate (HA), were tested for their manipulatable concentrations to generate the monodisperse droplet in the device. The two fluids mixing ratio and mixing efficiency were also investigate of the device. We used clickable groups (vinyl sulfone and thiol) modified dextran and HA as example material to formulate monodisperse hydrogel microparticles of different diameters. Fluorescein-labeled immunoglobulin G (F-IgG) were loaded as model drug in the hydrogel microparticles, and release profiles from hydrogel microparticles with different formulations and sizes were obtained and compared. Finally a polyacrylamide hydrogel with barcoding primer were synthesized using this device. The polymerized hydrogel microparticles were incorporated with barcodes by split and pool method and primer extension reaction. Primer extension reaction were carried out three time for barcoded the primer. Fluorescence in situ hybridization (FISH) technique was adopted to verify the extension efficiency of the three times extensions. In summary, high-throughput droplet generators provide a robust and controllable mean for scalable production of microparticles. This synthesis strategy has attracted a great deal of interest because in many applications such as drug delivery monodisperse size and specified composition are important for controlling the release dosage. Future efforts should focus on further reducing the emulsion size to nanoscale and surface functionalization with therapeutic agents, which will largely facilitate the targeted delivery.