This dissertation presents the fabrication of a silicate-based nanocomposite hydrogel with outstanding shear-thinning properties, viscoelastic behaviour, and water retention capacity. Due to their adaptable mechanical properties, bioavailability, and water retention capacity, these nanocomposite hydrogels have been extensively used for biomedical applications. Laponite nanoparticles are among the most utilized silicate-based minerals. These clay nanoparticles are composed of platelets that are positively charged on the edges and negatively charged on the surface. The high aspect ratio of the polyanionic surface of the Laponite nanoparticles can absorb and trap ionic functional groups with non-covalent interactions. These silicate-based nanocomposite hydrogels are produced by dispersing Laponite nanoparticles in deionized water, forming a homogenous colloid. The uniform dispersion of these nanoparticles in aqueous solutions forms a “house of cards” structure, which eliminates particle aggregation and improves their surface interaction with ionic compounds. The fabrication process is followed by the addition of the stable colloid to various organic and inorganic mixtures including, chitosan, alginate, graphene oxide, and gelatin. The chemical, physical, and mechanical properties of these nanocomposites are experimentally evaluated. Silicate-based nanocomposite hydrogels offer unique rheological characteristics, which facilitate the injection process while preserving the mechanical integrity of the construct following extrusion. The injectability of these nanocomposites was assessed by evaluating their shear-thinning properties through multiple rheological analyses. As per the definition of shear-thinning, the viscosity of nanocomposites is directly affected by the applied shear stress; the viscosity of these compositions decreases under shear stress and reverts to the original viscosity after removal of the force. Accordingly, nanocomposite hydrogels with shear-thinning properties can be utilized for extrusion-based 3D printing and for depositing drugs in localized tissue without the jeopardy of being washed away by circulating blood. In addition, the large number of surface interactions and cationic exchange capacity of Laponite nanoparticles improve electrostatic interactions between the nanocomposite components and a wide range of ionic compounds. Accordingly, these chemical properties facilitate the incorporation of stimuli-responsive materials into the polymeric structure of the nanocomposite, allowing for the utilization of these hydrogels in on-demand drug delivery applications. These properties of the silicate-based nanocomposite hydrogels are investigated through swelling and release studies, Fourier transforms infrared spectroscopy (FTIR), and zeta potential measurements. The results of these experiments indicate that the non-covalent electrostatic interactions and chemical properties of these hydrogels improve the solubility and loading efficiency of therapeutic agents. Silicate-based nanocomposite hydrogels may also be utilized for developing electrical conductive bioinks for extrusion-based three-dimensional (3D) printing. Adjusting the viscosity and shear-thinning properties of the hydrogel plays a significant role in the printability of a bioink. For instance, a highly viscous bioink disrupts extrusion, while a bioink with a low viscosity results in the formation of droplets instead of the desired cylindrical filaments. Optimized formulations of the nanocomposite hydrogels are investigated by conducting various mechanical property measurements. Consequently, the unique chemical and rheological properties of the proposed hydrogels make them superior candidates for drug delivery and tissue engineering applications. / Graduate / 2022-03-30

Microgels are solvent-swollen cross-linked gel particles with sub-micron diameters and have been widely investigated for drug delivery applications. Thermoresponsive microgels based on poly(N-isopropylacrylamide) (PNIPAM) have attracted particular attention given their potential to enable pulsatile or environment-specific drug release. However, current methods to make thermoresponsive microgels yield functionally non-degradable materials, significantly limiting their utility in vivo. Herein, hydrazone chemistry was applied to cross-link hydrazide and aldehyde-functionalized precursor polymers together to form degradable PNIPAM microgels on different length scales that enable potential use of thermoresponsive microgels in vivo in a way not currently possible. For micron-scale microgels, microfluidics was employed to create monodisperse microgels between 30-90 m. For nano-scale microgels, a temperature-driven aggregation/self-assembly technique was developed that resulted in the formation of microgels with sizes between 200-300 nm. In either case, the microgels can be slowly degraded through hydrazone hydrolysis. Functionalized microgels can be made by incorporating pH-responsive 2-dimethylaminoethylmethacrylate (DMAEMA) or glucose-responsive phenylboronic acid in the precursor polymers. The potential utility of degradable microgels in drug delivery was studied using in situ gelling microgel-hydrogel nanocomposites. Changing the microgel cross-link density and whether or not the microgels were physically entrapped or covalently cross-linked to the bulk hydrogel matrix resulted in significant changes in drug release kinetics, with burst release particularly mitigated by increasing the cross-link density of the microgels. Microgels made via microfluidics were then utilized to make fully degradable microgel-hydrogel composites consisting of chemically identical gel chemistries on both the bulk and micro length scales. Carbohydrates (carboxymethyl cellulose and dextran) and PNIPAM gel phases were oriented in different relative geometries to examine how the phase distribution impacted drug release. Results suggest that drug release can be controlled through the selection of polymer type of each phase, with the deswelling phase transitions of PNIPAM playing a particularly large role in slowing release of the drug. / Thesis / Doctor of Philosophy (PhD) / Microgels are solvent-swollen gel particles that have sub-micron diameters and have been widely investigated for a variety of biomedical applications. Temperature-responsive microgels based on poly(N-isopropylacrylamide) (PNIPAM) hold particular promise given that they can swell and deswell in response to changes in temperature, enabling pulsatile or environment-specific release of a drug. However, current thermoresponsive microgels are not degradable and therefore have limited utility in the body. In this thesis, degradable temperature-responsive microgels were developed on two length scales (micron and nano-sized) to enable their ultimate use in the body. Microgels responsive to changes in solution pH or the presence of glucose (both clinically-relevant stimuli) were made using similar techniques. Combinations of these microgels with injectable hydrogels enabled tuning of the rate of drug release by changing physical microgel and/or hydrogel, as investigated both experimentally and theoretically. The research conducted thus has the potential to impact clinical drug delivery vehicle design.