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.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/18303 |
| Date | 11 1900 |
| Creators | Sivakumaran, Daryl N |
| Contributors | Hoare, Todd, Chemical Engineering |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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