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|Title:||Design & Fabrication of Nanostructured Hydrogels From Biopolymer Nanoparticle Building Blocks for Biomedical and Environmental Applications|
|Abstract:||In recent years, there has been a growing interest within the field of soft materials engineering on the development of advanced hydrogel systems with well-defined chemistries and morphologies that can be customized to suit various applications ranging from biomedical to environmental to personal care. In any case, careful selection of the building block materials, crosslinking chemistry, degradation pathway, and overall hydrogel architecture is essential to ensure the final design (and the resulting degradation components if relevant) are safe/non-toxic, mechanically tunable, and overall translatable for their intended end use given industry safety/production standards. In this thesis, the utility of starch nanoparticles created by a reactive extrusion process was explored as one such building block for creating renewable hydrogels. Starch was reactively extruded by EcoSynthetix Inc. to create starch nanoparticles (SNPs) that are attractive as hydrogel building blocks due to their inherent small size (25-50 nm), generally safe degradation products, overall net neutral charge, high deformability/viscoelastic properties, stability in solution without collapsing or changing size (on the order of months), and the ability to be manufactured at a multiple kg/hr rate; in comparison, other manufacturing methods of SNPs suffer from a lack of scalability or require the use of potentially toxic solvents, making them less amenable to biological or environmental/agricultural applications. The amorphous nature of the starch also allows for facile functionalization to further chemically modify and/or crosslink the SNPs through surface functional group (i.e. hydroxyl) modification chemistries. The nanoparticle nature of the SNP building block, coupled with the facile functionalizability of the SNPs, also makes SNPs ideal building blocks for the design and fabrication of nanoparticle network hydrogels (NNHs) in which NPs create an interconnected network on their own on, in addition to, other polymeric networks at any desired length scale. There are a variety of NNH architectures that can be achieved through careful design considerations. More specifically, herein colloidal NNHs were created using UV photopolymerization post-functionalization with methacrylic anhydride, which leaves a vinyl group on the SNP surface. Alternately, plum pudding NNHs were created by mixing aldehyde-functionalized SNPs with amine-bearing O-carboxymethyl chitosan that were able to chemically react via hydrolytically labile imine bonds. The properties of various types of colloidal and plum-pudding hydrogels based on SNPs were tested and subsequently compared through a range of different performance tests such as rheological and micromechanical force testing, swelling/degradation kinetics, their potential for controlled bioactive release, and overall toxicity (cell and organ level). In addition to these macroscopic performance tests, the internal morphologies of both colloidal and plum pudding NNHs were assessed with small angle and very small angle neutron scattering experiments to glean insight into how these internal structures correlate to macroscopic properties. For all experiments, the effect of using SNPs versus typical cold water-soluble branched starch (SS) was assessed to further understand the impact of making hydrogels from nanoscale rather than soluble polymer building blocks, with the small size of SNPs compared to the large hydrodynamic radius of SS consistently allowing for greater control over the range of potential hydrogel properties. The results of these studies suggest that SNP-based NNHs are promising materials for studying the encapsulation and release of small molecules in both in vitro and in vivo settings. For example, the photopolymerization of methacrylated SNP-based NNH coatings can be fabricated at much higher concentrations than possible with conventional starch (35% for SNP, 10% for SS), leading to denser and stiffer gels compared to SS controls albeit with slightly longer gelation times due to the reduced conformational mobility of the polymerizable methacrylate groups on the SNPs. The addition of charge (cationic or anionic) to the SNP surface further increases the bulk gelation time while significantly reducing the observed changes in SNP deformation during photogelation as confirmed via very small angle neutron scattering experiments. Other functional groups were also demonstrated to be introduced to SNPs to enable different types of gelation for different applications. For example, in situ-gelling and degradable bulk nanoparticle network hydrogels consisting of oxidized starch nanoparticles (SNPs) and carboxymethyl chitosan (CMCh) were created for intranasal delivery that could be delivered into the nose via a commercial atomization device to enable high nasal mucosal retention and functional controlled release of the peptide drug PAOPA, a positive allosteric modulator of dopamine D2 receptor. Selected gels shown to alleviate negative behavioural abnormalities associated with for up to 72 hours in pre-clinical rat models of schizophrenia at a low drug dosage (0.5 mg/kg), compared to just a few hours with the drug alone. Finally, the functionalization of SNPs with hydrophobic groups (via grafting the starch with octenyl succinic acid (OSAn) or succinic anhydride (SAn)) was demonstrated as a promising delivery system for agricultural applications. Hydrophobization increased the contact angle of a sprayed watermelon and pumpkin leaves from <60˚ (unmodified) to ~80˚ when modified (DS 0.25), while confocal fluorescence microscopy confirmed that the hydrophobized SNPs can both adhere to the leaf surface as well as penetrate into the leaves when sprayed due to their small size (25-50 nm). Future work will look at other methods of crosslinking SNPs (i.e. Michael addition, hydrazone, and alkyne-azide “click” chemistry, amongst others) to see if there are beneficial differences compared to analogous hydrogels made from macroscopic alternatives (i.e. polymers alone) and to follow-up the findings already gleaned within this thesis. Further information on the impact and potential follow-up experiments for the work conducted in this thesis will be explained in Chapter 6 on final outlooks and conclusions of the following work.|
|Appears in Collections:||Open Access Dissertations and Theses|
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