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<p>  </p> <p>Cancer immunotherapies have revolutionized anticancer treatment, saving lives by utilizing patients’ immune systems. Immunogenic cell death inducing chemotherapies have recently gained interest as they can not only inhibit the growth of the tumor but also allows the patient to develop a long-lasting immune response to the tumor. However, due to the poor retention of chemotherapies in the tumor and immunosuppressive tumor microenvironment, the activity of immunogenic cell death inducing chemotherapy is limited. To overcome the limitations, I have developed immunofunctional poly(lactic-co-glycolic acid) nanoparticles to enhance the retention of immunogenic cell death inducers at the tumor and increase the recruitment of antigen-presenting cells to the tumor.</p> <p><br></p> <p>In our study, paclitaxel and carfilzomib were determined as immunogenic cell death inducers, supported by in vitro screening of damage-associated molecular patterns and in vivo vaccination study. Both drugs were identified as immunogenic cell death inducing chemotherapy agents. To deliver immunogenic cell death inducers, immunofunctional poly(lactic-co-glycolic acid) nanoparticles were developed by modifying the surface with adenosine triphosphate. The coating of adenosine triphosphate attracted dendritic cells in a concentration gradient manner and improved the stability of adenosine triphosphate against its degrading enzyme. Both paclitaxel and carfilzomib were successfully encapsulated into the developed nanoparticle formulation. Paclitaxel encapsulated nanoparticles were chosen as a lead candidate due to the inherent immunotoxicity of carfilzomib.</p> <p>Paclitaxel encapsulated nanoparticles coated with ATP effectively suppressed tumor growth in CT26 murine carcinoma and B16F10 murine melanoma. The formulation also increased the immune cell infiltration into the tumor, which may explain the enhanced efficacy of the nanoparticle formulation. Combinational therapy of nanoparticles with anti-PD-1 antibodies significantly increased the complete regression rate in tumor-bearing mice by invigorating the immunosuppressive environment. </p> <p><br></p> <p>In summary, paclitaxel (an immunogenic cell death inducer) encapsulated in adenosine triphosphate-coated poly(lactic-co-glycolic acid) nanoparticles attracted dendritic cells in a concentration gradient manner and effectively suppressed tumor. Additional anti-PD-1 antibodies further improved the antitumor effect, inducing complete tumor regression in 75% of CT26-bearing mice, by inhibiting the interactions between T cells and immunosuppressive cells (regulatory T cells and myeloid-derived suppressor cells). </p> <p><br></p> <p>Chapter 1 discusses the current understanding of immunotherapy and delivery systems to enhance immunotherapy. Chapter 2 describes the determination of immunogenic cell death inducers and the development of immunofunctional nanocarrier. The in vivo antitumor efficacy of the nanocarrier was tested in Chapter 3. </p>

<p>This work detailed in this thesis has developed two new technologies for modifying polymer surfaces with variable chemistry and topography: 1. Surfadditive (surface-active-additive) approach for polymer surface chemistry modification during molding. This concept was demonstrated by the synthesis and application of two types of surfadditives. The first type of surfadditive is a block copolymer having the “head-neck-body” structure. The “head” and “neck” of the chain molecule provides functionality and enables the surfadditive to migrate to the surface, while the “body” of the molecule provides rooting to the bulk material. The second type of surfadditive is a magnetic nanoparticle having an iron core and PMMA/POSS block copolymer shell. Both surfadditives were successfully applied in the molding processes of PMMA samples for surface chemistry modification. Various factors affecting the migration processes were investigated; 2. A one step “cutting-edge” based on controlled chattering for surface topography construction (patterning). This technology was developed by using an oscillating diamond knife in ultramicrotomy and was operated at high cutting speed with controlled oscillation. One dimensional wavy patterns on PMMA and epoxy sample surfaces were successfully fabricated by this one-step method. The sizes of patterns were tunable form 30 nm to 3 µm through adjusting cutting speed and oscillation frequency. Besides, this technology was also able to fabricate nanowires structures with high aspect ratios (10,000) and adjustable sizes from a variety of materials.</p> / Doctor of Philosophy (PhD)

<p>I put department up there as Biomedical Engineering. The full title should be: School of Biomedical Engineering.</p> / <p>The work presented in this thesis was focused on the surface modification of biomaterials with combinations of polyethylene glycol (PEG) and bioactive molecules (protein anticoagulants) for improved blood compatibility. Since the fate of biomaterials in contact with blood depends significantly on plasma protein-surface interactions, the objective of this work was to reduce non-specific protein adsorption using PEG and to promote specific protein interactions that could inhibit clot formation using protein anticoagulants as modifiers.</p> <p>Two anticoagulant molecules were used in this work: hirudin, a specific inhibitor of thrombin and corn trypsin inhibitor (CTI), a specific inhibitor of clotting factor XIIa. Gold, used as a model substrate, was modified with PEG and anticoagulant molecules using two methods referred to as sequential and direct. In the sequential method PEG was first immobilized on the surface and then the bioactive molecule was attached (conjugated) to the PEG. In the direct method, a PEG-bioactive molecule conjugate was first formed and then immobilized on the surface. Surfaces were characterized by contact angle, ellipsometry and x-ray photoelectron spectroscopy (XPS). Uptake of the bioactive molecules was measured by radiolabeling. Biointeraction studies included plasma protein adsorption, bioactivity assays using chromogenic substrates and clotting time assays. For PEG-hirudin and PEG-CTI surfaces (both direct and sequential) the protein resistance was similar to that of the PEG-alone surfaces. Despite having a lower density of bioactive molecule (both hirudin and CTI), the sequential surfaces showed superior bioactivity compared to the direct ones.</p> <p>To determine the optimal ratio of free PEG and bioactive molecule-PEG conjugate on the surface (best combination of protein resistance and bioactivity), PEG-CTI was immobilized on gold substrate with varying ratio of conjugated to free PEG using both direct and sequential methods. As the ratio increased, protein resistance was maintained while specific interactions (bioactivity) increased. The optimal composition appeared to be where all PEG molecules are conjugated to a CTI molecule.</p> <p>In the final part of this project, PEG and CTI were immobilized on polyurethane as a material with applicability to medical device construction. A sequential method was developed for this substrate. Comparison of the PEG-CTI surface with PEG only or CTI only surfaces indicated that the combination of PEG-CTI was effective both in reducing non-specific protein adsorption and promoting the specific interactions of CTI with its target plasma protein, factor XIIa. In fact, the presence of PEG improved CTI interactions with FXIIa compared with CTI only surfaces. Thus, sequential attachment of PEG and CTI may be effective for modifying polyurethane surfaces used in blood-contacting medical devices.</p> / Doctor of Philosophy (PhD)

<p> Collagen, due to its good biocompatibility and abundance in mammalian structures, has been widely applied in developing better biomaterials. There remains the need for yet more stable surfaces of biomaterials. One strategy to achieve this is improved binding to surfaces using covalent rather than physical linking. However, due to collagen's poor solubility in neutral or alkaline conditions, there are only a few papers describing covalently linked collagen so far, and they generally use acidic conditions to generate surfaces with only low collagen density. N-Hydroxysuccimide ester (NHS) chemistry has been widely used in covalently binding proteins, but the NHS activity and its preparation efficiency are plagued with undesired, premature hydrolysis. A two-step method was developed for making NHS functional surfaces with a non-fouling spacer, PEO. The process was more efficient and led to concentrated NHS surfaces. Collagen was successfully immobilized onto this NHS surface after optimizing the conditions for immobilization. The solubility problem was overcome by increasing the ionic strength of the solution. Abundant collagen molecules could then be immobilized on the silicone surface. ATR-FTIR was used as a diagnostic tool to prove the surface had been modified. The low water contact angle (40°) indicated the presence of collagen. XPS data showed a significant increase on the nitrogen content after tethering collagen molecules. Deep freezing ToF-SIMS displayed a decrease in the peak intensity for cationic fractions of collagen molecules when warming from -96 °C to room temperature, which suggested the surface rearrangement due to the hydrophilic character of collagen. Profilometer and tapping-mode AFM were used to investigate the surface morphology after modification. The latter showed a high density mesh work (immobilized collagen fibers) on the collagen-modified surface. Collagen stain with Sirius Red F3B allowed us to look into the tertiary structures of covalently tethered collagen on the surface. However, it was found that only some of them were still in their native form. Interestingly, a subsequent epithelial cell culture assay showed that the cells grew very well on this collagen rich silicone surface. This suggested collagen's tertiary structure may not be necessary to support cell growth on the silicone surface covalently modified with collagen through the PEO spacer. However, further biochemical experiments are required to establish the underlying source of this observation.</p> / Thesis / Master of Science (MSc)

Sustainable agriculture is a crucial factor to be considered in order to meet the growing demand for food production. The need for low cost and highly functional materials to provide the most efficient cultivation process has led the agriculture industry to consume petrochemical and mineral based material in an enormous amount. Thus, disposal of the used mulch materials has become a serious environmental issue. In this work, the possibility of using wood pulp fibre in two distinct applications in agriculture is investigated. First, agricultural mulching is the subject of the study and second, we focus on using wood pulp fibre as growing medium in greenhouses. Mulching in agriculture is an essential practice in order to have high crop yield, healthy products, and more efficient cultivation process. Over the years, agricultural mulch has been made out of a variety of materials. The most common of all is plastic mulch due to its low price and high functionality. However, the problems associated with applying and removing the enormous load of plastic and their disposal have made it an option far from ideal. Therefore, there is a need to develop mulches based on biodegradable materials. Paper-based mulch is one of the candidates, In the first chapter of this work, with a review of previous works in this area, we attempt to develop a new spray-able mulch based on wood pulp fibre. A novel foam forming method is utilised to deposit wood pulp fibres in combination with other chemicals as an evenly distributed fibre network on a porous bed. Currently available paper based-mulch is of a very high basis weight. In first part of this work, application of a foam formed low basis weight paper-based mulch is investigated. Whereas, in the second chapter, the use of wood pulp fibres in a similar function as “rockwool” in soilless greenhouse farming is investigated. Rockwool is named after fibres made of melted minerals at temperatures as high as 2000°C. Rockwool is used as blocks for seeds growth and propagation and as an alternative for soil in greenhouses. The feasibility of microenvironment control of the rockwool blocks in crop production plus its low cost have made is popular. However, their disposal has always been an environmental issue. The biodegradability of wood pulp fibres is a great advantage over mineral fibres used in rockwool. In the second chapter of current work, we study the possibility of using wood pulp fibres as carriers for agriculturally beneficial chemicals. Specifically, we focus on binding and release properties of small organic molecules from wood pulp fibres. The goal is to achieve an understanding of the capability of wood pulp fibres to be used in building biodegradable growing medium blocks in greenhouses. / Thesis / Master of Applied Science (MASc)

The process of TEMPO-mediated oxidation has gained broad usage towards the preparation of highly charged, carboxyl-functionalized polysaccharides. TEMPO-oxidized nanocelluloses (TONc) of high surface charge and measuring 3 to 5 nm in width have been recently prepared from TEMPO-oxidized pulp. This study examines as-produced and surface-hydrophobized TONc as reinforcing additives in cellulosic polymer matrices. In the first part of the work, covalent (amidation) and non-covalent (ionic complexation) coupling were compared as treatment techniques for the hydrophobization of TONc surfaces with octadecylamine (ODA). Subsequently, TONc and its covalently coupled derivative were evaluated as nanofiber reinforcements in a cellulose acetate butyrate (CAB) matrix. The properties of the resulting nanocomposites were compared with those of similarly prepared ones reinforced with conventional microfibrillated cellulose (MFC). It was found that both ionic complexation and amidation resulted in complete conversion of carboxylate groups on TONc surfaces. As a result of surface modification, the net crystallinity of TONc was lowered by 15 to 25% but its thermal decomposition properties were not significantly altered. With respect to nanocomposite performance, the maximum TONc reinforcement of 5 vol % produced negligible changes to the optical transmittance behavior and a 22-fold increase in tensile storage modulus in the glass transition region of CAB. In contrast, hydrophobized TONc and MFC deteriorated the optical transmittance of CAB by ca 20% and increased its tensile storage modulus in the glass transition region by only 3.5 and 7 times respectively. These differences in nanocomposite properties were attributed to homogeneous dispersion of TONc compared to aggregation of both the hydrophobized derivative and the MFC reference in CAB matrix. A related study comparing TONc with MFC and cellulose nanocrystals (CNC) as reinforcements in hydroxypropylcellulose (HPC), showed TONc reinforcements as producing the most significant changes to HPC properties. The results of dynamic mechanical analysis and creep compliance measurements could be interpreted based on similar arguments as those made for the CAB-based nanocomposites. Overall, this work revealed that the use of TONc (without the need for surface hydrophobization) as additives in cellulosic polymer matrices leads to superior reinforcing capacity and preservation of matrix transparency compared to the use of conventional nanocelluloses. / Ph. D.