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Structures in nature exhibit unique and complex architectures whose order propagates from nano- (10-9 m) to macro-scales (mm to m). These structures give rise to a rich diversity of adaptive function that allows for life in all environments on Earth. This complex functionality has driven research into bio-inspired materials where scientists investigate the complex relationship between sequence, structure and function of these materials. A good illustrative example of the effect that hierarchical structure can have is a brick wall. Bricks are laid so that the layer on top is shifted in either direction by half of a brick. This alternating pattern is what gives the wall its strength. If a crack occurs in the mortar, it will only propagate until it hits a boundary (a neighboring brick). Designing nanostructures can have similar effects on materials we use every day. Some of the most prevalent are adhesives that mimic the structures on gecko feet, which allow them to stick to any surface. This work presents bottom-up design strategies for self-assembling protein materials whose hierarchical structure may prove useful in a variety of applications in soft-robotics and energy storage. Proteins are a useful class of molecules, because they contain a level of structural complexity beyond that of synthetic materials. They are an inherently 'green' material feedstock; made in a lab using microbes like E. coli. Additionally, with the ease and availability of genetic engineering techniques we can easily modify the structure. This is especially true for the class of proteins, repeat proteins, which are the focus of this manuscript. Repeat proteins comprise small repeated sequences which are structurally independent from each other and can be strung together to create open, extended architectures. Here we explore the self-assembly emergent properties of the consensus tetratricopeptide repeat (CTPR18) . We show that this protein assembles into highly ordered 1D and 2D arrays that are shape tunable based the molecular environment (solvents, charge, etc). These nanomaterials may prove useful as molecular recognition scaffolds. We further explore the hierarchical self-assembled films of CTPR18. These films form highly oriented lamellar structures that seemingly propagate the entire length of the films. These lamellae directly affect the materials mechanical properties. Accordingly, by changing the film casting conditions, we can impart a structural gradient in the film, which proves useful in tuning the water-induced bending motion of these films. Herein, we show the ability to change the speed and directionality of actuation by simply changing the underlying film morphology. Lastly, we show that these films are electroresponsive as well, owing this function to ion transport through the inherently charged character of CTPR18. These dual responsive materials may prove useful in soft robotics. Additionally we are beginning investigations into the usefulness of CTPR18 films as alternate materials for ion-transport materials like those used in lithium polymer (more commonly LiPo) and sodium-ion batteries. / 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>Efficient delivery of therapeutic cell and pharmaceutical suspensions to the posterior segment of the eye remains an elusive goal. Delivery is made difficult by blood ocular barriers that separate the eye from systemic circulation, the compartmentalized structure of the eye that limits diffusion across the globe, and effective clearance mechanisms that result in short drug residence times. The work presented in this thesis focuses on the design, synthesis, evolution and refinement of novel biomaterial scaffolds ultimately intended to facilitate the minimally invasive delivery of therapeutic payloads into the posterior segment of the eye. The first generation materials presented in this work (Chapter 2) consist of linear chains of temperature-sensitive amine-terminated poly(N-isopropylacrylamide) (PNIPAAm) grafted onto the backbone of type I collagen. Second generation materials (Chapter 3) saw the inclusion of the lubricious polysaccharide, hyaluronic acid (HA), and replacement of the bulky collagen backbone, which was observed to impede scaffold gelation, with small cell adhesive RGD peptide sequences. The introduction of degradability was the emphasis of third generation copolymers (Chapter 4) and was achieved through copolymerization with dimethyl-γ-butyrolactone acrylate (DBA). The DBA lactone side group was found to undergo a hydrolysis dependent ring opening, which raises copolymer LCST above physiologic temperature, triggering the gelled scaffold to solubilize and be excreted from the body via renal filtration without the liberation of any degradation by-products. Degradation was found to occur slowly, which is favourable for long-term release scaffolds intended to decrease the frequency of injections required to maintain therapeutically relevant concentrations within the vitreous. Finally, the design of a fourth generation material is discussed (Chapter 5), in which optical transparency is achieved through copolymerization of third generation materials with polyethylene glycol (PEG) monomers of varying molecular weight. Synthesis, design and characterization of the various copolymers is described herein.</p> / Doctor of Philosophy (PhD)

<p><strong>A compatible interface between a biomedical material and host tissue is paramount to the continual function and life-span of medical devices that reside in the body. However, the unfavourable host response that ensues when foreign materials inhabit the body must be overcome for sophisticated medical devices, such as artificial organs and real-time biosensors, to be used clinically. My thesis research commenced with a search to find a pharmaceutical compound that could be incorporated into a medical device to suppress the accumulation of fibrous tissue. A prolyl hydroxylase inhibitor, a drug developed to inhibit collagen synthesis, was found to be effective at inhibiting collagen deposition within and on the outer surface of a poly(lactic-glycolic acid) disc, and also limited connective tissue ingrowth. Furthermore, the drug suppressed Scavenger Receptor A (SRA) expression on a macrophage-like cell culture, a receptor known to contain a collagenous domain. The latter finding prompted a review of the literature, upon which it was discovered that SRA mediates leukocyte adhesion and binding to an assortment of materials, such as silica, modified polystyrene, titanium, and iron(III) oxide. As a result, a series of studies were initiated to investigate whether leukocytes use SRA to detect a range of different biomedical materials. Consequently, we found that SRA contributes very little to leukocyte binding of two common medical polymers, polystyrene and poly(lactic-co-glycolic acid), but may interact with the materials to affect the cytokine profile in the local environment. In a subsequent study, SRA was found to be crucial to the leukocyte binding of polyanionic hydrogels. In summary, we have identified a unique pharmaceutical strategy for suppressing the accumulation of fibrous tissue on medical devices in vivo, and uncovered a mechanism of leukocyte stimulation in response to incubation with biomedical materials that the material science research community was not previously aware of. </strong></p> / Doctor of Philosophy (PhD)

<p>Medical devices used for diagnosis and treatment often involve the exposure of the patient’s blood to biomaterials that are foreign to the body, and blood-material contact may trigger coagulation and lead to thrombotic complications. Therefore, the risk of thrombosis and the issue of blood compatibility are limitations in the development of biomaterials for blood-contacting applications. The objective of this research was to develop a dual strategy for surface modification of polydimethylsiloxane (PDMS) to prevent thrombosis by (1) grafting polyethylene glycol (PEG) to inhibit non-specific protein adsorption, and (2) covalently attaching an antithrombin-heparin (ATH) covalent complex to the distal end of the PEG chains to inhibit coagulation at the surface.</p> <p>Surface characterization via contact angle measurements confirmed reductions in hydrophobicity for the modified surfaces and x-ray photoelectron spectroscopy (XPS) indicated that heparin and ATH were present. The predisposition of PDMS to induce blood coagulation was investigated, and advantages of ATH over heparin in inhibiting coagulation on PDMS were demonstrated. Studies of protein interactions using radiolabelling and Western blotting demonstrated the ability of PEG-modified surfaces to resist non-specific protein adsorption, and the ability of ATH- and heparin-modified surfaces to specifically bind AT present in plasma, thereby providing anticoagulant activity. Through specific interactions with the pentasaccharide sequence on the heparin moiety, the ATH-modified surfaces bound AT more efficiently than the heparin-modified surfaces. Thromboelastography (TEG) was used to evaluate further the anticoagulant potential of the ATH-modified surfaces. It was found that coagulation occurred at a slower rate on the ATH-modified surfaces compared to unmodified PDMS, and the resulting clot was mechanically weaker. By creating a surface with bioinert and bioactive properties, non-specific protein adsorption was reduced and anticoagulation at the surface through specific protein binding was promoted. This dual PEO/ATH modification strategy may therefore offer an improved approach for the minimization of thrombosis on PDMS and biomaterial surfaces more generally.</p> / Master of Applied Science (MASc)

The use of polymers in orthopaedics is steadily increasing. In some markets, such as spinal fusion and soft tissue anchors, the polymer polyetheretherketone (PEEK) is already the material of choice in the majority of implants. Despite PEEK’s widespread use, it is often associated with poor osseointegration, which can lead to implant loosening and ultimately failure of the device. Many attempts have been explored to improve the osseointegration of PEEK but none have had widespread clinical success. In this dissertation, a novel surface porous structure has been created, where limiting the porosity to the surface maintains adequate mechanical properties for load bearing applications while providing a surface for improved osseointegration. Careful control of the processing parameters resulted in tunable porous microstructures optimized for bone ingrowth: highly interconnected 200-500µm pores with porosity ranging from 60-85% and pore layers from 300-6000µm thick. Mechanical characterization, including monotonic tensile and compression, tensile fatigue, shear, and abrasion tests, were used to probe the effects of the surface porosity on the relevant mechanical properties of the material. In addition, the effect of surface porosity and surface roughness on the mechanical properties of a range of thermoplastics with varying chemistries and crystallinities was explored. This research showed that there is a great disparity in the notch sensitivity of polymers that correlates to the polymers fracture toughness as well as trends in the monotonic stress-strain curve. The results illustrate that care must be taken in the design of polymeric implants, especially when introducing topographical changes to promote osseointegration, in order to ensure they maintain adequate load-bearing capacity. Finally, preliminary in vitro and in vivo data demonstrated the ability of surface porous PEEK (PEEK-SP) to promote osseointegration. Cells grown on PEEK-SP demonstrated enhanced mineralization and differentiation, suggesting the ability of PEEK-SP to facilitate bone ingrowth. The potential of PEEK-SP was further demonstrated by implantation in a rat femoral segmental defect model which demonstrated bone ingrowth and reduced formation of a fibrous capsule.

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