This work deals with bioceramic materials based of hydroxyapatite, bioglass and their composites. These materials are commonly used in medicine, especially as hard tissue substituents. They can be prepared by different types of syntheses, from which the most common were picked for this work – precipitation of hydroxyapatite and sol-gel method for bioglass. Thermal analysis and X-ray diffraction were used for characterization of prepared powders. This thesis studies mostly their features within the composite materials, which were foamed for better bone stimulation. Properties and possibility in bio application of materials is firstly studied through their interaction in simulated body fluids, which mimics ionic concentration of human plasma. Experimental part covers synthesis of ceramic powders, their characterization, preparation of mixtures and scaffolds foamed through in situ foaming, their sintering at ideal temperatures, characterization of porosity and phase changes due to sintering. Basic tests of apatite formation ability were provided by incubation of prepared scaffolds in simulated body fluid for 3, 7, 14 and 21 days and their assay in scanning electron microscopy. Changes in concentration of Ca2+ a PO4 3- ions as well as in weight of the specimen were tracked within the incubation period.

Silicon nitride thin films are of interest in the biomedical engineering field due to their biocompatibility and favorable tribological properties. Evaluation and understanding of the properties of these films under diverse loading and failure conditions is a necessary prerequisite to their use in biomedical devices. Three wafers of silicon nitride-coated silicon were obtained from Lawrence Livermore National Laboratory and used to create 96 samples. Samples were subjected to nanoindentation testing to evaluate the mechanical properties of the film. Samples were subjected to nanoimpact testing to compare the damage resistance of the film to separate nanoimpact types. Samples were subjected to nanoscratch testing to evaluate the consistency of the critical load of the film. Results showed that there were no significant differences in the mechanical properties of the film across the tested groups. There was a significant difference observed in the rate of damage to the film between pendulum oscillation nanoimpact testing and sample oscillation nanoimpact testing, with the former causing more damage with all experiment variables controlled for. Results showed that the critical load measure for the film was significantly different between different nanoscratch test parameters. The conclusions from this study will support future work for in vitro and in vivo testing of ceramic thin films for biomedical applications.

Biomaterials are defined as non-viable materials whose functions strives to interact with biological systems, this makes biomaterials suitable for medical devices and applications. Biomaterials biological properties must be thoroughly investigated and evaluated in order to be approved for clinical usage. In vitro studies are used to characterize the materials biological properties, if promising results are achieved in vitro, in vivo studies may be performed to ensure that the material can interact with living animal models in the intended way. However, for a biomaterial such as calcium-deficient hydroxyapatite there is a gap between results observed in vitro and in vivo studies. Microfluidic systems have been highlighted as a possible evaluation model to achieve reliable results for in vitro studies. The aim of this thesis was to compare and evaluate a biomaterial- on-a-chip, i.e., a biomaterial integrated in a dynamic microfluidic system, with a traditional static in vitro system in the regards of drug release and protein adsorption. Two chemically identical calcium-deficient hydroxyapatites but with different topographies were integrated in the microfluidic system and manufactured as discs for static evaluation. Results from drug release and protein adsorption studies showed different behaviours for dynamic and static control, which is significant since it indicates that the outcome of the characterization correlates to the evaluation model used.

The biotechnology revenues in the United States exceeded $100 billion in 2010 and the potential impact of synthetic biological engineering has been identified nationally as an emerging technology to further expand the national bioeconomy. Synthetic biological engineering approaches biology from an engineering perspective to make biology easier to engineer. The potential to engineer microorganisms for novel applications can have far-reaching implications and benefits for society. Some of the potential applications range from biosensors, biofuels, therapeutics, and biomaterials. In this study two biomaterials were produced in genetically engineered Escherichia coli: polyhydroxybutyrates (PHBs) and spider silk. PHBs are bioplastics that have similar properties to petrochemical-derived plastics. Synthetic biological engineering can be used to optimize PHB extraction from E. coli by secretion of the PHB polymer outside of the cell. Another biomaterial, spider silk, was also produced in E. coli. Spider silk is a unique material with high tensile strength and elasticity and thus could have a wide range of potential applications. Since spider silk is not naturally produced in microorganisms, the DNA sequences were optimized for increased production in E. coli. In addition to optimization of bioproduct production in microorganisms using synthetic biology, another major cost is the carbon substrate. In this study wastewater microalgae were used as an alternative carbon substrate. Coupling synthetic biological engineering and sustainable engineering could potentially make production of bioproducts economically viable in the future.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18289号 / 工博第3881号 / 新制||工||1595(附属図書館) / 31147 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 岩田 博夫, 教授 木村 俊作, 教授 秋吉 一成 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

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Sight is the most powerful of all human senses. For the vast majority of people on Earth, the loss of that sense would be unimaginable. Without assistive technology, it would separate them from their ability to work, their ability to travel, and their ability to interact with their loved ones. And yet, this extraordinary process, carefully refined by billions of years of evolution, is threatened for millions of people all over the world from a wide array of diseases of the retina. Many of these diseases arise from malnutrition and infection and are being rapidly eradicated. However, many dozens more result from convoluted permutations of genetics, age, and diet that threaten blindness for millions more with little hope of treatment, even with the best of modern medicine. As our life expectancies extend and our population ages, these diseases will only become more prevalent. In humanity's ever-present pursuit of medicine and knowledge to improve our quality of life, cutting-edge treatments offer promise that one day soon, even these diseases may be eradicated. One key technology capable of treating these devastating illnesses, on the precipice of being translated to real-world clinical treatments, is pluripotent stem cell-derived therapies. Patient-specific pluripotent stem cells, meaning pluripotent stem cells sourced directly from the patient, have a wealth of applications ranging from drug identification to disease modeling to implantation and regeneration. This research has been developed and advanced remarkably in the approximately two decades since the early isolation of pluripotent stem cells. Naturally, this advancement has predominantly been focused on cell and molecular biology. However, this focus has left significant research questions to be answered from engineering perspectives across a wide latitude of sub-disciplines. This dissertation explores three independent avenues of engineering principles as they relate to improving 2D and 3D retinal tissues derived from pluripotent stem cells in materials, devices, and computation. The first aim explores how plant protein-based nanofibrous scaffolds can marry the advantages and minimize the disadvantages of synthetic and animal-derived scaffolds for the culture of 2D retinal pigment epithelium (RPE) constructs. The second aim describes the development and testing of a novel, perfusing rotating wall vessel (RWV) bioreactor to support culture of 3D retinal organoids. Finally, the third aim performs a meta-analysis of published RNA-Seq datasets to determine the precise mechanisms by which bioreactors support organoid growth and extrapolate how these conclusions can support future experiments. / Bioengineering

Effective delivery of drugs to the anterior segment of the eye is notoriously inefficient due to the anatomical barriers in place. Topical administration is the most common method of drug delivery to the anterior segment. When applied to the ocular surface, topical solutions encounter barriers such as lacrimal drainage, rapid tear turnover, and reflex blinking which result in < 5% of instilled therapeutic reaching the intended tissue. One potential method to evade some of these anatomical barriers and improve the delivery of therapeutics is the use of mucoadhesive nanoparticles. These materials are designed to encapsulate a relevant ocular therapeutic and provide a means of maintaining the vehicle on the ocular surface by adhering to the mucin layer of the tear film. To this end, the work presented herein describes the design, characterization, and testing of a novel mucoadhesive polymeric nano-micelle ocular drug delivery system. The base polymer used was selected from a system that has been previously used in the Sheardown Lab. It was composed of poly(D,L-lactide)-block-poly(methacrylic acid-co-3-(acrylamido)phenylboronic acid) (PLA-b-P(MAA-co-3-AAPBA); LMP-20). The formulation was modified to replace the 3-AAPBA monomer, which contains phenyl boronic acid as the mucoadhesive component, with a preactivated thiol monomer (pyridyl disulfide ethyl methacrylate; PDSMA) to generate a novel polymer (LMS-20) to investigate the potential for drug incorporation and mucoadhesion. Modifications of the polymer were made with small thiol molecules cysteamine (Cys; LMC-20), glutathione (GSH; LMG-20), and N-acetyl cysteine (NAC; LMA-20) with a goal of reducing cytotoxicity associated with the 2-pyridinethione leaving group. Synthesis of the PDSMA monomer, LMS-20 and LMP-20 polymers, and modified polymers LMC-20, LMG-20, and LMA-20 were confirmed by 1H NMR. LMA-20 was chosen for further examination as it contained the most relevant thiol modification for ocular applications and was capable of nanoprecipitation to form aqueous micelles with previously developed methods. Micelles were formed from LMA-20 and LMP-20, with spherical morphology as confirmed by TEM. Effective diameters of 64 ± 5 nm and 72 ± 3 nm are reported for LMA-20 and LMP-20, respectively, as confirmed by DLS. Critical micelle concentration for LMA-20 of 217 mg/L was found via a pyrene fluorescence study, significantly lower than the concentration of intended application. LMA-20 and LMP-20 are predicted to be mucoadhesive based on results of zeta-potential studies. However, oscillatory rheology studies were inconclusive based on a negative rheological synergism. LMA-20 micelles loaded with 0.16% (w/w) Cyclosporine-A were able to provide sustained release of drug up to 3 days in vitro. These results suggest the possible future use of these preactivated thiomer-based materials for the delivery of therapeutics to the anterior segment. / Thesis / Master of Applied Science (MASc)

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