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Ischemic cardiomyopathies, such as myocardial infarction (MI), are a leading cause of heart failure in both men and women throughout the world. Despite timely intervention post-MI, the loss of viable myocardium can lead to global remodeling and loss of function in many patients due to the limited regenerative potential of heart tissue. Thus, there is a critical need to better understand the repair mechanisms involved and to develop new preventative and reparative therapies for treating MI and preventing progression to heart failure. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite of glycolysis and the main precursor of advanced glycation end-products (AGEs), which can cause oxidative stress and wound healing delay. MG was shown to play an important causative role in the cellular changes, adverse remodeling and functional loss of the infarcted heart. This suggests MG as a target for therapy to restore cell-ECM signaling, inhibit oxidative stress and improve cardiac function post-MI. The aim of this PhD project was to develop new biomaterial therapies that can reduce the effects of MG, decrease oxidative stress, enhance electrical conductivity and improve cardiac contractility and function post-MI. There were three primary objectives: 1) To develop an injectable antioxidant and hydrogel system for minimizing the effects of MG and promoting cardiac repair post-MI; 2) To synthesize a nanoparticle system for targeted delivery of Glyoxalase-1 (Glo1) enzyme to cardiac tissue for reducing the accumulation of MG, limiting adverse remodeling and preserving cardiac function following MI; and 3) To design a sprayable nano-therapeutic that uses surface engineered custom designed multi-armed peptide grafted nanogold for on-the-spot coating of infarcted myocardial surface for increasing contractility of the myocardium post-MI. In the first study, a fisetin-loaded collagen type I hydrogel (fisetin-HG) was injected intramyocardially in mice at 3h post-MI, and compared to fisetin-alone, hydrogel-alone, or saline treatment. The fisetin-HG treatment increased the level of glyoxalase-1 (the main MG-metabolizing enzyme), reduced MG-AGE accumulation, and decreased oxidative stress in the MI heart, which was associated with smaller scar size and improved cardiac function. Treatment with fisetin-HG also promoted neovascularization and increased the number of pro-healing macrophages in the infarct area, while reducing the number of pro-inflammatory macrophages. The second study revealed that when delivered intravenously at 3h post-MI, our Glo1-loaded nanoparticles specifically targeted the damaged cardiac tissue, led to improved cardiac function, protected cell viability and limited infarct expansion by reducing oxidative stress post-MI. Lastly, the third study showed that, when applied at 1-week post-MI, the sprayed nanogold treatment remained at the treatment site for at least 28 days with no significant off-target organ infiltration. Our results demonstrated a remarkable increase in cardiac function, muscle contractility, and myocardial electrical conductivity post-MI. Overall, these findings show that reducing MG levels through both increased activity of Glo1 and direct MG scavenging as well as increasing cardiac contractility may be a promising approach to limit adverse cardiac remodeling, prevent damage, and preserve the function of the infarcted heart

Hydrogels are high water-content polymers that mimic the extracellular matrix of cells. The polymers can have many sources and be of natural origin from the extracellular matrix (ECM) of cells or be synthetically derived. Two such polymers are hyaluronic acid and gelatin, which can with the help of the release of free radicals from photoinitiators, initiated by UV light, polymerise, and form a hydrogel. In these hydrogels, cells can be encapsulated. The hydrogels can in turn be used to maintain cells as they are in the natural environment. For example, hydrogels can provide an in-vivo-like ECM for stem cells and endothelial cells by supporting “stemness” and cell-to-cell contact; respectively. We aim to establish a protocol for culturing cells in the hydrogelas a first milestone in a project focused on profiling the metabolome of cells grown in hydrogels. To accomplish this, four types of cells, namely mouse brain microvascular endothelial cells (bEnd.3), human umbilical vein endothelial cells (HUVECs), adult human lung fibroblast (hLFs) and mesenchymal stem cells (MSCs), were evaluated for growth in hyaluronic acid methacrylate (HA-ma), hyaluronic acid acrylamide (HA-am) as well as a QuattroGel composed by gelatin methacryloyl (GelMA), HA-ma, fibrinogen and thrombin. It was found that HA-masupported viability and the stemness of mesenchymal stem cells, of which the metabolome can be further studied in order to evaluate the difference between regular 2D maintenance and maintenance in 3D. No sprouting was observed for the other cells encapsulated in the hydrogel, and further experiments are needed to find the source of error.

Heavy metals, despite their essential roles as minerals in biological systems, pose a significant threat to human health and the environment due to their toxic properties. Even at low concentrations, heavy metals such as lead, mercury, arsenic, and cadmium can cause adverse effects on humans and animals. Consequently, stringent regulations have been established to limit heavy metal concentrations in water resources. However, existing laboratory-based analytical methods for heavy metal detection are time-consuming, expensive, and require skilled personnel. The current detection limit required by several health organizations around the globe is below 10 ppb for Lead, Mercury, Chromium, and Arsenic. The current state of the art which can accomplish low levels of detection is either expensive to operate or incapable of achieving the required trace level sensing. This thesis aims to address the need for a simple, cost-effective, and portable method for detecting heavy metals in water. The thesis begins by reviewing the current state-of-the-art heavy metal sensing methods, highlighting their limitations and the requirement for sample preconcentration. Various preconcentration techniques are discussed, emphasizing their performance parameters and advancements in trace-level detection. Furthermore, the thesis identifies the gaps in current technology, particularly in the context of developing a reliable and user-friendly method for testing heavy metal concentrations in drinking and surface waters. The primary objective of this thesis is to develop a preconcentration-based colorimetric method for detecting heavy metals in water. This method aims to overcome the limitations of existing techniques by offering high sensitivity and a limit of detection below regulatory ranges without the need for complex equipment or extensive sample preparation. The thesis contributes to the advancement of the state-of-the-art by providing a simplified, portable, and efficient solution for in-line detection of heavy metal contamination in water resources. This has been achieved through the design and deployment of sensor utilizing a novel architecture, measuring heavy metal ions down to the sub ppb level. we were able to detect ions such as copper and Lead at concentrations below 0.5 ppb with a limit of detection (LOD) of 0.14 ppb. Overall, this thesis combines knowledge from the fields of analytical chemistry, sensor technology, and environmental science to address the pressing need for a practical and accessible method for monitoring heavy metal concentrations in water. By achieving this goal, the research will contribute to safeguarding public health and promoting sustainable water resource management. / Thesis / Doctor of Philosophy (PhD) / Heavy metals can be found naturally and are needed in small amounts for our bodies to function properly. However, many heavy metals are toxic and can cause serious health problems even at very low concentrations. These metals can contaminate water sources through activities like mining and improper waste disposal. Currently, detecting heavy metals in water requires expensive equipment and skilled experts in a laboratory setting. This process is time-consuming and not easily portable for on-site testing. The existing methods also have limitations such as low sensitivity or the need for complex procedures. This thesis aims to improve the way we detect harmful heavy metals in water. The goal of this thesis is to develop a simpler and more sensitive method for detecting heavy metals in water. The focus is on using color-changing dyes that react to the presence of heavy metal ions. However, these dyes often have detection limits higher than what is considered safe, so the thesis also explores ways to concentrate the samples to improve sensitivity. By addressing these challenges, the thesis aims to contribute to the development of a reliable and easy-to-use method for testing heavy metal concentrations in drinking and surface waters, helping to protect public health and identify potential sources of contamination.

Due to the similar nature 3D synthetics share with in vivo cell conditions, peptide-based hydrogels pose an attractive strategy for the culturing of stem cells. One aspect of this unique cell culturing technique is the tunability of the hydrogel’s stiffness, a quality linked to stem cell differentiation. Due to this linkage, a methodology in which specific cell lineages are achieved within IIFK hydrogel cultures is proposed. This work provides an analysis for the peptide scaffold IIFK; it characterizes the effect between different peptide and PBS concentrations over the resulting hydrogel stiffness and develops a mathematical model to further elucidate this interaction. Nine different hydrogel formulations were made (with a minimum of eleven replicates each) and each of its replicate’s stiffness (storage modulus, Pa) was measured through rheological experiments. Then, two different methods of replicate selection were conducted and various models were derived, each using either of the two replicate selection methods and incorporating a specific number of replicates in their creation. Regardless of sample selection and replicate number, the generated models show extremely high significances between IIFK hydrogel stiffness and PBS concentrations over the resulting hydrogel stiffness. Data analysis shows that for IIFK, the hydrogel stiffness bears a strong behavior that can be modeled by a full quadratic equation. However, the data also shows that the dependency of the model is strongly correlated with the datasets chosen to produce it, with number of replicates and replicate values both resulting in differences in each model’s predictive reliability (e.g., 82% vs 91%). Therefore, while this thesis demonstrates the ability to model IIFK hydrogel behaviour with high predictability ratings, it also establishes the necessity of both producing more replicates as well as selecting the best values for IIFK-based hydrogel modelling.

The challenge of demolding during the cast molding process of silicone hydrogel contact lenses can be addressed with the application of hydrophobic coatings on the surface of lens mold. In particular, the adhesion between silicone hydrogel and silicate substrates was minimized by applying silane modification on the surface of silicate substrates. Peel tests were conducted to measure the adhesive strengths between silicone hydrogel and surface modified glass substrates. Water contact angle measurement and X-ray photoelectron spectroscopy (XPS) were utilized to characterize the surface properties of silane treated glass substrates.Silicone hydrogel was obtained by curing macromer mixture under UV for 6 minutes, with UV intensity of 95.0 mW/cm2. The obtained silicone hydrogel had a modulus of 0.87±0.09 MPa, within the same range of commercial contact lenses. And the hydrogel with a UV curing time of 6 minutes was unable to be peeled off from clean glass substrates. The effects of silane type and concentration on coating effectiveness were investigated and the most effective types of silane were found to be triethoxyphenylsilane (TEPhS) and octyltriethoxysilane (OTES), with an optimal concentration of 5 wt%. The peel strength between silicone hydrogel and silicate substrates was reduced to below 15.5 N/m with the application of TEPhS and OTES coatings. However, these silane coatings were not durable enough. Silane coupling agents need to be reapplied before each curing process of silicone hydrogel. / Thesis / Master of Applied Science (MASc)

京都大学 / 新制・課程博士 / 博士(工学) / 甲第24234号 / 工博第5062号 / 新制||工||1790(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 大塚 浩二, 教授 沼田 圭司, 教授 大内 誠 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

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<p dir="ltr">In the past decade, magnetic microrobots have gain lots of attention because of their potentials in biomedical applications, such as cell/tissue manipulation, biopsy, and drug delivery. Recent development on materials and microfabrication techniques also provide more opportunities for microrobots. Especially, the emergence of smart polymers that are responsive to environments like hydrogels has given microrobots an additional degree-of-freedom. In the meantime, the two-photon polymerization (TPP) microscale 3D printing technique has enable fabrication process that cannot be achieved easily by traditional microfabrication techniques. In general, the goal of the research presented in this dissertation is to use both hydrogels and TPP to realize novel microrobots with multiple advanced functionalities, including adaptive locomotion and micromanipulation, and modular microrobots capable of changing end-effectors for different modes of micromanipulation to facilitate the development of the field. </p><p dir="ltr">This dissertation can be divided into four main parts: (i) a proof-of-concept study on adaptive helical microrobots with finite element analysis (FEA) and dynamic calculation, (ii) material calibrations and property testing, (iii) a helical adaptive multi-material microrobot (HAMMR), and (iv) a modular microrobot achieved by a responsive mating component. A environment-responsive hydrogel is adopted here to realize the adaptive locomotion for helical microrobot and the responsive mating component for the modular microrobot. All microrobots fabricated in this dissertation are achieved by the combination of TPP and traditional photolithography techniques. </p><p dir="ltr">In part (i), FEA is applied with classic parameters for a proof-of-concept study of helical microrobot made of the classic hydrogel upon the stimulation of temperature. At different temperature, the hydrogel is going to deform and therefore the microrobot. Based on the geometrical parameters predicted by FEA before and after stimulations, dynamic calculations are then applied to predict the change of swimming performance accordingly. In part (ii), material calibrations have been done in order to realize a homogeneous material for testing (for oil-immersion mode). However, due to the limitation of the custom-built testing system, a different approach (dip-in mode) is adopted and the material properties are successfully obtained. In part (iii), two generations of HAMMRs are investigated. The first generation of HAMMR is prepared by the oil-immersion mode which shows a record-breaking swimmering velocity with the capability of adaptive locomotion. The second generation is obtained by the dip-in mode which provides the opportunities for combining FEA, dynamic calculation, and experiment to realize a comprehensive studied for such microrobot. Moveover, advances have been made to the microrobot with a functional end-effector for micromanipulation tasks. In part (iv), a modular microrobot is proposed and realized by the introduction of a responsive mating component. The responsive mating component provides a locking mechanism between different modules of the microrobot. The microrobot is able to change its end-effector to perform different types of tasks. </p><p dir="ltr">By using TPP to pattern microscale hydrogel structures, microrobots are able to be implemented with advanced functional structures. The helical microrobots capable of adaptive locomotion and micromanipulation, and the modular microrobot that can switch end-effectors for different applications are advances toward the next generation of microrobots. Moreover, a standardized method is proposed for adaptive helical microrobots towards future biomedical applications. Both the proposed helical microrobot and the modular microrobot show great potential for future application and we believe the development of these microrobots will facilitate the development of the field of microrobot.</p>