According to estimates, more than 40% of all new chemical entities developed in pharmaceutical industry are practically insoluble in water. Naturally, the demand for excipients which increase the water solubility and thus, the bioavailability of such hydrophobic drugs is enormous. Poly(2-oxazoline)s (POx) are currently intensively discussed as highly versatile class of biomaterials. Although selected POx based micellar drug formulations exhibit extraordinarily high drug loadings > 50 wt.% enabling high anti-tumor efficacies in vivo, the formulation of other hydrophobic compounds has failed. This casts doubt on the general understanding in which a hydrophobic active pharmaceutical ingredient is dissolved rather unspecifically in the hydrophobic core of the micelles following the fundamental concept of “like dissolves like”. Therefore, a closer look at the interactions between all components within a formulation becomes increasingly important. To do so, a large vehicle platform was synthesized, loaded with various hydrophobic drugs of different structure, and the formulations subsequently characterized with conventional and less conventional techniques. The obtained in-depth insights helped to develop a more thorough understanding about the interaction of polymer and incorporated API finally revealing morphologies deviating from a classical core/shell structure. During these studies, the scarcely investigated polymer class of poly(2-oxazine)s (POzi) was found as promising drug-delivery vehicle for hydrophobic drugs. Apart from this fundamental research, the anti-tumor efficacy of the two APIs curcumin and atorvastatin has been studied in more detail. To increase the scope of POx and POzi based formulations designed for intravenous administration, a curcumin loaded hydrogel was developed as injectable drug-depot. / Schätzungen zufolge sind mehr als 40% aller „new chemical entities“, welche in der pharmazeutischen Industrie entwickelt werden, wasserunlöslich. Aus diesem Grund ist der Bedarf an Zusatzstoffen, welche die Wasserlöslichkeit und dadurch die Bioverfügbarkeit erhöhen, enorm. Poly(2-oxazolin)e (POx) werden derzeitig intensiv als vielseitig einsetzbare Biomaterialien untersucht. Obwohl bestimmte POx basierte, mizellare Wirkstoffformulierungen außergewöhnlich hohe Beladungskapazitäten > 50 Gew.% aufwiesen und dadurch ausgeprägte anti-Tumor Effektivität in vivo ermöglichten, schlug die Formulierung anderer hydrophober Stoffe fehl. Dies lässt Zweifel an dem altbewährten Konzept aufkommen, in welchem hydrophobe Arzneistoffe mehr oder weniger unspezifisch im hydrophoben Kern einer Mizelle gelöst werden. Aus diesem Grund ist ein genauerer Blick auf die Interaktionen zwischen allen Bestandteilen einer Formulierung vonnöten. Deshalb wurde eine große Polymerplattform synthetisiert, mit verschiedenen hydrophoben Wirkstoffen unterschiedlicher Struktur beladen und die Formulierungen im Anschluss mit herkömmlichen und weniger herkömmlichen Methoden charakterisiert. Die daraus erhaltenen Einblicke ermöglichten es ein umfassenderes Verständnis über die Interaktionen von Polymer und Wirkstoff zu entwickeln. Innerhalb dieser Studien wurden Aggregate charakterisiert, welche von einer klassischen Kern/Schale Morphologie abwichen. Des Weiteren konnte die kaum erforschte Polymerklasse der Poly(2-oxazin)e (POzi) als vielversprechende Wirkstoffträgerplattform für hydrophobe Wirkstoffe charakterisiert werden. Von dieser Grundlagenforschung abgesehen, wurde die anti-Tumor Effektivität von Curcumin und Atorvastatin Nanoformulierungen untersucht. Um den Anwendungsbereich der POx und POzi basierten Wirkstoffformulierungen, welche für intravenöse Verabreichung entwickelt wurden, zu erweitern, wurde ein Curcumin beladenes Hydrogel als injizierbares Wirkstoffdepot entwickelt.

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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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