Parmi les bio-polymères issus des ressources renouvelables, les polysaccharides fournissent une alternative intéressante aux polymères de synthèse. Dans ce contexte, l’objectif de ce travail de thèse est basé sur la conception des copolymères amphiphiles pour la préparation de nouveaux biomatériaux. Ainsi, l’hydroxypropylméthylcellulose (HPMC) a été étudiée en raison de ses propriétés remarquables, dont la biocompatibilité, la biodégradabilité, la rétention d'eau et la gélification thermoréversible. Ces propriétés sont utiles pour de nombreuses applications telles que le relargage de médicament, la préparation des membranes et la formation de biomatériaux. L'hydrolyse enzymatique avec des endo cellulases issues de Trichoderma reesei a été étudiée pour produire des fragments d'HPMC ayant une masse molaire (Mw) entre 6000 et 30000 g mol-1. Les paramètres de l’activité enzymatique ont été étudiés en fonction de : la nature de substrat, le temps de réaction et la concentration de l'enzyme. Les polymères obtenus ont été comparés à ceux produits par hydrolyse acide. Il a été constaté que la structure des polymères issus d’un procédé d’hydrolyse, varie en termes de degré de substitution pour un même Mw. Cet effet donne lieu à différentes propriétés de gélification thermoréversible. Des copolymères amphiphiles tels que HPMC-b-poly (propylène glycol) et HPMC-b-PLA ont été préparés par amination réductrice et par couplage click thiol-ene, respectivement. Les propriétés d’agrégation ont été caractérisées par la diffusion de la lumière (DLS), le microscope électronique en transmission (TEM) et par la séparation de phase obtenue par la mesure du point de trouble. / Following the concept of bio-refinery, we propose to produce small fragments of biopolymers that can be used further as building blocks to prepare novel polymeric architectures. In the case of polysaccharides, enzymatic hydrolysis enables to form reducing end groups after each cleavage on the polymer chain. Reaction by reductive amination affords the possibility to introduce polysaccharides fragments in a large variety of materials going from amphiphilic copolymers to more sophisticated devices. Hydroxypropyl methylcellulose (HPMC) was used in this work because of its remarkable properties including biocompatibility, biodegradability, water retention and thermoreversible gelation beneficial for many applications such as drug delivery, film and biomaterial formation. Enzymatic hydrolysis using endo cellulases from Trichoderma reesei was investigated to produce a library of HPMC fragments with molecular weight (Mw) from 6000 to 30000 g mol-1. Mw control was carried out by varying the procedure conditions including the nature of starting HPMC, reaction time and enzyme concentration. The obtained polymers were compared to those produced by acidic hydrolysis.According to the preparation conditions, the structure of short chain polymers regarding substitution degrees varied for the same Mw giving rise to different clouding temperature and thermoreversible gelation properties. Amphiphilic block copolymers HPMC-b-poly(propylene glycol) and HPMC-b-PLA were prepared by reductive amination and by the thiol-ene click reaction, respectively. Self-assembly properties of these novel block copolymer were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and clouding point temperature.

The chemical properties of calcium phosphate cements (CPCs) are very similar to the mineral phase of bone. CPCs are, consequently, very effective substrates (scaffolds) for tissue engineering; bone and stem cells attach readily, and can proliferate and differentiate to form new bone tissue. Unlike other CPCs that may remain largely unchanged in the body for years, such as hydroxyapatite, dicalcium phosphates are remodelled by the body and rapidly converted to new bone. Unfortunately, the dicalcium phosphates are also typically too weak to support load bearing in the human body. Our laboratory has recently developed a novel, high strength brushite CPC, (hsCPC), which can reach 10-50 fold higher failure strength than many commercially available CPCs. The aim of this thesis was to investigate the physical, chemical and biological performance of hsCPCs in physiologically relevant model of drug release, load bearing, osteoconductivity, and as a scaffold for bone tissue engineering. Multiple CPCs were compared in a model of screw augmentation to determine whether the physical properties of the cement, such as bulk strength and porosity, affected orthopedic screw holding strength. In an in vitro model of bone regeneration stem cells were grown on macroporous scaffolds that were fabricated from hsCPC. Drug releasing scaffolds were fabricated to examine whether the low porosity of hsCPC impeded drug release during a 4 week incubation period. The biological activity of an incorporated drug, Rebamipide, was examined after acute and chronic incubation periods. In the drug release study it was noted that the biological response to hsCPC was significantly better than tissue culture grade polystyrene, even in groups without drug. The mechanism underlying this biological response was further investigated by testing the effect of pyrophosphate, a common cement additive, on bone cell proliferation and differentiation. This thesis concludes that a high strength cement can produce significant improvement in screw augmentation strength, if there is sufficient cortical bone near the augmentation site. The hsCPC is also cytocompatible, and can support bone and stem cell proliferation and differentiation. hsCPC scaffolds stimulated osteogenic gene expression comparable to native bone scaffolds. hsCPC scaffolds are also capable of delivering drug for up to 4 weeks, in vitro. Finally, a cement additive, pyrophosphate, stimulated differentiation, but not proliferation of bone cells.

Dans une logique d’éco-conception et de développement durable, de nombreux travaux ont pour objectif l’étude de polymères biosourcés. Parmi les recherches menées à ce jour, une piste d’étude consiste à les structurer aux échelles micro et nanoscopiques tout en valorisant certaines de leurs propriétés spécifiques, l’objectif étant la création de matériaux à propriétés fonctionnelles originales et performantes. Dans ce contexte, une attention particulière a été portée sur l’utilisation du dioxyde de carbone supercritique (CO2-sc). En effet, sa capacité à se solubiliser en grande quantité dans de nombreux polymères et donc d’en modifier les propriétés (viscosité, tension interfaciale, …) peut permettre une amélioration des matériaux composites fabriqués. Ce projet s’intéresse plus particulièrement à l’élaboration d’assemblages de biopolymères nanostructurés et revêt deux enjeux principaux : (1) la synthèse de nanoparticules de biopolymères (dans notre cas, du chitosane), (2) l’élaboration d’assemblages de biopolymères nanostructurés. La première étape a consisté à concevoir et développer de nouveaux procédés de génération de nanoparticules de chitosane par des procédés utilisant le CO2-sc soit comme antisolvant soit comme agent de dissolution et d'atomisation. Pour la deuxième étape, des films composites à base de poly (acide lactique) PLA et de poly (hydroxybutyrate-co-valérate) PHBV ont été préparés par la voie hot-melt par extrusion bi-vis. Des analyses thermiques, moléculaires et structurales, morphologiques et de granulométrie ont permis de caractériser les films biocomposites ainsi produits. / In a logic of eco-design and sustainable development, many works aim to study the bio-sourced polymers. Among these studies, a promising concept consists in structuring materials at micro and nanoscales while enhancing some of their properties, the objective being the creation of original materials with improved functional properties and performance. In this context, particular attention has been paid to the use of supercritical carbon dioxide (sc-CO2). Its ability to dissolve into many polymers in large quantities and thus to change their properties (viscosity, interfacial tension, ...), can improve both the composite material and its manufacturing process. This project focuses on the development of nanostructured biopolymers and addresses two main issues: (1) the synthesis of biopolymer nanoparticles (in this case, chitosan), and (2) the development of nanostructured biopolymers. The first step consisted in designing and developing new processing methods to generate biopolymer nanoparticles, using sc-CO2 as antisolvent agent or as dissolving and atomizing agent. For the second step, poly (lactic acid) PLA and poly (hydroxybutyric-co-hydroxyvaleric acid) PHBV based composite films were prepared by a hot-melt process by twin-screw extrusion of the nanoparticles and the matrix. Thermal, molecular and structural analysis, as well as morphological and particle size distribution studies allowed a good characterization of the biocomposite films.

<p>Type 1 Diabetes Mellitus (T1D), a chronic disease affecting over 1.5 million Americans, is characterized by the autoimmune destruction of insulin-producing β-cells within pancreatic islets. Islet/β-cell replacement therapies, where replenishable β-cell sources are implanted within protective microenvironments, have the potential to provide a long-term solution for individuals with T1D by restoring glucose-sensitive, insulin release and overall glycemic control. However, most conventional encapsulation materials elicit an immune reaction, known as a foreign body response (FBR), which compromises β-cell health and function. In this dissertation, we designed and evaluated various formulations of a polymerizable collagen, namely type I oligomeric collagen (Oligomer), as encapsulation materials for minimally invasive, subcutaneous delivery of replacement β-cells. Preclinical validation in chemically-induced diabetic mice demonstrated rapid (within 24 hours) reversal of diabetes for beyond 90 days with no signs of rejection or FBR after subcutaneous delivery of both allogeneic and xenogeneic (rat) islets. To further define this uncommon mechanism of protection, the tissue response to Oligomer, in comparison to commercial synthetic and collagen-based materials, was evaluated following subcutaneous implantation within rats, a well-established biocompatibility model. Histological and transcriptomics analyses were used to define the immune response at both cellular and molecular levels. Interestingly, Oligomer showed minimal and transient activation of innate immune cells similar to the sham surgical control, with no evidence of foreign body giant cell formation, inflammatory-mediated bioresorption, or fibrosis. Overall, this work evaluates preclinical efficacy and demonstrates mechanistic understanding of immune tolerance for Oligomer materials for β-cell replacement therapy and other regenerative medicine applications.</p>

Bioprinting is one of the most promising technologies for future healthcare as it may benefit the repairing of wounds and injuries, disease modeling and development, transplantation of organs and reduce animal testing. This thesis aim to investigate this industry further, as there is no excessive literature on how to handle the innovation in regards to entrepreneurial and biotechnological knowledge. Hence, a research gap can be spotted and the purpose of the conducted research questions should contribute to this gap. In order to fully understand the bioprinting industry, an outline of the technology is made as part of the research. In addition to this, secondary data for patents, market valuation and annual growth rates are collected to support arguments from previous literature. Also, interviews are conducted to gather specific knowledge. As a result, bioprinting may be presented as a disruptive innovation in an uncertain market, which places certain demands on companies to act more in line with the complexity of the technology. Such companies must think more strategically and design more complex and long-term strategies. The patent data shows that there has been a decline in the technological development as patent applications have decreased significantly. Even though the technology (regarding the patents) has started to slowly decline, there is still hope for some technological improvements to come. It can be concluded that developments in bioink, scaffolds, expansion of cells and diffusion is expected, and that the use of bioprinting is increasing and will most likely continue to do so.

No description available.

Mycelium-based composite (MBC) is being developed and researched in multiple commercial markets as an alternative sustainable material. MBC utilizes the mycelium ability to create a web-like structure in lignocellulosic structures. However, producing the material in a natural environment and subjecting it to various tests; the study aims to examine the distress of the southern Swedish climate on MBC grown in different substrates. The selection of substrates are based on their compatibility to fungal growth, the substrates are also locally sourced and grown. This is to explore MBC material production with a focus on circular economy as biodegradable material in architecture could help develop a reuse and recycle system. Various tests were done on the different substrate MBC to determine its characteristics, limitations and opportunities. The tests were developed with a focus on architectural construction and the southern Swedish climate; meaning experiments including MBC reaction to fire, water and temperatures. The results are based on the different MBC materials reaction, this ends with a description on how the materials could be used and developed in the future.

手術後の呼吸器からの空気漏出（エアリーク）と腹部及び胸部癒着はそれぞれ、未だに臨床にて大きな課題である。本研究では、安全性に優れた植物性多糖類のアルギン酸ナトリウムに着目し、ゲルやスポンジの材形に加工した。これをPGA不織布と併用して新規エアリーク防止材を開発した。この新規材料は、エアリーク防止だけでなく癒着防止に対しても優れた効果を発揮した。将来的に、この新規材料は、従来材料よりも優れた医療材料として臨床応用されることが期待できると考えられる。 / Sodium alginate is polysaccharide extracted from seaweed and used as a biomaterial clinically. The alginate in this study was used as gel- or sponge-formed and combined with a polyglycolic acid (PGA) mesh, a useful biomaterial clinically; namely this combination was the new sealing material. The purpose of this study was to prevent pulmonary air leak without inducing adhesion. This study was composed of the four animal experiments; the first half of them was about preventing air leak and the latter was about preventing adhesion. All experiments showed that new sealing material was superior to the conventional treatments. Therefore the new sealing material was expected to be applied clinically to a sealing material, which also has an anti-adhesive effect. / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University

Metallic biomaterials have an essential portion of uses in biomedical applications. Their properties can be tuned by many factors resulting in their process tuneability. Among metallic biomaterials for biomedical and specifically orthopedic applications, titanium and its alloys exhibit the most suitable characteristics as compared to stainless steels and Co-Cr alloys because of their high biocompatibility, specific strength (strength to density ratio), and corrosion resistance. According to their phase constitution, Ti-alloys are classified into three main groups, namely alpha, beta, and alpha+beta alloys. Depending on the degree of alloying and thermomechanical processing path, it is possible to tune the balance of α and β phases, which permits to tailor properties like strength, toughness, and fatigue resistance. (alpha+beta) Ti alloys, especially Ti-6Al-4V, are widely used alloys in biomedical applications; however, they have some drawbacks like the presence of toxic elements i.e., V and relatively high elastic modulus to that of bones. In view of the lower elastic modulus of body center cubic beta phase (50GPa&lt;100GPa) compared to the alpha+beta, as well as due to their good mechanical properties, excellent corrosion resistance, and biocompatibility, beta-Ti alloys have been recently proposed as a valid alternative to alpha+beta ones. The growing interest in additive manufacturing (AM) techniques opens new and very interesting perspectives to the production of biomedical prosthetic implants. AM will prospectively allow implant customization to the patient and produce it on demand, with large savings on times and costs. Moreover, AM is gaining increasing interest due to the possibility of producing orthopedic implants with functionally graded open-cell porous metals. The main advantages of porous materials are the reduction of the elastic modulus mismatch between bone and implant alloy reducing the stress shielding effect and improving implant morphology providing biological anchorage for tissue in-growth. In this scenario, the first goal of the present PhD thesis work was to identify a high-performance β-Ti alloy formulation suitable to Laser-Powder Bed Fusion (L-PBF) additive manufacturing. In particular, it explores the potential use of a β-metastable Ti alloy, namely Ti-15Mo-2.7Nb-3Al-0.2Si (Beta Ti21S, 21 wt.% of alloying additions, including Silicon) for biomedical applications. Through microstructural, mechanical, and cytotoxicity analyses, it could be shown that this alloy grade exhibits i) an unprecedented ultra-low elastic modulus, ii) improved cytocompatibility due to the lack of Vanadium, and iii) no martensitic transformation responsible for hard and brittle solidification structures. A second goal was to assess the manufacturability of metamaterials made of β-Ti21S via L-PBF. For this purpose, cubic cellular lattice structures of different unit cell sizes (and therefore different strut thickness) have been fabricated and characterized through microstructural analysis using different techniques, and computed tomography combined with linear elastic finite element simulations to identify the minimum cell size that can be printed with adequate dimensional and geometrical accuracy. Samples of the selected unit cell size were also tested to determine their static and fatigue properties. The main results show that i) the suitable manufacturing quality is obtained for strut thickness above 0.5 mm, ii) the mechanical tests place the present cellular structures among the best stretching dominated cellular lattice materials investigated to date in the literature, and iii) the fatigue tests showed a normalized fatigue strength at 107 cycles of close to 0.8, similar to cubic lattices made of Ti-6Al-4V, and higher than most cellular structures in the literature. In the last part of the thesis, a more complex octet truss structure was fabricated in the manufacturable cell size, and its mechanical properties were investigated. The octet truss topology can be beneficial both in terms of mechanical properties and biocompatibility by providing the different types of porosity suitable for bone in-growth.

No description available.