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京都大学 / 新制・課程博士 / 博士(工学) / 甲第24647号 / 工博第5153号 / 新制||工||1984(附属図書館) / 京都大学大学院工学研究科化学工学専攻 / (主査)教授 大嶋 正裕, 教授 佐野 紀彰, 教授 山本 量一 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

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The occurrence of plastic impaction in ruminants is a growing concern. As indiscriminate feeders, cattle may consume plastic foreign materials incorporated into their diets and it is currently estimated that 20% of cattle contain plastic foreign materials in their rumen. These materials are indigestible and accumulate for the lifetime of the animal. As these materials accumulate, they may reduce feed efficiency and production by erosion and ulceration of rumen epithelium, stunting of papillae, blockage of the reticulo-omasal orifice, and leaching of toxic heavy metals. It is necessary to reduce the incidences of plastic impaction in domestic ruminants. Using polyhydroxyalkanoate (PHA) and poly(butylene succinate-co-adipate) (PBSA) biodegradable materials for feed storage products such as bale netting could reduce the incidences and effects of polyethylene-based plastic impaction in ruminants. The objectives of these studies were to evaluate the degradability of PHA and PBSA materials in the reticulorumen via in vitro, in situ, and in vivo methods. Our hypothesis was that these materials would degrade in the rumen and that a melt-blend of PHA and PBSA may degrade faster than its individual components. An in vitro study incubated a proprietary PHA-based polymer, PBSA, and PBSA:PHA melt blend nurdles, and forage controls in rumen fluid for up to 240h in DaisyII Incubators. Mass loss was measured, and digestion kinetic parameters were estimated. Thermogravimetric and differential scanning calorimetry analyses were conducted on incubated samples. Results indicated that the first stage of degradation occurs within 24h and PHA degrades slowly. Degradation kinetics demonstrated that polymer treatments were still in the exponential degradation phase at 240h with a maximum disappearance rate of 0.0031%/h, and mass loss was less than 2% for all polymers. Melting temperature increased and onset thermal degradation temperature decreased with incubation time, indicating structural changes to the polymers starting at 24h. Further in situ degradation, however, indicated these biodegradable materials degrade at more accelerated rates in the rumen. Polyhydroxyalkanote, PBSA, PBSA:PHA blend, and low-density polyethylene (LDPE) films were incubated in the rumens of three cannulated, non-lactating Holsteins for 0, 1, 14, 30, 60, 90, 120, and 150d. In situ disappearance (ISD) and residue length were assessed after every incubation time. Polyhydroxyalkanoate achieved 100% degradation by 30d, with initiation occurring at 14d indicated by ISD and a reduction in residue length. The fractional rate of disappearance of PHA was 7.84%/d. Poly(butylene succinate-co¬-adipate) and Blend did not achieve any significant ISD, yet fragmentation of PBSA occurred at 60d and the blend at just 1d likely due to abiotic hydrolysis. Low-density polyethylene achieved no ISD and residue length did not change over incubation time. From these results, we proposed a PBSA:PHA blend is a valid alternative to polyethylene single-use agricultural plastic products based on its fragmentation within 1d of incubation. Administration of PBSA:PHA film boluses compared to LDPE films and a control further supported this dissemination. Holstein bull calves (n = 12, 62 ± 9d, 74.9 ± 8.0kg) were randomly allocated to one of three daily bolus treatments: 13.6g of PBSA:PHA in 4 gelatin capsules (Blend), 13.6g of LDPE in 4 gelatin capsules (LDPE), or 4 empty gelatin capsules (Control) for 30d. Hemograms were conducted on blood samples collected on d0 and d30. On d31, animals were sacrificed to evaluate gross rumen measurements and pathology, determine papillae length, and characterize polymer residues present in rumen contents. Feed intake, body weight, body temperature, and general health were determined throughout the study. No animals presented any symptoms related to plastic impaction and animal health was not particularly affected by treatment. Daily grain and hay intake, body weight, rectal temperature, hematological parameters, gross rumen measurements and pathology, and rumen pH and temperature were not affected by treatment. There was evidence that degradation of PBSA:PHA may release byproducts that support rumen functionality. Methylene blue reduction time of Blend calves tended to be decreased by 30% compared to LDPE calves, and caudal ventral papillae length of Blend calves were 50% longer than those of Control animals. Though studies are needed to specifically elucidate the production of byproducts due to degradation of PBSA:PHA and their correlations. Polymer accumulation and residue length differed among treatments. Calves dosed with LDPE retained 6.7% of the dosed polymer, undegraded, while Blend calves retained 0.4% of the dosed polymer. The polymer residues in Blend calves were 10% of their original size. Single-use agricultural plastics developed from PBSA:PHA may be a suitable alternative to LDPE-based products in the case of ingestion in ruminants due to no acute health inflictions, fragmentation of polymers with 1d, and improved clearance from the reticulorumen. As such, utilization of these materials may reduce the incidences of plastic impaction in ruminants in commercial operations. Further long-term feeding studies are needed to evaluate specific byproduct production of PBSA:PHA and their potential influences on rumen function and animal health and production in normal commercial conditions. / Master of Science in Life Sciences / Plastic feed-storage materials may unintentionally be incorporated into animal feeds. Net wraps and bale twines may be stuck or left on forages when they are ground and incorporated into mixed rations. As cattle are largely non-selective, they may inadvertently consume these plastic materials. Approximately 20% of cattle contain plastic foreign materials in their rumen. These materials are indigestible and accumulate for the animal's lifetime. As plastics build up in the rumen, they may reduce feed efficiency, body weight, and milk production by damaging the rumen lining, blocking the digestive tract, and leaching toxic heavy metals. Therefore, it is necessary to reduce the incidences of plastic impaction in domestic ruminants to improve their health and productivity. Using biodegradable materials that degrade by bacteria, such as polyhydroxyalkanoate (PHA) and poly(butylene succinate-co-adipate) (PBSA), for feed storage products could reduce the occurrence and effects of plastic impaction in ruminants due to the materials' potential degradation in and passage from the rumen. The objectives of these studies were to evaluate the breakdown of PHA and PBSA materials in the rumen. Our hypothesis was that these biodegradable materials would degrade in the rumen and that a blend of PHA and PBSA may degrade faster than its individual components. In our first study, PHA, PBSA, a PBSA:PHA blend, and forage controls were incubated in rumen fluid for up to 240h. Mass loss, degradation rate, and the structure of polymers were determined over incubation time. Results indicated that biodegradable polymers may begin to break down within 24h. Polymer treatments were still in the early stages of degradation at 240h with a maximum degradation rate of 0.0031%/h, and mass loss of polymers was less than 2%. However, within 24h, the structures of polymers may have altered to promote future degradation at longer incubation times. Accelerated degradation was observed when PHA, PBSA, PBSA:PHA (Blend), and polyethylene (LDPE) films were incubated in the rumens of three Holstein cows up to 150d. Mass loss and the length of the remaining polymers were assessed monthly. Polyhydroxyalkanoate began to degrade by 14d and completely degraded by 30d with a disappearance rate of 7.84%/d. The remaining polymer did not achieve any mass loss. However, PBSA and Blend residue size began to decrease by 60d and 1d, respectively. Based on Blend's structural degradation within 1d of incubation that may promote its clearance from the rumen if ingested, we proposed that the material may be an alternative to polyethylene single-use agricultural plastic products. When Blend films were fed to calves, breakdown of the material further supported our dissemination that PBSA:PHA may be a suitable alternative to LDPE in the case of animal ingestion. Holstein bull calves (n = 12, 62 ± 9d, 74.9 ± 8.0kg) were randomly allotted to one of three daily bolus treatments: 13.6g of PBSA:PHA (Blend), 13.6g of polyethylene (LDPE), or no polymer (Control) distributed over 4 gelatin capsules for 30d. Feed intake, body weight, body temperature, and general health were determined throughout the study. Blood analyses were conducted on blood samples collected before and after the experimental period. On d31, animals were sacrificed to evaluate rumen growth and health, measure rumen papillae length, and describe polymers that may reside in the rumen. No animals presented any signs related to plastic impaction and animal health was not particularly affected by treatment. Daily grain and hay intake, body weight, rectal temperature, blood parameters, and rumen growth and health were not affected by treatment. There was evidence that degradation of Blend may support rumen function. Methylene blue reduction time of Blend calves tended to be decreased by 30% compared to LDPE calves, which indicates the rumen microbiome of Blend calves may better ferment feeds. Papillae length of Blend calves were also 50% longer than those of Control animals, which would improve the absorption of nutrients. Byproduct formation from Blend degradation could explain this; however, studies are needed to specifically elucidate the production of byproducts and their relationship to rumen function. Polymer accumulation and residue length differed among treatments. Calves dosed with LDPE retained 6.7% of the dosed polymer, undegraded, while Blend calves retained 0.4% of the dosed polymer. The polymer residues in Blend calves were 10% of their original size. Single-use agricultural plastics developed from PBSA:PHA may be a suitable alternative to polyethylene-based products in the case of ingestion in ruminants due to no short-term health inflictions, the reduced polymer size within 1d, and improved clearance from the rumen. As such, utilization of these materials may reduce the incidences of plastic impaction in ruminants in commercial operations. Further long-term feeding studies are needed to evaluate specific byproduct production of PBSA:PHA and their potential influences on rumen function and animal health and production in normal commercial conditions.

Osteomyelitis is an infection of bone or bone marrow, usually caused by pyogenic bacteria. It can cultivate by hematogen way or it can cultivate by the help of local soft tissue infection. Osteomyelitis often requires prolonged antibiotic therapy and surgery. But for therapy / antibiotic must reach to effective dose in the bone. So that / for prevention and treatment of osteomyelitis controlled antibiotic release systems can be used. These systems have been developed to deliver antibiotics directly to infected tissue. As a carrier material / polymers are widely use. Polymer can be biodegradable or non biodegradable. The advantage of biodegradable polymers is / you do not need a second surgery for the removal of the carrier material from the body. In this study / vancomycin loaded PLLA/TCP composites were developed and characterized to treat implant related chronic osteomyelitis in experimental rat osteomyelitis model. Some of the composites were prepared by coating the vancomycin loaded composites with PLLA to observe the difference between the coated and uncoated composites. Also, some composites were developed free from the vancomycin to determine the biocompatibility of the composite for the bone tissue. The coating extended the release of the vancomycin up to 5 weeks and changed the surface morphology of the composites. According to the cell culture studies, vancomycin loaded PLLA/TCP composites promoted cell adhesion, cell proliferation and mineralization so / the composite was biocompatible with bone tissue. Radiological and microbiological evaluations showed that vancomycin loaded and coated vancomycin loaded PLLA/TCP composites inhibited MRSA proliferation and treat implant related chronic osteomyelitis.

L’absence de croissance en monocouche des cellules endothéliales sur la paroi des prothèses vasculaires est une des causes d’échec de leur implantation chez l’humain. Des études précédentes ont montré que le recouvrement de ces prothèses par un échafaudage de nanofibres d’acide polylactique (PLA), fabriqué par un système de filage par jet d’air innovant, peut être utilisé pour promouvoir la croissance des cellules endothéliales de façon adéquate. Ainsi, le caractère dégradable d’un matériau comme le PLA permettrait son remplacement graduel par la matrice extra-cellulaire produite par les cellules. D’autre part, la réussite d’une transition entre les nanofibres dégradables et la matrice extra-cellulaire nécessite un remplacement contrôlé et approprié. Or, la dégradation des nanofibres de PLA, dépendant de ses séquences stéréochimiques, est généralement trop longue et peut induire une cytotoxicité relative pendant sa dégradation. Dans ce contexte, les études de cette thèse ont pour objectifs de mieux comprendre la formation des fibres lors du filage, d’optimiser la fabrication des échafaudages permettant ainsi la création de nanofibres d’autres polymères, puis, de concevoir des nanofibres provenant d’un polymère mieux adapté à nos besoins, d’évaluer leur mécanisme de dégradation et sa cytotoxicité durant sa dégradation. Les travaux d’optimisation du système de filage ont démontré que la concentration avec un effet prépondérant. Ainsi, la mesure de la viscosité permet de trouver les paramètres adéquats pour le filage de polymère. Ensuite, un poly(L-lactide) semi-cristallin (PLLA) et un terpolymère de poly(lactide-co-ε-caprolactone) (PLCL) dédié pour des applications vasculaires ont été synthétisés et filés par jet d’air. Ces échantillons ont été dégradés en solution aqueuse et caractérisés par des méthodes physico-chimiques afin de mieux comprendre leurs mécanismes de dégradation et mis en présence de cellules endothéliales pour évaluer leur cytotoxicité. La comparaison entre les échafaudages des deux polymères a montré des comportements singuliers en dégradation, dépendants des caractéristiques thermiques des polymères. De plus, ces mécanismes de dégradation des nanofibres ont une influence directe sur la sensibilité des cellules endothéliales face aux produits de dégradation. En conclusion, ces travaux de doctorat présentent une solution prometteuse pour améliorer les prothèses vasculaires et qui pourrait être appliquée pour résoudre plusieurs problématiques en médecine régénératrice. / The absence of neo-endothelium on the intimal surface of vascular substitutes is known to be one cause of failure upon implantation of these prostheses in humans. Previous studies have shown that the coating of these substitutes with a nanofiber scaffold, made with an innovative air spinning device, can be used to promote a suitable endothelial cells growth. On one hand, the degradable feature of material as PLA enable the progressive replacement of the scaffold by the extracellular matrix of cells. On the other hand, the success of this replacement between degradable nanofibers and the extracellular matrix requires to be appropriate and controlled. Yet, the PLA nanofiber degradation process, which depends on its stereosequences, is generally too long for this application and could involve cell sensitivity during the degradation. In this context, studies from this thesis aim to understand the fibers formation during spinning, optimizing the scaffold fabrication as well as to promote the making of novel polymer scaffolds, then, design solution to polymeric nanofiber scaffolds for vascular application, evaluate its degradation mechanism and cytotoxicity during degradation process. The work on spinning device optimisation has demonstrated that the concentration had a dominant effect. Thus, viscosity measurements enable to find suitable parameters for polymer spinning. Then, a semi-cristalline poly(L-lactide) (PLLA) and a poly(lactide-co-ε-caprolactone) (PLCL) terpolymer specifically made for vascular application have been synthesized and air-spun. These samples were degraded in aqueous solution and characterized by physical and chemical methods to better understand their degradation mechanisms and seeded with endothelial cells to evaluate their cytotoxicity. The comparison between the two polymers scaffolds have shown surprising degradation behaviors depending on thermal properties of polymers. Moreover, these nanofiber degradation mechanisms have a direct influence on endothelial cells sensitivity with degradation by-products. To conclude, these works of doctorate display a promising solution to improve vascular prostheses and which could be applied to solve several issues in regenerative medicine field.

O alto nível de poluição gerado pelo descarte inadequado de materiais poliméricos vem motivando pesquisas por sistemas e técnicas ambientalmente corretos, tais como a aplicação de polímeros biodegradáveis e a substituição dos sistemas de pintura à base de solventes por aqueles com alto teor de sólidos, à base de água ou, praticamente isentos de compostos orgânicos voláteis (VOCs) e curáveis por radiação. Todavia, os revestimentos poliméricos curados são insolúveis e infusíveis, aumentando o grau de complexidade do seu reprocessamento, da sua reciclagem e da degradação desejável. Assim, este trabalho apresenta, como objeto de contribuição científica, a obtenção de tintas modificadas com agentes pró-degradantes, curadas por reações químicas induzidas por radiação ultravioleta ou feixe de elétrons (UV/EB), para impressão em embalagens plásticas, biodegradáveis ou não, para produtos de baixa vida útil. Foram estudadas combinações de seis revestimentos, sendo um verniz não pigmentado e cinco tintas nas cores amarela, azul, branca, preta e vermelha; três agentes pró-degradantes (estearatos de cobalto, cério e manganês), cinco substratos poliméricos (Ecobras®, polietileno de baixa densidade e suas respectivas modificações com os agentes pró-degradantes). Os revestimentos foram aplicados nos substratos e curados por radiação UV ou EB, resultando em 180 amostras. Estes materiais foram, então, expostos ao envelhecimento acelerado em câmara tipo QUV e à compostagem em ambiente natural. De modo a se compreender o efeito dos revestimentos poliméricos no processo de degradação das amostras, foram selecionadas aquelas com valores extremos de grau de conversão, a saber: amarela e preta, as quais foram expostas à compostagem em ambiente controlado via respirometria, reduzindo de 180 para 16 o número de amostras. O composto orgânico gerado pelo processo de biodegradação foi analisado por testes de ecotoxicidade. Foi observado que a camada de revestimento atua como barreira que inibe a degradação do plástico quando exposto às intempéries. Adicionalmente, constatou-se que quanto maior o grau de conversão das formulações pigmentadas pastosas em sólidas durante a cura por radiação ultravioleta, maior foi sua mineralização em ambiente de compostagem. As amostras curadas por EB apresentaram menor taxa de biodegradação do que as curadas por UV. Isso se deu em virtude da rede de ligações cruzadas entre as cadeias poliméticas, geradas na cura por EB. A adição dos agentes pró-degradantes promoveu uma aceleração no processo de degradação, ocasionando, inclusive, a migração do íon metálico para o meio, porém sem afetar a qualidade do meio de compostagem. / The high level of pollution generated by the inadequate disposal of polymeric materials has motivated the search for environmentally friendly systems and techniques such as the application of biodegradable polymers and the replacement of the solvent-based paint systems by those with high solids content, based water or cured by radiation, practically free of volatile organic compounds. However, the cured polymer coatings are neither soluble nor molten, increasing the complexity of the reprocessing, recycling and degradation. Thus, this work aimed to develop print inks modified with pro-degrading agents, cured by ultraviolet radiation or electron beam, for printing or decoration in plastic packaging products of short lifetime, which are biodegradable or not. Six coatings (varnish and inks in five colors: yellow, blue, white, black and red), three pro-degrading agents (cobalt stearate, cerium stearate and manganese stearate), five polymeric substrates (Ecobras®, low density polyethylene and its respective modifications with pro-degrading agents). The coatings were applied to the substrates and cured by ultraviolet radiation or electron beam, resulting in 180 samples. These materials were then exposed to accelerated aging chamber, type \"QUV\", and composting in natural environment. In order to assess the effects of the polymer coatings on the degradation process of the specimens, only the yellow and black samples were exposed to a controlled composting environment via respirometry, reducing to 16 the number of samples. The organic compound generated by the biodegradation process was analyzed by the ecotoxicity tests. It was observed that the coating layer acted as a barrier that inhibits degradation of the plastic when exposed to weathering. The addition of pro-degrading agents promoted acceleration in the degradation process, promoting the migration of the metal ion to the medium without affecting the final quality of the organic compost.

O alto nível de poluição gerado pelo descarte inadequado de materiais poliméricos vem motivando pesquisas por sistemas e técnicas ambientalmente corretos, tais como a aplicação de polímeros biodegradáveis e a substituição dos sistemas de pintura à base de solventes por aqueles com alto teor de sólidos, à base de água ou, praticamente isentos de compostos orgânicos voláteis (VOCs) e curáveis por radiação. Todavia, os revestimentos poliméricos curados são insolúveis e infusíveis, aumentando o grau de complexidade do seu reprocessamento, da sua reciclagem e da degradação desejável. Assim, este trabalho apresenta, como objeto de contribuição científica, a obtenção de tintas modificadas com agentes pró-degradantes, curadas por reações químicas induzidas por radiação ultravioleta ou feixe de elétrons (UV/EB), para impressão em embalagens plásticas, biodegradáveis ou não, para produtos de baixa vida útil. Foram estudadas combinações de seis revestimentos, sendo um verniz não pigmentado e cinco tintas nas cores amarela, azul, branca, preta e vermelha; três agentes pró-degradantes (estearatos de cobalto, cério e manganês), cinco substratos poliméricos (Ecobras®, polietileno de baixa densidade e suas respectivas modificações com os agentes pró-degradantes). Os revestimentos foram aplicados nos substratos e curados por radiação UV ou EB, resultando em 180 amostras. Estes materiais foram, então, expostos ao envelhecimento acelerado em câmara tipo QUV e à compostagem em ambiente natural. De modo a se compreender o efeito dos revestimentos poliméricos no processo de degradação das amostras, foram selecionadas aquelas com valores extremos de grau de conversão, a saber: amarela e preta, as quais foram expostas à compostagem em ambiente controlado via respirometria, reduzindo de 180 para 16 o número de amostras. O composto orgânico gerado pelo processo de biodegradação foi analisado por testes de ecotoxicidade. Foi observado que a camada de revestimento atua como barreira que inibe a degradação do plástico quando exposto às intempéries. Adicionalmente, constatou-se que quanto maior o grau de conversão das formulações pigmentadas pastosas em sólidas durante a cura por radiação ultravioleta, maior foi sua mineralização em ambiente de compostagem. As amostras curadas por EB apresentaram menor taxa de biodegradação do que as curadas por UV. Isso se deu em virtude da rede de ligações cruzadas entre as cadeias poliméticas, geradas na cura por EB. A adição dos agentes pró-degradantes promoveu uma aceleração no processo de degradação, ocasionando, inclusive, a migração do íon metálico para o meio, porém sem afetar a qualidade do meio de compostagem. / The high level of pollution generated by the inadequate disposal of polymeric materials has motivated the search for environmentally friendly systems and techniques such as the application of biodegradable polymers and the replacement of the solvent-based paint systems by those with high solids content, based water or cured by radiation, practically free of volatile organic compounds. However, the cured polymer coatings are neither soluble nor molten, increasing the complexity of the reprocessing, recycling and degradation. Thus, this work aimed to develop print inks modified with pro-degrading agents, cured by ultraviolet radiation or electron beam, for printing or decoration in plastic packaging products of short lifetime, which are biodegradable or not. Six coatings (varnish and inks in five colors: yellow, blue, white, black and red), three pro-degrading agents (cobalt stearate, cerium stearate and manganese stearate), five polymeric substrates (Ecobras®, low density polyethylene and its respective modifications with pro-degrading agents). The coatings were applied to the substrates and cured by ultraviolet radiation or electron beam, resulting in 180 samples. These materials were then exposed to accelerated aging chamber, type \"QUV\", and composting in natural environment. In order to assess the effects of the polymer coatings on the degradation process of the specimens, only the yellow and black samples were exposed to a controlled composting environment via respirometry, reducing to 16 the number of samples. The organic compound generated by the biodegradation process was analyzed by the ecotoxicity tests. It was observed that the coating layer acted as a barrier that inhibits degradation of the plastic when exposed to weathering. The addition of pro-degrading agents promoted acceleration in the degradation process, promoting the migration of the metal ion to the medium without affecting the final quality of the organic compost.

Acute liver failure is a major cause of death in the world, and effective treatments are greatly needed. Liver macrophages (Kupffer cells) play a major role in the pathology of acute liver failure, and drug delivery vehicles that can target therapeutics to Kupffer cells have great therapeutic potential for treating acute liver failure. Microparticles, formulated from biodegradable polymers, are advantageous for treating acute liver failure because they can passively target therapeutics to Kupffer cells. However, existing biomaterials are not suitable for the treatment of acute liver failure because of their slow hydrolysis and acidic degradation products. In this dissertation, I present the development of a new class of biodegradable materials, termed aliphatic polyketals, which have considerable potential as drug delivery vehicles for the treatment of acute liver failure because of their neutral degradation products and tunable hydrolysis kinetics. The anti-inflammatory enzyme, superoxide dismutase (SOD), was delivered using polyketal microparticles to the liver for treating acute liver Failure. Our results demonstrated that polyketal microparticles significantly improved the efficacy of SOD in treating LPS-induced acute liver damage in vivo, as evidenced by decreased levels of serum alanine transaminase, which corresponds to the extent of damage in the liver, and serum level of tumor necrosis factor-alpha, which corresponds to the secretion of pro-inflammatory cytokines. The completion of this thesis research demonstrates the ability of polyketal-based drug delivery systems for treating acute inflammatory diseases and creates a potential therapy for enhancing the treatment of acute liver failure.