生分解性有機-無機複合球状粒子の創製とその生物学的性質に関する研究

Antibiotic resistance in bacteria is a serious problem that requires researchers to engineer new strategies to tackle this growing threat. The limited intracellular bioavailability of antibiotics decreases the efficacy of the treatments and, as a consequence promotes bacterial resistance towards antibiotics. Therefore, the development and improvement of drug controlled release systems is vital to create new approaches to deliver in the most effective manner the drugs or other bioactive compounds to the desired location. Especially if the targeted site is the gastrointestinal track, where the environmental conditions are harsh for biomolecules to maintain its stability and function. Polymeric microspheres are attractive due to their biodegradability and ability to encapsulate drugs or bioactive agents, therefore increasing their bioavailability. To address these poor bioavailability or unsustained drug release challenges, chitosan microspheres are adequate as drug delivery carriers for the gastrointestinal track due to mucoadhesive properties, which allows the drug dosage to be retained in the gastrointestinal track for extended periods of time, in addition to the presence of reactive sites in chitosan which allow the interaction with biomolecules to be carried to the targeted site. Spherical particles were produced using chitosan and γ-glycidoxypropyltrimethoxysilane (GPTMS) as an organic-inorganic hybrid compound resorting to two different methods. The first method consisted in a microfluidic approach using chitosan–GPTMS–β-glycerophosphate (chitosan–GPTMS–β-GP) to produce microspheres with uniform size and spherical shape around 650 μm and 285 μm. Whereas, in the second method beads with diameter around 2 mm with micropores were synthetized by dropping the hybrid precursor sol into liquid nitrogen followed by a freeze drying process. The physicochemical characterization of the microspheres from the microfluidic system was performed in which the formation of siloxane (Si-O-Si) networks was confirmed in the chitosan polymeric matrix, as well as the spheres stability in solutions. The degradation of microspheres with different GPTMS molar ratios was evaluated under simulated gastric fluids (SGF) and neutral conditions. The microspheres incubated at pH 7.4 had the lowest weight loss (27%–32%), whereas those incubated at pH 1.7 and pH 5.4 showed greater weight losses of 43–59% and 69–77%, respectively. The inhibition of the degradation at low pH was dependent on the siloxane network formed in the chitosan matrix. Additionally, GPTMS was released with the chitosan chains via hydrolysis of the chitosan molecules. Pelargonidin is a natural antioxidant which was incorporated in the microspheres and the releasing behavior was observed under SGF conditions and simulated time of digestion cycle in humans. The release profile observed leads to believe that these microspheres are promising for gastrointestinal drug delivery applications due to its resistance to low pH conditions present in the upper gastrointestinal track, in addition to the controlled and sustained release rate of pelargonidin and its ability to retain it in the matrix even after 57 h. Cerium compounds have been described to possess antibacterial activity, and new strategies of treating pathogenic bacteria are needed due to the rapid increase of bacterial resistance towards common antibiotics. The bacterial behavior of Escherichia coli and Staphylococcus aureus was observed with the chitosan–GPTMS–β-GP spheres and hydrogels containing cerium(III) chloride (CeCl3), and no antibacterial effect was observed due to the immediate interaction between β-GP and cerium, via the complex formation of cerium with the amino groups of chitosan, making it inaccessible to the bacteria. Furthermore, the bacterial viability increased for both gram-negative and gram-positive strains on hydrogels with and without cerium. To achieve antibacterial applications using the chitosan-siloxane hybrid, beads without β-GP were prepared by dropping the chitosan-GPTMS precursor sols into liquid nitrogen. The beads were synthetized with and without cerium. The bacterial activity was greatly reduced with the highest tested amounts of cerium against both gram-negative (Escherichia coli) and gram-positive (Staphylococcus aureus) strains. This microporous beads have the potential to be applied for soft tissue defect fillers materials with antibacterial properties to reduce or eradicate in situ bacterial infection.九州工業大学博士学位論文 学位記番号：生工博甲第312号 学位授与年月日：平成30年3月23日1. GENERAL INTRODUCTION|2. SYNTHESIS OF CHITOSAN-SILOXANE HYBRID MICROSPHERES USING A MICROFLUIDIC APPROACH AND RELEASE OF PELARGONIDIN IN GASTROINTESTINAL SIMULATED CONDITIONS|3. BACTERIAL BEHAVIOR ON CHITOSAN-SILOXANE HYBRID MICROSPHERES AND HYDROGELS CONTAINING CERIUM|4. BACTERIAL BEHAVIOR WITH CHITOSAN-SILOXANE HYBRID SPHERICAL BEADS CONTAINING CERIUM九州工業大学平成29年

生分解性有機-無機複合球状粒子の創製とその生物学的性質に関する研究

九州工業大学博士学位論文（要旨）学位記番号：生工博甲第312号 学位授与年月日：平成30年3月23

Behavior of prostate cancer cells in a nanohydroxyapatite/collagen bone scaffold

Prostate cancer (PCa) is the second leading cause of death among men in Europe and U.S. The metastatic dissemination pattern of PCa is unique, developing bone metastasis as the only site of progression, consequently with a prognosis very poor. The cancer cells interactions within the surrounding bone environment are critical for tumor growth and progression. Secreted protein, acidic and rich in cysteine (SPARC) is described to be involved in PCa cells migration and invasion into bone. Three-dimensional (3D) in vitro systems that are able to closely resemble the in vivo microenvironment are recently taking importance in cancer research. Original nanohydroxyapatite/collagen scaffolds were designed to resemble bone microenvironment in order to be applied as substitutes in bone defects and as potential biomaterials to mimic skeletal tumors. In fact, these 3D structures were cytocompatible and able to support osteoblast (MC3T3-E1) colonization and to promote bone ingrowth. Additionally, SPARC adsorption onto the scaffolds affected PC3 and LNCaP PCa cell lines behavior. PC3 cells were found to adapt and colonize the scaffolds, differing from LNCaP where cells underwent morphogenic changes and grew as clusters. Furthermore, for the tested SPARC concentration, SPARC plays a role in retaining LNCaP cells at the latter time points while with PC3 cells no significant differences were observed. This characterization study is required to establish a bone model to provide new insights into the poorly understood PCa mechanisms of metastasis to bone and the generation of improved therapies.info:eu-repo/semantics/publishedVersio

Characterization and degradation study of chitosan-siloxane hybrid microspheres synthesized using a microfluidic approach

Chitosan microspheres can address challenges associated with poor bioavailability or unsustained drug release when used as drug delivery systems thanks to their mucoadhesiveness, which allows the drug dosage to be retained in the gastrointestinal track for extended periods. Chitosan-3-glycidoxypropyltrimethoxysilane-β-glycerophosphate (chitosan-GPTMS-β-GP) hybrid microspheres were synthetized through sol-gel processing using a microfluidic approach. Microspheres with uniform spherical shapes and sizes of approximately 650 μm were obtained. The microstructures of the microspheres consisted of four different siloxane structures. The degradation behaviors of the hybrid microspheres were examined under acidic pH conditions mimicking those found in the gastrointestinal track. Microspheres with different GPTMS molar ratios were incubated under several pH conditions for 2 weeks. The microspheres incubated at pH 7.4 extended the lowest weight loss (27%–32%), whereas those incubated at pH 1.7 and pH 5.4 showed greater weight losses of 43–59% and 69–77%, respectively. The inhibition of the degradation at low pH was dependent on the siloxane network in the chitosan matrix. Phosphate was mostly released in early stages, and the released amount of silicon was dependent on the composition. GPTMS was released with a chitosan chain via the hydrolysis of a chitosan molecule. The pelargonidin was incorporated in the microspheres and the slow releasing was observed at acidic condition. The resistance of these hybrid microspheres to low-pH conditions for longer than a full digestion cycle is promising for gastrointestinal drug delivery applications

Cytocompatible and Antibacterial Properties of Chitosan-Siloxane Hybrid Spheres

Microporous spheres in a hybrid system consisting of chitosan and γ-glycidoxypropyltrimethoxysilane (GPTMS) have advantages in a range of applications, e.g., as vehicles for cell transplantation and soft tissue defect filling materials, because of their excellent cytocompatibility with various cells. In this study, microporous chitosan-GPTMS spheres were prepared by dropping chitosan-GPTMS precursor sols, with or without a cerium chloride, into liquid nitrogen using a syringe pump. The droplets were then freeze dried to give the pores of size 10 to 50 μm. The cell culture tests showed that L929 fibroblast-like cells migrated into the micropores larger than 50 μm in diameter, whereas MG63 osteoblast-like cells proliferated well and covered the granule surfaces. The spheres with cerium chloride showed antibacterial properties against both gram-negative and gram-positive bacteria

O Museu da Universidade de Aveiro: uma viagem para além do espaço físico

Os museus universitários, para além da sua função de conservação do património cultural para as gerações futuras, como qualquer outro museu, podem tornar-se centros de excelência no apoio ao ensino-aprendizagem e à investigação. O Museu da Universidade de Aveiro (MusA) pode constituir-se uma mais-valia e um potencial de oportunidades de investigação sobre as coleções que o núcleo de museologia integra. No entanto, a pluralidade de objetos existentes nas diferentes coleções e a necessidade de tornar visível tanto as coleções como a produção académica e científica resultante do estudo das mesmas, conduziu o MusA a equacionar sobre qual a melhor solução ao nível das plataformas de Sistemas Integrados de Gestão Museológica (SIGM), em open source. Neste contexto, apresentam-se as alternativas estudadas e avaliadas para a seleção do Sistema Integrado de Gestão Museológica, em open source, com base no modelo de avaliação QSOS e tendo em conta as dimensões, variáveis e indicadores de interesse para o MusA. Os resultados da avaliação apontaram para o Collective Access, como o software em open source que melhor respondia as necessidades do MusA.publishe

Effect of surgical experience and spine subspecialty on the reliability of the {AO} Spine Upper Cervical Injury Classification System

OBJECTIVE The objective of this paper was to determine the interobserver reliability and intraobserver reproducibility of the AO Spine Upper Cervical Injury Classification System based on surgeon experience (< 5 years, 5–10 years, 10–20 years, and > 20 years) and surgical subspecialty (orthopedic spine surgery, neurosurgery, and "other" surgery). METHODS A total of 11,601 assessments of upper cervical spine injuries were evaluated based on the AO Spine Upper Cervical Injury Classification System. Reliability and reproducibility scores were obtained twice, with a 3-week time interval. Descriptive statistics were utilized to examine the percentage of accurately classified injuries, and Pearson’s chi-square or Fisher’s exact test was used to screen for potentially relevant differences between study participants. Kappa coefficients (κ) determined the interobserver reliability and intraobserver reproducibility. RESULTS The intraobserver reproducibility was substantial for surgeon experience level (< 5 years: 0.74 vs 5–10 years: 0.69 vs 10–20 years: 0.69 vs > 20 years: 0.70) and surgical subspecialty (orthopedic spine: 0.71 vs neurosurgery: 0.69 vs other: 0.68). Furthermore, the interobserver reliability was substantial for all surgical experience groups on assessment 1 (< 5 years: 0.67 vs 5–10 years: 0.62 vs 10–20 years: 0.61 vs > 20 years: 0.62), and only surgeons with > 20 years of experience did not have substantial reliability on assessment 2 (< 5 years: 0.62 vs 5–10 years: 0.61 vs 10–20 years: 0.61 vs > 20 years: 0.59). Orthopedic spine surgeons and neurosurgeons had substantial intraobserver reproducibility on both assessment 1 (0.64 vs 0.63) and assessment 2 (0.62 vs 0.63), while other surgeons had moderate reliability on assessment 1 (0.43) and fair reliability on assessment 2 (0.36). CONCLUSIONS The international reliability and reproducibility scores for the AO Spine Upper Cervical Injury Classification System demonstrated substantial intraobserver reproducibility and interobserver reliability regardless of surgical experience and spine subspecialty. These results support the global application of this classification system

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men