付記する学位プログラム名: グローバル生存学大学院連携プログラム / 京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20340号 / 工博第4277号 / 新制||工||1662(附属図書館) / 京都大学大学院工学研究科社会基盤工学専攻 / (主査)教授 寶 馨, 教授 角 哲也, 准教授 佐山 敬洋 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Biomaterials are designed to improve impaired healing of injured tissue. To accomplish better cell integration, we suggest to coat biomaterial surfaces with bio-functional proteins. Here, a mussel-derived surface-binding peptide is used and coupled to CXCL12 (stromal cell-derived factor 1α), a chemokine that activates CXCR4 and consequently recruits tissue-specific stem and progenitor cells. CXCL12 variants with either non-releasable or protease-mediated-release properties were designed and compared. Whereas CXCL12 was stabilized at the N-terminus for protease resistance, a C-terminal linker was designed that allowed for specific cleavage-mediated release by matrix metalloproteinase 9 and 2, since both enzymes are frequently found in wound fluid. These surface adhesive CXCL12 derivatives were produced by expressed protein ligation. Functionality of the modified chemokines was assessed by inositol phosphate accumulation and cell migration assays. Increased migration of keratinocytes and primary mesenchymal stem cells was demonstrated. Immobilization and release were studied for bioresorbable PCL-co-LC scaffolds, and accelerated wound closure was demonstrated in an ex vivo wound healing assay on porcine skin grafts. After 24 h, a significantly improved CXCL12-specific growth stimulation of the epithelial tips was already observed. The presented data display a successful application of protein-coated biomaterials for skin regeneration.

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Networked control over wireless networks is of growing importance in many application domains such as industrial control, building automation and transportation systems. Wide deployment however, requires systematic design tools to enable efficient resource usage while guaranteeing close-loop control performance. The control system may be greatly affected by the inherent imperfections and limitations of the wireless medium and malfunction of system components. In this thesis, we make five important contributions that address these issues.  In the first contribution, we consider event- and self-triggered control and investigate how to efficiently tune and execute these paradigms for appropriate control performance. Communication strategies for aperiodic control are devised, where we jointly address the selection of medium-access control and scheduling policies. Experimental results show that the best trade-off is obtained by a hybrid scheme, combining event- and self-triggered control together with contention-based and contention-free medium access control. The second contribution proposes an event-based method to select between fast and slow periodic sampling rates. The approach is based on linear quadratic control and the event condition is a quadratic function of the system state. Numerical and experimental results show that this hybrid controller is able to reduce the average sampling rate in comparison to a traditional periodic controller, while achieving the same closed-loop control performance. In the third contribution, we develop compensation methods for out-of-order communications and time-varying delays using a game-theoretic minimax control framework. We devise a linear temporal coding strategy where the sensor combines the current and previous measurements into a single packet to be transmitted. An experimental evaluation is performed in a multi-hop networked control scenario with a routing layer vulnerability exploited by a malicious application. The experimental and numerical results show the advantages of the proposed compensation schemes. The fourth contribution proposes a distributed reconfiguration method for sensor and actuator networks. We consider systems where sensors and actuators cooperate to recover from faults. Reconfiguration is performed to achieve model-matching, while minimizing the steady-state estimation error covariance and a linear quadratic control cost. The reconfiguration scheme is implemented in a room heating testbed, and experimental results demonstrate the method's ability to automatically reconfigure the faulty system in a distributed and fast manner. The final contribution is a co-simulator, which combines the control system simulator Simulink with the wireless network simulator COOJA. The co-simulator integrates physical plant dynamics with realistic wireless network models and the actual embedded software running on the networked devices. Hence, it allows for the validation of the complete wireless networked control system, including the study of the interactions between software and hardware components. / <p>QC 20140929</p>

The Electric/Electronic architecture of vehicle becomes more complex and costly, self-adaption can reduce the system, enhance the adaptive meanwhile reduce energy consumption and costs. The self-adaption needs the cooperation of both hardware and software reconfigurations, such that after the software is reconfigured the automotive network continues to fulfill the time constraints for time-critical applications. The thesis focuses on the real-time network reconfiguration. It uses EAST-ADL to model a real-time automotive system with timing events and constraints, which conforms to AUTOSAR timing extensions. The network media access is analyzed based on the model and a scheduling algorithm is developed. Then the concept is implemented by a use case, which is transformed from an EAST-ADL model to an executable simulation.

Cette thèse est dédiée à l'analyse de stabilité des systèmes à pas d'échantillonnage variable et à la commande dynamique de l'échantillonnage. L'objectif est de concevoir des lois d'échantillonnage permettant de réduire la fréquence d'actualisation de la commande par retour d'état, tout en garantissant la stabilité du système.Tout d'abord, un aperçu des récents défis et axes de recherche sur les systèmes échantillonnés est présenté. Ensuite, une nouvelle approche de contrôle dynamique de l'échantillonnage, "échantillonnage dépendant de l'état", est proposée. Elle permet de concevoir hors-ligne un échantillonnage maximal dépendant de l'état défini sur des régions coniques de l'espace d'état, grâce à des LMIs.Plusieurs types de systèmes sont étudiés. Tout d'abord, le cas de système LTI idéal est considéré. La fonction d'échantillonnage est construite au moyen de polytopes convexes et de conditions de stabilité exponentielle de type Lyapunov-Razumikhin. Ensuite, la robustesse vis-à-vis des perturbations est incluse. Plusieurs applications sont proposées: analyse de stabilité robuste vis-à-vis des variations du pas d'échantillonnage, contrôles event-triggered et self-triggered, et échantillonnage dépendant de l'état. Enfin, le cas de système LTI perturbé à retard est traité. La construction de la fonction d'échantillonnage est basée sur des conditions de stabilité L2 et sur un nouveau type de fonctionnelles de Lyapunov-Krasovskii avec des matrices dépendant de l'état. Pour finir, le problème de stabilisation est traité, avec un nouveau contrôleur dont les gains commutent en fonction de l'état du système. Un co-design contrôleur/fonction d'échantillonnage est alors proposé / This PhD thesis is dedicated to the stability analysis of sampled-data systems with time-varying sampling, and to the dynamic control of the sampling instants. The main objective is to design sampling laws that allow for reducing the sampling frequency of state-feedback control for linear systems while ensuring the system's stability.First, an overview of the recent problems, challenges, and research directions regarding sampled-data systems is presented. Then, a novel dynamic sampling control approach, "state-dependent sampling", is proposed. It allows for designing offline a maximal state-dependent sampling map over conic regions of the state space, thanks to LMIs.Various classes of systems are considered throughout the thesis. First, we consider the case of ideal LTI systems, and propose a sampling map design based on the use of polytopic embeddings and Lyapunov-Razumikhin exponential stability conditions. Then, the robustness with respect to exogenous perturbations is included. Different applications are proposed: robust stability analysis with respect to time-varying sampling, as well as event-triggered, self-triggered, and state-dependent sampling control schemes. Finally, a sampling map design is proposed in the case of perturbed LTI systems with delay in the feedback control loop. It is based on L2-stability conditions and a novel type of Lyapunov-Krasovskii functionals with state-dependent matrices. Here, the stabilization issue is considered, and a new controller with gains that switch according to the system's state is presented. A co-design controller gains/sampling map is then proposed

The Electric/Electronic architecture of vehicle becomes more complex and costly, self-adaption can reduce the system, enhance the adaptive meanwhile reduce energy consumption and costs. The self-adaption needs the cooperation of both hardware and software reconfigurations, such that after the software is reconfigured the automotive network continues to fulfill the time constraints for time-critical applications. The thesis focuses on the real-time network reconfiguration. It uses EAST-ADL to model a real-time automotive system with timing events and constraints, which conforms to AUTOSAR timing extensions. The network media access is analyzed based on the model and a scheduling algorithm is developed. Then the concept is implemented by a use case, which is transformed from an EAST-ADL model to an executable simulation.:1. Introduction 2. Research Fundamentals 2.1. AUTOSAR Specifications for Modeling Function Communication 2.2. Media Access Control in Real-time Network 3. Function Communication Model and Determination of Network Configuration 3.1. Function Communication Model 3.2. Scheduling Algorithm for Media Access 4. Implementation of Communication Model and Plugin for Model Transformation 4.1. EAST-ADL Modeling Language 4.2. Implementation of Function Communication Model in EAST-ADL 4.3. Model Transformation Plugin and Simulation Tool Integration 5. Evaluation of the Function Communication Model 5.1. Use-Case Model for Evaluation 5.2. Time Values of Use-Case Model 5.3. Analysis and Evaluation of Simulation Result 6. Conclusion and Outlook 6.1. Conclusion of the Work 6.2. Outlook of the Future Work A. OMNeT++ Simulation Log B. EAST-ADL Model to Artop Model Mapping Bibliography Nomenclature

This research is aimed at exploding a wire via electromagnetic induction, with a preference for obtaining restrike of the exploding wire in a ring shape or otherwise. Literature on both exploding wire and electromagnetic induction are introduced together. A mathematical framework to describe the wire explosion by induction is formulated from first principles using the idea of magnetic flux linkages. The environment in which the experiments took place is described, with reference to matters of laboratory safety and also measurement of transient electrical current and voltage in the wire explosion by induction. The results describe the approaches taken to explode a wire by induction to obtain a plasma conductor. Voltage and current data are displayed and described. Throughout this work, there are long-exposure digital photographic images of the experiments taking place. These contribute to determining the outcome of experiments, and support the conclusions. Wires were exploded by induction in an air-cored mutually coupled coils system, and restrike of those wires was achieved. Electrical characteristics of wire explosion by electromagnetic induction are displayed and discussed based on what is known about straight exploding wires. Future works involving creation of plasma rings, electromagnetic thrust and exploding wires in vacuum are discussed.

La maladie de Parkinson (MP) est la deuxième maladie neurodégénérative la plus commune. Les symptômes principalement observés chez les patients atteints de la MP sont la rigidité, les tremblements, la bradykinésie et une instabilité posturale. Leur sévérité est souvent asymétrique. La cause principale de ces symptômes moteurs est la dégénérescence du circuit dopaminergique nigro-striatal qui mène à un débalancement d’activité du circuit cortico-striatal. Ce débalancement de circuits est le point essentiel de cette thèse. Dans les protocoles de recherche décrits ici, des patients atteints de la MP (avant et après une dose de levodopa) et des participants contrôles sains ont effectué des mouvements auto-initiés ou en réponse à des stimulis externes pendant que l’on mesurait leur activité cérébrale en imagerie par résonance magnétique fonctionnelle (IRMf). Dans cette thèse, nous abordons et mettons en évidence quatre (4) points principaux. En première partie (chapitre 2), nous présentons un recensement de la littérature sur les cicruits cortico-striataux et cortico-cérébelleux dans la MP. En utilisant des méthodes de neuroimagerie, des changements d’activité cérébrale et cérébelleuse ont été observés chez les patients atteints de la MP comparés aux participants sains. Même si les augmentations d’activité du cervelet ont souvent été attribuées à des mécanismes compensatoires, nos résultats suggèrent qu’elles sont plus probablement liées aux changements pathophysiologiques de la MP et à la perturbation du circuit cortico-cérébelleux. En général, nous suggérons (1) que le circuit cortico-cérébelleux est perturbé chez les patients atteints de la MP, et que les changements d’activité du cervelet sont liés à la pathophysiologie de la MP plutôt qu’à des mécanismes compensatoires. En deuxième partie (chapitre 3), nous discutons des effets de la levodopa sur les hausses et baisses d’activité observés chez les patients atteints de la MP, ainsi que sur l’activité du putamen pendant les mouvements d’origine interne et externe. De nombreuses études en neuroimagerie ont montré une baisse d’activité (hypo-activité) préfrontale liée à la déplétion de dopamine. En revanche, l’utilisation de tâches cognitives a montré des augmentations d’activité (hyper-activité) corticale chez les patients atteints de la MP comparés aux participants sains. Nous avons suggéré précédemment que ces hypo- et hyper-activités des régions préfrontales dépendent de l’implication du striatum. Dans cette thèse nous suggérons de plus (2) que la levodopa ne rétablit pas ces hyper-activations, mais plutôt qu’elles sont liées à la perturbation du circuit méso-cortical, et aussi possiblement associées à l’administration de médication dopaminergique à long terme. Nous montrons aussi (3) que la levodopa a un effet non-spécifique à la tâche sur l’activité du circuit cortico-striatal moteur, et qu’elle n’a pas d’effet sur l’activité du circuit cortico-striatal cognitif. Nous montrons enfin (chapitre 4) que la levodopa a un effet asymétrique sur les mouvements de la main droite et gauche. À peu près 50% des patients atteints de la MP démontrent une asymétrie des symptômes moteurs, et ceci persiste à travers la durée de la maladie. Nos résultats suggèrent (4) que la levodopa pourrait avoir un plus grand effet sur les patrons d’activations des mouvements de la main la plus affectée. / Parkinson’s disease (PD) is the second most common neurodegenerative disease, mainly manifested by tremor, rigidity, bradykinesia and postural instability, and often an asymmetry of symptom severity of the left and right sides of the body. The depletion of dopamine of the nigrostriatal pathway is the primary cause of the motor symptoms observed in patients with PD, leading to an imbalance in basal-ganglia prefrontal circuits. In the protocols described here, patients with PD before and after levodopa administration and healthy participants performed self-initiated (SI) and externally triggered (ET) movements with the left and right hand during functional magnetic resonance imaging (fMRI). In the chapters of this thesis, we argue and provide evidence for four main points. The first portion (chapter 2) provides a literature review on cortico-striatal and cortico-cerebellar circuit disruption in PD. Using neuroimaging techniques, changes in cerebral and cerebellar activity have been observed in patients with PD compared with healthy participants. Although increases in activity in the cerebellum have often been interpreted as compensatory mechanisms, we provide evidence that they are more likely to be related to pathophysiological changes of the disease, and the disruption of the cortico- cerebellar circuit. In general, we argue (1) is that activity in the cerebellum is linked to the pathophysiology of PD. In the second section (chapter 3) we discuss the effect of levodopa on the patterns of cortical hypo- and hyper-activity in PD, as well as the activity of the putamen in SI and ET movements. Many studies have shown cortical hypo-activity in relation to nigrostriatal dopamine depletion. In contrast, some cognitive studies have also identified increases in cortical activity in patients with PD as compared with healthy control participants. We have previously suggested that cortical hypo- and hyper-activations depend on striatal recruitment. In this thesis, we further show that hyper-activations in the prefrontal cortex are not reestablished with levodopa administration. We suggest (2) that they are rather associated with mesocortical dopamine circuit dysfunction, and perhaps linked with long- term dopaminergic medication administration. Furthermore, we show (3) that levodopa has a non-task specific effect on the motor cortico-striatal loop, but does not affect the cognitive cortico-striatal circuit. Finally (chapter 4), we show that the effect of levodopa on movements of the left and right hands is not symmetrical. Previous studies have shown that in about 50% of patients, one side of the body is more severely affected, and this asymmetry persists throughout the duration of the disease. Our results suggest (4) that levodopa may have stronger effects on the cerebral hemodynamic patterns related to the movements of the more affected hand than on those of the less affected hand.

Nous avons optimisé des liposomes thermosensibles, encapsulant un principe actif anticancéreux, le 5-Fluorouracile (5-FU), afin de déclencher sa libération par une hyperthermie locale modérée (39-42°C) induite par des ultrasons focalisés. L'hyperthermie sera appliquée au niveau de la tumeur, afin d'améliorer l’efficacité thérapeutique et de réduire la toxicité systémique. Les liposomes ont été formulés par hydratation du film lipidique en mélangeant la 1,2-dipalmitoyl-sn-glycéro-3-phosphocholine (DPPC) pour sa thermosensibilité à 41,5 ± 0,5°C, le cholestérol (CHOL) pour favoriser la stabilité des liposomes vis-à-vis des composants du sang, et le 1,2-distéaroyl-sn-glycéro-3-phosphoéthanolamine-N-[méthoxy(polyéthylène glycol)-2000] (DSPE-PEG) pour assurer la furtivité de la formulation. Les expériences ont confirmé que les liposomes formulés à base de DPPC/CHOL/DSPE-PEG dans un ratio molaire 90 : 5 : 5 mol% sont thermosensibles. Des liposomes composés du même mélange lipidique dans un rapport 65 : 30 : 5 mol% ont été considérés comme contrôle négatif non thermosensible. L’optimisation de l’encapsulation passive du 5-FU a permis d’obtenir une efficacité d’encapsulation (5-FU encapsulé/5-FU total) de 13%, mais le 5-FU est très faiblement retenu (12%) dans la cavité aqueuse des liposomes du fait du gradient osmotique à la dilution. La rétention du 5-FU a été optimisée (93%) par la technique d’encapsulation active basée sur la complexation intraliposomale du 5-FU avec le complexe cuivre-polyéthylèneimine préalablement encapsulé dans les liposomes. Cette technique a également permis d’améliorer l’efficacité d’encapsulation d’un facteur trois environ (37%), avec un taux de charge (ratio final 5-FU/lipides, mole/mole) de 50% environ. Nous avons alors obtenu des liposomes thermosensibles d'un diamètre hydrodynamique de 65 nm et de charge de surface de -10 mV. Les liposomes non thermosensibles, ont été caractérisés par un diamètre hydrodynamique de 105 nm et une charge de surface de -4,9 mV. La libération du 5-FU déclenchée par une hyperthermie induite par des ultrasons focalisés a été mesurée in vitro. En réponse à une hyperthermie de 42°C, les liposomes thermosensibles libèrent 68% de leur contenu, au bout de 10 min, alors que les liposomes non thermosensibles en libèrent moins de 20%. En outre, la cytotoxicité des liposomes encapsulant le complexe 5-FU-cuivre-polyéthylèneimine a été évaluée vis-à-vis de la lignée cellulaire HT-29 du carcinome colorectal humain. Les résultats ont révélé que les lipides à une concentration de 800 µM ne sont pas cytotoxiques (80% de viabilité). De plus, la complexation du 5-FU n’influence pas sa cytotoxicité ce qui prouve que la toxicité provient du 5-FU et non des excipients. En revanche, l’encapsulation du complexe 5-FU-cuivre-polyéthylèneimine dans les liposomes induit une diminution de la concentration inhibitrice médiane de 115 (solution du complexe) à 49 µM environ, corrélée à leur internalisation cellulaire. La pharmacocinétique chez des souris porteuses d’un modèle de tumeur colorectale HT-29 xénogreffée a montré que les liposomes permettent de prolonger d’un facteur 1,4 la demi-vie plasmatique de distribution du 5-FU. De plus, les aires sous la courbe des concentrations plasmatiques sur 24 h sont 1,9 et 2,9 fois plus élevées lorsque le 5-FU est administré sous forme de liposomes thermosensibles et non thermosensibles, respectivement, par rapport à la solution de 5-FU. Enfin, les liposomes non thermosensibles augmentent significativement d'un facteur 2 l'accumulation du 5-FU dans la tumeur par rapport à la solution de 5-FU. En conclusion, les liposomes thermosensibles développés présentent un fort intérêt pour une application thérapeutique en combinaison avec des ultrasons focalisés. / We optimized thermosensitive liposomes encapsulating an anticancer drug, 5-Fluorouracil (5-FU), in order to trigger the release upon focused ultrasound-mediated mild hyperthermia at the tumor. This approach would improve drug efficacy and would lower side effects. Liposomes were prepared by the lipid hydration method by mixing 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) for its temperature sensitivity at 41.5 ± 0.5°C, cholesterol (CHOL) to promote liposome stability towards blood components, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) to confer stealthiness to the formulation. The experiments confirmed that the liposomes formulated with DPPC/CHOL/DSPE-PEG in a molar ratio 90:5:5 mol% are thermosensitive, while liposomes composed of the same lipid mixture in a ratio 65:30:5 mol% were considered non thermosensitive negative control. The optimization of passive encapsulation of 5-FU yielded an encapsulation efficacy (encapsulated 5-FU/total 5-FU) of 13%. 5-FU was, however, very weakly retained (12%) in the aqueous core of liposomes following dilution due to the generation of an osmotic gradient. The retention of 5-FU has been optimized (93%) by the active encapsulation technique based on the intraliposomal complexation of 5FU with copper-polyethylenimine complex encapsulated beforehand into liposomes. This technique also improved 5-FU encapsulation efficacy by 3-fold (37%), yielding a loading efficiency (final drug/lipid ratio, mol/mol) of approximately 50%. The resulting thermosensitive liposomes and non thermosensitive liposomes have a hydrodynamic diameter and a surface charge around 65 nm and -10 mV, and 105 nm and -4.9 mV, respectively. Heat-triggered drug delivery was evaluated using focused ultrasound, and showed a release of 68% of the encapsulated 5-FU from thermosensitive liposomes, within 10 min, whereas release remained below 20% for the non thermosensitive formulation. Furthermore, the cytotoxicity of 5-FU-copper-polyethylenimine complex-loaded liposomes towards HT-29 human colorectal carcinoma cell line was evaluated. Results revealed that lipids at a concentration of 800 µM are not cytotoxic (80% viability). Moreover, 5-FU complexation has no impact on its cytotoxic activity, disclosing that liposomes toxicity arose from 5-FU and not from the excipients. Nevertheless, 5-FU-copper-polyethylenimine complex-loaded liposomes exhibited a lower half maximal inhibitory concentration of 49 µM compared to 115 µM for complex solution. This enhancement of cytotoxicity was attributed to the cellular internalization of liposomes. Pharmacokinetics in mice bearing HT-29 xenograft tumor showed that liposomes can extend the plasma distribution half-life of 5-FU by a factor 1.4. Furthermore, areas under the concentration-time curve over 24 h were higher by 1.9- and 2.9-fold when the drug was encapsulated into thermosensitive and non thermosensitive liposomes, respectively, compared to free 5-Fluorouracil. Finally, non thermosensitive liposomes significantly increased 5-FU accumulation in tumor by 2-fold, compared to 5-FU solution. In conclusion, these 5-FU-loaded thermosensitive liposomes represent valuable carriers to investigate the therapeutic efficacy following focused ultrasound-mediated heat application.