Made available in DSpace on 2014-06-11T19:27:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-26Bitstream added on 2014-06-13T20:55:54Z : No. of bitstreams: 1 machado_da_me_ilha.pdf: 1511743 bytes, checksum: 02f8492fa42747b8dd47642f8ed0d7f9 (MD5) / Este projeto visa à análise cinemática de um arranjo experimental capaz de reproduzir o fluxo sanguíneo em artérias. O mecanismo procura realizar esse escoamento através de um sistema came-seguidor juntamente com um sistema hidráulico, utilizando êmbolo e duas válvulas controladoras de fluxo. O mecanismo came-seguidor será utilizado devido a sua versatilidade em garantir que o escoamento sanguíneo ocorra durante um ciclo cardíaco. A came será radial com seguidores de roletes. O seguidor de roletes será ligado ao cilindro hidráulico que controla o fluxo sanguíneo. Um tubo de látex foi acoplado ao sistema hidráulico representando a aorta abdominal, foi confeccionado com as dimensões reais desta artéria e o látex foi escolhido, pois possui um coeficiente de elasticidade muito próximo da artéria. Um manômetro foi acoplado ao sistema para medir a pressão no interior do tubo de látex. Na sequência um tubo de complacência simular as perdas de carga do sistema circulatório. O deslocamento radial do tubo de látex e variação de pressão do manômetro foram monitorados através de filmagem. Posteriormente, os resultados experimentais foram comparados e validados com os resultados numéricos obtidos com o programa ANSYS e com a literatura / This project aims to kinematic analysis of an experimental apparatus able to reproduce the blood flow in arteries. The mechanism cam-follower and the hydraulic system using piston and two controlling valves of flow were used to realize the fluid flow. The camfollower mechanism was used to ensure that the fluid flow occurs during the cardiac cycle. The cam is radial with roller followers. The follower roller is connected to the hydraulic cylinder which controls the fluid flow. A latex tube was attached to the hydraulic system representing the abdominal aorta. The latex tube has the same real dimensions of this artery and it was chosen due the modulus of elasticity very close to the artery. A manometer was used to measure the outlet pressure of latex tube. After latex tube there is a complacency tube to control the pressure drop of circulatory system. The radial displacement of the latex tube and pressure variation of the manometer were monitored through filming. The experimental results were compared and validated with numerical results obtained with ANSYS software and with literature

Abstract The aim of this study was to analyze angiographic findings and the presence and topography of cerebral ischemic and/or hemorrhagic lesions in cerebral CT or MRI, and to assess the long-term clinical outcome of a series of 136 consecutive cervicocephalic artery dissection (CCAD) patients. Pulsatile tinnitus was evaluated as a symptom of CCAD. Medical records and films were reviewed retrospectively. Irregular stenosis was found in angiography in 50% and occlusion in 33% of the dissected cervicocephalic arteries. Irregular stenosis normalized in 81% and occlusion recanalized in 34%. Other findings, such as pseudoaneurysms, intimal flaps, double lumens, and irregular dilatations were rare and often remained unchanged in follow-up. Pulsatile tinnitus was a presenting symptom in 12% of the CCAD patients, but the majority of patients had concomitant head or neck pain, ischemic brain symptoms, Horner's syndrome, or cranial neuropathies. Of the 131 patients who underwent brain imaging, 73 (56%) had signs of infarction in cerebral CT or MRI. Occlusion of the dissected vessel was accompanied by infarction in 76%, irregular stenosis in 40%, and other findings only rarely. Of the anterior circulation infarctions, 95% (39/41) were territorial, subcortical, or territorial infarctions with fragmentation and could thus be considered embolic. Subarachnoid hemorrhage was found in CT in 5 of the 22 patients (23%) with intracranial dissection. The patient's long-term clinical outcome was assessed using two methods: a classification into categories based on neurological symptoms and defects and the modified Rankin Scale (mRS). Of the 136 CCAD patients, 60% recovered with no or mild disability and 79% scored 0–2 on mRS. In the case of dissection of one or more cervicocephalic arteries without occlusion, the figures were 75% and 89%. In the case of occlusive dissection of one or more arteries, only about 35% of the patients recovered well, having no or mild disability, and 61% scored 0–2 on mRS. No significant differences were seen in recovery after intra- and extracranial dissections. In conclusion: irregular stenosis, which is the most common angiographic finding in CCAD, is associated with brain infarction less frequently than occlusion, and the long-term clinical outcome is good in most cases. Occlusion of the dissected vessel causes more brain infarctions, and only about 35% of the patients recover well, having no or mild disability. More than 10% of CCAD patients have pulsatile tinnitus as a presenting, and sometimes the only symptom.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mechanical conditioning has been shown to promote tissue formation in a wide variety of tissue engineering efforts. However the underlying mechanisms by which external mechanical stimuli regulate cells and tissues are not known. This is particularly relevant in the area of heart valve tissue engineering owing to the intense hemodynamic environments that surround native valves. Some studies suggest that oscillatory shear stress (OSS) caused by time-varying flow environments, play a critical role in engineered tissue formation derived from bone marrow derived stem cells (BMSCs). There is strong evidence to support this hypothesis in tissue engineering studies of bone. From observing native heart valve dynamics, OSS can be created by means of pulsatility or by cyclic specimen geometry changes. However, quantification of the individual or combined effects of these variables for the maximization of OSS environments in vitro is to date, not known. Accordingly, in this study we examined and quantified the role that i) physiologically relevant scales of pulsatility and ii) changes in geometry as a function of specimen flexure, have in creating OSS conditions for dynamic culture of tissue. A u-shaped custom made bioreactor capable of producing flow stretch and flexure was used. Computational Fluid Dynamic (CFD) simulations were performed through Ansys CFX (Ansys, Pittsburgh, PA) for both steady and pulsatile flow. We have shown that OSS can be maximized by inducing pulsatile flow over straight scaffolds. We believe that OSS promotes BMSCs tissue formation.

Solutes are often most efficiently deployed in discrete pulses, for example in the delivery of herbicides or drugs. Manual application of each pulse can be labor-intensive, automated application of each pulse can be capital intensive, and both are often costly and impractical. Barrier-Mediated Pulsatile Release (BMPR) systems offer a materials-based alternative for automated pulsatile drug delivery, without pumps, power supplies, or complex circuitry. While earlier materials-based approaches such as delayed-release microcapsules are limited to two or three pulses due to the independent nature of each pulse’s timing control, BMPR systems link the timing of each pulse to the previous pulse. Each dose of drug is sequestered in its own stimuli-sensitive depot, releasing only upon contact with the stimulant. These depots are stacked with sacrificial barriers in between, each of which block the stimulant for a predetermined time. For instance, layers of soluble drug may be separated by degradable polymer layers. Water, as the stimulant, will erode the polymer layer over a fixed period of time, followed by quick dissolution and release of the underlying drug and the start of degradation for the next polymer layer. This example, however, is quickly limited by irregular polymer erosion, a single stimulant (water), and difficulty in scaling delay times. The research work presented in this thesis reports the development of a generalized BMPR system which overcomes those limitations. Model drugs (methylene blue and methyl orange) were immobilized in a pH-sensitive polymer [poly(methyl methacrylate-co-dimethylaminoethyl methacrylate)] which released only at low pH. Zinc oxide (ZnO) nanoparticles immobilized in a pH-insensitive matrix [poly(vinyl alcohol)] served as the barrier layer. The time required for acid to penetrate the barrier layer scaled with the ZnO concentration and with the square of the polymer thickness, allowing wide scaling of the delay time with only minor changes to the barrier layer. Harnessing the swelling pressure of the acid-sensitive hydrogel, each barrier/depot bilayer can delaminate upon solute release, directly exposing the next bilayer to the stimulant source. This system has demonstrated tuned release using a citric acid stimulant to produce up to ten pulses of model drug (methylene blue) over various preset timescales. This system has also demonstrated the alternate release of multiple solutes (methylene blue and methyl orange) at regular time intervals up to five pulses from a single BMPR device. For non-delaminating BMPR systems, spent bilayers impede stimulant diffusion to the inner layers and solute diffusion from the inner layers, increasing the delay time and the pulse width. To predict these changes, a computational model was constructed in FORTRAN. This model was extensively explored over a wide range of parameter space to understand the release behavior of various kinds of non-delaminating BMPR systems. The computer model also validates the performances of experimental delaminating BMPR system. This model can be used to guide the physical modeling of BMPR systems. The model also allows to incorporate variety of stimulants other than just acid. BMPR technology introduces efforts to further generalize the delivery strategy by incorporating glucose as a stimulant.

No description available.

All organs, including the brain, need a pathway to remove neurotoxic extracellular proteins. In the brain this is called the glymphatic system. The glymphatic system works by exchanging proteins from interstitial fluids to cerebrospinal fluids. The extracellular proteins are then removed through the cerebrospinal fluid drains. The glymphatic system is believed to be driven by arterial pulsatility, cerebrospinal fluid production and respiration. Cerebrospinal fluids enters the brain alongside arteries. In this project, we investigate if a simulated pulsatile flow in a common carotid artery can drive cerebrospinal fluid flow running along the artery, using computational simulations of a linearly elastic and fluid-structure multiphysical model in COMSOL. Our simulations show that a heartbeat pulse increases the arterial radius of the common carotid artery by 6 %. Experimental data, assessed using 4D magnetic resonance imaging of a living human, show an increase of 13 %. Moreover, our results indicate that arterial displacement itself is not able to drive cerebrospinal fluid flow. Instead, it seems to create a back and forth flow that possibly could help with the protein exchange between the cerebrospinal and interstitial fluids. Overall, the results indicate that the COMSOL Multiphysics linearly elastic model is not ideal for approximations of soft non-linearly elastic solids, such as soft polydimethylsiloxane and artery walls work for stiffer materials. The long term aim is to simulate a part of the glymphatic system and the present work is a starting point to reach this goal. As the simulations in this work are simplified there are more things to test in the future. For example, using the same geometries a non-linear elastic model could be tested. The pulsatile waveform or the geometry could be made more complex. Furthermore the model could be scaled down to represent a penetrating artery in the brain instead of the common carotid artery.

Understanding the hemodynamics of the cardiovascular system and associated diseases is important for mitigating health risks. We applied flow diagnostic techniques to investigate pulsatile flow characteristics past sidewall cavities, which have implications to two biomedical problems in the cardiovascular system: sidewall aneurysms and the left atrial appendage. Superhydrophobically-coated mesh diverters and synthetic slippery surfaces were studied for their effects on flow diversion and cavity flow enhancements. The study of pulsatile flow over a coated mesh diverter showed that the formation of the primary vortex was prevented which prevents flow stagnation and downwash flow in the cavity. The second study indicates that the healthy heart cycle is essential to reducing flow stasis inside the left atrial appendage. After applying a synthetic slippery surface to the interior of a side wall cavity model, this surface reduced the wall shear stress and allowed vortical flow to reach deeper into the cavity.

In der Kinderherzchirurgie ist die Operation am kardiopulmonalen Bypass unter kardioplegen Herzstillstand ein Standardverfahren zur Korrektur angeborener Herzfehler. Dabei sorgt die Herz-Lungenmaschine (HLM) für die maschinelle Aufrechterhaltung von Blutfluss und Gasaustausch während des operativen Eingriffes. Dank stetiger Verbesserung von Technologie, Materialien sowie Anästhesieführung hat sich dieses Verfahren seit seiner ersten erfolgreichen Erprobung vor etwa 70 Jahren von einem hochriskanten Eingriff zu einem Standardverfahren in der Herzchirurgie mit jährlich sinkenden Morbiditäts- und Mortalitätsraten entwickelt. Dennoch bleibt der Eingriff ein Risikofaktor. Durch den veränderten Blutfluss an der HLM kann es zur Minderperfusion des Organismus mit hypoxisch-ischämischen und inflammatorischen Zellschäden kommen. Das Herz erfährt aufgrund der Kardioplegie eine zusätzliche Beeinträchtigung in seiner Funktion. Klinisch können sich die zellulären Schäden je nach Schweregrad in Form von Arrhythmien, kardialen Dysfunktionen bis hin zum Herzstillstand äußern. In dieser experimentellen Studie im Ferkelmodell wurden zwei potenziell kardioprotektive Strategien untersucht, durch die jene Schäden möglicherweise verringert werden könnten. Dabei handelt es sich zum einen um eine pulsatile Flussmodulation an der Herz-Lungenmaschine statt des herkömmlichen laminaren Flusses, wodurch eine bessere Oxygenierung der Organe erreicht werden könnte. Weiterhin soll eine pharmakologisch-therapeutische Möglichkeit zur Verringerung der oxidativen Zellschäden untersucht werden. Hierfür wurde Epigallocatechingallat gewählt. Dieses Polyphenol ist im grünen Tee enthalten und gilt als effektiver Radikalfänger sowie antiapoptotischer Wirkstoff. Ziel ist es festzustellen, in welchem Maße hypoxisch-ischämische und apoptotische Zellschäden nach Anwendung der HLM auftreten und inwiefern diese durch pulsatile Perfusion oder EGCG-Gabe beeinflussbar sind. Zu diesem Zweck wurden 5 Versuchsgruppen mit jeweils 6- 9 Ferkeln der Rasse Angler-Sattelschwein im Alter von ca. 4 Wochen und einem Gewicht zwischen 8-15 kg gebildet: „Kontrollgruppe“, „Kontrollgruppe + EGCG“, Versuchsgruppe „HLM laminar', Versuchsgruppe „HLM laminar + EGCG“ und Versuchsgruppe „HLM pulsatil“. Der operative Versuchsteil wurde nach einem einheitlichen OP-Protokoll unter moderater Hypothermie (28°C) mit 90-minütigem kardiopulmonalem Bypass, 30 min Reperfusionszeit und 90-minütiger Rekonvaleszenzzeit durchgeführt. Es kam die HLM vom Typ Stöckert SIII zum Einsatz, die sowohl pulsatilen als auch laminaren Blutfluss generieren kann. Den EGCG-Gruppen wurde zu zwei Zeitpunkten 10 mg/kg EGCG i.v. verabreicht. Die postoperativen Untersuchungen bestanden aus immunhistochemischen Färbungen des Herzgewebes auf hypoxisch-ischämische und apoptotische Marker (HIF-1α, AIF, Nitrotyrosin, cleaved Caspase 3, PAR, TNFα). Weiterhin wurde mittels Hochleistungsflüssigkeitschromatographie (HPLC) der Gehalt an energiereichen Phosphaten und deren Abbauprodukten (ATP, AMP, ADP) gemessen. Das intraoperative Kreislaufmonitoring wurde dokumentiert. Zur Verlaufsbestimmung von Parametern des Blutbildes und der klinischen Blutchemie wurde zu drei Zeitpunkten während der Operation Blut entnommen. Die Ergebnisse zeigen, dass alle immunhistochemischen Marker in der Gruppe „HLM laminar“ am höchsten waren und belegen das Vorkommen hypoxischer, inflammatorischer und apoptotischer Stoffwechselprozesse unter Nutzung der laminaren HLM. Bei pulsatiler Perfusion wurde signifikant weniger TNFα, Caspase 3, PAR sowie Nitrotyrosin nachgewiesen und die zellulären Energiereserven (ATP/ ADP + AMP) im Myokard waren höher. Vermutlich wurde durch das veränderte Flussmuster eine bessere Gewebsoxygenierung gewährleistet. Unter EGCG-Gabe war die Expression von HIF-1α, AIF, Nitrotyrosin, TNFα und PAR signifikant vermindert. Somit ist anzunehmen, dass EGCG toxische Metabolite (ROS/ RNS) neutralisierte und gleichzeitig apoptotische Zellschäden verringerte. Beide untersuchten Strategien zeigten kardioprotektive Wirkung, da sie in die pathophysiologischen Stoffwechselwege von Ischämie/Reperfusion und Apoptose eingriffen und in der Lage waren, zelluläre Schäden zu vermindern. Die Ergebnisse sind für die Kardioprotektion in der Kinderkardiologie von Bedeutung, da sie effektive therapeutische Möglichkeiten darstellen könnten, die ischämischen Zellschäden zu verringern und somit die klinischen Folgen für das Herz zu reduzieren.:Inhaltsverzeichnis ABKÜRZUNGSVERZEICHNIS TABELLENVERZEICHNIS ABBILDUNGSVERZEICHNIS 1 EINLEITUNG 2 LITERATURÜBERSICHT 2.1 ANWENDUNG DER HERZ-LUNGENMASCHINE 2.1.1 Entwicklung der Herz-Lungenmaschine- ein historischer Überblick 2.1.2 Aufbau der Herz-Lungenmaschine und Indikation für deren Einsatz 2.1.3 Besonderheiten der pädiatrischen Kardiochirurgie 2.1.4 Bedeutung der Herz-Lungenmaschine in der Veterinärmedizin 2.2 PATHOPHYSIOLOGIE DER HERZ-LUNGENMASCHINE 2.2.1 Häufige postoperative Komplikationen 2.2.2 Entzündungsreaktion 2.2.2.1 SIRS 2.2.2.2 Körpereigene Abwehrmechanismen 2.2.2.3 Störung der Hämostase 2.2.3 Ischämie-Reperfusionsschaden 2.2.4 Zelltod 2.3 KARDIOPROTEKTIVE STRATEGIEN 2.3.1 Perioperative Maßnahmen 2.3.2 Pulsatile Perfusion 2.3.3 Pharmakologische Kardioprotektion mit Epigallogatechingallat (EGCG) 2.4 HYPOXIE-, ENTZÜNDUNGS- UND APOPTOSEMARKER ZUR ANALYSE 2.4.1 Entzündungsmarker 2.4.2 Marker für Hypoxie und oxidativen Stress 2.4.3 Apoptosemarker 2.5 FRAGESTELLUNG 3 TIERE, MATERIAL UND METHODEN 3.1 VERSUCHSDURCHFÜHRUNG 3.1.1 Versuchstiere und Versuchsgruppen 3.1.2 Anästhesie und OP-Durchführung 3.1.2.1 Prämedikation und Narkoseeinleitung 3.1.2.2 Narkose 3.1.2.3 Monitoring 3.1.2.4 Versuchsablauf 3.1.3 Extrakorporale Zirkulation und Kardioplegie 3.1.3.1 Aufbau der HLM 3.1.3.2 Operativer Zugang und Kanülierung des Herzens 3.1.3.3 Vorbereitung der HLM 3.1.3.4 Herbeiführung der Kardioplegie 3.1.3.5 Durchführung der extrakorporalen Zirkulation 3.2 POSTOPERATIVE UNTERSUCHUNGEN 3.2.1 Probenentnahme und –aufbereitung 3.2.2 Histologische Färbung 3.2.3 Immunhistochemische Färbungen 3.2.3.1 Entparaffinierung und Rehydrierung 3.2.3.2 Permeabilisierung 3.2.3.3 Blocken der endogenen Bindungsstellen 3.2.3.4 Antikörper- Inkubation 3.2.3.5 Kernfärbung 3.2.3.6 Negativkontrollen 3.2.4 Mikroskopie 3.2.5 Auswertung 3.2.6 Blutwerte 3.2.7 RP-HPLC 3.3 STATISTISCHE AUSWERTUNG 4 ERGEBNISSE 4.1 ERGEBNISSE DER BLUTPROBEN UND NARKOSE- ÜBERWACHUNG 4.2 ERGEBNISSE DER IMMUNHISTOCHEMIE 4.2.1 HIF-1α-Färbung 4.2.2 AIF-Färbung 4.2.3 Nitrotyrosin-Färbung 4.2.4 TNFα-Färbung 4.2.5 PAR-Färbung 4.2.6 cC3-Färbung 4.3 ERGEBNISSE DER RP-HPLC 5 DISKUSSION 5.1 MODELLBETRACHTUNG 5.2 EINFLUSS DER HLM AUF DAS HERZGEWEBE 5.3 LAMINARE VS. PULSATILE PERFUSION DER HLM 5.4 EINFLUSS VON EGCG 6 ZUSAMMENFASSUNG 7 SUMMARY 8 LITERATURVERZEICHNIS 9 ANHANG 9.1 ANGABEN ZU MEDIKAMENTEN UND OP-MATERIAL 9.2 GERÄTE UND ZUBEHÖR FÜR DIE POSTOPERATIVEN UNTERSUCHUNGEN 9.3 HERSTELLUNGSPROTOKOLLE UND ZUSAMMENSETZUNG DER LÖSUNGEN FÜR DIE HISTOLOGIE UND IMMUNHISTOCHEMIE 9.3.1 Formalinfixierung nach LILLIE 9.3.2 Vollautomatische Paraffineinbettung 9.4 ZUBEHÖR FÜR DIE RP-HPLC 9.5 HPLC- PROTOKOLL FÜR DIE VORBEREITUNG DER HPLC-QUANTIFIZIERUNG METABOLISCHER KOMPONENTEN IM HERZGEWEBE 9.6 AUSWERTUNG 9.7 ANTIKÖRPER UND FÄRBEPROTOKOLLE DER IMMUNHISTOCHEMIE 9.7.1 Färbeprotokoll HIF-1α 9.7.2 Färbeprotokoll AIF 9.7.3 Färbeprotokoll Nitrotyrosin 9.7.4 Färbeprotokoll TNFα 9.7.5 Färbeprotokoll PAR 9.7.6 Färbeprotokoll cC3 9.7.7 Färbeprotokoll HE 9.8 TABELLEN UND ABBILDUNGEN 10 DANKSAGUNG

Indiana University-Purdue University Indianapolis (IUPUI) / The thesis includes two application studies of computational fluid dynamics. The first is new and efficient drug delivery to the posterior part of the eye, a growing health necessity worldwide. Current treatment of eye diseases, such as age-related macular degeneration (AMD), relies on repeated intravitreal injections of drug-containing solutions. Such a drug delivery has significant cant drawbacks, including short drug life, vital medical service, and high medical costs. In this study, we explore a new approach of controlled drug delivery by introducing unique porous implants. Computational modeling contains physiological and anatomical traits. We simulate the IgG1 Fab drug delivery to the posterior eye to evaluate the effectiveness of the porous implants to control the drug delivery. The computational model was validated by established computation results from independent studies and experimental data. Overall, the results indicate that therapeutic drug levels in the posterior eye are sustained for eight weeks, similar to those performed with intravitreal injection of the same drug. We evaluate the effects of the porous implant on the time evaluation of the drug concentrations in the sclera, choroid, and retina layers of the eye. Subsequent simulations were carried out with varying porosity values of a porous episcleral implant. Our computational results reveal that the time evolution of drug concentration is distinctively correlated to drug source location and pore size. The response of this porous implant for controlled drug delivery applications was examined. A correlation between porosity and fluid properties for the porous implants was revealed in this study. The second application lays in the computational modeling of the oscillating