Flow with separation and reattachment has been encountered in many thermo-fluidic devices. Although it causes energy loss due to pressure drops, it is sometimes intentionally used for heat transfer enhancement. To improve the performance of heat exchangers, understanding the details of such complicated flow and thermal structures is very important. Therefore, attention was paid in this study to a representative typical simple model that can generate separating and reattaching flow called backward-facing step (BFS) flow, the fundamental flow and thermal characteristics of a 3-D BFS flow have been investigated experimentally and a flow modification was also made by numerical simulation aimed to promote the heat transfer enhancement. / 博士(工学) / Doctor of Philosophy in Engineering / 同志社大学 / Doshisha University

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[pt] O trabalho apresenta uma ampla revisão de conceitos básicos associados ao fluxo multifásico (fluxo simultâneo de dois ou mais fluidos) em meios porosos, bem como técnicas de ensaios e equipamentos utilizados na determinação de permeabilidades efetiva e absoluta em solos saturados e não saturados com água. Com base nesta revisão, e visando a medida da permeabilidade de solos não saturados submetidos a fluxo de misturas gasolina-álcool, foi projetados, construído e colocado em operação um sistema de permeâmetros de parede flexível com controle de sucção; foi desenvolvido um software de controle e implementando um sistema automático de monitoramento da instrumentação eletrônica utilizada para medidas de variação de volume, de pressões e de deslocamentos axiais das amostras desolo; foi implementado um sistema de bomba de fluxo para aplicação de vazões constantes nos ensaios de permeabilidade, e forma desenvolvidos sistemas de medição do volume dos líquidos e gases passando pela amostra sob diferentes gradientes de pressão. Todos os desenvolvimentos projetados e implementados são descritos em detalhe. Características de uso dos equipamentos e aspectos de calibração da instrumentação eletrônica e demais acessórios são discutidos, procurando-se definir limites de trabalhabilidade, eventuais deficiências e técnicas alternativas de ensaios envolvendo o uso de misturas álcool gasolina. Visando avaliar o comportamento dos equipamentos e acessórios desenvolvidos, apresenta-se e discute-se resultados de um programa experimental envolvendo a) o uso de amostras de um solo inerte, incompressível dentro dos níveis de tensões efetivas aplicadas, preparadas em laboratório utilizando técnicas especiais de modo a se obter uma estrutura repetitiva, fracamente cimentada, simulando os solos residuais de gnaisse; b) execução de ensaios de vazão constante visando a determinação da permeabilidade absoluta de amostras saturadas utilizando como fluidos permeantes água, ar gasolina e álcool; c) execução de ensaios de vazão constante visando a determinação das permeabilidades efetivas à água e ao ar de amostras não saturadas, submetidas a sucções constantes variando de cerca de 10 a 60 kPa. Os resultados obtidos indicam que o equipamento desenvolvido e as técnicas experimentais implementadas constituem ferramentas versáteis que possibilitam a determinação direta das permeabilidades absolutas e efetivas de forma relativamente simples e confiáveis. / [en] This work presents a wide revision of basic concepts associated to the multiphase flow (simultaneous flow of two or more fluids) in porous media as well as techniques of test and equipment s used in the determination of effective and absolute permeability in saturated and not saturated soils with water.With basis in this revision, and locking for the measure of saturated soils permeability submitted to flow of mixtures gasoline-alcohol, it was projected, built and placed in operation a system of flexible wall permeameters with suction control; a control software was developed and implementing an automatic system of monitoring of the electronic instrumentation used for measures of change volume, pressures and axial displacements of the soil samples; a flow pump system was implemented for application of constant rate in the permeability test, and systems of measurement of the volume of the liquids and gases were developed going by the sample under different pressure gradients.All the projected developments and implemented are described in detail. Characteristics of the used equipment s and calibration aspects of the electronic instrumentation and other accessories are discussed, trying to define workability limits, eventual deficiencies and techniques alternatives of testing involving the use of alcohol gasoline mixtures. Look in for evaluate the performance of equipment s and developed accessories, are presented and it is discussed results of an experimental program involving a) the use of samples of a inert soil, incompressible between levels of applied effective tensions,prepared in labortory using special techniques in way obtaining a repetitive structure, weakly cemented, simulating the residual soils of gnaisse; b) execution of constant rate test looking for the absolute permeability determination of saturated samples using as percolate fluids water, air, gasoline and alcohol; c) execution of constant rate test looking for the determination of the effective permeability to the water and the air of non saturated samples, submitted to constant suctions varying about 10 to 60 kPa.The obtained results indicate that the developed equipment and the implemented experimental techniques constitute versatile tools that make possible the direct determination of the absolute and effective permeabilities in way relatively simple and you trusted. / [es] EL trabajo presenta una amplia revisión de conceptos básicos asociados al flujo multifásico (flujo simultáneo de Dos o más fluidos) en medios porosos, así como técnicas de ensayos y equipamentos utilizados en la determinación de permeabilidades efectiva y absoluta en suelos saturados y no saturados con agua. Con el objetivo de medir la permeabilidad de suelos no saturados sometidos a flujo de mezclas de gasolina y alcohol, fue proyectados, construido y colocado en operación un sistema de permeámetros de pared flexible con control de succión; se desarrolló un software de control y se implementó un sistema automático de monitoramiento de la instrumentación eletrónica utilizada para medidas de variación de volumen, de presiones y de desplazamientos axiales de las muestras de suelo. Se implementó además; un sistema de bomba de flujo para aplicación de desbordamientos constantes en los ensayos de permeabilidad, y se deasarrollaron sistemas de medición del volumen de los líquidos y gases pasando por la muestra bajo diferentes gradientes de presión. Se detallan todos los desarrollos proyectados e implementaciones. Se discute las características de uso de los equipamentos y aspectos de calibración de la instrumentación eletrónica y demás accesorios, con el objetivo de definir límites de trabajabilidad, eventuales deficiencias y técnicas alternativas de ensayos que envuelven el uso de mezclas de alcohol u gasolina. Para evaluar el comportamiento de los equipos y accesorios desarrollados, se presentan y discuten los resultados de un programa experimental que considera a) el uso de muestras de un suelo inerte, incompresible dentro de los níveles de tensiones efectivas que fueron aplicadas, preparadas en laboratorio utilizando técnicas especiales para obtener una extructura repetitiva, debilmente cimentada, simulando suelos residuales de gnaise; b) ejecución de ensayos de desbordamiento constante visando la determinación de la permeabilidad absoluta de muestras saturadas utilizando como fluidos permeantes agua, ar gasolina y álcool; c) ejecución de ensayos de desbordamiento constante con el objetivo de determinar las permeabilidades efectivas a agua y aire de muestras no saturadas, sometidas a succiones constantes variando entre 10 a 60 kPa. Los resultados obtenidos indican que el equipo desarrollado y las técnicas experimentales implementadas constituyen herramientas versátiles que hacen posible la determinación directa de las permeabilidades absolutas y efectivas de forma relativamente simple y confiables.

In the United States, nearly half a million bone graft operations are performed annually to repair defects arising from birth defects, trauma, and disease, making bone the second most transplanted tissue. Autogenous bone is the current gold standard for bone grafts; however it is in limited supply and results in a second injury at the donor site. A promising alternative is a tissue engineered bone graft composed of a biomaterial scaffold, pharmaceutics, and osteoprogenitor cells. One source of osteoprogenitor cells is bone marrow stroma, which can be obtained from the patient - minimizing the risk of an immune response - directed in vitro to proliferate, and differentiate into a bone-like tissue. To date, tissue engineered bone grafts have not been clinically effective; thus, strategies must be developed to improve efficacy. I hypothesize that to facilitate tissue healing in a manner similar to autogenous bone tissue engineering bone must possess a mineralized collagen matrix to support tissue integration, and angiogenic factors to stimulate vascular infiltration, and osteogenic factors to direct normal bone remodeling. I propose that these factors can be synthesized by osteoprogenitor cells in vitro when cultured under the appropriate conditions. Previous work has demonstrated that perfusion culture of osteoprogenitor cells within 3D scaffolds stimulates phenotypic markers of osteoblastic differentiation, but those studies did not determine whether the effects were a consequence of shear stress or increased nutrient availability. Consequently, this work has involved studies in a planar geometry, where nutrient effects are negligible. Three studies that characterize the effect of fluid flow on osteoblastic differentiation of osteoprogenitor cells are presented here. The objective of the first study was to determine the effect of shear stress magnitude on cell density and osteocalcin deposition. In this study, radial flow chambers were used to generate a spatially dependent range of shear stresses (0.36 to 2.7 dynes/cm2) across single substrates, and immunofluorescent techniques were used to assay cell phenotype as a function of shear stress. The objective of the second study was to determine the effect of the duration of fluid flow on cell density and phenotypic markers of differentiation. Here, parallel plate flow chambers were used to generate a single shear stress at the cell surface, and entire cell layers were assayed for expression of osteoblastic genes. The objective of the third study was to compare continuous and intermittent fluid flow strategies. In this study, a microprocessor-controlled actuator was added to the flow loop to periodically halt flow, and markers of mechanosensation and osteoblastic differentiation were measured. These studies demonstrated that shear stresses of 0.36 to 2.7 dynes/cm2 stimulate late phenotypic markers of osteoblastic differentiation but not cell proliferation. In addition, this osteogenic effect is sensitive to duration of fluid flow but insensitive to the magnitude of shear stress. Further, intermittent fluid flow enhances cell retention, biochemical markers of mechanotransduction, and synthesis of the angiogenic factor vascular endothelial growth factor (VEGF). Thus, these studies suggest that intermittent fluid flow may be an attractive component of a biodynamic bioreactor for in vitro manufacture of clinically effective tissue engineered bone grafts. Future studies will further investigate intermittent fluid flow strategies and three-dimensional studies with scaffolds suitable for bone tissue engineering. / Ph. D.

Glioblastoma is the most common and deadly primary brain tumor with an average survival of 15 months following diagnosis. Characterized as highly infiltrative with diffuse tumor margins, complete resection and annihilation of tumor cells is impossible following current standard of care therapies. Thus, tumor recurrence is inevitable. Interstitial fluid surrounds all of the cells in the body and has been linked to elevated invasion in glioma, which highlights the importance of this understudied fluid compartment in the brain. The primary objective of this dissertation was to identify specific interstitial fluid transport behaviors associated with elevated invasion surrounding glioma tumors. We first describe our methods to measure interstitial fluid flow in the brain using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), a clinically used, non-invasive imaging modality. We highlight the versatility of the technique and the possibilities that could arise from widespread adoption into existing perfusion-based imaging protocols. Using this method, we examined transport associated with invasion in a murine GL261 cell line. We found that elevated interstitial fluid velocity magnitudes, decreased diffusion coefficients and regions with accumulating flow were significantly associated with invasion. We tested the validity of our invasive trends by extending our analysis to multiple, clinically-relevant tumor locations in the brain. Interestingly, we found invasion did not follow the same trends across brain regions indicating location-specific structures may drive both interstitial flow and corresponding invasion heterogeneities. Lastly, we aimed to manipulate flow by engaging with the meningeal lymphatics, an established pathway for interstitial fluid drainage. Over-expression of VEGF-C in the tumor microenvironment neither enhanced drainage nor altered invasion in comparison to our control, indicating other tumor-secreted growth factors, such as VEGF-A, may play a larger role in mediating flow and invasion. Taken together, by identifying specific transport factors associated with invasion, we may be better equipped to target and treat infiltrative tumor margins, ultimately extending survival in patients diagnosed with this devastating disease. / Doctor of Philosophy / Glioblastoma is the most common and deadly primary brain tumor with an average survival of 15 months following diagnosis. Characterized as highly infiltrative with diffuse tumor margins, complete resection and annihilation of tumor cells is impossible following current standard of care therapies. Thus, tumor recurrence is inevitable. Interstitial fluid surrounds all of the cells in the body and has been linked to elevated invasion in glioma, which highlights the importance of this understudied fluid compartment in the brain. The primary objective of this dissertation was to identify specific interstitial fluid transport behaviors associated with elevated invasion surrounding glioma tumors. We first describe our methods to measure interstitial fluid flow in the brain using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), a clinically used, non-invasive imaging modality. We highlight the versatility of the technique and the possibilities that could arise from widespread adoption into existing imaging projects. Using this method, we examined transport associated with cancer cell invasion in a mouse tumor cell line. We found that interstitial fluid speeds were elevated while diffusion was decreased in regions of invasion. Further, regions that had interstitial fluid flow congregation were significantly associated with invasion. We tested the validity of these invasive trends by extending our analysis to multiple, clinically-relevant tumor locations in the brain. Interestingly, we found invasion did not follow the same trends across brain regions, indicating location-specific structures may drive both interstitial flow and invasion differences. Lastly, we aimed to manipulate flow by engaging with the meningeal lymphatics, an established pathway for interstitial fluid drainage. Following administration of a meningeal lymphatic-relevant protein, we saw no changes in flow or invasion in comparison to our untreated control, indicating other tumor-secreted proteins may play a larger role in these responses. Taken together, by identifying specific transport factors associated with invasion, we may be better equipped to target and treat infiltrative tumor margins, ultimately extending survival in patients diagnosed with this devastating disease.

The lymphatic system plays essential roles in regulating fluid balance and immunosurveillance. Across the body, local lymphatic vessels collect waste in the form of lymph and deliver it to nearby lymph nodes (LNs) to be filtered and screened for pathogens. With broad implications in adaptive immunity, cancer metastasis, and cancer treatment, developing novel in vitro models will provide new platforms to explore lymphatic function in health and disease. This dissertation sought to develop tissue-specific engineered models of the LN stroma and the meningeal lymphatics to examine the transport of cells and fluid. Within the LN, fibroblastic reticular cells (FRCs) maintain a network of extracellular matrix conduits that guide varying rates of interstitial fluid flow (IFF) based on inflammatory state. Eventually, that flow exits the LN through the afferent lymphatics, consisting of lymphatic endothelial cells (LECs). We first developed a spatially organized model of the LN stroma consisting of a monolayer of LECs on the underside of a tissue culture insert and an FRC-laden hydrogel within. We demonstrate that high magnitude IFF (3.0 µm/s) had positive impacts on FRCs but disrupted the integrity of the LEC barrier, and these effects were accompanied by increased secretion of a variety of inflammatory chemokines. We also show that IFF of any magnitude decreased T cell egress from the model. Next, we sought to apply the LN stroma model toward understanding metastasis. LN metastasis is the most important prognostic factor in breast cancer, with size of metastasis informing treatment plan. Metastasis greatly alters the structure of the LN, which in turn alters transport. However, the impact of altered transport on cancer progression is not well understood. We added different numbers of breast cancer cells to our LN stroma model to examine tumor burden. We found that tumor cells invaded the LEC barrier at similar numbers regardless of initial burden. Additionally, at the highest tumor burden, diffusivity in the stroma was significantly decreased. Most excitingly, flow velocity was positively correlated with FRC spread in the hydrogel, demonstrating the contributions of FRCs to transport. Finally, we looked to the central nervous system (CNS). The meningeal lymphatics are responsible for draining cerebrospinal fluid to the cervical lymph nodes for CNS immunosurveillance. We developed a simple model of a meningeal lymphatic vessel lumen consisting of a monolayer of LECs on the underside of a tissue culture insert and a monolayer of meningeal fibroblasts within. This is, to our knowledge, the very first in vitro model of the meningeal lymphatics. We demonstrate that our model has barrier function and is capable of immune cell transmigration and egress. We examined how systemic chemotherapy for breast cancer could cause off-target disruption of the meningeal lymphatics and found that docetaxel was significantly deleterious. We further began to explore leukemia cell behavior in our LN stroma and meningeal lymphatics model. Throughout this dissertation, we emphasize the importance of incorporating fluid and cell transport into engineered models of immunity. These models represent a step toward building up the complexity of in vitro lymphatic models to improve pre-clinical screening and understand pathophysiology. / Doctor of Philosophy / The lymphatic system plays essential roles in regulating fluid balance and immune system surveillance. Across the body, local lymphatic vessels collect waste in the form of lymph and deliver it to nearby lymph nodes (LNs) to be filtered and screened for pathogens like viruses or bacteria. With broad implications in immunity, cancer metastasis, and cancer treatment, developing novel models in the lab using human cells and 3-dimensional biomaterials will provide new platforms to explore lymphatic function in health and disease. This dissertation sought to develop engineered models that were specific to the lymph node stroma and the meningeal lymphatics to examine the transport of cells and fluid. Within the LN, fibroblastic reticular cells (FRCs) maintain a network of channels that guide varying rates of interstitial fluid flow (IFF) based on how inflamed the LN is. Eventually, that flow exits the LN through the afferent lymphatics, consisting of lymphatic endothelial cells (LECs). We first developed a spatially organized model of the LN stroma consisting of LECs on the underside of a porous membrane and an FRC-laden hydrogel above the membrane and demonstrated that high magnitude IFF altered morphology, immune cell behavior, and inflammatory protein secretion in the model. Next, we sought to apply the LN stroma model toward understanding cancer metastasis. LN metastasis is the most important prognostic factor in breast cancer, with size of metastasis informing treatment plan. Metastasis greatly alters the structure of the LN, which in turn alters the transport of lymph and immune cells. However, the impact of altered transport on cancer progression is not well understood. We added different numbers of breast cancer cells to our LN stroma model to examine tumor burden and found that tumor cells invaded the LECs at similar rates regardless of initial density, but that diffusion, a transport parameter, was significantly changed by high tumor cell density. Finally, we looked to the central nervous system (CNS). The meningeal lymphatics are responsible for draining cerebrospinal fluid to the cervical lymph nodes to screen for pathogens in the CNS. We developed a simple model of a meningeal lymphatic vessel lumen consisting of LECs and meningeal fibroblasts on either side of a porous membrane. This is, to our knowledge, the very first in vitro model of the meningeal lymphatics. We examined how systemic chemotherapy for breast cancer could cause off-target disruption of the meningeal lymphatics and found that docetaxel was significantly damaging to the model. Throughout this dissertation, we emphasize the importance of incorporating fluid and cell transport into engineered models of lymphatics. These models represent a step toward building up complexity to improve the toolset for pre-clinical screening and studying disease progression.

Doubling transistor count for every two years in a computer chip, transmitter and receiver (T/R) module of a phased-array antenna that demands higher power with smaller dimensions are all results of miniaturization in electronics packaging. These technologies nowadays depend on improvement of reliable high performance heat sink to perform in narrower volumes. Employing microchannels or open cell metal foam heat sinks are two recently developing promising methods of cooling high heat fluxes. Although recent studies especially on microchannels can give a rough estimate on performances of these two methods, since using metal foams as heat sinks is still needed further studies, a direct experimental comparison of heat exchanger performances of these two techniques is still needed especially for thermal design engineers to decide the method of cooling. For this study, microchannels with channel widths of 300 &micro / m, 420 &micro / m, 500 &micro / m and 900 &micro / m were produced. Also, 92% porous 10, 20 and 40 ppi 6101-T6 open cell aluminum metal foams with compression factors 1,2, and 3 that have the same finned volume of microchannels with exactly same dimensions were used to manufacture heat sinks with method of vacuum brazing. They all have tested under same conditions with volumetric flow rate ranging from 0,167 l/min to 1,33 l/min and 60 W of heat power. Channel height was 4 mm for all heat sinks and distilled water used as cooling fluid. After experiments, pressure drops and thermal resistances were compared with tabulated and graphical forms. Also, the use of metal foam and microchannel heat sinks were highlighted with their advantages and disadvantages for future projects.