Indiana University-Purdue University Indianapolis (IUPUI) / A pulsatile flow loop can be suitable for measurement of in vitro blood pressure. The pressure data collected from such a system can be used for evaluating stenosis in human arteries, a condition in which the arterial lumen size is reduced. The objective of this work is to develop an experimental system to simulate blood flow in the human arterial system. This system will measure the in vitro hemodynamics using 3-D prints of vessels extracted from patient CT images. Images are segmented and processed to produce 3-D prints of vessel geometry, which are mounted in the loop. Control of flow and pressure is made possible by the use of components such as a pulsatile heart pump, resistance, and compliance elements. Output data is evaluated by comparison with CFD and invasive measurement. The system is capable of measurement of the pressures such as proximal, Pa, and distal, Pd, pressures to evaluate in vivo conditions and to assess the severity of stenosis. This is determined by use of parameters such as fractional flow reserve (FFR=Pd/Pa) or trans-stenotic pressure gradient (TSPG=Pa-Pd). This can be done on a non-invasive, patient specific basis, to avoid the risk and high cost of invasive measurement. In its operation, the preliminary measurement of blood pressures demonstrates agreement with the invasive measurement as well as the CFD results. These preliminary results are encouraging and can be improved upon by continuing development of the experimental system. A working pulsatile loop has been reached, an initial step taken for continued development. This loop is capable of measuring the flow and pressure from in a 3-D printed artery. Future works will include more life-like material for the artery prints, as well as cadaver vessels.

The major drawback of crossflow membrane filtration is that permeate flux declines with time as a result of the increase in total membrane resistance. Pulsatile flow is well known to reduce the resistance and enhance permeate flux. This study applied pulsatile flow induced by the oscillation of a collapsible tube to microfiltration and ultrafiltration, to improve filtration performance expressed as permeate flux enhancement and backflushable resistance reduction. Three membranes (ceramic tubular microfiltration, PVDF spiral-wound microfiltration and PS hollow-fibre ultrafiltration) and two media (bentonite suspension and whey solution) were used. In bentonite pulsatile microfiltration with the tubular membrane, up to 300% of permeate flux enhancement and 90% of backflushable resistance reduction were achieved. In bentonite and whey pulsatile microfiltration with the spiral-wound membrane, moderate improvements were gained: for bentonite, the highest increase in permeate flux was 51% and decrease in backflushable resistance was 45%; for whey, the highest permeate flux enhancement and backflushable resistance reduction were 36% and 38% respectively. In ultrafiltration of both media, no significant performance improvement was found. This is thought due in the one case to the relatively minute membrane pore size, and in the other to the large irreversible resistance created by whey solution. Transmural pressure at the collapsible tube downstream end indicates the tube compression and influences the pulsation vigour. Increasing the transmural pressure was an effective way to improve filtration performance. In bentonite microfiltration with the tubular membrane, increasing crossflow velocity was also effective, but increasing transmembrane pressure was not. Analysis of pulsatility parameters showed that the pulsatile flow always resulted in enhanced wall shear, and induced pore backflush always in the tubular membrane and sometimes in the HF membrane. These mechanistic findings helped to understand the filtration performance improvements. The analysis of energy consumption in bentonite microfiltration with the tubular membrane clearly demonstrated the benefit of applying the collapsible-tube-induced pulsatile flow in energy utilisation. The system specific energy could be reduced more than 70 % relative to the equivalent steady microfiltration permeate flux. For a given specific energy, the permeate flux could be increased by a factor of nearly four.

Many complex biological systems, such as blood and polymeric materials, can be approximated as single constituent homogeneous fluids whose properties can change because of the chemical reactions that take place. For instance, the viscosity of such fluids could change because of the chemical reactions and the flow. Here, I investigate the pulsatile flow of a chemically-reacting fluid whose viscosity depends on the concentration of a species (constituent) that is governed by a convection-reaction-diffusion equation and the velocity gradient, which can thicken or thin the fluid. I study the competition between the chemical reaction and the kinematics in determining the response of the fluid. The solutions to the equations governing the steady flow of a chemicallyreacting, shear-thinning fluid are obtained analytically. The solution for the velocity exhibits a parabolic-type profile reminiscent of the Newtonian fluid profile, if the fluids are subject to the same boundary conditions. The full equations associated with the fluid undergoing a pulsatile flow are studied numerically. A comparison of the shear-thinning/chemical-thinning fluid to the shear-thinning/chemicalthickening fluid using a new non-dimensional parameter–the competition number (CN) shows that both the shear-thinning effects and the chemical-thinning/thickening effects play a vital role in determining the response of the fluid. For the parameter values chosen, the effects of chemical-thinning/thickening dominate the majority of the domain, while the effects due to shear-thinning are dominant only in a small region near the boundary.

Glucocorticoids (GCs) exert diverse effects on multiple cell types and tissues. The variability in GC sensitivity can give rise to disease states hence the importance of GC sensitivity modulators. GCs act through the glucocorticoid receptor (GR), a ligand-activated nuclear hormone receptor (NR), which interacts with the DNA to regulate gene transcription depending on the chromatin structure. GR itself modulates chromatin through epigenetic modification of histone residues. In the present study, novel modulators of GC sensitivity, altering GR-mediated gene expression through dynamic or epigenetic regulatory mechanisms, are identified and explored. Metastasis-related methyltransferase1 (Merm1/WBSCR22), is a histone methyltransferase, previously shown to methylate histone H3 Lysine 9 (H3K9), a repressive methyl mark, to inhibit target gene transcription. Our GR reporter transient transfections assays showed that Merm1 potentiated GR transactivation through its methyltransferase and SAM domains. Merm1 knockdown significantly impaired both GR transactivation, and transrepression of endogenous genes, including GILZ. The ChIP assay analysis confirmed that both GR and Merm1 bound the GILZ promoter and Merm1 regulated ligand-induced GR recruitment. Merm1 regulated tri-methylation of H3K4 (H3K4me3) and di-methylation of H3K79 (H3K79me2). At the GILZ locus, GR induced H3K4me3 and inhibited H3K79me2. Merm1 regulated both of these and also maintained basal H3K79me2. The GR-induced H3K4me3 followed by loss of H3K79me2 showed that these events were driven by H3K4 methylation. In conclusion, Merm1 regulates chromatin structure to affect GR recruitment, and mediates GR actions of transcription by histone methylation. In the second part of the thesis, the biological consequence of temporal dynamics of GC delivery to target cell gene expression and apoptosis has been investigated. For this purpose a flow-through culture system was designed and modified for pulsatile and continuous delivery of GC to HeLa cells and primary T cells. Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose in HeLa population. This was due to increased apoptosis. Transcription factor (TF) binding site analysis of the microarray data identified CCAAT-displacement protein (CDP) as a common TF binding site in the differentially regulated target genes. Mouse mammary tumour virus (MMTV) gene is regulated by CDP and is also GC responsive. MMTV-Luc was also differentially regulated between pulsatile and continuous cortisol. In primary T cells, GILZ and FKBP5 genes were more highly induced with continuous than with the same equivalent concentration given in pulses. In conclusion, cortisol oscillations exert important effects on target cell gene expression, and phenotype. In summary, GC sensitivity is modulated via different mechanisms. Our data illustrate a novel regulatory mechanism whereby GR activity is altered through histone modifications and chromatin remodelling. In addition, GC oscillations provide frequency modulation to GR-mediate gene expression with a resulting differential pattern of gene transcription and cellular response.

The main objective of this research was to better understand, predict and control of the periodic precipitation process and to apply such programmed periodic precipitation to the design of a pulsatile delivery system. In the first part of this study, a generalized model taking into account both nucleation, particle growth, and ripening process was refined and solved under various new concentration boundary conditions not previously investigated. The results clearly delineate the key differences between boundary conditions of infinite versus finite supply of inner electrolyte. When the inner electrolyte boundary concentration was allowed to increase exponentially with time, equidistant periodic precipitation was predicted and subsequently confirmed experimentally. In addition, the effects of product solubility and reaction rate constant were also shown to be important in determining the band number and band spacing. In the second part of this study, the effects of gel crosslinking and gel charge density on the periodic precipitation were investigated. The results indicate that by increasing either the gel crosslinking or decreasing the gel charge density will reduce the diffusion rate of the reactants resulting in closely spaced bands. In addition, a new and improved rotating disk method for characterizing polyelectrolyte gels with ion-penetrable soft surfaces has been established by taking into account the effect of surface conductivity which is usually ignored for ion-impenetrable hard surfaces. In the third part of this work, periodic precipitation formed in multi-component systems has been shown to be governed by a heterogeneous nucleation mechanism. Using this approach, periodic precipitation of an insulin mimetic compound VO2+ in gelatin gel, which cannot form alone in a single reaction system, was induced by the periodic precipitation of Mg(OH)2 in a multi-component system. Pulsatile release of VO2+ from the resulting multi-layered structure of VO(OH)2 via a surface erosion mechanism was subsequently demonstrated.

The main objective of this research was to better understand, predict and control of the periodic precipitation process and to apply such programmed periodic precipitation to the design of a pulsatile delivery system. In the first part of this study, a generalized model taking into account both nucleation, particle growth, and ripening process was refined and solved under various new concentration boundary conditions not previously investigated. The results clearly delineate the key differences between boundary conditions of infinite versus finite supply of inner electrolyte. When the inner electrolyte boundary concentration was allowed to increase exponentially with time, equidistant periodic precipitation was predicted and subsequently confirmed experimentally. In addition, the effects of product solubility and reaction rate constant were also shown to be important in determining the band number and band spacing. In the second part of this study, the effects of gel crosslinking and gel charge density on the periodic precipitation were investigated. The results indicate that by increasing either the gel crosslinking or decreasing the gel charge density will reduce the diffusion rate of the reactants resulting in closely spaced bands. In addition, a new and improved rotating disk method for characterizing polyelectrolyte gels with ion-penetrable soft surfaces has been established by taking into account the effect of surface conductivity which is usually ignored for ion-impenetrable hard surfaces. In the third part of this work, periodic precipitation formed in multi-component systems has been shown to be governed by a heterogeneous nucleation mechanism. Using this approach, periodic precipitation of an insulin mimetic compound VO2+ in gelatin gel, which cannot form alone in a single reaction system, was induced by the periodic precipitation of Mg(OH)2 in a multi-component system. Pulsatile release of VO2+ from the resulting multi-layered structure of VO(OH)2 via a surface erosion mechanism was subsequently demonstrated.

In this research, pulsatile blood flow through a modeled arterial stenosis assuming Newtonian and non-Newtonian viscous behavior is simulated using direct numerical simulation (DNS). A serial FORTRAN code has been parallelized using OpenMP to perform DNS based on available high performance shared memory parallel computing facilities. Numerical simulations have been conducted in the context of a channel with varying the degree of stenosis ranging from 50% to 75%. For the pulsatile flow studied, the Womersley number is set to 10.5 and Reynolds number varies from 500 to 2000, which are characteristic of human arterial blood flows. In the region upstream of the stenosis, the flow pattern is primarily laminar. Immediately after the stenosis, the flow recirculates and an adverse streamwise pressure gradient exists near the walls and the flow becomes turbulent. In the region far downstream of the stenosis, the flow is re-laminarized for both Newtonian and non-Newtonian flows.

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

Arterial pulse pressure is critically important to a number of diseases such as isolated systolic hypertension, coronary artery disease and heart failure. Determining the cause of increased pulse pressure has been hampered for two reasons. First, pulse pressure results from contraction of the heart and the load formed by the complex arterial tree. Pressure pulses travel from the heart to the peripheral arteries. As they reach a bifurcation or change in arterial wall properties, some of the pulses get reflected and propagate retrograde towards the heart. Second, two different modeling approaches (0-D and 1-D) describe the arterial system. The Windkessel model ascribed changes in pulse pressure to changes in total arterial compliance (Ctot) and total arterial resistance, whereas the transmission model ascribed them to changes in the magnitude, timing and sites of reflection. Our investigation has addressed both these limitations by finding that a complex arterial system degenerates into a simple 2-element Windkessel model when wavelength of the propagated pulse increases. This theoretical development has yielded three practical results. First, isolated systolic hypertension can be viewed as a manifestation of a system that has degenerated into a Windkessel, and thus increased pulse pressure is due to decreased Ctot. Second, the well-discussed Augmentation Index does not truly describe augmentation of pulse pressure by pulse reflection. Third, the simple 2-element Windkessel can be used to characterize the interaction among heart, arterial system and axial-flow left ventricular assist device analytically. The fact that arterial systems degenerate into Windkessels explains why it becomes much easier to estimate total arterial compliance in hypertension?total arterial compliance is the dominant determinant of pulsatile pressure.

In this study, we have considered the modal and non-modal stability of fluids with shear-dependent viscosity flowing in a rigid straight pipe. A second order finite-difference code is used for the simulation of pipe flow in the cylindrical coordinate system. The Carreau-Yasuda model where the rheological parameters vary in the range of 0.3 < n < 1.5 and 0.1 < λ < 100 is represents the viscosity of shear- thinning and shear thickening fluids. Variation of the periodic pulsatile forcing is obtained via the ratio Kω/Kο and set between 0.2 and 20. Zero and non-zero streamwise wavenumber have been considered separately in this study. For the axially invariant mode, energy growth maxima occur for unity azimuthal wave number, whereas for the axially non-invariant mode, maximum energy growth can be observed for azimuthal wave number of two for both Newtonian and non-Newtonian fluids. Modal and non-modal analysis for both Newtonian and non-Newtonian fluids show that the flow is asymptotically stable for any configuration and the pulsatile flow is slightly more stable than steady flow. Increasing the maximum velocity for shear-thinning fluids caused by reducing power-low index n is more evident than shear-thickening fluids. Moreover, rheological parameters of Carreau-Yasuda model have ignored the effect on the peak velocity of the oscillatory components. Increasing Reynolds number will enhance the maximum energy growth while a revers behavior is observed by increasing Womersley number.