Periacetabular osteolysis is a significant complication following total hip replacement surgery. It is believed to be caused by wear debris and high fluid pressures within the joint capsule. To investigate the mechanisms by which high fluid pressures are generated in total hip replacement, a physical model of the hip joint was constructed, the Acetabular Pressure Transmission Rig (APTR). An aluminium chamber held the bone analogue, a polyurethane hemisphere with a 52mm acetabular cavity, and the prosthetic components, a 28mm femoral head and various uncemented cups, were inserted without press-fit to simulate cup loosening. A synovial fluid analogue was introduced into the chamber through an elevated reservoir. Rigid transmission tubes conducted fluid pressures from the cup-cavity interface to external transducers. The APTR was loaded under various conditions and the pressures produced by the loading regimes were analysed. Pressures over 35kPa, previously shown by other groups to cause osteolysis, were measured within the APTR, reaching a maximum of 131.3kPa measured at the pole of the cup. Changes in load application led to pressure changes within the APTR, with higher loading frequency and magnitude leading to higher median pressure amplitudes. The presence of different component features, such as screw holes in the metal shell, was also shown to affect periacetabular pressures. Tests with a fibrous rim interposed between the prosthetic cup and the test cavity showed an 88% reduction in periacetabular pressures, as the increased rim interference between cup and cavity prevented fluid ingress behind the cup. A larger initial separation between the loading head and the acetabular cup caused a significant increase in measured pressures, with a 0.15mm increase in head-cup separation producing a 53% increase in pressures measured at the pole of the cup. Pressure differentials between different transducer sites indicated the ability for fluid flow behind the cup, which can be related in vivo to the movement of particulate debris to periacetabular bone. The APTR was able to measure clinically significant pressures and to analyse the effects of modifying component and loading characteristics with currently available prosthetic components. This makes the rig useful in a clinical context, as it has been shown to be capable of testing a broad range of component types under a wide range of conditions. Its use will ensure new prostheses and fixation modes can be designed in such a way as to eliminate the damaging fluid pressures currently observed in artificial hip joint replacements.

Gliomas are the most common and aggressive primary brain tumors. The most common treatment protocols for these brain tumors are combinations of surgery, chemotherapy and radiotherapy. However, even with the most aggressive combination of surgery and radiotherapy and/or chemotherapy schedules, gliomas almost always recur resulting in a median survival time for patients of not more than 12 months. This highly diffusive and invasive nature of brain tumors makes it very important to study the effects of these combined therapeutic strategies in an effort to improve the survival time of patients. It is also important to study the tumor microenvironment, since the complex nature of the cerebral vasculature, including the blood brain barrier and several other tumor-induced conditions such as hypoxia, high interstitial pressure, and cerebral edema affect drug delivery as well as the effectiveness of radiotherapy. Recently, a novel strategy using antiangiogenic therapy has been studied for the treatment of brain tumors. Antiangiogenic therapy interferes with the development of tumor vasculature and indirectly helps in the control of tumor growth. Recent clinical trials suggest that anti-angiogenic therapy is usually more effective when given in combination with other therapeutic strategies. In an effort to study the effects of the aforementioned therapeutic strategies, a spatio-temporal model is considered here that incorporates the tumor cell growth and the effects of radiotherapy and chemotherapy. The effects of different schedules of radiation therapy is then studied using a generalized linear quadratic model and compared against the published clinical data. The model is then extended to include the interactions of tumor vasculature and oxygen concentration, to explain tumor hypoxia and to study various methods of hypoxia characterizations including biomarker estimates and needle electrode measurements. The model predicted hypoxia is also used to analyze the effects of tumor oxygenation status on radiation response as it is known that tumor hypoxia negatively influences the radiotherapy outcome. This thesis also presents a detailed analysis of the effects of heterogenous tumor vasculature on tumor interstitial fluid pressure and interstitial fluid velocity. A mathematical modeling approach is then used to analyze the changes in interstitial fluid pressure with or without antiangiogenic therapy.

Gliomas are the most common and aggressive primary brain tumors. The most common treatment protocols for these brain tumors are combinations of surgery, chemotherapy and radiotherapy. However, even with the most aggressive combination of surgery and radiotherapy and/or chemotherapy schedules, gliomas almost always recur resulting in a median survival time for patients of not more than 12 months. This highly diffusive and invasive nature of brain tumors makes it very important to study the effects of these combined therapeutic strategies in an effort to improve the survival time of patients. It is also important to study the tumor microenvironment, since the complex nature of the cerebral vasculature, including the blood brain barrier and several other tumor-induced conditions such as hypoxia, high interstitial pressure, and cerebral edema affect drug delivery as well as the effectiveness of radiotherapy. Recently, a novel strategy using antiangiogenic therapy has been studied for the treatment of brain tumors. Antiangiogenic therapy interferes with the development of tumor vasculature and indirectly helps in the control of tumor growth. Recent clinical trials suggest that anti-angiogenic therapy is usually more effective when given in combination with other therapeutic strategies. In an effort to study the effects of the aforementioned therapeutic strategies, a spatio-temporal model is considered here that incorporates the tumor cell growth and the effects of radiotherapy and chemotherapy. The effects of different schedules of radiation therapy is then studied using a generalized linear quadratic model and compared against the published clinical data. The model is then extended to include the interactions of tumor vasculature and oxygen concentration, to explain tumor hypoxia and to study various methods of hypoxia characterizations including biomarker estimates and needle electrode measurements. The model predicted hypoxia is also used to analyze the effects of tumor oxygenation status on radiation response as it is known that tumor hypoxia negatively influences the radiotherapy outcome. This thesis also presents a detailed analysis of the effects of heterogenous tumor vasculature on tumor interstitial fluid pressure and interstitial fluid velocity. A mathematical modeling approach is then used to analyze the changes in interstitial fluid pressure with or without antiangiogenic therapy.

Salt tectonics is a key player in the evolution of many worldwide sedimentary basins on rifted continental margins. For more than a century, the evolving structures have been studied; but focus remained primarily on the onshore and shallow-water regions. The evolution of the poorly studied deep-water salt-tectonic structures is the focus of this thesis. Investigations are performed using 2D numerical models that comprise a viscous salt layer overlain by a frictional-plastic passive margin sedimentary sequence from shelf to deep water. This thesis addresses multiple salt-tectonic processes (gravity spreading, evolution of fold belts and salt canopies, diapirism) in a general context but with special focus on the structural evolution of the northwestern Gulf of Mexico (GoM). Here, multiple phases of gravity-spreading induced salt mobilization and thin-skinned deformation occurred throughout the Cenozoic. During the latest, late Oligocene-Miocene phase, the Perdido Fold Belt (PFB) formed from a 4.5km thick pre-kinematic section as a prominent salt-cored deep-water structure above the pinch-out of the autochthonous salt. It is here demonstrated with analytical as well as numerical calculations that the folding of the PFB can have formed by gravity spreading alone without basement tectonics. A requirement for this deformation is very high pore-fluid pressure in the sediments, which effectively reduces the sediments' mechanical strength. These values are refined using numerical models that couple compaction-induced fluid pressure to mechanical deformation. It is shown that very high fluid pressure is only necessary at the landward base of the deforming system; fluid pressure in other regions may remain moderate. This study shows, for the first time, the regional and dynamic evolution of pore-fluid pressure in a continental margin sedimentary system above salt. Additionally, the contribution of `lateral compaction' during fold-belt evolution is addressed. Landward of the PFB, a large-scale canopy developed during the Eocene. Its evolution is studied by investigating three different concepts of canopy evolution that have been proposed in the scientific literature. A canopy evolving via the mechanism of squeezed diapirs is most similar to the Eocene canopy of the northwestern GoM. A canopy evolving via the mechanism of breached anticlines is similar to that observed above the landward end of the PFB. Dynamic diapir growth is addressed in a neutral stress regime under uneven sedimentation employing a new mechanism of diapir initiation and evolution.

<p>This thesis aimed at studying mechanisms involved in control of tissue fluid homeostasis during inflammation.</p><p>The interstitial fluid pressure (P_IF) is of importance for control of tissue fluid balance. A lowering of P_IF <i>in vivo</i> will result in a transport of fluid from the circulation into the tissue, leading to edema. Loose connective tissues that surround blood vessels have an intrinsic ability to take up fluid and swell. The connective tissue cells exert a tension on the fibrous network of the tissues, thereby preventing the tissues from swelling. Under normal homeostasis, the interactions between the cells and the fibrous network are mediated by β1 integrins. Connective tissue cells are in this way actively controlling P_IF.</p><p>Here we show a previously unrecognized function for the integrin αVβ3, namely in the control of P_IF. During inflammation the β1 integrin function is disturbed and the connective tissue cells release their tension on the fibrous network resulting in a lowering of P_IF. Such a lowering can be restored by platelet-derived growth factor (PDGF) -BB. We demonstrated that PDGF-BB restored P_IF through a mechanism that was dependent on integrin αVβ3. This was shown by the inability of PDGF-BB to restore a lowered P_IF in the presence of anti-integrin β3 IgG or a peptide inhibitor of integrin αVβ3. PDGF-BB was in addition unable to normalize a lowered P_IF in β3 null mice. Furthermore, we demonstrated that extracellular proteins from <i>Streptococcus equi</i> modulated αVβ3-mediated collagen gel contraction. Because of the established concordance between collagen gel contraction <i>in vitro</i> and control of P_IF <i>in vivo</i>, a potential role for these proteins in control of tissue fluid homeostasis during inflammation could be assumed. Sepsis and septic shock are severe, and sometimes lethal, conditions. Knowledge of how bacterial components influence P_IF and the mechanisms for tissue fluid control during inflammatory reactions is likely to be of clinical importance in treating sepsis and septic shock.</p>

This thesis aimed at studying mechanisms involved in control of tissue fluid homeostasis during inflammation. The interstitial fluid pressure (PIF) is of importance for control of tissue fluid balance. A lowering of PIF in vivo will result in a transport of fluid from the circulation into the tissue, leading to edema. Loose connective tissues that surround blood vessels have an intrinsic ability to take up fluid and swell. The connective tissue cells exert a tension on the fibrous network of the tissues, thereby preventing the tissues from swelling. Under normal homeostasis, the interactions between the cells and the fibrous network are mediated by β1 integrins. Connective tissue cells are in this way actively controlling PIF. Here we show a previously unrecognized function for the integrin αVβ3, namely in the control of PIF. During inflammation the β1 integrin function is disturbed and the connective tissue cells release their tension on the fibrous network resulting in a lowering of PIF. Such a lowering can be restored by platelet-derived growth factor (PDGF) -BB. We demonstrated that PDGF-BB restored PIF through a mechanism that was dependent on integrin αVβ3. This was shown by the inability of PDGF-BB to restore a lowered PIF in the presence of anti-integrin β3 IgG or a peptide inhibitor of integrin αVβ3. PDGF-BB was in addition unable to normalize a lowered PIF in β3 null mice. Furthermore, we demonstrated that extracellular proteins from Streptococcus equi modulated αVβ3-mediated collagen gel contraction. Because of the established concordance between collagen gel contraction in vitro and control of PIF in vivo, a potential role for these proteins in control of tissue fluid homeostasis during inflammation could be assumed. Sepsis and septic shock are severe, and sometimes lethal, conditions. Knowledge of how bacterial components influence PIF and the mechanisms for tissue fluid control during inflammatory reactions is likely to be of clinical importance in treating sepsis and septic shock.

All blood vessels in the microvasculature are embedded in loose connective tissue, which regulates the transport of fluid to and from tissues. The intersti-tial fluid pressure (IFP) is one of the forces that control this transport. A lowering of IFP in vivo results in an increased transport of fluid from the circulation into the underhydrated connective tissues, resulting in edema formation. During homeostasis, contractile connective tissue cells exert a tension on the connective tissue fibrous network by binding with β1 in-tegrins, thereby actively controlling IFP. During inflammation, the IFP is lowered but platelet-derived growth factor (PDGF)-BB induces an IFP nor-malization dependent on integrin αVβ3. We demonstrate that extracellular proteins from Streptococcus equi subspecies equi modulated cell-mediated and integrin αVβ3-directed collagen gel contraction in vitro. One of these proteins, the collagen- and fibronectin binding FNE, stimulated contraction by a process dependent on fibronectin synthesis. This study identified a pos-sible novel virulence mechanism for bacteria based on the ability of bacteria to modulate the edema response. Another protein, the collagen-binding pro-tein CNE, inhibited contraction and this led to the identification of sites in collagen monomers that potentially are involved in connecting αVβ3 to the collagen network. PDGF-BB and prostaglandin E1 (PGE1) stimulate and inhibit collagen gel contraction in vitro and normalize and lower IFP, respec-tively. We showed that these agents affected both similar and different sets of actin-binding proteins. PDGF-BB stimulated actin cytoskeleton dynamics whereas PGE1 inhibited processes dependent on cytoskeletal motor and adhesive functions, suggesting that these different activities may partly ex-plain the contrasting effects of PGE1 and PDGF-BB on contraction and IFP. Mutation of the phosphatidylinositol 3’-kinase (PI3K), but not phospholipase C (PLC)γ activation site, rendered cells unable to respond to PDGF-BB in contraction and in activation of the actin binding and severing protein cofilin. Ability to activate cofilin after PDGF-BB stimulation correlated with ability to respond to PDGF-BB in contraction, suggesting a role for cofilin in this process downstream of PDGF receptor-activated PI3K. Many proteins can modulate contraction either by affecting the extracellular matrix and cell adhesions or by altering cytoskeletal dynamics. Knowledge on how these proteins might influence IFP is likely to be of clinical importance for treat-ment of inflammatory conditions including anaphylaxis, septic shock and also carcinoma growth.

A brief introduction to cancer biology and treatment is presented with a focus on current clinical advances in the delivery of chemotherapy and antiangiogenic therapies. Mathematical oncology is then surveyed with summaries of various models of tumor growth, tumor angiogenesis and other relevant biological entities such as angiogenic growth factors. Both strictly time-dependent ordinary differential equation (ODE)-based and spatial partial differential equation (PDE)-based models are considered. These biological models are first developed into an ODE model where various treatment options can be compared including different combinations of drugs and dosage schedules. This model gives way to a PDE model that includes the spatially heterogeneous blood vessel distribution found in tumors, as well as angiogenic growth factor imbalances. This model is similarly analyzed and implications are summarized. Finally, including the effects of interstitial fluid pressure into an angiogenic activity model is performed. This model displays the importance of factor convection on the angiogenic behaviour of tumours.

A brief introduction to cancer biology and treatment is presented with a focus on current clinical advances in the delivery of chemotherapy and antiangiogenic therapies. Mathematical oncology is then surveyed with summaries of various models of tumor growth, tumor angiogenesis and other relevant biological entities such as angiogenic growth factors. Both strictly time-dependent ordinary differential equation (ODE)-based and spatial partial differential equation (PDE)-based models are considered. These biological models are first developed into an ODE model where various treatment options can be compared including different combinations of drugs and dosage schedules. This model gives way to a PDE model that includes the spatially heterogeneous blood vessel distribution found in tumors, as well as angiogenic growth factor imbalances. This model is similarly analyzed and implications are summarized. Finally, including the effects of interstitial fluid pressure into an angiogenic activity model is performed. This model displays the importance of factor convection on the angiogenic behaviour of tumours.

I conducted an amplitude vs. offset (AVO) analysis on newly acquired 3D seismic reflection data to detect elevated pore fluid content and pore fluid pressure along the Costa Rica convergent margin to address dewatering processes of subduction zone sediments. These data provide the highest quality 3D seismic data acquired to date along a convergent margin for detailed analysis of geophysical properties along the plate boundary fault interface. In 2011, a 55 km by 11 km 3D seismic reflection survey was completed using the R/V Marcus G. Langseth offshore western Costa Rica at the convergent margin of the Cocos and Caribbean plates. We applied pre-stack Kirchhoff time migration to a subset of these data across the frontal prism where amplitude versus offset (AVO) attributes were extracted along the decollement. When pore fluid pressure, l , exceeds 0.7, the pressure at which Poisson’s ratio begins to approach that of water, the AVO response of a fluid-filled, clay-rich decollement requires a high Poisson’s ratio and an excessively low seismic P-wave and S-wave velocity. Acute wedge taper, undercompacted subducted hemipelagic and pelagic sediments, and a smooth decollement in the northwest half of the survey correspond with decollement AVO response of relatively high values of Poisson’s ratio. These findings suggest increased pore fluid content and vertical containment of near-lithostatic pore fluid pressures within the decollement. In contrast, increased wedge taper angles, thin hemipelagic and pelagic sediments, and a rugose decollement beneath the southeastern frontal prism produce an AVO response interpreted as due to lower pore fluid contents and pressures. We propose that large-offset subducting basement normal faults in this area, as close as 20 m from the decollement, induce vertical fractures within the decollement that allow for fluid expulsion into the frontal prism and lower fluid pressure. Lateral variability of overpressure within the decollement shear zone of subduction margins is important in understanding the evolution of frontal prism strain accumulation and seismogenic rupture. / text