Browsing by Author "Di Martino, Elena S."
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Item Open Access Acquired Mechanisms of Bicuspid Aortic Valve-Associated Aortopathy(2018-07-05) Guzzardi, David G.; Fedak, Paul; O'Brien, Edward; Di Martino, Elena S.Bicuspid aortic valve (BAV)-associated aortopathy is characterized by progressive aortic extracellular matrix (ECM) remodeling leading to aneurysm, dissection or rupture. The cause of this aortopathy is unclear; a genetically-driven basis has been favoured, but recent studies implicating an acquired valve-mediated hemodynamic mechanism have challenged this long-standing view despite no clear link between aortic hemodynamics and ECM remodeling having been delineated. We hypothesized that aortopathy in human BAV patients is influenced by valve-mediated wall shear stress (WSS) in a regionally-dependent manner. Aortic tissue specimens from BAV patients that received pre-operative 3-dimensional time-resolved phase-contrast magnetic resonance imaging (4D flow MRI) to compute regional WSS were assessed quantitatively for their expression of aortopathy. Compared to aortic tissue subjected to normal WSS, adjacent tissue from the same BAV aortas subjected to regionally-elevated WSS exhibited demonstrably worse elastic fiber histopathology, increased protease expression and elevated levels of transforming growth factor β-1 (TGFβ-1) consistent with maladaptive aortic ECM remodeling. We also observed that incremental increases in aortic WSS in the human BAV aorta correlate with increased severity of elastic fiber histopathology, and that this association is most strongly observed in BAV patients with primary stenosis and in mildly-dilated (< 4.5 cm) aortas in the earlier stages of disease. These novel data support a critical role for valve-mediated hemodynamics in coordinating the expression of BAV-associated aortopathy and dispute the assumption that aortic pathology in these patients is primarily driven by genetics. Fluoroquinolone (FQ) antibiotic use constitutes another acquired mechanism of aortopathy that may place BAV patients with pre-existing aortic pathology at risk of disease exacerbation. However, no cellular mechanism has been provided underlying this association. We hypothesized that in aortic myofibroblast cells from BAV-associated aortopathy patients, FQ exposure would alter the proteolytic profile favouring ECM dysregulation and modulate collagen expression. We observed that FQ exposure generates a functional increase in ECM degradation driven by reduced tissue inhibitors of matrix metalloproteinases (TIMPs) alongside impaired compensatory collagen-1 expression. These findings may explain the increased incidence of acquired FQ-associated aortopathy and encourage judicious use of FQ in BAV patients with pre-existing aortic pathology.Item Open Access Computational fluid dynamics as aid tool for the management of aortic wall diseases(2019-10-24) Forneris, Arianna; Di Martino, Elena S.; Frayne, Richard; Wood, David H.Aortic aneurysms and dissections are pathological conditions affecting the aorta. Despite being different in clinical presentation, these pathologies share a high mortality rate, as well as a lack of reliable prognostic predictors. Local fluid dynamics is assumed to play a role in aortic patho-physiology and to be a key factor responsible for aortic weakening and expansion. In this context, the numerical modeling of aortic hemodynamics, by means of image-based computational fluid dynamics (CFD), gives access to patient-specific flow-related information that may complement medical imaging in the assessment of individual aortas and support outcomes prediction. Moreover, the deformability of the aortic wall appears to be related to its strength: areas at elevated strain may, therefore, indicate structural weakening. Based on these understandings, this research work proposes the use of hemodynamic descriptors, derived from CFD simulations, to correlate local altered flow patterns with aortic remodeling and weakening, and ultimately help defining a rationale for improved rupture risk stratification. Wall shear stress-based hemodynamic descriptors were used to retrospectively assess a population of uncomplicated type B aortic dissections (ADs) with known individual outcomes. The effect of rigid versus moving wall assumption on aortic flow patterns was explored by means of fluid-structure interaction (FSI) simulation. The results highlighted the need for a patient-tailored approach when evaluating ADs, and showed the potential of CFD-derived hemodynamics to complement anatomical assessment and assist outcomes prediction. The inclusion of wall motion in the simulation of a type B AD, led to differences in value for the hemodynamic wall descriptors, however, regions of interest with respect to altered flow patterns were consistently localized by both the CFD and FSI models. Finally, a combined CFD and in-vivo strain analysis approach was developed to assess local weakening and rupture risk for a population of AAAs. A novel index, Regional Rupture Potential, was defined and proved able to capture aortic regional weakening. This thesis demonstrated the importance of accessing hemodynamic information when assessing individual aortas with prognostic purposes, along with the potential of a novel combined approach to improve aortic assessment for risk stratification.Item Open Access Damage and Remodelling in Recruitment-Based Models for Biological Tissues(2018-06-18) Hamedzadeh, Amirhossein; Federico, Salvatore; Epstein, Marcelo D.; Di Martino, Elena S.; Wan, Richard; Steigmann, David J.This thesis focuses on the continuum mechanical modelling of soft biological tissues seen as composite material reinforced by collagen fibres. The fibres have a progressive recruitment mechanism, and the tissue can undergo damage or remodelling. The thesis consists of two major parts. In the first part of the thesis, the recruitment and damage of soft tissues are modelled by introducing a rigorous continuum treatment of the fibre seen as a bundle of fibrils. The fibrils have different initial undulation, and this is represented by the means of a recruitment probability distribution. By exploiting the recruitment distribution, we construct a recruitment and damage model, where the fibrils are progressively recruited and damaged. The model is implemented in a Finite Element package and, as an example, the damage of a human Achilles tendon is studied. The Finite Element model is capable of capturing the qualitative behaviour of the tendon under uniaxial tension. The second part of the thesis focusses on the remodelling of biological tissues in the framework of the theory of material uniformity. A constitutive evolution model is introduced, including fibre recruitment and reorientation, and subjected to the entropy inequality, which enforces the Second Principle of Thermodynamics. The model is applied to a numerical example describing a pressurised fibre-reinforced cylinder, roughly representing an artery, and is able to capture the major characteristics of remodelling in arteries, as reported in the literature. To summarise, this thesis provides a framework for modelling of the interaction of fibril recruitment and damage and of whole fibre recruitment and remodelling, and constitutes a promising starting point for a more general model capable of studying the interaction of damage, remodelling and healing.Item Open Access Development of bioabsorbable braided vascular scaffolds for the intracranial circulation(2019-05-29) Jamshidi, Mehdi; Mitha, Alim Pyarali A.; Sundararaj, Uttandaraman; Ronsky, Janet L.; Di Martino, Elena S.An intracranial (or brain) aneurysm is a life-threatening disease that affects more than 3% of the population. The treatment techniques of cerebral aneurysms have significantly improved in the past decade, transitioning from open surgical procedures to less invasive endovascular procedures. A disruptive technology in aneurysm treatment was the advent of the metal flow-diverting stent, which made it relatively easy to treat the most complicated of brain aneurysms, and avoiding the need for a high-risk open surgical procedure. Despite these improvements, metal stents are still associated with major complications, mostly due to their thrombogenicity as well as their long-term implications. Although the need for a stent to treat aneurysms is only temporary, due to progressive neointima formation over the stent structure, they cannot be removed. This requires patients to remain on lifelong anti-platelet medications, which can cause other health problems. Bioabsorbable stents have been postulated as a way to overcome the long-term disadvantages of metal stents. Commercial bioabsorbable stents have been developed for coronary artery diseases, although the design of coronary stents is different than for intracranial aneurysms. Coronary stents are mostly balloon expandable, and can acquire good wall apposition simply by balloon inflation. Stents used for intracranial applications, on the other hand, are required to be flexible and self-expandable, and they should revert to at least close to their original diameter after deployment from the catheter. The challenges for the design of bioabsorbable flow-diverting stents for the treatment of intracranial aneurysms lies in differences with the deployment mechanism, the poor mechanical properties of bioabsorbable polymers, and their inability to show shape memory behavior. In this study, we designed and fabricated bioabsorbable flow-diverting stents for the treatment of aneurysms. Information acquired from existing stents, as well as the three initial iterations of our design, are reviewed and discussed. The mechanical properties and safety profile of our stents were studied in vitro, and the safety and efficacy were also studied in vivo with pilot animal experiments. The bioabsorbable flow-diverting stent that we developed demonstrated mechanical properties similar to existing intracranial stents. They further showed low potential for hemolysis and thrombus formation on the stent struts, as well as neointimal layer formation and persistent side branch patency in animal models at 1 month follow-up. The performance of the stent in terms of flow-diverting capabilities was also demonstrated in acute small and large animal models of intracranial aneurysms.Item Open Access Identifying indices of vulnerability in the aneurysmal abdominal aorta: The interplay between mechanics and morphology(2019-09-05) Ismaguilova, Alina; Di Martino, Elena S.; Matyas, John Robert; Tyberg, John V. T.; Edwards, William Brent; Natale, GiovanniantonioAn abdominal aortic aneurysm is the pathological dilatation of the abdominal aorta that can grow silently and rupture without warning. Over time, the vessel wall becomes weaker as inflammatory processes take over and the microarchitecture is compromised. Understanding the behaviour of the aneurysm wall at the macro and microscopic level can help elucidate the rupture potential of the vessel. This study proposes a novel method in assessing regions-specific differences by which we section the aorta into patches that can be traced back to specific areas on the aneurysm. The present study is thus an exploratory approach at assessing the aneurysms of multiple patients to establish differences between aneurysms, within aneurysms, and compare against healthy tissue. We established these differences, among others, using a variety of methods that assess the tissue microstructure, inflammation, composition, and mechanical response to loading. We also demonstrated the mechanical and structural heterogeneity in case studies exploring region-specific differences within the same patient. Coupling exploration into the pathophysiology of the aneurysm with its mechanical behaviour allowed us to paint a better picture of the disease, with mechanics often explaining biology and vice versa. We conclude that the pathological abdominal aorta exhibits a disruption in its extracellular matrix, profound inflammation, stiffer behaviour, and increased energy loss when compared with non-aneurysmal tissue. Ultimately, rupture risk assessment strategies need to utilize patient-specific parameters, and region-specific considerations need to be made.Item Open Access Settling Dynamics of Two Spheres in a Diluted Suspension of Brownian Rods(2019-08-23) Kumar, Gaurav; Natale, Giovanniantonio; Azaiez, Jalel; Di Martino, Elena S.Settling dynamics of two non-Brownian rigid spheres in a dilute suspension of Brownian rods at low Reynolds number is investigated via numerical simulations in this work. Specifically this work focuses on how the overall settling dynamics is affected by the coupling between the flow field around the spheres and the orientation of the rods. The Brownian motion introduces a finite relaxation time in the suspending medium which is modeled as a continuum. When the spheres settle in a dilute suspension of Brownian rods, the spheres experience two contributions: a Newtonian and a non Newtonian contribution due to the presence of the Brownian rods. Two configurations are studied: (1) end-to-end and (2) side-by-side settling. The interactions between the two settling spheres are evaluated as a function of Péclet number (Pe) and the distance between the centers of the spheres. Repulsive or attractive interactions are found based on configuration and these interactions are affected by Pe and distance between the centers of the spheres. An analysis of the flow fields highlights the origin of these interactions in non-Newtonian elongational effects.Item Open Access Studies of Structural and Mechanical Properties of Skin and Treated Split Thickness Skin Autografts(2018-09-06) Tarraf, Samar Andrea; Di Martino, Elena S.; Biernaskie, Jeff A.; Duncan, Neil A.; Matyas, John RobertSplit-thickness skin autografts (STSGs) are the gold standard treatment for full thickness burn wounds. Healthy skin from the patient is harvested and transplanted onto the wound. The graft, comprised of epidermis and superficial dermis, is missing cellular components adversely affecting functionality. One major contributor to reduced functionality is decreased elasticity. Understanding the biomechanical properties of grafts can help assess the efficacy of treatments. We hypothesize that combining STSGs with dermal stem cells could stimulate tissue remodeling, generation of neodermis and improve functionality. Coupling mechanics with microscopy assays gives a more encompassing understanding of the changes in mechanical properties. This study provides an initial comparison between skin tissue types and between graft treatments. We established differences between healthy and grafted skin and showed shortcomings of the xenograft model used. We also demonstrated the effects of graft treatment on mechanical response. Treatment cannot fully recover healthy skin behavior, but improves graft functionality.Item Open Access Transcriptomic Analysis for the Identification and Prioritization of Treatment of Abdominal Aortic Aneurysms(2020-01-13) Kennard, Jacob Justin; Rinker, Kristina D.; Moore Randy D.; Di Martino, Elena S.; McIntyre, John B.Abdominal aortic aneurysms are pathological dilations of the abdominal aorta, characterized by a high mortality rate, and a lack of effective prognostic predictors. As the disease progresses, the aortic wall becomes significantly degraded and eventually the structure is compromised, leading to rupture and often death. Understanding the changes in gene expression that correlate to altered hemodynamics and mechanical properties within the aorta can help elucidate the nature of this degradation and improve rupture risk predictions. The present study leverages a novel clinical study design to provide validation for a previously proposed non-invasive, in-vivo metric. The metric uses imaging information as well as computational fluid dynamics and in-vivo strain measurements to better assess aneurysm stability and improve risk management. This study demonstrated that areas of an aneurysm predicted to be of high risk by the relative rupture potential exhibited significant changes in gene expression related to disease progression. It was also demonstrated that the relative rupture potential better predicts gene expression related to disease progression than any single metric for aneurysm stability. In addition to validation of the relative rupture potential, evidence for the infiltration of specific immune cells in high risk areas was found, providing an excellent starting point for future studies investigating the peripheral blood of abdominal aortic aneurysm patients for markers of aneurysm presence or stability. These studies could lay the groundwork for a blood test to be used in conjunction with imaging technologies to further improve abdominal aortic aneurysm risk assessment.