Bridging spatiotemporal scales in biomechanical models for living tissues : from the contracting Esophagus to cardiac growth

Appropriate functioning of our body is determined by the mechanical behavior of our organs. An improved understanding of the biomechanical functioning of the soft tissues making up these organs is therefore crucial for the choice for, and development of, efficient clinical treatment strategies focused on patient-specific pathophysiology. This doctoral dissertation describes the passive and active biomechanical behavior of gastrointestinal and cardiovascular tissue, both in the short and long term, through computer models that bridge the cell, tissue and organ scale. Using histological characterization, mechanical testing and medical imaging techniques, virtual esophagus and heart models are developed that simulate the patient-specific biomechanical organ behavior as accurately as possible. In addition to the diagnostic value of these models, the developed modeling technology also allows us to predict the acute and chronic effect of various treatment techniques, through e.g. drugs, surgery and/or medical equipment. Consequently, this dissertation offers insights that will have an unmistakable impact on the personalized medicine of the future.Het correct functioneren van ons lichaam wordt bepaald door het mechanisch gedrag van onze organen. Een verbeterd inzicht in het biomechanisch functioneren van deze zachte weefsels is daarom van cruciale waarde voor de keuze voor, en ontwikkeling van, efficiënte klinische behandelingsstrategieën gefocust op de patiënt-specifieke pathofysiologie. Deze doctoraatsthesis brengt het passieve en actieve biomechanisch gedrag van gastro-intestinaal en cardiovasculair weefsel, zowel op korte als lange termijn, in kaart via computermodellen die een brug vormen tussen cel-, weefsel- en orgaanniveau. Aan de hand van histologische karakterisering, mechanische testen en medische beeldvormingstechnieken worden virtuele slokdarm- en hartmodellen ontwikkeld die het patiënt-specifieke orgaangedrag zo accuraat mogelijk simuleren. Naast de diagnostische waarde van deze modellen, laat de ontwikkelde modelleringstechnologie ook toe om het effect van verschillende behandelingstechnieken, via medicatie, chirurgie en/of medische apparatuur bijvoorbeeld, acuut en chronisch te voorspellen. Bijgevolg biedt deze doctoraatsthesis inzichten die een onmiskenbare impact zullen hebben op de gepersonaliseerde geneeskunde van de toekomst

Morphology and mechanical properties of abdominal aortic aneurysms

Abdominal Aortic Aneurysm (AAA) rupture is a life-threatening event, but can, when diagnosed timely, be avoided by either endovascular or conventional repair. Since these methods are accompanied by a high mortality rate, the decision to operate should only be made when the rupture risk exceeds the risks of repair. To date, the maximum diameter of the aneurysm is used as a measure for rupture risk and hence as a criterion for surgical intervention. It has, however, been shown already that small aneurysms do rupture sometimes, while some large aneurysms have not ruptured yet, and therefore the diameter criterion alone may not be suf??cient. Since rupture of an AAA occurs when locally the wall stress exceeds the strength of the vessel wall, it is generally believed that wall stress distribution could help to better assess AAA rupture. Patient speci??c models for wall stress computations do not only require the geometry of the aneurysm but also the mechanical properties of the aneurym tissue. Studies on the material properties of vessel wall have mainly focused on describing AAA vessel wall and thrombus as a homogeneous material. Local inhomogeneities can have large in??uences on the stress magnitude and distributions. AAA vessel wall may contain inhomogeneities such as calci??cations and atherosclerotic plaques. Furthermore, the thrombus, which is present in the majority of the aneurysms may in??uence the local mechanics considerably. It is a layered ??brin structure, that shows different levels of degeneration. The level of degeneration of the ??brin structure might have in??uence on the mechanical properties of the thrombus. To improve future wall rupture risk prediction based on wall stress, the objective of this study is to obtain the local mechanical properties of both thrombus and the AAA vessel wall. AAA vessel wall and thrombus are obtained from patients treated with conventional surgery. The viscoelastic behaviour of thrombus is determined using plate-plate rheomix etry. To study the changes in mechanical properties throughout the thickness of the thrombus a radially oriented stack of samples was used. In the small strain regime frequency sweep test are peformed and the elastic and viscous moduli are found to be in the range of 1.7 ?? 1.3 kPa and 0.2 ?? 0.1 kPa respectively. Since large deformations occur in thrombus the non-linear properties are determined by stress relaxation experiments. To describe the phenomena observed experimentally, a non-linear multi mode model is used. The parameters for this model are obtained by ??tting this model successfully to the experiments in both the linear and non-linear regime. To determine the morpholgy of the AAA vessel wall, the applicability of multi contrast MRI to discriminate the components of the vessel wall is studied. Multi contrast MR results are compared to the golden standards, histology and ??CT. Components like the media, calci??ed deposits, areas containing cholesterol, thrombus and the adventitia containing fat cells and vasa vasorum can be recognised in the MR images. The results obtained so far are not suitable for an automatic classi??cation by an unsupervised clustering algorithm. To obtain the mechanical properties of the components present in the vessel wall a mixed numerical experimental method is proposed. This method is a robust way to determine the mechanical properties of the individual components without having to isolate them. The method is applied to AAA vessel wall samples. The morphology is obtained with multi contrast MR. The Young's moduli of media, adventitia, calci??cation, an area with cholesterol crystals and thrombus are determined. Although the media is less stiff than the adventitia the moduli are in same the order of magnitude (?? 1.0 MPa). The stiffness of thrombus is found to be an order of magnitude lower (?? 40 kPa). An area with a lot of cholesterol is stiffer than the rest of the wall (?? 7.5 MPa) and a calci??ed area is even stiffer (?? 50 MPa). By implementing the ??ndings for thrombus in a patient speci??c model it is shown that thrombus does change the stress distribution and peak wall stresses, but the effect is much lower than reported in literature by others. The presence of calci??cation has a large effect on the wall stress distribution. It is shown that the wall stress distribution is in??uenced by the accuracy with which the geometry of the calci??cation is decribed. The limited resolution available in the clinical settting results in a non-realistic stress distribution. For correct implementation of inhomogeneities of the vessel wall the spatial resolution of both imaging techniques and computations should increase. The contribution of this work consists not only of the reported morphologies and mechanical properties. The observations reported in this work also suggest that effort should be put into development of clinical methods to include the morphology and mechanical properties of the aneurysm into the rupture risk analysis

Magnetic Resonance Imaging for the Functional Analysis of Tissues and Biomaterials

Articular cartilage provides mechanical load dissipation and lubrication between joints, and additionally provides protects from abrasion. At present, there are no treatments to cure or attenuate the degradation of cartilage. Early detection and the ability to monitor the progression of osteoarthritis is important for developing effective therapies. However, few reliable imaging biomarkers exist to detect cartilage disease before advanced degeneration in the tissue. One specialized MRI technique, termed displacements under applied loading by MRI (dualMRI), was developed to measure displacements and strain in musculoskeletal tissues, hydrogels and engineered constructs. However, deformation information does not directly describe spatial distributions of tissue properties (e.g. stiffness), which is critical to the understanding of disease progression. To achieve the stiffness measurement, we developed and validated an inverse modeling workflow that combined dualMRI, to directly measure intratissue deformation, with topology optimization in the application of heterogeneous (layered) materials representative of the complex gradient architecture of articular cartilage. We successfully reconstructed bi-layer stiffness from ideal displacements calculated from forward simulation as well as from experimental data measured from dualMRI. To monitor the progression of osteoarthritis, we measured and analyzed biomechanical changes of sheep stifle cartilage after meniscectomy. We found that 2nd principal strain and max shear strain in the femur contact region are sensitive to cartilage degeneration at different stages and compared to more conventional methods like quantitative MRI. To investigate the biomechanical changes in articular cartilage with defect and repair, we implanted decellularized cartilage implant into sheep cartilage defect and evaluate the repair results using quantitative MRI and dualMRI. We found that implants placed in joints demonstrated lower strains compared to joints with untreated defects

COMPUTATIONAL ULTRASOUND ELASTOGRAPHY: A FEASIBILITY STUDY

Ultrasound Elastography (UE) is an emerging set of imaging modalities used to assess the biomechanical properties of soft tissues. UE has been applied to numerous clinical applications. Particularly, results from clinical trials of UE in breast lesion differentiation and staging liver fibrosis indicated that there was a lack of confidence in UE measurements or image interpretation. Confidence on UE measurements interpretation is critically important for improving the clinical utility of UE. The primary objective of my thesis is to develop a computational simulation platform based on open-source software packages including Field II, VTK, FEBio and Tetgen. The proposed virtual simulation platform can be used to simulate SE and acoustic radiation force based SWE simulations, including pSWE, SSI and ARFI. To demonstrate its usefulness, in this thesis, examples for breast cancer detections were provided. The simulated results can reproduce what has been reported in the literature. To statistically analyze the intrinsic variations of shear wave speed (SWS) in the fibrotic liver tissues, a probability density function (PDF) of the SWS distribution in conjunction with a lossless stochastic tissue model was derived using the principle of Maximum Entropy (ME). The performance of the proposed PDF was evaluated using Monte-Carlo (MC) simulated shear wave data and against three other commonly used PDFs. We theoretically demonstrated that SWS measurements follow a non-Gaussian distribution for the first time. One advantage of the proposed PDF is its physically meaningful parameters. Also, we conducted a case study of the relationship between shear wave measurements and the microstructure of fibrotic liver tissues. Three different virtual tissue models were used to represent underlying microstructures of fibrotic liver tissues. Furthermore, another innovation of this thesis is the inclusion of “biologically-relevant” fibrotic liver tissue models for simulation of shear wave elastography. To link tissue structure, composition and architecture to the ultrasound measurements directly, a “biologically relevant” tissue model was established using Systems Biology. Our initial results demonstrated that the simulated virtual liver tissues qualitatively could reproduce histological results and wave speed measurements. In conclusions, these computational tools and theoretical analysis can improve the confidence on UE image/measurements interpretation

Stress-strain analysis of aortic aneurysms

Tato práce se zabývá problematikou aneurysmat břišní aorty a možností využít konečnoprvkovou deformačně-napěťovou analýzu těchto aneurysmat ke stanovení rizika ruptury. První část práce je věnována úvodu do problematiky, popisu kardiovaskulární soustavy člověka s důrazem na abdominální aortu, anatomii, fyziologii a patologii stěny tepny s důrazem na procesy vedoucí ke vzniku aneurysmatu. Dále se práce věnuje rizikovým faktorům přispívajících ke vzniku aneurysmat spolu s analýzou současných klinických postupů ke stanovení rizika ruptury spolu se srovnáním navrhovaného kritéria maximálního napětí. Dominantní část této disertace je věnována identifikaci faktorů ovlivňujících napjatost a deformaci stěny aneurysmatu spolu s návrhem nových postupů, prezentací vlastních poznatků vedoucích ke zpřesnění určení rizika ruptury pomocí deformačně- napěťové analýzy a metody konečných prvků. Nejprve je analyzován vliv geometrie, vedoucí k závěru, že je nezbytné používání individuálních geometrií pacienta. Dále je pozornost zaměřena na odbočující tepny, které ve stěně působí jako koncentrátor napětí a mohou tedy ovlivňovat napjatost v ní. Jako další podstatný faktor byl identifikován vliv nezatížené geometrie a bylo napsáno makro pro její nalezení, které bylo opět zahrnuto jako standardní součást do výpočtového modelu. Mechanické vlastnosti jak stěny aneurysmatu, tak intraluminálního trombu jsou experimentálně testovány pomocí dvouosých zkoušek. Také je zde analyzován vliv modelu materiálu, kde je ukázáno, že srovnávání maximálních napětí u jednotlivých modelů materiálu není vhodné díky zcela rozdílným gradientům napětí ve stěně aneurysmatu. Dále je zdůrazněna potřeba znalosti distribuce kolagenních vláken ve stěně a navržen program k jejímu získání. Intraluminální trombus je analyzován ve dvou souvislostech. Jednak je ukázán vliv jeho ruptury na napětí ve stěně a jednak je analyzován vliv jeho poroelastické struktury na totéž. Posledním identifikovaným podstatným faktorem je zbytková napjatost ve stěně. Její významnost je demonstrována na několika aneurysmatech a i tato je zahrnuta jako integrální součást do našeho výpočtového modelu.Na závěr jsou pak navrženy další možné směry výzkumu.This thesis deals with abdominal aortic aneurysms and the possibility of using finite element method in assessment of their rupture risk. First part of the thesis is dedicated to an introduction into the problem, description of human cardiovascular system where the abdominal aorta, its anatomy, physiology and pathology is emphasized. There Processes leading to formationing of abdominal aortic aneurysms are also discussed. Risk factors contributing to creation of aneurysms are discussed next. Finally, an analysis of current clinical criteria which determine rupture risk of an abdominal aortic aneurysm is presented and compared with the new maximum stress criterion being currently in development. Main part of the thesis deals with the identification of relevant factors which affect stress and deformation of aneurysmal wall. This is connected with proposals of new approaches leading to predicting the rupture risk more accurately by using finite element stress-strain analysis. The impact of geometry is analyzed first with the conclusion that patient-specific geometry is a crucial input in the computational model. Therefore its routine reconstruction has been managed. Attention is then paid to the branching arteries which were neglected so far although they cause a stress concentration in arterial wall. The necessity of knowing the unloaded geometry of aneurysm is then emphasized. Therefore a macro has been written in order to be able to find the unloaded geometry for any patient-specific geometry of aneurysm. Mechanical properties of both aneurysmal wall and intraluminal thrombus were also experimentally tested and their results were fitted by an isotropic material model. The effect of the material model itself has been also investigated by comparing whole stress fields of several aneurysms. It has been shown that different models predict completely different stresses due to different stress gradients in the aneurysmal wall. The necessity of known collagen fiber distribution in arterial wall is also emphasized. A special program is then presented enabling us to obtain this information. Effect of intraluminal thrombus on the computed wall stress is analyzed in two perspectives. First the effect of its failure on wall stress is shown and also the impact of its poroelastic structure is analyzed. Finally the residual stresses were identified as an important factor influencing the computed wall stress in aneurysmal wall and they were included into patient-specific finite element analysis of aneurysms. Further possible regions of investigation are mentioned as the last part of the thesis.

Development of a Biaxial Stretch Bioreactor and Finite Element Models for Mechanobiological Study of Aortic Valve Leaflets

Aortic heart valve disease is a significant cause of mortality worldwide; and replacement surgery is necessary in 70% of cases. Tissue engineered heart valves (TEHVs) are biocompatible and biodegradable, with ability to grow with the patient. However, to date, TEHVs mostly lack ability to withstand native mechanical forces since they are unable to mimic the heterogeneous and anisotropic structure of extracellular matrix (ECM) in native valves. Cyclic stretch is known to modulate ECM fiber synthesis and alignment. However, little tools are available for studying the interaction between aortic tissues and stretch condition. Finite element method is a powerful tool to simulate the complex structure of aortic valve, however, most current simulations modeled the leaflet as a homogenous material, and none of them took the distinctions between two surface layers into account, which were critical for the proper function of the aortic valve.To study the effects of cyclic stretch on extracellular matrix remodeling, the heterogeneous properties of the aortic leaflet, and the effects of heterogeneity on the function of valve, we have 1) Designed, fabricated and validated a biaxial stretch bioreactor; 2) Analyzed train patterns of native aortic leaflets using digital image correlation method; 3) Designed and validated an anisotropic and heterogeneous finite element (FE) model for leaflets. These studies provided insights into the interaction between aortic valve tissue and the mechanical environment, anisotropy and heterogeneity of aortic leaflets ECM due to the distribution of collagen fibers, and detailed distinct strain patterns in fibrosa vs. ventricularis sides and 3 aortic leaflets. Our novel biaxial stretch bioreactor and refined FE model of aortic leaflet will pave path for other scientists to study mechanobiology, design and condition engineered tissues and simulate engineered aortic valve grafts or pathology of calcium deposition

Toward quantitative limited-angle ultrasound reflection tomography to inform abdominal HIFU treatment planning

High-Intensity Focused Ultrasound (HIFU) is a treatment modality for solid cancers of the liver and pancreas which is non-invasive and free from many of the side-effects of radiotherapy and chemotherapy. The safety and efficacy of abdominal HIFU treatment is dependent on the ability to bring the therapeutic sound waves to a small focal ”lesion” of known and controllable location within the patient anatomy. To achieve this, pre-treatment planning typically includes a numerical simulation of the therapeutic ultrasound beam, in which anatomical compartment locations are derived from computed tomography or magnetic resonance images. In such planning simulations, acoustic properties such as density and speed-of-sound are assumed for the relevant tissues which are rarely, if ever, determined specifically for the patient. These properties are known to vary between patients and disease states of tissues, and to influence the intensity and location of the HIFU lesion. The subject of this thesis is the problem of non-invasive patient-specific measurement of acoustic tissue properties. The appropriate method, also, of establishing spatial correspondence between physical ultrasound transducers and modeled (imaged) anatomy via multimodal image reg-istration is also investigated; this is of relevance both to acoustic tissue property estimation and to the guidance of HIFU delivery itself. First, the principle of a method is demonstrated with which acoustic properties can be recovered for several tissues simultaneously using reflection ultrasound, given accurate knowledge of the physical locations of tissue compartments. Second, the method is developed to allow for some inaccuracy in this knowledge commensurate with the inaccuracy typical in abdominal multimodal image registration. Third, several current multimodal image registration techniques, and two novel modifications, are compared for accuracy and robustness. In conclusion, relevant acoustic tissue properties can, in principle, be estimated using reflected ultrasound data that could be acquired using diagnostic imaging transducers in a clinical setting

Modelling studies on biological tissue properties and mechanical responses under external stimuli

PhDBiological tissues maintain their homeostasis by remodelling under external mechanical stimuli. In order to understand the tissue remodelling process, it is important to characterize tissue properties before detailed mechanical responses can be investigated. This project aims to develop a computational modelling framework to characterise mechanical properties of biological tissues, and to quantify tissue responses under mechanical loading. The thesis presents, first, mechanical responses of articular cartilages under different loadings using a poroelastic model. Unique in this study, collagen fibrils are treated separately from the rest of ECM, as they only resists tension. This leads to a fibril-reinforced poroelastic model. Effects of the distribution of the collagen fibrils and their orientation on tissue mechanical responses are investigated. Most of the effort has been on the mechanical stress distribution of the human left atrium and its correlation to electrophysiology patterns in atrial fibrillation. Detailed mechanical responses of the atrial wall to a step pressure increase in the left atrium are calculated. The geometry of the left atrium is based on patient specific images using cardio CT and incorporates variations of the atrial wall thickness as well as unique fibre orientation patterns. We hypothesize that areas of high von Mises stress are correlated to foci of abnormal electrophysiology sites which sustain cardiac arrhythmia. Results from this study show a positive correlation between them. To our knowledge, this is the first study that establishes the relationship between the atrial wall stress distribution and the atrial abnormal electrophysiology sites. The project also investigates hyperelastic properties of endothelial cells and the overlying endothelial glycocalyx, based on data from AFM micro-indentation. Both endothelial cells with & without the glycocalyx layer (i.e. following enzymatic digestion) are used. This is the first time that the mechanical property of the glycocalyx is estimated using an inverse biomechanical model