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PURPOSE To evaluate corneal stiffening of porcine corneas induced by corneal crosslinking (CXL) with constant irradiance as a function of total fluence. METHODS Ninety corneas from freshly enucleated porcine eyes were divided into five groups of 18 eyes. Groups 1-4 underwent epi-off CXL using a dextran-based riboflavin solution and an irradiance of 18 mW/cm2, group 5 served as the control group. Groups 1 to 4 were treated with a total fluence of 20, 15, 10.8, and 5.4 J/cm2, respectively. Thereafter, biomechanical measurements were performed on 5 mm wide and 6 mm long strips using an uniaxial material tester. Pachymetry measurements were performed on each cornea. RESULTS At 10% strain, the stress was 76, 56, 52, and 31% higher in groups 1-4, respectively compared to the control group. The Young's modulus was 2.85 MPa for group 1, 2.53 MPa for group 2, 2.46 MPa for group 3, 2.12 MPa for group 4, and 1.62 MPa for the control group. The difference between groups 1 to 4 and the control group 5 were statistically significant (p =

The hemodynamic behavior following endovascular treatment of patients with peripheral arterial disease plays a significant role on the occurrence of restenosis in femoro-popliteal (FP) arteries. The atheroprone flow conditions that are generally accepted to promote restenosis can be calculated by computational fluid dynamics (CFD) analyses, and these results can be used to assess individualized treatment outcomes. However, the impact of endovascular therapy on the flow behaviors of FP arteries are still poorly understood, as the imaging modalities used in existing numerical works (X-ray angiography, computed tomography angiography) are unable to accurately represent the post-treatment arterial geometry due to their low resolutions. Therefore, this study proposes a new algorithm that combines intra-arterial lumen geometry obtained from high-resolution optical coherence tomography (OCT) images with centerlines generated from X-ray images to reconstruct the FP artery with an in-plane resolution of 10 µm. This superior accuracy allows modeling characteristic geometrical structures, such as angioplasty-induced arterial dissections, that are too small to be reconstructed with other imaging modalities. The framework is applied on the clinical data of patients treated either with only-percutaneous transluminal angioplasty (PTA) (n = 4) or PTA followed by stenting (n = 4). Based on the generated models, PTA was found to cause numerous arterial dissections, covering approximately 10% of the total surface area of the lumen, whereas no dissections were identified in the stented arteries. CFD simulations were performed to investigate the hemodynamic conditions before and after treatment. Regardless of the treatment method, the areas affected by low time-averaged wall shear stress (

The porcine cornea is a standard animal model in ophthalmic research, making its biomechanical characterization and modeling important to develop novel treatments such as crosslinking and refractive surgeries. In this study, we present a numerical model of the porcine cornea based on experimental measurements that captures both the depth dependence and orientation dependence of the mechanical response. The mechanical parameters of the established anisotropic hyperelastic material models of Gasser, Holzapfel and Ogden (HGO) and Markert were determined using tensile tests. Corneas were cut with a femtosecond laser in the anterior (100 μm), central (350 μm), and posterior (600 μm) regions into nasal-temporal, superior-inferior, and diagonal strips of 150 μm thickness. These uniformly thick strips were tested at a low speed using a single-axis testing machine. The results showed that the corneal mechanical properties remained constant in the anterior half of the cornea regardless of orientation, but that the material softened in the posterior layer. These results are consistent with the circular orientation of collagen observed in porcine corneas using X-ray scattering. In addition, the parameters obtained for the HGO model were able to reproduce the published inflation tests, indicating that it is suitable for simulating the mechanical response of the entire cornea. Such a model constitutes the basis for in silico platforms to develop new ophthalmic treatments. In this way, researchers can match their experimental surrogate porcine model with a numerical counterpart and validate the prediction of their algorithms in a complete and accessible environment.

INTRODUCTION The clinical tests currently used to assess spinal biomechanics preoperatively are unable to assess true mechanical spinal stiffness. They rely on spinal displacement without considering the force required to deform a patient's spine. We propose a preoperative method for noninvasively quantifying the three-dimensional patient-specific stiffness of the spines of adolescent idiopathic scoliosis patients. METHODS The technique combines a novel clinical test with numerical optimization of a finite element model of the patient's spine. RESULTS A pilot study conducted on five patients showed that the model was able to provide accurate 3D reconstruction of the spine's midline and predict the spine's stiffness for each patient in flexion, bending, and rotation. Statistically significant variation of spinal stiffness was observed between the patients. CONCLUSION This result confirms that spinal biomechanics is patient-specific, which should be taken into consideration to individualize surgical treatment.

Physical forces are recognized to play a critical role in shaping the micro-environment of tumors. Compression of cancer and stromal cells, as well as blood and lymphatic vessels, are direct consequences of mechanical solid stress, the compressive and tensile mechanical forces exerted by the solid components of the tissue. By altering the mechanical micro-environment of tumors, elevated solid stress can affect their pathophysiology, driving tumors to more aggressive phenotypes and compromise therapeutic outcome [1]. Mechanical stress also affects healthy tissue: It causes neuronal loss in brain tissue [2], and is linked to neurological deficits and reduced survival in patients with glioblastoma (GBM) [3], the most common malignant primary brain tumor in adults. Given their far-reaching micro- and macroscopic consequences, tumor-induced mechanical forces may provide mechanistic insights into inter and intra-tumor heterogeneities, differential response to treatment and other phenotypical characteristics. In this contribution, we survey the literature of spatial tumor growth modeling from a perspective of macroscopic tissue mechanics to assess the current status of mechanically-coupled growth models and to identify opportunities for further research: We summarize the types of modeling approaches previously used for capturing tumor-induced mechanical effects and their biological or physiological consequences. Based on this review, we identify the scenarios in which accounting for tissue mechanics proved to improve calibration to and prediction of clinical data. Drawing from examples of our [4] and others’ research on mechanically-coupled growth modeling for GBM, we discuss challenges involved in the implementation and calibration of such models. In this context, we identify areas of mechanically-coupled growth modeling where further research is needed and explore application opportunities that such models may open.

Glioblastoma (GBM), the most frequent malignant brain tumor in adults, is char- acterized by rapid growth and healthy tissue invasion. Long-term prognosis for GBM remains poor with median overall survival between 1 y to 2 y [15]. GBM presents with different growth phenotypes, ranging from invasive tumors without notable mass-effect to strongly displacing lesions. Biomechanical forces, such as those resulting from displacive tumor growth, shape the tumor environment and contribute to tumor progression [9]. We present an extended version of a mechanically–coupled reaction-diffusion model of brain tu- mor growth [1] that simulates tumor evolution over time and across different brain regions using literature-based parameter estimates for tumor cell proliferation, as well as isotropic motility, and mechanical tissue properties. This model yielded realistic estimates of the mechanical impact of a growing tumor on intra-cranial pressure. However, comparison to imaging data showed that asymmetric shapes could not be reproduced by isotropic growth assumptions. We modified this model to account for structural tissue anisotropy which is known to affect the directionality of tumor cell migration and may influence the mechanical behavior of brain tissue. Tumors were seeded at multiple locations in a human MR-DTI brain atlas and their spatio-temporal evolution was simulated using the Finite-Element Method. We evaluated the impact of tissue anisotropy on the model’s ability to reproduce the aspherical shapes of real pathologies by comparing predicted lesions to publicly available GBM imaging data. We found the impact on tumor shape to be strongly location dependent and highest for tumors located in brain regions that are characterized by a single dominant white matter direction, such as the corpus callosum. However, despite strongly anisotropic growth assumptions, all simulated tumors remained more spherical than real lesions at the corresponding location and similar volume. This finding is in agreement with previous studies [17, 6] suggesting that anisotropic cell migration along white matter fiber tracks is not a major determinant of tumor shape in the setting of reaction-diffusion based tumor growth models and for most locations across the brain.

The macroscopic growth of brain tumors has been studied by means of different computational modeling approaches. Glioblastoma multiforme (GBM) is the most common malignant type and is commonly modeled as a reaction--diffusion type system, accounting for its invasive growth pattern. Purely biomechanical models have been proposed to represent the mass effect caused by the growing tumor, but only a few models consider mass effect and tissue invasion effects in a single 3D model. We report first results of a comparative study that evaluates the ability of a simple computational model to reproduce the shape of pathologies found in patients. GBM invasion into brain tissue and the mechanical interaction between tumor and healthy tissue components are simulated using the finite element method (FEM). Cell proliferation and invasion are modeled as a reaction--diffusion process; simulation of the mechanic interaction relies on a linear elastic material model. Both are coupled by relating the local increase in tumor cell concentration to the generation of isotropic strain in the corresponding tissue element. The model accounts for multiple brain regions with values for proliferation, isotropic diffusion, and mechanical properties derived from literature. Tumors were seeded at multiple locations in FEM models derived from publicly available human brain atlases. Simulation results for a given tumor volume were compared to patient images. Simulated tumors showed a more symmetric growth pattern compared to their real counterparts. Resulting levels of tumor invasiveness were in agreement with simulation parameters and tumor-induced pressures of realistic magnitude were found.

BACKGROUND A large proportion of age-related fecal incontinence is attributed to weakness or degeneration of the muscles composing the anal continence organ. However, the individual role of these muscles and their functional interplay remain poorly understood. METHODS This study employs a novel technique based on the combination of MR imaging and FLIP measurements (MR-FLIP) to obtain anatomical and mechanical information simultaneously. Unlike previous methods used to assess the mechanics of the continence organ, MR-FLIP allows inter-individual comparisons and statistical analysis of the sphincter morpho-mechanical parameters. The anatomy as well as voluntary and involuntary mechanical properties of the anal continence organ were characterized in 20 healthy senior volunteers. RESULTS Results showed that the external anal sphincter (EAS) forms a funnel-like shape with wall thickness increasing by a factor of 2.5 from distal (6 ± 0 mm) to proximal (15 ± 3 mm). Both voluntary and involuntary mechanical properties in this region correlate strongly with the thickness of the muscle. The positions of least compliance and maximal orifice closing were both located toward the proximal EAS end. In addition, maximal contraction during squeeze maneuvers was reached after 2 s, but high muscle fatigue was measured during a 7 s holding phase, corresponding to about 60% loss of the energy produced by the muscles during the contraction phase. CONCLUSIONS This work reports baseline parameters describing the morpho-mechanical condition of the sphincter muscle of healthy elderly volunteers. New parameters were also proposed to quantify the active properties of the muscles based on the mechanical energy associated with muscle contraction and fatigue. This information could be used to assess patients suffering from AI or for the design of novel implants.

The objective of this work was to develop a system for three-dimensional (3D) reconstruction of the femoropopliteal artery from two angiographic views and to quantify the in vivo 3D deformations in 18 patients before balloon angioplasty and after primary stent implantation. The procedure had an insignificant effect on the bending behavior of the artery, as the average mean curvature change within the lesion remained constant before (0.04 cm-1 ± 0.03) and after stent implantation (0.03 cm-1 ± 0.04). A significant effect of stent implantation was measured in terms of a decrease in arterial shortening during leg flexion.

Background During placement of glenoid prosthesis, the surgeon aims at restoring the orientation of the natural glenoid. However, in case of degenerative disease or trauma, the original shape of the bone is unknown. In this case, the information of the contralateral scapula could be used to plan the intervention. However little is known on the symmetry/asymmetry of the scapula. Objectives The objective of this study was to measure and compare the version and curvature radius of the glenoid cavity, for the left and right side of healthy young subjects.

INTRODUCTION Continence results from a complex interplay between anal canal (AC) muscles and sensory-motor feedback mechanisms. The AC's passive ability to withstand opening pressure - its compliance - has recently been shown to correlate with continence. Functional lumen imaging probe (FLIP) is used to assess AC compliance, although it provides no anatomical information. Therefore, compliance assessment of specific anatomical structures has not been possible, and the anatomical position of critical functional zones remains unknown. In addition, FLIP assumes a circular orifice cross-section, which has not been shown for the AC. To address those shortcomings, a technique combining FLIP with a medical imaging modality is needed. METHOD We implemented a new research method (MR-FLIP) that combines FLIP with MR-imaging. Twenty healthy volunteers underwent MR-FLIP and conventional FLIP assessment. MR-FLIP was validated by comparison with FLIP results. Anatomical markers were identified, and the cross-sectional shape of the orifice was investigated. RESULTS MR-FLIP provides compliance measurements identical to those obtained by conventional FLIP. Anatomical analysis revealed that the least compliant AC zone was located at the proximal end of the external anal sphincter. The AC cross-sectional shape was found to deviate only slightly from circularity in healthy volunteers. CONCLUSION The proposed method was equivalent to classical FLIP. It establishes for the first time a direct mapping between local tissue compliance and anatomical structure, which is key for gaining novel insights into (in)continence. In addition, MR-FLIP provides a tool for better understanding conventional FLIP measurements in the AC by quantifying its limitations and assumptions. This article is protected by copyright. All rights reserved.

The CHIC (Computational Horizons in Cancer) project develops computational models for the cancer domain, as well as a secure infrastructure for data and model access, and reuse. It addresses challenges related to the development, validation and maintenance of multi-scale models by proposing the creation of complex disease models as composition of reusable component models. We present a versatile component model for the simulation of bio-mechanical aspects of macroscopic tumor growth. The model computes mechanical stresses and strains, resulting from tumor growth or shrinkage in a patient-specific anatomy, from a map of cancer cell concentration. In iterative coupled execution with other component models, its output can be used, for example, to guide the directionality of tumour expansion, or to simulate the effect of increased pressure on blood perfusion. Simulation of the bio-mechanic interaction relies on the finite element method (FEM); it is based on a hyper-elastic material model, as well as organ-specific boundary conditions and material properties. A pre-processing pipeline has been developed to automate the configuration process. In combination with automatic segmentation tools, this pipeline permits rapid generation of patient-specific FEM models for personalized simulations, including the assignment of suitable material parameters and boundary conditions from simple configuration options. Model and pre-processing pipeline are implemented using Open Source libraries and software packages (CGAL, VTK, FEBio). The model can be parametrised easily for different organs and body sites of interests; it has been applied to the simulation of kidney, lung and brain cancers in the context of CHIC.

Statistical models have been recently introduced in computational orthopaedics to investigate the bone mechanical properties across several populations. A fundamental aspect for the construction of statistical models concerns the establishment of accurate anatomical correspondences among the objects of the training dataset. Various methods have been proposed to solve this problem such as mesh morphing or image registration algorithms. The objective of this study is to compare a mesh-based and an image-based statistical appearance model approaches for the creation of nite element(FE) meshes. A computer tomography (CT) dataset of 157 human left femurs was used for the comparison. For each approach, 30 finite element meshes were generated with the models. The quality of the obtained FE meshes was evaluated in terms of volume, size and shape of the elements. Results showed that the quality of the meshes obtained with the image-based approach was higher than the quality of the mesh-based approach. Future studies are required to evaluate the impact of this finding on the final mechanical simulations.

Background: Statistical shape models are widely used in biomedical research. They are routinely implemented for automatic image segmentation or object identification in medical images. In these fields, however, the acquisition of the large training datasets, required to develop these models, is usually a time-consuming process. Even after this effort, the collections of datasets are often lost or mishandled resulting in replication of work. Objective: To solve these problems, the Virtual Skeleton Database (VSD) is proposed as a centralized storage system where the data necessary to build statistical shape models can be stored and shared. Methods: The VSD provides an online repository system tailored to the needs of the medical research community. The processing of the most common image file types, a statistical shape model framework, and an ontology-based search provide the generic tools to store, exchange, and retrieve digital medical datasets. The hosted data are accessible to the community, and collaborative research catalyzes their productivity. Results: To illustrate the need for an online repository for medical research, three exemplary projects of the VSD are presented: (1) an international collaboration to achieve improvement in cochlear surgery and implant optimization, (2) a population-based analysis of femoral fracture risk between genders, and (3) an online application developed for the evaluation and comparison of the segmentation of brain tumors. Conclusions: The VSD is a novel system for scientific collaboration for the medical image community with a data-centric concept and semantically driven search option for anatomical structures. The repository has been proven to be a useful tool for collaborative model building, as a resource for biomechanical population studies, or to enhance segmentation algorithms.

Endovascular therapy in patients suffering from peripheral arterial disease shows high rates of restenosis. The poor clinical outcomes are commonly explained by the demanding mechanical environment due to leg movements, but the mechanisms responsible for restenosis remain unknown. In this study, we hypothesized that restenosis following revascularization is associated with hemodynamical markers derived from blood flow during leg flexion. Therefore, we performed personalized computational fluid dynamics (CFD) analyses of 20 patients, who underwent routine endovascular femoro-popliteal interventions. The CFD analyses were conducted using 3D models of the arterial geometry in straight and flexed positions, which were reconstructed from 2D angiographic images. Based on restenosis rates reported at 6-month follow-up, logistic regression analyses were performed to predict restenosis from hemodynamical parameters. Results showed that severe arterial deformations, such as kinking, induced by leg flexion in stented arteries led to adverse hemodynamic conditions that may trigger restenosis. A logistic regression analysis based solely on hemodynamical markers had an accuracy of 75%, which showed that flow parameters are sufficient to predict restenosis (p = 0.031). However, better predictions were achieved by adding the treatment method in the model. This suggests that a more accurate image acquisition technique is required to capture the localized modifications of blood flow following intervention, especially around the stented artery. This approach, based on the immediate postoperative configuration of the artery, has the potential to identify patients at increased risk of restenosis. Based on this information, clinicians could take preventive measures and more closely follow these patients to avoid complications.

The femoro-popliteal (FP) segment is the most commonly diseased artery of the peripheral circulation. Obstructions of these lower-limb arteries are frequent and even with the new generation Nitinol stents (drug-eluting or otherwise), long-term restenosis rates following endovascular procedures range from 15 to 40% and are much higher compared with the long-term outcomes after coronary artery interventions. The major difference between peripheral and coronary arteries concerns their mechanical environments, with the FP arterial segments being subjected to repeated external deformations during leg flexion. It has been widely hypothesized that the high distortion of the tissues due to the un-physiological deformations of the arteries following stent implantation is the main cause for restenosis. However, there is very limited information on the FP artery deformations of patients with Peripheral Arterial Disease (PAD). Furthermore, the effects of endovascular therapy on the deformation behavior of the PAD-afflicted FP arteries are currently unknown. As such, further research on the deformations of the FP arteries is warranted to not only improve existing stent designs, but to also determine the correct interventional procedure. The main objectives of this thesis were to characterize the deformation behavior and mechanical response of the FP arterial tract through clinical and numerical investigations. The former was achieved by, first, investigating the pre-angioplasty deformations of the FP arteries during leg flexion in a pilot study of five patients with PAD and utilizing 3D rotational angiography. The methodology was then adapted to perform a clinical study of 35 patients with PAD, in which X-ray angiography was used to image the FP arteries in straight and flexed positions prior to endovascular therapy and following either Percutaneous Transluminal Angioplasty (PTA) or primary Nitinol stent implantation. The 3D models of the FP arteries were reconstructed from the 2D X-ray angiograms and the deformations of axial deformation and curvature were quantified. Both studies showed that the PAD-afflicted FP arterial segment undergoes significant shortening and an increase in curvature with leg flexion. Comparisons between the pre- and post-treatment deformations, as well as between the different treatment methods, suggested that the choice of the treatment method significantly affects the post-interventional axial deformations of the FP arteries (post-balloon: 7.6% ± 4.9%; post-stent: 3.2% ± 2.9%; P: 0.004). As such, while PTA results in a more flexible artery, stents restrict the arteries’ shortening capabilities. Depending on the anatomical position of the stents, this axial stiffening of the arteries may lead to chronic kinking, which may cause occlusions and, consequently, impact the long-term success of the procedure. As current stent designs were found to conform to the curvature behavior of the FP arterial tract, improvements should be focused on reproducing the native axial stiffness of the artery to reduce the risk of restenosis for patients that will have to undergo stent implantation. The complexities caused by leg flexion are further exacerbated by controversial clinical practices, such as Nitinol stent oversizing. The procedure is frequently performed in peripheral arteries to ensure a desirable acute lumen gain and strong wall apposition, and to prevent stent migration. However, the increased radial force exerted onto the arterial walls by the oversized stents could lead to significant arterial damage and, in turn, restenosis. The contradictory findings between animal and clinical studies, in conjunction with the majority of the numerical studies focusing on balloon-expandable stents, suggests that the efficacy of the procedure remains as an issue to be answered. The mechanical behavior of the FP artery under Nitinol stent oversizing was investigated by creating a validated finite element (FE) framework, which included numerical models of healthy FP arteries with patient-specific geometries and idealized arteries with clinically relevant levels of PAD. Based on the artery model, either only stent implantation or the complete endovascular therapy (PTA + stent implantation) was simulated. Four different stent-to-artery ratios ranging from 1.0 to 1.8 were used in the simulations. For the healthy arteries, additional analyses, in the form of computational fluid dynamics (CFD) analyses and fatigue behavior of the stents, were performed to observe the hemodynamic behavior of the arteries with respect to increased oversizing ratios. For the calcified arteries, three different plaque types were modeled to report the influence of the plaque behaviors on the outcomes of endovascular therapy and stent oversizing. Regardless of the presence of a plaque tissue, results showed that Nitinol stent oversizing was found to produce a marginal lumen gain in ix contrast to a significant increase in arterial stresses. For the lightly and moderately calcified arteries, oversizing was found to be non-critical; whereas for healthy and heavily calcified arteries, the procedure should be avoided due to a risk of tissue failure. These adverse effects to both the artery walls and stents may create circumstances for restenosis. Although the ideal oversizing ratio is stent-specific, the studies showed that Nitinol stent oversizing has a very small impact on the immediate lumen gain, which contradicts the clinical motivations of the procedure. In order to predict the possibility of restenosis through mechanical markers that are associated with the effects of leg movement following stent implantation, clinical investigations should be complimented with patient-specific numerical analyses. Combining intra-arterial imaging methodologies with in-vivo arterial deformations, which can be translated to FE simulations as boundary conditions, and building upon the numerical framework that is introduced in the 2nd part of this thesis, it’s possible to generate accurate patient-specific models. These models, evaluated in conjunction with clinical follow-ups, are expected to provide a deeper understanding of the mechanical background of restenosis in peripheral arteries.