Pelvic organ prolapse is characterized by the failure of vaginal wall support and protrusion of the pelvic organs through the vaginal orifice. Exact etiology of pelvic organ prolapse is not completely understood. The surgical procedures for pelvic organ prolapse utilize various biomaterials for holding the organs in place. However, the biomaterials used for restoring these organs have a high rate of failure in a complicated anatomical and biomechanical environment. With the given issues at hand, animal models are the best answer for understanding the pathophysiology of prolapse, and determining the cause of failure of these surgical interventions. For this study, we are investigating sheep as an animal model for human pelvic organ prolapse. We compared the anatomy of the sheep pelvic floor with humans. We found that anatomical parameters are a good measure/biomarker for estimating structural and anatomical changes in the body of the animal. As the anatomical measurements are applied to human vaginal prolapse, we can apply the same principles in sheep and further explore the feasibility of using sheep as an animal model for prolapse. Additionally, we evaluated location dependent biomechanical properties of the sheep vaginal tract. We have characterized the structure-property relationship of sheep vaginal wall tissue in the top third and middle third regions. We found that in contrast to current published research, sheep vaginal tissues are anisotropic in nature. This anisotropic characteristic of the sheep vaginal wall tissue is a direct function of the microstructural arrangement of collagen, elastin, smooth muscle and other extracellular matrix components. We also developed decellularized scaffolds as potential biomaterials, which can be potentially utilized in prolapse surgeries. We developed three different types of vaginal tissue scaffolds using SDS, Triton X-100, and trypsin for reconstructive surgery applications. During the decellularization, all of the cellular components are removed, which leaves the acellular ECM behind. We analyzed the biomechanical properties and microstructural properties of these scaffolds and found that the SDS samples were better in all aspects of the preclinical evaluation. Future studies will aim at applying the anatomical and biomechanical techniques used in this study to prolapsed sheep vaginal wall tissues.

The purpose of this dissertation was to study the effects of graft pretension in anterior cruciate ligament (ACL) reconstruction through a series of experiments. First, an in vitro study of 5 human knees was conducted to determine if intact joint kinematics could be restored when using the ideal graft - the intrinsic ACL. The ACL tibial insertion site was freed, and pretensions of 0, 10, 20, 30, and 40 N were applied to the ligament using a custom designed load cell connection. Kinematics during a simulated active extension were compared to those of the intact knee. Intact knee kinematics were not restored. Pretensions that best restored tibial anterior/posterior translation and internal/external rotation ranged from 0-40 N. Furthermore, the pretensions that best restored these kinematic variables were widely disparate in two specimens. Second, the in vitro kinematics during a simulated active extension of human and porcine knees were compared and contrasted both prior to and following transection of the ACL. The ACL limited: (1) tibial anterior translation in both species, (2) tibial internal rotation in humans, and (3) tibial external rotation in pigs. Differences in kinematic patterns for tibial internal/external rotation and abduction/adduction between the species was explained by requirements for biped and quadruped stances. Third, the mechanical characteristics of porcine patellar tendon (PT) were investigated by uniaxial tensile testing at two strain rates. Patella-PT-tibia complexes from freshly sacrificed skeletally immature and mature animals were loaded to failure at elongation rates of 20 and 200 mm/min. Both strain rate and skeletal maturity significantly affected failure mode, tangent modulus, and ultimate stress of the tendons, and hence are important considerations in the mechanical evaluation of porcine PT. Fourth, ACL reconstructions were performed using pretensions of 10 or 20 N in an in vivo porcine model with a specially designed load cell/telemetry system to monitor graft load. Graft pretension was seen to increase during fixation with interference screws. Following sacrifice at 4 weeks, tissues were mechanically, histologically, and biochemically analyzed. A pretension of 20 N resulted in a tissue more similar to the intrinsic ACL. / Ph. D.

During morphogenesis, epithelial tissues undergo dramatic changes in shape, transitioning from flat sheets to three-dimensional folded structures. This remarkable transformation relies on dynamic changes in mechanical tension at both their apical and basal surfaces. While it is well-established that the generation of mechanical tension at the apical side is driven by the actomyosin network, research on this process has often overlooked the generation of mechanical tension at the basal surface. Moreover, the mechanical response to stress, encompassing both elastic (spring-like) and viscous (fluid-like) properties, is important for epithelial transformations, yet this mechanical response is poorly understood for the basal cell surface. In this thesis, we investigated how basal tension is influenced by the basement membrane - an extracellular matrix layer which has been widely regarded as a passive scaffold for cells. We probed the material mechanical response of the basement membrane and directly measured and analyzed basal tension in the wing imaginal disc epithelium of Drosophila. To study the mechanical response, I used long-term confocal imaging and fluorescence recovery after photobleaching (FRAP) to analyze the turnover and mobility of Collagen IV, a component of the basement membrane. The low Collagen IV mobility and turnover (≈ 40 hours) suggest a solid-like behavior of the basement membrane at the time scale of hours. Moreover, Atomic Force Microscopy (AFM) force-indentation curves reveal low hysteresis and an elastic solid-like response. To measure basal mechanical tension, I probed the basement membrane with an AFM. Interpreting the results of AFM shallow indentations on the basal side of explanted wing discs as indenting into a fixed, elastic, stretched thin film, I investigated in control conditions and after molecular perturbations basal mechanical tension. Mechanical tension was ≈ 0.4 mN/m. The removal of collagen IV by collagenase significantly reduced basal tension while increasing basal cell surface area. In addition, inhibition of actomyosin activity through different reagents reduces basal tension while decreasing basal cell surface area. These results indicate that basal tension depends on both the ECM and actomyosin activity. They also indicate that the basement membrane is under expansile stress. Finally, to further investigate the mechanisms underlying the generation of stretch in the basement membrane, I analyzed the influence of hydrostatic pressure and actomyosin contractility along the lateral cell surfaces. These mechanisms exert mechanical forces that increase basal cell area, inducing a stretch in the basement membrane. Mild hypo- or hyperosmotic shocks resulted in increased or decreased basal cell area and basal tension, respectively. Moreover, optogenetic activation of actomyosin at lateral cell surfaces resulted in an increase in both basal cell area and basal tension. In summary, our research quantifies basal tension and unveils that the basement membrane is an elastic material (at time scale of hours). Furthermore, our data suggest that the basement membrane is under elastic stretch generated by hydrostatic pressure and actomyosin contractility. Thus, rather than being a passive scaffold for cells, the elastic properties of the basement membrane contribute to basal tension and thereby the shaping of cells and tissues.

Este trabalho é uma contribuição importante para o desenvolvimento de um modelo numérico de arênquima pulmonar capaz de simular manobras de ventilação mecânica. O pulmão é um órgão estruturalmente complexo e hierarquizado. Por isso uma revisão bibliográfica multidisciplinar foi realizada. A revisão apresenta as propriedades mecânicas do parênquima, sua morfologia e os efeitos da tensão superficial para a contração e adesão dos septos interalveolares. Um aspecto importante para o modelo de alvéolo é um modelo de contato com adesão causada pela tensão superficial. Um modelo de contato adesivo simplificado foi desenvolvido e simulado em uma estrutura com parâmetros de mesma ordem de grandeza de um alvéolo real. A simulação foi realizada com o método dos elementos finitos não-linear e foi necessário empregar o método da corda para evitar divergência em pontos limites. Os resultados numéricos se aproximaram de resultados experimentais globai no pulmão com pressões de mesma ordem de grandeza. / This work is an important step on the development of a computational model of lung parenchyma capable to simulate mechanical ventilation maneuveres. The lung has a complex and hierarchized structure. Therefore a multidisciplinary literature review was held. The review presents the mechanical properties of the parenchyma, its morphology and the effects of surface tension to septums contraction and adhesion. An important aspect for the alveolus model is a contact model which includes the adhesion caused by surface tension. Thus a simplified model was developed and then simulated in a structure with properties of the same order of magnitude of a real alveolus. The simulation was performed with the nonlinear finite element method. The implementation of the arc-length method was also necessary in order to prevent diversion at limit points. The numerical results were close to whole lung experimental results with pressure levels of the same order of magnitude.

Este trabalho é uma contribuição importante para o desenvolvimento de um modelo numérico de arênquima pulmonar capaz de simular manobras de ventilação mecânica. O pulmão é um órgão estruturalmente complexo e hierarquizado. Por isso uma revisão bibliográfica multidisciplinar foi realizada. A revisão apresenta as propriedades mecânicas do parênquima, sua morfologia e os efeitos da tensão superficial para a contração e adesão dos septos interalveolares. Um aspecto importante para o modelo de alvéolo é um modelo de contato com adesão causada pela tensão superficial. Um modelo de contato adesivo simplificado foi desenvolvido e simulado em uma estrutura com parâmetros de mesma ordem de grandeza de um alvéolo real. A simulação foi realizada com o método dos elementos finitos não-linear e foi necessário empregar o método da corda para evitar divergência em pontos limites. Os resultados numéricos se aproximaram de resultados experimentais globai no pulmão com pressões de mesma ordem de grandeza. / This work is an important step on the development of a computational model of lung parenchyma capable to simulate mechanical ventilation maneuveres. The lung has a complex and hierarchized structure. Therefore a multidisciplinary literature review was held. The review presents the mechanical properties of the parenchyma, its morphology and the effects of surface tension to septums contraction and adhesion. An important aspect for the alveolus model is a contact model which includes the adhesion caused by surface tension. Thus a simplified model was developed and then simulated in a structure with properties of the same order of magnitude of a real alveolus. The simulation was performed with the nonlinear finite element method. The implementation of the arc-length method was also necessary in order to prevent diversion at limit points. The numerical results were close to whole lung experimental results with pressure levels of the same order of magnitude.

<p>Breast cancer is the most commonly diagnosed cancer type worldwide. Given high survivorship, increased focus has been placed on long-term treatment outcomes and patient quality of life. While breast-conserving surgery (BCS) is the preferred treatment strategy for early-stage breast cancer, anticipated healing and breast deformation (cosmetic) outcomes weigh heavily on surgeon and patient selection between BCS and more aggressive mastectomy procedures. Unfortunately, surgical outcomes following BCS are difficult to predict, owing to the complexity of the tissue repair process and significant patient-to-patient variability. To overcome this challenge, we developed a predictive computational mechanobiological model that simulates breast healing and deformation following BCS. The coupled biochemical-biomechanical model incorporates multi-scale cell and tissue mechanics, including collagen deposition and remodeling, collagen-dependent cell migration and contractility, and tissue plastic deformation. Available human clinical data evaluating cavity contraction and histopathological data from an experimental porcine lumpectomy study were used for model calibration. The computational model was successfully fit to data by optimizing biochemical and mechanobiological parameters through the Gaussian Process. The calibrated model was then applied to define key mechanobiological parameters and relationships influencing healing and breast deformation outcomes. Variability in patient characteristics including cavity-to-breast volume percentage and breast composition were further evaluated to determine effects on cavity contraction and breast cosmetic outcomes, with simulation outcomes aligning well with previously reported human studies. The proposed model has the potential to assist surgeons and their patients in developing and discussing individualized treatment plans that lead to more satisfying post-surgical outcomes and improved quality of life.</p>

Numerous eye diseases are linked to biomechanical dysfunction of the retina. However, the underlying forces are almost impossible to quantify experimentally. Here, we show how biomechanical properties of adult neuronal tissues such as porcine retinae can be investigated under tension in a home-built tissue stretcher composed of nanostructured TiO2 scaffolds coupled to a self-designed force sensor. The employed TiO2 nanotube scaffolds allow for organotypic long-term preservation of adult tissues ex vivo and support strong tissue adhesion without the application of glues, a prerequisite for tissue investigations under tension. In combination with finite element calculations we found that the deformation behavior is highly dependent on the displacement rate which results in Young’s moduli of (760–1270) Pa. Image analysis revealed that the elastic regime is characterized by a reversible shear deformation of retinal layers. For larger deformations, tissue destruction and sliding of retinal layers occurred with an equilibration between slip and stick at the interface of ruptured layers, resulting in a constant force during stretching. Since our study demonstrates how porcine eyes collected from slaughterhouses can be employed for ex vivo experiments, our study also offers new perspectives to investigate tissue biomechanics without excessive animal experiments.

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Five image processing algorithms are proposed to measure the average orientation, eccentricity and size of cells in images of biological tissue. These properties, which can be embodied by an elliptical 'composite cell', are crucial for biomechanical tissue models. To automatically determine these properties is challenging due to the diverse nature of the image data, with tremendous and unpredictable variability in illumination, cell pigmentation, cell shape and cell boundary visibility. One proposed algorithm estimates the composite cell properties directly from the input tissue image, while four others estimate the properties from frequency domain data. The accuracy and stability of the algorithms are quantitatively compared through application to a wide variety of real images. Based on these results, the best algorithm is selected.

This thesis presents a whole-embryo finite element model of neurulation -- the first of its kind. An advanced, multiscale finite element approach is used to capture the mechanical interactions that occur across cellular, tissue and whole-embryo scales. Cell-based simulations are used to construct a system of constitutive equations for embryonic tissue fabric evolution under different scenarios including bulk deformation, cell annealing, mitosis, and Lamellipodia effect. Experimental data are used to determine the parameters in these equations. Techniques for obtaining images of live embryos, serial sections of fixed embryo fabric parameters, and material properties of embryonic tissues are used. Also a spatial-temporal correlation system is introduced to organize and correlate the data and to construct the finite element model. Biological experiments have been conducted to verify the validity of this constitutive model. A full functional finite element analysis package has been written and is used to conduct computational simulations. A simplified contact algorithm is introduced to address the element permeability issue. Computational simulations of different cases have been conducted to investigate possible causes of neural tube defects. Defect cases including neural plate defect, non-neural epidermis defect, apical constriction defect, and convergent extension defect are compared with the case of normal embryonic development. Corresponding biological experiments are included to support these defect cases. A case with biomechanical feedbacks on non-neural epidermis is also discussed in detail with biological experiments and computational simulations. Its comparison with the normal case indicates that the introduction of biomechanical feedbacks can yield more realistic simulation results.