No description available.

<p>Breast cancer affects 12.5\% of women over their life time and tissue expansion (TE) is the most common technique for breast reconstruction after mastectomy. However, the rate of complications with TE can be as high as 15\%. Even though the first documented case of TE happened in 1957, there has yet to be a standardized procedure established due to the variations among patients and the TE protocols are currently designed based on surgeon's experience. There are several studies of computational and theoretical framework modeling skin growth in TE but these tools are not used in the clinical setting. This dissertation focuses on bridging the gap between the already existing skin growth modeling efforts and it's potential application in the clinical setting.</p> <p><br></p> <p>We started with calibrating a skin growth model based on porcine skin expansions data. We built a predictive finite element model of tissue expansion. Two types of model were tested, isotropic and anisotropic models. Calibration was done in a probabilistic framework, allowing us to capture the inherent biological uncertainty of living tissue. We hypothesized that the skin growth rate was proportional to stretch. Indeed, the Bayesian calibration process confirmed that this conceptual model best explained the data. </p> <p><br></p> <p>Although the initial model described the macroscale response, it did not consider any activity on the cellular level. To account for the underlying cellular mechanisms at the microscopic scale, we have established a new system of differential equations that describe the dynamics of key mechanosensing pathways that we observed to be activated in the porcine model. We calibrated the parameters of the new model based on porcine skin data. The refined model is still able to reproduce the observed macroscale changes in tissue growth, but now based on mechanistic knowledge of the cell mechanobiology.  </p> <p><br></p> <p>Lastly, we demonstrated how our skin growth model can be used in a clinical setting. We created TE simulations matching the protocol used in human patients and compared the results with clinical data with good agreement. Then we established a personalized model built from 3D scans of a patient unique geometry. We verified our model by comparing the skin growth area with the area of the skin harvested in the procedure, again with good agreement.</p> <p><br></p> <p>Our work shows that skin growth modeling can be a powerful tool to aid surgeons design TE procedures before they are actually performed. The simulations can help with optimizing the protocol to guarantee the correct amount of skin is growth in the shortest time possible without subjecting the skin to deformations that can compromise the procedure.</p>

The purpose of this study is to further quantify adult ovine ovariectomized bone for new remodeling characteristics to obtain a better understanding of how remodeling is occurring and the effectiveness of this animal model for the study of postmenopausal osteoporosis. Postmenopausal osteoporosis is a major health concern and animal models to test new treatment options are needed. The ovine model is a good option because the ewes undergo Haversian remodeling, are a large sized animal, and have a similar hormone profile to humans. Ewes, however, do not undergo a natural menopause, so an ovariectomy surgery was conducted in the sheep to simulate the decreased levels in estrogen. Columbia-Rambouillet sheep were used in this study: some that have been ovariectomized as a model for postmenopausal osteoporosis and some that underwent a sham surgery to serve as a control. The sheep were sacrificed 12 months post operatively in the month of August, so the seasonal effects of remodeling were accounted for. The left radius was then processed into microradiographs of 6 regional cortical beams, where the cranial (tensile side) and caudal (compressive side) anatomical sections were analyzed in this study to determine regional differences in remodeling. Previous students’ theses have analyzed the similar samples for basic bone remodeling histology measurements, resulting in some significant seasonal, anatomical, and treatment differences. However, most of the results showed no particular increase in the amount of remodeled area for the ovariectomized sheep compared to the sham sheep, even though an ovariectomy is believed to cause a burst of remodeling in bone due to the decreased levels in estrogen. In this study, a new repeatable method was developed that further examines secondary bone by quantifying the extent to which secondary osteons encroach on previously-existing secondary osteons. Encroached and unencroached secondary osteons were quantified using two different methods: a point count method that measured the percentage of the area the encroached and unencroached secondary osteons inhabited and an osteon count method that measured the number of encroached and unencroached secondary osteons per area. These raw measurements were calculated into 18 parameters and 2-way repeated measures ANOVAs were run to determine the effects of surgery and anatomical region on each of the bone remodeling parameters. The results found significant effects from estrogen deletion which were different depending on if the bone region was predominately in compression or tension. The ovariectomy surgery caused an increase in remodeling, which was mostly confined on the compressive side to areas that have been previously remodeled, but on the tensile side, bone remodeling expanded into areas that used to be primary bone. The new secondary osteons, as a result of the ovariectomy surgery, were larger than in the control animals. There however, was not an increase in porosity from the ovariectomy surgery, which is one of the main characteristics of osteoporosis. The model could be further studied to determine what sheep are doing that prevents them from losing bone and that knowledge could be greatly beneficial for human treatment plans of postmenopausal osteoporosis.

Dilated (DCM) and ischemic cardiomyopathies (ICM) are associated with cardiac remodeling, where the ubiquitin–proteasome system (UPS) holds a central role. Little is known about the UPS and its alterations in patients suffering from DCM or ICM. The aim of this study is to characterize the UPS activity in human heart tissue from cardiomyopathy patients. Myocardial tissue from ICM (n = 23), DCM (n = 28), and control (n = 14) patients were used to quantify ubiquitinylated proteins, E3-ubiquitin-ligases muscle-atrophy-F-box (MAFbx)/atrogin-1, muscle-RING-finger-1 (MuRF1), and eukaryotic-translation-initiation-factor-4E (eIF4E), by Western blot. Furthermore, the proteasomal chymotrypsin-like and trypsin-like peptidase activities were determined fluorometrically. Enzyme activity of NAD(P)H oxidase was assessed as an index of reactive oxygen species production. The chymotrypsin- (p = 0.71) and caspase-like proteasomal activity (p = 0.93) was similar between the groups. Trypsin-like proteasomal activity was lower in ICM (0.78 ± 0.11 µU/mg) compared to DCM (1.06 ± 0.08 µU/mg) and control (1.00 ± 0.06 µU/mg; p = 0.06) samples. Decreased ubiquitin expression in both cardiomyopathy groups (ICM vs. control: p < 0.001; DCM vs. control: p < 0.001), as well as less ubiquitin-positive deposits in ICM-damaged tissue (ICM: 4.19% ± 0.60%, control: 6.28% ± 0.40%, p = 0.022), were detected. E3-ligase MuRF1 protein expression (p = 0.62), NADPH-oxidase activity (p = 0.63), and AIF-positive cells (p = 0.50). Statistical trends were detected for reduced MAFbx protein expression in the DCM-group (p = 0.07). Different levels of UPS components, E3 ligases, and UPS activation markers were observed in myocardial tissue from patients affected by DCM and ICM, suggesting differential involvement of the UPS in the underlying pathologies.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.