The application of cellular therapies for the treatment of myocardial infarction has provided encouraging evidence for the possibility of cellular therapies to restore normal heart function. However, questions still remain as to the optimal cell source, pre-conditioning methods and delivery techniques for such an application. Here I propose the use of a unique population of stem cells arising from the embryonic neural crest. These cells were shown to express neural crest markers as well as pluripotency-associated markers. Furthermore, the cells were shown to express proteins essential to the formation of gap junctions and to possess a cardiomyogenic differentiation potential by several means. Furthermore, I explore the use of mechanical strain as an inducer of cardiomyogenesis and possibly pre-conditioning stimulus for the better engraftment of the cells while in the heart. Mechanical strain was shown to elicit a cardiomyogenic response from the cells following just a couple of hours of stimulation. The mode in which mechanical strain elicited these responses was demonstrated to be via the mediation of the reactive oxygen species (ROS) pathways. Given the results presented here, the use of these periodontal ligament-derived stem cells (PDLSC) in combination with mechanical strain preconditioning of the cells prior to their delivery into the heart may pose a valuable alternative for the treatment of myocardial infarction and merits further exploration for its capacity to augment the already observed beneficial effects of cellular therapies.

Bone and bone cells have been shown to respond to mechanical forces placed upon them. Particularly, strain plays an important role in osteogenic differentiation of marrow cells around artificial implants in bone. These strains, depending on their magnitude, duration, and repetition, can alter the proliferation and matrix synthesis of osteoblasts. To test how strain parameters influence osteoblast behavior, a four-point bending apparatus was used to impose cyclic strain on osteogenic stem cells isolated from rats and seeded on titanium plates. Cells were stimulated at 1 Hz for 15 minutes daily and compared to an unstrained control. Stimulation occurred at two magnitudes: 400 and 1000 micro-strain, and three levels of repetition: one, three, and five consecutive days. DNA, protein, alkaline phosphatase, and calcium levels were measured to determine the proliferation and matrix synthesis activity of the cells. No statistically significant effect was found for the tested parameters under these conditions.

This work investigates the influence of gate-induced floating body effect (GIFBE) on negative bias temperature instability (NBTI) in partial depleted silicon-on-insulator p-type metal-oxide-semiconductor field effect transistors (PD-SOI p-MOSFETs). The results indicate GIFBE causes a reduction in the electrical oxide field, leading to an underestimate of NBTI degradation. This can be attributed to the electrons tunneling from the process-induced partial n+ poly gate, and at higher voltages is dominated by the proposed anode electron injection (AEI) model. Moreover, when introducing the mechanical strain to PD-SOI p-MOSFETs result in decreasing the NBTI degradation for BC and FB devices, because increase of effective mass of hole and barrier height to decrease the probability of reaction of NBTI. The degradation of NBTI on FB device less than BC device because of strain-induced band gap narrowing to substrate and p+ poly gate, resulting in the rising of rate of impact ionization in AEI model to increase the accumulation of electrons on body. After that, giving the drain voltage in NBTI stress, the threshold voltage, Vth, shift decreases as drain voltage (VD) rising within the stress condition of VD= -1V. This phenomenon can be attributed to the shorter effective reaction time of hole and Si-H bonds after applying drain voltage during NBTI stress. However, beyond the condition at VD= -1V, the Vth shift rises as the drain voltage increasing. This behavior is resulted from the self-heating effect induced by the higher stress VD to increase the degradation of NBTI.

No description available.

In this study different bioactive agents were used to investigate their single and combined effects on biomechanical properties of osteoporotic bone. Estrogen, the most common hormon replacement therapy (HRT) agent, was used in single and combined with raloxifen, a well known osteoporosis drug. Despite their high clinical uses, they have not been tried before, in combination. They act as agonist of each other in bone and antagonist of each other in uterus and mammary glands. Hence it was expected to prevent HRT side effects by using combinations while enhancing the healing on osteoporotic bone. So, the study was designed to see the interaction effects of these two agents on bone and uterus, to observe the mechanical behaviour upto fracture, and to investigate the bone mechanical properties by strain gauges and bending theory with ovariectomized rat model. Second approach to osteoporosis treatment, VitK2 was chosen to be used alone or in combination with raloxifen in same model. Although recent studies mentioned the effects of VitK2 on bone, its rebuilding or repair effect was not completely established. So, VitK2-bone relation was aimed to be clarified with the project.VitK2 raloxifen combination was also a new study, that has not been carried out so far. As a result of mechanical tests, it was found that E+R combination is the most effective treatment. All treatment&amp / #8217 / s were resulted in numerically (though not statistically significant) higher values on femur mechanical properties, and significantly better on tibia compared to the untreated controls. VitK2 performs well in energy absorption upto fracture, but worse in others (PL, YL etc.) compared to other treatments indicating that it plays a specific role in modifying bone structure thus, rendering bone stronger under high stress. However, similar to estrogen case, its combination with raloxifen performs better than its individual administration. With combinations it was aimed to reduce the adverse effects of estrogen on uterus and mammary glands by using raloxifen. This idea appears to be achieved with better histological results of uterus in combinations than estrogen groups. Additionally it was observed that direct strain data obtained by strain gauge experiments can be more informative than theoretical model in calculating modulus of elasticity, and shown that shear contribution can be neglected if depth/span ratio and set up dimensions properly chosen. Biochemical analysis of the blood showed an increment in bone formation (ALP activity) compared to both controls. ALP activity was the highest in R group, which was lower in combinations. Thus existence of a different mechanism in osteoporotic bone repair in combinations was suggested.

Mechanical ventilation (MV) is a system that partially or fully assists patients whose respiratory system fails to achieve a gas exchange function. However, MV can cause a ventilator-associated lung injury (VALI) or even contribute to a multiple organ dysfunction syndrome (MODS) in acute respiratory distress syndrome (ARDS) patients. Despite advances in today technologies, mortality rates for ARDS patient are still high. A better understanding of the interactions between airflow from mechanical ventilator and the airway could provide useful information used to develop a better strategy to ventilate patients. The mechanisms, which mechanical ventilation induces airway inflammation, are complex processes and cover a wide range of spatial scales. The multiscale model of the airway have been developed combining the computational models at organ, tissue, and cellular levels. A model at the organ level was used to study behaviors of the airway during mechanical ventilation. Strain distributions in each layer of the airway were investigated using a model at the tissue level. The cellular inflammatory responses during mechanical ventilation were investigated through the cellular automata (CA) model incorporating all biophysical processes during inflammatory responses. The multiscale modeling framework started by obtaining airway displacements from the organ-level model. They were then transferred to the tissue-level model for determining the strain distributions in each airway layer. The strain levels in each layer were then transferred to the cellular-level model for inflammatory responses due to strain levels. The ratio of the number of damage cells to healthy cells was obtained through the cellular-level model. This ratio, in turn, modulated changes in the Young’s modulus of elasticity at the tissue and organ levels. The simulation results showed that high tidal volume (1400 cc) during mechanical ventilation can cause tissue injury due to high concentration of activated immune cells and low tidal volume during mechanical ventilation (700 cc) can prevent tissue injury during mechanical ventilation and can mitigate tissue injury from the high tidal volume ventilation. The multiscale model developed in this research could provide useful information about how mechanical ventilation contributes to airway inflammation so that a better strategy to ventilate patients can be developed.

Aquaporin proteins significantly increase water permeability across tissues and cell membranes. Ocular tissues, including the trabecular meshwork (TM) and retinal pigment epithelium (RPE), are especially reliant on aquaporin mediated water movement for ocular homeostasis. Even though bulk fluid movement is paracellular through the TM and transcellular through the RPE, both express aquaporin-1 (AQP1). The role and regulation of AQP1 as it relates to homeostasis in different ocular tissues is not well understood. I hypothesized that ocular tissues respond to external mechanical and molecular cues by altering AQP1 expression and function in order to regulate ocular fluid movement and maintain homeostasis.To test how AQP1 function is altered in response to external cues in order to maintain tissue-specific homeostasis, I addressed the following two aims. The first aim was directed at determining how mechanical strain, an external stimulus that routinely affects TM function, influences AQP1 expression and TM homeostasis. Primary cultures of human TM were subjected to static and cyclic stretch and then analyzed for changes in AQP1 expression by western blot and cell damage by activity of lactate dehydrogense (LDH) in conditioned media. The results show AQP1 expression and LDH release significantly increased with static stretch. Analysis of LDH release with respect to AQP1 expression revealed an inverse linear relationship (r² = 0.7780).The second aim was directed at characterizing signaling mechanisms responsible for regulating fluid transport in RPE, previously shown to be dependent upon AQP1. I treated primary cultures of human RPE with either atrial natriuretic peptide (ANP) or 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP) in the presence or absence of Anantin (ANP-receptor inhibitor) or H-8 (Protein Kinase G inhibitor). The results show that ANP and 8-Br-cGMP significantly increased apical to basal net fluid movement (p < 0.05, n = 3). Inhibition of these effects was successful with Anantin treatment but not with application of H-8.The data presented demonstrate a novel role of protection for AQP1 in TM, and also expand upon cGMP dependent regulation of RPE fluid transport. The combined studies indicate tissue specific AQP1 regulation may offer new avenues to target water movement in treatment of ocular pathologies.

This Thesis investigates the damage sensing capabilities of the electrical potential measurement technique in carbon fibre reinforced polymer composites. Impact damage was introduced in multidirectional laminates and its effect on potential distribution studied. It was found that delaminations and fibre breakages within the laminate can be detected and located by measuring potential changes on the external composite surface. The extent and size of potential changes were significantly affected by the position of the current electrodes in relation to the potential measurement probes. A numerical model was developed investigating the effect of different size delaminations, located in various positions within the lamina, on electrical potential distributions on the external ply, and a quantitative analysis of the numerical results is presented. The numerical simulations demonstrated that the measured potential changes on the external ply were in proportion to the delamination size. The numerical and experimental results were compared and the optimum configuration of current electrodes and potential probes for damage detection selected. The response of electrical potential to mechanical strain, in unidirectional and multidirectional samples was also investigated. It was found that the conductive medium, used for introducing the current, defines the piezo-resistance performance of the composite. A finite element model was developed able to predict the effect of inhomogeneous current introduction in unidirectional specimens on electrical potential and piezo-resistance. The effects of temperature and water absorption on potential measurements were also presented.

Abstract Type XIII collagen is a type II transmembrane protein which is expressed in many tissues throughout development and adult life. It is located in focal adhesions of cultured cells and in the adhesive structures of tissues such as the myotendinous junctions in muscle, intercalated discs in the heart and the cell-basement membrane interphases. To further characterize the function of this protein, we generated transgenic mice overexpressing it in normal and mutant forms. A large in-frame deletion in the COL2 domain of type XIII collagen led to synthesis of truncated α1(XIII) chains in transgenic mice, disrupting the assembly of normal type XIII collagen trimers. Fibroblasts derived from the mutant mice expressed shortened α1(XIII) chains, and no intracellular accumulation of the mutant protein was detected, suggesting that the mutant molecules were expressed on the cell surface. Transgene expression led to an embryonally lethal phenotype in offspring from heterozygous mating at two distinct stages of development. The early phenotype fetuses died due to the lack of chorioallantoic fusion and functioning placenta at 10.5 dpc, while the death of the late phenotype fetuses was caused by cardiac and placental defects around 13.5 dpc. The phenotype resembles closely several other cell adhesion molecule mutants, indicating that type XIII collagen has an essential role in certain adhesive interactions that are necessary for normal development. Mice overexpressing type XIII collagen with or without a point mutation developed postnatally an unexpected skeletal phenotype marked by a massive increase in bone mass. The cortical bone cross-sectional area and volumetric bone mineral density were highly increased, but trabecular bone volume was not significantly altered. The bone formation rate was several times higher in the mutant mice than in their normal littermates, while the osteoclast number and resorption activity were normal. Type XIII collagen was expressed highly in primary osteoblasts derived from the transgenic mice. Overexpression of type XIII collagen in osteoblasts enhanced both cell proliferation and differentiation while lack of it had opposite effects. Furthermore, mutant cells responded to mechanical strain differently than wild-type cells. The findings suggest that type XIII collagen has an important role in bone modeling, and it may in particular have a function in coupling the regulation of bone mass to mechanical usage.

This project involves the design and development of a cell stretching bioreactor device that can work in conjunction with a Random Positioning Machine (RPM) apparatus. Microgravity environments, such as in space, have been shown to induce alterations in cellular development due to inadequate mechanical loading of biological tissue. Because of this, long-term spaceflight has led to many health concerns, including osteoporosis and muscle atrophy. Space travel is rare and costly, making this research difficult to conduct, however; techniques to simulate microgravity on Earth can be achieved by using a Random Positioning Machine. This device has been a beneficial tool used to study the effect gravity has on cellular growth, yet certain tissues in the body, such as bone and muscle, require mechanical stress, strain, and mechanical loading to develop properly. Because of this, a device that can induce strain on cells while subjected to microgravity conditions is needed to further improve cellular research for space exploration. The constructed bioreactor consists of 3D printed and custom-made components that can induce uniaxial cyclic strain on cells adhered to an elastic membrane. Validation and testing of the device have shown that this bioreactor is suitable for cellular experimentation to work in conjunction with an RPM to deliver a controlled amount of strain while under microgravity conditions. / Bioengineering