In electronic devices solder joints form a mechanical as well as an electrical connection between the circuit board and the component (e.g. a chip or a resistor). Temperature variations occurring during field use cause crack initiation and crack growth inside the joints. Accurate prediction of the lifetime requires a method to simulate the damage process based on microstructural properties. Numerical simulation of developing cracks and microstructural entities such as grain boundaries and grain junctions gives rise to several problems. The solution contains strong and weak discontinuities as well as weak singularities. To obtain reasonable solutions with the finite element method (FEM) the element edges have to align with the cracks and the grain boundaries, which imposes geometrical restrictions on the mesh choice. Additionally, a large number of elements has to be used in the vicinity of the singularities which increases the computational effort. Both problems can be circumvented with the extended finite element method (X-FEM) by using appropriate enrichment functions. In this thesis the X-FEM will be developed for the simulation of complex microstructural geometries. Due to the anisotropy of the different grains forming a joint and the variety of different microstructural configurations it is not always possible to write the enrichment functions in a closed form. A procedure to determine enrichment functions numerically is explained and tested. As a result, a very simple meshing scheme, which will be introduced here, can be used to simulate developing cracks in solder joint microstructures. Due to the simplicity of the meshing algorithm the simulation can be automated completely. A large number of enrichment functions must be used to realize this. Well-conditioned equation systems, however, cannot be guaranteed for such an approach. To improve the condition number of the X-FEM stiffness matrix and thus the robustness of the solution process a preconditioning technique is derived and applied. This approach makes it possible to develop a new and fully automated procedure for addressing the reliability of solder joints numerically. The procedure relies on the random generation of microstructures. Performing crack growth calculations for a series of these structures makes it possible to address the influence of varying microstructures on the damage process. Material parameters describing the microstructure are determined in an inverse procedure. It will be shown that the numerical results correspond well with experimental observations.

Incremental sheet forming (ISF) is a novel metal shaping technology that is economically viable for low-volume manufacturing, customisation and rapid-prototyping. It uses a small tool that is controlled by a computer-numerically controlled sequence and the path taken by this tool over the sheet defines the product geometry. Little is currently known about how to design the tool-path to minimise geometric errors in the formed part. The work here addresses this problem by developing a model based tool-path optimisation scheme for ISF. The key issue is how to generate an efficient model for ISF to use within a path optimisation routine, since current simulation methods are too slow. A proportion of this thesis is dedicated to evaluating the applicability of the rigid plastic assumption for this purpose. Three numerical models have been produced: one based on small strain deformation, one based on limit analysis theory and another that approximates the sheet to a network of rods. All three models are formulated and solved as second-order cone programs (SOCP) and the limit analysis based model is the first demonstration of an upper-bound shell finite element (FE) problem solved as an SOCP. The models are significantly faster than commercially available FE software and simulations are compared with experimental and numerical data, from which it is shown the rigid plastic assumption is suitable for modelling deformation in ISF. The numerical models are still too slow for the path optimisation scheme, so a novel linearised model based on the concept of spatial impulse responses is also formulated and used in an optimal control based tool-path optimisation scheme for producing axisymmetric products with ISF. Off-line and on-line versions of the scheme are implemented on an ISF machine and it is shown that geometric errors are significantly reduced when using the proposed method. This work provides a new structured framework for tool-path design in ISF and it is also a novel use of feedback to compensate for geometrical errors in ISF.

S.absconditiflora is one of the endemic Salvia species grown in Turkey, which is consumed as a herbal tea. Because of the presence of high amounts of vesicles on their leaves, S.absconditiflora is very rich in active compounds. S.absconditiflora water extract was investigated for its antioxidant capacity by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Total phenolic and total flavonoid contents were quantified by spectrophotometric methods. LC-MS/MS analyses revealed the presence and quantities of caffeic acid, luteolin rutin and coumaric acid. Cytotoxic effects of water extract of S.absconditiflora on breast cancer cell lines (MCF-7 and MDA-MB-231) were examined via XTT colorimetric assay and Trypan Dye Exclusion cell viability assay. IC50 values for each cell line at 24 and 48 hours were determined. The results indicated that water extract of leaves of S.absconditiflora could inhibit cell proliferation in MCF-7 and MDA-231 cells in dose dependent but not in time dependent manner. Effects of S.absconditiflora water extract on the expression of glutathione-S-transferases (GSTs) in MCF-7 and MDA-MB-231 cells were investigated with qRT-PCR technique. IC50 values calculated in XTT experiment for 24h incubation was used as cytotoxic extract concentration. It was found that treatment of MCF-7 cells with 1,558 mg/ml of extract enhanced an increase in expression as 2 and 2,8 fold in GSTO1 and GSTZ1 genes, respectively. Treatment of MDA-MB-231 cells with 1,131 mg/ml of extract resulted in 1,57 fold increase for GSTO1 and 1,56 fold increase for GSTZ1.

Chemotherapy is one of the common treatments in cancer therapy. The effectiveness of chemotherapy is limited by several factors one of which is the emergence of multidrug resistance (MDR). MDR is caused by the activity of diverse ATP binding cassette (ABC) transporters that pump drugs out of the cells. There are several drugs which have been used in treatment of cancer. One of them is doxorubicin that intercalates and inhibits DNA replication. However, doxorubicin has been found to cause development of MDR in tumors. It has been reported that there is a correlation between multidrug resistance and invasiveness of cancer cells. Vimentin is a type III intermediate filament protein that is expressed frequently in epithelial carcinomas correlating with invasiveness and also poor prognosis of cancer. There are several studies that have shown the connection between expression level of vimentin and invasiveness. In this study, MCF-7 cell line (MCF-7/S), which is a model cell line for human mammary carcinoma, and doxorubicin resistant MCF-7 cell line (MCF-7/Dox) were used. The resistant cell line was previously obtained by stepwise selection in our laboratory. The main purpose of this study was to investigate changes of metastatic behaviour in MCF-7/Dox cell line, after transient silencing of vimentin gene by siRNA. In conclusion, down-regulation of vimentin gene expression in MCF-7/Dox cell lines was expected to change the characteristics in migration and invasiveness shown by migration and invasion assays.

Complexed microspheres of poly(4-vinyl pyridine) (P4VN) and alginic acid were prepared by internal gelation method and subsequent freeze drying. The 4% and 10% microspheres were loaded with Bone Morphogenetic Protein-2 (BMP-2) and Bone Morphogenetic Protein-7 (BMP-7), respectively for in vitro studies and were entrapped in PLGA foams. Foams containing only 4%, BMP-2 microspheres, only 10%, BMP-7 microspheres and both populations were prepared. Control samples of each group were prepared with drug free microspheres. Bone marrow derived stem cells from rat femur and tibia isolated by a surgical operation, were seeded onto foams. Proliferation of cells on foams containing both microsphere populations was higher at all time points regardless of the presence of BMPs. This was attributed to different porosity characteristics. Proliferation was higher at all times in control samples in comparison to their positive samples for all groups, suggesting proliferation attenuation related enhancement in osteogenic activity due to BMP supply. Alkaline phosphatase (ALP) activities were lower at all time points for foams containing both microsphere populations regardless of BMP presence. This was attributed to different physical characteristics of foams confirmed by the inverse correlation between proliferation and osteogenic differentiation. Total and specific ALP activity results demonstrated the significant positive influence of all BMP containing types in enhancing osteogenic differentiation. Best results were obtained with co-administration of sequential delivery performing 4% and 10% microspheres loaded with BMP-2 and BMP-7, respectively.

Osteoarthritis (OA) is a disease characterized by the progressive degradation of articular cartilage. Current strategies for the disease are mainly towards relieving symptoms. This study was aimed to investigate the therapeutic potentials of Bone Morphogenetic Protein-9 (BMP-9), Raloxifene (Ral) and Pluronic F-68 (PLF-68) with a three-dimensional in vitro OA model. Articular chondrocytes isolated from rats were cultured in growth media and embedded in agarose to obtain agarose-chondrocyte discs. Dynamic hydrostatic mechanical stress was applied to discs. The discs were incubated with Aza-C for 48 hours for OA development. After its removal, chondrocytes were treated with different doses of BMP-9, Ral and PLF-68 for 10 days. The efficacies of treatments were evaluated by measuring cell number, glycosaminoglycan and collagen amount, and mechanical properties of the v discs. Measurements of these properties were performed with MTT, quantitative colorimetric assays, histochemical staining and mechanical tests, respectively. According to comparative results with healthy groups and controls (osteoarthritic chondrocytes without any treatment), it was found that BMP-9 had negative effect on osteoarthritic chondrocytes. On the other hand, Ral showed positive results related with matrix synthesis and mechanical properties especially at 5 &amp / #956 / M dose suggesting that it holds promise for the treatment of OA. The therapeutic effect of Ral on OA was documented for the first time in literature. The potential of PLF-68 for treatment of OA was also supported by this study considering its positive effects on cell number, collagen synthesis and mechanical properties. Yet, further investigations are also suggested for conclusive results on this agent.

In this study, extracts from bark, leaves and catkins of Salix aegyptiaca L. were investigated for their antioxidant content by 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) free radical quenching assay, total phenolic and total flavonoid assays. The highest antioxidant activity (19 ug/ml IC50 for inhibition of DPPH radical activity), total phenolic content (212 mg gallic acid equivalents/g of dried extract) and total flavonoid (479 mg catechin equivalents/g of dried extract) was observed in the ethanolic extract of bark. High performance liquid chromatography (HPLC) analyses revealed the presence of gallic acid, caffeic acid, vanillin and p-coumaric acid, myricetin, catechin, epigallocatechin gallate, rutin, quercetin as well as salicin. In addition, the anti-proliferative effects of the ethanolic extracts on colorectal cancer cell lines (HCT-116 and HT-29) were examined by an MTT cell viability assay while their apoptotic effects were assayed by acridine orange staining and caspase 3 activity. The results indicate that the ethanolic extract of bark of S. aegyptiaca can strongly inhibit cell proliferation and induces apoptosis in a dose dependent manner on both cell lines. We propose that extracts from this plant may be utilized as a source of health promoting antioxidants. Our data provide a perspective for more detailed study of biochemical pathways associated with the cancer preventive effects of active components of the extracts from S. aegyptiaca.

Nerve injury is a serious clinical problem that has a direct impact on the quality of life. Nerve tissue engineering (NTE) is one of the most promising methods in human health care to restore the function of damaged neural tissues. The current state of the art involves the construction of a tissue engineered, nano or micropatterned 3-D nerve tube that has fibers or channels in the inside. The scope of this study is to construct a 3-D, biodegradable nerve tube which consists of an aligned, electrospun mat seeded with stem cells that is wrapped in a porous micropatterned film which contains support cells. In two separate approaches human mesenchymal stem cells (MSCs) and mouse neural stem cells (NSCs) were used. In the design with the MSCs, the micropatterned exterior part of the nerve tube contained undifferentiated MSCs as support cells and this was wrapped around the fibers seeded with MSCs which were induced to neural differentiation. In the other case, NSCs differentiated into astrocytes were used as support cells seeded on the micropatterned film and the mat was loaded with undifferentiated NSCs. Differentiation into neural cells and astrocytes were shown with immunocytochemistry and RT-PCR. The neuron-like MSCs and NSCs were shown to express neural marker &amp / #946 / -Tubulin III whereas astrocytes expressed glial fibrillary acidic protein (GFAP), an astrocyte marker. RT-PCR showed that early neural markers, nestin and Nurr 1, were expressed at passage 4 by undifferentiated MSCs and by MSCs induced to neural differentiation, while these markers were not expressed in undifferentiated MSCs at passages 2 and 3. The cells aligned along the axis of the micropattern of the film and along the axis of the fiber on the fibrous mat. This behavior was also maintained after construct formation. MTS and confocal microscopy revealed that the cells were viable and homogeneously distributed over the two parts of the scaffold. This indicates that the construct has a potential to be tested in vivo for nerve tissue engineering purposes.

One of the major causes of death in developed countries is cardiovascular disease that affects small and medium sized blood vessels. In most cases autologous grafts have to be used which have limited availability. A functional tissue engineered vessel can be the ultimate solution for vascular reconstruction. Tissue engineered constructs with cells growing in an organized manner have been shown to have improved mechanical properties. In the present study collagen scaffolds with 650 nm, 500 nm and 332.5 nm wide channels and ridges were seeded with human vascular smooth muscle cells (VSMC) and human endothelial cells seperately and then co-cultured on tubular scaffolds. When the films were seeded with endothelial cells it was observed that nanopatterns do not affect cell proliferation or initial cell alignment / however, they significantly influenced cell retention under shear (fluid flow). While 35 &plusmn / 10 % of the cells were retained on unpatterned films, 75 &plusmn / 4 % was retained on 332.5 nm patterned films and even higher, 91 &plusmn / 5 % was retained on 650 nm patterned films. It was shown that nanopatterns as small as 332.5 nm could align the vascular smooth muscle cells (VSMC) and that alignment significantly improved mechanical properties. Presence of nanopatterns increased the ultimate tensile strength (UTS) from 0.55 &plusmn / 0.11 on Day 0 to as much as 1.63 &plusmn / 0.46 MPa on Day 75, a value within the range of natural arteries and veins. Similarly, Young&amp / #8217 / s Modulus values were ca. 4 MPa, again in the range of the natural vessels. Since the films would be ultimately rolled into tubes of collagen, nutrient transfer through the films is quite crucial. Diffusion coefficient for 4-acetaminophenol and oxygen through the collagen films were found to be 1.86 &plusmn / 0.39 x 10-7 cm2.s-1 and 5.41 &plusmn / 2.14 x 10-7 cm2.s-1, repectively in the unseeded form, and increased by 4 fold after cell seeding, which is comparable to that in natural tissues. When both cell types were co-cultured on the nanopatterned tubes (a both-side nanopatterned collagen tube), it was shown that on the outside of the tube VSMCs proliferated in an oriented manner and on the inside endothelial cells proliferated as a monolayer. Therefore, this study showed that cell guidance enhances the mechanical properties of engineered vessels, and help overcome the two most important challenges in vascular tissue engineering / the need for adequate mechanical properties and continuous lining of endothelial cells even under physiological shear stress.

Cereal loss due to fungal pathogens is an ongoing setback in agriculture. Elucidating plant&rsquo / s resistance and susceptibility mechanisms against these cereal killers, promises progress in agriculture. In the way of understanding barley resistance against fungus Blumeria Graminis we silenced FAS-Associated Factor 1 (FAF1) gene in its mRNA level with Virus Induced Gene Silencing (VIGS) technique. Previous research in our lab had shown an augmentation in mRNA levels of FAF1 gene in fungus infected wheat, suggesting a role of this gene in the resistance mechanism. We hypothesized that the apoptotic role of FAF1 protein in metazoan is conserved in plants by including FAF1 as a factor in hypersensitive response. Barley lines Pallas01 and Pallas03 which are respectively resistant and susceptible against fungus Blumeria graminis hordei 103 (Bgh103) were used for fungal inoculations after FAF1 silencing, to test if the hypersensitive response against fungus Bgh103 was prevented. In this aspect the formation of death lesions on the Pallas01 leaf due to fungal resistance was not prevented demonstrating that FAF1 silencing with VIGS in the resistant Pallas01 line of barley is not sufficient to stop apoptosis. On the other hand the FAF1-silenced barley susceptible line Pallas03 became more sensitive to fungal stress based on conidia (body part of the fungus) counting after trypan blue staining of the infected leaves. In the C-terminus of FAF1 an ubiquitin like domain-X (UBX) is found, which is the cause of stress sensitivity based on the reported data obtained about this domain&rsquo / s loss of function in other proteins. These results suggest that FAF1 is a catalyst in the hypersensitive response and its loss of function makes barley more susceptible to fungal stress. On the other hand a short mRNA homology was found among FAF1 and many pathogen disease related proteins making this homology a possible target site for VIGS of FAF1 generated siRNAs, which might cause some other protein to be responsible for the barley susceptibility against the fungus.