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National Projects

Modeling of Hypertension in the Blood-Brain Barrier on a Chip and Evaluation of the Transition of Monocytes
TÜBİTAK (Scientific and Technological Research Council of Turkey) 1001,  221M092
Şendemir A.(Coordinator), Gürses B.O., Pesen Okvur D., Özoğlu Turunç E. S., Güliçli B., Gökçe B., Morçimen Z.G.

Hypertension is the stress factor on endothelial cells due circular stretching of vessel walls caused by the blood flowing with high pressure. Although the effects of hypertension on the periphery have been studied more, in vivo studies investigating its effect on brain capillaries have shown that acute hypertension disrupts the Blood Brain Barrier (BBB). Hypertension is thought to disrupt BBB and cause harmful substances in the bloodstream to reach the brain, thus it could be one of the causes of neurodegenerative diseases. Changes in the permeability of BBB in hypertensive patients directly affect monocyte leakage from the capillaries. Monocytes and other immune cells can be effective in both the pathogenesis of hypertension and the deterioration of the BBB structure. In the literature, in vitro BBB models, which are frequently used in drug targeting and drug development studies to the central nervous system (CNS), do not fully reflect its in vivo physiology. By means of dynamic in vitro lab-on-a-chip platforms under physiological fluid flow conditions that allow 3D cell-cell interactions with a biomimetic approach and that can provide nutrient and oxygen support with flow, disadvantages of static, traditional 2D in vitro and animal models can be eliminated. In this scope, the related project proposal is firstly aimed to produce an in vitro 3D microfluidic platform mimicking physiological BBB in terms of cellular organization and mechanobiology. Then, it is aimed to realize a model in which the effects of hypertension on BBB and monocyte migration and differentiation potential is demonstrated.

Developing 3 Dimensional Vascularized Tumor Models Using Bacterial Cellulose as Scaffold in vitro
TUBITAK 1001, 111M243
Sendemir A. (Coordinator), Gülce İz S., Vatansever H.S., Gürhan S.İ.

Traditional two-dimensional (2D) cell culture system was a convenient way to study cancer cells in vitro, but it failed to mimic the tumour structures in vivo, as means of cell-cell communications, cell-extracellular matrix (ECM) interactions, expression of cell surface receptors, cell proliferation characteristics, cell polarity, growth factor synthesis and cell differentiation characteristics which plays a key role in cancer cells. Thus, to develop cancer therapeutics and to understand signal transduction in cancer cells, three dimensional (3D) cell culture systems are gaining importance. In this study, two different endothelial cell lines will be co-cultured with cancer and cancer stem cells in 2D systems. The one which shows the greater proliferation will be used for further vascularization studies. In addition the composition of the cell culture medium for co-culture will be determined by adding different growth factors. The optimized media will be used to promote vascularization in micro-tissues and scaffolds.

3D cancer model will be developed in nano-fibrous tissue scaffold by cancer stem cells (CSCs) which possess high tumorogenicity. Three different cell lines will be used for comparative studies; Saos-2 (human osteosarcoma cell line), human parental osteosarcoma cancer stem cell and CSCs bearing CD133(+) surface marker which will be isolated from Saos-2 cells. The scaffold material will be bacterial cellulose which is highly biocompatible but not biodegradable. Bacterial cellulose will be produced with several different porosities and the most convenient one will be determined for cancer cell lines and CSCs for tumour formation. The scaffold porosity will be optimized by changing the culture conditions of Acetobacter Xylinum. To mimic osteosarcoma micro-environment hydroxyapatite will be added to the bacterial cellulose fibrils. At the same time, parental osteosarcoma cancer stem cell, Saos-2 and CSCs will be cultivated in 3D agar gels to determine their micro-tissue formation abilities. The cells either in micro-tissues or in suspensions will be cultured on developed bacterial cellulose fibrils to determine the most convenient structures for in vivo tumour formation, To show the presence of CSCs in different 3D culture conditions, immunofluorescence staining, gene expression analysis of CSCs by PCR, magnetic cell sorting techniques will be used. Scanning electron microscope (SEM) will be used to determine the morphology of tumour model. Chorioallantoic membrane of the embriyonated eggs will be used as an ex-vivo tumour model for comparative studies of the developed 3D vascularized tumour model. The histologic, immunochemical, structural features of the model as well as tissue integrity (average lifespan of the tumour model) will be evaluated. We anticipate our 3D vascularised tumour model will provide a valuable tool to investigate pre-clinical cancer treatment studies, angiogenesis pathways of the tumours. Insights gained with using this model can help identification of new therapeutic targets and more effective treatment options for cancer

Effects of mechanical loading on development of central nervous system (CNS) cells and neurite extension has been recognized recently. Effects of loading are very complicated since until a threshold, tension plays a positive role while after the threshold value, it is degenerative. The situation gets more complicated since CNS is made up of several different cell types that respond to different loads differently. There are some mechanicak trauma models in the literature, but they usually employ hard and two dimensional culture substrates, which fail to mimic the natural nische of the cells. The aim of this project is to create an experimental model that can mimic the physiological habitat and normal loading conditions on CNS cells. Electrospun chitosan/poly-l-lysine scaffolds and PC12 model cell line will be used. Effects of mechanical strain on cell morphology, neurite extension, and after the threshold value, on apoptosis will be examined in molecular level. By proposed model, a powerful system will be built to simulate traumatic berain injury. This model will allow experimentation with new drugs and treatments in vitro.

Investigation of Central Nervous System Neurons under Mechanical Tension and an in vitro Traumatic Brain Injury Model
TUBITAK 3501, 111M605 
Şendemir A. (Coordinator), Armağan G., Balkan B., Yalçın A., Sarıkanat M., Sarıkanat Ö., Duman M., Çelik C.

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