Urna Kansakar

Date of Award

Winter 2-23-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Mark DeCoster

Abstract

Gliomas are brain tumors that primarily arise from glial cells. Gliomas account for 70% of the brain tumors and they are more prevalent in older adults. About 60% of the people with gliomas experience at least one seizure. Brain tumors can grow and metastasize to neighboring areas, thereby destroying normal brain cells. In a brain tumor microenvironment, both malignant cancer cells and healthy brain cells are present. Studies have shown that astrocytes may have a role in tumor growth in the brain. Monocultures cannot evaluate interactions between two cell types and does not accurately represent in vivo conditions. Thus, a co-culture in vitro cell model is needed to gain better insight into the dynamics of the system. However, co-cultures are challenging as the two different cell types have different growth rates and the population ratios must be optimized to achieve a stable system. A co-culture experimental model comprised of normal brain cells and cancer cells will be beneficial as it mimics the brain tumor microenvironment. In this work, a mixed co-culture method was employed to simulate a diseased state of the brain and study cell-cell interactions between normal brain astrocytes and glioma cells. In addition, tumor invasion in the presence of normal brain cells was studied. This research enhances understanding on the brain tumor microenvironment and cancer progression. Signaling molecules such as neurotransmitter will be considered in this system, one of these, glutamate, is a major excitatory neurotransmitter and plays a major role in normal functioning of the brain. However, iv excess glutamate is present in numerous neurological disorders such as seizure, and epilepsy. Moreover, few studies have examined the uptake of glutamate in co-culture of glioma cells and normal brain astrocytes. In the present study, glutamate uptake was measured in normal brain astrocytes, glioma cells and combination of both cell types using a quantitative colorimetric assay kit. Results showed that co-culture of glioma cells with astrocytes enhanced the uptake of glutamate by astrocytes as compared with uptake by astrocytes alone. Furthermore, changes in morphology in normal brain cells were observed in sodium-free medium when sodium-dependent transporters were blocked. New approaches were developed to modify brain cell microenvironment using engineered micro/nano materials and chemical treatments such as staurosporine. Finally, the potential applications of Copper-containing High Aspect Ratio Structures (CuHARS), a promising novel biomaterial, were explored for biomedical purposes such as incorporating them with cellulose to construct a stable matrix for CuHARS delivery in glioma cells. In addition, interaction of sonicated CuHARS was investigated in a coculture model developed earlier in this project and degradation of the sonicated CuHARS was studied to quantify degradable biomaterials.

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