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Note: thesis: Thesis (Sc. M.)--Brown University, 2017
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Abstract: Chapter 2: Of recent, the National Institutes of Health (NIH) has pushed for the inclusion of sex as a variable in basic science research and clinical trials. In this study, we describe a method to determine the sex of postnatal rat pups and then, using sexed animals, fabricate sex-specific 3D cortical microtissues. Bridging 2D neural cell culture and in vivo brain studies, 3D neural cell culture has the potential to advance studies in complex neurodegenerative diseases and proffer a more realistic model of the brain (Dingle et al., 2015). Furthermore, the creation of sex-specific 3D cortical microtissues allows for the inclusion of sex as a variable in neuroscience research. Our results demonstrate that sex-specific 3D cortical microtissues contain a heterogeneous population of cells, including neurons, astrocytes, and neural progenitor cells. In addition, differential expression of estrogen receptors revealed preliminary sex differences between male and female cultures. It is our goal to study sex differences in traumatic brain injury and ischemic stroke using sex-specific 3D cortical microtissues in order to promote sex inclusion in basic science and biomedical engineering research. Chapter 3: Traumatic brain injury (TBI) is a significant public health issue affecting over 2 million Americans annually. TBI is caused by a bump, blow, or jolt to the head that disrupts normal function of the brain. TBI can be caused through a variety of incidents, including falls, motor vehicle accidents, and sporting events. TBI can cause severe deficits that hinder patient quality of life, including paralysis, memory loss, and dementia; however, in severe cases, TBI can result in death. The severity and injury from TBI vary from person to person. Furthermore, despite successes in in vivo studies, therapeutics for TBI successful in small animal models have no led to significant improvement in patients suffering from TBIs (Xiong et al., 2013). Therefore, clinically relevant in vitro TBI models are necessary in order to establish reproducible injuries that can be explored and eventually, to test pharmaceutical preventions and treatments for TBI. In vitro TBI models have the potential to elucidate, in controlled, consistent experimental conditions, the complex cellular cascades that occur during TBI that lead to cell death. The goal of this study is to develop a TBI model using 3D cortical microtissues. Bridging the gap between 2D and in vivo studies, 3D cortical microtissues would allow TBI to be studied in a heterogeneous population of cells with a cell density and stiffness similar to the in vivo environment. In this study, gel compression platforms for 3D cortical microtissues were engineered using agarose, polyacrylamide, and polydimethylsiloxane. Chapter 4: Stroke is an important public health issue, affecting a significant portion of the population. Sexual dimorphism exists in stroke in humans, animals, and in vitro studies. Previous work has suggested that steroidal sex hormones, specifically estrogens, are responsible for sex differences in response to stroke. There is therefore a significant need to develop clinically relevant models of stroke to elucidate the mechanisms surrounding sex differences in response to stroke. The goal of this work was to model stroke in vitro with oxygen-glucose deprivation and validate the model. The stroke model was then used to determine sex differences in response to stroke and to determine the neuroprotective effects of 17β-estradiol on male and female 3D cortical microtissues exposed to stroke. We developed a stroke model using the GasPak EZ Anaerobe Container System coupled with glucose-free media. We demonstrated that our model showed several hallmarks of stroke, including two phases of injury (ischemia and reperfusion/recovery), disrupted neuronal networks, reactive astrocytes, and the production of reactive oxygen species. We also determined that male samples were more prone to ischemia than female samples, as indicated by the results of a lactate dehydrogenase assay. We also began preliminary studies to determine the neuroprotective effects of 17β-estradiol in male and female samples. In this work, we developed a robust model of ischemic stroke in vitro using 3D cortical microtissues that we then used to study sex differences in response to stroke.
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Identifier: DOI: 10.7301/Z0QC0206
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