UBC Theses and Dissertations
Conceptualization and development of in vitro vascular models for studying Alzheimer’s Disease Cameron, Tiffany
The human brain is an extraordinarily complex organ that is regulated by the input of nutrients and oxygen and the removal of waste via the vascular network. Understanding how the local microenvironment of cells that make up the neurovascular unit influences the health of the human brain could allow for better understanding of disease pathology, such as Alzheimer’s Disease (AD). Traditional animal-based models are limited in some of their physiological similarities with humans; therefore, human-based in vitro models are desirable. Standard cell culture is often performed in a 2-dimensional, static well plate, which lacks many of the physiological properties seen in the human brain. Moving towards in vitro models that include defined cellular architectures and includes flow on the endothelial cell layer could overcome some of the challenges associated with standard well plate models. In this thesis, in vitro models of the capillary and arteriole are conceptualized and developed. Two capillary-based microfluidic designs are developed, with a focus on the fabrication techniques used for the master molds, as well as the endothelial cell layer optimization. Having a tight endothelial cell layer is important to ensure that transport into and out of the brain is based on transcellular transport and not due to a leaky barrier. The first capillary model described includes a hydrogel-based extracellular matrix, and the second contains a planar membrane acting as a substrate for the endothelial cell barrier. In addition, this work highlights improvements to a previously used tissue chamber that contains a cell-laden scaffold. The motivation for these improvements includes the fragility of the tissue chamber and only being able to perform in-line sampling from the circulating fluid within the “blood” side, limiting the ability to perform in-line vessel transport studies. The fabrication of custom end-caps, to improve the tissue chamber stability, and the inclusion of sampling ports to the “brain” side are also described.
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