Transport models and in vitro study for the permeability of the blood-brain barrier to water and solutes
Item
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Title
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Transport models and in vitro study for the permeability of the blood-brain barrier to water and solutes
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Identifier
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d_2009_2013:abff1dd1ce68:10621
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identifier
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10913
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Creator
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Li, Guanglei,
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Contributor
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Bingmei Fu
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Date
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2010
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biomedical engineering | astrocyte | blood-brain barrier | brian endothelium | central nervous system | drug delivery | permeability
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Abstract
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The blood-brain barrier (BBB) is a dynamic barrier between blood circulation and central nervous system (CNS). Its unique structure provides a protective role for the CNS as well as a barrier to drug delivery to the brain. Although numerous studies have been conducted to understand the transport mechanism of the BBB, they are rather qualitative. Therefore, one objective of this thesis is to quantitatively investigate the structural mechanism by which the BBB controls the transport of water and solutes. Another objective is to build and characterize in vitro BBB models for drug delivery study.;For water and small hydrophilic solutes, the major route across the BBB is a paracellular pathway. In the first part of this study, a mathematical model for water and neutral solute transport through the paracellular pathway was developed to predict the permeability of the BBB to water and neutral solutes. The endothelial surface glycocalyx (SGL) and the basement membrane (BM) of the BBB carry negative charge due to their glycosaminoglycan compositions. In the second part of this study, an electro-diffusion model for the transport of charged molecules across the BBB was developed. In this model, constant charge densities were assumed in the SGL and in the BM. Both electrostatic and steric interaction and exclusion to charged molecules were considered within the SGL and the BM, and at their interfaces with non-charged regions of the BBB. The model predicted that the charge density in both SGL and BM would be ∼30 mEq/L based on the permeability data for positively and negatively charged solutes measured in intact rat mesenteric and pial microvessels.;In vitro BBB models have been widely used due to their advantages over in vivo models. In the third part of this study, several in vitro BBB models were developed: endothelial monoculture (immortal mouse brain microvascular endothelial cell line, bEnd3), coculture of bEnd3 and primary rat astrocytes, coculture with basement membrane substitutes. The hydraulic conductivity, transendothelial electrical resistance and diffusive solute permeability of these in vitro models to various-sized solutes were quantified. The expression of the BBB tight junction proteins in these models was also assessed using RT-PCR and immunofluorescence. The results suggest that the endothelial monoculture and the coculture models are fairly good models for studying the transport of relatively large solutes across the BBB.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Engineering
