| dc.description.abstract | Neurological diseases are a major challenge to reach new therapies. However,
physiological signals that regulate neurodegeneration in the central nervous system
(CNS) are still little known since there is no suitable in vitro model for studying the
basis of localized cells and molecules. Here this dissertation presents the development of
biomimetic microsystems that reconstitute neurophysiologically important functional
brain and neurovascular interface in the CNS.
The brain organs-on-chips can recapitulate pharmacological responses and
complex interactions between different types of cells that are mediated by the
extracellular matrix and intercellular junctions within the organ model. Since the
developed microsystems have a biomimetic tissue structure, it is possible to more
accurately function and simulate the delivery and penetration of the drug compound in
vivo than the 2D cell monolayer in the conventional culture model or the prior
microfluidics.
The developed brain chip is composed of four culture chambers with 10
aggregate traps and multi-electrode arrays enable electrical stimulation for 40 neuronal
aggregates as well as drug stimulation. Uniform 150 μm aggregates from the microwell
can be cultured for 4 weeks. This system developed for the study of CNS myelin
formation showed that the 10Hz of electrical stimulation for the promotion of
myelination was successfully confirmed with 500 nM retinoic acid treatment results in
the automatic image analysis.
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The other developed blood-brain barrier (BBB) chip consists of 4 × 4
microfluidic channel arrays and 16 channel multi-electrode arrays, able to electrically
analyze 16 sites. Co-culture BBB-on-a-chip contains neurovascular endothelium
separated from primary astrocyte by a porous membrane that allows cell-cell interactions
through the membrane. In this platform, the effects of astrocyte-coculture, extracellular
matrix, and in vivo shear stress level on barrier permeability were characterized through
TEER measurements and dextran permeability assays.
Also, despite the presence of BBB, monocyte infiltration into the CNS was
observed by monocyte chemotactic protein (CCL2), which corresponds to the early
event of brain injury. Finally, the system developed to address these pharmacological
problems for drug development showed how drugs work in brain vessels (histamine) and
brain tissues (tetrodotoxin), as well as delivering drugs from brain vessels to brain tissue
(atenolol). | en |
