Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology.
Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.
BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States.|Mechanical Engineering and Engineering Science, Center for Biomedical Engineering and Science, University of North Carolina at Charlotte, 28223, United States.
Hansang
H
Cho
Neuroprotection Research Laboratory Center, Mass General Hospital, Harvard Medical School, Charlestown, 02129, United States.
Ji Hae
JH
Seo
BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States.
Keith H K
KH
Wong
Neuroprotection Research Laboratory Center, Mass General Hospital, Harvard Medical School, Charlestown, 02129, United States.
Yasukazu
Y
Terasaki
Mechanical Engineering and Engineering Science, Center for Biomedical Engineering and Science, University of North Carolina at Charlotte, 28223, United States.
Joseph
J
Park
BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States.
Kiwan
K
Bong
Neuroprotection Research Laboratory Center, Mass General Hospital, Harvard Medical School, Charlestown, 02129, United States.
Ken
K
Arai
Neuroprotection Research Laboratory Center, Mass General Hospital, Harvard Medical School, Charlestown, 02129, United States.
Eng H
EH
Lo
BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States.
Daniel
D
Irimia
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000473:pathology*; D002460:Cell Line; D002560:Cerebrovascular Circulation; D006801:Humans; D066298:In Vitro Techniques; D051381:Rats