A Reconfigurable In Vitro Model for Studying the Blood–Brain Barrier

Moya, Monica L.; Triplett, Michael; Simon, Melinda; Alvarado, Javier; Booth, Ross; Osburn, Joanne; Soscia, David; Qian, Fang; Fischer, Nicholas O.; Kulp, Kristen; Wheeler, Elizabeth K.

doi:10.1007/s10439-019-02405-y

Title: A Reconfigurable In Vitro Model for Studying the Blood–Brain Barrier

Journal Article · 18 November 2019 · Annals of Biomedical Engineering

DOI: https://doi.org/10.1007/s10439-019-02405-y · OSTI ID:1583040

^[1]; Triplett, Michael ^[1]; Simon, Melinda ^[2]; Alvarado, Javier ^[1]; Booth, Ross ^[3]; Osburn, Joanne ^[1]; Soscia, David ^[1]; Qian, Fang ^[1];

^[1]; Kulp, Kristen ^[1]; Wheeler, Elizabeth K. ^[1]

Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); San Jose State Univ., San Jose, CA (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Millipore Sigma, Hayward, CA (United States)

Much of what is currently known about the role of the blood–brain barrier (BBB) in regulating the passage of chemicals from the blood stream to the central nervous system (CNS) comes from animal in vivo models (requiring extrapolation to human relevance) and 2D static in vitro systems, which fail to capture the rich cell–cell and cell–matrix interactions of the dynamic 3D in vivo tissue microenvironment. In this work we have developed a BBB platform that allows for a high degree of customization in cellular composition, cellular orientation, and physiologically-relevant fluid dynamics. The system characterized and presented in this study reproduces key characteristics of a BBB model (e.g. tight junctions, efflux pumps) allowing for the formation of a selective and functional barrier. We demonstrate that our in vitro BBB is responsive to both biochemical and mechanical cues. This model further allows for culture of a CNS-like space around the BBB. As a result, the design of this platform is a valuable tool for studying BBB function as well as for screening of novel therapeutics.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1583040

Report Number(s):: LLNL-JRNL-758697; 946385

Journal Information:: Annals of Biomedical Engineering, Vol. 48, Issue 2; ISSN 0090-6964

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 27 works

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References (62)

Astrocyte–endothelial interactions at the blood–brain barrier Abbott, N. Joan; Rönnbäck, Lars; Hansson, Elisabeth Nature Reviews Neuroscience, Vol. 7, Issue 1 https://doi.org/10.1038/nrn1824	journal	January 2006
A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood–brain barrier Adriani, Giulia; Ma, Dongliang; Pavesi, Andrea Lab on a Chip, Vol. 17, Issue 3 https://doi.org/10.1039/C6LC00638H	journal	January 2017
Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells Appelt-Menzel, Antje; Cubukova, Alevtina; Günther, Katharina Stem Cell Reports, Vol. 8, Issue 4 https://doi.org/10.1016/j.stemcr.2017.02.021	journal	April 2017
Development of a Micromanipulator-Based Loading Device for Mechanoregulation Study of Human Mesenchymal Stem Cells in Three-Dimensional Collagen Constructs Au-yeung, Kwan Lok; Sze, Kam Yim; Sham, Mai Har Tissue Engineering Part C: Methods, Vol. 16, Issue 1 https://doi.org/10.1089/ten.tec.2008.0707	journal	February 2010
Patterning the differentiation of C2C12 skeletal myoblasts Bajaj, Piyush; Reddy, Bobby; Millet, Larry Integrative Biology, Vol. 3, Issue 9 https://doi.org/10.1039/c1ib00058f	journal	January 2011
A Low Permeability Microfluidic Blood-Brain Barrier Platform with Direct Contact between Perfusable Vascular Network and Astrocytes Bang, Seokyoung; Lee, Seung-Ryeol; Ko, Jihoon Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-07416-0	journal	August 2017
Developing drugs that can cross the blood-brain barrier: applications to Alzheimer's disease Banks, William A. BMC Neuroscience, Vol. 9, Issue S3 https://doi.org/10.1186/1471-2202-9-S3-S2	journal	December 2008
Limitations of the hCMEC/D3 cell line as a model for Aβ clearance by the human blood-brain barrier: Limitations hCMEC/D3 Model to Study Aβ Clearance Biemans, Elisanne A. L. M.; Jäkel, Lieke; de Waal, Robert M. W. Journal of Neuroscience Research, Vol. 95, Issue 7 https://doi.org/10.1002/jnr.23964	journal	October 2016
Gene expression perturbation in vitro—A growing case for three-dimensional (3D) culture systems Birgersdotter, Anna; Sandberg, Rickard; Ernberg, Ingemar Seminars in Cancer Biology, Vol. 15, Issue 5 https://doi.org/10.1016/j.semcancer.2005.06.009	journal	October 2005
Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB) Booth, Ross; Kim, Hanseup Lab on a Chip, Vol. 12, Issue 10 https://doi.org/10.1039/c2lc40094d	journal	January 2012
Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor Brown, Jacquelyn A.; Pensabene, Virginia; Markov, Dmitry A. Biomicrofluidics, Vol. 9, Issue 5 https://doi.org/10.1063/1.4934713	journal	September 2015
Effects of shear stress on endothelial cells: go with the flow Chistiakov, D. A.; Orekhov, A. N.; Bobryshev, Y. V. Acta Physiologica, Vol. 219, Issue 2 https://doi.org/10.1111/apha.12725	journal	June 2016
Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents Cho, Choi-Fong; Wolfe, Justin M.; Fadzen, Colin M. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms15623	journal	June 2017
A Dynamic in vitro BBB Model for the Study of Immune Cell Trafficking into the Central Nervous System Cucullo, Luca; Marchi, Nicola; Hossain, Mohammed Journal of Cerebral Blood Flow & Metabolism, Vol. 31, Issue 2 https://doi.org/10.1038/jcbfm.2010.162	journal	July 2010
A Novel Dynamic Neonatal Blood-Brain Barrier on a Chip Deosarkar, Sudhir P.; Prabhakarpandian, Balabhaskar; Wang, Bin PLOS ONE, Vol. 10, Issue 11 https://doi.org/10.1371/journal.pone.0142725	journal	November 2015
Benchmarking in vitro tissue-engineered blood–brain barrier models DeStefano, Jackson G.; Jamieson, John J.; Linville, Raleigh M. Fluids and Barriers of the CNS, Vol. 15, Issue 1 https://doi.org/10.1186/s12987-018-0117-2	journal	December 2018
Effect of shear stress on iPSC-derived human brain microvascular endothelial cells (dhBMECs) DeStefano, Jackson G.; Xu, Zinnia S.; Williams, Ashley J. Fluids and Barriers of the CNS, Vol. 14, Issue 1 https://doi.org/10.1186/s12987-017-0068-z	journal	August 2017
Shuttle-mediated nanoparticle transport across an in vitro brain endothelium under flow conditions: Functionalized-NP Transport Through a BBB on a Chip Falanga, Andrea P.; Pitingolo, Gabriele; Celentano, Maurizio Biotechnology and Bioengineering, Vol. 114, Issue 5 https://doi.org/10.1002/bit.26221	journal	November 2016
Differential effects of hydrocortisone and TNFα on tight junction proteins in an in vitro model of the human blood-brain barrier : Hydrocortisone and BBB properties in brain endothelial cell line Förster, Carola; Burek, Malgorzata; Romero, Ignacio A. The Journal of Physiology, Vol. 586, Issue 7 https://doi.org/10.1113/jphysiol.2007.146852	journal	March 2008
7.0-T Magnetic Resonance Imaging Characterization of Acute Blood-Brain-Barrier Disruption Achieved with Intracranial Irreversible Electroporation Garcia, Paulo A.; Rossmeisl, John H.; Robertson, John L. PLoS ONE, Vol. 7, Issue 11 https://doi.org/10.1371/journal.pone.0050482	journal	November 2012
BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function Griep, L. M.; Wolbers, F.; de Wagenaar, B. Biomedical Microdevices, Vol. 15, Issue 1 https://doi.org/10.1007/s10544-012-9699-7	journal	September 2012
Development of a three-dimensional, all-human in vitro model of the blood–brain barrier using mono-, co-, and tri-cultivation Transwell models Hatherell, Kathryn; Couraud, Pierre-Olivier; Romero, Ignacio A. Journal of Neuroscience Methods, Vol. 199, Issue 2 https://doi.org/10.1016/j.jneumeth.2011.05.012	journal	August 2011
In vitro models of the blood–brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use Helms, Hans C.; Abbott, N. Joan; Burek, Malgorzata Journal of Cerebral Blood Flow & Metabolism, Vol. 36, Issue 5 https://doi.org/10.1177/0271678X16630991	journal	February 2016
Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip Herland, Anna; van der Meer, Andries D.; FitzGerald, Edward A. PLOS ONE, Vol. 11, Issue 3 https://doi.org/10.1371/journal.pone.0150360	journal	March 2016
Bypassing P-Glycoprotein Drug Efflux Mechanisms: Possible Applications in Pharmacoresistant Schizophrenia Therapy Hoosain, Famida G.; Choonara, Yahya E.; Tomar, Lomas K. BioMed Research International, Vol. 2015 https://doi.org/10.1155/2015/484963	journal	January 2015
Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications Hynynen, Kullervo; McDannold, Nathan; Sheikov, Nickolai A. NeuroImage, Vol. 24, Issue 1 https://doi.org/10.1016/j.neuroimage.2004.06.046	journal	January 2005
Engineering the human blood-brain barrier in vitro Jamieson, John J.; Searson, Peter C.; Gerecht, Sharon Journal of Biological Engineering, Vol. 11, Issue 1 https://doi.org/10.1186/s13036-017-0076-1	journal	December 2017
A Three-Dimensional Arrayed Microfluidic Blood–Brain Barrier Model With Integrated Electrical Sensor Array Jeong, Sehoon; Kim, Sunja; Buonocore, John IEEE Transactions on Biomedical Engineering, Vol. 65, Issue 2 https://doi.org/10.1109/TBME.2017.2773463	journal	February 2018
Recent Progress in Microfluidic Models of the Blood-Brain Barrier Jiang, Lili; Li, Shu; Zheng, Junsong Micromachines, Vol. 10, Issue 6 https://doi.org/10.3390/mi10060375	journal	June 2019
Why Clinical Modulation of Efflux Transport at the Human Blood–Brain Barrier Is Unlikely: The ITC Evidence-Based Position Kalvass, J. C.; Polli, J. W.; Bourdet, D. L. Clinical Pharmacology & Therapeutics, Vol. 94, Issue 1 https://doi.org/10.1038/clpt.2013.34	journal	February 2013
Three-dimensional (3D) tetra-culture brain on chip platform for organophosphate toxicity screening Koo, Youngmi; Hawkins, Brian T.; Yun, Yeoheung Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-20876-2	journal	February 2018
A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood–brain barrier, and the transporting mechanism to glioma cells Liu, Chang; Liu, Xiao-Na; Wang, Gui-Ling International Journal of Nanomedicine, Vol. Volume 12 https://doi.org/10.2147/IJN.S131367	journal	January 2017
Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood–brain barrier Mairey, Emilie; Genovesio, Auguste; Donnadieu, Emmanuel The Journal of Experimental Medicine, Vol. 203, Issue 8 https://doi.org/10.1084/jem.20060482	journal	July 2006
Blood-brain barrier disruption in multiple sclerosis Minagar, Alireza; Alexander, J. Steven Multiple Sclerosis Journal, Vol. 9, Issue 6 https://doi.org/10.1191/1352458503ms965oa	journal	December 2003
A new blood–brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes Nakagawa, Shinsuke; Deli, Mária A.; Kawaguchi, Hiroko Neurochemistry International, Vol. 54, Issue 3-4 https://doi.org/10.1016/j.neuint.2008.12.002	journal	March 2009
Microfluidic approach for the fabrication of cell-laden hollow fibers for endothelial barrier research Nguyen, Thi Phuong Thuy; Tran, Buu Minh; Lee, Nae Yoon Journal of Materials Chemistry B, Vol. 6, Issue 38 https://doi.org/10.1039/C8TB02031K	journal	January 2018
TNFα alters occludin and cerebral endothelial permeability: Role of p38MAPK Ni, Yawen; Teng, Tao; Li, Runting PLOS ONE, Vol. 12, Issue 2 https://doi.org/10.1371/journal.pone.0170346	journal	February 2017
Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems Odijk, Mathieu; van der Meer, Andries D.; Levner, Daniel Lab on a Chip, Vol. 15, Issue 3 https://doi.org/10.1039/C4LC01219D	journal	January 2015
The blood-brain barrier: Bottleneck in brain drug development Pardridge, William M. NeuroRX, Vol. 2, Issue 1 https://doi.org/10.1602/neurorx.2.1.3	journal	January 2005
Mechanical stress regulates transport in a compliant 3D model of the blood-brain barrier Partyka, Paul P.; Godsey, George A.; Galie, John R. Biomaterials, Vol. 115 https://doi.org/10.1016/j.biomaterials.2016.11.012	journal	January 2017
Blood–brain Barrier: Structural Components and Function Under Physiologic and Pathologic Conditions Persidsky, Yuri; Ramirez, Servio H.; Haorah, James Journal of Neuroimmune Pharmacology, Vol. 1, Issue 3 https://doi.org/10.1007/s11481-006-9025-3	journal	July 2006
SyM-BBB: a microfluidic blood brain barrier model Prabhakarpandian, Balabhaskar; Shen, Ming-Che; Nichols, Joseph B. Lab on a Chip, Vol. 13, Issue 6 https://doi.org/10.1039/c2lc41208j	journal	January 2013
Human brain microvascular endothelial cells resist elongation due to shear stress Reinitz, Adam; DeStefano, Jackson; Ye, Mao Microvascular Research, Vol. 99 https://doi.org/10.1016/j.mvr.2015.02.008	journal	May 2015
The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system? Saunders, Norman R.; Habgood, Mark D.; Møllgård, Kjeld F1000Research, Vol. 5 https://doi.org/10.12688/f1000research.7378.1	journal	January 2016
An optically transparent membrane supports shear stress studies in a three-dimensional microfluidic neurovascular unit model Sellgren, Katelyn L.; Hawkins, Brian T.; Grego, Sonia Biomicrofluidics, Vol. 9, Issue 6 https://doi.org/10.1063/1.4935594	journal	November 2015
Diverse Functions of Endothelial NO Synthases System: NO and EDH Shimokawa, Hiroaki; Godo, Shigeo Journal of Cardiovascular Pharmacology, Vol. 67, Issue 5 https://doi.org/10.1097/FJC.0000000000000348	journal	January 2016
Morphological and functional characterization of an in vitro blood–brain barrier model Stanness, Kathe A.; Westrum, Lesnick E.; Fornaciari, Eleonora Brain Research, Vol. 771, Issue 2 https://doi.org/10.1016/S0006-8993(97)00829-9	journal	October 1997
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders Sweeney, Melanie D.; Sagare, Abhay P.; Zlokovic, Berislav V. Nature Reviews Neurology, Vol. 14, Issue 3 https://doi.org/10.1038/nrneurol.2017.188	journal	January 2018
Microfluidic Gel Patterning Method by Use of a Temporary Membrane for Organ-On-Chip Applications Tibbe, Martijn P.; Leferink, Anne M.; van den Berg, Albert Advanced Materials Technologies, Vol. 3, Issue 3 https://doi.org/10.1002/admt.201700200	journal	January 2018
Multicellular Self-Assembled Spheroidal Model of the Blood Brain Barrier Urich, Eduard; Patsch, Christoph; Aigner, Stefan Scientific Reports, Vol. 3, Issue 1 https://doi.org/10.1038/srep01500	journal	March 2013
Microfluidic organ-on-chip technology for blood-brain barrier research van der Helm, Marinke W.; van der Meer, Andries D.; Eijkel, Jan C. T. Tissue Barriers, Vol. 4, Issue 1 https://doi.org/10.1080/21688370.2016.1142493	journal	January 2016
Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia Walsby, Elisabeth; Buggins, Andrea; Devereux, Stephen Blood, Vol. 123, Issue 23 https://doi.org/10.1182/blood-2013-12-544569	journal	June 2014
Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening: Microfluidic BBB Model Mimics In Vivo Properties Wang, Ying I.; Abaci, Hasan Erbil; Shuler, Michael L. Biotechnology and Bioengineering, Vol. 114, Issue 1 https://doi.org/10.1002/bit.26045	journal	July 2016
Organization of Endothelial Cells, Pericytes, and Astrocytes into a 3D Microfluidic in Vitro Model of the Blood–Brain Barrier Wang, Jack D.; Khafagy, El-Sayed; Khanafer, Khalil Molecular Pharmaceutics, Vol. 13, Issue 3 https://doi.org/10.1021/acs.molpharmaceut.5b00805	journal	January 2016
Brain tumor-targeted drug delivery strategies Wei, Xiaoli; Chen, Xishan; Ying, Man Acta Pharmaceutica Sinica B, Vol. 4, Issue 3 https://doi.org/10.1016/j.apsb.2014.03.001	journal	June 2014
The hCMEC/D3 cell line as a model of the human blood brain barrier Weksler, Babette; Romero, Ignacio A.; Couraud, Pierre-Olivier Fluids and Barriers of the CNS, Vol. 10, Issue 1 https://doi.org/10.1186/2045-8118-10-16	journal	January 2013
Brain microvascular endothelial cells resist elongation due to curvature and shear stress Ye, Mao; Sanchez, Henry M.; Hultz, Margot Scientific Reports, Vol. 4, Issue 1 https://doi.org/10.1038/srep04681	journal	April 2014
Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier Zhao, Chen; Wang, Hongyan; Xiong, Chenghao Biochemical and Biophysical Research Communications, Vol. 502, Issue 3 https://doi.org/10.1016/j.bbrc.2018.05.140	journal	July 2018
The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders Zlokovic, Berislav V. Neuron, Vol. 57, Issue 2 https://doi.org/10.1016/j.neuron.2008.01.003	journal	January 2008
Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood–brain barrier Mairey, Emilie; Genovesio, Auguste; Donnadieu, Emmanuel Journal of Cell Biology, Vol. 174, Issue 4 https://doi.org/10.1083/jcb1744oia7	journal	August 2006
The blood-brain barrier: Bottleneck in brain drug development Pardridge, William M. Neurotherapeutics, Vol. 2, Issue 1 https://doi.org/10.1007/bf03206638	journal	January 2005
Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells Appelt-Menzel, Antje; Cubukova, Alevtina; Günther, Katharina Charité - Universitätsmedizin Berlin https://doi.org/10.17169/refubium-24787	text	January 2017

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