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Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening
Biotechnology and bioengineering, 2017-01, Vol.114 (1), p.184-194
Wang, Ying I.
Abaci, Hasan Erbil
Shuler, Michael L.
2017
Details
Autor(en) / Beteiligte
Wang, Ying I.
Abaci, Hasan Erbil
Shuler, Michael L.
Titel
Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening
Ist Teil von
Biotechnology and bioengineering, 2017-01, Vol.114 (1), p.184-194
Ort / Verlag
United States: Wiley Subscription Services, Inc
Erscheinungsjahr
2017
Link zum Volltext
Quelle
Wiley Online Library Journals Frontfile Complete
Beschreibungen/Notizen
ABSTRACT Efficient delivery of therapeutics across the neuroprotective blood–brain barrier (BBB) remains a formidable challenge for central nervous system drug development. High‐fidelity in vitro models of the BBB could facilitate effective early screening of drug candidates targeting the brain. In this study, we developed a microfluidic BBB model that is capable of mimicking in vivo BBB characteristics for a prolonged period and allows for reliable in vitro drug permeability studies under recirculating perfusion. We derived brain microvascular endothelial cells (BMECs) from human induced pluripotent stem cells (hiPSCs) and cocultured them with rat primary astrocytes on the two sides of a porous membrane on a pumpless microfluidic platform for up to 10 days. The microfluidic system was designed based on the blood residence time in human brain tissues, allowing for medium recirculation at physiologically relevant perfusion rates with no pumps or external tubing, meanwhile minimizing wall shear stress to test whether shear stress is required for in vivo‐like barrier properties in a microfluidic BBB model. This BBB‐on‐a‐chip model achieved significant barrier integrity as evident by continuous tight junction formation and in vivo‐like values of trans‐endothelial electrical resistance (TEER). The TEER levels peaked above 4000 Ω · cm2 on day 3 on chip and were sustained above 2000 Ω · cm2 up to 10 days, which are the highest sustained TEER values reported in a microfluidic model. We evaluated the capacity of our microfluidic BBB model to be used for drug permeability studies using large molecules (FITC‐dextrans) and model drugs (caffeine, cimetidine, and doxorubicin). Our analyses demonstrated that the permeability coefficients measured using our model were comparable to in vivo values. Our BBB‐on‐a‐chip model closely mimics physiological BBB barrier functions and will be a valuable tool for screening of drug candidates. The residence time‐based design of a microfluidic platform will enable integration with other organ modules to simulate multi‐organ interactions on drug response. Biotechnol. Bioeng. 2017;114: 184–194. © 2016 Wiley Periodicals, Inc. Wang and coworkers developed a microfluidic blood‐brain barrier model by coculturing human brain microvascular endothelial cells derived from a stem cell source and primary astrocytes that, for the first time, achieved barrier tightness at in vivo levels. Continuous tight junction networks were formed and sustained and permeability for tracer molecules and drugs approached in vivo values. Their pumpless platform provides flow perfusion matching physiological residence time and will enable integration with other organ modules to simulate multi‐organ interactions to drugs.
Sprache
Englisch
Identifikatoren
ISSN: 0006-3592
eISSN: 1097-0290
DOI: 10.1002/bit.26045
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6650146
Format
–
Schlagworte
Barriers
,
Bioengineering
,
Blood-brain barrier
,
Blood-Brain Barrier - metabolism
,
Brain
,
Cell Line
,
Drug Evaluation, Preclinical - methods
,
Drugs
,
Electric Impedance
,
Equipment Design
,
human iPS cells
,
Humans
,
In vivo methods and tests
,
Induced Pluripotent Stem Cells - metabolism
,
Induced Pluripotent Stem Cells - physiology
,
Mathematical models
,
Microfluidic Analytical Techniques - instrumentation
,
Microfluidic Analytical Techniques - methods
,
Microfluidics
,
Models, Biological
,
organ on a chip
,
Permeability
,
Pharmacology
,
Screening
,
TEER
,
Tissue Array Analysis - methods
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