Journal
BIOMATERIALS
Volume 180, Issue -, Pages 117-129Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.07.014
Keywords
Human blood-brain barrier; In vitro modeling; Microfluidic device; Self-assembled microvascular network; Induced pluripotent stem cell-derived endothelial cells; Drug delivery test platform
Funding
- Ermenegildo Zegna Founder's scholarship
- MIT-POLITO grant (BIOMODE - Compagnia di San Paolo) under the joint Doctorate of Bioengineering and Medical-Surgical Sciences of University of Turin
- Politecnico di Torino
- Cure Alzheimer's Fund
- Japan Society for the Promotion of Science
- National Science Foundation for a Science and Technology Center on Emergent Behaviors of Integrated Cellular Systems [CBET-0939511]
- National Cancer Institute [U01 CA202177]
- MIT
- POLITO (MITOR project NANOCAB)
- NATIONAL CANCER INSTITUTE [U01CA202177, U01CA214381] Funding Source: NIH RePORTER
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The blood-brain barrier (BBB) regulates molecular trafficking, protects against pathogens, and prevents efficient drug delivery to the brain. Models to date failed to reproduce the human anatomical complexity of brain barriers, contributing to misleading results in clinical trials. To overcome these limitations, a novel 3-dimensional BBB microvascular network model was developed via vasculogenesis to accurately replicate the in vivo neurovascular organization. This microfluidic system includes human induced pluripotent stem cell-derived endothelial cells, brain pericytes, and astrocytes as self-assembled vascular networks in fibrin gel. Gene expression of membrane transporters, tight junction and extracellular matrix proteins, was consistent with computational analysis of geometrical structures and quantitative immunocytochemistry, indicating BBB maturation and microenvironment remodelling. Confocal microscopy validated microvessel-pericyte/astrocyte dynamic contact-interactions. The BBB model exhibited perfusable and selective microvasculature, with permeability lower than conventional in vitro models, and similar to in vivo measurements in rat brain. This robust and physiologically relevant BBB microvascular model offers an innovative and valuable platform for drug discovery to predict neurotherapeutic transport efficacy in pre-clinical applications as well as recapitulate patient-specific and pathological neurovascular functions in neurodegenerative disease. (C) 2018 Elsevier Ltd. All rights reserved.
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