3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes
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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 neuro-therapeutic transport efficacy in pre-clinical applications as well as recapitulate patient-specific and pathological neurovascular functions in neurodegenerative disease.
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A 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes, and astrocytes resembles the characteristics of a physiologic BBB similar to the rat brain, with perfusable and selective microvascularization and lower permeability than the conventional in vitro model.
“For example, a 3D self-organized microvascular model of the human blood-brain barrier (BBB) with endothelial cells, pericytes, and astrocytes resembles the characteristic of a physiologic BBB similar to those of the rat brain, with perfusable and selective microvascularization and lower permeability than the conventional in vitro model [37].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [37]
Recently, 3D self-organized microvascular BBB models with endothelial cells, pericytes, and astrocytes have been created.
“To overcome this weakness and to achieve physiological barrier function, three-dimensional self-organized microvascular models of the BBB containing endothelial cells, pericytes and astrocytes have been recently developed [225–228].”
From Mechanisms of fungal dissemination (2021) · cites this paper as [225]
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Bouquerel, C., Dubrova, A., Hofer, I., Phan, D. T. T., Bernheim, M., Ladaigue, S., Cavaniol, C., Maddalo, D., Cabel, L., Mechta-Grigoriou, F., et al. (2023) · Lab on a Chip · doi:10.1039/d3lc00531c · Cited by 58 · see citing works
Tanaka, M., Araujo, A. C., Valenti, V. E., Guiguer, E. L., Catharin, V. C. S., Gualhardi, C. M., de Souza Bastos Mazuqueli Pereira, E., de Alvares Goulart, R., de Argolo Haber, R. S., de Carvalho, A. C. A., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052370 · Cited by 13 · see citing works
- Authors
- Campisi, M., Shin, Y., Osaki, T., Hajal, C., Chiono, V., & Kamm, R. D.
- Affiliations
- Politecnico di Torino (IT)
- Massachusetts Institute of Technology (US)
- Singapore-MIT Alliance for Research and Technology (SG)
- Corresponding author
- Kamm, Roger D.
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 180
- Pages
- 117-129
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC6201194
- OpenAlex
- W2883212753
- Cited by
- 718
- References
- 75
- Citations by year
- 2026: 77 · 2025: 99 · 2024: 78 · 2023: 94 · 2022: 107 · 2021: 118 · 2020: 94 · 2019: 46 · 2018: 4
- FWCI
- 29.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 292 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Biomaterials (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PORTO@Iris (submittedVersion, cc-by-nc-nd)
- Funders
- Ermenegildo Zegna Founder's scholarship
- MIT
- POLITO
- BIOMODE - Compagnia di San Paolo
- 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)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- blood-brain barrier, vasculogenesis, induced pluripotent stem cell-derived endothelial cells, pericytes, astrocytes, fibrin gel, microfluidics, blood-brain barrier permeability, tight junctions, extracellular matrix, brain drug delivery, neurodegenerative diseases, patient-specific models
- MeSH terms
- Astrocytes, Blood-Brain Barrier, Humans, Microscopy, Confocal, Pericytes, Endothelial Cells, Lab-On-A-Chip Devices, Induced Pluripotent Stem Cells
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