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REVIEW ARTICLE

Simulating the blood-brain barrier by using artificial membranes, multicellular culturing systems, and high-tech applications

Hamdam Hourfar1* ,  Arghavan Fattahi1 ,  Mohammad Raeiji1 ,  Kimia Marzookian1 ,  Naser Safari1 ,  Narges Nasrollahi Boroujeni1 ,  Farhang Aliakbari1 ,  Daniel E. Otzen2 ,  Michael J. Strong3,4,5 ,  Dina Morshedi1*
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1 Department of Bioprocess Engineering, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
2 Department of Molecular Biology and Genetics, Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus C, Denmark
3 Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
4 Department of Clinical Neurological Sciences, Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
5 Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
JCTR, 025390064 https://doi.org/10.36922/JCTR025390064
Received: 23 September 2025 | Revised: 16 November 2025 | Accepted: 4 December 2025 | Published online: 19 February 2026
(This article belongs to the Special Issue Biomedicine and Bioinformatics Engineering)
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Background: The blood-brain barrier (BBB) is an intricate structure of the vascular endothelium that regulates trafficking required for cerebral homeostasis via tightly regulated influx and efflux transport mechanisms. It also performs a critical function in mediating communication between the periphery and the central nervous system (CNS). The BBB is designed to maintain a precisely regulated microenvironment conducive to normal neuronal activity. The development of in vitro BBB models has been driven by the need for a fast, reliable, and cost-effective tool to study the complexities of the BBB and to screen potential CNS drugs. Aim: This review provides readers with a concise yet comprehensive introduction to the fundamental histology of the BBB. This background is essential for interpreting model design constraints and limitations in BBB simulation. Following that, we thoroughly examine in vitro models, providing a comprehensive analysis of their applications and the equations used to assess specific BBB parameters. Relevance for patients: From a translational and clinical perspective, in vitro models of the BBB have the potential to provide novel insights into brain pathophysiology under adverse conditions, including brain tumors, traumatic injuries, strokes, and neurodegenerative disorders, and ultimately aid in the discovery of effective treatment strategies.

Graphical abstract
Keywords
Blood-brain barrier
In vitro blood-brain barrier models
Integrity assays
Neurovascular unit
Funding
Michael J. Strong receives funding from the Canadian Institutes of Health Research (SOP-160442) and the Temerty Family Foundation.
Conflict of interest
The authors declare they have no competing interests.
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