New experimental models of the blood-brain barrier for CNS drug discovery

ABSTRACT

Introduction: The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases.

Area covered: This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms.

Expert opinion: Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms.

KEYWORDS:

• In vitro
• alternative
• technology
• cell culture
• brain
• cerebrovascular
• drug testing
• permeability
• brain disorders

Article highlights

• Blood-brain barrier models are to be considered companion tools designed to facilitate basic and translational studies in the field of CNS drug discovery and cerebrovascular diseases

• Complex co-culture systems may prove effective in the development of quasi-physiological system at the expenses of increased complexity and higher cost.

• Microfluidic tissue-on-a-chip approaches have emerged as promising tools to establish in vitro BBB models but the technology is not yet available mainstream.

• 3D bioprinting technologies are also emerging as tools to develop cerebrovascular models

• Cord blood stem cell or hPSC-derived BMEC are valuable alternative sources to generate the BBB cells necessary in the making of in vitro BBB models.

• The use of multiple in vitro systems featuring complementary characteristics could help reducing the shortcomings of each platform as standalone systems.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by a National Institutes of Health (NIH)/ National Institute on Drug Abuse (NIDA) grant (R01DA029121) and by the Alternatives Research and Development Foundation.