Cell-Culture Models of the Blood–Brain Barrier
With the increase in average life span, the percentage of patients with neurological diseases is getting higher and higher.1 Thus, developing effective neuropharmaceuticals is critically important and urgent. Sadly, many promising candidates fail to show expected effects because of their inability to cross the blood–brain barrier (BBB), a dynamic interface that separates the central nervous system (CNS) from the circulation system.1 BBB maintains the homeostasis of CNS microenvironment and proper neurological functions by regulating the exchange of substances between the 2 systems.2 Perturbation of BBB has been found in many neurological disorders, including neurodegenerative diseases,3–6 trauma,7,8 brain tumors,9,10 and stroke.11–13 Restoring BBB integrity in pathological conditions to maintain brain homeostasis and opening BBB temporarily to allow efficient delivery of drugs to the CNS are potential therapeutic options for patients with these disorders. For these purposes, a lot of research has focused on the regulation of BBB permeability. Because of the complexity of the in vivo BBB, many simplified in vitro BBB models have been developed and studied, including the monolayer models, coculture models, dynamic models, and microfluidic BBB models. Because no in vitro BBB models can fully replicate the in vivo conditions, there is no perfect in vitro BBB model. Understanding the limitations of these in vitro BBB models would be critical to the design of experiments and interpretation of data.
There have been a large number of excellent reviews on in vitro BBB models in the literature. For example, Gumbleton and Audus14 reviewed immortalized cell lines and primary cells used in in vitro BBB models and suggested that an ideal model should have low permeability, possess endothelial-like morphology, express functional transporters, and be easy to …