Current Status of Models of the Blood-brain Barrier.

Disorders of the brain constitute the most debilitating situation globally with increased mortality rates every year, while brain physiology and cumbersome drug development processes exacerbate this. Although blood-brain barrier (BBB) and its components are important for brain protection, their complexity creates major obstacles for brain drug delivery, and the BBB is the primary cause of treatment failure, leading to disease progression. Therefore, developing an ideal platform that can predict the behavior of a drug delivery system in the brain at the early development phase is extremely crucial. In this direction, in the last two decades, numerous in vitro BBB models have been developed and investigated by researchers to understand the barrier properties and how closely the in vitro models mimic in vivo BBB. In-vitro BBB models mainly involve the culture of endothelial cells or their coculture with other perivascular cells either in two or three-dimensional platforms. In this article, we have briefly summarized the fundamentals of BBB and outlined different types of in vitro BBB models with their pros and cons. Based on the available reports, no model seems to be robust that can truly mimic the entire properties of the in vivo BBB microvasculature. However, human stem cells, coculture and threedimensional models have been found to mimic the complexity of the barrier integrity not completely but more precisely than other in vitro models. More studies aiming towards combining these models together would be needed to develop an ideal in vitro model that can overcome the existing limitations and unravel the mysterious BBB vasculature.