## 1 Introduction  
While neurological disorders continue to be the world's leading cause of disability and death, their associated costs are expected to exponentially increase in the coming years [1, 2]. Neurology has always been one of the therapeutic areas with the highest attrition rates [3, 4, 5]. Effective brain targeting is a prerequisite for the treatment of neurological disorders [6]. One of the main difficulties is the presence of the blood-brain barrier (BBB), which restricts access to the brain for more than 98% of drugs [2]. This structural and functional barrier separates the vasculature from the central nervous system (CNS). The BBB is primarily composed of brain microvascular endothelial cells (BMEC), forming the wall of cerebral capillaries. Their particularities are the high polarization and expression of a panel of specialized inter-endothelial junctions, which contribute to their sealing feature. The drug transport restrictions imposed by the BBB must be reliably predicted as early as possible in the drug development process by testing the ability of new therapeutic entities to enter the brain on relevant models. In vitro BBB models offer faster and more simplified approaches for targeted drug screening as well as for fundamental research. Theycould be humanized to overcome translatability issues. Both primary cultured BMEC and cell line models are classically used for studying the mechanisms for specific transport and kinetics of drug exchanges across the BBB. Some brain properties are maintained in freshly isolated brain capillaries but decline in culture after a few passages. Dedifferentiating processes were observed with the loss of BBB characteristics. Moreover, many BMEC lines exhibit a reduced expression of specific transporters and tight junctions, and these models are not as tight as it was observed in vivo [7]. These difficulties led to a considerable challenge for improving in vitro models with new developing technologies. The aim is to create an ideal in vitro tool that combines the benefits of both in vivo animal and in vitro human models, by mimicking the original microenvironment on a culture of human BMEC. Today, the addition of hemodynamic forces seems to be a promising way to achieve cell differentiation. Hemodynamic forces appear to be particularly important in the cell differentiation processes, as in vivo BMEC are directly and permanently exposed to the intraluminal blood flow. Blood pressure creates a tangential force across the luminal vascular endothelium called shear stress. This phenomenon underlies the activation of mechano-sensitive proteins able to convert the mechanical force into biochemical responses [8]. The endothelial response greatly varies depending on the nature and magnitude of fluid shear stress, thus generating diverse structural and functional phenotypes [9; 10; 11]. Usually, shear stress levels ranging from 5 to 23 dyn\(\cdot\)cm\({}^{-2}\) are considered comparable to those reported in vivo in the brain capillaries [11; 12; 13; 14]. It was shown that a steady unidirectional laminar flow is responsible for a quiescent endothelial response, and a subsequent better BMEC differentiation. This improves the BMEC polarization through the expression of specific BBB transporters and junctions at the luminal and/or abluminal faces of BMEC membrane. Shear stress thus contributes to the induction and maintenance of a BBB phenotype, resulting in a more physiologically relevant model [11]. Dynamic devices were created to perfuse cells with medium culture in order to provide shear stress.