Permeability Analysis of Neuroactive Drugs Through a Dynamic Microfluidic In Vitro Blood–Brain Barrier Model

Abstract

This paper presents the permeability analysis of neuroactive drugs and correlation with in vivo brain/plasma ratios in a dynamic microfluidic blood-brain barrier (BBB) model. Permeability of seven neuroactive drugs (Ethosuximide, Gabapentin, Sertraline, Sunitinib, Traxoprodil, Varenicline, PF-304014) and trans-endothelial electrical resistance (TEER) were quantified in both dynamic (microfluidic) and static (transwell) BBB models, either with brain endothelial cells (bEnd.3) in monoculture, or in co-culture with glial cells (C6). Dynamic cultures were exposed to 15 dyn/cm(2) shear stress to mimic the in vivo environment. Dynamic models resulted in significantly higher average TEER (respective 5.9-fold and 8.9-fold increase for co-culture and monoculture models) and lower drug permeabilities (average respective decrease of 0.050 and 0.052 log(cm/s) for co-culture and monoculture) than static models; and co-culture models demonstrated higher average TEER (respective 90 and 25% increase for static and dynamic models) and lower drug permeability (average respective decrease of 0.063 and 0.061 log(cm/s) for static and dynamic models) than monoculture models. Correlation of the resultant logP e values [ranging from -4.06 to -3.63 log(cm/s)] with in vivo brain/plasma ratios (ranging from 0.42 to 26.8) showed highly linear correlation (R (2) > 0.85) for all model conditions, indicating the feasibility of the dynamic microfluidic BBB model for prediction of BBB clearance of pharmaceuticals.

Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening

“…5B). The corresponding calculated apparent permeability coefficient P app was (5.57 ± 0.52) × 10 -5 cm s -1 , which was consistent with literature reported values [18,41]. According to permeability assays, drugs with a measured P app value of > 3 × 10 -6 cm s -1 was considered to be highly permeable, but P app values less than 1 × 10 -6 cm s -1 means a poor permeability across the BBB [42].…”

“…Especially, several microfluidic BBB models have been developed to closely imitate human blood flow, cerebrovascular construction and co-cultured microenvironment [16,17]. However, most of them mainly focused on the BBB model design, but the drug permeability across the BBB and efficacy at brain targets were rarely exploited [18].…”

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

“…For example, flow might be employed through inlet and outlet channels that push liquid through a hydrogel reservoir in which the cells are cultured [118]. Alternatively, cells might be grown on a membrane within a microfluidic device with a flow channel on top of the cells, as described by Booth and Kim in 2014 [119]. Importantly, shear stress might act on only one side of the ECs (apical or basal), and the flow can be used to transport nutrients and waste products as well.…”

Apicobasal polarity of brain endothelial cells

“…199 Applying this level of shear stress to brain endothelial cells in vitro increases their barrier properties and the expression of tight junction components. 93,200,201 …”