A Microfluidic In Vitro Three-Dimensional Dynamic Model of the Blood–Brain Barrier to Study the Transmigration of Immune Cells

Abstract

To study the biodistribution of new chemical and biological entities, an in vitro model of the blood–brain barrier (BBB) may become an essential tool during early phases of drug discovery. Here, we present a proof-of-concept of an in-house designed three-dimensional BBB biochip designed by us. This three-dimensional dynamic BBB model consists of endothelial cells and astrocytes, co-cultured on opposing sides of a polymer-coated membrane under flow mimicking blood flow. Our results demonstrate a highly effective BBB as evidenced by (i) a 30-fold increase in transendothelial electrical resistance (TEER), (ii) a significantly higher expression of tight junction proteins, and (iii) the low FITC–dextran permeability of our technical solution as compared to a static in vitro BBB model. Importantly, our three-dimensional BBB model effectively expresses P-glycoprotein (Pg-p), a hallmark characteristic for brain-derived endothelial cells. In conclusion, we provide here a complete holistic approach and insight to the whole BBB system, potentially delivering translational significance in the clinical and pharmaceutical arenas.

Progresses in the establishment, evaluation, and application of in vitro blood–brain barrier models

“…The dynamic in vitro BBB models with an incorporated microfluidic system can overcome most of the limitations of the static BBB models and makes it possible to create BBB models that more closely match the real situation in the human brain. Microfluidic BBB models are typically built on microchips that can simulate key features of in vivo BBB (Meena et al., 2022; Noorani et al., 2021).…”

Modelling the innate immune system in microphysiological systems

“…Meena et al developed a dynamic model to observe the aforementioned interaction in 2022. 74 This pump-based model contained human cerebral microvascular endothelial cells and primary astrocytes, plated on either side of a coated permeable membrane. Custom slides with removable micropore membranes were fabricated, allowing for cell seeding and exposure to continuously flowing media on both sides of the membrane.…”

Small extracellular vesicles in breast cancer brain metastasis and the prospect of clinical application

“…Tight junction complexes between BMECs are abundant and are the main contributors to BBB barrier function ( Liu et al, 2012 ; Meena et al, 2022 ). They are primarily composed of proteins such as transmembrane tight junction proteins claudins (e.g., claudin-5), occludin, and cytoplasmic proteins zonula occludens (e.g., ZO-1, ZO-2) ( Chow and Gu, 2015 ) ( Figure 3C ).…”