Materials for blood brain barrier modeling in vitro

Abstract

Brain homeostasis relies on the selective permeability property of the blood brain barrier (BBB). The BBB is formed by a continuous endothelium that regulates exchange between the blood stream and the brain. This physiological barrier also creates a challenge for the treatment of neurological diseases as it prevents most blood circulating drugs from entering into the brain. In vitro cell models aim to reproduce BBB functionality and predict the passage of active compounds through the barrier. In such systems, brain microvascular endothelial cells (BMECs) are cultured in contact with various biomaterial substrates. However, BMEC interactions with these biomaterials and their impact on BBB functions are poorly described in the literature. Here we review the most common materials used to culture BMECs and discuss their potential impact on BBB integrity in vitro. We investigate the biophysical properties of these biomaterials including stiffness, porosity and material degradability. We highlight a range of synthetic and natural materials and present three categories of cell culture dimensions: cell monolayers covering non-degradable materials (2D), cell monolayers covering degradable materials (2.5D) and vascularized systems developing into degradable materials (3D).

Keywords: Basement membrane; Biomaterial; Blood brain barrier; Extracellular matrix; Mechanotransduction; Organ-on-chip; Shear stress.

Fig. 1.

Select history of in vitro BBB models. [,,,,–68] A review of literature on BBB models showing year of publication and type of model, whether 2D,2.5D or 3D. Publications were grouped for their focus on substrate biomechanics, substrate biochemistry or shear stress. IPS: induced pluripotent stem cells.

Fig. 2.

Illustration of the cellular and extracellular architecture of the blood brain barrier.

Fig. 3.

Comparison of 2D blood brain barrier models. [–104].

Fig. 4.

Blood brain barrier-on-a-chip system, from 2D to 3D configuration.

Fig. 5.

Conducting polymers as new material for the characterization of in vitro models. A. The chemical structure of the conducting polymer PEDOT:PSS and B. commonly described spatial polymer rearrangement to form a film with PEDOT:PSS rich (blue) and PSS-rich (grey) phases. [178] C. Transfer curve showing the operation of an organic electrochemical transistor (OECT) with a channel made of PEDOT:PSS. [179] D. A picture of a platform integrating planar OECTs with microfluidics and located on a microscope stage. E. Fluorescence image of a fully confluent layer of epithelial cells (red fluorescent protein-labelled F-actin) grown inside the microfluidic channel integrated with a planar OECT. F. Time evolution of the OECT frequency-dependent response during the healing process of an electrical wound generated on a confluent epithelial cell layer. [180] G. A picture of PEDOT:PSS scaffolds of various sizes and shapes. H. Fluorescence image of a PEDOT:PSS scaffold seeded with epithelial cells after 3 days of cell culture. I. OECT frequency-dependent response before and after cell culture. [172] J. A picture of PEDOT:PSS hydrogel of various size and shape. K. Table describing different formulation of PEDOT:PSS/acrylic acid (AAc) hydrogels and their corresponding electronic and mechanical properties [181]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).