Advances in modeling permeability and selectivity of the blood-brain barrier using microfluidics

Abstract

The blood-brain barrier (BBB) protects the brain by actively allowing the entry of ions and nutrients while limiting the passage of from toxins and pathogens. A healthy BBB has low permeability and high selectivity to maintain normal brain functions. Increased BBB permeability can result from neurological diseases and traumatic injuries. Modern engineering technologies such as microfluidics and fabrication techniques have advanced the development of BBB models to simulate the basic functions of BBB. However, the intrinsic BBB properties are difficult to replicate. Existing in vitro BBB models demonstrate inconsistent BBB permeability and selectivity due to variations in microfluidic design, cell types and arrangement, expression of tight junction (TJ) proteins, and use of shear stress. Specifically, microfluidic designs have flow channels of different sizes, complexity, topology, and modular structure. Different cell types are selected to mimic various physiological conditions. These factors make it challenging to compare results obtained using different experimental setups. This paper highlights key factors that play important roles in influencing microfluidic models and discusses how these factors contribute to permeability and selectivity of the BBB models.

Keywords: Blood-brain barrier; Cells; Design; Microfluidics; Permeability; Selectivity.

Fig. 1

An illustration of the blood-brain barrier. The basement membrane serves as a barrier between the astrocyte endfoot and the endothelial cells, with the pericytes being embedded within the basement membrane. Astrocytes are also in close contact to neurons. The subfigure on the right shows tight junction proteins between endothelial cells: ZO proteins, claudins and adhesion molecules. The transporters (P-gp and Glut-1) are on the plasma membrane of endothelial cells

Fig. 2

Selected factors influence the microfluidic blood-brain barrier (BBB) model: a Channel Design: blue channels are for cell injection and red channels are used for tracers and drugs injection. These two channels are separated by a membrane with cell attached; b Commonly cell types: endothelial cells, astrocytes, pericytes and neurons; c Membrane: The extracellular matrix (ECM) can work alone or coated on the thin film with porous media; d Tracers: small molecules such as dextrans and drugs (e.g., caffeine); and e Shear Stress: it is applied to mimic physiological conditions, modulate cellular functions,) and simulate molecule movement in the injection channel

Fig. 3

Collected microfluidic devices of permeability coefficients with respect to 4–70 kDa