Three-Dimensional Dynamic Blood-Brain Barrier Model Incorporating Native Cell Culture Systems Based on Shape Memory Biomaterials.

Abstract

An engineered three-dimensional (3D) dynamic in vitro blood-brain barrier (BBB) model with vascular-like architecture and fluid shear forces is integrated. The model is comprised of a supply pool, fluid transport pump, flow chamber, 3D cell-scaffold, and receiving pool. The flow chamber is designed with three parallel fluid channels connected to the pump and receiving pool, thus simplifying operation and facilitating assembly with standard instruments. A disposable 3D cell-scaffold made from biocompatible shape memory material can realize configuration transformation from 2D planar structure for cell seeding to 3D tubular structure for cell culture at physiological temperature, which provides cells convenient seeding and desirable attachment. The barrier function of this model is characterized: the maximum transendothelial electrical resistance value is 523 Ω cm² for co-cultured cell model; the apparent permeability coefficient of phenol red is in the range of 2.8-3.8 × 10^-6 cm^-1s; highly expressed BBB-related proteins (VE-cadherin, Occludin, Claudin-5, ZO-1 and P-gp) and the polarized transport of P-gp ligand rhodamine 123 are shown. Further, the differentiating transport characteristics of seven model drugs across BBB are presented using the integrated model. In summary, a high-fidelity 3D dynamic BBB model, suitable for researching drug trafficking across BBB and developing therapeutics for brain diseases, is constructed.