Human iPS-derived blood-brain barrier model exhibiting enhanced barrier properties empowered by engineered basement membrane

Abstract

The basement membrane (BM) of the blood-brain barrier (BBB), a thin extracellular matrix (ECM) sheet underneath the brain microvascular endothelial cells (BMECs), plays crucial roles in regulating the unique physiological barrier function of the BBB, which represents a major obstacle for brain drug delivery. Owing to the difficulty in mimicking the unique biophysical and chemical features of BM in in vitro systems, current in vitro BBB models have suffered from poor physiological relevance. Here, we describe a highly ameliorated human BBB model accomplished by an ultra-thin ECM hydrogel-based engineered basement membrane (nEBM), which is supported by a sparse electrospun nanofiber scaffold that offers in vivo BM-like microenvironment to BMECs. BBB model reconstituted on a nEBM recapitulates the physical barrier function of the in vivo human BBB through ECM mechano-response to physiological relevant stiffness (∼500 kPa) and exhibits high efflux pump activity. These features of the proposed BBB model enable modelling of ischemic stroke, reproducing the dynamic changes of BBB, immune cell infiltration, and drug response. Therefore, the proposed BBB model represents a powerful tool for predicting the BBB permeation of drugs and developing therapeutic strategies for brain diseases.