Advances in microphysiological blood-brain barrier (BBB) models towards drug delivery

Though the blood-brain barrier (BBB) is vital for the maintenance of brain homeostasis, it also accounts for a high attrition rate of therapies targeting the central nervous system (CNS). The challenge of delivery across the BBB is attributed to a combination of low permeability through an endothelium closely knit by tight and adherens junctions, extremely low rates of endothelial transcytosis, and efflux transporters. In the past decade, enormous research efforts have been spent to develop BBB penetration strategies using biochemical or physical stimuli, aided by BBB-on-chips or microphysiological BBB models to facilitate in vitro studies. Here, we discuss recent advances in BBB-chip technology that have enabled effective preclinical screenings of brain targeting therapeutics and external stimulation, such as sonoporation and electroporation, for improved BBB penetration.