14TSB_NAT Neurotox: A novel integrated BBB-brain model for comprehensive drug permeability and toxicity testing

The blood-brain barrier (BBB) is composed of different specialised cell types and regulates exchange of substances between the blood and the brain. There are a large number of diseases including stroke, brain trauma and tumours in which the permeability of the BBB is increased. Conversely, many drugs are unable to cross the BBB to reach the brain making the BBB one of the major obstacles in the treatment of the brain diseases. Proper regulation and maintenance of BBB is, therefore, essential for effective drug delivery to the brain to cure brain diseases and preventing its further damage. In this project we aim to develop a three dimensional in vitro BBB model using the Kirkstall Quasi-Vivo system which allows multiple cell types to be cultured in inter-connected culture chambers and a method of assaying the passage of of potential drugs across the BBB by electrochemical and laser bio-sensors. This in vitro model will be an important tool for investigation of different aspects of BBB function and testing potential drugs for their permeability and toxicity and reducing animal usage in this area. Human cell based models should be more accurate and predictive than animals.

The blood-brain barrier (BBB) is a highly organised microvasculature system composed of different cell types including brain endothelial cells, pericytes and astrocytes. Disruption of the BBB results in various brain diseases including stroke and Alzheimer's disease. Understanding of BBB integrity and maintenance is, therefore, essential to developing measures for preventing its disruption and also for effective drug delivery to the brain. Currently, most studies on BBB integrity and damage are performed on in vivo models and the current in vitro models do not reflect the cellular interactions that occur in in vivo, as different BBB cell types are cultured and studied in different types of media. The present project aims to develop a three dimensional (3D) in vitro BBB construct within the Kirkstall Quasi-Vivo culture system, which allows multiple cell types to be cultured in inter-connected chambers. Real time tracking of solutes across the BBB will be undertaken using a novel combination of laser and electrochemical bio-sensor based interrogation. Once developed, this in vitro model will be more accessible than an in vivo animal model for investigation of drug transport across the BBB.

Please see the application submitted by the TSB partner