An in vitro sensor integrated blood brain barrier model for the investigation of circadian transport of xenobiotics into the brain

Programme overview:
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address important applied biomedical research questions in priority areas aligned with industry. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.

Project:
Diseases affecting the central nervous system are some of the most poorly treated due to the difficulty in delivering drugs across the blood brain barrier (BBB). The BBB is a complex and highly dynamic barrier between the blood and the central nervous systems, which tightly regulates the influx of molecules to the brain. It is widely accepted that one of the main challenges in developing new brain penetrating drugs is the poor predictive power of existing pre-clinical models for the BBB.

Here, we will design an in vitro microfluidic device to study time-resolved drug transport across the BBB. Electrodes will be integrated into the device to allow for real-time monitoring of trans-endothelial-epithelial electrical resistance and impedance. Impedance spectroscopy will allow for a novel and more detailed analysis of transport across the BBB and its integrity. Using genetically encoded reporters in the cells used in the device will enable us to elucidate the underlying mechanisms for the dynamic changes of BBB propertied. Together, this will allow to define a better translational model of the BBB. This model will then be validated against in vivo data and used to characterise a library of drug candidates.

Furthermore, recent studies have shown that BBB permeability is dynamically regulated by the circadian clock. This means that throughout a 24-hour period, the ability of a drug to cross this barrier may significantly vary. If understood, this time dependent permeability could be used to both increase treatment efficacy and reduce off-site toxicity. The developed integrated microfluidic model will be ideal to test this assumption and develop meaningful predictions for clinical use of brain penetrating drugs.

Thus, we are confident that our BBB on-a-chip model will not only help to elucidate relevant biomedical questions but is also fully aligned with the ABT theme of NPIF as organ-on-chip technologies are 6th among the top ten emerging technologies (WEF 2016).