Development of an in vitro microfluidic platform to mimic the blood-brain barrier

Abstract

There are very few models able to simulate with precision the complex structure of the blood-brain barrier (BBB): our body’s most restrictive barrier which, while protecting our brain from pathogens, toxins, inflammation, injury and disease, is also the main obstacle for the delivery of drugs to the brain. This paper examines all the aspects that have to be taken into account to properly develop, from scratch, an in vitro microfluidic platform to mimic the human BBB. The thesis details every step of the fabrication of the device, provides an economic and technical analysis of its feasibility, and considers the ethical and legal aspects of its implementation to the market. Following a thorough analysis of the different existing models of the BBB and their benefits, this work develops a design incorporating a tri-culture of human astrocytes, pericytes and endothelial cells ensembled in a 3D environment of hydrogel within a structure of PDMS . The resulting BBB-on-a-chip (BBB-oC) is an accurate, reproducible, animal-free and cheaper alternative to in vivo models for mimicking the function and structure of the BBB. Evaluation techniques carried out in this project showed a suitable environment for the cells inside the chip, confirming their correct morphology and viability up to the 7th day. Permeability assays revealed that the barrier is size restrictive, thus allowing smaller molecules to pass through faster than bigger molecules. To provide a clinical application to the model, permeability performance tests were conducted on two different nanotherapeutic systems which target the inhibition of Aβ fibrillation as a possible treatment for Alzheimer’s disease.