Development of and Transport Through a Microfluidic Blood-Brain Barrier

Abstract

Diseases of the brain and central nervous system are perhaps the most devastating and difficult to treat class of ailments in existence. While nothing can change their impact, therapies could be substantially improved in a number of ways. One major factor hindering progress in this area is the difficulty of crossing the blood-brain barrier (BBB). Even though substantial research has been conducted in this area, the lack of clinical successes indicates that there is a marked need for better models to study transport across the BBB, ones that are simultaneously more representative than traditional in vitro models but also more accessible than complex and dynamic in vitro or in vivo models. To fill this niche, we developed the µHuB, which is well-suited for investigating numerous aspects of the BBB and transport through it. In the first section of this thesis, we discuss the general principles of drug delivery to the brain and specifically through the BBB. Next, we survey existing models of the BBB, highlighting their strengths and weaknesses, as well as identifying some of the key insights that they have been used to gain. After a summary of the rationale and design choices made for the µHuB, we detail its development and validation. Section 3 discusses the details of measuring transport of a simple macromolecule through the µHuB and the insight such measurements can provide. We then utilize the µHuB to investigate the influence of nanoparticle physical properties on their ability to cross the BBB, which is to our knowledge the first such investigation reported to date. Finally, we investigate the suitability of the µHuB to study cell-mediated delivery to the brain.