In-vitro Blood-Brain Barrier Models: An Emerging Platform for Central Nervous System Drug Discovery and Delivery

Purpose: Blood-brain barrier (BBB) and its components protects the brain, but drug delivery sufficient to induce clinical effects is hindered causing challenges for therapeutic translation. To study drugs and their delivery systems across the BBB, numerous in-vitro BBB models have been studied. However, the limitations among them are still unanswered causing poor in-vivo imitation. Therefore, we performed an exhaustive literature study on in-vitro BBB models/methods to summarize which model/method could be futuristic. Method: Literature search in PubMed showed that nearly 400 research and review reports were published in last two decades. Three major models including two-dimensional (2D), stem cell and three-dimensional (3D) models were discussed and compared. Each type of model was reviewed in depth to identify an ideal in-vitro model that could closely mimic the in-vivo BBB microvasculature. Results: In 2D models, while cocultures over monocultures showed improved barrier integrity none of them mimicked shear stress. Additionally, the results between double and triple cocultures were controversial. Irrespective of model types, human stem cells revealed an excellent barrier phenotype against other cellular sources. 3D models such as chip-based and microfluidic encompassing multiple compartments and shear stress imitated the BBB microenvironment more realistically than 2D models. However, cost, complex design and poor scalability are few setbacks of 3D models. Conclusion: Considering key limitations of current in-vitro BBB models, the microfluidic technology in combination with stem cells would be the next generation in-vitro models that could best mimic the BBB phenotype.