Microfluidic models of the neurovascular unit: a translational view

The vasculature of the brain consists of specialized endothelial cells that form a blood-brain barrier (BBB). This barrier, in conjunction with supporting cell types, forms the neurovascular unit (NVU). The NVU restricts the passage of certain substances from the bloodstream while selectively permitting essential nutrients and molecules to enter the brain. This protective role is crucial for optimal brain function, but presents a significant obstacle in treating neurological conditions, necessitating chemical modifications or advanced drug delivery methods for most drugs to cross the NVU. A deeper understanding of NVU in health and disease will aid in the identification of new therapeutic targets and drug delivery strategies for improved treatment of neurological disorders.To achieve this goal, we need models that reflect the human BBB and NVU in health and disease. Although animal models of the brain's vasculature have proven valuable, they are often of limited translational relevance due to interspecies differences or inability to faithfully mimic human disease conditions. For this reason, human in vitro models are essential to improve our understanding of the brain's vasculature under healthy and diseased conditions. This review delves into the advancements in in vitro modeling of the BBB and NVU, with a particular focus on microfluidic models. After providing a historical overview of the field, we shift our focus to recent developments, offering insights into the latest achievements and their associated constraints. We briefly examine the importance of chip materials and methods to facilitate fluid flow, emphasizing their critical roles in achieving the necessary throughput for the integration of microfluidic models into routine experimentation. Subsequently, we highlight the recent strides made in enhancing the biological complexity of microfluidic NVU models and propose recommendations for elevating the biological relevance of future iterations.Importantly, the NVU is an intricate structure and it is improbable that any model will fully encompass all its aspects. Fit-for-purpose models offer a valuable compromise between physiological relevance and ease-of-use and hold the future of NVU modeling: as simple as possible, as complex as needed.