Organ‐On‐A‐Chip Models of the Blood–Brain Barrier: Recent Advances and Future Prospects

Abstract

refers to a multicellular unit in the brain including cells of the cerebral vasculature and brain parenchyma. [2] As part of the NVU, the blood-brain barrier (BBB) acts as a physiological barrier at the interface between peripheral blood circulation and the central nervous system (CNS). The BBB is indispensable for the proper CNS function and regulation of CNS homeostasis; it controls the transport of substances between the CNS and the blood via various transport mechanisms. [3] The BBB also protects the brain from neurotoxic plasma components, certain chemicals, and pathogens. Functional and structural changes of the BBB are implicated in several neurological diseases and disorders, which have severely impacted individuals worldwide. For example, there are currently estimated to be about 5.7 million people living with Alzheimer's disease (AD), and the number is projected to reach 13.8 million by 2050. [4] Stroke is the second leading cause of death and the third most common cause of disability. [5] Glioblastoma multiforme (GBM), which accounts for almost 50% of all brain tumors (i.e., glioma), is relatively rare with a global incidence rate of 3.19 per 100 000 people; however, it has a devastatingly poor prognosis with a typical survival rate of 14-15 months rendering it a critical public health problem. [6] The human brain and central nervous system (CNS) present unique challenges in drug development for neurological diseases. One major obstacle is the blood-brain barrier (BBB), which hampers the effective delivery of therapeutic molecules into the brain while protecting it from blood-born neurotoxic substances and maintaining CNS homeostasis. For BBB research, traditional in vitro models rely upon Petri dishes or Transwell systems. However, these static models lack essential microenvironmental factors such as shear stress and proper cell-cell interactions. To this end, organ-on-a-chip (OoC) technology has emerged as a new in vitro modeling approach to better recapitulate the highly dynamic in vivo human brain microenvironment socalled the neural vascular unit (NVU). Such BBB-on-a-chip models have made substantial progress over the last decade, and concurrently there has been increasing interest in modeling various neurological diseases such as Alzheimer's disease and Parkinson's disease using OoC technology. In addition, with recent advances in other scientific technologies, several new opportunities to improve the BBB-on-a-chip platform via multidisciplinary approaches are available. In this review, an overview of the NVU and OoC technology is provided, recent progress and applications of BBB-on-a-chip for personalized medicine and drug discovery are discussed, and current challenges and future directions are delineated.The ORCID identification number(s) for the author(s) of this article can be found under

Complex in vitro model: A transformative model in drug development and precision medicine

“…Biological barriers are important for the maintenance of organ homeostasis and are essential for drug testing and disease modeling. 59 In vitro models of functional biological barriers, such as blood-brain barrier (BBB), 60 have previously been created through the development of 3D cell culture techniques and microfluidic organ-onchip technology. Yu et al 61 developed 3D microfluidic BBB chips by co-culturing rat primary brain microvascular ECs, pericytes, and astrocytes from neonates in a collagen matrix.…”

Lab-on-a-chip models of the blood–brain barrier: evolution, problems, perspectives

“…Diverse complex BBB-on-chip models have been developed to study brain disease mechanisms, such as neurodegenerative diseases, stroke, tumor pathology and more (for reviews see 119–121 ). Damage of BBB function can often also lead to neuroinflammation, while systemic inflammation caused by viral, bacterial or fungal infections can lead to brain and microvessel dysfunction.…”

Organ‐on‐a‐chip technologies for biomedical research and drug development: A focus on the vasculature

“…Out of all the components, the brain is the main player of the nervous system, and the major obstacle in research translation as it contains the blood‐brain barrier (BBB). OOC models are able to replicate key aspects of the BBB microenvironment, such as mechanical queues and cell–cell interactions 95 . In the past decade, OOC models highlight the importance of a hierarchical multidimensional structure and the use of organoids for the recapitulation of the native nervous system 96 .…”

“…OOC models are able to replicate key aspects of the BBB microenvironment, such as mechanical queues and cell-cell interactions. 95 In the past decade, OOC models highlight the importance of a hierarchical multidimensional structure and the use of organoids for the recapitulation of the native nervous system. 96 Other specific models of the nervous system attempt to mimic the bone marrow, 97 nerves, 98,99 and most recently, sensory organs.…”