Blood–brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood–central nervous system interface

Abstract

The blood-brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood-brain barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer's disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface. Current research relies heavily on animal models (mostly mice) or on two-dimensional (2D) in vitro models, neither of which fully capture the complexities of the human blood-brain barrier. Physiological differences between humans and mice make translation to the clinic problematic, while monolayer cultures cannot capture the inherently three-dimensional (3D) nature of the blood-brain barrier, which includes close association of the abluminal side of the endothelium with astrocyte foot-processes and pericytes. Here we discuss the central nervous system diseases associated with blood-brain barrier pathology, recent advances in the development of novel 3D blood-brain barrier -on-a-chip systems that better mimic the physiological complexity and structure of human blood-brain barrier, and provide an outlook on how these blood-brain barrier-on-a-chip systems can be used for central nervous system disease modeling. Impact statement The field of microphysiological systems is rapidly evolving as new technologies are introduced and our understanding of organ physiology develops. In this review, we focus on Blood-Brain Barrier (BBB) models, with a particular emphasis on how they relate to neurological disorders such as Alzheimer's disease, multiple sclerosis, stroke, cancer, and vascular malformations. We emphasize the importance of capturing the three-dimensional nature of the brain and the unique architecture of the BBB - something that until recently had not been well modeled by in vitro systems. Our hope is that this review will provide a launch pad for new ideas and methodologies that can provide us with truly physiological BBB models capable of yielding new insights into the function of this critical interface.

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

“…Nonetheless, results should be interpreted carefully, as these cells do not represent exactly the mechanisms driving brain permeability due to considerably lower tightness and differences in the expression of ABC transporters [133]. Therefore, there are continuous efforts to develop in vitro models of the blood-brain interfaces to improve the evaluation of drug delivery into the CNS, which will be briefly summarized in the following subsections, as their advantages, disadvantages and molecular characterization have been thoroughly reviewed recently [4,7,136,[139][140][141][142][143]. Importantly, for a wide review on the receptor and transporter expression in diverse in vitro models of the BBB, including data on ABC transporters, please refer to [7].…”

“…BBB-on-chip models created using 3D devices allow a better representation of the barrier function by including a laminal flow of culture medium to mimic the blood stream and often coculturing endothelial and glial cells (reviewed in [139,141]). The team of professor Janigro pioneered the development of BBB coculture models under flux in the late 1990s, allowing for the first time the real time measurement of permeability for dynamic studies [200,202,204,205].…”

“…Although none of these was perfect, the 3D models are nearer to the in vivo assays, while conserving the advantages of controlled conditions of in vitro assays. Furthermore, using differentiated human iPSC cells, these in vitro systems can better mimic the human BBB and its changes in disease by using patient cells, which could even lead to the development precision medicine strategies (reviewed in [139]).…”

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

“…[105][106][107] Ultimately, the NVU will have a self-organized, hierarchical vasculature and BBB and will inform the development of computational QSP in vitro to in vivo extrapolation. 108,109 MPS models of the BBB allow observation of a cross-section of the BBB 110 and the binding of nanoparticle drug carriers to the brain endothelium, 111 organophosphate toxicity, 112 and the effects of methamphetamine on the BBB and metabolic coupling of the BBB and neurons. 113 Other examples include a human brain spheroid model that was recently validated for neurodevelopmental toxicity 114 and for drug development and potentially for personalized medicine.…”

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

“…As evidence of the MPS community moving far past monocultures on 2D plastic, there are a growing number of testimonials regarding the advantages of combining multiple cell types in a single organ and linking multiple organs. [15][16][17][18][19][20][21]48 As multiple organs are being combined to produce MPS homunculi, the "volume problem" is becoming better appreciated, 26,52 and efforts are under way by a number of groups to minimize the ratio of perfusion volume to cell volume lest drug metabolites and cellular signaling molecules be diluted below the threshold of physiological effect.…”