In Vitro Cerebrovascular Modeling in the 21st Century: Current and Prospective Technologies

Abstract

The blood-brain barrier (BBB) maintains the brain homeostasis and dynamically responds to events associated with systemic and/or rheological impairments (e.g., inflammation, ischemia) including the exposure to harmful xenobiotics. Thus, understanding the BBB physiology is crucial for the resolution of major central nervous system CNS) disorders challenging both health care providers and the pharmaceutical industry. These challenges include drug delivery to the brain, neurological disorders, toxicological studies, and biodefense. Studies aimed at advancing our understanding of CNS diseases and promoting the development of more effective therapeutics are primarily performed in laboratory animals. However, there are major hindering factors inherent to in vivo studies such as cost, limited throughput and translational significance to humans. These factors promoted the development of alternative in vitro strategies for studying the physiology and pathophysiology of the BBB in relation to brain disorders as well as screening tools to aid in the development of novel CNS drugs. Herein, we provide a detailed review including pros and cons of current and prospective technologies for modelling the BBB in vitro including ex situ, cell based and computational (in silico) models. A special section is dedicated to microfluidic systems including micro-BBB, BBB-on-a-chip, Neurovascular Unit-on-a-Chip and Synthetic Microvasculature Blood-Brain Barrier.

Assessment of Conjunctival Microvascular Hemodynamics in Stages of Diabetic Microvasculopathy

“…WSS is an important hemodynamic parameter in cardiovascular pathophysiology39 and affects endothelial functions, such as migration of leukocytes, adhesion, control of vessel diameter, cytoskeletal structure, and energy metabolism39404142. WSS is generally lower in subjects at risk of vascular diseases43, and causes vessel wall remodeling and pathophysiology4445.…”

New experimental models of the blood-brain barrier for CNS drug discovery

“…Microfluidic tissue-on-a-chip approaches have emerged as promising techniques to establish in vitro barrier tissues as potential tools in discovery biology and to study BBB endothelial responses to shear stress [46, 47]. These systems combine microengineering techniques with living cell populations to recapitulate salient organizational features of the in vivo environment including spatially defined co-cultures and polarized cell architectures [48].…”

“…Such inert gels are simple to manufacture, adapts to the mechanical forces conveniently and are highly reproducible. An example of a synthetic hydrogel is Corning PuraMatrix™ peptide hydrogel which is composed of 99% water and 1% w/v standard amino acids [46, 67]. However, in future there will be a need for ECM with combined properties of natural and synthetic hydrogels as it seems likely that different 3D matrices will induce different cellular responses which will in turn foster the development of more sophisticated 3D models.…”

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

“…[25][26][27][28][29] As shown in Figure 1, pericytes, astrocyte end feet processes, and neurons within the neurovascular unit (NVU) induce and regulate the barrier functions of BBB. [30][31][32] Structurally, the inter-endothelial tight junction complexes comprising occludin, claudins, and membrane-directed scaffolding proteins (such as zonula occludentes-1 (ZO-1)) contribute to physical barrier nature of BBB and strictly limit the molecular/ cellular influx from circulation. 33,34 Furthermore, the uniqueness of the BBB endothelium is endorsed by abundant expression of efflux pumps and stereospecific solute transporters.…”