In vitro modeling of the neurovascular unit: advances in the field

Abstract

The blood-brain barrier (BBB) is a fundamental component of the central nervous system. Its functional and structural integrity is vital in maintaining the homeostasis of the brain microenvironment. On the other hand, the BBB is also a major hindering obstacle for the delivery of effective therapies to treat disorders of the Central Nervous System (CNS). Over time, various model systems have been established to simulate the complexities of the BBB. The development of realistic in vitro BBB models that accurately mimic the physiological characteristics of the brain microcapillaries in situ is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the Neurovascular Unit (NVU) would provide an invaluable tool that would aid in dissecting out the pathological factors, mechanisms of action, and corresponding targets prodromal to the onset of CNS disorders. The field of BBB in vitro modeling has seen many fundamental changes in the last few years with the introduction of novel tools and methods to improve existing models and enable new ones. The development of CNS organoids, organ-on-chip, spheroids, 3D printed microfluidics, and other innovative technologies have the potential to advance the field of BBB and NVU modeling. Therefore, in this review, summarize the advances and progress in the design and application of functional in vitro BBB platforms with a focus on rapidly advancing technologies.The BBB consists of highly specialized vascular endothelial cells (EC) lining the brain microvessels in juxtaposition with closely associated pericytes [1], extracellular matrix components, and astrocytic end-feet processes [2]. Along with other cells such as neurons and microglia, this cellular milieu modulates the BBB properties, supports its viability and functions [3]. At the brain microvascular level, the BBB functions as a highly dynamic and active interface between the systemic circulation and the CNS. The BBB maintains a stable brain environment to protect the CNS from unsolicited cells, bacteria, viruses, and potentially harmful substances (either endogenous or exogenous) apart from protecting against systemic fluctuations. The BBB also regulates the transport of essential molecules and nutrients necessary to maintain the optimal CNS environment and support neuronal activities [4]. The BBB responds to many physiological and pathological cues, including rheological changes [5], inflammatory stimuli, oxidative stress [6], diabetes, and hypercholesterolemia [7-10], acute brain injury [3], etc. The intrinsically unique and utmost complex functional interaction between the BBB endothelium and the surrounding cellular milieu (including astrocytes, pericytes, neurons, microglia, myocytes as well as specialized cellular compartments such as endothelial glycocalyx [11,12] has been termed "neurovascular unit (NVU)" [2,13]. In addition, the basement membrane, which exerts essential functions in cellular support and signal transduction,

A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity

“…Overall, BBB studies must consider the effect of shear stress as it is playing an essential role in BBB maturation and homeostasis. In this respect, our group has summarized the advances in in-vitro BBB models [ 99 , 100 ].…”

Multiplexed blood–brain barrier organ-on-chip

“…16,17 Over the last decade, researchers have been able to fabricate chips for studying the BBB, and other organs demonstrating the ability of OOC to capture physiologically relevant conditions in vitro. [18][19][20][21][22] To date, most reported microfluidic models of the BBB are fabricated using the biocompatible polydimethylsiloxane (PDMS) organic polymer. The permeability to CO 2 and O 2 of this polymer makes it ideal for cell studies.…”

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

“…cm/s) of astrocytes 12 or to published values (reviewed in 43 ). However, dextran and TEER assays require external non-physiological chemicals to be circulated through the model, or electrical probes to be placed in the vascular lumen that could potentially lead to cellular disturbance.…”