The blood-brain barrier (BBB) is a highly selective barrier in the brain. It protects the brain from exogenous substances by strictly regulating the transport of molecules from the blood vasculature into the brain. The BBB has a multicellular structure. It mainly comprises endothelial cells (ECs), pericytes, and astrocytes (1). Brain ECs are core cellular components of the BBB. They line the inner surface of cerebral blood vessels. Pericytes wrap around brain ECs and astrocytes extend their endfeet to contact with blood vessels. ECs, pericytes, and astrocytes interplay with each other to maintain the structural and functional integrity of the BBB (2). Additionally, with surrounding neurons, microglia and extracellular matrix (ECM) cooperate with BBB, forming a more functional structure called a neurovascular unit (NVU) which plays a critical role in regulating cerebral blood flow and BBB functions to maintain brain homeostasis (Fig. 1A) (3).
As a gate-keeper, BBB protects the brain from toxic substances and pathogens (4). The barrier function results from the restriction of both paracellular and transcellular transport. The paracellular transport of ions and hydrophilic solutes is severely limited by tight junctions between adjacent ECs with proteins including zonula occludens 1 (ZO-1) and claudin (5). Transporters such as P-glycoprotein serve as efflux pumps to remove harmful agents from the brain (Fig. 1B) (6). In addition, a low level of transcytosis in cerebral ECs further increases the selectivity of the BBB (7). Owing to the presence of the BBB, the entry of many therapeutic drugs targeting human brain are prevented, as more than 98% and approximately 100% of small- and large-molecule drugs cannot cross the BBB, respectively (8).
Many BBB research studies have been conducted to resolve neurological complications (9). Development of a physiologically relevant BBB model has been a great interest as current BBB models could not represent the complexity of the human BBB. Animal models have been used in pharmaceutical development to predict drug efficacy and toxicity. They provide major human health benefits as good models to predict human physiology and pathology. The clear advantage of utilizing animals is that they provide basic biological knowledge of a living organism. Therefore, animal testing has been considered as the default and gold standard in preclinical research. It has been widely accepted for a long time. While mouse and rat are the most widely used animal models, various other animal species (
To overcome these limitations of animal models, human cell-based
Over the last decade, organoid technology which harnesses the developmental process of organogenesis has been developed to generate
Although animal models and recently advanced
Organ-on-a-chip technology, a microphysiological system on which cells and tissues can be cultured, has been applied to overcome limitations of conventional
To replicate the complex structures and functions of the BBB, advances have been made for the design of BBB-on-a-chip (Fig. 2). One of the widely used BBB-on-a-chip design is the use of a porous membrane to separate chambers (39). One chamber comprises ECs and the opposite side of the chamber consists of astrocytes and pericytes (Fig. 2A). ECs can be seeded on the porous membrane or cultured to form monolayer with vascular lumen inside the chamber. Blood vessels can also be generated inside hydrogels with or without perivascular cells embedded in the hydrogel (Fig. 2B). These platforms can further recapitulate the
Various neurological diseases are known to be associated with BBB (45-47). Brain disease can affect the BBB by disrupting tight junctions. Chronic BBB malfunction is also related to the development of multiple neurological disorders. The following sections discuss applications of BBB-on-a-chip in Alzheimer’s disease, ischemic stroke, infectious disease, brain cancer, and transport mechanism studies.
BBB disruption and impairment of barrier functions are associated with various neurological disorders and neurodegenerative diseases (48). In Alzheimer’s disease (AD), the decreased expression of tight junction proteins increases the BBB permeability and the efflux pathway through receptor-mediated trans-cytosis, the major mechanism of beta-amyloid (Aβ) clearance across the BBB, is disrupted (49). Animal models are not suit-able for human AD modeling due to their different genetic profiles and pathophysiology. The accumulation of Aβ and hyper-phosphorylated tau is observed in animals, but they cannot be considered as AD models since other biological features of human AD, such as neurofibrillary tangle pathology and sporadic forms of AD, are not exhibited in animal models (50, 51). Thus, pre-clinical results from animal models rarely translate into humans (52). Shin
In ischemic stroke, inadequate supply of blood leads to neurological pathologies where BBB is disrupted, resulting in the breakdown of tight junctions and ionic shifts in the brain (54, 55). However, drugs validated in animal models have failed in clinical trials probably because of physiological and patholog-ical differences between human and animals (56). Lyu
Bacteria and viruses can enter the BBB via receptor-mediated active transport or because of an increase of barrier permeability (58). The infection of pathogens can also be recapitulated in a functional BBB model. Kim
Pharmaceutical treatments for brain cancer are limited because of the poor BBB penetration of drugs and the aggressiveness of primary brain tumors as well as the occurrence of metastatic brain tumors from various primary sites (61). Additionally, tumors can interact with the surrounding microenvironment including cellular and noncellular components to resist therapeutics. Thus, more effective
Poor BBB penetration of pharmaceutical drugs is one of the major issues in neurological disease treatments (63). Thus, BBB targeting studies have been conducted to deliver drugs across the BBB (9). Park
The high selectivity of the BBB has hampered the therapeutical treatment for neurological diseases. In addition, inappropriate
This work was supported by Samsung Research Funding & Incubation Center of Samsung Electronics (Project Number SRFC-TC2003-03).
The authors have no conflicting interests.