To overcome these limitations of animal models, human cell-based in vitro testing methods have been adopted. Additionally, ethical issues as well as high costs also hamper the use of animals ( 14). Moreover, in some diseases, even pathological mechanisms are different between human and animal models ( 13). Over 80% drugs validated in animal models have failed in human clinical trials ( 12) mainly due to genetic, molecular, and immunologic differences between human and other animals. However, the reliability and predictability of animal testing for drug responses and physiological alterations in human have been revealed to be very low. Animal models have elucidated fundamental cellular architecture and morphological features, barrier permeability, and transport mechanisms ( 11). While mouse and rat are the most widely used animal models, various other animal species ( e.g., zebrafish) have also been exploited as alternatives ( 10). It has been widely accepted for a long time. Therefore, animal testing has been considered as the default and gold standard in preclinical research. The clear advantage of utilizing animals is that they provide basic biological knowledge of a living organism. They provide major human health benefits as good models to predict human physiology and pathology. Animal models have been used in pharmaceutical development to predict drug efficacy and toxicity. 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. Many BBB research studies have been conducted to resolve neurological complications ( 9). 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). In addition, a low level of transcytosis in cerebral ECs further increases the selectivity of the BBB ( 7). Transporters such as P-glycoprotein serve as efflux pumps to remove harmful agents from the brain ( Fig. 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). The barrier function results from the restriction of both paracellular and transcellular transport. 1A) ( 3).Īs a gate-keeper, BBB protects the brain from toxic substances and pathogens ( 4). 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. ECs, pericytes, and astrocytes interplay with each other to maintain the structural and functional integrity of the BBB ( 2). Pericytes wrap around brain ECs and astrocytes extend their endfeet to contact with blood vessels. They line the inner surface of cerebral blood vessels. Brain ECs are core cellular components of the BBB. It mainly comprises endothelial cells (ECs), pericytes, and astrocytes ( 1). It protects the brain from exogenous substances by strictly regulating the transport of molecules from the blood vasculature into the brain. The blood-brain barrier (BBB) is a highly selective barrier in the brain.
Keywords: Blood-brain barrier, In vitro modeling, Neurological diseases, Organ-on-a-chip In this review, we summarize major features of human BBB and current BBB models and describe organ-on-chip models for BBB modeling and their applications in neurological complications. Therefore, a more physiologically relevant alternative BBB model needs to be developed. Different physiologies between human and animal BBB hinder the prediction of drug responses.
Human BBB has a unique cellular architecture. However, many drugs validated in in vitro models and animal models have failed in clinical trials primarily due to the lack of an appropriate BBB model. Thus, a large amount of time and cost have been paid for the development of BBB targeted therapeutics. Owing to this highly selective barrier, many drugs targeting brain diseases are not likely to pass through the BBB. As a gate keeper, BBB regulates passage of nutrients and exogeneous compounds. ABSTRACT The blood-brain barrier (BBB) is an interface between cerebral blood and the brain parenchyma.
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