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Review
. 2021 Aug;10(15):e2002285.
doi: 10.1002/adhm.202002285. Epub 2021 Jun 2.

Advanced Human BBB-on-a-Chip: A New Platform for Alzheimer's Disease Studies

Jeong-Kee Yoon  1 , Jaehoon Kim  2 , Zachary Shah  3 , Ashi Awasthi  3 , Advay Mahajan  3 , YongTae Kim  1   2   3   4   5
Affiliations
Review

Advanced Human BBB-on-a-Chip: A New Platform for Alzheimer's Disease Studies

Jeong-Kee Yoon et al. Adv Healthc Mater. 2021 Aug.

Abstract

The blood-brain barrier (BBB) is a unique vascular structure that serves as a molecular transport gateway for the maintenance of brain homeostasis. Chronic disruption or breakdown of the BBB reportedly leads to neurodegenerative diseases. Nonetheless, research on human BBB pathophysiology and drug development remains highly dependent on studies using inherently different animals. Moreover, more studies have shown that animal models are not appropriate in modeling Alzheimer's disease (AD), underlining the importance of in vitro models of the human BBB with physiological relevance. In this review, recent advances in human BBB-on-a-chip technologies are highlighted and their potential for pathogenesis studies and drug prescreening for AD treatment are discussed.

Keywords: Alzheimer's disease; blood−brain barrier; drug delivery; neurodegeneration; organs-on-a-chip.

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Figures

Figure 1.
Figure 1.. Schematic illustration of the blood-brain barrier (BBB) structure and its role.
(A) BBB consists of endothelial monolayer supported by pericytes and astrocyte end-feet, redrawn from [79]. (B) To keep brain homeostasis, the BBB expresses tight junctions for high integrity, and transporters for selective molecule exchange.
Figure 2.
Figure 2.. Schematic illustration of blood-brain barrier (BBB) disruption in Alzheimer’s disease (AD) patients.
BBB disruption is one of the earliest pathogenic symptoms observed in AD patients. In AD patients, (1) endothelial cells lose their integrity and impair transporter expression, which promotes influx or pathogens and leukocytes and impedes beta-amyloid (Aβ) efflux; (2) pericytes are detached from endothelial cells, and Aβ degradation process is inhibited; (3) astrocyte show depolarization of AQP4 which should be expressed on end-feet and inhibition of Aβ degradation process. Loss of homeostasis and failure of Aβ clearance result in Aβ aggregation, proceeding AD into the irreversible pathogenic cascades.
Figure 3.
Figure 3.. Illustrated top and side views of recent BBB-on-a-chip models.
(A) A microfluidic 2D cell culture model consists of an apical channel with media flow for endothelial shear stress, and a static basolateral channel with 2D pericytes on the membrane and 2D astrocytes on the membrane or the bottom layer of the channel. (B) A microfluidic 3D perivascular culture model also contains a channel with an endothelial monolayer subjected by shear stress and 2D pericytes on the opposite layer. The perivascular channel consists of 3D astrocytes cultured in hydrogel with side channels for media supply. (C) A microfluidic 3D vasculogenesis model consists of a spontaneously formed angiogenic tubulars. Pericytes and astrocytes are randomly distributed nearby the endothelial cells.
Figure 4.
Figure 4.. Recent advances on BBB-on-a-chips.
(A) A microfluidic device showed a tubular endothelial monolayer on the basolateral channel cultured with 2D astrocytes and pericytes on the apical channel. Reproduced with permission from [42]. (B) Two BBB-on-a-chips consisting of a tubular endothelial monolayer with 2D pericytes and astrocytes were connected to a brain chip consisting of neurons and astrocytes, to observe the metabolic pathway throughout the brain cells. Reproduced with permission from [43]. (C) A microfluidic device with 3D cultured astrocytes exhibited the end-feet polarization of Aquaporin 4 which is one of the key features of BBB structure. Reproduced with permission from [47]. (D) An angiogenic system of endothelial cells interacting with pericytes, and astrocytes spontaneously created perfusable vasculatures with BBB properties. Reproduced with permission from [51].
Figure 5.
Figure 5.. BBB-on-a-chips for AD studies.
(A) A polymeric tubular scaffold was prepared to mimic brain cerebral artery with BBB structure. Abluminal Aβ was introduced for AD modeling, and luminal HDL was introduced as a potential biomolecule for Aβ clearance. Reproduced with permission from [68]. (B) Human neuroprogenitor cell-derived AD-conditioned neurons were co-cultured with a tubular endothelial monolayer to show Aβ deposition followed by BBB disruption. Reproduced with permission from [69]. (C) Endothelial cells differentiated from iPSCs with different ApoE genotype (ApoE3 or E4) underwent spontaneous vascularization in the presence of pericytes and astrocytes, to show the pathogenic role of ApoE4 on perivascular Aβ accumulation. Reproduced with permission from [52]. (D) CD4+ T cell extravasation across the BBB which have been an important step on AD pathogenesis was recapitulated using a 2D microfluidic device under shear stress. Reproduced with permission from [40a]. (E) The engineered HDL, a potential AD drug, crossed the BBB through receptor-mediated transcytosis and its distribution has been evaluated in a 2D microfluidic device. Reproduced with permission from [47].
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