The Influence of Chronic Liver Diseases on Hepatic Vasculature: A Liver-on-a-chip Review

Abstract

In chronic liver diseases and hepatocellular carcinoma, the cells and extracellular matrix of the liver undergo significant alteration in response to chronic injury. Recent literature has highlighted the critical, but less studied, role of the liver vasculature in the progression of chronic liver diseases. Recent advancements in liver-on-a-chip systems has allowed in depth investigation of the role that the hepatic vasculature plays both in response to, and progression of, chronic liver disease. In this review, we first introduce the structure, gradients, mechanical properties, and cellular composition of the liver and describe how these factors influence the vasculature. We summarize state-of-the-art vascularized liver-on-a-chip platforms for investigating biological models of chronic liver disease and their influence on the liver sinusoidal endothelial cells of the hepatic vasculature. We conclude with a discussion of how future developments in the field may affect the study of chronic liver diseases, and drug development and testing.

Keywords: chronic liver diseases; hepatology; microfluidics; organ-on-a-chip; tissue engineering; vascular diseases.

Figure 1

The liver lobule and the associated anatomy. (a) Biochemical pathways, gradients and endothelial properties alternation across the zones of liver lobule. Zone 1 is defined as the region closest to the “portal triad,” consisting of the portal vein, the hepatic artery, and the bile duct. The innermost zone is located near the central vein and is referred to as the pericentral region. Different anabolic and catabolic pathways are differentially active in different zones. A key “zonation modulator,” the Wnt/β-catenin and triglycerides (TG) pathways are active in the pericentral region near the central vein. The glucagon pathway, in contrast, displays its highest activity near the periportal region. (b) Composition of the liver sinusoid. (c) Variation of CYP3A4 expression across the lobule. Metabolic activity (brown) increases from the portal vein to the central vein. Reproduced from [35] with permission from Taylor & Francis Group.

Figure 2

Novel vascularized liver-on-a-chips. (a) Vascularized liver-on-a-chip incorporated with tumor-on-a-chip to investigate enhanced permeability retention (EPR) effect of different nanoparticles under physiological wall shear stress. Flow direction could be controlled to simulate targeted delivery (tumor to liver) and IV injection (liver to tumor). Scales are 500 μm. Reproduced from [8] with permission from Wiley. (b) The vascularized liver acinus microphysiology system (vLAMPS). The vLAMPS is constructed from 3 glass layers. The intermediate layer contains an elliptical opening with a Polyethylene terephthalate (PET) membrane with pores that spans the opening and is attached to the bottom. Reproduced from [67] with permission from the Royal Society of Chemistry. (c) The three-dimensional liver organoid consists of a vascular layer formed by endothelial cells and primary macrophages, and a hepatic layer comprising hepatocyte-like HepaRG cells co-cultured with stellate cells. The space of Dissé (SD) is mimicked by the biochip-embedded membrane serving as a scaffold allowing cell-cell communication through its pores. Reproduced from [100] with permission from Elsevier. (d) Exploded view of a multi-MPS platform. The top plate (shown in yellow polysulfone) contains MPS compartments and distributes culture medium through micromachined channels and pumps on its bottom face. The bottom plate (shown in clear acrylic) distributes compressed air and vacuum to small ports below each pump/valve chamber. Reproduced from [94] with permission from Wiley.