Liver-on-a-Chip Models of Fatty Liver Disease

Abstract

As a consequence of the obesity epidemic and increasing incidence of metabolic syndrome fatty liver disease now affects a large portion of the world’s population. Left untreated, fatty liver disease can progress to more severe pathologic conditions such as cirrhosis and liver cancer. In an effort to probe the pathophysiology of fatty liver disease and its progression, research over the last decade has led to the engineering of in vitro models of the liver to aid in drug discovery and study of liver pathophysiology. In this review, we discuss advances in modeling liver tissue and the latest developments in understanding disease etiology and treatment from the perspective of engineered in vitro models spanning from conventional planar, static monolayer cultures to those based on the more recently developed bioprinted and liver-on-a-chip platforms. These technologies promise to transform basic biological research, the pharmaceutical industry, and clinical medicine of the liver.

Figure 1.

Overview of various medical applications of liver-on-a-chip and liver-disease-on-a-chip systems. These systems can be used to discover new drugs, study their biotransformation, and test their toxicities. Chips provide a means to study the mechanisms and progression of liver diseases in vitro and to test drugs to inhibit or treat them. Chips, where the patients’ own cells are incorporated, can also be used for personalized medicine to generate models for individualized treatment testing.

Figure 2.

a) A microfluidic perfused three-dimensional human liver model. b) Scaffold-free liver-on-a-chip model with multiscale organotypic cultures. c) VLSLL-on-a-chip model showing the fabrication of liver lobules. d) An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. e) Perfused multiwell plate for 3D liver tissue engineering. Reprinted a) with permission from Elsevier (16), b) and d) from John Wiley & Sons (17) and (18), respectively, c) from IOP publishing (19), and e) from Royal Society of Chemistry (20). VLSLL: Very large-scale liver-lobule, HUVEC: Human umbilical vein endothelial cells, PDMS: Polydimethylsiloxane, PLCs: Primary liver cells.

Figure 3.

a) Schematics of microarchitecture and geometric configuration of the NAFLD-on-a-chip device. b) Chip mimicking the early stages of NAFLD by treatment with FFA. c) The gut-liver chip to mimic the absorption and accumulation of fatty acids in the intestines and the liver. d) A reversibly-and irreversibly-injured ALD model where the development of fibrosis can be seen. Reprinted a) with permission from Public Library of Science (22), b) from Baishideng Publishing Group (23), c) from John Wiley & Sons (24), and d) from Royal Society of Chemistry (25). ALD: Alcoholic liver disease, FFA: Free fatty acids.