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These changes are part of multiple liver disease phenotypes including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.

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11– 13 Upon activation by a variety of drugs and disease “molecular drivers” such as lipopolysaccharides (LPS) and transforming growth factor beta (TGF-β) from the intestine, free fatty acids (FFA) from adipose tissue, and epidermal growth factor (EGF) from kidney 14 the resident Kupffer cells, along with circulating immune x`cells, transmigrate into the hepatic layer where they either cause damage from inflammation or aid in damage repair, while the stellate cells undergo a transformation into myofibroblasts that dramatically change shape, proliferate and produce collagen. Stellate cells in the inactive state reside in the hepatic layer with the hepatocytes and store vitamin A and fat, while the resident Kupffer cell macrophages reside in the endothelial wall of the sinusoid to aid digestion, detoxifying the portal blood and are a key contributor in liver damage or repair as a response to challenges. 8, 10 The sinusoids are lined with liver sinusoidal endothelial cells (LSECs), a special type of endothelial cell that does not form tight junctions and is perforated by fenestrations, allowing rapid, “leaky” physical transfer of macromolecules and small molecules through the space of Disse, the thin protein matrix that together with the LSECs protects hepatocytes from the shear-stress of direct blood flow. The liver acinus is the basic structural and functional unit of the liver, where the blood flows from the portal triads through the network of sinusoidal capillaries (sinusoids) to the central vein. 1– 7 The liver gained particular interest for MPS development due to its central role in metabolism, liver-specific diseases and drug toxicity. Organ-on-a-chip microphysiological systems (MPS) have emerged as a powerful platform to mimic a particular human tissue, organ and/or multiple organs for in vitro preclinical studies, drug discovery and drug development, as well as environmental toxicology.

The vLAMPS is a valuable platform to investigate the functions of the healthy and diseased human liver using all primary human cell types and/or iPSC-derived cells.

The vascular channel is lined with human LSECs, recapitulating partial immunologic functions within the liver sinusoid, including the activation of LSECs, promoting the binding of polymorphonuclear leukocytes (PMNs) followed by transmigration into the hepatic chamber.

This allows the direct investigation of the role of zonation in physiology, toxicology and disease progression. We have successfully created continuous oxygen zonation by controlling the flow rates of media in the distinct vascular and hepatic channels and validated the computational modeling of zonation with oxygen sensitive and insensitive beads. The vascular channel can be used to deliver drugs, immune cells, as well as various circulating cells and other factors to a stand-alone liver MPS and/or to couple the liver MPS to other organ MPS. The assembly of the three layered device with primary human hepatocytes and liver sinusoidal endothelial cells (LSECs), and human cell lines for stellate and Kupffer cells, creates a vascular channel separated from the hepatic channel (chamber) by a porous membrane that allows communication between channels, recapitulating the 3D structure of the liver acinus. This primarily glass microfluidic device is optimal for real-time imaging, while minimizing the binding of hydrophobic drugs/biologics to the materials that constitute the device. The vLAMPS is a human, biomimetic liver MPS, in which the ECM and cell seeding of the intermediate layer prior to assembly, simplifies construction of the model and makes the platform user-friendly.