A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX

Abstract

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. 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 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. 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. 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. This allows the direct investigation of the role of zonation in physiology, toxicology and disease progression. 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. 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.

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

“…Specifically, these technologies have been successfully used to culture microphysiological biomimetics of liver sinusoids (Figure ). Taylor and colleagues developed a microfluidic chip, in which PHH and NPCs are cocultured at physiological ratios in a layered 3D organization, consisting of a vascular channel separated from the hepatic chamber by a porous membrane that resembles the liver acinus . The system can mimic hepatic oxygen gradient‐drive zonation and allows to study leukocytic infiltration of the hepatic chamber.…”

Improving natural product research translation: From source to clinical trial

“…Elucidating details (light bulbs) of molecular mechanisms of action prior to initiating a NPCT can help "de-risk" the planned trial by both providing evidence for the hypothesized outcome and its underlying causes, and supporting the development of methods to test that hypothesis. 59,65 Models incorporating elements of the human immune system are beginning to be developed. Elucidation of the bioactive NP constituents or metabolites (B) is critical for quality control, for assessing bioavailability, PK and PD, and determining whether minimal effective concentrations of bioactives have been achieved in plasma or at the targets (C).…”

Engineering tissue‐specific blood vessels

“…(d) A blood–brain‐barrier model displaying human‐induced pluripotent stem endothelial cells and motor neuron networks with dextran perfusion . (e) The vascularized liver acinus microphysiology system showing the various layers and location of liver sinusoidal endothelial cells . (f) Three‐dimensional rendering of blood vessel perfusion in skin constructs with immunofluorescence staining depicting physiological orientation of the blood vessels .…”

“…The Taylor group has developed a microfluidic organ‐on‐a‐chip microphysiological system called the vascularized liver acinus microphysiological system (Figure e). They are one of the few groups to incorporate tissue specific vasculature into their model.…”

“…65 (e) The vascularized liver acinus microphysiology system showing the various layers and location of liver sinusoidal endothelial cells. 72 (f) Three-dimensional rendering of blood vessel perfusion in skin constructs with immunofluorescence staining depicting physiological orientation of the blood vessels. 78 (g) Airway organoid displaying vasculature in the center with airbuds on the outside of the organoid 79 vessel density, and occupied more than double the area of the patch percentage wise.…”