Development of a Human Liver Microphysiological System For Alcoholic Liver Disease - PROJECT SUMMARY
Alcoholic liver disease (ALD) includes a broad range of progressive disease stages: fatty liver, alcoholic
steatohepatitis (ASH), liver fibrosis, liver cirrhosis, and hepatocellular carcinoma.1-3 In spite of being one of the
major causes of morbidity and mortality in the world, there are currently no effective strategies that can prevent,
treat or monitor the progress of ALD owing primarily to lack of human and physiologically-relevant research
models. At Emulate we have developed proprietary technology to build human microphysiological systems
recapitulating tissue architecture to achieve organ level physiological functions. We have recently used this
technology and developed a mature, functional human Liver-Chip we can maintain for more than four weeks in
culture. Our proposed research will focus on developing the ALD-Chip based on the current model of Liver-Chip.
The goal of the proposed Phase I SBIR is to develop a human, physiologically relevant ALD model on chip and
recapitulate the different stages of human disease progression from potential for reversibility as it has been well
described in human patients1,3-5 to the different stages of the irreversible disease. Along these lines we will
develop the ALD-Chip to model the main aspects of ALD, including alcoholic fatty liver and alcoholic hepatitis
steatosis (ASH) (Phase I), and eventually (Phase II) the alcoholic fibrotic disease stage.
Emulate's developed Liver-Chip is a microphysiological system constructed with primary human hepatic cells
(the gold standard in the field) inside a microengineered environment incorporating flow, that emulates the liver
sinusoid space architecture and allows for dynamic assessment of liver functions over time. Based on this recent
development that provides significant improvements as compared to the previously described in vitro systems
for human liver studies,4-6 we are now enabled to apply ethanol concentrations relevant to those measured in
human patients blood and monitor development of human ALD on the Chip using clinically relevant endpoints.
Combination of ethanol dosing and length of experimentation should recapitulate the different stages in ALD
progression including capability for reversibility of the established phenotype.
The proposed research for Phase I of this SBIR has two aims: (i) The development and optimization of human
ALD-Chip by characterizing the dose-response to physiological relevant ethanol dosing conditions (Aim I), and
(ii) to validate the in vivo relevance of human ALD-Chip developed in Aim 1 by the characterization of the
progression of different ASH stages in the ALD-Chip: (1) alcoholic fatty liver and (2) alcoholic hepatitis and
determine the reversibility of the pathology in association to severity and time as in the human disease.
We plan to optimize the ALD-Chip to provide the scientific community with a platform for new drug development
and screening for liver injury therapies, treatments for protection of alcohol users from transitioning to more
severe disease stages associated with a number of co-morbidities. Further, as all Emulate's Organ Chips are
based on human primary cells they can be used to provide insights on patient-specific responses, as needed,
and to support targeted diagnostic and prognostic biomarkers discovery. In conclusion, we propose to develop
an ALD-Chip to translate ALD preclinical data into a testable and clinically relevant ALD model enabling a better
understanding of this disease and support of drug discovery.
