# Re-engineering a human 3D liver tissue model for non-alcoholic fatty liver disease for drug screening

> **NIH NIH UH2** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $436,677

## Abstract

Project Summary
Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health problem, occurring in ~25% of the global
adult population. Despite major investments by the pharmaceutical industry, there are no approved drugs for
the treatment of NAFLD, probably reflecting the heterogeneous pathophysiology involving multiple pathways.
We have recently implemented the human biomimetic, vascularized Liver Acinus Microphysiology System
(vLAMPS) using all-human primary liver cells (hepatocytes, liver sinusoidal endothelial, stellate and Kupffer
cells) from the same genotyped patients in a NAFLD experimental model. We have initiated the testing of more
than 100 drugs and drug combinations recently predicted through the application of quantitative systems
pharmacology (QSP). We have also been working toward the implementation of all iPSC-derived liver cells
from the same patients that will be completed at the time of starting the proposed study. The use of patient-
specific iPSC-derived cells is critical to produce reproducible patient cohorts for precision medicine. We also
harness the Microphysiology Systems Database (MPS Db) to manage, analyze and to determine
reproducibility of the NAFLD experimental models. There is a critical need to develop and implement high
content and throughput NAFLD MPS models based on iPSC-derived cells that demonstrate maximal
reproducibility. The goal of this collaborative effort between the University of Pittsburgh Drug Discovery
Institute (UPDDI) and the NCATS 3D Tissue Bioprinting Laboratory (3DTBL) is to harness the liver acinus
design into a higher throughput biomimetic by developing a bioprinted all-iPS plate-based, NAFLD model to
maximize throughput of testing the predicted drugs and combinations, model functionality and reproducibility
with selected primary screen metrics. We will also bioprint the middle layer of the existing high content
vLAMPS to improve the reproducibility of this secondary drug testing platform that will use the full panel of
metrics that have been previously published resulting in an improved compound selection platform for the
development of precision NAFLD therapeutics. The lack of approved therapeutics for treatment of NAFLD is
due in large part to the heterogenous pathology of the disease involving multiple pathways and the use of
animal models that do not fully recapitulate the human disease. The development of a combined high
throughput and high content NAFLD experimental model for a primary screen of predicted drugs and optimal
combinations using human, patient-specific iPSC-derived liver cells bioprinted in transwell plates will transform
the approach to NAFLD drug discovery to precision medicine. The more detailed analysis of the best drugs
and drug combinations in the bioprinted version of the vLAMPS models will refine the selection of
drugs/combinations for select patient cohorts.

## Key facts

- **NIH application ID:** 10440015
- **Project number:** 1UH2TR004124-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Mark T. Miedel
- **Activity code:** UH2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $436,677
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440015

## Citation

> US National Institutes of Health, RePORTER application 10440015, Re-engineering a human 3D liver tissue model for non-alcoholic fatty liver disease for drug screening (1UH2TR004124-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10440015. Licensed CC0.

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