# Development of an integrated 4-organ animal model

> **NIH NIH R44** · HESPEROS, LLC · 2020 · $744,745

## Abstract

Project Summary/Abstract
 We propose to construct multi organ microphysiological systems (“Body-on-a-Chip” or BoaCs) from human
and rat cells to use as a basis to understand species differences in response to exposure to drugs or chemicals
in this new platform. The results will then be compared to clinical data, where available, and to archived in vivo
animal data. This work will directly test whether such in vitro models can accurately reproduce species
differences in response to known drugs. A preclinical model based on human cells that can accurately predict
human response should lead to better decisions on whether exposure to a chemical or chemical mixture will be
harmful to humans. An advantage of this in vitro approach, compared to standard in vitro systems (e.g. such as
multiwell plates), is that the tissues can exchange metabolites and the dose dynamics in the body of both parental
compounds and metabolites are better represented than when a single cell type is exposed to a bolus dose.
Also, by comparing acute to chronic effects it will enable prediction on clinical trial success as well for determining
PK of the compounds. In addition, the comparison of animal cells derived from iPSCs will enable the assessment
of whether they can be substituted for primary animal cells. If successful, this could lead to stable cell sources
for the animal models and reduce the number of animals needed for these studies.
 For this proposal we will build upon a four-organ model we recently published in Nature Scientific Reports
(Oleaga, et al. 2016) which included model tissues for the liver, cardiac, skeletal muscle, and neuronal
compartments that correctly predicted clinical response to five compounds. To construct a well defined system
we will use a common serum free medium which mimics key features of blood. Hickman has developed
microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic
and mechanical readouts for not only acute but also chronic tests as well. To improve operability and enable a
low volume system for eventual metabolite evaluation, we will use a pumpless system (Sung, et al. 210) and self
contained devices.
 We will also utilize microfluidic analytical components for rapid and sensitive biomarker assessment.
However, the number of biomarkers to be monitored for cell health and function will be greatly reduced in our
systems from use of the function readouts. The system will be modeled by simulation using CFD to establish
acceptable ranges for consumption of nutrients and drug metabolism as well as shear stress and to predict drug
concentration profiles in the system to also enable PK/PD prediction capabilities. We believe that this technique
will lead to more accurate and cost-effective assessment of the efficacy and toxicological potential of drugs
chemicals or chemical mixtures and this approach will have a major impact on improving human health.

## Key facts

- **NIH application ID:** 9994307
- **Project number:** 5R44ES029892-03
- **Recipient organization:** HESPEROS, LLC
- **Principal Investigator:** James J Hickman
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $744,745
- **Award type:** 5
- **Project period:** 2018-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994307

## Citation

> US National Institutes of Health, RePORTER application 9994307, Development of an integrated 4-organ animal model (5R44ES029892-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9994307. Licensed CC0.

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