# Multi-organ human-on-a-chip system to address overdose and acute and chronic efficacy and off-target toxicity

> **NIH NIH UH3** · UNIVERSITY OF CENTRAL FLORIDA · 2021 · $2,381,424

## Abstract

Project Summary
 Addiction to pain medications, especially opiates, has become a major health problem and systems to guide
the understanding of repeat overdose treatments are needed. Our proposal seeks to build overdose models for
four drugs (fentanyl, methadone, codeine, and morphine) in a multi-organ system and evaluate the acute and
repeat dose, or chronic effects, of overdose treatments such as Naloxone on overdose recovery, efficacy as well
as off-target toxicity for cardiac, muscle, kidney and liver. We have developed a low cost system using human
cells in a pumpless multi-organ platform that allows continuous recirculation of a blood surrogate for up to 28
days. This system emulates the distribution of a parental compound and the formation of metabolites among all
“organ” compartments and predicts potential toxicity and efficacy of drugs better than in vitro single human organ
or animal models. We will develop two different overdose models for both male and female phenotypes based
on nociceptors and B?tzinger Complex (B?tC) neurons as they contain µ-opioid receptors but are thought to
have different roles in response to overdose and treatment. We will also integrate functional immune components
in the UH3 Phase that has been demonstrated to enable organ specific or systemic monocyte actuation. In
addition, models for cardiomyopathy and an infection model will be utilized to more accurately represent the
effects of therapeutics on comorbidities. We will establish a PKPD in vitro model of overdose and treatment to
enable prediction in clinical environments for a range of variables including age and drug-drug interactions. Once
established the system could be used to evaluate novel pain therapeutics for efficacy and off-target toxicity as
well as additional overdose treatments in future studies. Interconnected systems with continuous recirculation of
a blood surrogate allows both the parent compound and its metabolites to be evaluated in the same system
since it is a low volume platform. This interconnected system is better suited for preclinical drug testing than
single organ systems for the same reason that human and animal models are currently the gold standards for
toxicity and efficacy determination as they allow communication between the organ systems in the body. To
construct a well defined system we will use a common serum free medium with microelectrode arrays and
cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts of
organ function. UCF and Hesperos in collaboration with clinicians seek to radically change established practice
in drug discovery by bypassing animal experiments and extensive clinical trials to provide treatments for diseases
and clinical conditions such as overdose. We have already been working with regulatory authorities to prepare
for eventual acceptance of the systems for regular use in INDs. Since Hesperos is already offering multi-organ
evaluations as a ser...

## Key facts

- **NIH application ID:** 10351973
- **Project number:** 4UH3TR003081-02
- **Recipient organization:** UNIVERSITY OF CENTRAL FLORIDA
- **Principal Investigator:** James J Hickman
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,381,424
- **Award type:** 4N
- **Project period:** 2019-09-27 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10351973

## Citation

> US National Institutes of Health, RePORTER application 10351973, Multi-organ human-on-a-chip system to address overdose and acute and chronic efficacy and off-target toxicity (4UH3TR003081-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10351973. Licensed CC0.

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