# A Microphysiological Mimicry of Human Lung-Bone Marrow Organ-Organ Crosstalk On-a-Chip

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $389,613

## Abstract

PROJECT SUMMARY.
 Several new viral respiratory tract infectious diseases with epidemic potential that threaten global health security
have emerged in the past 20 years. Influenza A viruses (IAVs) comprise 50% of the emerging respiratory viruses and can
cause substantial morbidity and mortality. IAVs can infect a diversity of avian and mammalian species, including
humans, and have the remarkable capacity to evolve and adapt to new hosts. Despite the tremendous progress made in
virology and epidemiology, which subtype or strain of IAV will cause the next outbreak remains unpredictable.
Importantly, there is no clinically simulating, pathophysiologically relevant, and readily available in vitro
multi-organ system for predicting the pathogenicity of emerging and re-emerging influenza viruses in humans.
Recent compelling evidence have revealed opposing roles for two major classes of bone marrow (BM)-produced innate
immune cells in shaping the outcome of IAV infection, with neutrophils offering protection and increase in circulating
monocytes being associated with increased pathology. Thus, selective mobilization of either of these two distinct cell
types in response to pulmonary infection with IAV can indirectly reveal potential pathogenicity of a given viral
strain. The overarching goal of this project is to develop a highly innovative, reductionist, yet advanced and complex,
physiologically relevant in vitro model of influenza infection in humans utilizing Organ-on-Chip technology in order to
predict virulence and infectivity of different IAV strains, by reproducing clinically and in vivo-observed immunological
correlates of infection severity. More specifically, we will engineer a first-in-kind fluidically integrated multi-
organ system that recreates BM-lung axis, using primary human-derived cells, for real-time analysis of
inflammation and leukocyte mobilization in response to influenza challenge. Our central hypothesis is that this
dynamic living microsystem can recapitulate differential immune cell mobilization and tissue pathology in
response to high-pathogenicity vs. low-pathogenicity IAV infections in vitro. To address the hypothesis, we
propose the following specific aims: (1) to engineer a living and hematopoietically active human BM-on-a-Chip and
microfluidically link it to a human Lung Small Airway-on-a-Chip that our team has previously developed and
characterize homeostatic physiology and organ-organ crosstalk; and (3) to challenge the BM-Lung microsystem with
airborne IAVs under rhythmic breathing and reproduce differential leukocyte mobilization and tissue damage in
response to distinctly pathogenic viral strains. Such a novel platform holds great potential in emulating and predicting
pathogenicity of IAVs (e.g., during outbreaks, pandemics or when presence of a highly virulent strain is speculated),
utilizing human cells isolated from desired donor/patient populations, and without needing to adapt the virus for host
(as required for...

## Key facts

- **NIH application ID:** 10237309
- **Project number:** 5U01EB029085-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kambez Hajipouran Benam
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,613
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237309

## Citation

> US National Institutes of Health, RePORTER application 10237309, A Microphysiological Mimicry of Human Lung-Bone Marrow Organ-Organ Crosstalk On-a-Chip (5U01EB029085-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10237309. Licensed CC0.

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