# Microscale models of inflammation and its resolution

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $752,278

## Abstract

Project Summary
Neutrophils are primary cells of the innate immune system that are necessary for host defense,
however, persistent neutrophil inflammation contributes to tissue damage and chronic inflammation in
broad diseases including cardiovascular disease, autoimmune disease and cancer. It was previously thought
that resolution of neutrophil inflammation occurred through neutrophil death and macrophage
phagocytosis; however, we recently discovered that neutrophils also leave sites of tissue inflammation
through a process referred to as neutrophil reverse migration. Here we apply microscale
organotypic models to analyze onset and resolution of inflammation by 1) analyzing migration
and signaling through 3D co-culture of primary neutrophils or induced pluripotent stem cells
(iPSCs) derived neutrophils, 2) spatiotemporally separating and retrieving neutrophils during
forward and reverse migration and 3) modeling neutrophil migration and reverse migration in a
physiologically relevant 3D microenvironment, and. It is our goal to develop a physiologically relevant
in vitro model to replicate key steps in neutrophil recruitment to and clearance from a site of
inflammation. A key strength in this application is the use of organotypic microscale models that allow for
the replication of the essential geometries and cellular interactions that induce and resolve neutrophil
inflammation. A broad goal for the proposed research is to provide a collaborative, multi-disciplinary
(engineering, biologists, clinicians) approach to a fundamental problem relevant to human health – namely,
inflammation and its resolution at sites of tissue injury. We strive to develop practical tools and
methods that will transform our ability to identify signaling pathways that modify neutrophil forward and
reverse migration and have therapeutic potential. A particular focus is the paracrine signals
generated by macrophages, endothelial cells, and neutrophils in co- and tri-culture and the
characterization of induced pluripotent stem cell derived neutrophils as a model for primary human
neutrophils (Aim 1). Furthermore, the use of layered open microfluidics technology will allow us to
separate neutrophils at different stages in bidirectional migration to identify spatiotemporal regulation
of neutrophil behavior (Aim 2). Finally, we will investigate the trafficking of human neutrophils and their
interactions with macrophages and endothelial cells in response to different inflammatory stimuli in a
physiologically relevant organotypic in vitro model to examine neutrophil reverse migration and how it is
altered in disease (Aim 3). We expect our findings to address a gap in understanding how cells
communicate during the onset and resolution of inflammation, and the further development of iPS
derived neutrophils that may provide novel avenues for therapeutic interventions for human disease.

## Key facts

- **NIH application ID:** 9904469
- **Project number:** 5R01AI134749-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** David J Beebe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $752,278
- **Award type:** 5
- **Project period:** 2018-04-25 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904469

## Citation

> US National Institutes of Health, RePORTER application 9904469, Microscale models of inflammation and its resolution (5R01AI134749-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904469. Licensed CC0.

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