# The Role of C-Flip in Mediating Pro-Survival Macrophages in the Foreign Body Response

> **NIH NIH R21** · UNIVERSITY OF COLORADO · 2021 · $236,194

## Abstract

Macrophages are key players in the foreign body response (FBR) to implanted biomaterials, in which an
avascular fibrous capsule walls off the implant. However, the cellular mechanisms that contribute to the fibrous
capsule have not yet been elucidated. As a result, synthetic-based biomaterials have been limited to those that
the body tolerates and which function despite a FBR and does not lead to biomaterial-host integration. In this
highly exploratory project, we put forth a novel hypothesis that is based on our team’s recent published findings
in tissue fibrosis. We demonstrated that inhibition of cellular FLICE-like inhibitory protein (cFLIP), which is a
major regulator of macrophage cell fate, can prevent tissue fibrosis. In this project, we test the hypothesis that
that macrophage persistence in the FBR is mediated by intracellular cFLIP and inhibiting cFLIP resensitizes
macrophages to apoptotic death signals to prevent or resolve fibrous encapsulation. We developed two specific
aims to test the hypothesis and to translate this idea to a biomaterial strategy that targets cFLIP in macrophages
to prevent fibrous encapsulation. In specific Aim #1, we will determine the kinetics of macrophage
persistence in the FBR to distinct implants. This aim will use the hCD68-rtTA transgenic mouse that is coupled
with a Tet-on Cre system and fluorescent tdTomato expression. Using this mouse model, a series of lineage
tracing experiments will be performed that combine multiparameter flow cytometry to identify myeloid subsets,
including recruited and tissue-resident macrophages, distinguish their temporal patterns in the FBR and
determine changes in their expression profiles for fibrosis-relevant genes. In specific Aim #2, we will temporally
inhibit c-FLIP in macrophages to promote their programmed cell death and attenuate formation and
maintenance of the fibrous capsule in the FBR. The first part of Aim #2 will determine the temporal effects of
cFLIP inhibition in macrophages using a similar transgenic mouse model as in Aim 1, but which is coupled
with a tet-On Cre system that deletes cFLIP. This mouse model will enable the temporal effects of cFLIP deletion
to be determined on both the formation of fibrous capsule and on its dissolution. The second part of Aim #2 will
focus on designing a phototriggerable biomaterial to inhibit cFLIP temporally and locally in macrophages.
This will be achieved through photo-labile microparticles that are embedded within a biomaterial, which when
triggered by light lead to the slow release of YM155, a small molecule inhibitor of cFLIP. By tightly controlling
when YM155 is released, the temporal effects of local cFLIP inhibition by a biomaterial-based strategy will be
determined. At the conclusion of this project, we will have a) determined the temporal patterns of macrophage
accumulation and when they begin to persist in the FBR, b) elucidated the role of cFLIP in mediating pro-survival
programming in macrophages and its eff...

## Key facts

- **NIH application ID:** 10210394
- **Project number:** 5R21EB029261-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Stephanie J Bryant
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $236,194
- **Award type:** 5
- **Project period:** 2020-07-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210394

## Citation

> US National Institutes of Health, RePORTER application 10210394, The Role of C-Flip in Mediating Pro-Survival Macrophages in the Foreign Body Response (5R21EB029261-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10210394. Licensed CC0.

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