# Role of Wnt Signaling in Macrophage Response to Biomaterials

> **NIH NIH R56** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $361,785

## Abstract

Biomaterials are clinically used to replace lost or damaged tissue, but the surgical implantation procedure
initiates an inflammatory response, which is orchestrated by macrophages. The long-term goal is to understand
the signaling pathways used by macrophages to recognize biomaterial features and the resulting inflammatory
processes that lead to tissue healing and regeneration. The objective of this proposal is to determine the
contribution of cell-biomaterial interactions and danger-associated molecular patterns (DAMPs) in the regulation
of Wnt ligands, and to elucidate the effect of macrophage-secreted Wnt ligands on T cell activation and stem cell
recruitment and differentiation. The central hypothesis is that macrophages interact with biomaterials and
DAMPs, triggering Wnt release that regulates bone healing by modulating T cell polarization and MSC
proliferation. Our rationale is that macrophage activation is dependent on the physicochemical properties of
biomaterials and the local environment. Macrophages respond to biomaterials by secreting inflammatory
molecules, including Wnt ligands. Ablating Wnt ligand secretion in macrophages decreases their activation and
disrupts the inflammatory response and bone-biomaterial integration. By identifying key signaling pathways that
trigger Wnt ligand secretion, we can identify biomaterial surface modifications and signaling pathways that can
be targeted to modulate and ameliorate the inflammatory process after biomaterial implantation to improve
clinical outcomes. The central hypothesis will be tested in three aims: 1) Elucidate the role of integrin signaling
in triggering Wnt secretion by macrophages in response to biomaterial physicochemical cues.; 2) Establish the
effect of DAMPs in altering macrophage-secreted Wnt ligands; 3) Determine the effect of macrophage-secreted
Wnt ligands on T cell polarization and MSC proliferation and differentiation after biomaterial implantation. We
will pursue these aims using a combination of in vitro and in vivo studies with conditional transgenic knockouts
in macrophages, pharmacological inhibitors, and macrophage adoptive transfer and CRISPR-mediated
transcriptional activation to the activation of endogenous Wnt3a and Wnt5a expression. The study of Wnt
signaling on macrophage behavior and as an orchestrator of the inflammatory response after biomaterial
implantation is innovative and has yet to be studied. The proposed work is significant because it will determine
the role of Wnt proteins in macrophage activation and will provide evidence of the importance of Wnt signaling
in the inflammatory milieu that can be translated into other areas like chronic inflammatory diseases and cancer.
The near-term expected outcome of this work is the understanding of Wnt signaling in macrophage activation
and its contribution to the inflammatory and healing process in response to biomaterial surface characteristics.
Results from this proposal will have an immediate positive im...

## Key facts

- **NIH application ID:** 11137237
- **Project number:** 2R56DE028919-06
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Rene Olivares-Navarrete
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $361,785
- **Award type:** 2
- **Project period:** 2019-07-01 → 2026-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11137237

## Citation

> US National Institutes of Health, RePORTER application 11137237, Role of Wnt Signaling in Macrophage Response to Biomaterials (2R56DE028919-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11137237. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*