# Targeting Macrophage to Improve the Outcomes of Urogynecologic Meshes in Diabetic Women

> **NIH NIH R21** · MAGEE-WOMEN'S RES INST AND FOUNDATION · 2020 · $240,470

## Abstract

PROJECT ABSTRACT
Pelvic floor disorders (PFDs) such as stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP) are
common and costly situation in women with a lifetime risk of surgical repair of 20%. For the treatment of SUI,
placement of a mid-urethral sling manufactured from polypropylene mesh is the most widely used procedure.
For POP, polypropylene meshes are also used to improve on the high failure rates (up to 40% at 2 years; 60%
at 7 years) of native tissue repairs. Unfortunately, these meshes are associated with mesh related
complications, most commonly exposure of mesh through vaginal epithelium and pain. These complications
occur more frequently in diabetic women, roughly 3 times more in comparison to the general population.
However, research into mechanisms by which diabetes increases the risks of mesh complications has been
scant. It is estimated that among the 350,000 women who receive meshes annually in the US, over 14% are
known diabetics. Since the number of women undergoing SUI and POP surgeries is predicted to increase by
50% by 2050, more diabetic women will receive meshes. Therefore, insight into the mechanisms has the
potential to markedly impact health care.
Typical of any host responses to a foreign material, studies from our group have shown that macrophage is the
key cell type that mediates the responses to meshes. However, an irreversible aging process of macrophages
(senescence) is accelerated by high level of blood glucose in diabetic patients. These premature senescent
macrophages are associated with functional deficit in phagocytosis and regulation of immune response to
foreign bodies such as mesh. In addition, we found that macrophage phenotypic transition from pro-
inflammatory M1 to pro-healing M2 was impaired in mesh-tissue specimens excised from diabetic women with
mesh complications. Based on the findings from our group and others, we hypothesized that macrophage
senescence associated dysfunction with impaired M1 to M2 transition is the primary mechanism leading to the
increased risk of mesh complications in diabetic women. We propose the following aims to test our hypothesis
in a middle-aged diabetic rat model: Aim 1: To determine the impact of diabetes on the host response and
mesh-tissue incorporation following mesh implantation; Aim 2: To determine the impact of diabetes on the
acquisition of macrophage senescence and HDAC3/IL-4 signaling pathway in macrophages at the mesh
implantation site; Aim 3: To improve mesh incorporation with tissue by replacing dysfunctional macrophages
with monocytes isolated from healthy rats or promoting M1 to M2 transition via selective HDAC3 inhibition
mediated by a novel viral vector (AAV-CD68p-shHDAC3).
The data from this proposal will offer the following innovative deliverables: 1) address the knowledge gap by
defining the mechanism by which diabetes increases the risk of mesh complications; 2) develop novel
macrophage-based therapies that is clinically translat...

## Key facts

- **NIH application ID:** 9994323
- **Project number:** 5R21HD099549-02
- **Recipient organization:** MAGEE-WOMEN'S RES INST AND FOUNDATION
- **Principal Investigator:** Rui Liang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $240,470
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994323

## Citation

> US National Institutes of Health, RePORTER application 9994323, Targeting Macrophage to Improve the Outcomes of Urogynecologic Meshes in Diabetic Women (5R21HD099549-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9994323. Licensed CC0.

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