Impact of hyperglycemic memory on innate immune response to urogynecologic mesh

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Urogynecologic meshes are often implanted in women to treat stress urinary incontinence and pelvic organ prolapse, two most common pelvic floor disorders. While peri-operative glycemic control is the standard of care, women with diabetes experience ~5-fold higher risk of developing mesh-related complications such as mesh exposure into vaginal cavity and pelvic chronic pain. These complications significantly impair women’s life quality and increase health costs. Since diabetes affects 1 in 10 adult women in the US and the incidence continues to increase, defining the mechanism underlying the diabetes-associated risk of mesh complications is critical to improve patient care and decrease societal expenses. Studies have demonstrated that the beneficial effects of intensive glycemic control are markedly decreased if long episodes of hyperglycemia precede the treatment, referred to as “hyperglycemic memory” (HgM). To date, there has been no investigation into how this phenomenon impacts the outcomes of women receiving urogynecologic meshes. Our preliminary data in a rat model support that hyperglycemia is harmful to vaginal immune response to mesh in the long term and that HgM in bone marrow (BM) cells may impact mesh outcomes. Here we hypothesize that hyperglycemia leaves epigenetic marks in BM progenitor cells, which drives macrophage dysfunction at mesh-tissue interface, leading to an increased risk of mesh complications despite later glucose normalization. As epigenetic modification is reversible with long-term glycemic normalization, we further hypothesize that tight and long-term peri-operative glycemic control attenuates the negative impact of HgM, thereby improves mesh outcomes in women with diabetes. We have assembled an interdisciplinary team to test the hypotheses with the following specific aims: (1) Define the role of HgM in host response to mesh. In vitro experiments using hyperglycemia-impacted vs. normal BM cells will be performed to define impact of HgM on macrophage phenotype and function. In vivo experiments using BM transplantation in a diabetic rat model with mesh implanted via sacrocolpopexy will be performed to define the impact of HgM in BM cells vs. HgM in vaginal tissue on the long-term mesh outcomes at 90 days. (2) Define the effect of peri-operative glycemic control regimens on host response to mesh and long-term mesh outcomes. Three peri-operative glycemic control procedures – early and strict, immediately before surgery, and poor glycemic control will be implemented. Mesh outcomes at short-, medium-, and long-terms (i.e., 7-, 42-, and 90-days post-surgery) will be compared between groups. (3) Define the relationship between HgM and diabetes- associated risk of mesh complications via an in-depth analysis of host response in human mesh-tissue samples obtained from women with mesh complications. This study will provide insight into the mechanism of long-term implant complications in women with diabetes and inform future preventive strategies to improve health outcomes in this rapidly expanding demographic.