Proteomic insights into vaginal mesh complications and treatment targets.

Abstract

<h4>Objective</h4>To characterize differences in vaginal proteomic profiles among women with mesh exposure, mesh-related pain, and controls.<h4>Methods</h4>10 well-integrated mesh samples (removed incidentally or normally incorporated distant from complication), 10 mesh exposure samples, 10 mesh-pain samples and 10 control vaginal biopsies of participants without mesh from a Mesh and Pelvic Floor Tissue Biorepository were analyzed. Differentially expressed protein analysis, gene ontology enrichment, clinical covariate modeling and a hypothesis-driven assessment of 100 a priori specified proteins were performed.<h4>Results</h4>Participant age of well-integrated mesh specimens (62 ± 13 years) was similar to complication samples (exposure 52 ± 7, pain 49 ± 14 years) but older than controls (42 ± 6 years). Mean BMI (28 ± 6 kg/m²) and median implantation duration (6 ± 5 years) were similar between groups. Extracellular remodeling proteins, including MMP9 and TIMP3 and neutrophil activation proteins showed the greatest difference between complications and controls. GO terms related to immunity, response to stress, cell proliferation, apoptosis, and inflammatory and fibrosis mediators were enriched in exposure. Mesh related pain group showed enrichment in collagen fibril organization and cartilage development compared to well-integrated mesh, while only morphogenesis of an epithelium and cornification were different between pain and exposure. Clinical covariate analysis revealed similar pathways. ELISA performed on a separate cohort supports elevation of TIMP3 in well-integrated mesh samples.<h4>Conclusions</h4>Even well-integrated polypropylene mesh dramatically alters the local environment. Pain and exposure complications progress through epithelial remodeling, dysregulated extracellular matrix, and fibrosis pathways similarly regardless of clinical risk factors, supporting that constructive matrix remodeling therapies and neutrophil targeting may be useful therapeutics.<h4>Statement of significance</h4>Polypropylene mesh is used in urogynecologic surgery to improve the durability and reduce invasiveness of surgical repairs, however it is associated with a high complication rate. In order to improve the response to polypropylene mesh implanted on the vagina and to design better materials, we must understand the pathways through which these complications develop. This proteomic analysis showed that inflammation, disordered extracellular and epithelial remodeling, apoptosis and fibrosis were the most different between complications and controls, both validating prior mechanistic studies and providing potential therapeutic targets, including matrix degradation protein inhibitors and neutrophil pathways.