Development of a Tissue-Based Extracellular Matrix Vulnerability Score (ECM-V) for Women Undergoing Primary Pelvic Organ Prolapse Surgery.

Background/Objectives: Pelvic organ prolapse (POP) is increasingly recognized as a localized extracellular matrix (ECM) remodeling disorder. Conventional clinical predictors do not fully explain interindividual variation in tissue quality or surgical durability. This study aimed to characterize the ECM failure phenotype in surgically obtained pelvic support tissue and to derive an exploratory tissue-based ECM Vulnerability (ECM-V) score. Methods: This single-center exploratory translational biomarker derivation study included 121 women: 60 undergoing primary reconstructive surgery for POP with or without concomitant stress urinary incontinence, and 61 benign gynecological controls. Standardized intraoperative anterior vaginal wall biopsies and preoperative plasma samples were obtained. Seven ECM biomarkers (COL1, COL3, ELN, MMP1, MMP2, MMP3, MMP9) were quantified in both compartments. Receiver operating characteristics (ROC) analysis adjusted logistic regression and stratified 10-fold cross-validation were performed. An exploratory integer-weighted ECM-V score was derived from COL3, MMP2 and MMP9 tissue values. Results: Tissue biomarkers demonstrated substantially stronger discrimination than plasma biomarkers. Surgical cases showed reduced COL1 (AUC 0.898) and ELN (AUC 0.846), elevated COL3 (AUC 0.818), MMP2 (AUC 0.958) and MMP9 (AUC 0.977) (all p < 0.001). The compact COL3-MMP2-MMP9 tissue model achieved a cross-validated AUC of 0.986 ± 0.035, substantially outperforming the best plasma model (AUC 0.719). The ECM-V score demonstrated derivation-level AUC of 0.995, sensitivity of 0.967 and specificity of 0.967. Tissue MMP9 and MMP2 correlated strongly with POP-Q severity and validated symptom scores (rho up to 0.806, p < 0.001). Conclusions: Women undergoing primary POP surgery demonstrate a distinct localized ECM failure phenotype. The exploratory COL3-MMP2-MMP9 framework provides a biologically coherent basis for the ECM-V score requiring prospective validation with longitudinal recurrence outcomes.