Introduction: Diabetic foot ulcers (DFUs) remain a major cause of morbidity and chronic wound burden, yet the molecular determinants that drive failure of healing are not fully defined. MicroRNAs (miRNAs) regulate inflammation, epithelialization, and extracellular matrix remodelling, and their dysregulation may contribute to chronicity. This study examined three mechanistically relevant miRNAs—miR-21, miR-365, and miR-31—to identify a molecular signature associated with non-healing diabetic wounds.
Methods: A prospective observational study was conducted involving 160 patients with diabetic foot wounds and 40 non-diabetic acute wound controls. Wound-edge tissue samples were collected at presentation. Quantitative RT-PCR was used to measure expression levels of miR-21, miR-365, and miR-31. Clinical data including ulcer duration, HbA1c, infection status, and healing outcome at 12 weeks were recorded. Group comparisons and multivariate analyses were performed to assess associations between miRNA expression and wound chronicity.
Results: Chronic diabetic wounds demonstrated a significant reduction in miR-21 (p < 0.001) and miR-365 (p < 0.01) compared to controls, alongside a persistent upregulation of miR-31 (p < 0.001). This triad was strongly associated with non-healing status at 12 weeks. miR-21 and miR-365 levels showed inverse correlations with ulcer duration and inflammatory burden, while elevated miR-31 correlated with delayed epithelialization. In multivariate logistic regression adjusting for HbA1c, infection, and peripheral arterial disease, the combined miRNA signature independently predicted non-healing (adjusted OR 3.8, 95% CI 2.1–6.9). ROC analysis demonstrated good discriminatory ability (AUC 0.82) for identifying wounds likely to remain chronic.
Discussion: This study identifies a distinct microRNA signature—downregulation of miR-21 and miR-365 with persistent elevation of miR-31—as a molecular marker of chronicity in diabetic wounds. The pattern reflects failure to transition beyond the inflammatory phase and impaired epithelial repair. These findings offer a potential biomarker panel for early risk stratification and highlight signal regulatory pathways that may be targeted to improve healing outcomes in diabetic foot ulcers.
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