Differences in Plasma Cytokine and Wound Biopsy Gene Expression Profiles in Patients with Healed Versus Non-Healed Venous Ulcerations

Wound healing involves three discrete stages: inflammatory, proliferative and remodeling. Wounds that do not progress through each stage successfully result in chronic non-healing wounds that pose a significant health hazard and financial burden to patients. At the time of chronic wound diagnosis, there are few biomarkers available to predict likelihood of wound resolution with standard of care treatment. The objective of our study was to 1) determine whether plasma cytokine profiles differ between patients with healing versus non-healing wounds and 2) generate gene expression profiles from wound biopsies of venous stasis ulcer patients where wound status is known.

At enrollment 3cc of whole blood and a wound biopsy were obtained from patients meeting study criteria (venous stasis ulceration, ulcer size >1cm, non-diabetic, no infection). 3cc of blood was drawn weekly for 10 weeks (or until the wound was healed). Plasma samples collected at time of enrollment and at 10 weeks (or when the wound was healed) were analyzed for 16 inflammation-related cytokines by multiplex ELISA (MSD). The relative change in IL-15 over time differed significantly between patients with healing versus non-healing wounds, while the relative change in IFNg, TNF, TARC, RANTES, and CIRP had p-values smaller than 0.2. Total RNA was isolated from wound biopsies and sequenced.

Differential gene expression analysis of healed versus non-healed wounds showed several significant differences between these two groups. Of particular interest were the overexpression of genes related to tissue remodeling, including THBS4, WISP2 and ITGBL1, in the non-healed wounds.

The results of this pilot study reveal systemic (plasma) and local (wound site) differences in patients with healing versus non-healing wounds. Validation of these changes in a larger cohort of patients may lead to identification of plasma biomarkers that have prognostic utility and allow for better assessment of wound healing status and improved treatment.

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