Do diabetes- related foot ulcer wound fluid measures have clinical utility as biomarkers for healing? A systematic review

Objective: This study aimed to identify potential biomarkers reported in wound fluid of diabetes-related foot ulcers (DRFUs), and their ability to reflect current and prospective wound healing. Method: A systematic search was executed following the PRISMA methodology across five chosen databases: MEDLINE, Embase, Scopus, Cochrane Clinical Trials and Cochrane Systematic Reviews. Using keywords and phrases, it yielded 5022 results. Results: Based on predetermined inclusion and exclusion criteria, 19 papers were included in the final analysis, among which: seven reported serial temporal biomarker changes in wounds; six reported measures from baseline and related them to healing rate and/or final healing outcome; four papers reported both end-points, and two papers reported solely on baseline biomarker levels in a generalised diabetic foot ulcer group. Across the studies, a total of 46 distinct markers were described from the wound fluid of n=1141 participants. Biomarkers examined included proteases, protease inhibitors, growth factors, chemokines and cytokines, with proteases being the largest subcategory making up 16 (34.8%) of the markers investigated (n=7). Matrix metalloproteinase-9 (MMP-9) was the most frequently investigated protease and it currently holds the most biomarker promise (n=5). Wound bacterial profiles variably related to wound healing outcome (n=5). One study reported biophysical markers rather than biomarkers, including measurement of wound fluid pH. Study quality was generally good. Drawing quantitative comparisons between papers was not possible due to variability in experimental design including sampling and assessment methods. Conclusion: These studies collectively indicate several wound fluid measures that could identify DRFU status and outcomes, and that methodological standardisation in the field is needed to determine reliable predictive thresholds for healing. Declaration of interest: The authors have no conflicts of interest to declare.