Diabetic foot ulcers (DFUs) often develop into hard-to-heal wounds due to complex factors. Several biomarkers capable of identifying those at risk of delayed wound healing have been reported. Controlling or targeting these biomarkers could prevent the progression of DFUs into hard-to-heal wounds. This scoping review aimed to identify the key biomarkers that can predict hard-to-heal DFUs. Studies that reported biomarkers related to hard-to-heal DFUs, from 1980 to 2023, were mapped. Studies were collected from the following databases: MEDLINE, CINAHL, EMBASE, and ICHUSHI (Japana Centra Revuo Medicina), search terms included "diabetic," "ulcer," "non-healing," and "biomarker." A total of 808 articles were mapped, and 14 (10 human and 4 animal studies) were included in this review. The ulcer characteristics in the clinical studies varied. Most studies focused on either infected wounds or neuropathic wounds, and patients with ischemia were usually excluded. Among the reported biomarkers for the prediction of hard-to-heal DFUs, the pro-inflammatory cytokine CXCL-6 in wound fluid from non-infected and non-ischemic wounds had the highest prediction accuracy (area under the curve: 0.965; sensitivity: 87.27%; specificity: 95.56%). CXCL-6 levels could be a useful predictive biomarker for hard-to-heal DFUs. However, CXCL6, a chemoattractant for neutrophilic granulocytes, elicits its chemotactic effects by combining with the chemokine receptors CXCR1 and CXCR2, and is involved in several diseases. Therefore, it's difficult to use CXCL6 as a prevention or treatment target. Targetable specific biomarkers for hard-to-heal DFUs need to be determined.
Keywords: Delayed wound healing; prediction; prevention; treatment target.