Impaired wound healing in the diabetic foot is a major problem often leading to amputation. Mast cells have been shown to regulate wound healing in diabetes. We developed an indole-carboxamide type mast cell stabilizer, MCS-01, which proved to be an effective mast cell degranulation inhibitor in vitro and can be delivered topically for prolonged periods through controlled release by specifically designed alginate bandages. In diabetic mice, both pre-and post-wounding, topical MCS-01 application accelerated wound healing comparable to that achieved with systemic mast cell stabilization. Moreover, MCS-01 altered the macrophage phenotype, promoting classically activated polarization. Bulk transcriptome analysis from wounds treated with MCS-01 or placebo showed that MCS-01 significantly modulated the mRNA and microRNA profile of diabetic wounds, stimulated upregulation of pathways linked to acute inflammation and immune cell migration, and activated the NF-kB complex along with other master regulators of inflammation. Single-cell RNA sequencing analysis of 6,154 cells from wounded and unwounded mouse skin revealed that MCS-01 primarily altered the gene expression of mast cells, monocytes, and keratinocytes. Taken together, these findings offer insights into the process of diabetic wound healing and suggest topical mast cell stabilization as a potentially successful treatment for diabetic foot ulceration.

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Our main objective was to validate that hyperspectral imaging via a new portable camera carries the potential to provide a reliable clinical biomarker that can predict DFU healing. We recruited patients with diabetic foot ulceration (DFU) without peripheral arterial disease, infection or other serious illness. Using an hyperspectral imaging (HSI) apparatus, post-debridement hyperspectral images were taken evaluating the ulcer size, periwound oxyhemoglobin (OxyHb), deoxyhemoglobin level (DeoxyHb) and oxygen saturation (O 2 Sat) for four consecutive visits. Twenty-seven patients were followed, out of whom seven healed their DFU while the remaining 20 failed to heal their DFU. The average time between each visit was 3 weeks. Binary logistic regression of healers versus non-healers on Visit 1 oxyHb and on Visit 2 showed a significant inverse association, OR = 0.85 (95% CI: 0.73-0.98, p < 0.001).An inverse correlation was observed between the Visit 1 oxyHb and the percentage of ulcer size reduction between Visit 1 and Visit 4 (r = À0.46, p = 0.02) and between the Visit 2 oxyHb and the percentage of ulcer size reduction between Visits 2 and 4 (r = À0.65, p = 0.001). Using oxyHb 50 as the cut-off point to predict DFU complete healing, Visit 1 oxyHb measurement provided 85% sensitivity, 70% specificity, 50% positive predictive value and 93% negative predictive value. For Visit 2, oxyHb had 85% sensitivity, 85% specificity, 66% positive predictive value and 94% negative predictive value. We conclude that this preliminary study, which involved a relatively small number of patients, indicates that hyperspectral imaging is a simple exam that can easily be added to daily clinical practice and has the potential to provide useful information regarding the healing potential of DFU over a short period of time.