Introduction and Objective: Most diabetic foot ulcers (DFUs) fail to heal or recur, leading to amputation and five-year mortality exceeding many cancers. Biomarkers that distinguish healing trajectories are needed to guide targeted therapy to improve healing and reduce amputations. We evaluated whether circulating biomarkers associate differently with longitudinal changes in wound area versus depth in a prospective, observational study. Methods: Ten participants identified as non-healers with corresponding plasma biospecimens and baseline and 12-week wound dimensions were included. Non-healing was defined as failure to achieve wound closure while receiving standard of care + total contact casting. Plasma was analyzed for 30 DFU-related proteins using Olink Flex, and advanced glycation end products (AGEs) were quantified by LC-MS/MS. Results: Participants (age 54±4y; BMI 36±2kg/m²; 9 male) decreased wound surface area by 50±24% (p=0.04) but wound depth was unchanged (116±155%; p=0.4). CXC ligand 10 decreased (p0.01) and oncostatin M increased (p0.01) over the study period, but no proteins correlated with change in wound area. Inflammatory and angiogenic proteins were correlated with changes in wound depth, including TNF (p0.01), placental growth factor (p=0.02), oxidized LDL receptor 1 (p=0.03), and IF-gamma (p=0.04). After adjusting for baseline wound depth, changes in IL-17A (p0.01), IL-10 (p=0.01), and vascular endothelial growth factor A (p=0.03) were associated with longitudinal change in wound depth. No functional protein clustering patterns were observed, and AGEs were unchanged and showed no associations. Conclusion: In this pilot cohort of non-healers, biomarker associations differed by wound dimension. Although no single predictive biomarker emerged, signals converged on inflammatory and angiogenic pathways, suggesting pathway-level dysregulation rather than isolated protein effects. Larger studies with expanded proteomic depth are warranted. Disclosure J.E. Nakamura: None. A. Howitt: None. Z. Powrozek: None. B.M. Schmidt: None. J. Haus: None.
Nakamura et al. (Fri,) studied this question.