Diabetic foot ulcers are challenging to treat. Current strategies to treat these wounds focus on preventing infection and promoting tissue regrowth but are ineffective in many individuals. Low-grade chronic inflammation is present in individuals with diabetes, and altering the inflammatory responses at the wound site could be an alternate approach to promote healing. We hypothesized that immunomodulation of the wound microenvironment would result in accelerated healing. To test this hypothesis, we began by characterizing the changes in the myeloid cell phenotype in a mouse model [leptin receptor knockout (KO) mouse] that closely mimics the type 2 diabetes condition observed in humans. We observed increased numbers of monocytes and neutrophils in the circulation of the KO mice compared to that in wild-type control mice. We also observed several phenotypic changes in neutrophils from the KO diabetic mice, suggesting low-grade systemic inflammation. Hence, we developed a rapamycin-loaded chitosan scaffold that may be used to modulate immune responses. The use of these immunomodulatory scaffolds at a wound site resulted in accelerated healing compared to the healing using blank scaffolds. In summary, our data suggest that immunomodulation may be a viable strategy to promote the healing of wounds in individuals with diabetes.

ObjectiveThe goal of this study was to identify biochemical and immunological parameters from the blood as predictors of non-healing in early-stage diabetic foot ulcers.Research Design and MethodsWe performed a cross-sectional prospective cohort study among individuals with early-stage foot ulcers visiting the Karnataka Institute of Endocrinology Research over a 2.5-year period. Histopathological, biochemical, and immunological data (a total of 31 parameters) from 52 individuals were collected and analyzed to determine if predictors of non-healing may be identified. Data analysis was performed using traditional univariate analyses as well as univariate and multivariable logistic regression.ResultsIndividual histopathological and biochemical parameters did not show any differences between healed and non-healed individuals. However, conventional univariate analysis and univariate logistic regression analysis showed that the expression of the cell-surface proteins CD63, HLA-DR and CD11b on monocytes (CD14+) was significantly lower in non-healed individuals, but with moderate discriminative ability as assessed by area under the curve (AUC) of Receiver Operating Characteristics (ROC) curve. In comparison, a multivariable logistic regression model identified four of the 31 parameters to be salient predictors and demonstrated high discrimination ability with an AUC of ROC value of 0.87. Among the four identified parameters, LDL cholesterol (OR 18.83, CI 18.83-342) and cell-surface expression of CD63 on monocytes (OR 0.12, CI 0.12-0.45) were significant.ConclusionThrough this study we conclude that LDL cholesterol and cell-surface expression of CD63 on monocytes are strong positive and negative predictors of non-healing, respectively, in individuals with early-stage DFU. Following validation in a larger cohort, these parameters may be used by the clinician for early identification of non-healers.

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.