High-dose folic acid and its effect on early stage diabetic foot ulcer wound healing.

High-dose folic acid (HDFA; vitamin B9)-5 mg, given daily, has not been evaluated as a treatment to improve early stage-diabetic foot ulcer (ES-DFU) wound healing. However, HDFA has been demonstrated to correct: (a) endothelial dysfunction and decreased nitric oxide (NO) bioavailability, associated with type-2 diabetes mellitus (T2DM); and (b) hyperhomocysteinemia (HHcy) that may promote impaired DFU-wound healing. Measures of wound area (cm2 ) reduction (wound closure; WC), over a 4-week period (4 W-WC), greater than 50% of the wound area, have been reported as a robust indicator of the potential for DFU-wound healing. By using this model, we examined the effectiveness of a wound treatment in promoting progressive healing and complete wound closure for the chronic, nonhealing DFU-wound. To investigate this possible relationship between HDFA and ES-DFU wound healing, a retrospective cohort study of medical records, between November 2018 and April 2019, was performed for Veterans with T2DM and ES-DFUs following treatment with HDFA. During the study period 29 (n = 29) Veterans with ES-DFU wounds who received HDFA treatment were identified. Medical record reviews of this retrospective cohort of ES-DFU Veterans receiving HDFA report 90% (26/29) experiencing complete DFU-wound closure during the study period. Of the 29 Veterans with ES-DFUs receiving HDFA, the medical records of nine (30%), with healed wounds, provided documentation suitable for 4 W-WC, pre- and post-HDFA treatment study comparisons. This study documents significant (P < .05) improvements comparing 4 W-WC values for standard treatment for Veterans with poorly progressing, worsening or stagnating ES-DFU-wounds to those for the same subjects following HDFA treatment. These observations suggest that chronic ES-DFUs treated with HDFA may experience significantly improved wound closure and complete healing (re-epithelialization) when compared with standard treatments without HDFA. With validation from RCTs, HDFA may be established as an effective treatment to promote wound healing and closure for nonhealing ES-DFUs.

Atypical Diabetic Foot Ulcer Keratinocyte Protein Signaling Correlates with Impaired Wound Healing.

Diabetes mellitus is associated with chronic diabetic foot ulcers (DFUs) and wound infections often resulting in lower extremity amputations. The protein signaling architecture of the mechanisms responsible for impaired DFU healing has not been characterized. In this preliminary clinical study, the intracellular levels of proteins involved in signal transduction networks relevant to wound healing were non-biasedly measured using reverse-phase protein arrays (RPPA) in keratinocytes isolated from DFU wound biopsies. RPPA allows for the simultaneous documentation and assessment of the signaling pathways active in each DFU. Thus, RPPA provides for the accurate mapping of wound healing pathways associated with apoptosis, proliferation, senescence, survival, and angiogenesis. From the study data, we have identified potential diagnostic, or predictive, biomarkers for DFU wound healing derived from the ratios of quantified signaling protein expressions within interconnected pathways. These biomarkers may allow physicians to personalize therapeutic strategies for DFU management on an individual basis based upon the signaling architecture present in each wound. Additionally, we have identified altered, interconnected signaling pathways within DFU keratinocytes that may help guide the development of therapeutics to modulate these dysregulated pathways, many of which parallel the therapeutic targets which are the hallmarks of molecular therapies for treating cancer.