Developing Cellular Biomarkers for Non-Healing Diabetic Foot Ulcers

Funded by NIH grant No. RC1DK086364

Co-Principal Investigators: Harold Brem, MD, and Marjana Tomic-Canic, PhD

The goal of this project is to identify objective, quantitative bio-molecular parameters that correlate with healing outcomes for DFUs. Chronic non-healing DFUs are a widespread and serious clinical problem with high rates of morbidity, disability and mortality, including a high risk for lower limb amputations. About half of all DFUs fail to heal promptly or completely in response to the current standard of care. One of the major obstacles to prompt and complete DFU healing is the inability to predict which wounds are not likely to respond to standard treatment protocols and will require alternative interventions.

The edges of chronic wounds contain tissue that expresses inhibitors of healing and does not respond to wound-healing stimuli. The challenge of this project is to develop a feasible quantitative method of distinguishing between tissue that has the capacity to heal and tissue that does not, thus identifying non-healing phenotype. We propose to identify biomarkers that objectively and quantifiably identify non-healing tissue in DFUs. Two protein markers—nuclear localization of β-catenin and induced expression of c-myc—are associated with healing impairment in other chronic wounds but have not been studied in DFUs.

The objective of this project is to determine whether expression of β-catenin and/or c-myc at the wound edge is correlated with objective quantitative measures of DFU wound closure. Fifty consecutive patients receiving the current standard of care for chronic DFUs will provide small wound tissue biopsies at the initial treatment (week 0) and four weeks later. The extent of wound closure at four weeks will be used as a surrogate outcome for wound healing and will be confirmed by histopathology.

This project will advance the science of wound healing by identifying objective cellular biomarkers that predict healing outcomes and providing quantitative techniques that can be used to monitor treatment efficacy and clinical outcomes. These biomarkers will be used to: 1) predict which diabetic foot ulcers are not likely to heal with standard therapy and therefore require adjuvant advanced intervention; and 2) provide markers that can be used as determinants in future clinical trials. Ultimately, this work will support our goal of reducing the number of amputations and improving healing outcomes for millions of individuals suffering from the consequences of chronic non-healing skin ulcers.

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