ORF33-06 - Unveiling the Podiome: Biomarkers for Prediction, Prognosis and Treatment of (non)Healing Chronic Diabetic Foot Ulcers

Diabetic foot ulcers (DFUs) are a potentially life-threatening and major complication of diabetes mellitus. While the morphological changes associated with diabetic foot ulcers are well-characterized, the cellular and molecular biomarkers driving tissue changes and wound healing in DM patients remain poorly understood. The four phases of wound healing are inflammation, migration, proliferation, and remodeling. Acute wounds progress through healing, but in chronic wounds healing is “frozen” at the inflammation stage. Our goal is to detect and treat the one-quarter of diabetics with DFUs exhibiting significant impaired healing mechanisms due to cellular and biochemical processes involved in the injury and inflammatory response. The approach is to vet biomarkers which are measurable characteristic(s) that indicates a biological process, disease, or a treatment response. These can be used for diagnosis, prognosis and treatment.
In this study, we recruited 42 patients in three different categories: non-diabetic/non-healing ulcer, diabetic/healing ulcer, and diabetic/non-healing ulcer to examine the biologically relevant pathophysiology involved in wound healing. Blood samples were collected using either sharp debridement or hydro-scalpel and then multi-omic analyses involving: elucidating altered levels of cytokines, interrogating genes of wound pathways, and de novo protein discovery via high throughput proteomics.
An initial six potential biomarkers progressed through successive stringent rounds of our discovery phase. The end of the discovery workflow employed robust bioinformatic analyses of both Data Dependent analysis (DDA) and Data Independent analysis (DIA). Novel biomarkers in this process include: Tenascin involved in wound healing, WNK3 a cell survival protein, Galectin-1 a marker of inflammation, CAP-G a regulator of actin motility, HSP-90 a chaperone that is a key component of proper protein folding and cyclooxygenase 2 involved in the creation of prostaglandins and thromboxane inflammatory molecules. In the validation phase, we have taken a subset of our patient population and confirmed that COX-2 is overexpressed in the serum of diabetic ulcer patients who did not heal. We are exploring a FDA approved treatment to inhibit this enzyme.
The aim of this study was to predict what patients with diabetic ulcers will ultimately heal under standard antiseptic care and load bearing relief versus those requiring immediate and intensive intervention protocols. Identification of prominent biomarkers that are associated in the wound healing process of DFUs can provide a more accurate prediction of clinical diagnoses, prognoses, and creation of treatments in the care of these chronic wounds.
This work approved by RFUMS IRB Protocol #178 and supported by NIH S10 OD010662