Topical Biological Agents as Adjuncts to Improve Wound Healing in Chronic Diabetic Wounds: A Systematic Review of Clinical Evidence and Future Directions

Diabetes is a leading chronic illness in the modern world and 19-34% develop chronic diabetic foot ulcers (DFUs) in their lifetime, often necessitating amputation. The reduction in tissue growth factors and resulting imbalance between proteolytic enzymes and their inhibitors, along with systemic factors impairing healing appear particularly important in chronic wounds. Growth factors applied topically have thus been suggested to be a non-invasive, safe, and cost-effective adjunct to improve wound healing and prevent complications. Comprehensive database searches of MEDLINE via PubMed, EMBASE, Cochrane, and ClinicalTrials.gov were performed to identify clinical evidence and ongoing trials. The risk of bias analysis included randomized controlled trials (RCTs) was performed using the Cochrane Risk of Bias 2.0 tool. We included randomized controlled trials that compared the use of a topical biologic growth factor-containing regimen to any other regimen. Primary outcomes of interest were time to wound closure, healing rate, and time. Secondary outcomes included the incidence of adverse events such as infection. A total of 41 trials from 1992-2020 were included in this review, with a total recorded 3,112 patients. Platelet-derived growth factors (PDGF) in the form of becaplermin gel are likely to reduce the time of closure, increase the incidence of wound closure, and complete wound healing. Human umbilical cord-related treatments, dehydrated human amnion and chorion allograft (dHACA), and hypothermically stored amniotic membrane (HSAM), consistently increased the rates and incidence of complete ulcer healing while reducing ulcer size and time to complete ulcer healing. Fibroblast growth factor-1 (FGF1) showed only a slight benefit in multiple studies regarding increasing complete ulcer healing rates and incidence while reducing ulcer size and time to complete ulcer healing, with a few studies showing no statistical difference from placebo. Platelet-rich fibrin (PRF) is consistent in reducing the time to complete ulcer healing and increasing wound healing rate but may not reduce ulcer size or increase the incidence of complete ulcer healing. Targeting the wound healing pathway via the extrinsic administration of growth factors is a promising option to augment wound healing in diabetic patients. Growth factors have also shown promise in specific subgroups of patients who are at risk of significantly impaired wound healing such as those with a history of secondary infection and vasculopathy. As diabetes impairs multiple stages of wound healing, combining growth factors in diabetic wound care may prove to be an area of interest. Evidence from this systematic literature review suggests that topical adjuncts probably reduce time to wound closure, reduce healing time, and increase the healing rate in patients with chronic DFUs.