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

Abstract

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 cordrelated 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.

Wound healing approach based on excretory-secretory product and lysate of liver flukes

“…Also, using complex broad morphological approach, for the first time we have shown that O. felineus proteins promote: (i) acceleration of wound healing timeline; (ii) angiogenesis activation; (iii) decreased inflammation and (iv) ECM remodeling in vivo. We also used the model of multiple application of proteins for the first time for maximum effect, and approximation to treatment regimens in humans 12 .…”

“…Normally, skin regeneration is a natural homeostatic process that includes four successive stages:(1) hemostasis (platelet activation, clot formation to prevent blood loss and fibrin matrix formation, up to 48 h);(2) inflammation (immune response, activation of inflammatory cells, up to 96 h); (3) proliferation (modulated M2 to M1 polarization of macrophages, keratinocyte migration, angiogenesis activation, tissue granulation, epithelial folds and wet crust/eschar, up to 10-14 days); (4) remodeling (maturation of epidermis, overall reduction of wound area, regression of blood vessels, structuring of extracellular matrix, more than 10 days) 4-6 . In case of pathological no overgrowth, wounds do not undergo normal stages of healing, linger at stage of inflammation or proliferation and remain incurable despite intense therapeutic treatment 7,8 .Promising therapeutic approaches to wound healing correction include various gels, growth factors, herbal preparations, natural polysaccharides (chitosan) and bioactive peptides of various origins [9][10][11][12] . Due to this, proteins of parasitic trematodes may potentially become novel perspective agents for wound healing, as well as treatment of autoimmune diseases [13][14][15] .…”

“…Promising therapeutic approaches to wound healing correction include various gels, growth factors, herbal preparations, natural polysaccharides (chitosan) and bioactive peptides of various origins [9][10][11][12] . Due to this, proteins of parasitic trematodes may potentially become novel perspective agents for wound healing, as well as treatment of autoimmune diseases [13][14][15] .…”

Combined Amniotic Membrane and Self-Powered Electrical Stimulator Bioelectronic Dress Promotes Wound Healing

“…21 Despite these limitations, ongoing research aims to optimize the application of AM and address its drawbacks to realize its considerable potential as a resource for wound healing. 22,23…”

“…AM has been utilized in the treatment of chronic wounds, partial-thickness burns, and massive post-traumatic wounds. − However, it does have limitations, such as rapid degradation, handling difficulties, limited availability, and high cost . Despite these limitations, ongoing research aims to optimize the application of AM and address its drawbacks to realize its considerable potential as a resource for wound healing. , …”