International Journal of Molecular Sciences · 3 authors, 1 centre
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This review summarizes current pro-healing drugs for chronic wounds, including natural products, human-derived factors, and pharmaceuticals. It highlights that while many treatments show promise, their mechanisms are often poorly understood and underlying patient comorbidities complicate therapy. The paper underscores the need for more effective, mechanism-driven treatments to improve outcomes for the millions affected by chronic wounds.
**Background:** Chronic wounds affect approximately 2% of the population, translating to 5.7 million people in the United States with an annual cost of around $20 billion. They precede 85% of all amputations, with diabetic ulcers responsible for 70% of all lower limb amputations, and the 5-year mortality rate following amputation is between 40–70%. Normal wound healing progresses through hemostasis, inflammation, proliferation/repair, and remodeling, but chronic wounds stagnate between inflammation and proliferation, often with increased inflammatory cells and cytokines, oxidative stress, and bacterial biofilms present in at least 60% of cases.
**Methods:** This is a narrative review that examines the literature on pro-healing drugs for chronic wounds. The authors categorize treatments into natural products (antibiotics, silver, medicinal honey, curcumin, aloe vera, birch bark), human-derived factors (mesenchymal stem cells, macrophages, collagenase, placental-derived products, autologous leucocyte/platelet/fibrin patch), and pharmaceutical drugs (PDGF/becaplermin, phenytoin, vitamin A/retinoids, hypochlorous acid, pentoxifylline, metformin). For each, they summarize proposed mechanisms and key evidence from preclinical and clinical studies.
**Key Results:** - **Natural Products:** Antibiotics like gentamicin and ciprofloxacin have shown increased wound healing in animal models, with ciprofloxacin increasing CD34 expression. Silver dressings are antimicrobial but can be toxic to fibroblasts and keratinocytes; silver sulfadiazine led to slower epithelialization in multiple RCTs. Medicinal honey (e.g., Medihoney™) achieved 90% closure in chronic wounds in one clinical series and significantly reduced healing time in pressure ulcers. Curcumin promotes wound contraction and angiogenesis in rats and improves collagen alignment. Aloe vera reduces TNF-α and IL-1 and stimulates fibroblast activity. Birch bark extract (Episalvan®) accelerated re-epithelialization in partial thickness wounds and burns. - **Human-Derived Factors:** MSCs seeded on amniotic membrane reduced wound size and healing time; a collagen membrane with autologous MSCs achieved wound closure by day 29 in diabetic foot ulcers. Macrophage modulation with anti-TNF-α antibodies accelerated healing in diabetic wound models; intradermal injection of stimulated macrophages increased healing in pressure and diabetic ulcers. Collagenase (Santyl®) improved wound bed appearance and enhanced re-epithelialization and wound closure in mini-pig models. Placental-derived products (EPIFIX, EPICORD) increased fibroblast and MSC migration in vitro and showed positive clinical effects. Autologous leucocyte/platelet/fibrin patches (3C PATCH®) showed good efficacy in diabetic foot ulcers. - **Pharmaceutical Drugs:** Becaplermin (Regranex®) accelerated wound healing and improved breaking strength in rat incision wounds; its black box warning for cancer mortality was removed in 2018 after studies showed no increased risk. Phenytoin increased healing in rat burn wounds and improved outcomes in acute burns compared to silver sulfadiazine. Vitamin A/retinoids: tretinoin significantly increased diabetic ulcer healing in one study but retarded re-epithelialization in another. Hypochlorous acid increased keratinocyte and fibroblast migration in vitro and significantly increased wound closure in a murine model. Pentoxifylline improved perioral burns and scarring in a clinical study. Metformin improved wound healing in aged rats and accelerated healing in a murine diabetic wound model.
**Clinical Implications:** The review highlights that while multiple therapeutic options exist, substantial unmet needs remain. Many treatments have ill-defined mechanisms, and chronic wounds are complicated by underlying pathologies like diabetes. The authors emphasize the need for precise spatial and temporal drug delivery systems, such as hydrogels that can release therapeutics in response to environmental triggers. They also note that recent advances in single-cell multi-omics and spatial profiling may lead to new mechanism-driven treatments. Overall, the paper calls for more effective therapies to improve quality of life for chronic wound patients.