Disrupting Mechanotransduction Pathways to Improve Wound Healing and Prevent Fibrosis

Cutaneous wound healing following injury is a complex biological process involving the orchestration of the immune system, inflammatory pathways, mechanotransduction pathways, and various types of participating cells. In adult humans, the wound repair process results in the replacement of the damaged functional tissue with a patch of cells (i.e., mostly fibroblasts) and disorganized collagen-rich extracellular matrix that is commonly defined as a scar. While scarring occurs in almost all tissues, it is most apparent in the skin. Cutaneous scarring poses a significant psychological and physiological burden on patients, and an estimated $12 billion are spent annually on scar treatments in the U.S. alone. Keloidal scars, which are characterized by excessive fibrosis in areas of the skin with acne or other minor injuries, represent another major fibrotic skin disorder. Several other skin fibrotic diseases such as Dupuytren’s disease, psoriasis, and systemic sclerosis lead to cutaneous scarring.

Recent progress in the identification of key signaling pathways involved in fibrosis and scar formation has led to the emergence of new therapeutic agents for scar treatment, with promising results in animal studies. Over the past 15 years, our laboratory has demonstrated that activation of mechanotransduction pathways underlie fibrotic wound healing and result in exuberant fibro-proliferation and hypertrophic scar (HTS) formation. In preclinical studies, we have shown that inhibition of the focal adhesion kinase (FAK) pathway significantly attenuates fibrotic HTS formation while accelerating healing of deep dermal injury. To optimally deliver small molecule inhibitors to cutaneous wounds, our laboratory has developed a therapeutic hydrogel dressing that releases FAK inhibitor (FAK-I, VS-6062) in a controlled manner upon contact with open wounds. Large animal studies prove that FAK-I therapy promotes skin regeneration with reduced scar formation and skin appendage reappearance and is safe for topical use in animal models.