Topical Focal Adhesion Kinase Inhibitor Promotes Skin Regeneration and Scar Prevention in a Preclinical Porcine Model
Sun Hyung Kwon, PhD, Britta Kuehlmann, MD, Teruyuki Dohi, MD, Artem A. Trotsyuk, BS, Michael S. Hu, MD, Geoffrey C. Gurtner, MD.
Stanford University, Stanford, CA, USA.
PURPOSE: Focal adhesion kinase (FAK) plays a pivotal role in transducing mechanical signals to cells during cutaneous wound repair resulting in increased fibrosis. We have previously shown that pharmacological inhibition of FAK signaling suppresses fibrotic cellular events and attenuates hypertrophic scar (HTS) formation following deep dermal injury. Clinical translation of FAK inhibitor (FAKI) therapy has been challenging, however, due to the lack of an effective localized drug delivery system especially for extensive burn and large-sized injuries. In our previous studies, pullulan-collagen hydrogel-mediated FAKI delivery to excisional and burn wounds accelerated healing and reduced HTS formation in mice. Here we evaluated the efficacy and safety of topical FAKI hydrogel therapy in a preclinical human-like large animal model. METHODS: Seven female red Duroc pigs (16-20 kg) were used to create 6 to 8 deep partial-thickness dorsal wounds each of about 25 cm2 per animal. With multiple dermatome passes, each wound depth was uniformly excised to be 0.070 in. to create near full-thickness excision in the center and deep partial-thickness in the periphery as previously described in the literature. Animals received either standard bandage dressings, blank hydrogel alone (placebo), or FAKI-releasing hydrogel dressings immediately after wounding. Dressings and hydrogels were changed every 2 days until the wounds closed and then every 4 days thereafter. Wound closure rate, HTS formation, and regrowth of hair follicles and skin appendages were evaluated over 6 months. RESULTS: Excisional wound healing was significantly accelerated with localized FAKI hydrogel treatment. FAKI-treated wounds closed significantly faster on day 14±2.3 vs. day 24±1.6 for control wounds vs. 24±0.8 for placebo wounds (N=8 for each group, statistical difference at p<0.01). Visually inspected scars were dramatically reduced with FAKI hydrogel treatment compared to untreated control or placebo wounds. Lower Visual Analog Scale (VAS) scores relative to untreated control wounds determined by a panel of blinded scar experts indicated improved scar appearance evaluated at Day 90 and at Day 180 (control VAS=100 vs. placebo 93±4.6 vs. FAKI 58±6.5, N=8 for each group, statistical difference at p<0.001). FAKI-treated wounds regenerated skin appendages including hair follicles and eccrine glands. Histology and immunoblotting analyses demonstrated that α-smooth muscle actin expression in the scar lesions was substantially attenuated with FAKI treatment suggesting that FAKI blocks myofibroblast recruitment and activation. Lastly, the collagen fibril architecture of FAKI-treated wound was very similar to the basket weave pattern of unwounded pig skin while collagen organization of untreated control and placebo wounds appeared randomly disorganized. CONCLUSION: Biomaterial-based topical delivery of FAKI was effective in improving wound healing, reducing scar formation, and promoting regeneration in a large animal model, and holds great potential as an effective therapeutic strategy for wound and scar management of large and deep dermal wounds.
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