163. Determining How Early Disruption Of Mechanotransduction Affects Incisional Healing

PURPOSE: Mechanical strain across a wound promotes hypertrophic scar (HTS) formation. Previous work has determined that focal adhesion kinase inhibitor (FAKI) can mitigate mechanotransduction-mediated fibrosis and inflammation after 14 days of treatment. We sought to determine how targeted inhibition of FAK affected incisional wound healing during acute time periods with only 3 days of treatment. METHODS: A 3 cm incision was made on the mouse dorsum and sutured closed. After 4 days, we attached a mechanical strain device to the dorsum to apply mechanical strain across the wound to create hypertrophic scar (HTS) formation. Of a total of 18 mice, (n=2) received an incision but no device (control); (n=10) received an incision with mechanical strain (HTS); and (n=6) were treated with FAKI hydrogels in conjunction with mechanical strain (S+FAKI). After 3 days of treatment, the mice were sacrificed. These groups and unwounded skin were compared by measuring scar width, analyzing collagen ultrastructure using picrosirius staining and collagen quantification algorithms, and immunofluorescent staining of Thrombospondin1 (THBS1). RESULTS: The average width of the HTS was significantly greater than the width of both the FAKI treated and control scars. The HTS collagen fibers were also significantly longer and more highly aligned than FAKI treated and control scars, as well as unwounded skin. The scars in the HTS mice also had significantly elevated levels of a pro-fibrotic extracellular matrix marker thrombospondin1 compared to FAKI treated and control scars. CONCLUSION: Acute pharmacological FAKI therapy effectively narrowed scar widths and promoted regenerative collagen architecture formation. HTS promoted thrombospondin1 formation; however, treated wounds exhibited significantly less thrombospondin1. Thrombospondin1 is a proteoglycan secreted by macrophages which promotes initial ECM formation, so a pharmacological blockade reducing thrombospondin1 expression levels prevents collagen deposition in HTS. Thus, early timing of FAKI therapy promotes more regenerative macrophage phenotypes, which improves healed tissue quality. Further understanding of targeting and timing of FAKI therapy can prove important for future therapies.