Use Of Surgical Epibole For Modeling Chronic Unresolved-inflammation And Granulation In Murine Wounds.
Phoebe Lee, BS, David Guerrero, BS, Shawn J. Loder, MD, Wayne Nerone, BS, J Peter Rubin, MD, Lauren Kokai, PHD.
University of Pittsburgh, Pittsburgh, PA, USA.
BACKGROUND: Research toward improved recalcitrant wound care is limited by inadequate granulation healing in small animal chronic wound models. We have previously demonstrated that tissue-edge in-folding to mimic epibole architecture mitigates contracture, restricts epithelialization, and prolongs wound opening. Here we demonstrate that murine epibolous wounds generate an environment of sustained inflammatory infiltration and proliferative granulation.
METHODS: Male C57BL/6J control (wt/wt) and diabetic (db/db) mice received bilateral 6mm excisional wounds. Each wound was stratified as either untreated control or chronic model. Chronic wounds were generated by incising skin flaps, which were sutured to the dermis side to create a folded skin edge. Wounds were maintained for 14-days until all control wounds had closed and/or epithelialized and were harvested for flow cytometry for neutrophils and/or macrophages and/or histology for pan-keratin (epithelium) and alpha-smooth-muscle actin (myofibroblasts).
RESULTS: The epibolous wound environment maintained prolonged neutrophil-dominant inflammatory infiltrate for the 2-week study period with simultaneous enrichment of macrophage/monocyte populations (p<0.05). Further, epibolous wounds demonstrated reduced frequency of epithelialization as defined by pan-keratin signaling compared to untreated controls. In epibolous wounds without epithelialization strong alpha-smooth-muscle actin signal was noted.
CONCLUSIONS: Previously we demonstrated that wound-edge inversion mimicking epibole significantly delayed wound closure beyond alternative surgical approaches such as edge splinting. Here we demonstrate that this translates to prolongs inflammation and a transition of murine healing to a more human-relevant granulation pattern. Progression towards more patient-applicable wounds in our small animal models further enhances our ability to more reliably evaluate therapeutic options in the pre-clinical space.
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