Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Stress Offloading Through Mechanomodulation Is Associated With Down-regulation Of Inflammatory Pathways In A Large Animal Model
Michael Januszyk, MD, Victor W. Wong, MD, Kirit Bhatt, MD, Ivan N. Vial, MD, Reinhold Dauskardt, PhD, Michael T. Longaker, MD, Geoffrey C. Gurtner, MD.
Stanford University, Stanford, CA, USA.

PURPOSE:
Cutaneous scarring represents a major source of morbidity in the United States, and understanding the mechanisms underlying this process is critical to develop effective therapies to mitigate scar formation. Although wound fibrosis and inflammation are highly linked, only recently have mechanical forces been suggested to directly modulate these pathways, both in animal and clinical studies. Our group previously developed a topical polymer device that significantly reduces post-injury scar formation via the manipulation of mechanical forces. Here we extend these studies to examine the transcriptional effects of mechanomodulation during scar formation using a validated large animal model, the red Duroc pig.
METHODS:
Full-thickness incisional wounds measuring three centimeters in length were created on the pig dorsum. Polymer devices were applied immediately after closure, and separate wounds were allowed to heal under physiologic, elevated stress, and stress-shielded conditions (n = 3). Wounds were harvested for DNA microarray analysis at eight weeks post-injury. Hierarchical clustering of gene expression data for each group of wounds was performed, followed by canonical pathway calculations and network analyses.
RESULTS:
Genes associated with connective tissue disorders and inflammation networks were up-regulated in elevated stress wounds and down-regulated in stress-shielded wounds. A super-network was generated, including all genes associated with either top pathway target (Figure 1). The central element linking these networks is extracellular-related kinase (ERK)1/2, which has previously been associated with inflammation and scarring. Further, when we artificially grew our network using a relationship database, we found that focal adhesion kinase (FAK) assumed a central position among genes associated with both pathways. These data suggest a molecular link between inflammation and fibrosis that can be mechanically regulated via FAK and ERK1/2.
CONCLUSION:
We demonstrate that mechanical loading of incisional wounds up-regulates inflammatory and fibrotic pathways, and that device-mediated off-loading of these wounds can reverse these effects. These pathways appear linked by ERK1/2 and FAK, suggesting a common molecular mechanism underlying the mechanomodulation of cutaneous wound healing.


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