Role of mechanical strain in incisional hernia fibroblast function.

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DESCRIPTION (provided by applicant): Description: Incisional hernias occur in 7-11% of laparotomy wounds, a substantial health care burden with an annual cost of $2.5 billion. Our laboratory found that a fibroblast wound .healing defect is induced when laparotomy wounds are mechanically disrupted and form incisional hernias. Models of muscle and tendon injury suggest that load-bearing tissues like the abdominal wall are dependent on mechanical strain to signal repair, believed to occur through mechano-transduction pathways that activate wound repair fibroblasts. This proposal is founded on the premise that wound healing in load-bearing tissues is critically dependent on the mechanical strain sensed by fibroblasts. This new concept challenges the surgical paradigm that "tension-free" techniques are best and asks whether a load-force is in fact required to signal abdominal wall wound repair. We aim 1. to test whether mechanical strain In vitro stimulates wound healing activity in fibroblasts isolated from disrupted surgical laparotomy wounds and hernias, and 2. to confirm that these fibroblasts lose proliferative and synthetic function when strain is removed in vitro. Using an established rat hernia model, we will culture fibroblasts from unwounded controls. Mechanically Intact, Disrupted and Hernia wounds. To test the first aim, these cultured fibroblasts will be subjected to cyclic and static stretch, and assessed for: microscopic morphological evidence of mechanical strain and actin stress fiber expression; measurement of the proliferative (PCNA) and synthetic fibroblast response to mechanical strain; integrin and o-smooth muscle actin (aSMA) as molecular markers for fibroblast differentiation; and blockade of fibroblast response to strain signals following MAP kinase blockade supporting activation of a mechanotransduction pathway in these repair cells in vitro. The second aim will be tested by culturing the above groups under constant strain and measuring the effect of removing this strain signal on the same outcomes. We anticipate our findings will clarify the role of mechanical strain in fibroblast proliferation, with implications for strategies for prevention and repair of laparotomy wound hernias. PUBLIC HEALTH RELEVANCE: The rate of incisional hernia formation in the U.S. approaches 400,000 yearly, occurring in approximately 11 % of all laparotomy wounds, with reoccurrences in 24-58% of hernia repairs. This is a substantial health care burden and a significant cause of patient morbidity. Although the advent of the "tension-free" approach to hernia repair, considered the standard, has reduced recurrence rates, we hypothesize that an appropriate load-force is required for abdominal wall fibroblasts to heal the load-bearing wound, and "tension-free" approaches may circumvent an important mechanism for abdominal wall repair.