The long-term objective of this project is to expand the horizons and improve the healing after fetal surgery in humans as well as develop better clinical treatments for the management of adult human wound healing problems. Wounds in the fetus heal by mechanisms which are significantly different than those involved in adult healing. There is an absence of acute inflammation, fibrosis, and contraction with resultant minimal or no scar formation. This healing is both cosmetically and functionally superior to adult repair in that fetal wounds regain up to 60% of normal skin breaking strength within two weeks of injury, whereas, in adults this takes many months and only gets to 40% (See page 20 of this application.) Because scarring is a result of synthesis, deposition, and degradation of collagen and hyaluronate (HA), this proposal focuses on the differences in extracellular matrix metabolism by fetal and adult fibroblasts. The major focus of this proposal tests the hypothesis that collagen and HA expression and their regulation in fetal fibroblasts is fundamentally different from adult fibroblasts. Initial studies will characterize the expression of collagen and collagenolytic enzymes by adult and fetal fibroblasts in vitro and in vivo (primarily closed wounds, and open wounds). This characterization will involve morphological and biochemical analyses of four different cell types consisting of normal fetal and adult fibroblasts as well as fetal and adult wound fibroblasts. To determine the mechanisms underlying the differential expression of matrix this analysis will be extended to the molecular level. Collagen, collagenase, HA, and cytokine transcript synthesis and accumulation will be examined. Once these baseline parameters are determined, the response of these cells to mediators which regulate cell proliferation and matrix metabolism will be tested. In addition, the mechanisms responsible for non-contraction of open fetal wounds will be examined. Information generated by this study will provide a better understanding of fetal physiology and development. Understanding the basic biology of the fetal repair process should improve successful in utero surgical intervention of birth anomalies. In addition, this understanding will lead to better clinical rationales for treating the many human wound healing problems such as keloid, hypertrophic burn scar, and contractures as well as chronic non-healing wounds such as pressure sores, diabetic ulcers, venous stasis ulcers that are a growing health care problem and result in major morbidity and costs. New treatments for these pathologic processes may be developed based on knowledge of fetal healing which could result in a marked reduction in the morbidity, mortality, and expense associated with these problems.
|Alaish, S M; Yager, D; Diegelmann, R F et al. (1994) Biology of fetal wound healing: hyaluronate receptor expression in fetal fibroblasts. J Pediatr Surg 29:1040-3|
|Frantz, F W; Bettinger, D A; Haynes, J H et al. (1993) Biology of fetal repair: the presence of bacteria in fetal wounds induces an adult-like healing response. J Pediatr Surg 28:428-33;discussion 433-4|
|Mast, B A; Diegelmann, R F; Krummel, T M et al. (1993) Hyaluronic acid modulates proliferation, collagen and protein synthesis of cultured fetal fibroblasts. Matrix 13:441-6|