Using an animal model, investigators find that Mitomycin C, a common chemotherapy agent, offers limited benefit in reducing keloid or hypertrophic scars.
The tendency for extreme scarring is one reason many African Americans avoid plastic surgery and other surgical incisions. Though surgeons continue to develop less invasive techniques that minimize scarring, other options are needed to help these individuals who are prone to developing keloid scars.
Keloid scars are caused by an overproduction of fibroblasts, the structure on which cells build tissue to heal a wound. The fibroblasts continue to multiply after the wound is filled in and become a raised scar that grows beyond the original wound or point of incision. Dark skinned individuals tend to form keloids more readily than lighter skinned individuals. Hypertrophic scars are more common and occur in all racial groups. They appear raised but stay within the confines of the initial wound or point of incision. Both types of scars can occur through skin injuries such as surgical incisions, traumatic wounds, vaccination sites, burns, chickenpox, acne, or even minor scratches.
Mitomycin C (MMC) is a common chemotherapy agent that inhibits cell growth. It is also known to decrease the proliferation of fibroblasts, an essential element in the development of scar tissue. If too many fibroblasts are produced, a keloid of hypertrophic scar is produced.
Researchers set out to determine if the use of Mitomycin C can reduce keloid or hypertrophic scarring. To do this, they used an animal model that most closely parallels normal wound healing in humans. Clinical observations were used to assess the effect of topical and intradermal MMC on wound healing while evaluating for the presence of the protein, TGF-B1, to determine how MMC works to decrease fibroblast proliferation and scarring.
The authors of the study, “The Effects of Intradermal and Topical Mitomycin C on Wound Healing,” are Glen T. Porter, MD, and Swarupa Gadre, MD, of the University of Texas Medical Branch in Galveston, TX, and Karen Calhoun, MD Chair of University of Missouri Medical School. Their findings are being presented at the American Academy of Otolaryngology-Head and Neck Surgery Foundation Annual Meeting & OTO EXPO, being held September 19-22, 2004, at the Jacob K. Javits Convention Center, New York City, NY.
Twenty-four adult male Sprague-Dawley rats (375-400g) were anesthetized and two incisions were placed on the back. Wound treatment was then administered according to randomization to one of the three study groups: injected MMC group, received intradermal injection with 1.0 ml of Mitomycin C (0.5mg/ml) into each wound; topical MMC group, received a four minute application of topical MMC (0.5mg/ml); saline group, received topical or intradermal saline in a similar manner. After treatment each wound was irrigated and closed with sterile staples. Two animals in each study arm were sacrificed at one and two weeks and one and six months after surgery. The wounds were then visually inspected and then a small sample was excised. Each wound was then serially sectioned. One section was sent for microscopic examination (blinded) with H&E staining and TGF-B1-specific immunohistochemical staining. Using a tensiometer, the remaining wound sections were tested to evaluate the force necessary to cause wound dehiscence (unblinded).
Results were evaluated using the SPSS software. Kruskal-Wallis and Mann-Whitney tests were used for statistical comparison. Study animals were treated in accordance to federal and state-mandated standards.
Wound evaluation at the time of harvest showed an 88 percent (7/8) incidence of skin necrosis in the intradermal MMC group. Frank necrosis was noted in the wounds harvested at one and two weeks. Wounds harvested at one and six months showed corresponding areas of scarring consistent with areas of healing by secondary intention. No skin necrosis was noted in topical MMC and control animals. Wounds treated with topical MMC had poorer wound integrity compared with controls at one week (p<.001), two weeks (p<.001), one month (p<.001) and six months (p<.001). When compared to controls this represents a 3-4-fold decrease in wound strength at each time period. Intradermal MMC showed poorer wound integrity at two weeks (p<.001), one month (p<.001), and six months (p<.001) when compared with controls. Again, this represented at least a 3-fold decrease for the latter three time periods. There was a significant difference in wound strength when comparing topical and intradermal MMC only at the first week (p<.001) with injected wounds being weaker.
Blinded evaluation of H&E and immunohistochemical staining of wound sections showed no consistently identifiable difference between wounds in the three treatment groups. TGF-?1 was not consistently identified in any group.
The results of this study indicate that the application of MMC, whether topical or injected, will result in decreased wound strength which is still significantly different at six months after wounding. Intradermal injection appears to have no more affect on wound strength than topical, but carries an increased risk of skin necrosis. No consistently identifiable changes in histology or TGF-B1 expression was noted, which does not mean that TGF-B1 is not involved, only that the instrument of detection did not pick it up as the protein may not be present in quantities large enough to detect with immunohistochemical staining. This data suggests cautious use of MMC in clinical situations where wound breaking strength is critical. Intradermal MMC should be avoided as skin necrosis and scarring may result. Further study in humans is necessary to determine the effect of MMC on keloid and hypertrphic scars.