Decreased Incidence of Hypertrophic Burn Scar Formation with the Use of Collagenase, an Enzymatic Debriding Agent

Author(s): 
Karen E. Frye, MD, FACS, and Arnold Luterman, MD, FRCS(C), FACS

  Scar control is a major concern in burn wound management. When scarring occurs, the outcome may be associated with a loss of function or an undesirable cosmetic result. The functional problems may be severe enough to result in the inability to perform one’s usual work tasks. An unacceptable cosmetic result may lead to psychosocial concerns.
Early wound closure results in less hypertrophic scarring. Early excision and grafting of deeper injuries expedites wound closure. A significant challenge remains in how to avoid hypertrophic scar formation in partial-thickness wounds that are allowed to heal spontaneously.

  In 1994, the authors’ institution began using an enzymatic debriding agent, collagenase, in the treatment of superficial burn wounds. Collagenase is a metalloproteinase derived from the fermentation of Clostridium histolyticum. Collagenase has been shown to expedite wound debridement.1,2 Furthermore, with earlier debridement to a clean dermis, re-epithelization occurs faster.1,2 The authors believe that a decrease in hypertrophic scar formation also occurs.

  The purpose of this study was to compare the incidence of hypertrophic scar formation in patients with partial-thickness burns not treated with collagenase to those treated with collagenase. The authors’ intent was to report an observation that needs further investigation. The hypothesis for this study was that the use of collagenase in the partial-thickness burn wound decreased the incidence of hypertrophic scar formation.

Methods

  This was a retrospective review of patients treated for partial-thickness burn injuries at the University of South Alabama Burn Center. Only patients who received their entire care and follow-up care at the University of South Alabama were included in this study.

  Burn wound management from 1989 to 1993 consisted of first placing a silver sulfadiazine dressing on the wound. The dressing was changed daily for 3 days and then changed to a daily wet-to-dry dressing. The wet-to-dry dressing part of this routine was changed in 1993 to a collagenase enzymatic debriding dressing. Daily wound care then continued until a barrier dressing could be applied or until the wound spontaneously re-epithelized.

  The criteria for inclusion in the study consisted of patient age between 8 and 70 years and no need for excision and grafting. Patients treated for a burn injury in 1993 were excluded from the review, because this was a transition year when the burn care management shifted from a normal saline dressing to the collagenase dressing. Data was not available as to which patients were treated with a wet-to-dry dressing and which patients were treated with collagenase.

  The patients treated between 1989 and 1992 for acute partial-thickness burns were classified as the Saline Wet-to-Dry group. Those patients treated between 1994 and 1997 were labeled the Collagenase group.

  An outpatient chart review was performed for patients meeting the stated criteria. The number of months a patient was followed as an outpatient depended on the level of concern regarding possible scar formation. Care was taken to record whether or not scarring had been an issue in the patient’s care. The criteria for considering scarring as an issue included a description of the scar as “moderate” or “severe” in intensity, the need for use of pressure garments, or the use of silicone gel sheets. Patients were not placed into garments unless scar concerns existed. Age, race, sex, percent total body surface burn, and the mechanism of the burn were also recorded.

Results

  For the years 1989 to 1992, the Saline Wet-to-Dry group comprised 225 patients. For the years 1994 to 1997, the Collagenase group comprised 207 patients. The mean age for both groups was 32 years. The sex distribution was 169 (75%) men and 56 (25%) women for the Saline Wet-to-Dry group and 162 (78%) men and 45 (22%) women for the Collagenase group. This was not significantly different (Table 1). The race distribution was 67% white and 31% black for both groups. The mean percent total body surface area burned was 7.8% for the Saline Wet-to-Dry group and 5.7% for the Collagenase group. This was not significantly different.

  The mechanisms of the burn injury for the Saline Wet-to-Dry and Collagenase groups were also similar. Flash/flame burns were the most common (51% of the injuries in both groups). Scald injuries were the second most common mode of injury with 23% in the Saline Wet-to-Dry group and 19% in the Collagenase group. Grease burns accounted for 10% of the Saline Wet-to-Dry group injuries and 14% in the Collagenase group, while chemical burns represented 8% of the Saline Wet-to-Dry group and 4% of the Collagenase group. There was no statistical difference between the 2 groups with respect to the mechanism of injury (Table 2).

  The major significant finding of this study was that 46 (20.4%) of the 225 patients treated with saline wet-to-dry dressings developed scarring as compared to only 19 (9.2%) of the 207 patients treated with collagenase (Table 3). This difference was statistically significant (p

  Further confirmation that the decreased incidence of hypertrophic scar formation was related to the use of collagenase was obtained by analyzing the operative rates in the Saline Wet-to-Dry and Collagenase groups. If the operative rate was different in these 2 groups, it might have caused a decreased incidence of scarring by eliminating deeper injuries in either group through operation. This data was collected on all patients between the ages of 8 and 70 years with 20% total body surface area burn and no inhalation injury. A total of 407 patients from 1989 to 1992 were identified. Operations consisting of excision and grafting were performed in 136 (33%) of these patients. From 1994 to 1997, 706 patients met the stated criteria. Of these 706 patients, 243 (34%) had excision and grafting performed. No significant difference was found in operative rates between the 2 groups. Therefore, a more aggressive surgical approach was not the explanation for the decreased scarring observed in the Collagenase group.

Discussion

  Collagenase is a metalloproteinase and is specific for native and denatured collagen. In 1994, Soroff and Sasvary1 reported on a group of 15 patients where the use of collagenase ointment plus polymyxin B sulfate/bacitracin spray was compared to silver sulfadiazine cream. The results from this study indicated a significantly shorter time to achieve a clean wound bed with the use of collagenase ointment plus polymyxin B sulfate/bacitracin (p = 0.0012). Also, more rapid healing occurred in the wounds treated with collagenase plus polymyxin B sulfate/bacitracin (p = 0.0007).
In 1995, Hansbrough et al.2 compared the efficacy of collagenase ointment plus polymyxin B sulfate/bacitracin powder to the efficacy of silver sulfadiazine cream in a multicenter trial of 79 patients with partial-thickness wounds. The wounds treated with collagenase debrided to a clean wound bed in significantly less time (p p

  Despite both of these studies showing more rapid debridement as well as a shorter time to wound closure with the use of collagenase, neither of these articles reported anything regarding the final scar result. The present study addressed the scar outcome and found that the scar incidence was lower with the use of collagenase. Indeed, this was a retrospective review, which limited the validity of the conclusion. However, the observation made in this review should serve to prompt a prospective study.

  It is currently accepted that earlier wound closure results in less scarring. Though this is a generally accepted fact, the mechanism of early wound closure that decreases scar formation is unclear. The question remains as to whether the decreased hypertrophic scar is related to an earlier wound closure secondary to a more rapid debridement of the eschar or if it is related to the increased level of collagenase that decreases the rate of collagen production.

  Garner3 hypothesized the lack of an overlying epidermis resulted in excess fibroblast collagen synthesis. To test this hypothesis, human keratinocytes were added to a human fibroblast culture. A significant decrease in fibroblast collagen synthesis was demonstrated. Furthermore, this suppression of collagen synthesis was dose dependent, that is, the greater the percentage of keratinocyte conditioned medium, the greater the suppression of collagen synthesis. The addition of an unconditioned medium did not have any effect. A question remains: was this result simply related to the mere presence of the keratinocytes or were the keratinocytes releasing something, such as collagenase, which in turn decreased the collagen synthesis?

  Laboratory studies by Ghahary et al.4 involved establishing cultures of fibroblasts from both normal skin and hypertrophic tissue. Separate collagenase assays were then performed using both of these fibroblast cultures. Their findings revealed that the amount of mRNA for collagenase was lower in the hypertrophic fibroblasts than in the normal control fibroblasts. This study indicated that the reduced collagenase production and activity contributed to the excessive collagen deposition seen in hypertrophic scar.

  Arakawa et al.5 performed a similar study. Dermal fibroblasts were cultured from hypertrophic scar as well as normal skin. Collagenase assays of the fibroblasts were performed. Their results indicated reduced collagenase gene expression in the hypertrophic scar fibroblasts. These findings were consistent with those of Ghahary et al.4

  The tissue inhibitor of metalloproteinase (TIMP) is known to naturally regulate the action of collagenase and, thus, raises the question as to whether the increased collagen production is related to an increase in TIMP rather than a decrease in actual production of collagenase. Ghahary et al.4 and Arakawa et al.5 discovered similar levels of TIMP mRNA in hypertrophic scar and normal cells. Thus, one would conclude that the increased hypertrophic scar is related to a decrease in the production of collagenase and not an increased inhibition on the existing collagenase.

Conclusion

  Scar formation as a result of burn injury remains a challenge to the burn care professional. Scar in functional areas can result in decreased function and even lead to an inability to perform one’s usual work tasks. Also, hypertrophic scar can leave unacceptable cosmetic results, especially when dealing with the face. The mechanism of scar is not well understood. Independent studies by Ghahary et al.4 and Arakawa et al.5 have indicated that there is a decreased expression of collagenase in hypertrophic scar fibroblasts.

  The clinical study reported here suggests a decreased incidence of hypertrophic scar formation in the partial-thickness burn wound with the application of topical collagenase to the wound. The use of collagenase should be considered for management of the partial-thickness burn wound because of this decrease in hypertrophic scar formation. However, a prospective study is needed to confirm these findings as well as to define a mechanism for the effects of collagenase on scarring.

References

1. Soroff HS, Sasvary DH. Collagenase ointment and polymyxin B sulfate/bacitracin spray versus silver sulfadiazine cream in partial-thickness burns: a pilot study. J Burn Care Rehabil. 1994;15(1):13–17.

2. Hansbrough JF, Achauer B, Dawson J, et al. Wound healing in partial-thickness burn wounds treated with collagenase ointment versus silver sulfadiazine cream. J Burn Care Rehabil. 1995;16(3 Pt 1):241–247.

3. Garner WL. Epidermal regulation of dermal fibroblast activity. Plast Reconstr Surg. 1998;102(1):135–139.

4. Ghahary A, Shen YJ, Nedelec B, Wang R, Scott PG, Tredget EE. Collagenase production is lower in post-burn hypertrophic scar fibroblasts than in normal fibroblasts and is reduced by insulin-like growth factor-1. J Invest Dermatol<.i>. 1996;106(3):476–481.

5. Arakawa M, Hatamochi A, Mori Y, Mori K, Ueki H, Moriguchi T. Reduced collagenase gene expression in fibroblasts from hypertrophic scar tissue. Br J Dermatol. 1996;134(5):863–868.

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