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  1. 1. Scar Quality and Physiologic Barrier Function Restoration After Moist and Moist-Exposed Dressings of Partial-Thickness Wounds BISHARA S. ATIYEH, MD, FACS,n KUSAI A. EL-MUSA, MD,n AND RUWAYDA DHAM, PHDw n Division of Plastic and Reconstructive Surgery, American University of Beirut Medical Center, Beirut, Lebanon, and w Drug Research Center, Dubai, United Arab of Emirates BACKGROUND. There is growing evidence of improved healing of full- and partial-thickness cutaneous wounds in wet and moist environments. Retention of biologic fluids over the wound prevents desiccation of denuded dermis or deeper tissues and allows faster and unimpeded migration of kerati- nocytes over the wound surface. It allows also the naturally occurring cytokines and growth factors to exert their beneficial effect on wound contracture and re-epithelialization. Despite all of these documented benefits, applying the moist healing principles to large surface areas, in particular to large burns, is hindered by the major technical handicap of creating and maintaining a sealed moist environment over these areas. METHODS. From January to September 2001, healing of partial-thickness skin graft donor sites was studied in a prospective comparative study of two types of moist dressings, Tegaderm (3M Health Care, St. Paul, MN), a semipermeable membrane occlusive dressing, and moist exposed burn ointment (MEBO) (Julphar; Gulf Pharmaceutical Industries, United Arab of Emirates), an ointment that can provide a moist environment without the need of an overlying occlusive dressing. Healing was assessed both clinically and with serial measurements of transepidermal water loss (TEWL) and moisture. Following healing, scar quality was evaluated by two members of the team separately using a visual analog scale. Results were statistically analyzed. RESULTS. Faster healing was observed clinically with MEBO application. Physiologic healing as determined by TEWL measurements occurred at an extremely significant earlier stage for MEBO, and this was associated with better scar quality, demonstrating a positive relationship between function and cosmetic appearance. Moreover, the ointment is definitely easier to apply than the occlusive self-adhesive membrane, which requires some degree of dexterity and expertise. CONCLUSION. MEBO application is an effective and valid alternative to conventional occlusive dressings. Moreover, the observed improved anatomic and physiologic healing indicates that MEBO may have a positive effect on healing more that the mere fact of passive moisture retention. B.S. ATIYEH, MD, FACS, K.A. EL-MUSA, AND R. DHAM, PhD HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS. A WOUND is a tissue disruption of normal anatomic structure and function. Wound healing, on the other hand, does not culminate in tissue regeneration but rather in tissue restoration.1 Healing of open cuta- neous wounds involves three processes: epithelializa- tion, connective tissue deposition, and contraction. The contribution of each process varies according to the type of wound.2 Epithelialization is the main healing mechanism of partial-thickness wounds, re- sulting in restoration of the stratified squamous epithelium that protects the body from fluid loss, bacterial invasion, electromagnetic radiation, and general trauma.3 Ever since Winter4–6 proposed his classic hypothesis that the optimum environment for epithelialization is a moist environment, there is more recent evidence in the literature that good hydration is the single most important external factor responsible for optimal wound healing.7–14 Possible mechanisms explaining the observed improved healing include easier migration of epidermal cells over the moist wound surface instead of under a dry scab, increased partial pressure of oxygen, and the preservation of growth factors and proteinases present in fluid exudates that are hence allowed to exert their potentiating effect on wound healing.8 The clot- inducing environment caused by increased precipita- tion of fibrinogen and fibronectin observed under moist conditions helps also in promoting re-epithelia- lization. Moist wound healing is one of the most frequently used but least understood terms in wound care nowadays. Although no reliable operational defini- tions exist of too little or too much wound surface r 2003 by the American Society for Dermatologic Surgery, Inc. Published by Blackwell Publishing, Inc. ISSN: 1076-0512/02/$15.00/0 Dermatol Surg 2003;29:14–20 Address correspondence and reprint requests to: Kusai A. El-Musa, MD, Division of Plastic and Reconstructive Surgery, American University of Beirut, 18th Floor, 850 3rd Avenue, New York, NY 10022, or e-mail: elmusakusai@hotmail.com.
  2. 2. moisture, it is clear that dressings with controlled permeability provide a protective barrier, prevent eschar formation, reduce the dermal necrosis seen in wounds that have been allowed to dry, and signifi- cantly accelerate wound re-epithelialization.15 Healing under both wet and moist environments is significantly faster than under dry conditions. Speed of healing, however, in moist or wet wounds may not be significantly different,16 although in an experimental study, full-thickness wounds of pigs contracted more and healed faster in wet rather than moist or dry environments.8 Some have proposed that the optimum environment would be an intermediate gelatinous environment between moist and dry such as seen under highly vapor-permeable dressings,16,17 and even others have demonstrated accelerated healing of full- thickness skin wounds in a wet environment in contradistinction to a moist environment.8 Irrespective of this apparent controversy, allowing traumatized or ischemic tissues to dehydrate produces further tissue loss by transforming the ‘‘zone of stasis’’ adjacent to the zone of injury into a ‘‘zone of necrosis.’’8,18 Clinical healing of similar wounds during similar time frames follows patterns predicted by dressing moisture retention. This observation suggests that when other variables are held constant, the use of more moisture- retentive dressings generally achieves environments supportive of earlier healing outcomes when compared with less moisture-retentive dressings.15 Enthusiasm generated by these results has been tempered by concerns over tissue maceration and infection after prolonged cutaneous water exposure.5,19 These con- cerns may not be justified. In fact, prolonged exposure of skin to physiologic fluids such as amniotic fluid20 or saline5 does not seem to produce maceration and is not comparable to the conditions encountered in World War I associated with trench foot.5 Anyway, macera- tion may well be an unwelcomed occurrence with moisture-retentive dressing use on highly exuding wounds; however, it is not consistently associated with increased adverse events. Evidence further suggests that greater dressing moisture retention is associated with fewer clinical infections, greater patient comfort, and reduced scarring.15 Although re-epithelialization of partial thickness wounds constitutes anatomic healing and restoration of skin integrity, it does not, however, necessarily mean physiologic healing and recovery of the cutaneous barrier function. It remains to be determined whether earlier physiologic healing affects the final outcome of anatomic healing and scar quality. This question remains unresolved. It has been though well estab- lished that altered cutaneous barrier provides access to infectious organisms and toxins and increases basal metabolic rate and oxygen demand. Moreover, the resultant high water loss leads to poor temperature control and difficulty in fluid balance.21 In a prospective clinical study performed between January and September 2001, healing of partial- thickness skin graft donor sites was evaluated under two different types of moist dressings: Tegaderm (3M Health Care, St. Paul, MN), a semipermeable mem- brane conventional moisture retentive dressing, and moist exposed burn ointment (MEBO; Julphar; Gulf Pharmaceutical industries), a recently described burn ointment providing moist environment for optimal healing without the need of secondary dressing application. Anatomical healing was assessed clini- cally, whereas barrier function recovery was mon- itored by transepidermal water loss (TEWL) measurements by Dermalab 900 (Denmark). Scar quality was evaluated by the visual analog scale for scar assessment described by Beausang et al.22 The purpose of this study was to determine whether the two types of moisture retentive dressings produced comparable anatomic and physiologic healing with good quality scars as speculated and whether MEBO could be a valid alternative in the management of large partial-thickness wounds such as second-degree burns for which the application of currently available occlusive moist dressings is not practical or even associated with a high complication rate. MEBO is a Chinese burn ointment with a U.S. patented formulation since 1995. The active compo- nent of the ointment is -sitosterol in a base of beeswax, sesame oil, and other components. Clinical and experimental studies reported in the Chinese literature have demonstrated that MEBO reduces markedly evaporation from the wound surface.23 It has an inhibitory effect on smooth muscle cells that is dose related24 and has no evident effect on the humoral and cellular immune defense mechanisms.25 Although MEBO does not have any demonstrable in vitro bacteriostatic and bactericidal activity probably be- cause of its oily composition that does not allow proper diffusion in a watery culture medium,26,27 it has been shown that in vivo, it had similar action to 1% silver sulfadiazine in controlling burn wound sepsis and systemic infection with Pseudomonas aeroginosa.28 It has also been demonstrated experi- mentally that MEBO exhibited a statistically signifi- cant wound healing potential on rabbit corneal epithelium as compared with saline, homologous serum, vitamin A, and dexamethasone.29 Moreover, rabbit skin burns healed at a much faster rate with better quality scars when treated with MEBO than similar burns treated with vaseline with demonstrable histologic differences on repeated serial biopsies.30 The ointment produces good analgesia and has a good debriding effect; moreover, it drastically reduces water Dermatol Surg 29:1:January 2003 ATIYEH ET AL.: MOIST AND MOIST-EXPOSED DRESSINGS 15
  3. 3. loss and exudation from the open wound surface. The required frequent application of the ointment is easy and can be performed by the patient or a member of his or her family. The most remarkable practical advantage of MEBO over other types of dressings is that it provides an effective wet environment favorable for optimal wound healing without the need of any covering or occlusive dressing. In some cases, however, particularly when the patient is not confined in bed or at home, a simple covering dressing may be more convenient. In a recent experimental study on pigs31 and another clinical study about the healing of skin graft donor sites,32,33 MEBO has been shown to produce fast re-epithelialization and healing with excellent quality scars. In a recent report, MEBO has been found to be a useful alternative for the treatment of partial-thickness facial burns because of its con- venient method of application that allows easier assessment of healing progression.34 Methods Thirteen adult patients with no underlying medical conditions requiring split-thickness skin grafts to cover open defects accepted to participate in the study; 0.012-in thick skin grafts were harvested uniformly in all patients by the same investigator using the Padget electric dermatome. A total of 20 donor site study fields were available. They were assigned randomly for MEBO (10 fields) or Tegaderm (10 fields) application. In 5 patients, MEBO and Tegaderm could be applied simultaneously on two separate fields, and in one additional patient, three donor fields were available for investigation (Figure 1). The ointment was applied daily in a thick layer after gently removing the previously applied layer with sterile gauze, and the site was covered by a simple semiopen dressing. The Tegaderm layer, on the other hand, was changed whenever indicated, either when excessive fluid has accumulated or fluid leakage has occurred or whenever the membrane has lost its adherent occlusive property. Ointment or Tegaderm application was continued until anatomic healing was observed. Epidemiologic data regarding age, gender, and skin type were recorded. Wound healing by surface re-epithelializa- tion was evaluated qualitatively by clinical assessment and quantitatively by measuring the wound TEWL as an indicator of skin barrier function restoration. Before completion of surface re-epithelialization, TEWL measurements of the MEBO-treated fields were made after wiping gently the ointment, while it was measured over and through the semipermeable mem- brane or directly on the wound surface whenever the Tegaderm membrane needed to be changed. The membrane was not removed intentionally to effect TEWL measurements in order to avoid any unwar- ranted injury to the regenerating epithelium. Following anatomic healing, direct measurement was possible in all study fields. Three readings were made at each recording, the average of which was adopted as the representative measurement. In order to avoid the wide variation in TEWL caused by ambient tempera- ture and humidity, the calculated ratio of wound or subsequent scar TEWL measurement over TEWL of the adjacent normal skin on any given day was adopted for statistical analysis. Because of the rela- tively small number of study fields included in the study, only nonparametric statistical analysis using the Mann–Whitney test was possible. Resultant scar quality was evaluated by two members of the team separately along a visual analog scale.40 Scars with total scores of 5 and 6 were considered to be excellent. Good scars had scores of 7 to 9, fair scars 10 to 14, and poor scars 14 to 18. Total recorded scores as well as scores of each parameter (color, contour, distortion, texture, and aspect) were analyzed independently. Variations over time at 1, 2, and 6 months within each group were analyzed statistically using nonparametric repeated-measures analysis of variance, the Friedman test followed by Dunn’s multiple comparisons test, which compares any two particular time points within a particular Figure 1. Split thickness skin graft (STSG) donor site appearance at Days 0 (A), 3 (B), and 19 (C). 16 ATIYEH ET AL.: MOIST AND MOIST-EXPOSED DRESSINGS Dermatol Surg 29:1:January 2003
  4. 4. treatment group. On the other hand, differences between the two treatment groups at any one particular time point (months 1, 2, or 6) were analyzed statistically using nonparametric test, the Mann– Whitney test, followed by Dunn’s multiple comparison test. Results Because direct biopsy examination is not possible in this clinical study for obvious reasons, anatomic healing was determined by clinical observation. Although definitely not very objective, criteria for healing included the absence of bleeding or exudating points and a shiny congruent epithelial covering sheath. Anatomical healing time for MEBO was 8.972.846 and 13.13472.268 days for Tegaderm. The observed difference between the two study groups was significant (P 5 0.0185). It is worth mentioning that all MEBO-treated areas re-epithelialized unevent- fully, whereas 3 Tegaderm-covered fields developed local wound complications. In one case, extensive granulation tissue developed, necessitating skin graft- ing. Although initially in the first 3 days TEWL values in the MEBO-treated group increased sharply from initial base line values, average TEWL at the time of anatomic healing was 10.58 and 11.93 times greater than normal for MEBO and Tegaderm, respectively. On the other hand, average functional barrier recovery time was 67.4713.368 days for MEBO and 150746.476 days for Tegaderm (Figure 2). The difference between the two groups was extremely significant (P 5 0.0005). Although TEWL measure- ments through an intact Tegaderm membrane in the early stages of the study may not give an accurate reading, this did not have any effect on the validity of the observed results that were manifested long after anatomic healing has occurred at a time were both the ointment and membrane were not in use anymore. This, however, may have yielded falsely lower TEWL values, which explains the observed higher TEWL in the MEBO-treated group as compared with the Tegaderm group during the first week. Although three fields in the Tegaderm group developed local wound complications compared with none in the MEBO group, the difference in complication rate between the two groups was not significant (chi-square test and Fisher’s exact test). Significantly better scar quality was also observed in the MEBO group, as evidenced by photographic documentation and scar assessment scores at 1, 2, and 6 months (Table 1). Total scores of both treatment groups are shown in Table 2. Table 3 demonstrates the significance levels of the observed differences between the two study groups. The difference at 1 month is extremely significant (Po0.001). At 2 and 6 months, it is only significant (Po0.05). On the other hand, a decrease of total scores over time from month 1 to month 6 reflecting scar quality improvement was statistically extremely significant (Po0.001) for MEBO and very significant (Po0.01) for Tegaderm (Table 4). Separate score analysis of the various parameters investigated indicates that contour, texture, and aspect of the MEBO group did not change significantly over time, indicating that for these Table 1. Classification of Scars According to Scar Assessment Scores as E (Excellent), G (Good), F (Fair), and P (Poor) MEBO Tegaderm 1 Month 2 Months 3 Months 1 Month 2 Months 3 Months E 20% 60% 90% 0% 10% 40% G 80% 40% 10% 10% 30% 40% F 0% 0% 0% 80% 50% 10% P 0% 0% 0% 10% 10% 10% Figure 2. Cutaneous functional barrier restoration with Tegaderm and MEBO. Dermatol Surg 29:1:January 2003 ATIYEH ET AL.: MOIST AND MOIST-EXPOSED DRESSINGS 17
  5. 5. parameters the good results were reached at the first month in contradistinction to the Tegaderm group. No significant difference (P40.05) was observed regard- ing distortion between the two groups, although distortion scores tended to improve with time. Changes in color scores with time, on the other hand, were statistically extremely significant (Po0.001) in the MEBO group and were very significant (Po 0.01) in the Tegaderm group. Although both treatment modalities induced a decrease in color counts over time, it seems that MEBO acted faster than Tegaderm as the difference in counts between the two was initially not significant and grew to be significant from month 2 onward. Discussion Wound healing is a complex process to study, especially in humans because the endpoint(s) of wound induction and healing is subjective and therefore difficult to quantitate.35 In studies comparing the effects of various topical preparations as well as the effect of various dressing materials on wound healing, the rate of healing is often judged by clinical observation of re-epithelialization alone. Although it Table 2. Descriptive Statistics of the Two Study Groups (Mean Score7SD at 1, 2, and 6 Months) Mean7SD Month 1 Month 2 Month 6 MEBO (N 5 10) 7.370.949 6.670.843 5.570.707 Tegadermn (N 5 9) 10.471.014 9.0072.062 6.971.691 One patient was excluded from the statistics because of severe complication requiring skin grafting. Table 3. Significance of observed differences between the two groups MEBO Versus Tegaderm Month 1 Month 2 Month 6 Total nnn n n Color NS n n Contour Not possible to analyze data because SD 5 0 Distortion NS NS Identical Texture Not possible to analyze data because SD 5 0 Aspect Not possible to analyze data because SD 5 0 NS, P40.05. n Significant, Po0.05. nn Very significant, Po0.01. nnn Extremely significant, Po0.001. Table 4. Nondescriptive Statistics of the Significance Levels Over Time Within Each Study Group Dunn’s Multiple Comparison Test Month 1 Versus Month 2 Month 2 Versus Month 6 Month 1 Versus Month 6 Friedman test (variations with time) Total MEBO NS n nnn nnn Tegaderm NS NS nn nnn Color MEBO NS n nn nnn Tegaderm NS NS NS nn Contour MEBO NS NS NS NS Tegaderm NS NS n nn Distortion MEBO NS NS NS NS Tegaderm NS NS NS NS Texture MEBO NS NS NS NS Tegaderm NS NS n n Aspect MEBO NS NS NS NS Tegaderm NS NS NS nn NS, P40.05. n Significant, Po0.05. nn Very significant, Po0.01. nnn Extremely significant, Po0.001. 18 ATIYEH ET AL.: MOIST AND MOIST-EXPOSED DRESSINGS Dermatol Surg 29:1:January 2003
  6. 6. constitutes restoration of anatomical integrity of the skin, simple re-epithelialization does not necessarily mean physiologic healing and recovery of the barrier function of the skin. Restoration of cutaneous barrier function unfortunately is a property not routinely assessed.36 Moreover, various noninvasive investiga- tions of skin morphology and function that are standard tools to study the pathophysiology of several cutaneous disorders37 have not been routinely used in the study of wound healing. Biopsies, obviously, constitute a more objective monitoring method to study wound healing namely re-epithelialization, angiogenesis, and characteristics of the epidermal–dermal junction. Their invasive nature, however, precludes their routine application to most human studies. Measuring protein perme- ability across the wound surface can monitor re- epithelialization objectively and reliably. This, how- ever, is possible only during fluid-phase wound treatment with an occlusive chamber.5 Evaporimetry, on the other hand, has been proposed as an alternative noninvasive technique to assess healing. Although TEWL measurements correlate very well with dynamic function testing of the stratum corneum, namely sorption–desorption, moisture accumulation tests,38 and skin capacitance measurements,36 they may not be valid indicators of re-epitheliali- zation, as TEWL values remain elevated for several weeks beyond complete epithelial resurfacing.36 TEWL testing is nevertheless a reliable noninvasive method to evaluate the functional barrier recovery of skin after wounding and subsequent re-epitheliali- zation.38–41 The outermost layer of the skin, the stratum corneum, is the layer that controls the diffusion and penetration of substances and drugs into and through the skin39 and functions as an important barrier to maintain biological homeostasis.42 Surpris- ingly, knowledge of the stratum corneum structure and reaction to the various irritants is still poorly understood. The epidermal lipids, as evidenced by experimental delipidization,43,44 represent mo- rphologically the water permeability barrier. The multilamellar structures formed by intercellular lipids present in the stratum corneum as well as the amount of covalently bound ceramides that are essential for the formation of lamellar structures play an important role in the maintenance of the barrier function.42 In the early 1970s, a major revolution in the management of wounds began. Simple woven absor- bents that kept the wound as dry as possible were superseded by occlusive dressings that provided moist environment for optimal re-epithelialization and wound healing.45 Semipermeable adhesive membrane dressing (Tegaderm) and moist-exposed ointment (MEBO) have been demonstrated to produce a moist environment favorable for re-epithelialization of partial thickness wounds.32,33,46 However, dressings even in the same product category may be asso- ciated with significantly different environments for healing.15 The end point of the healing should not be anatomical healing but rather physiologic functional healing and restoration of barrier function. The ability to modulate epidermal barrier function and integrity relies largely at present on the topical use of protective materials and substances such as oil-in-oil ointments and manipulation of the external environment as practiced in neonatology.47 As understanding of epidermal barrier development advances, perhaps pharmacologic manipulation will become a reality.47 Studies in the rat have shown that epidermal barrier maturation, both structurally and functionally, can be accelerated by the use of antenatal steroids.48 It is suggested by this clinical study that MEBO is pointing in the direction of improved barrier maturation in human subjects in addition to improved scar quality. This warrants further investigation with histologic study of biopsy specimens. Based on this study, healing of partial thickness wounds with the two types of moisture-retentive dressings under investigation was not comparable. Functional healing as expressed by TEWL was significantly much faster for the moist-exposed oint- ment, suggesting a more rapid epithelial maturation and stratum corneum formation in the MEBO-treated areas that cannot be explained only by the mere fact of moisture preservation. It may be due to yet an unexplored positive action of the ointment promoting more rapid maturation of the regenerating keratino- cytes. In that event, the MEBO would be more an interactive type of dressing rather than a simple passive dressing that simply retains moisture. MEBO treatment resulted also in earlier anatomic healing with significantly superior cosmetic appearance of the resultant scars over 6 months of follow-up. The study demonstrates a positive correlation between improved scar quality and early physiologic recovery of barrier function, indicating that better cosmesis and improved function go hand in hand. It is also safe to say that MEBO is a valid substitute to semipermeable occlusive dressings. Acknowledgment The study was presented at the XVI Congress of International Society of Aesthetic Plastic Surgery (May 2002, Istanbul, Turkey), at the European Association of Plastic Surgeons 13th Annual Meeting (May–June 2002, Crete, Greece), and at the 11th Quadrennial Congress of Inter- national Society for Burn Injuries (August 2002, Seattle, WA). Dermatol Surg 29:1:January 2003 ATIYEH ET AL.: MOIST AND MOIST-EXPOSED DRESSINGS 19
  7. 7. We acknowledge the contribution of Maha Al-Farhan, MPhil, MBA, in tabulating the data and performing the statistical analysis. References 1. Cohen KI. The biology of wound healing. Contemp Surg Suppl 2000;4:2–3. 2. Grinnel F. Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol 1994;124:401–4. 3. Winter GD. Epidermal wound healing under a new polyurethane foam dressing (Lyofoam). Plast Reconstr Surg 1975;56:531–7. 4. Winter GD. A note on wound healing under dressings with special reference to perforated-film dressings. J Invest Dermatol 1965;45:299–302. 5. Breuing K, Erikson E, Liu P, Miller DR. Healing of partial thickness porcine skin wounds in a liquid environment. J Surg Res 1992;52:50–8. 6. Winter GD. Epidermal regeneration studied in the domestic pig. In: Maibach HI, Rovee DT, eds. Epidermal Wound Healing. Chicago: Year Book Medical Publishers, 1972:71–112. 7. Chen WYJ, Rogers AA, Lydon MJ. 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Arch Dis Child Fetal Neonatal Ed 2000;83:F112. 20 ATIYEH ET AL.: MOIST AND MOIST-EXPOSED DRESSINGS Dermatol Surg 29:1:January 2003