Post-burn Hypertrophic Scars Research Articles

Intralesional pentoxifylline as an adjuvant treatment for perioral post-burn hypertrophic scars

Pentoxifylline (PTF), a methylxanthine derivative, has therapeutic use as an antifibrotic agent. In vitro, PTF inhibits the production of collagen and reduces the proliferation of fibroblasts in hypertrophic scars. This study aimed to evaluate changes in the elasticity of hypertrophic scars in the peribuccal area in burned patients, who presented with mouth-opening limitation. Eighteen patients were divided into two groups. The case group ( n = 10) was treated with PTF 1 mg ml −1, while in the control group ( n = 8) no treatment was performed. Measurements of mouth opening (lip-to-lip and tooth-to-tooth distances in mm) were taken, before and after five therapeutic sessions with pentoxifylline with weekly intervals. The variations of these measures ( Δ%) were calculated and submitted to statistical analyses. There was a significant improvement in the opening of the mouth, in vermilion distance ( V = 3.20 mm) as much as the dental distance (DD = 4.19 mm) in the treated group, than in the control group. It was noted that pentoxifylline increases the elasticity of hypertrophic scars in the perioral area.

Prosthodontist contribution in treating post-burn hypertrophic facial scars

The formation of hypertrophic scars is common following healing of the burn wound, particularly in children. The face is one of the areas of the body most frequently affected by burns. Scar formation as a result of burn wounds leads to contraction of the formed granulation tissue, which causes both aesthetic and functional impairment for the patient. Scarring has major psychological and physical repercussions. Scarring on the face and visible regions of the body can be very distressing for the patient. Prevention of scars involves early and continuous use of a compressive orthesis. However, their efficacy is often limited to the facial region because of the contours of this area of body. This paper describes a clinical case of post-burn hypertrophic scars treated with silicone gel sheeting applied with pressure under custom made auto-polymerizing resin stent.

Comparison of efficacy of silicone gel, silicone gel sheeting, and topical onion extract including heparin and allantoin for the treatment of postburn hypertrophic scars

We compared the efficacy of silicone gel (Scarfade ®), silicone gel sheet (Epi-Derm™), and topical onion extract including heparin and allantoin (Contractubex ®) for the treatment of hypertrophic scars. Forty-five postburn scars were included in the study. Patients with scars less than 6 months from injury were assigned at random to three groups each containing 15 scars, and their treatment was continued for 6 months. Scars were treated with Scarfade ®, Epiderm™ and Contractubex ®. Scar assessment was performed at the beginning of the treatment, and at the end of the sixth month when the treatment was completed by using the Vancouver scar scale. The difference between before and after treatment scores for each three groups was statistically significant. The difference between Scarfade ® group and Epi-Derm™ group was not significant; however, the differences of the other groups (Scarfade ®-Contractubex ®, Epiderm™-Contractubex ®) were significant. Silicone products, either in gel or sheet, are superior to Contractubex ® in the treatment of the hypertrophic scar. The therapist should select the most appropriate agent according to the patient's need and guidelines of these signs.

Neurophysiological and clinical study of pain in postburn hypertrophic scars

Neurophysiological and clinical study of pain in postburn hypertrophic scars

Pentoxifylline modifies three-dimensional collagen lattice model contraction and expression of collagen types I and III by human fibroblasts derived from post-burn hypertrophic scars and from normal skin

Fibroblasts are thought to be partially responsible for the persisting contractile forces that result in burn contractures. Using a monolayer cell culture and fibroblast populated collagen lattice (FPCL) three-dimensional model we subjected hypertrophic scar and non-cicatricial fibroblasts to the antifibrogenic agent pentoxifylline (PTF – 1 mg/mL) in order to reduce proliferation, collagen types I and III synthesis and model contraction. Fibroblasts were isolated from post-burn hypertrophic scars (HSHF) and non-scarred skin (NHF). Cells were grown in monolayers or incorporated into FPCL's and exposed to PTF. In monolayer, cell number proliferation was reduced (46.35% in HSHF group and 37.73% in NHF group, p < 0.0001). PTF selectively inhibited collagen III synthesis in the HSHF group while inhibition was more evident to type I collagen synthesis in the NHF group. PTF also reduced contraction in both (HSHF and NHF) FPCL.

Prevention and Management of Hypertrophic Scars and Keloids After Burns in Children

Hypertrophic scars and keloids are challenging to manage, particularly as sequelae of burns in children in whom the psychologic burden and skin characteristics differ substantially from adults. Prevention of hypertrophic scars and keloids after burns is currently the best strategy in their management to avoid permanent functional and aesthetical alterations. Several actions can be taken to prevent their occurrence, including parental and children education regarding handling sources of fire and flammable materials, among others. Combination of therapies is the mainstay of current burn scar management, including surgical reconstruction, pressure therapy, silicon gels and sheets, and temporary garments. Other adjuvant therapies such as topical imiquimod, tacrolimus, and retinoids, as well as intralesional corticosteroids, 5-fluorouracil, interferons, and bleomycin, have been used with relative success. Cryosurgery and lasers have also been reported as alternatives. Newer treatments aimed at molecular targets such as cytokines, growth factors, and gene therapy, currently in developing stages, are considered the future of the treatment of postburn hypertrophic scars and keloids in children.

Laser in the treatment of hypertrophic burn scars.

This prospective study looked at the outcome of laser (light amplification by stimulated emission of radiation) treatment for hypertrophic scarring. Dermatrade mark K laser (a set of combined lasers erbium:yttrium aluminium garnet/carbon dioxide, qualified as a class IV laser) was used. Between 21 June 2000 and 19 November 2002, at the Siemianowice Burn Center, Poland, 592 interventions, using laser, were performed on N= 327 patients (220 women and 107 men, aged between 3 and 80 years). The majority of cases [N= 223 (68.9%)] were patients with post-burn hypertrophic scars, and 104 cases (31.8%) had various types of hypertrophic scars. Evaluation took place using an adapted Vancouver Scar Scale and digital photographs as well as the patient's opinion. It was noted that after laser treatment, satisfactory results were achieved in 72% of cases. The scars had become less red (192/327 scored no redness at the end of the study versus 92/327 upon initial), less raised (272/327 scored a flat scar versus 72/327 upon initial) and demonstrated an improved viscoelasticity (192/327 scored a soft skin versus 62/327 upon initial). Laser treatment did not improve contractures in post-burn hypertrophic scars. Results were not confirmed using objective measurement tools, as these were not available to us.

Improvement in Postburn Hypertrophic Scar After Treatment with IFN-α2b Is Associated with Decreased Fibrocytes

Hypertrophic scar (HTS) following thermal injury is a dermal fibroproliferative disorder that leads to considerable morbidity. Previous clinical studies from our laboratory have suggested that interferon-alpha2b (IFN-alpha2b) improves scar quality as a result of suppression of fibroblast functions. Fibrocytes, which constitute a unique cell population, have recently been reported to contribute to wound healing and to a variety of fibrotic conditions, including HTS. Therefore, we hypothesize that improvement of scar in HTS patients after IFN-alpha2b treatment may be associated with a decreased number of fibrocytes or altered fibrocyte function. Using flow cytometry, immunofluorescent staining, and confocal microscopy, we demonstrate here that the marker protein leukocyte-specific protein 1 (LSP1) is stably expressed by fibrocytes for at least 2 months, whereas other potential fibrocyte markers, such as CD34 and CD45, gradually disappear. Using dual staining immunohistochemistry for LSP1 and procollagen, we demonstrated a significant reduction in numbers of fibrocytes in HTS tissue from patients after treatment with systemic IFN-alpha2b. IFN-alpha2b was shown to abolish fibrocyte differentiation from peripheral blood mononuclear cells (PBMCs) in vitro in a dose-dependent fashion. In addition, IFN-alpha2b inhibits proliferation of fibrocytes and T lymphocytes and reduces transforming growth factor-beta (TGF-beta)-mediated alpha-smooth muscle actin (alpha-SMA) expression in fibrocytes. Taken together with our previous study in which we showed that fibrocytes could indirectly regulate dermal fibroblasts in burn patients, the present study suggests that the improvement of scar quality in HTS patients after IFN-alpha2b treatment is associated with decreased numbers and activities of fibrocytes.

Experience with integra in the management of post-burn hypertropic scars and contractures

Development of hypertropic scars, keloids and contractures is a common outcome affecting burn victims. This induces aesthetic and functional problems. The quality of skin cover after burns is a matter of concern to the patient and to the treating surgeon. This article is meant to discuss our clinical experience, using Integra dermal regeneration templates for the treatment of post-burn contractures and hypertropic scars. We also describe our clinical experience in the management of post-burn complications and add some practical points that we learned using this new technique. From July 2003 to December 2004, Integra was used to cover various parts of the body including trunk, limbs, neck and perineum in 12 patients requiring reconstructive surgery. The Integra was used mainly for the treatment of post-burn contractures and hypertrophic scars, resulting in diffuse tightness causing restriction of movements particularly of the joints along with an unacceptable appearance. After the application of Integra, all the post-burn complications recovered remarkably well and the quality of skin improved significantly in texture, feel, pinching and overall appearance. Function was restored completely to the involved joints and appearance improved to acceptable levels in all concerned.

Imbalance between activin A and follistatin drives postburn hypertrophic scar formation in human skin

Hypertrophic scarring is a skin disorder characterized by persistent inflammation and fibrosis that may occur after wounding or thermal injury. Altered production of cytokines and growth factors, such as TGF-beta, play an important role in this process. Activin A, a member of the TGF-beta family, shares the same intra-cellular Smad signalling pathway with TGF-beta, but binds to its own specific transmembrane receptors and to follistatin, a secreted protein that inhibits activin by sequestration. Recent studies provide evidences of a novel role of activin A in inflammatory and repair processes. The aim of this study was to evaluate the importance of activin A and follistatin expression in the different phases of scar evolution. Immunostaining of sections obtained from active phase hypertrophic scars (AHS) revealed the presence of a high number of alpha-SMA(+) myofibroblasts and DC-SIGN(+) dendritic cells coexpressing activin A. Ex-vivo AHS fibroblasts produced more activin and less follistatin than normal skin or remission phase hypertrophic scar (HS) fibroblasts, both in basal conditions and upon TGF-betas stimulation. We demonstrate that fibroblasts do express activin receptors, and that this expression is not affected by TGF-betas. Treatment of HS fibroblasts with activin A induced Akt phosphorylation, promoted cell proliferation, and enhanced alpha-SMA and type I collagen expression. Follistatin reduced proliferation and suppressed activin-induced collagen expression. These results indicate that the activin/follistatin interplay has a role in HS formation and evolution. The impact of these observations on the understanding of wound healing and on the identification of new therapeutic targets is discussed.

Identification of fibrocytes in postburn hypertrophic scar

Fibrocytes are a unique leukocyte subpopulation implicated in wound healing. They are derived from peripheral blood mononuclear cells, display fibroblast-like properties, and synthesize extracellular matrix macromolecules. This study investigated whether fibrocytes are present in healing burn wounds and whether the number of fibrocytes in tissue correlates with the degree of burn injury and the development of hypertrophic scar. Proteins extracted from cultured fibrocytes and nonadherent lymphocytes were found to be similar using two-dimensional gel electrophoresis and quite distinct from those obtained from fibroblasts. However, one protein, identified as leukocyte-specific protein 1 using mass spectrometric peptide mapping, was found in significantly larger amounts in fibrocytes than in lymphocytes but was undetectable in fibroblasts. Double immunostaining with antibodies to leukocyte-specific protein-1 and to the N-terminal propeptide of type I collagen was performed on cryosections of hypertrophic scar, mature scar, and normal skin. Fibrocytes were seen in scar tissue as dual-labeled spindle-shaped cells but were absent from normal skin. Moreover, the number of fibrocytes was higher in hypertrophic than in mature scar tissue. We conclude that fibrocytes, which have been reported to be antigen-presenting cells, are recruited to wounds following extensive burn injury and could potentially upregulate the inflammatory response and synthesize collagen and other matrix macromolecules, thus contributing to the development of hypertrophic scarring.

Gene Expression of Early Hypertrophic Scar Tissue Screened by Means of cDNA Microarrays

Hypertrophic scar is an excessive healing response that often follows thermal injury. The most outstanding morphologic change is the overdeposition of collagen, which is caused by imbalance between synthesis and metabolism of collagen. Previous studies also found that transforming growth factor-beta was the key factor controlling scar formation. However, neither anti-transforming growth factor-beta nor other methods could completely control scar formation and contraction. This fact suggests a multifactorial cause. Fortunately, cDNA microarray throws light on the general alteration at the gene level, and thus could allow us to find some new clues for understanding scar formation and contraction. In this article, we report the results obtained from the scanning of gene expression of hypertrophic scar by means of cDNA microarray. Five cases of early human postburn hypertrophic scars were selected. Total tissue RNA was extracted from each hypertrophic scar sample and the corresponding uninjured region skin tissue; mRNA was further purified by Oligotex and then was reversely transcribed to cDNAs with the incorporation of fluorescent dUTP to prepare the hybridization probes. The mixed probes were hybridized to the cDNA microarray containing 4,096 genes on a type of chemical material-coated glass slide. After high-stringent washing, the hybridized slides were scanned for fluorescent signal detection. Then, the expression and distribution of cytoskeletal genes such as alpha-smooth muscle actin (alpha-SMA) gene; fibroblast tropomyosin TM30(pl) gene; vimentin gene; profilin gene; and BM40 gene of hypertrophic scar at 3, 6, 9, and 12 months age were further quantitatively studied by in situ hybridization or immunohistochemistry. Our data indicated that there were 94 genes overexpressed and 3 genes down-regulated in early postburn hypertrophic scar. These altered genes were related to proto-oncogenes, apoptosis, immune regulatory genes, cytoskeletal elements, metabolism, and so forth. We also found that the detected cytoskeletal gene expression was much more intense at all time points than the control group. Consistent with clinical observation, cytoskeletal genes reached a peak at an early stage and gradually decreased. Our study implied that multiple genes are involved in scar formation and contraction. Interferon is an autosecreted cytokine that might be responsible for self-control of overgrowth of cells in wounds. The early period of hypertrophic scar formation might be a good time for preventing overgrowth and contraction of hypertrophic scar by gene therapy.

ROLE OF PHENERGAN IN ABNORMAL SCARS AND KELOIDS

Hypertrophic scar and keloids have affected patients and frustrated physicians for centuries. Hypertrophic scar (HSc) and keloids are a major problem for patients who survive extensive thermal and traumatic skin injuries. HSc and other fibroproliferative disorders are associated with excessive accumulation of collagen and extracellular matrix proteins due to an imbalance between synthesis and degradation. The therapeutic management of hypertrophic scars and keloids include occlusive dressings, compression therapy, intralesional corticosteroid injections, cryosurgery, excision, radiation therapy, laser therapy, interferon therapy and other promising lesser known therapies directed at collagen synthesis. In this study we investigated the effect of phenergan (promethazine hydrochloride) as one of the most potent histamine antagonists on cell proliferation, DNA synthesis and collagen production in fibroblast isolated from human post burn hypertrophic scar, keloids and normal skin. The proliferation of normal skin fibroblast was slightly decreased but hypertrophic scar and keloids showed significant (p&lt;0.001) level of decrease after 72 hours of phenergan (750 μM) treatment. The results of DNA synthesis also significantly (p&lt;0.001) decreased in hypertrophic scar and keloid fibroblasts. Phenergan (1.5 mM) decreased the collagen synthesis upto 61% and 66% in HSc and keloids in comparison to normal skin fibroblast, which showed reduction of 38% after 72 hours. Improved understanding of such regulatory mechanisms may eventually be of therapeutic significance in the control of hypertrophic scar and keloids.

Analysis of gene expression patterns in human postburn hypertrophic scars.

Hypertrophic scars cause cosmetic disfigurement and limited mobility in burn patients. To better understand the molecular pathophysiology of hypertrophic scar formation, microarray analyses were performed on normal skin and hypertrophic scars from four burn patients. Microarray analyses were determined in an effort to identify genes whose expression discriminated between normal skin and mature, hypertrophic scars. Surgical biopsies were obtained from two pediatric and two adult patients 6 to 15 months after burn injury. Total RNA was isolated from the samples and subjected to microarray analysis using the Affymetrix U95Av2 GeneChip. Results from this analysis revealed 31 probe sets representing genes that were consistently up-regulated at least two-fold in hypertrophic scar specimens from all four patients and four probe sets that were down-regulated. The significance analysis of microarrays algorithm also identified 35 probe sets whose increased expression resulted in the hierarchal clustering of the hypertrophic scar and normal tissue, seven of which were identical to the six genes identified by paired analyses. These six genes all displayed elevated levels of expression in the scar tissue. Proteins encoded by the genes identified included germline oligometric matrix protein, matrix metalloproteinase-16, collagen type 1alpha, pleiotrophin, and thrombospondin-4. Although the results presented here suggest that there may be unique patterns of gene expression in hypertrophic scars that may be important in the evaluation and treatment of hypertrophic scarring, the results must be confirmed with larger datasets.

Microarray Analysis of Gene Expression Patterns in Human Post-Burn Hypertrophic Scars Compared to Normal Skin

Microarray Analysis of Gene Expression Patterns in Human Post-Burn Hypertrophic Scars Compared to Normal Skin

Myofibroblasts and apoptosis in human hypertrophic scars: The effect of interferon-α2b

Background. Hypertrophic scars (HSc) are a dermal fibroproliferative disorder that leads to considerable morbidity. Preliminary evidence suggests that interferon (IFN) may improve HSc clinically. The aims of this study were (1) to compare the cell density in HSc and in wounds that heal without the development of HSc (normotrophic scars), (2) to examine the presence of myofibroblasts and apoptosis in normotrophic and HSc scars over time, and (3) to determine if the systemic administration of IFN-α2b can induce apoptosis. Methods. Two groups of patients underwent serial tissue biopsies. Six burn patients were studied prospectively by obtaining biopsy specimens from wound granulation tissue, normal skin, post-burn HSc, and normotrophic scars (healed donor sites). A second patient group with HSc was treated with systemic IFN-α2b and had biopsy material taken before, during, and after IFN therapy. The tissue was analyzed by immunohistochemical staining for α-smooth muscle actin (α-SMA) and in situ DNA fragmentation terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay for apoptosis. Results. The total numbers of fibroblasts in HSc were found to be similar to granulation tissue and twice that of normal skin and normotrophic scar. Over time the numbers of cells in HSc tissue decreased toward normal skin levels. There was a significantly higher percentage of fibroblasts staining for α-SMA in HSc as compared with normotrophic scar or normal skin obtained from the same patient (P >.05). Serial biopsy specimens of resolving HSc tissue obtained from the patients who received systemic IFN-α2b showed a general reduction in total number of fibroblasts and myofibroblasts associated with a significant increase in the percentage of apoptotic cells compared with normal dermis from the same patient. Conclusions. HSc tissues have greater numbers of fibroblasts and myofibroblasts than normal skin and normotrophic scars. As HSc remodels, the numbers of fibroblasts and myofibroblasts reduces, possibly by the induction of apoptosis. Systemic IFN-α2b may contribute to the resolution of HSc in part by the enhanced induction of apoptosis. (Surgery 2001;130:798-808.)

Collagenase, Type I and Type III Collagen mRNA Expression in Fibroblasts Established from Different Layers of Normal Skin: Comparison with Post-Burn Hypertrophic Scar Fibroblasts

Collagenase, Type I and Type III Collagen mRNA Expression in Fibroblasts Established from Different Layers of Normal Skin: Comparison with Post-Burn Hypertrophic Scar Fibroblasts

Expression and Role of IL-15 in Post-Burn Hypertrophic Scars

Hypertrophic scarring is a skin disorder that occurs after wounding and thermal injury. There is accumulating evidence that immunologic processes such as infiltration of activated T lymphocytes and altered cytokine production may play a role in the formation of hypertrophic scars. Interleukin-15, a cytokine identified as a T cell growth factor, also acts as a chemoattractant for T cells and has pro-inflammatory properties. We investigated the expression and the role of this cytokine in hypertrophic scarring. IL-15 expression was compared in skin biopsies of hypertrophic scars (HS) both in active (AHS) and in remission (RHS) phases, in normotrophic scars (NTS) and in normal skin using reverse transcriptase-polymerase chain reaction and immunohistochemistry. IL-15 expression in HS was significantly higher than in NTS or normal skin. Furthermore, AHS expressed higher levels of IL-15 than RHS. Immunohistologic analysis of AHS samples showed strong IL-15 immunoreactivity in keratinocytes and Langerhans cells in the epidermis and in macrophages, fibroblasts, and dermal dendritic cells in the dermis. High levels of IL-15 expression in AHS correlated with abundant infiltration of activated CD3+ cells. Ex vivo experiments indicate that IL-15 can sustain the proliferative response of T cells derived from AHS but not from RHS and NTS. In addition, IL-15 prevents both cytokine deprivation and activation-induced apoptosis of T cells derived from AHS. Taken together, these results suggest that IL-15 can be involved in the recruitment, proliferation, and apoptosis inhibition of T cells in AHS. The findings that the evolution from an AHS to a RHS is associated with a decrease in IL15 expression, and with a loss of IL-15 responsiveness in ex vivo-cultured T cells, indicate that this cytokine plays an important role in the biology of pathologic scar formation.

Fibroblasts from post-burn hypertrophic scar tissue synthesize less decorin than normal dermal fibroblasts.

1. Fibroblast cultures were established from biopsies of hypertrophic scar and normal dermis taken from nine patients recovering from second- and third-degree burns. The capacity of these fibroblasts to synthesize the small proteoglycan decorin was assessed by quantitative Western blot analysis of conditioned medium collected from confluent cultures. Levels of mRNA for decorin were assessed by quantitative Northern analysis. Since transforming growth factor-beta 1 is implicated in various fibrotic conditions, including post-burn hypertrophic scar, its effect on decorin synthesis by these paired fibroblast cell strains was assessed. 2. Production of decorin was lower in all cell strains of hypertrophic scar fibroblasts tested, compared with normal dermal fibroblasts cultured from the same patients (mean 49 +/- 23%; P < 0.001, n = 9). Levels of mRNA for decorin were also lower (mean 59 +/- 28%; P < 0.02, n = 7) but those for biglycan and versican were not significantly different. Four pairs of cell strains were examined at more than one passage and the differences in decorin protein were found to be phenotypically persistent. Treatment of confluent cultures with transforming growth factor-beta 1 for 3 days caused a reduction in both decorin protein and mRNA in all six strains of hypertrophic scar fibroblasts tested and in five of six strains of normal dermal fibroblasts. An increase in the length of the dermatan sulphate chain on decorin, a previously reported characteristic of this glycosaminoglycan in hypertrophic scar, was seen in all but two of the strains treated with transforming growth factor-beta 1. The depression of decorin synthesis by transforming growth factor-beta 1 was reversed on removal of the agent and passaging the fibroblasts. 3. The reduced capacity of fibroblasts in hypertrophic scar tissue to synthesize decorin may have implications for the development of the condition since this small proteoglycan is involved in tissue organization and may also play a role in modulating the activity in vivo of fibrogenic cytokines such as transforming growth factor-beta 1.

Expression and localization of insulin-like growth factor-1 in normal and post-burn hypertrophic scar tissue in human.

The migration of epithelial cells from dermal appendages toward the wound surface is essential for re-epithelialization of partial thickness burn injuries. This study provides evidence that these cells in vivo synthesize a mitogenic and fibrogenic factor, insulin-like growth factor-1 (IGF-1), which may promote the development of the post-burn fibroproliferative disorder, hypertrophic scarring (HSc). An evaluation of 7 post-burn hypertrophic scars, 7 normal skin samples obtained from the same patients and 4 mature scars revealed that IGF-1 expressing cells from the disrupted sweat glands tend to reform small sweat glands of 4-10 cells/gland in post-burn HSc. The number of these cells increases with time and the glands become larger in mature scar. Other epithelial cells such as those found in sebaceous glands and basal and suprabasal keratinocytes, also express IGF-1 protein and mRNA as detected by Northern and RT-PCR analysis of RNA obtained from whole skin and separated epidermis and dermis. However, cultured keratinocytes did not express mRNA for IGF-1. Histological comparisons between normal and HSc sections show no mature sebaceous glands in dermal fibrotic tissues but the number of IGF-1 producing cells including infiltrated immune cells was markedly higher in the dermis of hypertrophic scar tissues relative to that of the normal control. In these tissues, but not in normal dermis, IGF-1 protein was found associated with the extracellular matrix. By in situ hybridization, IGF-1 mRNA was localized to both epithelial and infiltrated immune cells. Collectively, these findings suggest that in normal skin, fibroblasts have little or no access to diffusible IGF-1 expressed by epithelial cells of the epidermis, sweat and sebaceous glands; while following dermal injury when these structures are disrupted, IGF-1 may contribute to the development of fibrosis through its fibrogenic and mitogenic functions. Reformation of sweat glands during the later stages of healing may, therefore, limit this accessibility, and lead to scar maturation.