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Background: Keloids are benign tumors that occur only in response to injury, for which there is no effective treatment. We demonstrated previously that keloid keratinocytes (KKs) promote fibroblast proliferation more than normal keratinocytes (NKs) and that transforming growth factor (TGF)-beta is a component of that signal. We used the transcriptional response to serum stimulation to examine how TGF-beta expression is stimulated in KKs., Materials and Methods: Quiescent KKs and NKs were stimulated using serum; harvested using RNA at 0, 1, 6, 12, and 24 h; and analyzed using quantitative real-time polymerase chain reaction. TGF-beta activity in the conditioned medium was measured with an MLEC/PAI-luciferase assay. Inhibition of ERK1/2, p38 kinase, and JNK pathways was performed with PD98059, SB203580, and SP600125, respectively., Results: Increased transcription of TGF-beta2 occurs within 1 h of serum stimulation in KKs but not in NKs. In contrast, TGF-beta3 transcription was suppressed in KKs compared with NKs. No significant differences were observed in the transcriptional response of TGF-beta1. Increased TGF-beta2 mRNA correlated with increased TGF-beta biological activity in the conditioned medium. Inhibition of the ERK, p38 kinase or JNK signal transduction pathways blocked the transcriptional up-regulation of TGF-beta2, TbetaR1, and TbetaR2 in KKs., Conclusions: KKs produce more TGF-beta2 mRNA than NKs in response to serum stimulation, resulting in increased TGF-beta activity in conditioned medium. Combining these results with our previous data lead us to propose a model of keloid formation characterized by an exaggerated response to cellular stress and abnormal epithelial-mesenchymal signaling promoting keloid formation.

Keloids, partially considered as benign tumors, represent the most extreme example of cutaneous scarring that uniquely afflicts humans as a pathological response to wound healing. It is characterized by excessive deposition of collagen and other extracellular matrix components by dermal fibroblasts. Upon cutaneous injury, cocktails of chemokines, cytokines and growth factors are secreted temporally and spatially to direct appropriate responses from neutrophils, macrophages, keratinocytes and fibroblasts to facilitate normal wound healing. Signal transducer and activator of transcription 3 (Stat3) is an oncogene and a latent transcription factor activated by various cytokines and growth factors. We investigated the possible role of Stat3 in keloid scar pathogenesis by examining skin tissue and cultured fibroblasts from keloid-scarred patients. We observed enhanced expression and phosphorylation of Stat3 in keloid scar tissue, and in cultured keloid fibroblasts (KFs) in vitro. Increased activation of Janus kinase (Jak)2, but not Jak1, was detected in KFs, and suppression of Jak2 by its inhibitor repressed Stat3 Y705 phosphorylation. Inhibition of Stat3 expression and phosphorylation by short interfering RNA or Cucurbitacin I resulted in the loss of collagen production, impaired proliferation and delayed cell migration in KFs. We show, for the first time, a role of Stat3 in keloid pathogenesis. Inhibitors of Stat3 may be useful therapeutic strategies for the prospective treatment of keloid scars.

Purpose of Review: The precise mechanisms of normal and abnormal scar formation have long remained a mystery despite the extensive literature regarding wound healing. Only recently have researchers begun to delineate the complex biochemical signaling pathways that regulate these processes. This article reviews basic wound healing, while focusing on medicine's latest understanding of the development and treatment of keloids and hypertrophic scars., Recent Findings: The importance of the transforming growth factor-beta signaling pathways and the related downstream effector molecules has proven to offer a new detailed view of scar biology. Regulation of scar metabolism with regards to collagen and wound matrix degradation is likewise showing promise in generating alternate therapies to treat abnormal scars., Summary: Understanding the exact process of normal and abnormal scar formation will help define better ways to successfully manage and potentially prevent abnormal healing like hypertrophic scars and keloids.

Background: Many studies have shown that up-regulation of angiotensin-converting enzyme (ACE) participates in adverse fibrous remodeling. Although this has become an accepted fact in the cardiovascular field, the relationship between ACE and cutaneous fibrous remodeling, such as keloid or hypertrophic scars, remains unknown., Objective: We sought to investigate ACE in normal skin, wounded skin, and pathologic scars., Methods: Ten samples undergoing a normal wound-healing process, 14 samples of pathologic scar tissue, and 15 samples of normal skin were used in this study. Cutaneous tissue ACE activities were measured with high-pressure liquid chromatography. Localization of ACE was assessed by immunohistochemistry., Results: The ACE activity in pathologic scar tissue was significantly higher than in normal and wounded skin. Immunohistochemical studies demonstrated that myofibroblasts were stained with anti-ACE antibody., Limitations: The study is small., Conclusions: These results suggest that up-regulated ACE may participate in cutaneous pathologic scar formation the same as the cardiovascular system.

Background: Keloid management can be difficult and frustrating, and the mechanisms underlying keloid formation are only partially understood., Methods: Using original and current literature in this field, this comprehensive review presents the major concepts of keloid pathogenesis and the treatment options stemming from them., Results: Mechanisms for keloid formation include alterations in growth factors, collagen turnover, tension alignment, and genetic and immunologic contributions. Treatment strategies for keloids include established (e.g., surgery, steroid, radiation) and experimental (e.g., interferon, 5-fluorouracil, retinoid) regimens., Conclusion: The scientific basis and empiric evidence supporting the use of various agents is presented. Combination therapy, using surgical excision followed by intradermal steroid or other adjuvant therapy, currently appears to be the most efficacious and safe current regimen for keloid management.

Keloid and hypertrophic scars are the result of abnormal processes in scar formation. This paper reviews the literature and the many debates concerning the processes that cause abnormal scarring.

Background: Keloids are benign proliferations of fibroblasts, but their exact etiology and molecular pathogenesis are unknown., Materials and Methods: Fibroblasts were isolated from the central and peripheral regions of keloids, and the growth behavior and molecular characteristics of the keloid fibroblasts were compared with those of age-adjusted normal dermal fibroblasts., Results: Central (but not peripheral) keloid fibroblasts exhibited significantly increased growth and high levels of expression of transforming growth factor-beta (TGF-beta) receptor 1 and Smad 2/3., Conclusion: Proliferation of central keloid fibroblasts, which results in keloid formation, appears to mainly involve the TGF-beta/Smad pathway.

Objective: To disclose whether there is difference in nerve regeneration between human hypertrophic scars and keloids after deep burns so as to provide a basis for new clinical treatment., Methods: Fifty-seven samples that were clinically and pathologically diagnosed as hypertrophic scars or keloids after deep burns were examined by use of two-label immunohistochemistry to define the nerves in scars. Then, the Mean Integrated Optical Density (MIOD) of S-100 and the MIOD of neurofilament (NF) proteins were measured and analyzed., Results: In hypertrophic scars or keloids, the nerve regeneration was growing gradually. The speed was high 3-5 months after burn and it slowed down 18 months after burn. The expression of S-100 and NF varied with different period of time (P<0.05). The expression of S-100 and NF in hypertrophic scars was higher than that in keloids. There was no difference 3-5 months after burn, but there was difference 6 months after burn., Conclusion: S-100 and NF are good markers to define the nerve regeneration in scars. The nerve regeneration in hypertrophic scars or keloids changes with the times. The nerve regeneration is more conspicuous in hypertrophic scars than in keloids.

Keloids are tumor-like lesions that result from excessive scar formation during healing of wounds. Histologically, keloids show an increased blood vessel density compared with normal dermis or normal scars. However, the angiogenic activity of keloid fibroblasts remains unknown. In this study, we investigated angiogenic activity of keloid fibroblasts. Transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) were investigated as elements of the angiogenic factors. Expressions of TGF-beta1 and VEGF in conditioned medium were measured with enzyme-linked immunosorbent assay (EIA) and Northern blot analysis. Participation of TGF-beta1 in the production of VEGF was also investigated with addition of TGF-beta1 and a neutralizing anti-TGF-beta1 antibody. A modified Boyden chamber assay was performed to assess the chemotactic activity of vascular endothelial cells. Angiogenic activity in vivo was evaluated by neovascularization of nodules formed by implantation of fibroblasts into severe combined immunodeficiency (SCID) mice. EIA showed that the concentrations of TGF-beta1 and VEGF in conditioned medium were increased 2.5- and 6-fold, respectively, after the culture of keloid fibroblasts compared with normal fibroblasts. Northern blot analysis revealed that the expression of TGF-beta1 and VEGF mRNA was upregulated 3.6- and 6-fold, respectively, in keloid fibroblasts compared with normal fibroblasts. Addition of TGF-beta1 to keloid fibroblast cultures increased VEGF production by 3.5-fold, while there was a 6-fold in culture of normal fibroblasts. A neutralizing anti-TGF-beta1 antibody reduced VEGF secretion to control levels, suggesting that TGF-beta1 mediated the upregulation of VEGF expression. A modified Boyden chamber assay demonstrated that the chemotactic activity of vascular endothelial cells was more strongly (sevenfold) induced by keloid fibroblast-conditioned medium than by normal fibroblast-conditioned medium. Anti-VEGF antibody inhibited chemotaxis to basal levels. When SCID mice underwent implantation of fibroblasts into the back, the nodules formed by keloid fibroblasts were three times larger than those formed by normal fibroblasts. Although abundant neovascularization was observed in keloid fibroblast nodules, neovascularization was scarce in normal fibroblast nodules. Both in vitro and in vivo studies confirmed the significantly higher angiogenic activity of keloid fibroblasts compared with normal fibroblasts, and TGF-beta1 and VEGF were clearly shown to be involved. These results suggest that angiogenesis in keloids is promoted by endogenous TGF-beta1 and VEGF.

Keloid and hypertrophic scars are 2 types of excessive scarring observed clinically that require different therapeutic approaches. The clinical course and physical appearance define keloids and hypertrophic scars as separate entities; however, they are often confused because of an apparent lack of morphologic differences. Nevertheless, clinical differences between hypertrophic scars and keloids have long been recognized by plastic surgeons and dermatologists. Yet, translating these differences into morphologic or biochemical distinctions has prompted much conflict in the literature. The present report is an attempt to clarify the longstanding controversy regarding these 2 similar yet separate and nonidentical entities by highlighting the reported points of differentiation as well as the similarities.

Not all scars are the same. They vary from normal skin scars to distinct types of abnormal scars, such as hypertrophic and disfiguring keloids. Physicians need to identify different types of skin scars and treat them appropriately. Misdiagnosis and mismanagement of scars can be costly for both the patient and physician. Patients with scars often face aesthetic, physical, psychological, and social consequences that result in substantial emotional and financial costs. This article reviews the spectrum of abnormal scar types and problems associated with scarring.

Keloid is a dermal fibroproliferative lesion of unknown etiology that commonly recurs after surgical excision. Post-operative adjuvant electron beam (EB) irradiation has been successfully used to reduce keloid recurrences. To provide new insights into the molecular mechanism behind the effect of EB irradiation, we used a cDNA microarray screening of more than 5000 genes to assess early changes in gene expression between EB-irradiated and non-irradiated keloid and non-lesional dermal fibroblasts. Primary fibroblast cultures from keloid and associated non-lesional dermis obtained from five patients were exposed to 15 Gy EB irradiation and analyzed after 15 min incubation. Early response to EB irradiation showed that 96 (1.8%) genes were modulated 2-fold or more in keloid fibroblasts. Upregulated genes accounted for 29.2% (28 genes), whereas downregulated genes comprised 70.8% (68 genes), indicating a silencing of many genes in keloid fibroblasts after EB irradiation. Many of the downregulated genes play roles in the enhancement of cell proliferation and extracellular matrix production, whereas several of the upregulated genes involves in the promotion of apoptosis and extracellular matrix (ECM) degradation. Using emerging bioinformatic tools and further corroboration, the interleukin 6 (IL-6) signaling pathway was found to be mainly involved in EB irradiation response. We also showed co-expression of IL-6 and its specific receptor (IL-6Ralpha) in keloid fibroblasts that points to the existence of an IL-6 autocrine loop in these cells. These results suggested that at the molecular level, EB irradiation might hinder keloid formation by regularizing disturbances in the homeostatic equilibrium between inducer and inhibitor activities in the matrix system most likely through the IL-6 pathway. Our study provides clues for the molecular mechanism(s) behind the beneficial effect of EB irradiation in reducing keloid recurrences and may help develop alternative strategies for the therapy and prophylaxis of this lesion.

This article examines the formation of abnormal scars and describes how the different types can be treated. Psychological issues may result from scarring. The authors discuss how nurses can help patients to come to terms with altered body image.

Background: Keloid scars can itch and hurt, but little is known about the characteristics of these symptoms in keloids. Because itch and pain are carried by small nerve fibers, abnormal function of these fibers could be an explanation for such phenomena., Objective: We sought to assess the characteristics of itch and pain in keloid scars, and to assess the function of small nerve fibers in keloids., Methods: We studied the location and intensity of itch and pain in keloids that had been present for at least 1 year. We further studied the function of small nerve fibers by assessing allodynia and alloknesis (which are pain and itch, respectively) from innocuous stimuli that do not normally provoke pain and itch, and we used quantitative thermosensory testing (in keloid lesions, perikeloidal skin, and contralateral normal skin as a control). Results In all, 28 patients (13 men and 15 women) with a mean age of 34 years were enrolled and completed the study. Of the patients, 86% experienced itch and 46% experienced keloid-related pain. Of those who experienced itch, 92% felt the itch at the edge of their keloids. Of the patients with pain, 77% felt pain at the center of the keloid. Mechanical allodynia was noted in 43% of the patients, and only 14% experienced alloknesis. Abnormal thermosensory thresholds to warmth, cold, and heat pain were noted in the keloids. Visual analogue scale of itch correlated significantly to warmth ( r = 0.65), heat pain ( r = 0.4), and cold pain ( r = -0.41)., Conclusion: Itch and pain are common presentations in keloids and are associated with abnormalities in small nerve fiber function, suggesting a small nerve fiber neuropathy.

Background: Keloids are characterized by abnormal proliferation and overproduction of extracellular matrix. Quercetin, a dietary compound, has strong antioxidant and anticancer properties. Previous studies by the authors have shown that quercetin inhibits fibroblast proliferation, collagen production, and contraction of keloid and hypertrophic scar-derived fibroblasts. Quercetin also blocks the signal transduction of insulin-like growth factor-1 in keloid fibroblasts. This study assessed the effects of quercetin on the transforming growth factor (TGF)-beta/Smad-signaling pathway in keloid-derived fibroblasts, which may be an important biologic mechanism of this proliferative scarring., Methods: Keloid fibroblasts were isolated from keloid tissue specimens. Cells were treated with quercetin at different concentrations, then harvested, and subjected to immunoblotting analysis., Results: Quercetin significantly inhibited the expression of TGF-beta receptors 1 and 2 in keloid fibroblasts at three concentrations (low, medium, and high). Quercetin also strongly suppressed the basal expression of Smad2, Smad3, and Smad4 as well as the phosphorylation of Smad2 and Smad3 and the formation of the Smad2-Smad3-Smad4 complex., Conclusions: Taken together, these data suggest that quercetin effectively blocks the TGF-beta/Smad-signaling pathway in keloid fibroblasts. These data indicate that quercetin-based therapies for keloids should be investigated further.

Keloids are defined as excessive scar tissue formation extending beyond the area of the original skin injury and occurring in predisposed individuals. They are considered to be a result of abnormal wound healing. The pathogenetic mechanisms that cause keloids remain unknown. Experiments with cells derived from keloid tissue revealed a number of abnormalities in cellular functions, such as in proliferation, apoptosis, or expression of growth factors and extracellular matrix proteins. Furthermore, several studies have reported altered keratinocyte-fibroblast interactions in keloids. Despite the diverse pathological changes in cellular functions and expression profiles of cells derived from keloid tissue, recent genetic studies have provided evidence that single genes may act as major regulators of keloid formation. We provide an overview of the pathogenetic mechanisms of keloid formation in the context of their clinical characteristics and current therapeutic approaches.

Keloids are proliferative dermal growths representing a pathologic wound healing response. We have previously demonstrated that coculture of fibroblasts derived from either keloid or normal skin have an elevated proliferation rate when cocultured with keloid-derived keratinocytes vs. normal keratinocytes. In these studies, we examined the contribution of transforming growth factor-beta (TGF-beta) to this phenomenon using a two-chamber coculture system. Fibroblast proliferation in coculture was slower with the addition of a pan-TGF-beta neutralizing antibody. Keloid keratinocytes in coculture expressed more TGF-beta1, -beta3, and TGF-beta receptor 1 than normal keratinocytes. Keloid fibroblasts cocultured with keloid keratinocytes expressed more mRNA for TGF-beta1, -beta2, TGF-beta receptor 1, and Smad2. Keloid fibroblasts also produced more type I collagen, connective tissue growth factor, and insulin-like growth factor-II/mannose-6-phosphate receptor when cocultured with keloid keratinocytes vs. normal keratinocytes. Levels of total and activated TGF-beta activity increased when fibroblasts were cocultured with keratinocytes, correlating with the changes in transcriptional activity of TGF-beta. In conclusion, we find a complex paracrine interaction regulates TGF-beta mRNA expression and activation between keratinocytes and fibroblasts. These data suggest that keloid pathogenesis may result from both an increased TGF-beta production and activation by the keloid keratinocyte, and elevated TGF-beta expression, utilization, and signaling in keloid fibroblasts.

Keloids are characterized as an "over-exuberant" healing response resulting in a disproportionate extracellular matrix (ECM) accumulation and tissue fibrosis. In view of the integral role of inflammation and cytokines in the healing response, it is logical to assume that they may play a part in orchestrating the pathology of this "abnormal" healing process. Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine involved in activation of signaling events and transcriptional programs, such as NFkappaB. This study attempts to determine the difference in NFkappaB and its related genes expression and DNA binding activity between keloid and normal skin fibroblasts. Three keloid and normal skin tissues (NSk) and their derived fibroblasts were used to determine NFkappaB signaling pathway expression using specific cDNA microarrays, Western blot analysis and immunohistochemistry. Electrophoretic mobility gel shift assay (EMSA) was used to assess NFkappaB-binding activity, all assays were performed in the presence and absence of TNF-alpha. TNF-alpha up-regulated 15% of NFkappaB signal pathway related genes in keloid fibroblast compared to normal skin. At the protein level, keloid fibroblasts and tissues showed higher basal levels of TNF- receptor-associated factors-TRAF1, TRAF2-TNF-alpha, inhibitor of apoptosis (c-IAP-1), and NFkappaB, compared with NSk. Keloid fibroblasts showed a constitutive increase in NFkappaB-binding activity in comparison to NSk both with and without TNF-alpha treatment. NFkappaB and its targeted genes, especially the antiapoptotic genes, could play a role in keloid pathogenesis; targeting NFkappaB could help in developing therapeutic interventions for the treatment of keloid scarring.

Background: Keloids and hypertrophic scars result from aberrant wound healing and remain a potential complication of any surgical procedure or trauma. Investigation of aberrant wound healing has been limited to the study of growth factors, collagen precursors, and DNA synthesis in simple in vitro systems, which necessitate removal or destruction of cells or factors in the growth environment of cell cultures. Multiphoton microscopy (MPM) can use endogenous chromophores such as collagen and nicotinamide adenine dinucleotide hydrogenase to produce thin optical sections of thick living tissues without the use of dyes or stains. Endogenous second-harmonic-generation (SHG) signals in collagen can be collected to form an MPM image., Objective: To present a novel wound-healing model used to investigate keloid-derived fibroblast activity and collagen production in the same intact tissue-engineered construct over time., Methods: Artificial tissue constructs called RAFTs (produced by suspension of keloid or normal dermal fibroblasts in type I collagen gel with an overlying keratinocyte layer) were cultured at air-fluid interface. Multiphoton microscopy SHG images of collagen in the intact tissue constructs consisting of normal or keloid-derived fibroblasts were obtained. The constructs were then incised with a scalpel. Serial MPM and phase-contrast microscopy images were obtained to monitor changes in the extracellular matrix in response to wounding of the artificial skin construct over 8 days., Results: The tissue-engineered constructs formed a bilayer resembling the dermis and epidermis of human skin. Phase-contrast microscopy revealed migration of keratinocytes into the defect created by scalpel wounding. The constructs were found to contract with time after wounding. The MPM SHG images showed collagen deposition in the tissue constructs after wounding. Tissue constructs with keloid-derived fibroblasts were found to deposit collagen at a higher rate than those with normal fibroblasts., Conclusions: The MPM model described herein permits serial observation of the same intact specimens without the need for fixation or cytotoxic stains. Furthermore, it demonstrates the biologic activity of RAFT artificial tissue constructs.

Oxygen reaches the skin from the blood as well as from the atmosphere. The diffusion gradient is a key factor in oxygen delivery. Measurements with puncture electrodes show a maximum oxygen partial pressure on the skin surface and a minimum in the deeper dermis. Non-invasive measures show that oxygen uptake depends on location. Assuming the oxygen consumption is 0.276+/-0.029 ml O(2).100 g(-1).min(-1) (37 degrees) and no oxygen is removed by capillaries, then the skin can be supplied by atmospheric oxygen to a depth of 0.25 to 0.40 mm, well into the dermis. Only the deeper dermis receives oxygen from the blood. The stratum corneum is a significant barrier to diffusion from the atmosphere. When this barrier is damaged, the oxygen diffusion increases Keratinocytes in culture proliferate in response to increased oxygen pressure; the same mechanism may explain epidermal hyperplasia following stratum corneum damage in vivo.

Today, wound management to avoid excessive scar formation is increasingly important, especially in populations with Fitzpatrick 3 or higher skin pigmentation. Medical science and industrial development are devoting more effort toward understanding and offering better therapy to control scars. However, advances in scar management have been hampered by the confusing or ambiguous terminology. There is no consensus on what amount of post-traumatic skin scar formation is "normal" and what should be considered "hypertrophic". In the World Health Organization's ICD-9, there is no diagnostic code for hypertrophic scar--only keloid is listed. Yet, the medical and scientific literature distinguishes them as different conditions. Our experience suggests that the diagnosis of keloid disease is greatly over-rendered. For black patients, an elevated scar seems, by default, diagnosed as keloid by most. This confusion results in inappropriate management of scar formation, and occasionally contributes to decision making related to elective or cosmetic surgery. Given that patients are expecting better outcomes from wound care today than in the past, this review article attempts to capture the essential biological factors related to wound scar production and discusses treatment options and indications used by the authors.

Surgical researchers were among the first to describe the different phases of wound healing and the events in tissue repair and regeneration that were taking place during each phase. The understanding of these events has been significantly enhanced in recent years by modern techniques in molecular and cellular biology. In this article, we discuss new findings in scarless fetal repair, angiogenesis in wound healing, and keloid pathogenesis. This serves to highlight the advances that have been made and also how much remains to be understood.

Keloids are proliferative dermal growths representing a pathological wound-healing response. We report high proliferation rates in normal (NF) and keloid-derived fibroblasts (KF) cocultured with keloid-derived keratinocytes (KK). IGF binding protein (IGFBP)-3 mRNA and secreted IGFBP-3 in conditioned media were increased in NF cocultured with KK compared with NF but markedly reduced in KF cocultured with KK or normal keratinocytes (NK). IGFBP-2 and IGFBP-4 mRNA levels were elevated, whereas IGFBP-5 mRNA was decreased in KF cocultured with KK or NK. Significant increases in IGFBP-2 and -4 mRNA in KF cocultured with KK did not correlate with protein secretion. Downstream IGF signaling cascade components, phospho-Raf, phospho-MEK1/2, phospho-MAPK, PI-3 kinase, phospho-Akt, and phospho-Elk-1, were elevated in KF cocultured with KK. Addition of recombinant human IGFBP-3 or antibodies against IGF-I or IGF-IR significantly inhibited proliferation of KF. The bioavailability of IGF-I may be related to the levels of IGFBP-3 produced, which in turn influences KF proliferation, suggesting that modulation of IGF-I, IGF-IR, and IGFBP-3, individually or in combination, may represent novel approaches to the treatment of keloids.

Keloid and hypertrophic scars have affected patients and frustrated physicians for centuries. Keloid and hypertrophic scars result from excessive collagen deposition, the cause of which remains elusive. Clinically, these scars can be disfiguring functionally, aesthetically, or both. A thorough understanding of the pathophysiology and clinical nature of the scar can help define the most appropriate treatment strategy. Although many articles have been published on the management of hypertrophic and keloid scars, there is no universally accepted treatment protocol. Prevention of keloid and hypertrophic scars remains the best strategy; therefore, those patients with a predisposition to develop excessive scar formation should avoid nonessential surgery. Once a scar is present, there are many treatments from which to choose. Hypertrophic scars and keloids have been shown to respond to radiation, pressure therapy, cryotherapy, intralesional injections of corticosteroid, interferon and fluorouracil, topical silicone or other dressings, and pulsed-dye laser treatment. Simple surgical excision is usually followed by recurrence unless adjunct therapies are employed. Biologic agents that are directed towards the aberrant collagen proliferation that characterizes keloid and hypertrophic scars might be an important addition to the current armamentarium of modalities in the near future.

Fibroproliferative scars remain an ongoing clinical challenge. Both hypertrophic scars and keloids require multimodal therapy toachieve partally successful treatment. At the present time incomplete understanding about the pathogenesis of fibroproliferative scars makes targeted, mechanistic treatment impossible. As understanding of these abnormal wound problems increases, more effective treatments will likely be available. Until that time, clinicians must utilize existing knowledge to treat patients while continuing to experiment with new approaches.

Background: Wounds in the nonglabrous skin of keloid-prone individuals tend to cause large disordered accumulations of collagen which extend beyond the original margins of the wound. In addition to abnormalities in keloid fibroblasts, comparison of dermal fibroblasts derived from nonwounded glabrous or nonglabrous skin revealed differences that may account for the observed location of keloids., Methods: Fibroblast apoptosis and the cellular content of alpha-smooth-muscle actin, TGFbeta1 receptorII and ED-A fibronectin were estimated by FACS analysis. The effects of TGFbeta1 and serum were examined., Results: In monolayer cultures non-glabrous fibroblasts were slower growing, had higher granularity and accumulated more alpha-smooth-muscle actin than fibroblasts from glabrous tissues. Keloid fibroblasts had the highest level of alpha-smooth-muscle actin in parallel with their expression level of ED-A fibronectin. TGFbeta1 positively regulated alpha-smooth-muscle actin expression in all fibroblast cultures, although its effects on apoptosis in fibroblasts from glabrous and non-glabrous tissues were found to differ. The presence of collagen I in the ECM resulted in reduction of alpha-smooth-muscle actin. A considerable percentage of the apoptotic fibroblasts in attached gels were alpha-smooth-muscle actin positive. The extent of apoptosis correlated positively with increased cell and matrix relaxation. TGFbeta1 was unable to overcome this apoptotic effect of matrix relaxation., Conclusion: The presence of myofibroblasts and the apoptosis level can be regulated by both TGFbeta1 and by the extracellular matrix. However, reduction of tension in the matrix is the critical determinant. This predicts that the tension in the wound bed determines the type of scar at different body sites.

Mast cell(MC) takes an important role in trauma and the process of wound healing, and the pathophysiology reaction has a relationship to the time since trauma, which is helpful to determine the post-trauma and postmortem interval, and to distinguish the wound shaped whether before or after death. In this paper, the role of MC and its chemic medium in the process of wound healing, scar shaping, postburns inflammatory response, healing of bone fracture, as well as the signification for forensic medicine and the progress of researching in this field were reviewed.

Both transepidermal water loss (TEWL) and skin surface high-frequency conductance are functions of the skin barrier. Systemic sclerosis (SSc) and hypertrophic scar (HS)/keloid are characterized by abnormal fibrotic changes in the dermis. Since the close interrelationship between the epidermis and the dermis has been well established, we analyzed the stratum corneum functions of forearm skin in 39 SSc patients after assessing the degree of the skin thickening and compared those functions with 10 age-matched normal controls. We also analyzed the stratum corneum functions of HS or keloid lesions in seven patients using the same methods, and compared those functions to adjacent or contralateral normal skin in identical patients. Neither the TEWL, nor high-frequency conductance of forearm skin in SSc patients were significantly different from those in normal controls. There was no correlation between the levels of TEWL or high-frequency conductance and the degree of skin thickening in SSc. In HS or keloid conditions, high-frequency conductance was significantly elevated (42.5+/-8.9 vs. 26.4+/-5.7, P<0.001). Although TEWL was elevated, there was no statistical significance (48.6+/-39.7 vs. 25.1+/-10.1). Our results revealed that stratum corneum functions are distinct between SSc and HS or keloid. This may reflect the various natures of dermal changes, which in turn differentiate the functions of the stratum corneum in the diseases.

Keloidal scars are abnormal scars of uncertain etiology with a predilection for certain racial groups. Although many articles have been published on the management of these scars, there are no definitive treatment protocols. Our objective was to examine the scientific quality of the literature on therapy for keloidal scars. There are many problems with the study designs of existing keloidal scar research. These include lack of consistent disease definitions and outcome measures, inadequate follow-up, and inconsistent therapeutic interventions. Suggestions are given for future studies.

Recent studies have suggested that the regulation of apoptosis during wound healing is important in scar establishment and the development of pathological scarring. In this study, we demonstrate that keloid fibroblasts can be identified as apoptotic cells because of their highly condensed chromatin and discrete nuclear fragments. To further reveal the phenomenon of apoptosis, we quantified the number of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in surgically resected tissues of keloids (N = 10), hypertrophic scars (N = 10), normal healed flat scars (N = 10), and dermatofibroma (N = 10). The number of TUNEL-positive cells was relatively low, but was significantly higher for the keloid group compared with the normally healed flat scar group (p = 0.004), suggesting reduced cell survival and increased apoptotic cell death in a subpopulation of keloid fibroblasts. Furthermore, the number of TUNEL-positive cells was significantly higher for the keloid group compared with the dermatofibroma group (p = 0.044), suggesting that a subpopulation of keloid fibroblasts may suppress tumorgenicity at a greater rate than dermatofibroma by undergoing cell death. Hypertrophic scars had significantly higher levels of apoptosis than normally healed flat scars (p = 0.033). Therefore, these results suggest that selected fibroblasts in keloids and hypertrophic scars undergo apoptosis, which may play a role in the process of pathological scarring.

Keloid and hypertrophic scars are a type of scarring pathology which is characterised by excess collagen deposition produced during the wound healing process. The mechanism by which this occurs is not understood and although hypertrophic scars can regress spontaneously, keloids do not, and currently no effective treatment exists. In this paper we hypothesise that nitric oxide, a free radical molecule synthesised by numerous mammalian cells, is involved in the formation of these scars. We suggest that the excess collagen production in keloid lesions can be attributed to higher than normal levels of nitric oxide, as the free radical is a known stimulus for fibroblast collagen synthesis. Furthermore, we propose that the basal epidermis is a source of this additional nitric oxide and we discuss this in relation to known histological characteristics of keloid and hypertrophic lesions., (Copyright 2001 Harcourt Publishers Ltd.)

Keloids are disfiguring, proliferative scars that represent a pathological response to cutaneous injury. The overabundant extracellular matrix formation, largely from collagen deposition, is characteristic of these lesions and has led to investigations into the role of the fibroblast in its pathogenesis. Curiously, the role of the epidermis in extracellular matrix collagen deposition of normal skin has been established, but a similar hypothesis in keloids has not been investigated. The aim of this study was to investigate the influence of keloid epithelial keratinocytes on the growth and proliferation of normal fibroblasts in an in vitro serum-free co-culture system. A permeable membrane separated two chambers; the upper chamber contained a fully differentiated stratified epithelium derived from the skin of excised earlobe keloid specimens, whereas the lower chamber contained a monolayer of normal or keloid fibroblasts. Both cell types were nourished by serum-free medium from the lower chamber. Epithelial keratinocytes from five separate earlobe keloid specimens were investigated. Four sets of quadruplicates were performed for each specimen co-cultured with normal fibroblasts or keloid-derived fibroblasts. Controls consisted of (1) normal keratinocytes co-cultured with normal fibroblasts, and (2) fibroblasts grown in serum-free media in the absence of keratinocytes in the upper chamber. Fibroblasts were indirectly quantified by 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay, with results confirmed by DNA content measurement, at days 1 and 5 after the co- culture initiation.Significantly, increased proliferation was seen in fibroblasts co-cultured with keloid keratinocytes, as compared with the normal keratinocyte controls at day 5 (analysis of variance, p < 0.001). These results strongly suggest that the overlying epidermal keratinocytes of the keloid may have an important, previously unappreciated role in keloid pathogenesis using paracrine or epithelial-mesenchymal signaling.

Sucrose has been used to treat wounds with excellent results and with minimal abnormal scarring. In this study the effects of sucrose on collagen metabolism in fibroblast culture was evaluated. Sucrose (5.5, 15, or 25 mM) was added to granulation tissue, hypertrophic scar, and keloid fibroblast cultures, mRNA levels and procollagen aminopropeptides for type I and III collagens in cell culture medium were studied. Sucrose decreased mRNA levels for pro alpha 1(I) and pro alpha 1(III) collagens in fibroblast cultures derived from hypertrophic scar and keloid. In normal granulation tissue fibroblast cultures, 5.5 mM sucrose increased mRNA levels for pro alpha 1(I) and pro alpha 1(III) collagen, and higher concentrations decreased them. The synthesis of type I collagen decreased dose-dependently in all cell strains, whereas the synthesis of type III collagen decreased only in granulation tissue fibroblasts. To conclude, in vitro high concentrations of sucrose down-regulate both collagen gene expression and synthesis in normal granulation tissue fibroblasts, whereas in fibroblasts derived from abnormal scar sucrose down-regulates only type I collagen gene expression and synthesis, changing the pattern of collagen metabolism toward normal.

Excessive scarring caused by pathologically overabundant collagen deposition is a problem known by all surgeons. Complications to wound healing, such as hypertrophic scars and keloids, can lead to an aesthetically unacceptable result or even lead to anatomic dysfunction. An overwhelming amount of hypotheses concerning treatment of these problems is available. There seems to be no absolutely effective treatment for hypertrophic scars and keloids and the number of treatment modalities illustrate the lack of understanding concerning this kind of pathologic scar healing. Most studies reported have not been well controlled and have produced conflicting results.

With recent progress in stem cell-based research, there has been tremendous interest in stem cell-based tissue regeneration. Stem cells can be differentiated into specialized cells/tissues by growth factors and cytokines. These small molecules are thought to play an important role in both wound healing and tissue regeneration. However, their biological activity and signal transduction during tissue regeneration are poorly understood. With recent advances in signal transduction by growth factors, the receptor kinases and G protein-coupled receptors, an understanding in the underlying mechanism of how these factors regulate tissue regeneration beginning to take place. In this review, the potential underlying mechanisms of growth factor signaling in normal tissue regeneration and chronic wound healing is discussed. Thus, it is an aim to provide a basis for designing more specific therapies for tissue regeneration in the near future.

The pathogenesis of keloid remains poorly understood. As no effective therapy for keloid is as yet available, an insight into its pathogenesis may lead to novel approaches. Apoptosis has been found to mediate the decrease in cellularity during the transition between granulation tissue and scar. Here, we report that in contrast to hypertrophic scar-derived and normal skin-derived fibroblasts, keloid-derived fibroblasts are significantly resistant to both Fas-mediated and staurosporine-induced apoptosis. The caspases-3, -8, and -9 were not activated indicating that the block in the apoptotic pathway in keloid is upstream of the caspases. There were no significant differences in the level of expression of Fas, Bcl-2, and Bax between the three groups but addition of transforming growth factor (TGF)-beta1 significantly inhibited Fas-mediated apoptosis in hypertrophic scar-derived and normal skin-derived fibroblasts and neutralization of autocrine TGF-beta1 with anti-TGF-beta1 antibody abrogated the resistance of keloid-derived fibroblasts. Anti-apoptotic activity was not observed with TGF-beta2. This is the first study linking refractory Fas-mediated apoptosis to cellular phenotype in keloids and indicating a pivotal role for the anti-apoptotic effect of TGF-beta1 in this resistance. Hence, it becomes important to treat keloids as a separate entity different from hypertrophic scars and enhancement of Fas-sensitivity could be a promising therapeutic target.

Cutaneous injury, whether by laser, chemical, or scalpel, results in scar formation. The normal response to such an insult occurs in the middle of a continuum of wound repair processes. On one end of the continuum are the overhealed responses (i.e., keloids). On the opposite end are tissue regeneration and scarless healing as seen in fetal wounds. This article reviews the molecular biology and mechanisms leading to these various clinical phenotypes and discusses future potential modalities that may replicate the scarless wound healing mechanism in adults.

Introduction: A great deal of progress has been made in the last few decades in understanding the cellular and biochemical interplay that comprises the normal wound healing response. This response is a complex process involving intricate interactions among a variety of different cell types, structural proteins, growth factors and proteinases., Phases of Wound Healing: Acute wounds maturate through phases of coagulation, inflammation, matrix synthesis and deposition, angiogenesis, fibroplasia, epithelialization, contraction and remodelling, but three classic phases of wound healing are inflammation, fibroplasia and maturation., Dermal Fibroproliferative Disorders: Two main forms of fibroproliferative disorders are hypertrophic scars and keloids. These disorders are characterized by an overabundance of wound collagen through overproduction of collagen or impaired degradation of collagen. Hypertrophic scars are raised, pruritic and edematous lesions that do not exceed the margins of the original wound (in contrast to keloids). Histologically, these lesions are indistinguishable and are characterized by thick, hyalinized collagen bundles arranged in nodules. The degree of hypertrophic scarring is believed to be related to the duration of time during which the wound is allowed to remain in inflammatory phase of healing. Wound closure tension may also play a role by altering the intracellular cytoskeletion of fibroblasts and increased secretion of TGF-beta and cytokines., Conclusion: Healing of chronic cutaneous wounds is still a great problem of modern society--huge costs, impaired quality of life. In the last few decades a great progress was made in understanding the cellular and biochemical interplay.

An in vitro model was used to determine the effect of superpulsed CO2 laser energy on normal dermal and keloid-producing fibroblast proliferation and release of growth factors. Growth factors assayed included basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGF-beta1). bFGF is mitogenic, inhibits collagen production, and stabilizes cellular phenotype. TGF-beta1 stimulates growth and collagen secretion and is thought to be integral to keloid formation. Growth in a serum-free medium allowed measurement of these growth factors without confounding variables. Keloid and normal dermal fibroblasts cell lines were established from facial skin samples using standard explant techniques. Samples consisted of three separate keloid and three separate normal dermal fibroblast cell lines. Cells were used at passage 4 to seed 24-well trays at a concentration of 6 x 10(4) cells per milliliter in serum-free medium. At 48 hours, 18.8 percent of each cell well was exposed to a fluence of 2.4, 4.7, and 7.3 J/cm2 using the superpulsed CO2 laser. Cell viability and counts were established at four time points: 0 (time of superpulsed CO2 laser treatment), 24, 72, and 120 hours. Supernatants were collected and assessed for bFGF and TGF-beta1 using a sandwich enzyme immunoassay. All cell lines demonstrated logarithmic growth through 120 hours (conclusion of experiment), with a statistically significant shorter population doubling time for keloid fibroblasts (p < 0.05). Use of the superpulsed CO2 laser shortened population doubling times relative to that of controls; the differences were statistically significant in keloid dermal fibroblasts when fluences of 2.4 and 4.7 J/cm2 were used (p < 0.05 and 0.01, respectively). bFGF was present in greater levels in normal dermal fibroblasts than in keloid dermal fibroblasts. Application of superpulsed CO2 demonstrated a trend toward increased bFGF secretion in both fibroblast types; the increase was significant in the keloid group at 4.7J/cm2. A consistent trend in suppression of TGF-beta1 was seen in both groups exposed to superpulsed CO2, with the maximal effect occurring at 4.7 J/cm2. Serum-free culture sustains logarithmic cell growth and allows growth factor measurement without confounding variables from serum-containing media. Superpulsed CO2 enhances fibroblast replication and seems to stimulate bFGF secretion and to inhibit TGF-beta1 secretion. Given the function of these growth factors, the application of superpulsed CO2 may support normalized wound healing. These findings may explain the beneficial effects of laser resurfacing on a cellular level and support the use of superpulsed CO2 in the management of keloid scar tissue.

Activation of signals for insulin-like growth factor-I receptor (IGF-IR) is thought to be closely linked to abnormal cell proliferation and differentiation in various diseases. The keloid in which fibroblasts invade beyond the margins of the original wound, is a dermal fibroproliferative tissue of unknown etiology. Clinically, keloids are most commonly observed in subjects at ages between 10 and 30 years. Interestingly, plasma levels of growth hormone and IGF-I are also high during the same period, suggesting that IGF-I might be involved in the patho-physiology of keloid fibroblasts. We therefore first examined the expression level of IGF-IR in normal and keloid tissues. Immunohistochemical analysis confirmed increased expression of IGF-IR in keloid fibroblasts, but not in normal fibroblasts. On the other hand, the staining intensity of IGF-IR in the epidermis of normal tissues was almost equal to that in keloids. Next, to study the functional properties of the IGF-I/IGF-IR axis in both normal and keloid fibroblasts, we investigated invasion activities. The invasive activity of IGF-IR overexpressing keloid fibroblasts was greatly increased in the presence of IGF-I, and inhibited by a neutralizing antibody to IGF-I. In contrast, its activity of IGF-IR weak-expressing normal fibroblasts was not changed. Our results indicate the involvement of the activated IGF-I/IGF-IR axis in the pathogenesis of the invasive activity of fibroblasts.