Keloids and hypertrophic scars are caused by cutaneous injury and irritation, including trauma, insect bite, burn, surgery, vaccination, skin piercing, acne, folliculitis, chicken pox, and herpes ...zoster infection. Notably, superficial injuries that do not reach the reticular dermis never cause keloidal and hypertrophic scarring. This suggests that these pathological scars are due to injury to this skin layer and the subsequent aberrant wound healing therein. The latter is characterized by continuous and histologically localized inflammation. As a result, the reticular layer of keloids and hypertrophic scars contains inflammatory cells, increased numbers of fibroblasts, newly formed blood vessels, and collagen deposits. Moreover, proinflammatory factors, such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α are upregulated in keloid tissues, which suggests that, in patients with keloids, proinflammatory genes in the skin are sensitive to trauma. This may promote chronic inflammation, which in turn may cause the invasive growth of keloids. In addition, the upregulation of proinflammatory factors in pathological scars suggests that, rather than being skin tumors, keloids and hypertrophic scars are inflammatory disorders of skin, specifically inflammatory disorders of the reticular dermis. Various external and internal post-wounding stimuli may promote reticular inflammation. The nature of these stimuli most likely shapes the characteristics, quantity, and course of keloids and hypertrophic scars. Specifically, it is likely that the intensity, frequency, and duration of these stimuli determine how quickly the scars appear, the direction and speed of growth, and the intensity of symptoms. These proinflammatory stimuli include a variety of local, systemic, and genetic factors. These observations together suggest that the clinical differences between keloids and hypertrophic scars merely reflect differences in the intensity, frequency, and duration of the inflammation of the reticular dermis. At present, physicians cannot (or at least find it very difficult to) control systemic and genetic risk factors of keloids and hypertrophic scars. However, they can use a number of treatment modalities that all, interestingly, act by reducing inflammation. They include corticosteroid injection/tape/ointment, radiotherapy, cryotherapy, compression therapy, stabilization therapy, 5-fluorouracil (5-FU) therapy, and surgical methods that reduce skin tension.
Previous reports on the treatment of hypertrophic scars and keloids have not described clear algorithms for multimodal therapies. This article presents an evidence-based review of previous articles ...and proposes algorithms for the treatment and prevention of hypertrophic scars and keloids.
The methodologic quality of the clinical trials was evaluated, and the baseline characteristics of the patients and the interventions that were applied and their outcomes were extracted.
Important factors that promote hypertrophic scar/keloid development include mechanical forces on the wound, wound infection, and foreign body reactions. For keloids, the treatment method that should be used depends on whether scar contractures (especially joint contractures) are present and whether the keloids are small and single, or large and multiple. Small and single keloids can be treated radically by surgery with adjuvant therapy (which includes radiation or corticosteroid injections) or by nonsurgical monotherapy (which includes corticosteroid injections, cryotherapy, laser, and antitumor/immunosuppressive agents such as 5-fluorouracil). Large and multiple keloids are difficult to treat radically and are currently only treatable by multimodal therapies that aim to relieve symptoms. After a sequence of treatments, long-term follow-up is recommended. Conservative therapies, which include gel sheeting, taping fixation, compression therapy, external and internal agents, and makeup (camouflage) therapy, should be administered on a case-by-case basis.
The increase in the number of randomized controlled trials over the past decade has greatly improved scar management, although these studies suffer from various limitations. The hypertrophic scar/keloid treatment algorithms that are currently available are likely to be significantly improved by future high-quality clinical trials.
Mechanobiology of scarring Ogawa, Rei
Wound repair and regeneration,
September/October 2011, Letnik:
19, Številka:
s1
Journal Article
Recenzirano
ABSTRACT
The mechanophysiological conditions of injured skin greatly influence the degree of scar formation, scar contracture, and abnormal scar progression/generation (e.g., keloids and hypertrophic ...scars). It is important that scar mechanobiology be understood from the perspective of the extracellular matrix and extracellular fluid, in order to analyze mechanotransduction pathways and develop new strategies for scar prevention and treatment. Mechanical forces such as stretching tension, shear force, scratch, compression, hydrostatic pressure, and osmotic pressure can be perceived by two types of skin receptors. These include cellular mechanoreceptors/mechanosensors, such as cytoskeleton (e.g., actin filaments), cell adhesion molecules (e.g., integrin), and mechanosensitive (MS) ion channels (e.g., Ca2+ channel), and sensory nerve fibers (e.g., MS nociceptors) that produce the somatic sensation of mechanical force. Mechanical stimuli are received by MS nociceptors and signals are transmitted to the dorsal root ganglia that contain neuronal cell bodies in the afferent spinal nerves. Neuropeptides are thereby released from the peripheral terminals of the primary afferent sensory neurons in the skin, modulating scarring via skin and immune cell functions (e.g., cell proliferation, cytokine production, antigen presentation, sensory neurotransmission, mast cell degradation, vasodilation, and increased vascular permeability under physiological or pathophysiological conditions). Mechanoreceptor or MS nociceptor inhibition and mechanical force reduction should propel the development of novel methods for scar prevention and treatment.
Scars are the final result of the four processes that constitute cutaneous wound healing, namely, coagulation, inflammation, proliferation, and remodeling. Permanent scars are produced if the wounds ...reach the reticular dermis. The nature of these scars depends on the four wound healing processes. If the remodeling process is excessive, collagen degradation exceeds collagen synthesis and atrophic scars are produced. If the inflammation phase is prolonged and/or more potent for some reason, inflammatory/pathological scars such as keloids or hypertrophic scars can arise. If these pathological scars are located on joints or mobile regions, scar contractures can develop. When used with the appropriate timing and when selected on the basis of individual factors, surgical techniques can improve mature scars. This review paper focuses on the surgical techniques that are used to improve mature scars, burn scars, and scar contractures. Those methods include z-plasties, w-plasties, split-thickness skin grafting, full-thickness skin grafting, local flaps (including the square flap method and the propeller flap), and expanded flaps, distant flaps, regional flaps, and free flaps.
Keloids and hypertrophic scars are pathological cutaneous scars. They arise from excessive wound healing, which induces chronic dermal inflammation and results in overwhelming fibroblast production ...of extracellular matrix. Their etiology is unclear. Inflammasomes are multiprotein complexes that are important in proinflammatory innate-immune system responses. We asked whether inflammasomes participate in pathological scarring by examining the literature on scarring, diabetic wounds (also characterized by chronic inflammation), and systemic sclerosis (also marked by fibrosis). Pathological scars are predominantly populated by anti-inflammatory M2 macrophages and recent literature hints that this could be driven by non-canonical inflammasome signaling. Diabetic-wound healing associates with inflammasome activation in immune (macrophages) and non-immune (keratinocytes) cells. Fibrotic conditions associate with inflammasome activation and inflammasome-induced transition of epithelial cells/endothelial cells/macrophages into myofibroblasts that deposit excessive extracellular matrix. Studies suggest that mechanical stimuli activate inflammasomes via the cytoskeleton and that mechanotransduction-inflammasome crosstalk is involved in fibrosis. Further research should examine (i) the roles that various inflammasome types in macrophages, (myo)fibroblasts, and other cell types play in keloid development and (ii) how mechanical stimuli interact with inflammasomes and thereby drive scar growth. Such research is likely to significantly advance our understanding of pathological scarring and aid the development of new therapeutic strategies.
In 2010, this Journal published my comprehensive review of the literature on hypertrophic scars and keloids. In that article, I presented evidence-based algorithms for the prevention and treatment of ...these refractory pathologic scars. In the ensuing decade, substantial progress has been made in the field, including many new randomized controlled trials. To reflect this, I have updated my review.
All studies were evaluated for methodologic quality. Baseline characteristics of patients were extracted along with the interventions and their outcomes. Systematic reviews, meta-analyses, and comprehensive reviews were included if available.
Risk factors that promote hypertrophic scar and keloid growth include local factors (tension on the wound/scar), systemic factors (e.g., hypertension), genetic factors (e.g., single-nucleotide polymorphisms), and lifestyle factors. Treatment of hypertrophic scars depends on scar contracture severity: if severe, surgery is the first choice. If not, conservative therapies are indicated. Keloid treatment depends on whether they are small and single or large and multiple. Small and single keloids can be treated radically by surgery with adjuvant therapy (e.g., radiotherapy) or multimodal conservative therapy. For large and multiple keloids, volume- and number-reducing surgery is a choice. Regardless of the treatment(s), patients should be followed up over the long term. Conservative therapies, including gel sheets, tape fixation, topical and injected external agents, oral agents, and makeup therapy, should be administered on a case-by-case basis.
Randomized controlled trials on pathologic scar management have increased markedly over the past decade. Although these studies suffer from various limitations, they have greatly improved hypertrophic scar and keloid management. Future high-quality trials are likely to improve the current hypertrophic scar and keloid treatment algorithms further.
In 2006, we established a scar/keloid-specialized unit in the Department of Plastic, Reconstructive, and Aesthetic Surgery at Nippon Medical School (NMS) in Tokyo, Japan. In the ensuing 15 years, we ...treated approximately 2,000 new scar/keloid patients annually. This extensive experience has greatly improved the efficacy of the treatments we offer. Therefore, we discuss here the latest NMS protocol for preventing and treating keloids and hypertrophic scars. While this protocol was optimized for Japanese patients, our experience with a growing body of non-Japanese patients suggests that it is also effective in other ethnicities. The extensive evidence-based experience underlying the NMS protocol suggests that it may be suitable as the foundation of a standard international prevention/treatment algorithm for pathological scars.
Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result ...of chronic but progressive accumulation of fibroblasts and their production of extracellular matrix components such as collagens. Research on pathological scars, namely, hypertrophic scars and keloids, may provide important clues about the mechanisms that drive soft tissue fibrosis, in particular the vascular involvement. This is because these dermal fibrotic lesions bear all of the fibrotic characteristics seen in soft tissue fibrosis. Moreover, their location on the skin surface means they are readily observable and directly treatable and therefore more accessible to research. We will focus here on the roles that blood vessel-associated cells play in cutaneous scar pathology and assess from the literature whether these cells also contribute to other soft tissue fibroses. These cells include endothelial cells, which not only exhibit aberrant functions but also differentiate into mesenchymal cells in pathological scars. They also include pericytes, hepatic stellate cells, fibrocytes, and myofibroblasts. This article will review with broad strokes the roles that these cells play in the pathophysiology of different soft tissue fibroses. We hope that this brief but wide-ranging overview of the vascular involvement in fibrosis pathophysiology will aid research into the mechanisms underlying fibrosis and that this will eventually lead to the development of interventions that can prevent, reduce, or even reverse fibrosis formation and/or progression.
Summary Keloid and hypertrophic scars (HSs) are fibroproliferative diseases (FPDs) of the skin. It is well known that stretching tension of skin, in other words mechanical force (mechanical loading, ...mechanical stress) on the skin, is an important factor that promotes their growth. Currently, the widely held view is that while mechanical force is a factor that aggravates keloid/HS growth after their induction, it is not a causative factor. However, there is no evidence that supports this view and recent observations from studies of keloids/HSs suggest that mechanical force in fact not only promotes the growth of such scars, it also drives their generation. Here, I hypothesize that FPDs of the skin, including keloids and HSs, are the result of an excessive responsiveness or functional failure of either dermal cell mechanoreceptors (mechanosensors) or mechanosensitive nociceptors of sensory fibers in the skin. In other words, FPDs of the skin are mechanoreceptor/mechanosensor or mechanosensitive nociceptor (mechanosensory) disorders, respectively. Moreover, by examining the site specificity of keloids, I show that stretching tension may be a major mechanical force that drives their generation. While further experimental studies of signaling pathways related to mechanotransduction, mechanosensitive (MS) channels, cell adhesion molecules, and cytoskeleton dynamics are needed, this hypothesis may provide new insights into the etiology and pathology of FPDs of the skin such as keloids and HSs.
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