Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment.
TL;DR: The pathophysiology of keloid and hypertrophic scar is described to compare differences with the normal wound healing process, and various treatment options including prevention, conventional therapies, surgical therapies, and adjuvant therapies are described in detail.
Abstract: BACKGROUNDKeloid and hypertrophic scars represent an aberrant response to the wound healing process. These scars are characterized by dysregulated growth with excessive collagen formation, and can be cosmetically and functionally disruptive to patients.OBJECTIVEObjectives are to describe the pathoph
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TL;DR: The defensive components of the skin are discussed and the function of skin-resident immune cells in homeostasis and their role in wound healing are focused on.
Abstract: The skin is a complex organ that has devised numerous strategies, such as physical, chemical, and microbiological barriers, to protect the host from external insults. In addition, the skin contains an intricate network of immune cells resident to the tissue, crucial for host defense as well as tissue homeostasis. In the event of an insult, the skin-resident immune cells are crucial not only for prevention of infection but also for tissue reconstruction. Deregulation of immune responses often leads to impaired healing and poor tissue restoration and function. In this review, we will discuss the defensive components of the skin and focus on the function of skin-resident immune cells in homeostasis and their role in wound healing.
274 citations
TL;DR: The anatomy and histology of a previously unrecognized, though widespread, macroscopic, fluid-filled space within and between tissues, a novel expansion and specification of the concept of the human interstitium is described.
Abstract: Confocal laser endomicroscopy (pCLE) provides real-time histologic imaging of human tissues at a depth of 60–70 μm during endoscopy. pCLE of the extrahepatic bile duct after fluorescein injection demonstrated a reticular pattern within fluorescein-filled sinuses that had no known anatomical correlate. Freezing biopsy tissue before fixation preserved the anatomy of this structure, demonstrating that it is part of the submucosa and a previously unappreciated fluid-filled interstitial space, draining to lymph nodes and supported by a complex network of thick collagen bundles. These bundles are intermittently lined on one side by fibroblast-like cells that stain with endothelial markers and vimentin, although there is a highly unusual and extensive unlined interface between the matrix proteins of the bundles and the surrounding fluid. We observed similar structures in numerous tissues that are subject to intermittent or rhythmic compression, including the submucosae of the entire gastrointestinal tract and urinary bladder, the dermis, the peri-bronchial and peri-arterial soft tissues, and fascia. These anatomic structures may be important in cancer metastasis, edema, fibrosis, and mechanical functioning of many or all tissues and organs. In sum, we describe the anatomy and histology of a previously unrecognized, though widespread, macroscopic, fluid-filled space within and between tissues, a novel expansion and specification of the concept of the human interstitium.
253 citations
TL;DR: This review provides an overview of dermal cell heterogeneity and their participation in skin repair, scar formation, and in the composition of skin substitutes in the context of cell population characteristics and extracellular matrix composition and properties.
Abstract: There are many studies on certain skin cell specifications and their contribution to wound healing. In this review, we provide an overview of dermal cell heterogeneity and their participation in skin repair, scar formation, and in the composition of skin substitutes. The papillary, reticular, and hair follicle associated fibroblasts differ not only topographically, but also functionally. Human skin has a number of particular characteristics that are different from murine skin. This should be taken into account in experimental procedures. Dermal cells react differently to skin wounding, remodel the extracellular matrix in their own manner, and convert to myofibroblasts to different extents. Recent studies indicate a special role of papillary fibroblasts in the favorable outcome of wound healing and epithelial-mesenchyme interactions. Neofolliculogenesis can substantially reduce scarring. The role of hair follicle mesenchyme cells in skin repair and possible therapeutic applications is discussed. Participation of dermal cell types in wound healing is described, with the addition of possible mechanisms underlying different outcomes in embryonic and adult tissues in the context of cell population characteristics and extracellular matrix composition and properties. Dermal white adipose tissue involvement in wound healing is also overviewed. Characteristics of myofibroblasts and their activity in scar formation is extensively discussed. Cellular mechanisms of scarring and possible ways for its prevention are highlighted. Data on keloid cells are provided with emphasis on their specific characteristics. We also discuss the contribution of tissue tension to the scar formation as well as the criteria and effectiveness of skin substitutes in skin reconstruction. Special attention is given to the properties of skin substitutes in terms of cell composition and the ability to prevent scarring.
138 citations
TL;DR: In this paper, a review of the promising characteristics and recent advances in the use of silk fibroin for skin wound healing and/or soft-tissue repair applications is presented.
111 citations
TL;DR: In this article, the authors explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq and find that fibroblasts can be divided into four subpopulations: secretory-papillary, secretory reticular, mesenchymal and pro-inflammatory.
Abstract: Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. In this study, we explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq. Our results indicate that keloid fibroblasts can be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory. Interestingly, the percentage of mesenchymal fibroblast subpopulation is significantly increased in keloid compared to normal scar. Functional studies indicate that mesenchymal fibroblasts are crucial for collagen overexpression in keloid. Increased mesenchymal fibroblast subpopulation is also found in another fibrotic skin disease, scleroderma, suggesting this is a broad mechanism for skin fibrosis. These findings will help us better understand skin fibrotic pathogenesis, and provide potential targets for fibrotic disease therapies.
108 citations
References
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TL;DR: Knowing how organisms retain the ability to regenerate tissue throughout adult life might help to unlock latent regenerative pathways in humans, which would change medical practice as much as the introduction of antibiotics did in the twentieth century.
Abstract: The repair of wounds is one of the most complex biological processes that occur during human life. After an injury, multiple biological pathways immediately become activated and are synchronized to respond. In human adults, the wound repair process commonly leads to a non-functioning mass of fibrotic tissue known as a scar. By contrast, early in gestation, injured fetal tissues can be completely recreated, without fibrosis, in a process resembling regeneration. Some organisms, however, retain the ability to regenerate tissue throughout adult life. Knowledge gained from studying such organisms might help to unlock latent regenerative pathways in humans, which would change medical practice as much as the introduction of antibiotics did in the twentieth century.
2,513 citations
TL;DR: This study clearly demonstrates isoform specific differences in the role of T GF-betas in wound healing and cutaneous scarring and suggests a novel therapeutic use of exogenous recombinant, TGF-beta 3 as an anti-scarring agent.
Abstract: Exogenous addition of neutralising antibody to transforming growth factor-beta 1,2 to cutaneous wounds in adult rodents reduces scarring. Three isoforms of transforming growth factor-beta (1, 2 and 3) have been identified in mammals. We investigated the isoform/isoforms of TGF-beta responsible for cutaneous scarring by: (i) reducing specific endogenous TGF-beta isoforms by exogenous injection of isoform specific neutralising antibodies; and (ii) increasing the level of specific TGF-beta isoforms by exogenous infiltration into the wound margins. Exogenous addition of neutralising antibody to TGF-beta 1 plus neutralising antibody to TGF-beta 2 reduced the monocyte and macrophage profile, neovascularisation, fibronectin, collagen III and collagen I deposition in the early stages of wound healing compared to control wounds. Treatment with neutralising antibodies to TGF-betas 1 and 2 markedly improved the architecture of the neodermis to resemble that of normal dermis and reduced scarring while the control wounds healed with scar formation. Exogenous addition of neutralising antibody to TGF-beta 1 alone also reduced the monocyte and macrophage profile, fibronectin, collagen III and collagen I deposition compared to control wounds. However, treatment with neutralising antibody to TGF-beta 1 alone only marginally reduced scarring. By contrast, wounds treated with neutralising antibody to TGF-beta 2 alone did not differ from control wounds. Interestingly, exogenous addition of the TGF-beta 3 peptide also reduced the monocyte and macrophage profile, fibronectin, collagen I and collagen III deposition in the early stages of wound healing and markedly improved the architecture of the neodermis and reduced scarring. By contrast, wounds treated with either TGF-beta 1 or with TGF-beta 2 had more extracellular matrix deposition in the early stages of wound healing but did not differ from control wounds in the final quality of scarring. This study clearly demonstrates isoform specific differences in the role of TGF-betas in wound healing and cutaneous scarring. TGF-beta 1 and TGF-beta 2 are implicated in cutaneous scarring. This study also suggests a novel therapeutic use of exogenous recombinant, TGF-beta 3 as an anti-scarring agent.
1,195 citations
"Keloids and Hypertrophic Scars: Pat..." refers result in this paper
...Exogenous addition of neutralizing antibodies to TGF-b 1 and 2 reduced neovascularization, fibronectin, collagen III and collagen I deposition in early wound healing; it also improved architecture of the neodermis to more closely resemble that of normal dermis.(13) Likewise, exogenous administration of TGF-b 3 peptide had similar effects, whereas wounds treated with TGF-b 1 or 2 had more extracellular matrix deposition....
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TL;DR: The mechanical properties of the underlying ECM regulate Rho‐mediated contractility in SMCs by disrupting a presumptive cell‐ECM force balance, which in turn regulates cytoskeletal assembly and ultimately, cell migration.
Abstract: Increasing evidence suggests that mechanical cues inherent to the extracellular matrix (ECM) may be equally as critical as its chemical identity in regulating cell behavior. We hypothesized that the mechanical properties of the ECM directly regulate the motility of vascular smooth muscle cells (SMCs) and tested this hypothesis using polyacrylamide substrates with tunable mechanical properties. Quantification of the migration speed on uniformly compliant hydrogels spanning a range of stiffnesses (Young's moduli values from 1.0 to 308 kPa for acrylamide/bisacrylamide ratios between 5/0.1% and 15/1.2%, respectively) revealed a biphasic dependence on substrate compliance, suggesting the existence of an optimal substrate stiffness capable of supporting maximal migration. The value of this optimal stiffness shifted depending on the concentration of ECM protein covalently attached to the substrate. Specifically, on substrates presenting a theoretical density of 0.8 microg/cm(2) fibronectin, the maximum speed of 0.74 +/- 0.09 microm/min was achieved on a 51.9 kPa gel; on substrates presenting a theoretical density of 8.0 microg/cm(2) fibronectin, the maximum speed of 0.72 +/- 0.06 microm/min occurred on a softer 21.6 kPa gel. Pre-treatment of cells with Y27632, an inhibitor of the Rho/Rho-kinase (ROCK) pathway, reduced these observed maxima to values comparable to those on non-optimal stiffnesses. In parallel, quantification of TritonX-insoluble vinculin via Western blotting, coupled with qualitative fluorescent microscopy, revealed that the formation of focal adhesions and actin stress fibers also depends on ECM stiffness. Combined, these data suggest that the mechanical properties of the underlying ECM regulate Rho-mediated contractility in SMCs by disrupting a presumptive cell-ECM force balance, which in turn regulates cytoskeletal assembly and ultimately, cell migration.
655 citations
"Keloids and Hypertrophic Scars: Pat..." refers background in this paper
...Increased rigidity has also be shown to affect migration, proliferation, and differentiation of cells, and compression therapy may affect these functions within fibroblasts by increasing rigidity of the extracellular matrix.(22)...
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TL;DR: The Transforming Growth Factor beta superfamily (TGF beta) is one of the most complex groups of cytokines with widespread effects on many aspects of growth and development as mentioned in this paper.
603 citations
TL;DR: A novel therapeutic approach to reducing scarring in post-natal life is suggested by using neutralising antibody to transforming growth factor-beta 1,2 to alter the growth factor profile of cutaneous wounds in adult rodents and studying the effect on scar tissue formation.
Abstract: Scarring is a major cause of many clinical problems. Scar tissue interferes with growth, impairs function and is aesthetically unpleasant. However, scarring does not appear to be a problem of embryonic life. Embryonic wounds heal with a lower inflammatory and angiogenic response and have a different growth factor profile compared to adult wounds. We have used neutralising antibody to transforming growth factor-beta 1,2 (TGF-beta 1,2) to alter the growth factor profile of cutaneous wounds in adult rodents and studied the effect on scar tissue formation. This paper extends our preliminary report that neutralising antibody to TGF-beta reduces cutaneous scarring in adult rodents. To be effective, the neutralising antibody to TGF-beta needs to be administered at the time of wounding or soon thereafter. The antiscarring effects of this neutralising antibody to TGF-beta were dose dependent. Exogenous addition of neutralising antibody to TGF-beta to incisional wounds reduced the inflammatory and angiogenic responses and reduced the extracellular matrix deposition in the early stages of wound healing without reducing the tensile strength of the wounds. Importantly, the architecture of the neodermis of wounds treated with neutralising antibody to TGF-beta resembled more closely that of normal dermis compared to the unmanipulated control wounds, which healed with an abnormal neodermal architecture resulting in obvious scarring. This study suggests a novel therapeutic approach to reducing scarring in post-natal life.
529 citations