Proliferative Scarring Research Articles

Inhibitory effects and mechanisms of low-temperature plasma on hypertrophic scar

Recent advancements in comprehending the properties of low-temperature plasmas (LTPs) have spurred the creation of plasma medicine. Nonetheless, there exists limited scientific evidence concerning its mechanism of impeding proliferative scarring. This study aims to investigate the role of LTPs in hypertrophic scar (HS) formation. Establishing rabbit ear scar models, two groups were individually treated with salvianolic acid B (SAB) gel and low-temperature plasmas for six weeks, while the control group was not treated. The expression levels of cytokines, including TGF-β1, p-Smad3, and MMP-2, in rabbit serum were assessed using ELISA in this study. Additionally, hematoxylin-eosin staining and Masson’s trichrome staining were conducted on proliferative scar tissue to observe the arrangement of collagen fibers and determine the density of fibroblasts. Immunohistochemical analysis was also performed to obtain the percentage of type I collagen and α-SMA positive expression area. The findings indicated that the scars in both the SAB and LTP groups were narrower than those in the model group. The scar tissues treated with LTP or SAB showed a lower level of TGF-β1 and p-Smad3. In addition, α-SMA was significantly reduced in the LTP-treated group. Furthermore, the type I collagen expression was lower in the LTP group. These results suggest that LTP could have a comparable effect to SAB in hindering the development of HSs. It could potentially enhance skin scarring by impeding collagen deposition and fibroblast proliferation in HSs via the TGF-β/Smad signaling pathway. This investigation may provide a new perspective on HS treatment.

Prevention and management of scarring after thermal injury

Survival from burn injury has improved considerably over the past two decades such that the quality of life of the victim of thermal injuries has become a major concern. Severe proliferative scarring or hypertrophic scarring (HTS) is an all too frequent complication of burn wound healing that severely compromises quality of life for surviving burn victims. Prevention of such scarring in burn patients involves better understanding of the pathophysiology of scar formation, development of newer methods for determining depth of burn injury and earlier and advanced surgical interventions. Many established and evolving novel treatments for HTS in patients after thermal injury exist and include antifibrotic pharmaceuticals and cellular-based therapies as reviewed herein.

The role of Th1/Th2 cell chemokine expression in hypertrophic scar.

The aim of this study was to study the role of Th1/Th2 cell-associated chemokines in the formation of hypertrophic scars in rabbit ears. Twenty-six New Zealand white rabbits were used to establish the hypertrophic scar model of rabbit ear and the normal scar model of rabbit's back. Two rabbits were sacrificed on days 0 and 21, 28, 35, 42, 49, 56, and 63 after operation. The specimens were stained with haematoxylin-eosin (HE). Scar elevation index (SEI) was used to detect the expression of 10 chemokines related to Th1/Th2 cells in both scar formation expressions. Real-time polymerase chain reaction (PCR) results showed that two chemokines (CXCL10, CXCL12) were highly expressed during the formation of normal scar, and there was almost no expression during the formation of hypertrophic scar (*P < 0.05). The chemokines (CCL2, CCL3, CCL4, CCL5, CCL7, CCL13, CX3CL1) were almost non-expressed in the formation of normal scars but were expressed for a long time in the formation of hypertrophic scars. The four chemokines, CCL2, CCL4, CCL5, and CX3CL1, maintained a long-term high expression level during the formation of hypertrophic scars (P < 0.01). There were also three chemokines (CCL14, CCL19, CCL21) that were almost undetectable in normal scarring, but there was transiently low-level expression (P < 0.05) only during the peak proliferative phase in proliferative scarring. Th1/Th2 cell-associated chemokines are different in the type, quantity and expression, and maintenance time of rabbit ear hypertrophic scars.

Fibromodulin reduces scar size and increases scar tensile strength in normal and excessive-mechanical-loading porcine cutaneous wounds.

Hypertrophic scarring is a major postoperative complication which leads to severe disfigurement and dysfunction in patients and usually requires multiple surgical revisions due to its high recurrence rates. Excessive‐mechanical‐loading across wounds is an important initiator of hypertrophic scarring formation. In this study, we demonstrate that intradermal administration of a single extracellular matrix (ECM) molecule—fibromodulin (FMOD) protein—can significantly reduce scar size, increase tensile strength, and improve dermal collagen architecture organization in the normal and even excessive‐mechanical‐loading red Duroc pig wound models. Since pig skin is recognized by the Food and Drug Administration as the closest animal equivalent to human skin, and because red Duroc pigs show scarring that closely resembles human proliferative scarring and hypertrophic scarring, FMOD‐based technologies hold high translational potential and applicability to human patients suffering from scarring—especially hypertrophic scarring.

Impact of breastfeeding or bottle-feeding on surgical wound dehiscence after cleft lip repair in infants: a systematic review protocol.

REVIEW QUESTION / OBJECTIVE The objective of this systematic review is to examine the impact of breastfeeding or bottle-feeding on surgical wound dehiscence after cleft lip repair in infants. INCLUSION CRITERIA Types of participants This review will consider studies that include infants who have undergone cleft lip repair. The review will exclude studies that include patients who have undergone cleft lip or palate repair over the age of one year. Types of intervention(s) This review will consider studies that evaluate the impact of breastfeeding or bottle-feeding on surgical wound dehiscence after cleft lip repair in infants. Particular focus will be given to studies in which the same feeding method (breastfeeding or bottle-feeding) as that used preoperatively is compared with alternative feeding methods (spoon-, cup-, or syringe-feeding). Types of outcomes This review will consider studies that include the following outcome measure: incidence of surgical wound dehiscence as ascertained by health professionals. Secondary outcomes include weight gain, length of postoperative stay and hospital discharge, if enough data is available.

Regeneration and control of human fibroblast cell density by intermittently delivered pulsed electric fields

Proliferative scarring is a human disease with neither available effective treatment nor relevant animal model. One of the hypotheses for scar formation involves deregulation of fibroblast signaling and delayed apoptosis. Here, we introduce a new chemical-free method for fibroblast density control in culture by intermittently delivered pulsed electric fields (IDPEF), which cause irreversible damage to cell membranes. Using 5-100 pulses with electric field strength of 150 V/mm, pulse duration 70 µs, and frequency of 1 Hz, we investigated the effects of PEF application on growth, death, and regeneration of normal human dermal fibroblasts in culture. We found that the fraction of fibroblasts that survive depends on the number of pulses applied and follows a Weibull distribution. We have successfully developed an IDPEF protocol that controls fibroblasts density in culture. Specifically, through application of IDPEF every 72 h for 12 days, we maintain a normal human dermal fibroblast density in the 3.1 ± 0.2 × 10(5) -1.4 ± 0.2 × 10(5) cell/mL range. Our results suggest that IDPEFs may prove useful as a non-chemical method for fibroblast density control in human wound healing.

Regeneration and control of human fibroblast cell density by intermittently delivered pulsed electric fields

Proliferative scarring is a human disease with neither available effective treatment nor relevant animal model. One of the hypotheses for scar formation involves deregulation of fibroblast signaling and delayed apoptosis. Here, we introduce a new chemical-free method for fibroblast density control in culture by intermittently delivered pulsed electric fields (IDPEF), which cause irreversible damage to cell membranes. Using 5–100 pulses with electric field strength of 150 V/mm, pulse duration 70 µs, and frequency of 1 Hz, we investigated the effects of PEF application on growth, death, and regeneration of normal human dermal fibroblasts in culture. We found that the fraction of fibroblasts that survive depends on the number of pulses applied and follows a Weibull distribution. We have successfully developed an IDPEF protocol that controls fibroblasts density in culture. Specifically, through application of IDPEF every 72 h for 12 days, we maintain a normal human dermal fibroblast density in the 3.1 ± 0.2 × 105–1.4 ± 0.2 × 105 cell/mL range. Our results suggest that IDPEFs may prove useful as a non-chemical method for fibroblast density control in human wound healing. Biotechnol. Bioeng. 2013; 110: 1759–1768. © 2013 Wiley Periodicals, Inc.

Mechanical Receptor–Related Mechanisms in Scar Management: A Review and Hypothesis

The physiopathogenesis of proliferative scarring in human skin is not well understood. Furthermore, knowledge of the precise mechanisms of action for physical treatment modalities is limited. Compression garments, occlusive/adhesive skin taping, and silicone gel sheets are applied to form an occlusion on the scar surface, reduce tension, and/or increase pressure on the scar itself. The mechanisms by which the external or superficial actions of these treatments cause remission of a protruding scar may be related to mechanoreceptor (nociceptor and cellular mechanoreceptor) responses. Basic research studies about mechanoreceptor-related (nociceptors and cellular mechanoreceptors, separately) events are reviewed and discussed based on proliferative scarring background. Scar management-related studies were corrected from the standpoint of mechanotransduction mechanisms. The methodologic quality of the clinical trials and basic studies was evaluated and reviewed. It was suggested that many of the physical scar management methods, including compression therapy, silicone therapy, adhesive tape, and occlusive dressing therapy, are related to mechanotransduction mechanisms. A unifying perspective of basic research findings and clinical observations may be obtained by considering the mechanoreceptor-related events in scar management. Moreover, a precise understanding of the roles that cellular mechanoreceptors and mechanosensitive nociceptors play in proliferative scarring may lead to the development of innovative treatment strategies and new pharmacologic therapies targeting cellular mechanoreceptors and mechanosensitive nociceptors in fibroproliferative diseases.

Down-Regulating Causes of Fibrosis With Tamoxifen

Fibrosis and proliferative scarring are prominent features of the severe forms of rhinophyma. Up-regulation of growth and fibroblast kinetics are hallmarks of fibrosis. Persistent overexpression or dysregulated activation of the fibrogenic isoforms of transforming growth factor beta (TGF-beta) is associated with the increased fibroblast function leading to fibrotic conditions such as rhinophyma. Tamoxifen, a synthetic nonsteroidal antiestrogen, can neutralize or down-regulate TGF-beta. Fibroblast-populated collagen lattices (FPCLs) were constructed from fibroblasts cultured from rhinophyma or normal nasal skin. One-half of each set of FPCLs was treated with Tamoxifen. Lattice contraction was serially measured over 5 days, and the supernatants of the cultures were analyzed for TGF-beta-2 by immunoassay. Tamoxifen significantly decreased fibroblast activity by decreasing contraction of the treated lattices (P < 0.05) and significantly decreased the production/secretion of TGF-beta-2 by rhinophyma fibroblasts (P < 0.001). These results suggest a possible new cellular/molecular approach to the treatment of the fibrotic varieties of rhinophyma.

Overexpression of transforming growth factor beta-2 and its receptor in rhinophyma: an alternative mechanism of pathobiology.

Proliferative scarring is one of the clinical features of rhinophyma. The following study was undertaken to test the authors' hypothesis that fibrosis might also play an important role in the pathobiology of rhinophyma. The rhinophyma specimens were obtained from 5 white men (mean age, 67.8 years). Normal skin biopsies near benign facial lesions from 5 additional white men of similar age were obtained to serve as controls. Peroxidase-labeled immunohistochemical staining was performed in the rhinophyma and normal skin specimens for the presence of transforming growth factor (TGF) beta-2 and/or TGF-beta II receptor. Histological slides were then measured for the intensity of staining for TGF-beta2 and TGF-beta II receptor using a computer-aided imaging system. The dermis of the rhinophyma tissue displayed stronger immunoreactivity of TGF-beta2 (p = 0.014) and TGF-beta II receptor (p = 0.006) compared with the normal skin. The results of this study demonstrate the overexpression of the fibrogenic protein TGF-beta 2 and TGF-beta II receptor in rhinophyma tissues. These findings support the authors' hypothesis that fibrosis may also play an important role in the pathobiology of rhinophyma.

Effect of TGF-β2 on Proliferative Scar Fibroblast Cell Kinetics

Keloids, hypertrophic scars, and burn hypertrophic scars are all forms of proliferative scarring characterized by overabundant matrix formation. Recently these dermal proliferative disorders have been linked clinically to the cytokine transforming growth factor beta (TGF-beta), and in vitro tests have shown it to be responsible for the activation of fibroblasts and their production and deposition of collagen. Using an established in vivo animal model of proliferative scarring, the effects of this cytokine, specifically the isoform TGF-beta2, on these scars were examined. Proliferative scar specimens were implanted into athymic, asplenic nude rats and isolated in sandwich island flaps based on the superficial inferior epigastric pedicle. After establishment of the transferred flap, the scars were injected with varying doses of TGF-beta2 or vehicle for 5 consecutive days and then again on days 10, 15, and 20. The specimens were measured weekly during the period of dosing, and a biopsy was acquired on days 30 and 60. Fibroblasts from the explanted biopsies and the original scars were grown in cell culture, and cell proliferation studies were performed and the results compared. There was a dose response to TGF-beta2, with 200 ng showing the greatest effect. From the original scar specimens, keloid scars demonstrated the greatest cell proliferation kinetics--significantly faster than nonburn and burn hypertrophic scars. After treatment with TGF-beta2, both keloids and burn hypertrophic scars showed an increase in their cell proliferation kinetics compared with vehicle alone. This was not demonstrated with the nonburn hypertrophic scars. Elevated levels of TGF-beta2 are a major contributing factor to the process of proliferative scars, but because nonburn hypertrophic scars do not result in an equally increased response to this cytokine, a truly causative role for this cytokine cannot be promulgated. Rather, it is the combination of the proliferative scar fibroblasts' abnormal response to TGF-beta2 stimulation and elevated levels of this cytokine that controls more accurately the process of keloid and burn hypertrophic scar formation.