Rynchopeterine inhibits the formation of hypertrophic scars by regulating the miR-21/HIF1AN axis.

Hypertrophic scar (HS) is a fibroproliferative skin disease characterized by abnormal wound healing and pathological excessive fibrosis of the skin. Currently, the molecular mechanism of the disease is still largely unknown, and there is no effective drug treatment. In this study, we explored the effect of Rynchopeterine on the formation of HS. HS fibroblasts (HSFs) were isolated from the HS tissues of patients recovering from severe burns. After treating HSFs with different concentrations of Rynchopeterine, CCK-8, EdU, and Annexin V-FITC/PI assays were used to detect the proliferation, apoptosis, and contractile ability of HSFs. RT-qPCR and Western blotting were performed to evaluate the effect of Rynchopeterine on the expression of miR-21 and hypoxia-inducible factor 1-alpha subunit suppressor (HIF1AN). The dual-luciferase reporter gene was used to verify the targeting relationship between miR-21 and HIF1AN. Rynchopeterine reduced the expression of Col1a2, Col3a1, and α-SMA, inhibited proliferation and contraction of HSFs, and increased apoptosis in a dose-dependent manner. miR-21 was highly expressed in HS tissues and HSFs, and Rynchopeterine could inhibit miR-21 expression. Overexpression of miR-21 and knockdown of HIF1AN increased proliferation, activation, contraction, and collagen synthesis of HSFs, and inhibited their apoptosis. In vivo, Rynchopeterine could reduce the collagen content of the dermis and the positive ratio of PCNA and α-SMA. Rynchopeterine is a good therapeutic agent for HS, which up-regulates the expression of HIF1AN by inhibiting miR-21, thereby inhibiting the formation of HS.

HOXC10 promotes hypertrophic scar fibroblast fibrosis through the regulation of STMN2 and the TGF-ß/Smad signaling pathway.

The pathophysiology of hypertrophic scar (HS) shares similarities with cancer. HOXC10, a gene significantly involved in cancer development, exhibits higher expression levels in HS than in normal skin (NS), suggesting its potential role in HS regulation. And the precise functions and mechanisms by which HOXC10 influences HS require further clarification. Gene and protein expressions were analyzed using raeal-time quantitative polymerase chain reaction (RT-qPCR) and western blot techniques. Cell proliferation and migration were evaluated using EdU proliferation assays, CCK-8 assays, scratch assays, and Transwell assays. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were conducted to investigate the interactions between HOXC10 and STMN2. HOXC10 and STMN2 expression levels were significantly higher in HS tissues compared with NS tissues. Silencing HOXC10 led to decreased activation, proliferation, migration, and fibrosis in hypertrophic scar fibroblasts (HSFs). Our findings also indicate that HOXC10 directly targets STMN2. The promotional effects of HOXC10 knockdown on HSF activation, proliferation, migration, and fibrosis were reversed by STMN2 overexpression. We further demonstrated that HOXC10 regulates HSF activity through the TGF-ß/Smad signaling pathway. HOXC10 induces the activation and fibrosis of HSFs by promoting the transcriptional activation of STMN2 and engaging the TGF-ß/Smad signaling pathway. This study suggests that HOXC10 could be a promising target for developing treatments for HS.

Association of Cutaneous Keloids, Hypertrophic Scarring, and Fibrosis with Risk of Postoperative Proliferative Vitreoretinopathy.

PURPOSE: To assess an association between cutaneous keloids, hypertrophic scarring, and fibrosis (KHF) and risk of postoperative proliferative vitreoretinopathy (PVR) after rhegmatogenous retinal detachment (RRD) repair. DESIGN: Retrospective, population-based cohort study. PARTICIPANTS: Patients aged ≥ 18 years who underwent initial retinal detachment (RD) repair with pars plana vitrectomy with or without scleral buckle (SB) (Current Procedural Terminology [CPT] 67108), pneumatic retinopexy (67110), and primary SB (67107) from January 1, 2003, to March 1, 2023. METHODS: A de-identified electronic health record database through TriNetX, a global health research network, was used to analyze patients. Patients were queried for International Classification of Diseases, 10th Revision (ICD-10) codes L91.0 (hypertrophic scar) and L90.5 (scar conditions and fibrosis of skin). Frequency of subsequent diagnosis of PVR (H35.2) and CPT codes for secondary surgery including complex RD repair (67113) were determined. Patients with proliferative diabetic retinopathy (PDR) (ICD-10 H10.35/H11.35) were excluded. Descriptive statistics (Z-test) and propensity score matching (PSM) were used to match for age, sex, and race. MAIN OUTCOME MEASURES: Prevalence of H35.2 and CPT 67113 within 180 days after RRD repair in the KHF cohort versus the non-KHF cohort. RESULTS: Among patients with CPT 67108, 1061 in each cohort (KHF and non-KHF) were analyzed after PSM. The mean (standard deviation) age was 60.7 (15.2) years. Within 180 days, 10.1% of patients in the KHF cohort and 3.4% in the non-KHF cohort had a diagnosis of PVR (H35.2) (P < 0.001, odds ratio [OR], 3.2; 95% confidence interval [CI], 2.13-4.71). A total of 8.3% of patients in the KHF cohort and 5.4% of patients in the non-KHF cohort underwent complex RD repair (CPT 67113) (P = 0.008; OR, 3.2; 95% CI, 1.13-2.25). When including all RD repair types (CPT 67108, 67110, 67107), the rate of PVR diagnosis was still significantly greater in the KHF cohort than in the non-KHF cohort (9.0% vs 4.2%, P < 0.01; OR, 2.28; 95% CI, 1.64-3.16). CONCLUSIONS: A dermatologic history of KHF may be a risk factor for PVR after RD repair. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The effects of TGF-ß1 and IFN-α2b on decorin, decorin isoforms and type I collagen in hypertrophic scar dermal fibroblasts.

Hypertrophic scars (HTS) develop from an excessive synthesis of structural proteins like collagen and a decreased expression of proteoglycans such as decorin. Previous research has demonstrated that decorin expression is significantly down-regulated in HTS, deep dermal tissue, and thermally injured tissue, reducing its ability to regulate pro-fibrotic transforming growth factor-beta 1 (TGF-ß1) and normal fibrillogenesis. However, treatment of HTS fibroblasts with interferon-alpha 2b (IFN-α2b) has been shown to reduce excessive collagen synthesis and improve HTS by reducing serum TGF-ß1 levels. The expression of decorin isoforms in HTS is currently unknown and the effects of TGF-ß1 and IFN-α2b on decorin, decorin isoform expression and type 1 collagen are of great interest to our group. Dermal fibroblasts were treated with TGF-ß1 and/or IFN-α2b, for 48 h. The expression and secretion of decorin, decorin isoforms and type 1 collagen were quantified with reverse transcription-quantitative polymerase chain reaction, immunofluorescence staining and enzyme-linked immunosorbent assays. The mRNA expression of decorin and each isoform was significantly reduced in HTS fibroblasts relative to normal skin. TGF-ß1 decreased the mRNA expression of decorin and decorin isoforms, whereas IFN-α2b showed the opposite effect. IFN-α2b significantly inhibited TGF-ß1's effect on the mRNA expression of type I collagen alpha 1 in papillary dermal fibroblasts and overall showed relative effects of inhibiting TGF-ß1. These data support that a further investigation into the structural and functional roles of decorin isoforms in HTS pathogenesis is warranted and that IFN-α2b is an important agent in reducing fibrotic outcomes.

Clinical efficacy of CO2 fractional laser in treating post-burn hypertrophic scars in children: A meta-analysis: CO2 fractional laser in treating post-burn hypertrophic scars in children.

OBJECTIVE: To evaluate and explore the efficacy of CO2 fractional laser in treating post-burn hypertrophic scars in children through Meta-analysis. METHODS: English databases (PubMed, Web of Science and The National Library of Medicine), as well as Chinese databases (China National Knowledge Infrastructure and Wanfang Data) were searched. RevMan 5.3 software was used to data analysis. RESULTS: A total of 10 pieces of literature were included, involving 413 children. Meta-analysis showed that: (1) The average Vancouver Scar Scale after surgery was significantly lower than that before surgery [weight mean difference (WMD) = -3.56, 95% confidence interval (CI):-4.53,-2.58, p < 0.001]; (2) After CO2 fractional laser, pigmentation [WMD = -0.74, 95% CI:-1.10,-0.38, p < 0.001], pliability [WMD = -0.92, 95% CI:-1.20,-0.65, p < 0.001], vascularity [WMD = -0.77, 95% CI:-1.09,-0.46, p < 0.001], height [WMD = -0.57, 95% CI:-0.95,-0.19, p < 0.001] were improved compared with those before surgery. (3) The average Visual Analogue Scale (VAS) after surgery was significantly lower than that before surgery [WMD = -3.94, 95% CI:-5.69,-2.22, p < 0.001]. (4) Both Patient and Observer Scar Assessment Scale (POSAS)-Observer [WMD = -3.98, 95% CI:-8.44,0.47, p < 0.001] and POSAS-Patient [WMD = -4.98, 95% CI:-8.09,-1.87, p < 0.001] were significantly lower than those before surgery. (5) Erythema and vesicles were the most common complications after CO2 fractional laser therapy, with an incidence of 4.09%. CONCLUSION: CO2 fractional laser is beneficial to the recovery of hypertrophic scar after burn in children, and can effectively improve the scar symptoms and signs in children, with desirable clinical efficacy.

The Potential of Chat-Based Artificial Intelligence Models in Differentiating Between Keloid and Hypertrophic Scars: A Pilot Study.

BACKGROUND: Lasting scars such as keloids and hypertrophic scars adversely affect a patient's quality of life. However, these scars are frequently underdiagnosed because of the complexity of the current diagnostic criteria and classification systems. This study aimed to explore the application of Large Language Models (LLMs) such as ChatGPT in diagnosing scar conditions and to propose a more accessible and straightforward diagnostic approach. METHODS: In this study, five artificial intelligence (AI) chatbots, including ChatGPT-4 (GPT-4), Bing Chat (Precise, Balanced, and Creative modes), and Bard, were evaluated for their ability to interpret clinical scar images using a standardized set of prompts. Thirty mock images of various scar types were analyzed, and each chatbot was queried five times to assess the diagnostic accuracy. RESULTS: GPT-4 had a significantly higher accuracy rate in diagnosing scars than Bing Chat. The overall accuracy rates of GPT-4 and Bing Chat were 36.0% and 22.0%, respectively (P = 0.027), with GPT-4 showing better performance in terms of specificity for keloids (0.6 vs. 0.006) and hypertrophic scars (0.72 vs. 0.0) than Bing Chat. CONCLUSIONS: Although currently available LLMs show potential for use in scar diagnostics, the current technology is still under development and is not yet sufficient for clinical application standards, highlighting the need for further advancements in AI for more accurate medical diagnostics. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online instructions to authors www.springer.com/00266 .

Efficacy and Safety of Corticosteroid in Combination with 5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Systematic Review and Meta-analysis.

BACKGROUND: Addressing hypertrophic scars and keloids poses a significant challenge in the realm of preventive and curative medicine. Combination corticosteroid with 5-fluorouracil (5-FU) is presumed to enhance the treatment of hypertrophic scars and keloids, although supportive evidence is lacking. This study is aimed at comparing the efficacy and safety profile of a combined corticosteroid and 5-FU regimen in treating hypertrophic scars and keloids. METHODS: A comprehensive search was conducted for pertinent studies across various databases, including Web of Science, PubMed, Google Scholar, Cochrane Library, and Medline. The calculation of weighted mean difference (WMD), risk ratios (RR), odds ratios (OR), and 95% confidence intervals (CIs) was executed. Additionally, the Cochrane Collaboration's Risk of Bias Tool was utilized to evaluate potential bias risks. RESULTS: A total of 15 studies were involved. The effectiveness based on patient self-assessment and the effectiveness based on observer assessment were significantly higher in the corticosteroid+5-FU group compared to those treated with control. A meta-analysis of scar height showed that the corticosteroid+5-FU group performed better than the control group (WMD = -0.38, 95% CI -0.58 to -0.18). There was no significant difference between the corticosteroid+5-FU group and the control group in improving scar vascularity, pliability and pigmentation. The result revealed that the corticosteroid+5-FU group of patients had less adverse effect of hypopigmentation, skin atrophy and telangiectasia than the control group. CONCLUSION: The combined use of corticosteroids and 5-FU appears to be a more effective strategy for the treatment and prevention of hypertrophic scars and keloids, as evidenced by greater improvements in scar height and overall effectiveness, coupled with a reduced incidence of side effects. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Laser Therapy in Hypertrophic and Keloid Scars: A Systematic Review and Network Meta-analysis.

BACKGROUND: Laser therapy has emerged as a promising treatment modality for improving the appearance and symptoms associated with hypertrophic and keloid scars. In this network meta-analysis, we aimed to evaluate the efficacy of different laser types in treating hypertrophic and keloid scars. METHODS: A comprehensive search of four databases was conducted to identify relevant studies published up until July 2023. Data were extracted from eligible studies and pooled as mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous data in a network meta-analysis (NMA) model, using R software. RESULTS: A total of 18 studies, comprising 550 patients, were included in the analysis. Pooling our data showed that fractional carbon dioxide (FCO2) plus 5-fluorouracil (5-FU) was superior to control in terms of Vancouver Scar Scale (VSS), pliability score, and thickness; [MD = - 5.97; 95% CI (- 7.30; - 4.65)], [MD = - 2.68; 95% CI (- 4.03; - 1.33)], [MD = - 2.22; 95% CI (- 3.13; - 1.31)], respectively. However, insignificant difference was observed among FCO2 plus 5-FU compared to control group in terms of erythema, vascularity, redness and perfusion, and pigmentation [MD = - 0.71; 95% CI (- 2.72; 1.30)], [MD = - 0.44; 95% CI (- 1.26; 0.38)], respectively. CONCLUSION: Our NMA found that the FCO2 plus 5-FU was the most effective intervention in decreasing the VSS and thickness, while FCO2 plus CO2 was the most effective intervention in decreasing the pliability score. Further research is needed to determine the optimal laser parameters and long-term efficacy of laser therapy in hypertrophic and keloid scars. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Combined Stromal Vascular Fraction and Fractional CO2 Laser Therapy for Hypertrophic Scar Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: Hypertrophic scars (HTSs) result from aberrant wound healing processes, leading to raised, thickened tissue with functional discomfort and cosmetic concerns. Current treatments, including corticosteroid injections and laser therapy, have limitations. Stromal vascular fraction (SVF) therapy and CO2 laser treatment offer promising avenues, with SVF therapy showing regenerative potential and CO2 laser therapy promoting precise tissue removal and wound healing. This study aims to investigate the combined application of SVF therapy and CO2 laser treatment for HTS, aiming to enhance treatment efficacy, tissue remodeling, and aesthetic outcomes, ultimately improving patient satisfaction in HTS management. METHOD: PubMed, Scopus, Embase, and Web of Science databases have been searched for relevant studies. The "R" software (version 4.3.1) along with the "tidyverse" and "meta" statistical packages utilized to analyze data related to the efficiency of this combined method. A random-effects model was fitted to the data. For each study, continuous outcomes were pooled by calculating the standardized mean difference, along with their 95% confidence intervals. The assessment of heterogeneity utilized the I2 and chi-squared tests, applying the random effect model. RESULTS: Six articles fulfilled our inclusion criteria and were included in our review. Results from the pooled analysis of Vancouver Scar Scale (VSS) scores across three included studies indicated a significant impact of the SVF+CO2 method on VSS scores post-treatment (SMD=-3.0144; 95% CI:-4.3706 to -1.6583, p<0.0001). However, analysis of transepidermal water loss levels before and after treatment showed no significant difference (SMD=-2.7603; 95% CI: -6.8729 to 1.3522; p=0.1883). Comparatively, in a pooled analysis of two studies, the combined SVF+CO2 method demonstrated superior efficacy in VSS scores compared to other methods (SMD= -1.3573; 95% CI: -2.2475 to -0.4672, p = 0.0028), with moderate heterogeneity across studies (I^2=23.0%, p = 0.2545). CONCLUSION: The combined application of SVF and CO2 laser treatment shows significant promise in improving hypertrophic scars' appearance and texture. The SVF+CO2 method demonstrates superior efficacy compared to other modalities, suggesting its potential as a valuable therapeutic approach for hypertrophic scar management. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Losartan in Situ Forming Gel as a New Treatment for Hypertrophic Scars.

Hypertrophic scars are defined as visible lesions formed by excessive wound healing that cause cosmetic and, in some cases, functional challenges in patients. This study aimed to assess the efficacy of intralesional injections of losartan-loaded in situ forming gel and compare it with the common treatment (triamcinolone) in preventing scar formation. The formulation was prepared using a thermosensitive PLGA-PEG-PLGA triblock copolymer. Ear scar tissue in rabbits represented the hypertrophic scar, and the animals were treated with three treatments in three groups. Nine weeks following the single treatment, images of the scars were obtained and quantitatively analyzed using ImageJ and light microscopy was used to evaluate the fibroblast cell number, vascularization, inflammation and collagen deposition and fibrosis in H&E-stained sample tissue. According to the results based on the ImageJ and the Vancouver criteria, the losartan in situ forming gel (F-LG) indicated significantly higher improving effects on decreased vascularity and pigmentation in comparison with triamcinolone (F-TA) and placebo as a control (F-Ctl), although the effect F-LG was almost similar to F-TA on pliability and scar height, and they were better than the control. Histological findings showed F-LG and F-TA have less inflammatory and fibroblast cells compared to F-Ctl. Also, results indicated the dermal layers of the F-TA and F-LG groups' scar were thinner, and the deposition of collagens was reduced compared to the control. Consequently, F-LG was found to be an effective treatment in reducing scarring and promoting wound healing.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Microneedling in the Treatment of Post-burn Hypertrophic Scars.

INTRODUCTION: Post-burn hypertrophic scars are an important cause of physical discomfort, limitation of movements, psychological disorders, low self-esteem and reduced quality of life. Treatment for this condition is complex and involves several options. Microneedling, also known as minimally invasive percutaneous collagen induction, is an affordable minimally invasive option that can be combined with other treatments, including ablative ones. OBJECTIVE: The goal of this study was to present our microneedling approach for the treatment of hypertrophic scars after burns. METHOD: A prospective study of 15 patients with post-burn hypertrophic scars was conducted between October 2016 and June 2022. All patients were treated with microneedling and drug delivery of triamcinolone. Scars were evaluated using Vancouver Scar Scale (VSS), Burn Scar Assessment Scale (BSAS) and angle measurement for amplitude of movement evaluation of joints. RESULTS: A significant improvement in the VSS score was obtained after microneedling (8.8 ± 0.44 to 4.1 ± 0.98; p = 0.012), especially in the acute group (less than 1 year after burns): 9.3 ± 0.49 to 3.5 ± 1.36; p = 0.041. There was a significant and progressive improvement of the scars throughout the treatment sessions in all criteria evaluated and in the ranges of joint movement (p = 0.012). CONCLUSION: Our microneedling protocol promoted a significant improvement of post-burn scars, especially in acute hypertrophic scars, and in the amplitude of joint motion. Sequential treatments provided progressive improvement. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Pharmacotherapy for Keloids and Hypertrophic Scars.

Keloids (KD) and hypertrophic scars (HTS), which are quite raised and pigmented and have increased vascularization and cellularity, are formed due to the impaired healing process of cutaneous injuries in some individuals having family history and genetic factors. These scars decrease the quality of life (QOL) of patients greatly, due to the pain, itching, contracture, cosmetic problems, and so on, depending on the location of the scars. Treatment/prevention that will satisfy patients' QOL is still under development. In this article, we review pharmacotherapy for treating KD and HTS, including the prevention of postsurgical recurrence (especially KD). Pharmacotherapy involves monotherapy using a single drug and combination pharmacotherapy using multiple drugs, where drugs are administered orally, topically and/or through intralesional injection. In addition, pharmacotherapy for KD/HTS is sometimes combined with surgical excision and/or with physical therapy such as cryotherapy, laser therapy, radiotherapy including brachytherapy, and silicone gel/sheeting. The results regarding the clinical effectiveness of each mono-pharmacotherapy for KD/HTS are not always consistent but rather scattered among researchers. Multimodal combination pharmacotherapy that targets multiple sites simultaneously is more effective than mono-pharmacotherapy. The literature was searched using PubMed, Google Scholar, and Online search engines.

Fibrosis in burns: an overview of mechanisms and therapies.

Scar development remains a common occurrence and a major healthcare challenge affecting the lives of millions of patients annually. Severe injuries to the skin, such as burns can lead to pathological wound healing patterns, often characterized by dermal fibrosis or excessive scarring, and chronic inflammation. The two most common forms of fibrotic diseases following burn trauma are hypertrophic scars (HSCs) and keloids, which severely impact the patient's quality of life. Although the cellular and molecular mechanisms are similar, HSC and keloids have several distinct differences. In this review, we discuss the different forms of fibrosis that occur postburn injury, emphasizing how the extent of burn influences scar development. Moreover, we highlight how a systemic response induced by a burn injury drives wound fibrosis, including both the role of the inflammatory response, as well as the fate of fibroblast during skin healing. Finally, we list potential therapeutics aimed at alleviating pathological scar formation. An understanding of the mechanisms of postburn fibrosis will allow us to effectively move studies from bench to bedside.

Microfat exerts an anti-fibrotic effect on human hypertrophic scar via fetuin-A/ETV4 axis.

BACKGROUND: Hypertrophic scar is a fibrotic disease following wound healing and is characterized by excessive extracellular matrix deposition. Autologous microfat grafting proves an effective strategy for the treatment thereof as it could improve the texture of scars and relieve relevant symptoms. This study aims to explore the potential mechanisms underlying the anti-fibrotic effect of microfat on hypertrophic scars. METHODS: In this study, we injected microfat into transplanted hypertrophic scars in mouse models and investigated the subsequent histological changes and differential expression of mRNAs therein. As for in vitro studies, we co-cultured microfat and hypertrophic scar fibroblasts (HSFs) and analyzed molecular profile changes in HSFs co-cultured with microfat by RNA sequencing. Moreover, to identify the key transcription factors (TFs) which might be responsible for the anti-fibrotic function of microfat, we screened the differentially expressed TFs and transfected HSFs with lentivirus to overexpress or knockdown certain differentially expressed TFs. Furthermore, comparative secretome analyses were conducted to investigate the proteins secreted by co-cultured microfat; changes in gene expression of HSFs were examined after the administration of the potential anti-fibrotic protein. Finally, the relationship between the key TF in HSFs and the microfat-secreted anti-fibrotic adipokine was analyzed. RESULTS: The anti-fibrotic effect of microfat was confirmed by in vivo transplanted hypertrophic scar models, as the number of α-SMA-positive myofibroblasts was decreased and the expression of fibrosis-related genes downregulated. Co-cultured microfat suppressed the extracellular matrix production of HSFs in in vitro experiment, and the transcription factor ETV4 was primarily differentially expressed in HSFs when compared with normal skin fibroblasts. Overexpression of ETV4 significantly decreased the expression of fibrosis-related genes in HSFs at both mRNA and protein levels. Fetuin-A secreted by microfat could also downregulate the expression of fibrosis-related genes in HSFs, partially through upregulating ETV4 expression. CONCLUSIONS: Our results demonstrated that transcription factor ETV4 is essential for the anti-fibrotic effect of microfat on hypertrophic scars, and that fetuin-A secreted by microfat could suppress the fibrotic characteristic of HSFs through upregulating ETV4 expression. Microfat wields an alleviative influence over hypertrophic scars via fetuin-A/ETV4 axis.

Immune cells and associated molecular markers in dermal fibrosis with focus on raised cutaneous scars.

Raised dermal scars including hypertrophic, and keloid scars as well as scalp-associated fibrosing Folliculitis Keloidalis Nuchae (FKN) are a group of fibrotic raised dermal lesions that mostly occur following cutaneous injury. They are characterized by increased extracellular matrix (ECM) deposition, primarily excessive collagen type 1 production by hyperproliferative fibroblasts. The extent of ECM deposition is thought to be proportional to the severity of local skin inflammation leading to excessive fibrosis of the dermis. Due to a lack of suitable study models, therapy for raised dermal scars remains ill-defined. Immune cells and their associated markers have been strongly associated with dermal fibrosis. Therefore, modulation of the immune system and use of anti-inflammatory cytokines are of potential interest in the management of dermal fibrosis. In this review, we will discuss the importance of immune factors in the pathogenesis of raised dermal scarring. The aim here is to provide an up-to-date comprehensive review of the literature, from PubMed, Scopus, and other relevant search engines in order to describe the known immunological factors associated with raised dermal scarring. The importance of immune cells including mast cells, macrophages, lymphocytes, and relevant molecules such as cytokines, chemokines, and growth factors, antibodies, transcription factors, and other immune-associated molecules as well as tissue lymphoid aggregates identified within raised dermal scars will be presented. A growing body of evidence points to a shift from proinflammatory Th1 response to regulatory/anti-inflammatory Th2 response being associated with the development of fibrogenesis in raised dermal scarring. In summary, a better understanding of immune cells and associated molecular markers in dermal fibrosis will likely enable future development of potential immune-modulated therapeutic, diagnostic, and theranostic targets in raised dermal scarring.

Mimicking fat grafting of fibrotic scars using 3D-organotypic skin cultures.

Wound healing of deep burn injuries is often accompanied by severe scarring, such as hypertrophic scar (HTS) formation. In severe burn wounds, where the subcutis is also damaged, the scars adhere to structures underneath, resulting in stiffness of the scar and impaired motion. Over the recent years, a promising solution has emerged: autologous fat grafting, also known as lipofilling. Previous clinical reports have shown that the anti-fibrotic effect has been attributed to the presence of adipose-derived stromal cells (ADSC). In the proposed study, we aim to investigate the effect of fat grafting in 3D organotypic skin cultures mimicking an HTS-like environment. To this end, organotypic skin cultures were embedded with normal skin fibroblasts (NF) or HTS-derived fibroblasts with or without incorporation of human adipose subcutaneous tissue (ADT) and one part was thermally wounded to examine their effect on epithelialization. The developed skin cultures were analysed on morphology and protein level. Analysis revealed that ADT-containing organotypic skin cultures comprise an improved epidermal homeostasis, and a fully formed basement membrane, similar to native human skin (NHS). Furthermore, the addition of ADT significantly reduced myofibroblast presence, which indicates its anti-fibrotic effect. Finally, re-epithelialization measurements showed that ADT reduced re-epithelialization in skin cultures embedded with NFs, whereas HTS-fibroblast-embedded skin cultures showed complete wound closure. In conclusion, we succeeded in developing a 3D organotypic HTS-skin model incorporated with subcutaneous tissue that allows further investigation on the molecular mechanism of fat grafting.

The combined application of bleomycin and triamcinolone for the treatment of keloids and hypertrophic scars: An effective therapy for treating refractory keloids and hypertrophic scars.

BACKGROUND: Keloids and hypertrophic scars frustrate patients by the deformity of appearance and organ dysfunction. Many modalities had been tried in clinic practice, but the results are unsatisfied. OBJECTIVE: We retrospectively analysed the combined application of bleomycin and triamcinolone for the treatment of keloids and hypertrophic scars. METHODS: The combination of bleomycin and triamcin acetonide was applied to the treatment of keloids and hypertrophic scars, 86 cases accepted the treatment. Follow-up 2-5 years after treatment. RESULTS: (1) The pain of scars and itching symptoms have basically subsided through treatment. (2) After drug injection treatment, the keloid began to shrink, some of the keloids disappeared. (3) Small keloids did not recur after treatment. Large keloids had local recurrence after treatment. When further treatment was given, the recurrence disappeared. CONCLUSION: The combined application of bleomycin and triamcin acetonide can effectively cure keloids and hypertrophic scars.

The Molecular Mechanisms Involved in the Hypertrophic Scars Post-Burn Injury.

Scar formation is a normal response to skin injuries. During the scar-remodeling phase, scar tissue is usually replaced with normal, functional tissue. However, after deep burn injuries, the scar tissue may persist and lead to contractures around joints, a condition known as hypertrophic scar tissue. Unfortunately, current treatment options for hypertrophic scars, such as surgery and pressure garments, often fail to prevent their reappearance. One of the primary challenges in treating hypertrophic scars is a lack of knowledge about the molecular mechanisms underlying their formation. In this review, we critically analyze studies that have attempted to uncover the molecular mechanisms behind hypertrophic scar formation after severe burn injuries, as well as clinical trials conducted to treat post-burn hypertrophic scars. We found that most clinical trials used pressure garments, laser treatments, steroids, and proliferative inhibitors for hypertrophic scars, with outcomes measured using subjective scar scales. However, fundamental research using human burn injury biopsies has shown that pathways such as Transforming Growth factor ß (TGFß), Phosphatase and tensin homolog (PTEN), and Toll-like receptors (TLRs) could be potentially regulated to reduce scarring. Therefore, we conclude that more testing is necessary to determine the efficacy of these molecular targets in reducing hypertrophic scarring. Specifically, double-blinded clinical trials are needed, where the outcomes can be measured with more robust quantitative molecular parameters.

The efficacy and safety of low-energy carbon dioxide fractional laser use in the treatment of early-stage pediatric hypertrophic scars: A prospective, randomized, split-scar study.

BACKGROUND: Various laser therapies have been introduced in scar management. However, pain during treatment has limited the application of laser therapy in pediatrics. OBJECTIVES: To evaluate whether the use of the low-energy mode of a carbon dioxide (CO2 ) laser improves hypertrophic scars in a pediatric population. METHODS: This prospective, randomized, split-scar trial was designed to assess the safety and efficacy of low-energy CO2 laser use. Patients aged <12 years with hypertrophic scars were enrolled. Each hypertrophic scar was equally divided into three parts: the two ends of each scar were randomly assigned to control and experimental groups, and the center portion was considered a transition zone and was not included in the analysis. A total of three laser treatments were performed at 1-month intervals. Scar scale scores 6 months after the final treatment was the primary outcome. Additionally, the Visual Analog Scale (VAS) was used to evaluate pain after each treatment. RESULTS: Of the 23 patients enrolled, 20 completed the study. The total Patient and Observer Scar Assessment Scale (POSAS) score at the 6-month follow-up was significantly lower for the treated site (44.95 for the treated group vs. 64.85 for the control group, p < 0.0001). Both the patient and observer POSAS scores showed an obvious difference between the treated and control groups (19.95 vs. 29.95 for patient scores, respectively, p < 0.0001, and 26.00 vs. 34.90 for observer scores, respectively, p < 0.0001). All observer and patient scores describing pain, pruritus, color, stiffness, and thickness were statistically different and favored the treated site. No significant difference was found in patient score of irregularity. The average VAS therapeutic pain score was 3.5 ± 1.43 out of 10. CONCLUSIONS: Low-energy CO2 fractional laser therapy improved hypertrophic scars in a pediatric population. Therefore, for children with hypertrophic scar, low-energy CO2 laser with less procedure pain may be more appropriate.

Fractional microneedle radiofrequency versus fractional carbon dioxide laser in the treatment of postburn hypertrophic scars.

BACKGROUND AND OBJECTIVE: New and improved treatment modalities, including lasers and energy-based devices, are promising treatment options for hypertrophic scars. This study aimed to assess the efficacy and safety of fractional microneedle radiofrequency (FMR) compared with fractional carbon dioxide (CO2 ) laser in the treatment of postburn hypertrophic scars. PATIENTS AND METHODS: Twenty patients with hypertrophic scars were enrolled in the study. Two areas in each patient were randomly assigned to fractional CO2 laser or FMR. Four sessions, 6-8 weeks apart were performed. The Patient and Observer Scar Assessment Scale (POSAS) was used for clinical evaluation, H & E and orcein-stained samples were examined for histopathological assessment, and tissue transforming growth factor beta 1 (TGFß1 ) levels were measured for biochemical evaluation. RESULTS: Both fractional CO2 and FMR-treated areas showed significant improvement in all parameters 1 month after treatment. Fractional CO2-treated areas showed a higher degree of improvement compared with FMR in OSAS (p = 0.025), elastin grading (p = 0.004), and TGFß1 levels (p = 0.000). Patients reported less downtime and showed less postinflammatory hyperpigmentation with FMR compared with fractional CO2, but this did not reach statistical significance (p = 0.327, p = 0.231; respectively). CONCLUSION: Our results demonstrate the value of FMR as an effective alternative to fractional CO2 in the treatment of hypertrophic scars, with a potentially favorable safety profile.