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Background: Hypertrophic scar (HS) is associated with cosmetic defects, mobility, and functional impairments, pruritus, and pain. Previous circRNA microarray analysis identified reduced expression of circRNA_SLC8A1 in HS tissues. Therefore, this study aims to investigate the role of circRNA_SLC8A1 in modulating the abnormal behavior of HS-derived fibroblasts (HSFs) in vitro. Methods: RT-qPCR and FISH assays were used to assess the differential expression and localization of circRNA_SLC8A1 in normal and HS tissues. Following modulation of circRNA_SLC8A1 expression, CCK-8, flow cytometry, Transwell, and wound healing assays were employed to evaluate the effects of circRNA_SLC8A1 on the biological behaviors of HSFs. The Starbase database, dual-luciferase reporter assays, and Ago2-RIP assays were utilized to predict and validate the interaction between circRNA_SLC8A1 and downstream miRNAs. Results: CircRNA_SLC8A1 was found to be downregulated in HS tissues and was primarily localized in the cytoplasm. Overexpression of circRNA_SLC8A1 reduced cell viability, cell invasion, wound healing, and the expression of Vimentin, N-cadherin, Col I, and Col III, while enhancing apoptosis and E-cadherin expression in HSFs. CircRNA_SLC8A1 activates the Nrf2-ARE pathway by competitively binding to miRNA-27a-3p. miRNA-27a-3p and Nrf2 exhibited high and low expression, respectively in HS tissues, with an inverse correlation between their levels. Overexpression of miRNA-27a-3p counteracted the effects of circRNA_SLC8A1 in HSF proliferation, apoptosis, migration, EMT, collagen deposition, and Nrf2-ARE pathway activity. Conclusion: CircRNA_SLC8A1 inhibits the proliferation, migration, EMT, and collagen deposition of HSF through competitive binding with miRNA-27a-3p, thereby activating the Nrf2-ARE pathway. The circRNA_SLC8A1/miRNA-27a-3p/Nrf2-ARE axis may offer a promising molecular target for HS therapy. [ABSTRACT FROM AUTHOR]

The hypertrophic scar (HS) is a prevalent cutaneous fibrotic disorder that impacts both the aesthetic and functional aspects of the skin, there is an urgent need for a highly safe and effective approach to address the challenge of HS with thick and deep types. Inspired by the superior deep tissue penetrative ability of near-infrared-II (NIR-II) light and potential mitochondria ROS inducing effect of Chinese medicine lycorine (LYC), we fabricated a Cu2Se@LYC (CL) composite by encapsulating LYC on polyvinyl pyrrolidone (PVP) modified Cu2Se nanoparticles. After NIR-II irradiation, CL could induce the generation of reactive oxygen species (ROS) and mitochondrial damage in hypertrophic scar fibroblasts (HSFs). The subsequent release of cytochrome C (cyt-c) from mitochondria into the cytoplasm and upregulation of beclin1 leads to the activation of endogenous apoptosis and autophagy-mediated cell death. The CL + NIR-II treatment exhibited a pronounced anti-scarring effect in both in vitro and in vivo rabbit ear scar models, leading to a significant reduction in the fibrotic markers including Collagen I/III and α-smooth muscle actin (α-SMA). This study comprehensively investigated the crucial role of HSFs' autophagy in scar management and proposed a safe and effective therapy based on NIR-II laser for clinical application. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of brace masks on controlling facial hypertrophic scars. Method: Totally 63 patients with 286 post-burn facial hypertrophic scars samples were recruited for the study. And they were divided into the brace mask group with 28 cases(152 scars), cloth mask group with 26 cases (100 scars), and control group with 9 cases (34 scars). Patients in the brace mask group and cloth mask group received eight weeks of pressure therapy, while the control group did not receive pressure therapy intervention. Pre- and post-treatment, chromatography was used to evaluate the scar color(lightness, redness and yellowness). An ultrasonic measuring instrument was used to evaluate the scar thickness. The Vancouver scar scale (VSS) was used. Patient satisfaction with eight weeks of treatment was evaluated with satisfaction scale. Result: ① Pre- and post- treatment comparison: The brightness decreased in control group and increased in mask group(P<0.001). The redness increased in control group and decreased in mask group(P<0.001). The thickness and VSS score increased in three groups bu more in control group(P=0.001). There was no change in yellowness for all the three groups(P=0.981). ②compared the two mask groups, there was no significant difference for all parameters(P>0.05). ③satisfaction: the overall satisfaction of the brace mask group and the cloth mask group are 75% and 69.2% respectively. The comfort and appearance satisfaction of the brace mask group is better than the cloth mask group. The price satisfaction of the mask group is lower. Conclusion: For the facial hypertrophic scars, this short-term efficacy study showed that the brace mask and cloth mask could improve the lightness and redness and inhibit the thickness of it. The overall satisfaction of patients is high after using brace masks and cloth masks. [ABSTRACT FROM AUTHOR]

Background: Patients with hypertrophic scarring tend to experience recurrence after treatment, which often occurs in areas of the body with high skin tension. Aims: To evaluate better treatments aimed at reducing the risk of scar recurrence in areas of high skin tension. Methods: Patients were randomly divided into the following three treatment groups: botulinum toxin type A (BTA) via dual‐plane micro‐drop injections, triamcinolone acetonide (TAC) suspension, and CO2 via fractional CO2 laser. Interventions were implemented in all three groups once a month for three consecutive sessions. After the final treatment, scarring was evaluated at 1, 3, 6, 12, and 24 months using the Patient and Observer Scar Assessment Scale (POSAS). Results: The 3‐month POSAS score for each scar indicator in the treatment groups was significantly lower than that in the preoperative groups (p < 0.001). The scar score in the TAC group decreased at 3 months and increased thereafter. For other groups, the scar score continually decreased at all time points according to the Patient Scar Assessment Scale. Based on the Observer Scar Assessment Scale, the scar score continuously decreased at all time points in the BTA group; in the TAC group, it decreased at 1 month and increased thereafter; and in the CO2 group, the scar score decreased at 3 months and subsequently stabilized. Conclusions: All three treatment methods were effective. However, the BTA group experienced a reduced risk of scar recurrence and maintained long‐term treatment effects. [ABSTRACT FROM AUTHOR]

Hypertrophic scar (HS) results from burns or trauma, causing aesthetic and functional issues. However, observational studies have linked inflammatory cytokines to HS, but the causal pathways involved are unclear. We aimed to determine how circulating inflammatory cytokines contribute to HS formation. Two-sample Mendelian randomization (MR) was used to identify genetic variants associated with hypertrophic scar in a comprehensive, publicly available genome-wide association study (GWAS) involving 766 patients and 207,482 controls of European descent. Additionally, data on 91 plasma proteins were drawn from a GWAS summary involving 14,824 healthy participants. Causal relationships between exposures and outcomes were investigated primarily using the inverse variance weighted (IVW) method. Furthermore, a suite of sensitivity analyses, including MR‒Egger and weighted median approaches, were concurrently employed to fortify the robustness of the conclusive findings. Finally, reverse MR analysis was conducted to evaluate the plausibility of reverse causation between hypertrophic scar and the cytokines identified in our study. In inflammatory cytokines, there was evidence of inverse associations of osteoprotegerin(OPG) levels(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01), and leukemia inhibitory factor(LIF) levels(OR = 0.51, 95% CI = 0.32 ∼ 0.82, p = 0.01) are a nominally negative association with hypertrophic scar risk, while CUB domain-domain-containing protein 1(CDCP1) level(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01) glial cell line-derived neurotrophic factor(GDNF) levels(OR = 1.42, 95% CI = 1.03 ∼ 1.96, p = 0.01) and programmed cell death 1 ligand 1(PD-L1) levels(OR = 1.47, 95% CI = 1.92 ∼ 2.11, p = 0.04) showed a positive association with hypertrophic scar risk. These associations were similar in the sensitivity analyses. According to our MR findings, OPG and LIF have a protective effect on hypertrophic scar, while CDCP1, GDNF, and PD-L1 have a risk-increasing effect on Hypertrophic scar. Our study adds to the current knowledge on the role of specific inflammatory biomarker pathways in hypertrophic scar. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for hypertrophic scar prevention and treatment. [ABSTRACT FROM AUTHOR]

Background and objective: Adipose-derived mesenchymal stem cells (ADSCs) can accelerate wound healing, reduce scar formation, and inhibit hypertrophic scar (HTS). ADSCs can secrete a large amount of CCL5, and CCL5 has been proved to be pro-inflammatory and pro-fibrotic. CXCL12 (SDF-1) is a key chemokine that promotes stem cell migration and survival. Therefore, this study selected normal skin and HTS conditioned medium to simulate different microenvironments, and analyzed the effects of different microenvironments on the expression of CCL5 and CXCL12 in human ADSCs (hADSCs). Materials and methods: hADSCs with silenced expression of CCL5 and CXCL12 were co-cultured with hypertrophic scar fibroblasts to verify the effects of CCL5 and CXCL12 in hADSCs on the proliferation ability of hypertrophic scar fibroblasts. A mouse model of hypertrophic scar was established to further confirm the effect of CCL5 and CXCL12 in hADSCs on hypertrophic scar formation. Results: CCL5 level was found to be significantly high in hADSCs cultured in HTS conditioned medium. CXCL12 in HTS group was prominently lowly expressed compared with the normal group. Inhibition of CCL5 in hADSCs enhanced the effects of untreated hADSCs on proliferation of HTS fibroblasts while CXCL12 knockdown exerted the opposite function. Inhibition of CCL5 in hADSCs increased the percentage of HTS fibroblasts in the G0/G1 phase while down-regulation of CXCL12 decreased those. Meanwhile, the down-regulated levels of fibroblast markers including collagen I, collagen III, and α-SMA induced by CCL5 knockdown were significantly up-regulated by CXCL12 inhibition. hADSCs alleviate the HTS of mice through CCL5 and CXCL12. Conclusion: In summary, our results demonstrated that hADSCs efficiently cured HTS by suppressing proliferation of HTS fibroblasts, which may be related to the inhibition of CXCL12 and elevation of CCL5 in hADSCs, suggesting that hADSCs may provide an alternative therapeutic approach for the treatment of HTS. [ABSTRACT FROM AUTHOR]

Background/Objectives: Dermal fibroblasts (DFs) are key participants in skin hypertrophic scarring, and their properties are being studied to identify the molecular and cellular mechanisms underlying the pathogenesis of skin scarring. Methods: In the present work, we performed a comparative analysis of DFs isolated from normal skin (normal dermal fibroblasts, NDFs), and hypertrophic scar skin (hypertrophic scar fibroblasts, HTSFs). The fibroblasts were karyotyped and phenotyped, and experiments on growth rate, wound healing, and single-cell motility were conducted. Results: Comparative analysis revealed a minor karyotype difference between cells. However, HTSFs are characterized by higher proliferation level and motility compared to NDFs. These significant differences may be associated with quantitative and qualitative differences in the cell secretome. A proteomic comparison of NDF and HTSF found that differences were associated with metabolic proteins reflecting physiological differences between the two cells lines. Numerous unique proteins were found only in the vesicular phase of vHTSFs. Some proteins involved in cell proliferation (protein-glutamine gamma-glutamyltransferase K) and cell motility (catenin delta-1), which regulate gene transcription and the activity of Rho family GTPases and downstream cytoskeletal dynamics, were identified. A number of proteins which potentially play a role in fibrosis and inflammation (mucin-5B, CD97, adhesion G protein-coupled receptor E2, antileukoproteinase, protein S100-A8 and S100-A9, protein caspase recruitment domain-containing protein 14) were detected in vHTSFs. Conclusions: A comparative analysis of primary cell cultures revealed their various properties, especially in the cell secretome. These proteins may be considered promising target molecules for developing treatment or prevention strategies for pathological skin scarring. [ABSTRACT FROM AUTHOR]

Managing burn scars in children presents significant challenges. This study investigates effective treatment methods for burn scars, focusing on efficacy, safety, standard protocols and tolerability. Major databases such as PubMed, Scopus and Web of Science were thoroughly searched up to August 2024, emphasizing procedural treatments for burn scars in children. Key data collected included participant demographics, sample sizes, intervention methods, follow‐up protocols, treatment effectiveness and reported adverse events. A total of 256 children were assessed, with all procedural treatments yielding satisfactory outcomes. Among the various methods, trapeze‐flap plasty and percutaneous collagen induction showed improvements in all patients. In the laser treatment group, which included 161 children, the Vancouver Scar Scale (VSS) score reduction ranged from 55.55% to 76.31%, with outcomes rated as good (24.61%) to excellent (60%). Laser treatment using local anaesthesia proved to be well tolerated by children. Our findings indicate that various methods—including trapeze‐flap plasty, percutaneous collagen induction, phototherapy and fractional CO2 laser—demonstrate a relatively good response and an acceptable safety profile. Notably, light‐based therapies/lasers may serve as safe, effective and tolerable options for scar treatment in this age group, often eliminating the need for general anaesthesia. [ABSTRACT FROM AUTHOR]

Background: Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis. Methods: In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFβ1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches. Results: The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFβ-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFβ1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings. Conclusions: Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition. [ABSTRACT FROM AUTHOR]

Background: Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6‐methyladenosine (m6A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m6A influences ECM deposition remains unclear. Methods: In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM‐related diseases. We focused on the role of ALKBH5‐mediated m6A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high‐throughput analysis, RNA‐binding protein immunoprecipitation and RNA pull‐down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models. Results: ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high‐throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m6A from mRNAs, thereby decreasing their stability in a YTHDF1‐dependent manner. Conclusions: Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A‐targeted therapy for HTSs. [ABSTRACT FROM AUTHOR]

Background: Current strategies for hypertrophic scar prevention and treatment are limited. Objective: To facilitate these efforts, a minimally invasive hypertrophic scar model was created in a rabbit ear for the first time based on previous methods used to induce ischemia. Methods: Six New Zealand white rabbits (12 ears total) were studied. First, ischemia was achieved by ligating the cranial artery, cranial vein and central artery, while preserving the caudal artery, caudal vein and central vein, respectively. The relative level of ischemia induced at time of surgery, both baseline and maximum perfusion, was assessed with a fluorescent light-assisted angiography and demonstrated lower rates of perfusion in the ischemic ears. Following vascular injury, a 2-cm full thickness linear wound was created on the ventral ear and closed with 4 − 0 Nylon sutures under high tension. For each rabbit, one ear received a combination of ischemia and wounding with suture tension (n = 6), while the other ear was non-ischemic with wounding and suture tension alone (n = 6). Results: Four weeks post-operatively, ischemic ears developed scar hypertrophy (histological scar thickness: 1.1 ± 0.2 mm versus 0.5 ± 0.1 mm, p < 0.05). Conclusion: Herein, we describe a novel, prototypical minimally invasive rabbit ear model of hypertrophic scar formation that can allow investigation of new drugs for scar prevention. [ABSTRACT FROM AUTHOR]

Abstract The hypertrophic scar (HS) is a prevalent cutaneous fibrotic disorder that impacts both the aesthetic and functional aspects of the skin, there is an urgent need for a highly safe and effective approach to address the challenge of HS with thick and deep types. Inspired by the superior deep tissue penetrative ability of near-infrared-II (NIR-II) light and potential mitochondria ROS inducing effect of Chinese medicine lycorine (LYC), we fabricated a Cu2Se@LYC (CL) composite by encapsulating LYC on polyvinyl pyrrolidone (PVP) modified Cu2Se nanoparticles. After NIR-II irradiation, CL could induce the generation of reactive oxygen species (ROS) and mitochondrial damage in hypertrophic scar fibroblasts (HSFs). The subsequent release of cytochrome C (cyt-c) from mitochondria into the cytoplasm and upregulation of beclin1 leads to the activation of endogenous apoptosis and autophagy-mediated cell death. The CL + NIR-II treatment exhibited a pronounced anti-scarring effect in both in vitro and in vivo rabbit ear scar models, leading to a significant reduction in the fibrotic markers including Collagen I/III and α-smooth muscle actin (α-SMA). This study comprehensively investigated the crucial role of HSFs’ autophagy in scar management and proposed a safe and effective therapy based on NIR-II laser for clinical application.

Abstract Background Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis. Methods In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFβ1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches. Results The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFβ-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFβ1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings. Conclusions Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition.

Background: Keloids and hypertrophic scars are a commonly encountered problem in dermatology. There are many treatment modalities available with variable efficacy and recurrences. This study highlights the use of hyaluronidase with triamcinolone acetonide (TAC) and 5-fluorouracil (5-FU). Purpose: To assess the utility of hyaluronidase in combination with TAC and 5-FU in treatment of hypertrophic scars and keloids. Methods: In this study a combination of hyaluronidase along with TAC and 5-FU was given in one part and a combination of TAC and 5-FU was given in another half of same hypertrophic scar/keloid keeping 1cm gap in between the two untreated at 4 weekly interval for 24 weeks. Results were assessed by measuring height, volume of lesion and their percentage decrease. Also, pliability, vascularity, pigmentation of lesion and Vancouver scar assessment scale score were assessed. Side effects like ulceration, surrounding skin atrophy and telangiectasias were noted. Results: There was a reduction in all the parameters in both the treatment segments. Faster improvement in height, volume, pliability, vascularity, pigmentation, and Vancouver scar assessment scale score was noted with combination of hyaluronidase, TAC, and 5-FU compared to TAC and 5-FU alone. Side effect profile of ulceration, surrounding skin atrophy and telangiectasias was comparable in both the segments. Conclusion: Combination of hyaluronidase along with TAC and 5-FU offered a better outcome and faster response when compared to combination of TAC and 5-FU.

Chunyan Guo,1,2,&ast; Xiaoxiao Liu,1,&ast; Keqing Qiu,2 Longxiang Tu,1 Dewu Liu1 1Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Dermatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dewu Liu, Email ndyfy00706@ncu.edu.cnPurpose: Hypertrophic scarring (HS) is commonly described as an abnormal post-traumatic tissue repair characterized by excessive hypercellularity and extracellular matrix (ECM) deposition. Mounting evidence suggests that MALAT1 is maladjusted in many fibrotic diseases, but its contribution to HS progression remains poorly understood. Hence, we sought to elucidate the fundamental role of MALAT1 in HS.Methods: The expression of MALAT1, miR-29a-3p, and Smurf2 in skin tissues and fibroblasts was assessed by RT-qPCR and Western blotting. Furthermore, lentiviruses, RNAi, or plasmids were utilized to transfect hypertrophic scar fibroblasts (HSFs) for gene overexpression or downregulation. The biological behaviors of HSFs were quantified by the CCK-8 assay, wound healing assay, transwell assay, and flow cytometry. Mechanistically, bioinformatics analysis, dual-luciferase reporter assays, and rescue experiments were performed to verify the relationship between miR-29a-3p and MALAT1 or Smurf2.Results: Our data indicate that MALAT1, Smurf2 were overexpressed while miR-29a-3p was suppressed in HS tissues and fibroblasts. Downregulation of MALAT1 may lead to decreased proliferation, migration, and invasion of fibroblasts, accompanied by enhanced apoptosis, reduced TGF-β signal transduction, and ECM accumulation in HSFs, by enhancing miR-29a-3p and suppressing Smurf2 expression. Mechanistically, MALAT1 acted as a sponge for miR-29a-3p, while miR-29a-3p directly targeted Smurf2. More importantly, rescue experiments suggested that MALAT1 downregulation induced impact on the proliferation, migration, and invasion of HSFs could be partially overturned through miR-29a-3p knockdown or Smurf2 overexpression.Conclusion: MALAT1 knockdown inhibits the proliferation, migration, invasion, and collagen deposition of HSFs via targeting the miR-29a-3p/Smurf2 axis, which may reveal a promising therapeutic exploitable vulnerability to HS. Keywords: hypertrophic scar, fibroblasts, MALAT1, miR-29a-3p, Smurf2, TGF-β signaling pathway

Hypertrophic scarring is an aberrant wound-healing response to reestablish dermal integrity after an injury and can cause significant abnormalities in physical, aesthetic, functional, and psychological symptoms, impacting the patient's quality of life. There is currently no gold standard for preventing and treating hypertrophic scars. Therefore, many researchers have attempted to search for antihypertrophic scar agents with greater efficacy and fewer side effects. Natural therapeutics are becoming attractive as potential alternative anti-scarring agents because of their high efficacy, safety, biocompatibility, low cost, and easy accessibility. This review demonstrates various kinds of natural product-based therapeutics, including onion, vitamin E, Gotu kola, green tea, resveratrol, emodin, curcumin, and others, in terms of their mechanisms of action, evidence of efficacy and safety, advantages, and disadvantages when used as anti-scarring agents. We reviewed the literature based on data from in vitro, in vivo, and clinical trials. A total of 23 clinical trials were identified in this review; most clinical trials were ranked as having uncertain results (level of evidence 2b; n = 16). Although these natural products showed beneficial effects in both in vitro and in vivo studies of potential anti-scarring agents, there was limited clinical evidence to support their efficacy due to the limited quality of the studies, with individual flaws including small sample sizes, poor randomization, and blinding, and short follow-up durations. More robust and well-designed clinical trials with large-scale and prolonged follow-up durations are required to clarify the benefits and risks of these agents. [ABSTRACT FROM AUTHOR]

Dermal fibrosis is a consequence of damage to skin and is accompanied by dysfunction and cosmetic disfigurement. Improved understanding of the pathological factors driving skin fibrosis is critical to development of therapeutic modalities. Here, we describe that the Wnt signalling antagonist SFRP2 is upregulated in organotypic keratinocyte cultures upon experimental reduced hydration, a model that simulates the aberrant epidermal barrier state characteristic of several skin pathologies, including those that manifest in development of fibrosis. Consistent with this, we find that SFRP2 is overexpressed in both the dermis and epidermis of human hypertrophic scar tissue and lesional tissue of a mouse scleroderma model. Knockdown of SFRP2 expression in human fibroblasts antagonises proliferation and myofibroblast differentiation, including deposition of type I collagen, suggesting that SFRP2 signalling in fibroblasts may contribute to propagation of fibrosis in hypertrophic scar, as well as in other clinical indications characterised by skin fibrosis. [ABSTRACT FROM AUTHOR]

Hypertrophic scarring (HS) is a common skin injury complication with unmet needs. Verteporfin (VP) should be an ideal HS‐targeted therapeutic drug due to its efficient fibrosis and angiogenesis inhibitory abilities. However, its application is restricted by its side effects such as dose‐dependent cytotoxicity on normal cells. Herein, the bioadhesive nanoparticles encapsulated VP (VP/BNPs) are successfully developed to attenuate the side effects of VP and enhance its HS inhibition effects by limiting VP releasing slowly and stably in the lesion site but not diffusing easily to normal tissues. VP/BNPs displayed significant inhibition on the proliferation, migration, collagen deposition, and vessel formation of human hypertrophic scar fibroblasts (HSFBs) and dermal vascular endothelial cells (HDVECs). In a rat tail HS model, VP/BNPs treated HS exhibits dramatic scar repression with almost no side effects compared with free VP or VP‐loaded non‐bioadhesive nanoparticles (VP/NNPs) administration. Further immunofluorescence analysis on scar tissue serial sections validated VP/BNPs effectively inhibited the collagen deposition and angiogenesis by firmly confined in the scar tissue and persistently releasing VP targeted to nucleus Yes‐associated protein (nYAP) of HSFBs and HDVECs. These findings collectively suggest that VP/BNPs can be a promising and technically advantageous agent for HS therapies. [ABSTRACT FROM AUTHOR]

Wound healing is a highly programmed process, in which any abnormalities result in scar formation. MicroRNAs are potent regulators affecting wound repair and scarification. However, the function of microRNAs in wound healing is not fully understood. Here, we analyzed the expression and function of microRNAs in patients with cutaneous wounds. Cutaneous wound biopsies from patients with either hypertrophic scarring or normal wound repair were collected during inflammation, proliferation, and remodeling phases. Fourteen candidate microRNAs were selected for expression analysis by qRT-PCR. The expression of genes involved in inflammation, angiogenesis, proliferation, and migration were measured using qRT-PCR. Cell cycle and scratch assays were used to explore the proliferation and migration rates. Flow cytometry analysis was employed to examine TGF-β, αSMA and collagen-I expression. Target gene suggestion was performed using Enrichr tool. The results showed that miR-16-5p, miR-152-3p, miR-125b-5p, miR-34c-5p, and miR-182-5p were revealed to be differentially expressed between scarring and non-scarring wounds. Based on the expression patterns obtained, miR-182-5p was selected for functional studies. miR-182-5p induced RELA expression synergistically upon IL-6 induction in keratinocytes and promoted angiogenesis. miR-182-5p prevented keratinocyte migration, while overexpressed TGF-β3 following induction of inflammation. Moreover, miR-182-5p enhanced fibroblast proliferation, migration, differentiation, and collagen-1 expression. FoxO1 and FoxO3 were found to potentially serve as putative gene targets of miR-182-5p. In conclusion, miR-182-5p is differentially expressed between scarring and non-scarring wounds and affect the behavior of cells involved in cutaneous wound healing. Deregulated expression of miR-182-5p adversely affects the proper transition of wound healing phases, resulting in scar formation. [ABSTRACT FROM AUTHOR]

Hypertrophic scarring is a fibro-proliferative disorder caused by abnormal cutaneous wound healing. Circulating metabolites and the gut microbiome may be involved in the formation of these scars, but high-quality evidence of causality is lacking. To assess whether circulating metabolites and the gut microbiome contain genetically predicted modifiable risk factors for hypertrophic scar formation. Two-sample Mendelian randomization (MR) was performed using MR-Egger, inverse-variance weighting (IVW), Mendelian Randomization Pleiotropy RESidual Sum and Outlier, maximum likelihood, and weighted median methods. Based on the genome-wide significance level, genetically predicted uridine (P = 0.015, odds ratio [OR] = 1903.514, 95% confidence interval [CI] 4.280–846,616.433) and isovalerylcarnitine (P = 0.039, OR = 7.765, 95% CI 1.106–54.512) were positively correlated with hypertrophic scar risk, while N-acetylalanine (P = 0.013, OR = 7.98E-10, 95% CI 5.19E-17–0.012) and glycochenodeoxycholate (P = 0.021, OR = 0.021 95% CI 0.003–0.628) were negatively correlated. Gastranaerophilales and two unknown gut microbe species (P = 0.031, OR = 0.378, 95% CI 0.156–0.914) were associated with an decreased risk of hypertrophic scarring. Circulating metabolites and gut microbiome components may have either positive or negative causal effects on hypertrophic scar formation. The study provides new insights into strategies for diagnosing and limiting hypertrophic scarring. [ABSTRACT FROM AUTHOR]

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The management of hypertrophic scars (HSs), characterized by excessive collagen production, involves various nonsurgical and surgical interventions. However, the absence of a well‐defined molecular mechanism governing hypertrophic scarring has led to less‐than‐ideal results in clinical antifibrotic treatments. Therefore, our study focused on the role of decorin (DCN) and its regulatory role in the TGF‐β/Smad signalling pathway in the development of HSs. In our research, we observed a decrease in DCN expression within hypertrophic scar tissue and its derived cells (HSFc) compared to that in normal tissue. Then, the inhibitory effect of DCN on collagen synthesis was confirmed in Fc and HSFc via the detection of fibrosis markers such as COL‐1 and COL‐3 after the overexpression and knockdown of DCN. Moreover, functional assessments revealed that DCN suppresses the proliferation, migration and invasion of HSFc. We discovered that DCN significantly inhibits the TGF‐β1/Smad3 pathway by suppressing TGF‐β1 expression, as well as the formation and phosphorylation of Smad3. This finding suggested that DCN regulates the synthesis of collagen‐based extracellular matrix and fibrosis through the TGF‐β1/Smad3 pathway. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic scars (HS) are a common disfiguring condition in daily clinical encounters which brings a lot of anxieties and concerns to patients, but the treatment options of HS are limited. Black cloth ointment (BCO), as a cosmetic ointment applicable to facial scars, has shown promising therapeutic effects for facial scarring. However, the molecular mechanisms underlying its therapeutic effects remain unclear. Material and methods: Network pharmacology was first applied to analyze the major active components of BCO and the related signaling pathways. Subsequently, rabbit ear scar model was successfully established to determine the pharmacological effects of BCO and its active component β‐elemene on HS. Finally, the molecular mechanism of BCO and β‐elemene was analyzed by Western blot. Results: Through the network pharmacology, it showed that β‐elemene was the main active ingredient of BCO, and it could significantly improve the pathological structure of HS and reduce collagen deposition. BCO and β‐elemene could increase the expression of ER stress‐related markers and promote the increase of apoptotic proteins in the Western blot experiment and induce the apoptosis of myofibroblasts. Conclusions: Our findings indicate that the material basis for the scar‐improving effects of the BCO is β‐elemene, and cellular apoptosis is the key mechanism through which the BCO and β‐elemene exert their effects. [ABSTRACT FROM AUTHOR]

Scarring is the primary complication of anyone suffering a burn injury. Despite years of research, there have been few advances in the prevention and treatment of any scar. Recent studies have identified many factors that contribute to scar formation, but despite understanding mechanisms, clinicians are unable to stop the inevitable processes of scarring. The goal of this review is to describe current methods to reduce scarring in burns. At the same time, key questions that should direct future research will be presented. Like many maladies, optimal early care should reduce these complications.

Abstract Background Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6‐methyladenosine (m6A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m6A influences ECM deposition remains unclear. Methods In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM‐related diseases. We focused on the role of ALKBH5‐mediated m6A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high‐throughput analysis, RNA‐binding protein immunoprecipitation and RNA pull‐down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models. Results ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high‐throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m6A from mRNAs, thereby decreasing their stability in a YTHDF1‐dependent manner. Conclusions Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A‐targeted therapy for HTSs.

Abstract Purpose To investigate the application and effectiveness of tension-reducing suture in the repair of hypertrophic scars. Methods A retrospective analysis of clinical data was conducted on 82 patients with hypertrophic scars treated at the Department of Burns and Plastic Surgery of Nanjing Drum Tower Hospital from September 2021 to December 2022. Patients were operated with combination of heart-shaped tension-reducing suturing technique and looped, broad, and deep buried (LBD) suturing technique or conventional suture method. Outcomes of surgical treatment were assessed before and 6 months after surgery using the Patient and Observer Scar Assessment Scale (POSAS) and the Vancouver Scar Scale (VSS). Results Improvements were achieved on scar quality compared to that preoperatively, with a reduction in scar width (1.7 ± 0.6 cm vs. 0.7 ± 0.2 cm, P

Hypertrophic scarring (HTS) is an aberrant form of wound healing that is associated with excessive deposition of extracellular matrix and connective tissue at the site of injury. In this review article, we provide an overview of normal (acute) wound healing phases (hemostasis, inflammation, proliferation, and remodeling). We next discuss the dysregulated and/or impaired mechanisms in wound healing phases that are associated with HTS development. We next discuss the animal models of HTS and their limitations, and review the current and emerging treatments of HTS.

Although postoperative scarring may be considered a cosmetic concern, it can greatly impact a patient's quality of life. This extends beyond psychosocial burden influenced by hypertrophic scars and keloids, as patients also experience discomfort and pain. This systematic review evaluates the efficacy of silicone gel (SG)-based products in preventing postoperative abnormal scar formation. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a PubMed search was performed to find randomized, controlled trials investigating the effect of SG-based products on postoperative wound healing. The search yielded 359 publications, but only 30 studies published between 1991-2022 were found to fit the inclusion criteria. Outcomes were extracted from the literature and subsequent quality and risk of bias assessments were performed. Most studies indicated improvement of at least one quality of the scar with the use of SG-based products. The greatest potential variable increasing bias was an inadequate control group. Studies also suffered from small sample sizes, use of unvalidated scar assessment scales, lack of double-blinding, and short follow-up periods. Overall, SG-based products demonstrated potential in preventing abnormal scar formation during postoperative healing, but further studies are required to validate the results of current literature.

BACKGROUND: Hypertrophic scar is a skin fibrosis disease characterized by excessive proliferation of fibroblasts, epidermal thickening, and stratum corneum dysfunction. At present, the pathogenesis of Hypertrophic scar is still unclear. OBJECTIVE: To screen the core (Hub) genes and important signaling pathways in hypertrophic scar-related datasets based on bioinformatics, and then verify them by cell experiments to predict small molecule drugs that may have therapeutic effects on hypertrophic scar. METHODS: Datasets related to hypertrophic scar were searched from Gene Expression Omnibus (GEO) database, and differentially expressed genes were identified by R software analysis. Gene ontology and KEGG enrichment analyses were performed for differentially expressed genes. Protein-protein interaction network of differentially expressed genes was constructed using String online platform. Then, the key genes and core modules in the protein-protein interaction network were screened by Cytohubba and MCODE plugin-in Cytoscape software respectively, and the Hub genes were obtained by the intersection of the above key genes and the genes that formed the core module. Real-time fluorescent quantitative PCR was used to verify the difference in Hub gene mRNA expression between human hypertrophic scar and normal skin epidermal stem cells. The histological data from the Human Protein Atlas were used to verify the differences in the expression and distribution of Hub gene-encoded proteins in the two kinds of human tissues. Finally, the potential drugs for hypertrophic scar were predicted by the connectivity map database. RESULTS AND CONCLUSION: Among the identified differentially expressed genes, 102 genes were up-regulated and 702 genes were down-regulated. Gene ontology and KEGG analysis showed that the enriched signaling pathways and biological processes were mainly involved in tight junction, arachidonic acid metabolism, extracellular matrix receptor interaction, epidermal development and keratinization. Eight Hub genes were found to be closely related to the mevalonate pathway that regulates cholesterol metabolism, including HMGCS1, DHCR7, MSMO1, FDPS, MVK, HMGCR, MVD and ACAT2. Compared with the normal skin group, the mRNA expression of HMGCS1, DHCR7, MSMO1, FDPS, HMGCR, MVD and ACAT2 in the hypertrophic scar group decreased significantly (P < 0.05), while MVK mRNA expression had no significant change (P > 0.05). Except for MVK, the expression levels of other Hub gene-encoded proteins in normal skin tissue were higher than those in hypertrophic scar tissue (P < 0.05). The top 10 candidate drugs included protein kinase A inhibitor (H-89), serine protease inhibitor (Dabigatran-Etexilate), FLT3 inhibitor (sunitinib), among which resveratrol and β-sitosterol are plant extracts. To conclude, Hub genes closely related to mevalonate metabolism may affect the structure and function of the epidermis by regulating lipid metabolism, which may an important pathogenesis of hypertrophic scar. The small-molecule compounds identified in this study can be used as candidate drugs for the treatment of hypertrophic scar. [ABSTRACT FROM AUTHOR]

Chronic wounds pose a significant clinical challenge worldwide, which is characterized by impaired tissue regeneration and excessive scar formation due to over‐repair. Most studies have focused on developing wound repair materials that either facilitate the healing process or control hyperplastic scars caused by over‐repair, respectively. However, there are limited reports on wound materials that can both promote wound healing and prevent scar hyperplasia at the same time. In this study, VR23‐loaded dendritic mesoporous bioglass nanoparticles (dMBG) are synthesized and electrospun in poly(ester‐curcumin‐urethane)urea (PECUU) random composite nanofibers (PCVM) through the synergistic effects of physical adsorption, hydrogen bond, and electrospinning. The physicochemical characterization reveals that PCVM presented matched mechanical properties, suitable porosity, and wettability, and enabled sustained and temporal release of VR23 and BDC with the degradation of PCVM. In vitro experiments demonstrated that PCVM can modulate the functions and polarization of macrophages under an inflammatory environment, and possess effective anti‐scarring potential and reliable cytocompatibility. Animal studies further confirmed that PCVM can efficiently promote re‐epithelialization and angiogenesis and reduce excessive inflammation, thereby remarkably accelerating wound healing while preventing potential scarring. These findings suggest that the prepared PCVM holds promise as a bidirectional regulatory dressing for effectively promoting scar‐free healing of chronic wounds. [ABSTRACT FROM AUTHOR]

Background: Our study aims to delineate the miRSNP–microRNA–gene–pathway interactions in the context of hypertrophic scars (HS) and keloids. Materials and Methods: We performed a computational biology study involving differential expression analysis to identify genes and their mRNAs in HS and keloid tissues compared to normal skin, identifying key hub genes and enriching their functional roles, comprehensively analyzing microRNA‐target genes and related signaling pathways through bioinformatics, identifying MiRSNPs, and constructing a pathway‐based network to illustrate miRSNP‐miRNA‐gene‐signaling pathway interactions. Results: Our results revealed a total of 429 hub genes, with a strong enrichment in signaling pathways related to proteoglycans in cancer, focal adhesion, TGF‐β, PI3K/Akt, and EGFR tyrosine kinase inhibitor resistance. Particularly noteworthy was the substantial crosstalk between the focal adhesion and PI3K/Akt signaling pathways, making them more susceptible to regulation by microRNAs. We also identified specific miRNAs, including miRNA‐1279, miRNA‐429, and miRNA‐302e, which harbored multiple SNP loci, with miRSNPs rs188493331 and rs78979933 exerting control over a significant number of miRNA target genes. Furthermore, we observed that miRSNP rs188493331 shared a location with microRNA302e, microRNA202a‐3p, and microRNA20b‐5p, and these three microRNAs collectively targeted the gene LAMA3, which is integral to the focal adhesion signaling pathway. Conclusions: The study successfully unveils the complex interactions between miRSNPs, miRNAs, genes, and signaling pathways, shedding light on the genetic factors contributing to HS and keloid formation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the application and effectiveness of tension-reducing suture in the repair of hypertrophic scars. Methods: A retrospective analysis of clinical data was conducted on 82 patients with hypertrophic scars treated at the Department of Burns and Plastic Surgery of Nanjing Drum Tower Hospital from September 2021 to December 2022. Patients were operated with combination of heart-shaped tension-reducing suturing technique and looped, broad, and deep buried (LBD) suturing technique or conventional suture method. Outcomes of surgical treatment were assessed before and 6 months after surgery using the Patient and Observer Scar Assessment Scale (POSAS) and the Vancouver Scar Scale (VSS). Results: Improvements were achieved on scar quality compared to that preoperatively, with a reduction in scar width (1.7 ± 0.6 cm vs. 0.7 ± 0.2 cm, P < 0.001). Assessment using the POSAS and VSS scales showed significant improvements in each single parameter and total score compared to preoperative values (P < 0.05). The Combination method group achieved better score in total score of VSS scale, in color, stiffness, thickness and overall opinion of PSAS scale, and in vascularity, thickness, pliability and overall opinion of OSAS scale. Conclusion: The amalgamation of the heart-shaped tension-reducing suturing technique and the LBD suturing technique has shown promising outcomes, garnering notably high levels of patient satisfaction in the context of hypertrophic scar repair. Patients have exhibited favorable postoperative recoveries, underscoring the clinical merit and the prospective broader applicability of this approach in the realm of hypertrophic scar management. [ABSTRACT FROM AUTHOR]

Objective To explore the therapeutic effect of miR-194 on hypertrophic scars in rabbit ears. Methods From August 2022 to August 2023, the Plastic Surgery and Cosmetic Center of the First Affiliated Hospital of Harbin Medical University established a rabbit ear scar model on 6 New Zealand white rabbits, and treated the rabbit ear scars by injecting miR-194. Detect the effect of miR-194 on the morphology of rabbit ear scars through gross observation, HE staining, and MASSON staining. Protein immunoblotting assay was used to detect the effects of miR-194 on the expression of TGF-β1, VEGF, and COL-1. ELISA detection of the effect of miR-194 on the expression of TGF-β1, IL-1β and TNF-α. Results General observation showed that the scars in the treatment group are smaller, softer, and smoother, with a color closer to normal skin color. HE staining sections showed that miR-194 treatment can reduce the formation of rabbit ear scars, flatten the arrangement of fibroblasts, downregulate the release of inflammatory factors, and promote angiogenesis. The results of protein immunoblotting experiments showed that miR-194 can significantly inhibit the expression of TGF-β1、VEGF and COL-1. The ELISA results showed that miR-194 could reduce the expression of TGF-β1、IL-1β and TNF-α (P=0.02, P=0.01, P=0.02). Conclusion MiR-194 can inhibit the formation of hypertrophic scars by reducing the expression of TGF-β1, VEGF, and COL-1 in tissues and downregulating the activity of inflammatory factors. [ABSTRACT FROM AUTHOR]

• The POSAS can reliably be used to evaluate burn scars via live videoconferencing. • Vascularity and pigmentation are subject to larger variations in scoring. • Scores within two points constitute clinically acceptable inter-rater agreement. Telemedicine in outpatient burn care, particularly in burn scar management, may provide cost-effective care and comes highly rated by patients. However, an effective scar scale using both video and photographic elements has not been validated. The purpose of this study is to test the reliability of the Patient and Observer Scar Assessment Scale (POSAS) using live video-conferencing. A prospective study was conducted with individuals with healed burn scars in Kathmandu, Nepal. Three independent observers assessed 85 burn scars from 17 subjects, using the Observer portion to evaluate vascularity, pigmentation, thickness, relief, pliability, surface area, and overall opinion. The on-site observer was physically present with the subjects and used a live videoconferencing application to show the scars to two remote observers in the United States. Subjects used the Patient portion to evaluate the scar that they believed appeared the worst appearance and had the greatest impact on function. The single-rater reliability of the Observer scale was acceptable (ICC > 0.70) in overall opinion, thickness, pliability, and surface area. The average-rater reliability for three observers was acceptable (ICC > 0.70) for all parameters except for vascularity. When comparing Patients' and Observers' overall opinion scores, patients consistently reported worse opinion. Evaluation of burn scars using the Patient and Observer Scar Assessment Scale can be accurately performed via live videoconferencing and presents an opportunity to expand access to burn care to rural communities, particularly in low- and middle-income countries, where patients face significant access barriers to appropriate follow-up care. [ABSTRACT FROM AUTHOR]

Hypertrophic scars affect a significant number of individuals annually, giving rise to both cosmetic concerns and functional impairments. Prior research has established that an imbalance in the composition of gut microbes, termed microbial dysbiosis, can initiate the progression of various diseases through the intricate interplay between gut microbiota and the host. However, the precise nature of the causal link between gut microbiota and hypertrophic scarring remains uncertain. In this study, after compiling summary data from genomewide association studies (GWAS) involving 418 instances of gut microbiota and hypertrophic scarring, we conducted a bidirectional Mendelian randomization (MR) to investigate the potential existence of a causal relationship between gut microbiota and the development of hypertrophic scar and to discern the directionality of causation. By utilizing MR analysis, we identified seven causal associations between gut microbiome and hypertrophic scarring, involving one positive and six negative causal directions. Among them, Intestinimonas, Ruminococcus2, Barnesiella, Dorea, Desulfovibrio piger, and Ruminococcus torques act as protective factors against hypertrophic scarring, while Eubacterium rectale suggests a potential role as a risk factor for hypertrophic scars. Additionally, sensitivity analyses of these results revealed no indications of heterogeneity or pleiotropy. The findings of our MR study suggest a potential causative link between gut microbiota and hypertrophic scarring, opening up new ways for future mechanistic research and the exploration of nanobiotechnology therapies for skin disorders. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical effect of skin and soft tissue expansion to repair hyperplastic scar in children's neck and chest. Methods A retrospective analysis was performed on 6 cases of children with cervicothoracic hypertrophic scar admitted to Department of Skin Wound Repair Center, Tongren Hospital of Wuhan University＆Wuhan Third Hospital from January 2015 to December 2021. The skin and soft tissue dilator was implanted into the normal skin on the scar side of the neck and chest in the first stage. The dilator was dilated by water injection for about 3 months after the operation, and remained for 2 weeks after the dilation was sufficient. In the second stage, the expanded skin flap was repaired. The dilator was removed, the hyperplastic scar was removed, and the expanded skin flap was pushed toward the chest to repair the wound. The survival of the flap and the complications of each stage of operation were observed. Regular follow-up was conducted by telephone interview and outpatient review to observe scar hyperplasia and postoperative satisfaction of the children and their families. Results There was no infection occurred, no dilator was exposed, the skin flap survived well, and no incision split occurred in 6 patients after dilator implantation. All the children were followed up for 1 to 5 years after the extended flap repair, and the scar hyperplasia of the neck and chest of the children was not obvious, some of the children left flat scars, and the symptoms of pain and itching were significantly improved, and the children and their families were highly satisfied. Conclusion It is safe, reliable and effective to use skin and soft tissue dilation to repair hyperplastic scar in children's neck and chest. The normal skin on the side of scar is the preferred location for the design of arbitrarily expanded flaps. [ABSTRACT FROM AUTHOR]

Hypertrophic scarring is a potential consequence of wound healing that causes functional and aesthetic disability. Common treatments include intralesional pharmacotherapy (e.g., triamcinolone), surgical excision, and energy-based laser devices. While numerous treatment methods have been described for hypertrophic scarring, an optimal treatment strategy has yet to be established given variability in clinical presentation. This study aims to identify patient- and provider-preferred treatment patterns. This is a single-center, retrospective study of adult patients that developed post-surgical hypertrophic scarring between 2007 and 2017. Specifically, trends in procedural management for hypertrophic scarring among this cohort were examined. A total of 442 procedures (intralesional steroid injection, surgical excision, laser-based treatment) were identified in 218 patients with a clinical diagnosis of hypertrophic scarring. Approximately 73% were female; 87% were Caucasian. The median age at first procedure was 45.6 years (SD = 17.4). The most frequent anatomical locations for procedures were the trunk (n = 242; 54.8%), followed by head/neck (n = 86; 19.5%), upper extremities (n = 67; 15.2%), and lower extremities (n = 45; 10.2%). Procedural therapies included intralesional steroid injection (n = 221; 50%), surgical excision (n = 112; 25.3%) and laser (fractional non-ablative laser vs. pulsed dye laser; n = 109; 24.5%). Treatment modality varied by stage of treatment, scar anatomical location, and scar size. This single-center series of patients with hypertrophic scarring highlights a patient-centered management approach and offers clinical guidelines for provider-patient shared decision making. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect of Smurf1 on fibrosis process in hypertrophic scar formation and its molecular mechanism. Methods: Hypertrophic scar tissue and normal skin tissue samples of 12 patients who underwent hyperplastic scar resection in the department of burn and plastic surgery of the Second Affiliated Hospital of Air Force Medical University from June 2021 to June 2022 were collected. And the pathological examination was performed by HE and Masson staining. After sterile treatment of hypertrophic scar tissue, human hypertrophic scar fibroblasts (HSF) were isolated and cultured by tissue block method. HSF cells were divided into some groups according to the experimental scheme, (1) Smurf1 overexpression treatment group, control group 1 (Con-1 group), empty vector group (Vector group) and Smurf1 overexpression group (OE-Smurf1 group), (2) Smurf1 interference expression treatment group, control group 2 (Con-2 group), negative group (si-NC group) and Smurf1 interference expression group (si-Smurf1 group). Then pcDNA3.1 empty plasmid, pcDNA3.1+Smurf1 plasmid, si-NC and si-Smurf1 were transfected into HSF cells in Vector group, OE-Smurf1 group, si-NC group and si-Smurf1 group, respectively. Smurf1 mRNA expression level was detected by qRT-PCR. Protein expression level was detected by Western blot. Cell proliferation level was detected by CCK-8. Cell apoptosis level was detected by flow cytometry. Cell invasion level was detected by Transwell assay and cell migration level was detected by cell scratch assay. Results: The results of HE staining and Masson staining showed that compared with normal skin tissue, the dermis thickness of hypertrophic scar tissue increased significantly, and there were a large number of blue-dyed collagen fibers in the dermis, which were disordered and dense. Compared with normal skin tissue, the protein expression levels of TGF-β1, α-SMA, COL1, COL3, TβR-I, p-Smad3 and Smad7 in hypertrophic scar tissue were increased (P<0.05), while the expression level of Smurf1 was decreased (P<0.05). Compared with Con-1 or Vector groups, the expression levels of TGF-β1, α-SMA, COL1, COL3, TβR-I, p-Smad3 and Smad7 proteins in HSF cells of OE-Smurf1 group were decreased (P<0.05), and the proliferation, invasion and migration levels of HSF cells were decreased (P<0.05), the apoptosis level was increased (P<0.05). Compared with Con-2 group or si-NC group, the expression levels of TGF-β1, α-SMA, COL1, COL3, TβR-I, p-Smad3 and Smad7 proteins in HSF cells of si-Smurf1 group were increased (P<0.05), and the proliferation, invasion and migration levels of HSF cells were increased (P<0.05), the apoptosis level was decreased (P<0.05). Conclusion: Smurf1 may inhibit the fibrotic process of hypertrophic scars by inhibiting TGF-β1/Smad pathway. [ABSTRACT FROM AUTHOR]

Hypertrophic scar (HS) is a chronic inflammatory skin disorder characterized by excessive deposition of extracellular matrix, and the mechanisms underlying their formation remain poorly understood. We analysed scRNA‐seq data from samples of normal skin and HS. Using the hdWGCNA method, key gene modules of fibroblasts in HS were identified. Non‐negative matrix factorization was employed to perform subtype analysis of HS patients using these gene modules. Multiple machine learning algorithms were applied to screen and validate accurate gene signatures for identifying and predicting HS, and a convolutional neural network (CNN) based on deep learning was established and validated. Quantitative reverse transcription‐polymerase chain reaction and western blotting were performed to measure mRNA and protein expression. Immunofluorescence was used for gene localization analysis, and biological features were assessed through CCK8 and wound healing assay. Single‐cell sequencing revealed distinct subpopulations of fibroblasts in HS. HdWGCNA identified key gene characteristics of this population, and pseudotime analysis was conducted to investigate gene variation during fibroblast differentiation. By employing various machine learning algorithms, the gene range was narrowed down to three key genes. A CNN was trained using the expression of these key genes and immune cell infiltration, enabling diagnosis and prediction of HS. Functional experiments demonstrated that THBS2 is associated with fibroblast proliferation and migration in HS and affects the formation and development of HS through the TGFβ1/P‐Smad2/3 pathway. Our study identifies unique fibroblast subpopulations closely associated with HS and provides biomarkers for the diagnosis and treatment of HS. [ABSTRACT FROM AUTHOR]

Hypertrophic scar (HS) is a fibrous proliferative disorder that occurs in the dermis after skin injury. Studies have confirmed that Botulinum toxin type A (BTA) is effective in scar prevention and treatment. However, the specific mechanism remains uncertain. Hypertrophic scar fibroblasts (HSFs) and normal skin fibroblasts (NSFs) from the skin tissues of HS patients were isolated and cultured. Western blot analysis was conducted to measure the expression of JAK2/STAT3 pathway-related proteins. HSFs were treated with the JAK2 inhibitor (AG490) or agonist (C-A1). The CCK-8 assay, EdU staining, scratch-wound assay and transwell assay were used to examine the biological properties of HSFs. Western blot, immunofluorescence, and Sirius red staining were used to assess the fibrosis of HSFs. Additionally, a mouse full-thickness wound model was constructed to investigate the role of BTA in wound healing. The results showed that the JAK2 and STAT3 phosphorylation levels were markedly increased in HS tissues and HSFs. AG490 treatment reduced cell viability, proliferation and migration capacity, and inhibited the fibrosis of HSFs, whereas C-A1 treatment had the opposite effect. BTA treatment inhibited the JAK2/STAT3 pathway. BTA reduced cell viability, proliferation and migration ability, and inhibited the fibrosis of HSFs, while C-A1 intervention weakened the impact of BTA. Meanwhile, BTA promoted wound healing and reduced collagen deposition in vivo. In conclusion, BTA inhibited the JAK2/STAT3 pathway, which in turn hindered the proliferation, migration and fibrosis of HSFs, and promoted wound healing in mice.

Objective: To validate the feasibility of ultrasound in assessing the curative effect of botulinum toxin type A (BTXA) in treating hypertrophic scar (HS). Methods: Eight healthy New Zealand long-eared rabbits were utilized in the study. Four wounds, each measuring 1.0 cm in diameter, were created on both ears of each rabbit. Immediately after surgery, each of these wounds received an injection containing a distinct concentration of BTXA. On postoperative week 6, scar thickness, vascularity, and hardness were assessed based on high frequency ultrasound (HFUS), superb microvascular imaging (SMI), shear wave elastography (SWE), Masson staining, and immunohistochemical staining for CD31. Results: All wounds healed well, and HSs formed after 6 weeks post-surgery. Scar thickness based on HFUS presented a significant decrease with increasing BTXA concentration (p

BackgroundRecent advancements in basic medicine and epidemiology suggest a potential influence of blood pressure on scar formation, yet the specifics of this relationship are not fully understood. This study aims to clarify the causal link between blood pressure and the development of pathological scars using Mendelian randomization (MR).MethodsThis study employed genetic variants closely linked to blood pressure as instrumental variables to explore the relationship between blood pressure and pathological scars. The inverse variance weighted (IVW) method was used for analysis.ResultsOur analysis identified a notable association where higher blood pressure was correlated with a lower risk of pathological scars. Specifically, an increase in diastolic blood pressure (odds ratio [OR] per standard deviation increase: 0.67 [95% Confidence Interval [CI], 0.49–0.99]), systolic blood pressure (OR per standard deviation increase: 0.66 [95% CI, 0.46–0.93]), and hypertension (pooled OR: 0.39 [95% CI, 0.18–0.85]) were significantly associated with a reduced risk of keloids. Similarly, a genetic predisposition to hypertension (pooled OR: 0.31 [95% CI, 0.11–0.89]) was significantly associated with a reduced risk of hypertrophic scars. Neither reverse MR analysis nor Steiger’s test indicated a significant reverse causal relationship between hypertension and either keloids or hypertrophic scars.ConclusionThe findings suggest a protective role of higher blood pressure against the development of pathological scars, including keloids and hypertrophic scars. However, the inconsistency observed across different MR methods warrants cautious interpretation and underscores the need for further investigation to confirm these findings.

Background: Hypertrophic scar (HS) is a common fibrotic skin disease that occurs secondary to burns or injuries. The activation of the TGF-β signaling pathway contributes immensely to HS formation. Isorhamnetin (ISO) is a type of flavonoid compound that exerts an antifibrotic effect via TGF-β signaling suppression. However, whether ISO can inhibit HS formation via TGF-β signaling is yet to be elucidated. This study aimed to examine the influence of ISO on HS pathogenesis and TGF-β signaling, especially the downstream molecules and networks of TGF-β signaling that facilitate HS formation. Methods: Hypertrophic scar fibroblasts (HSFBs) were isolated from human HS tissues. The in vitro proliferation, migration, contractile ability, cell cycle, and apoptosis of HSFBs after ISO treatment were determined using cell viability assay, EdU staining, wound healing assay, collagen gel contraction assay, and flow cytometry. The expressions of genes and proteins involved in TGF-β signaling and its downstream molecules in ISO-treated HSFBs were determined using quantitative PCR (qPCR), immunofluorescence, and western blotting. In vivo, a rabbit HS model was established, and the effects of ISO on rabbit HS formation were investigated using histological analysis, immunohistochemical staining, and qPCR. Results: In vitro studies indicated that ISO treatment suppressed the proliferation, migration, and contractile ability of HSFBs; attenuated the expressions of COL Ⅰ, COL Ⅲ, and α-SMA; and inhibited TGF-β1 signaling-induced activation of HSFBs by decreasing the levels of phosphorylated Smad2/3 and cleaved CREB3L1 in a dose-dependent manner. Furthermore, ISO augmented apoptosis and G2 phase cell cycle arrest of HSFBs by upregulating the expressions of the proapoptotic proteins Bax and cleaved caspase-3 and downregulating the expression of the antiapoptotic protein Bcl-2. In vivo studies revealed that ISO ameliorated HS formation in the rabbit ear by lowering the scar elevation index, attenuating the collagen density, facilitating the regular arrangement of collagen fibers, and downregulating the expressions of TGF-β1, CREB3L1, COL Ⅰ, COL Ⅲ, and α-SMA. Conclusions: ISO suppressed HS pathogenesis by dampening TGF-β1/Smad and TGF-β1/CREB3L1 signaling pathways, which suggests that it may serve as a candidate inhibitor of TGF-β1 signaling and a promising anti-HS drug with a high therapeutic potential.

Abstract Background Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars. Methods To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-β-mediated responses in pathologic scars. Results The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-β1 signaling through binding with and stabilizing TGF-β receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids. Conclusions Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-β signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.

Yixiu Zhong,1 Youfan Zhang,2 Beibei Lu,1 Zhenjun Deng,1 Zhiwen Zhang,2 Qi Wang,2 Jianglin Zhang1 1Department of Dermatology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China; 2Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Yixiu Zhong; Jianglin Zhang, Email 846783501@qq.com; zhang.jianglin@szhospital.comAbstract: Hypertrophic scars and keloids are common fibroproliferative diseases following injury. Patients with pathologic scars suffer from impaired quality of life and psychological health due to appearance disfiguration, itch, pain, and movement disorders. Recently, the advancement of hydrogels in biomedical fields has brought a variety of novel materials, methods and therapeutic targets for treating hypertrophic scars and keloids, which exhibit broad prospects. This review has summarized current research on hydrogels and loaded components used in preventing and treating hypertrophic scars and keloids. These hydrogels attenuate keloid and hypertrophic scar formation and progression by loading organic chemicals, drugs, or bioactive molecules (such as growth factors, genes, proteins/peptides, and stem cells/exosomes). Among them, smart hydrogels (a very promising method for loading many types of bioactive components) are currently favoured by researchers. In addition, combining hydrogels and current therapy (such as laser or radiation therapy, etc.) could improve the treatment of hypertrophic scars and keloids. Then, the difficulties and limitations of the current research and possible suggestions for improvement are listed. Moreover, we also propose novel strategies for facilitating the construction of target multifunctional hydrogels in the future. Keywords: hydrogel, wound healing, hypertrophic scar, keloid