Macrophage Polarization: A Novel Target and Strategy for Pathological Scarring.

BACKGROUND: Abnormal scarring imposes considerable challenges and burdens on the lives of patients and healthcare system. Macrophages at the wound site are found to be of great concern to overall wound healing. There have been many studies indicating an inextricably link between dysfunctional macrophages and fibrotic scars. Macrophages are not only related to pathogen destruction and phagocytosis of apoptotic cells, but also involved in angiogenesis, keratinization and collagen deposition. These abundant cell functions are attributed to specific heterogeneity and plasticity of macrophages, which also add an extra layer of complexity to correlational researches. METHODS: This article summarizes current understanding of macrophage polarization in scar formation and several prevention and treatment strategies on pathological scarring related to regulation of macrophage behaviors by utilizing databases such as PubMed, Google Scholar and so on. RESULTS: There are many studies proving that macrophages participate in the course of wound healing by converting their predominant phenotype. The potential of macrophages in managing hypertrophic scars and keloid lesions have been underscored. CONCLUSION: Macrophage polarization offers new prevention strategies for pathological scarring. Learning about and targeting at macrophages may be helpful in achieving optimum wound healing.

Motion-mimicking Robotic Finger Prosthesis for Burn-induced Partial Hand Amputee: A Case Report.

Burn injuries often result in severe hand complications, including joint contractures and nerve damage, sometimes leading to amputation. Despite early treatment, hypertrophic scarring frequently hampers hand function recovery, and the thick raised scar blocks electromyography (EMG) sensing. A promising solution involves motion-mimicking robotic finger prostheses tailored to individual patient requirements. By utilizing the versatility of motion-capturing technology on a sound finger, a robotic finger prosthesis can mimic the movement of a sound finger simultaneously with less latency than EMG-based sensory mechanisms through hypertrophic scars. This case study evaluated the clinical efficacy of a customized three-dimensional printed robotic finger prosthesis in a 24-year-old man who sustained left second finger loss due to electrical burns. Despite undergoing reconstructive surgery, the patient struggled with manual dexterity. Following the adoption of a personalized robotic finger prosthesis with a finger motion-capturing device, significant improvements in grip strength and daily task performance were observed. This innovative approach has advantages such as customization, reduced latency time for finger movements, and affordability from low-cost manufacturing, suggesting its potential for broader adoption among burn-induced amputees.

A novel model of post-burn hypertrophic scarring in rat tail with a high success rate and simple methodology.

BACKGROUND: Hypertrophic scars present a serious concern after surgeries and trauma, particularly with the highest risk following burn injury. The current modeling methods usually involve relatively complicated surgical operations and special equipment, and have unstable reproducibility and reliability. This study aimed to establish a simple and reliable model of post-burn hypertrophic scarring in the rat tail. METHODS: Wet gauze saturated with hot water (94-98 °C) was applied to the dorsal side of the rat tail for varying durations to induce burn injury. Wounds were left exposed until completely healed, and the optimal duration for scalding treatment was determined based on gross examination. Thereafter, the optimal scalding duration was used again to evaluate scar formation over time, which was tracked through hematoxylin-eosin (HE) and Masson staining, immunohistochemistry of scar-related proteins and number/distribution of vascular endothelial cells, and picrosirius red staining to measure the quantities and proportion of type I and III collagen. RESULTS: The scalding duration which led to optimal post-burn scarring was 15 s, with an overall success rate of 87.5 %. Complete healing of the wound occurred after roughly 30 days, leading to the formation of scars grossly red in appearance, tough to the touch and raised compared to the surrounding skin. Microscopically, the epidermis and dermis of the scar were significantly thicker than normal rat tail skin, and the dermis of scar contained a large number of disorganized bundles of fine filamentous collagen. We also observed a significant increase in the number of TGF-ß1-positive cells and capillaries in the dermis (p < 0.05). Picrosirius red staining showed that compared to type III collagen, the expression of type I collagen was more dominant in scar tissue, and was more finely distributed than in normal rat tail skin. CONCLUSION: We successfully established a model for post-burn hypertrophic scarring, utilizing reliable and simple techniques and materials, which could simulate the biological characteristics of post-burn scarring. Our innovative model has the potential to facilitate the study of post-burn wound healing and scar formation.

Characterization and Physiological Differences of Two Primary Cultures of Human Normal and Hypertrophic Scar Dermal Fibroblasts: A Pilot Study.

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.

CircRNA_SLC8A1 alleviates hypertrophic scar progression by mediating the Nrf2-ARE pathway.

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.

Suture-anchored cutaneous tension induces persistent hypertrophic scarring in a novel murine model.

Background: Hypertrophic scars cause impaired skin appearance and function, seriously affecting physical and mental health. Due to medical ethics and clinical accessibility, the collection of human scar specimens is frequently restricted, and the establishment of scar experimental animal models for scientific research is urgently needed. The four most commonly used animal models of hypertrophic scars have the following drawbacks: the rabbit ear model takes a long time to construct; the immunodeficient mouse hypertrophic scar model necessitates careful feeding and experimental operations; female Duroc pigs are expensive to purchase and maintain, and their large size makes it difficult to produce a significant number of models; and mouse scar models that rely on tension require special skin stretch devices, which are often damaged and shed, resulting in unstable model establishment. Our group overcame the shortcomings of previous scar animal models and created a new mouse model of hypertrophic scarring induced by suture anchoring at the wound edge. Methods: We utilized suture anchoring of incisional wounds to impose directional tension throughout the healing process, restrain wound contraction, and generate granulation tissue, thus inducing scar formation. Dorsal paired incisions were generated in mice, with wound edges on the upper back sutured to the rib cage and the wound edges on the lower back relaxed as a control. Macroscopic manifestation, microscopic histological analysis, mRNA sequencing, bioinformatics, and in vitro cell assays were also conducted to verify the reliability of this method. Results: Compared with those in relaxed controls, the fibrotic changes in stretched wounds were more profound. Histologically, the stretched scars were hypercellular, hypervascular, and hyperproliferative with disorganized extracellular matrix deposition, and displayed molecular hallmarks of hypertrophic fibrosis. In addition, the stretched scars exhibited transcriptional overlap with mechanically stretched scars, and human hypertrophic and keloid scars. Phosphatidylinositol 3-kinase-serine/threonine-protein kinase B signaling was implicated as a profibrotic mediator of apoptosis resistance under suture-induced tension. Conclusions: This straightforward murine model successfully induces cardinal molecular and histological features of pathological hypertrophic scarring through localized suture tension to inhibit wound contraction. The model enables us to interrogate the mechanisms of tension-induced fibrosis and evaluate anti-scarring therapies.

NIR-II light based combinatorial management of hypertrophic scar by inducing autophagy in fibroblasts.

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.

A systematic review of procedural treatments for burn scars in children: Evaluating efficacy, safety, standard protocols, average sessions and tolerability based on clinical studies.

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.

Spatial metabolomics to discover hypertrophic scar relevant metabolic alterations and potential therapeutic strategies: A preliminary study.

Spatially mapping the metabolic remodeling of hypertrophic scar and surrounding normal skin tissues has the potential to enhance our comprehension of scar formation and aid in the advancement of therapeutic interventions. In this study, we employed matrix-assisted laser desorption/ionization (MALDI), a mass spectrometry imaging technique, to visualize the hierarchical distribution of metabolites within sections of hypertrophic scar and surrounding normal skin tissues. A comprehensive analysis identified a total of 1631 metabolites in these tissues. The top four classes that were identified included benzene and substituted derivatives, heterocyclic compounds, amino acids and its metabolites, and glycerophospholipids. In hypertrophic scar tissues, 22 metabolites were upregulated and 66 metabolites were downregulated. MetaboAnalyst pathway analysis indicated that glycerophospholipid metabolism was primarily associated with these altered 88 metabolites. Subsequently, six metabolites were selected, their spatial characteristics were analyzed, and they were individually added to the cell culture medium of primary hypertrophic scar fibroblasts. The preliminary findings of this study demonstrate that specific concentrations of 1-pyrrolidinecarboxamide, 2-benzylideneheptanal, glycerol trioleate, Lyso-PAF C-16, and moxonidine effectively inhibited the expressions of COL1A1, COL1A2, COL3A1, and ACTA2. These bioactive metabolites exhibit mild and non-toxic properties, along with favorable pharmacokinetics and pharmacodynamics, making them promising candidates for drug development. Consequently, this research offers novel therapeutic insights for hypertrophic scar treatment.

Post-surgical Hypertrophic Scar in a Patient With Unilateral Temporomandibular Joint Ankylosis.

Wound healing is nature's response to injury. It is a complex and dynamic process involving multiple biological systems aimed at restoring the integrity of damaged tissue. The temporomandibular joint (TMJ) is a critical anatomical structure that facilitates jaw movement and function. TMJ ankylosis is a pathological condition characterized by fusion of the mandibular condyle to the glenoid fossa resulting in severe restriction in mouth opening and significantly reduced mandibular movements. This condition affects the patient's quality of life by deteriorating major functions such as mastication, speech, oral hygiene, breathing, facial growth, and esthetics. Gap arthroplasty is the mainstay of treatment. There are various surgical approaches to TMJ such as Al-Kayat Bramley, Popowich's modification, Blair's inverted hockey stick, Dingman's, Thoma's, endaural, postauricular, and rhytidectomy incisions. Wound healing in the TMJ region poses unique challenges due to its complex anatomy and the high level of mechanical stress it endures. Following trauma to TMJ, hematomas are organized by fibrous granulation tissues and mesenchymal stem cells are recruited from adjacent bone by cytokines and chemokines such as bone morphogenetic proteins, transforming growth factor-beta and stromal cell-derived factor 1. These recruited mesenchymal cells differentiate into osteoprogenitors and osteoblasts to form new bone and fibroblasts to form a scar. In humans, scarring is the final outcome of the wound healing process, which has evolved to rapidly repair injuries. Scarring from injuries, surgeries, and burns places a significant burden on the healthcare system. Patients with major scars, especially children and adolescents, often experience long-term functional and psychological issues. This article aims to present a case of post-surgical hypertrophic scar in a patient after gap arthroplasty through Al-Kayat Bramley incision and the role of a multi-professional team to treat such wounds.

Single-cell sequencing analysis and bulk-seq identify IGFBP6 and TNFAIP6 as novel differential diagnosis markers for postburn pathological scarring.

BACKGROUND: If not accurately diagnosed and treated, postburn pathological scars, such as keloids and hypertrophic scars, can lead to negative clinical outcomes. However, differential diagnosis at the molecular level for postburn pathological scars remains limited. Using single-cell sequencing analysis, we investigated the genetic nuances of pathological scars at the cellular level. This study aimed to identify molecular diagnostic biomarkers to distinguish between postburn keloids and hypertrophic scars. METHODS: Single-cell sequencing, differential expression, and weighted co-expression network analyses were performed to identify potential key genes for discriminating between keloids and hypertrophic scars. Postburn clinical samples were collected from our centre to validate the expression levels of the identified key genes. RESULTS: Single-cell sequencing analysis unveiled 29 and 30 cell clusters in keloids and hypertrophic scars, respectively, predominantly composed of fibroblasts. Bulk differential gene analysis showed 96 highly expressed genes and 69 lowly expressed genes in keloids compared to hypertrophic scars. By incorporating previous research, Gene Set Enrichment Analysis was conducted to select fibroblasts as the focus of research. According to the single-cell data, 301 genes were stably expressed in fibroblasts from both types of pathological scars. Consistently, Weighted Gene Co-expression Network Analysis revealed that the blue module genes were mostly hub genes associated with fibroblasts. After intersecting fibroblast-related genes in single-cell data, Weighted Gene Co-expression Network Analysis-hub module genes, and bulk differential expression genes, insulin-like growth factor binding protein 6 and tumour necrosis factor alpha-induced protein 6 were identified as key genes to distinguish keloids from hypertrophic scars, resulting in diagnostic accuracies of 1.0 and 0.75, respectively. Immunohistochemical Staining and Quantitative Reverse Transcription PCR revealed that the expression levels of tumour necrosis factor alpha induced protein 6 and insulin-like growth factor binding protein 6 were significantly lower in postburn keloids than in hypertrophic scars- CONCLUSIONS: Tumour necrosis factor alpha induced protein 6 and insulin-like growth factor binding protein 6, exhibiting high diagnostic accuracy, provide valuable guidance for the differential diagnosis and treatment of postburn pathological scars.

The Causal Role of Uterine Fibroid in Keloid and Hypertrophic Scar: A Bidirectional Mendelian Randomization Study on European Populations.

BACKGROUND: The relationship between uterine fibroids and keloid/hypertrophic scars has been contradictory. Our research employs a bidirectional Mendelian Randomization (MR) approach to establish a clearer understanding of this potential causal link. OBJECTIVE: This study aimed to determine the effect of uterine fibroids on keloid/hypertrophic scars and the effect of keloid/hypertrophic scars on uterine fibroids. PURPOSE: We aimed to demonstrate the relationship between uterine fibroids and keloid/ hypertrophic scars. METHOD: Our bidirectional MR study utilized summarized data from genome-wide association studies (GWAS) focused on European populations. Our primary tool for establishing causality was the Inverse-Variance Weighted (IVW) method. To reinforce the IVW findings, we also applied four alternative MR methods: MR-Egger, Maximum Likelihood, Weighted Mode, and Weighted Median. RESULT: The IVW method indicated a significant causal link, with uterine fibroids greatly raising the likelihood of developing keloids (Odds Ratio [OR] = 1.202, 95% Confidence Interval [CI]: 1.045-1.381; P=0.010) and hypertrophic scars (OR = 1.256, 95% CI: 1.039-1.519; P=0.018). Parallel results were observed with the MR-Egger, Maximum Likelihood, Weighted Mode, and Weighted Median methods. Sensitivity analyses indicated robustness in these findings, with no evidence of heterogeneity or horizontal pleiotropy. Conversely, the reverse MR analysis did not demonstrate an increased risk of uterine fibroids due to keloids or hypertrophic scars. CONCLUSION: This study elucidates a significant causal effect of uterine fibroids on the development of keloid and hypertrophic scars, offering valuable insights into their pathogenesis and potential therapeutic targets.

A New Strategy to Inhibit Scar Formation by Accelerating Normal Healing Using Silicate Bioactive Materials.

Inspired by the scar-free wound healing in infants, an anti-scar strategy is proposed by accelerating wound healing using silicate bioactive materials. Bioglass/alginate composite hydrogels are applied, which significantly inhibit scar formation in rabbit ear scar models. The underlining mechanisms include stimulation of Integrin Subunit Alpha 2 expression in dermal fibroblasts to accelerate wound healing, and induction of apoptosis of hypertrophic scar fibroblasts by directly stimulating the N-Acylsphingosine Amidohydrolase 2 expression in hypertrophic scar fibroblasts, and indirectly upregulating the secretion of Cathepsin K in dermal fibroblasts. Considering specific functions of the bioactive silicate materials, two scar treatment regimes are tested. For severe scars, a regenerative intervention is applied by surgical removal of the scar followed by the treatment with bioactive hydrogels to reduce the formation of scars by activating dermal fibroblasts. For mild scars, the bioactive dressing is applied on the formed scar and reduces scar by inducing scar fibroblasts apoptosis.

ALKBH5-mediated m6A demethylation ameliorates extracellular matrix deposition in cutaneous pathological fibrosis.

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.

Phosphodiesterase 4 is overexpressed in keloid epidermal scars and its inhibition reduces keratinocyte fibrotic alterations.

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 TGFß1-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 TGFß-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 TGFß1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFß1-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.

Oregano essential oil-infused mucin microneedle patch for the treatment of hypertrophic scar.

Hypertrophic scar (HS) manifests as abnormal dermal myofibroblast proliferation and excessive collagen deposition, leading to raised scars and significant physical, psychological, and financial burdens for patients. HS is difficult to cure in the clinic and current therapies lead to recurrence, pain, and side effects. In this study, a natural amphiphilic polymer mucin is used to prepare a dissolving microneedle (muMN) that is loaded with oregano essential oil (OEO) for HS therapy. muMN exhibits sufficient skin/scar tissue penetration, quick skin recovery time after removal, good loading of natural essential oil, fast dissolution and detachment from the base layer, and good biocompatibility to applied skin. In the rabbit HS model, OEO@muMN shows a significant reduction in scar thickness, epidermal thickness index, and scar elevation index. OEO@muMN also attenuates the mean collagen area fraction and decreases the number of capillaries in scar tissues. Biochemical Assay reveals that OEO@muMN significantly inhibits the expression of transforming growth factor-ß1 (TGF-ß1) and hydroxyproline (HYP). In summary, this study demonstrates the feasibility and good efficacy of using the anti-proliferative and anti-oxidative OEO for HS treatment. OEO@muMN is an efficient formulation that holds the potential for clinical anti-HS application. muMN is an efficient platform to load and apply essential oils transdermally.

Exosomal miR­194 from adipose­derived stem cells impedes hypertrophic scar formation through targeting TGF­ß1.

Hypertrophic scars, which result from aberrant fibrosis and disorganized collagen synthesis by skin fibroblasts, emerge due to disrupted wound healing processes. These scars present significant psychosocial and functional challenges to affected individuals. The current treatment limitations largely arise from an incomplete understanding of the underlying mechanisms of hypertrophic scar development. Recent studies, however, have shed light on the potential of exosomal non­coding RNAs interventions to mitigate hypertrophic scar proliferation. The present study assessed the impact of exosomes derived from adipose­derived stem cells (ADSCs­Exos) on hypertrophic scar formation using a rabbit ear model. It employed hematoxylin and eosin staining, Masson's trichrome staining and immunohistochemical staining techniques to track scar progression. The comprehensive analysis of the present study encompassed the differential expression of non­coding RNAs, enrichment analyses of functional pathways, protein­protein interaction studies and micro (mi)RNA­mRNA interaction investigations. The results revealed a marked alteration in the expression levels of long non­coding RNAs and miRNAs following ADSCs­Exos treatment, with little changes observed in circular RNAs. Notably, miRNA (miR)­194 emerged as a critical regulator within the signaling pathways that govern hypertrophic scar formation. Dual­luciferase assays indicated a significant reduction in the promoter activity of TGF­ß1 following miR­194 overexpression. Reverse transcription­quantitative PCR and immunoblotting assays further validated the decrease in TGF­ß1 expression in the treated samples. In addition, the treatment resulted in diminished levels of inflammatory markers IL­1ß, TNF­α and IL­10. In vivo evidence strongly supported the role of miR­194 in attenuating hypertrophic scar formation through the suppression of TGF­ß1. The present study endorsed the strategic use of ADSCs­Exos, particularly through miR­194 modulation, as an effective strategy for reducing scar formation and lowering pro­inflammatory and fibrotic indicators such as TGF­ß1. Therefore, the present study advocated the targeted application of ADSCs­Exos, with an emphasis on miR­194 modulation, as a promising approach to managing proliferative scarring.

Suction-Based Optical Coherence Elastography for the Biomechanical Characterization of Pathological Skin Conditions: A Pilot Study.

Accurate characterization of mechanical properties is crucial in the evaluation of therapeutic effects for problematic skin conditions. A pilot study was carried out using a novel optical coherence elastography (OCE) device, combining mechanical characterization through suction-based deformation and imaging through optical coherence tomography. Using AI-assisted image segmentation and a power-law model, we were able to describe the mechanical behavior, comparing with measurements from the most commonly used commercial instrument (Cutometer) and subjective analyses of stiffness using the Patient and Observer Scar Assessment Scale. Twenty subjects were included with either keloids or hypertrophic scars. Measurements were fast and produced no discomfort. Mechanical and structural (epidermal thickness and rugosity) descriptors in pathologic skin conditions differed significantly from those in control tissue. We showed for the first time, the clinical feasibility of this novel suction-based OCE device in evaluating mechanical and structural properties in pathological skin conditions such as scars.

Randomized, controlled, within-patient, single-blinded pilot study to evaluate the efficacy of 12-weeks of endermotherapy with adult burn survivors.

BACKGROUND: Vacuum massage, or endermotherapy, is applied to scar tissue with the primary therapeutic goal of promoting structural or physiological changes. These changes are intended to enhance pliability, enabling the skin to possess the strength and elasticity required for normal mobility. The advantage of vacuum massage compared to therapist-generated manual massage is that it provides a standardized dosage using rollers and suction valves to mobilize the tissue. However, research documenting and supporting its impact on post-burn hypertrophic scar is lacking. Thus, this study was designed to objectively characterize the changes in scar elasticity, erythema, melanin, thickness, and transepidermal water loss immediately after a vacuum massage session and after a 12-week course of treatment compared to intra-individual matched control scars. METHODS: We conducted a prospective, randomized, controlled, within-patient, single-blinded clinical trial, initially designed as a fully-powered study but limited to a pilot study due to COVID-19 restrictions. Nineteen burn survivors consented to participate and 16 completed the study. Two homogeneous, intra-individual scars were randomized to usual care control or vacuum massage therapy plus usual care. Vacuum massage interventions were provided by a certified massage therapist three times per week for 12 weeks. Scar characteristics were evaluated every four weeks immediately before and after mechanical massage treatment. The evaluations included measurements of elasticity (Cutometer), erythema and melanin (Mexameter), transepidermal water loss (TEWL) (Tewameter), and thickness (high-frequency ultrasound). Linear mixed-model analyses were performed to test for immediate and long-term treatment effects. RESULTS: The ANOVA analyses revealed a non-significant time:treatment interaction for elasticity, erythema, melanin, thickness, or TEWL. There was a significant increase in elasticity and erythema and a decrease in TEWL in both the control and treatment sites over time with consistent standard care. However, there was no statistically significant immediate or long-term treatment effect for any of the skin characteristics. Nonetheless, the mean participant satisfaction was 4/5 (SD = 1.5) and the mean participant perception of effectiveness was 8/10 (SD = 1.9). CONCLUSIONS: This pilot study did not find a treatment benefit of vacuum massage therapy for elasticity, erythema, melanin, thickness or TEWL, but it did find an improvement with time in elasticity, erythema and TEWL. Despite the lack of objective improvement of the treated scar site, participants were satisfied with the results and believed vacuum massage was very effective. Further high-quality research is required to better inform clinicians patient education and treatment decisions for this costly, burdensome treatment approach that has high participant satisfaction.