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Radial sclerosing lesions (RS, also referred to as "radial scars") and complex sclerosing lesions (CSL) are uncommon breast lesions often grouped together as a single entity in practice. RS/CSL have an incidence of <0.1% to 1% at core needle biopsy (CNB). When detected on CNB, imaging and pathology features must be carefully evaluated to determine appropriate surgical management or imaging follow-up due to potential for malignant upgrade at surgery. Detection of RS/CSL has increased with the advent of tomosynthesis, in which an RS/CSL is typically detected as architectural distortion with or without associated mass with spiculated margins. On US, an RS/CSL is most often occult or manifests as subtle distortion with adjacent cysts. Imaging findings cannot distinguish benign RS/CSL from those upgraded to malignancy at surgery, although larger lesion size may be associated with higher upgrade rates. Histologically, an RS has a central fibroelastotic nidus with entrapped-appearing ducts and proliferative changes at the periphery appearing to radiate from the center; CSL are larger than RS, more disorganized, and typically include multiple patterns of epithelial proliferations, including sclerosing adenosis, sclerosing papillomas, usual ductal hyperplasia, and cysts. RS/CSL with associated atypia at CNB have a 16%to 29% rate of upgrade to malignancy on surgical excision, thus rendering surgical excision essential. Conversely, an RS/CSL without associated atypia, particularly when ≤1 cm in size, has <3% rate of upgrade to malignancy at surgery, allowing consideration of imaging follow-up in lieu of excision. Here, we review recent literature as well as radiology and pathology findings of RS/CSL., (© Society of Breast Imaging 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Acne scarring results from the inflammation associated with acne papules, which alters dermal collagen, typically producing depressed scars. Lasers have been used to remodel skin improving the texture and appearance of acne scars. Herein, we investigate a new 2910 nm, erbium-doped, fluoride glass, fiber laser for improving acne scars. This novel laser delivers up to 5000 Hz low-energy pulses, providing a unique treatment modality., Methods: Fourteen subjects with rolling and/or boxcar acne scars were enrolled in this study. Thirteen subjects completed the final visit and received three treatments with the 2910 nm fiber laser at 6-8-week intervals. Eight subjects were Fitzpatrick type II and five were Fitzpatrick type III. Digital images were taken pre- and 1- and 3-months posttreatment and evaluated by two blinded reviewers in a randomized fashion for improvement. Subjects and the treating physician completed a Global Aesthetic Improvement Scale (GAIS) before treatment and at each visit to subjectively evaluate treatment effect. Histological analysis was performed on ex vivo lower eyelid skin samples. Side effects were evaluated by the treating physician and included erythema, edema, and pinpoint bleeding., Results: Evaluation of blinded digital images revealed a mean improvement of 47.3% ± 14.2% (mean ± SEM) 3 months following the final treatment. GAIS scores demonstrated improvement as evaluated by both the subjects and the treating physician. Side effects averaged trace-to-mild erythema, edema, and pinpoint bleeding., Conclusion: This study shows that the 2910 nm, erbium-doped, fluoride glass, fiber laser is safe and effective for improving the appearance of acne scars., (© 2024 The Author(s). Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Background: Fibrotic scar formation is a critical pathological change impacting tissue reconstruction and functional recovery after ischemic stroke. The regulatory mechanisms behind fibrotic scarring in the central nervous system (CNS) remain largely unknown. While macrophages are known to play a role in fibrotic scar formation in peripheral tissues, the involvement of microglia, the resident immune cells of the CNS, in CNS fibrosis requires further exploration. The Sonic Hedgehog (Shh) signaling pathway, pivotal in embryonic development and tissue regeneration, is also crucial in modulating fibrosis in peripheral tissues. However, the impact and regulatory mechanisms of Shh on fibrotic scar formation post-ischemic stroke have not been thoroughly investigated., Methods: This study explores whether Shh can regulate fibrotic scar formation post-ischemic stroke and its underlying mechanisms through in vivo and in vitro manipulation of Shh expression., Results: Our results showed that Shh expression was upregulated in the serum of acute ischemic stroke patients, as well as in the serum, CSF, and ischemic regions of MCAO/R mice. Moreover, the upregulation of Shh expression was positively correlated with fibrotic scar formation and M2 microglial polarization. Shh knockdown inhibited fibrotic scar formation and M2 microglial polarization while aggravating neurological deficits in MCAO/R mice. In vitro, adenoviral knockdown or Smoothened Agonist (SAG) activation of Shh expression in BV2 cells following OGD/R regulated their polarization and influenced the expression of TGFβ1 and PDGFA, subsequently affecting fibroblast activation., Conclusion: These results suggest that Shh regulates M2 microglial polarization and fibrotic scar formation after cerebral ischemia., Competing Interests: Declaration of competing interest The authors have no conflicts of interest, financial or otherwise, that may have biased the research presented in this paper. The illustration was partly created with BioRender.com., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Frontal fibrosing alopecia (FFA) is an inflammatory cicatricial alopecia, which is considered to be a variant of lichen planopilaris. In addition to follicular changes, FFA often presents with associated cutaneous manifestations in most patients, including lichen planus pigmentosus, implantation line hypochromia and facial papules. The objective of the present article is to provide a detailed overview of the non-follicular cutaneous clinical manifestations of FFA and discuss their impact on the diagnosis and treatment of patients with this condition., (Copyright © 2024 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The assessment of scar outcomes is important to both patient care and research focused on understanding the results of medical and surgical interventions. The Vancouver Scar Scale (VSS) and Patient and Observer Scar Assessment Scale (POSAS) are validated and simple instruments to assess scars. However, these subjective scales have shortcomings. The VSS fails to capture patient perception and has indeterminate validity and reliability. The POSAS captures patient perception, but the observer scale has been shown to have moderate amounts of interrater variability. Studies highlighting the ability of objective scar assessment tools to produce reliable and reproducible results are needed. In this study, the authors aimed to validate the use of the FibroMeter, ElastiMeter, and SkinColorCatch as objective adjuncts in the assessment of hypertrophic scar and keloid outcomes., Methods: In this prospective single-center study, scars were assessed using the VSS, the POSAS, and the objective study tools (FibroMeter, ElastiMeter, and SkinColorCatch). Correlations between the different methods of scar assessment were measured., Results: The FibroMeter and SkinColorCatch showed significant correlations with the VSS total and the observer POSAS total. The ElastiMeter showed significant correlations with both the patient and observer POSAS totals. Unexpected correlations between ElastiMeter measurements and the vascularity or pigmentation of scars indicate that scoring of these categories may be influenced by how severe the scar looks to the observer subjectively, underscoring the need for reliable objective scar assessment tools., Conclusion: The results highlight the ability of the FibroMeter, ElastiMeter, and SkinColorCatch to assess scars, and demonstrate their potential in serving as important adjuncts to previously validated scar assessment scales., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Background: The Patient and Observer Scar Assessment Scale (POSAS) is frequently used to assess scar quality after burns. It is important to be aware of the minimal important change (MIC) and the minimal clinically important difference (MCID) to establish if a POSAS score represents a clinically relevant change or difference. The aim of this study is to explore the MIC and MCID of POSAS version 2.0., Methods: This prospective study included 127 patients with deep dermal burns that underwent split thickness skin grafting with a mean age of 44 years (range 0 - 87) and total body surface area burned of 10 % (range 0.5 - 55). POSAS data was obtained for one burn scar area at three, six, and 12 months after split skin grafting. At the second and third visits, patients rated the degree of clinical change in scar quality in comparison to the previous visit. At 12 months, they completed the POSAS for a second burn scar area and rated the degree of clinical difference between the two scar areas. Two anchor-based methods were used to determine the MIC and MCID., Results: MIC values of the patient POSAS ranged from - 0.59 to - 0.29 between three and six months and from - 0.75 to - 0.38 between six and 12 months follow-up. Both had a poor discriminatory value. MCID values ranged from - 0.39 and - 0.08, with a better discriminatory value., Conclusion: Results suggest that patients consider minor differences (less than 0.75 on the 1-10 scale) in POSAS scores as clinically important scar quality changes. MCID values can be used to evaluate the effects of burn treatment and perform sample-size calculations., Competing Interests: Declaration of Competing Interest Dr. van Zuijlen is the developer of the Patient and Observer Scar Assessment Scale. The authors have no financial interest to declare in relation to the content of this communication., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Members of the cellular communication network family (CCN) of matricellular proteins, like CCN1, have long been implicated in the regulation of cellular processes underlying wound healing, tissue fibrogenesis, and collagen dynamics. While many studies suggest antifibrotic actions for CCN1 in the adult heart through the promotion of myofibroblast senescence, they largely relied on exogenous supplementation strategies in in vivo models of cardiac injury where its expression is already induced-which may confound interpretation of its function in this process. The objective of this study was to interrogate the role of the endogenous protein on fibroblast function, collagen structural dynamics, and its associated impact on cardiac fibrosis after myocardial infarction (MI)., Methods/results: Here, we employed CCN1 loss-of-function methodologies, including both in vitro siRNA-mediated depletion and in vivo fibroblast-specific knockout mice to assess the role of the endogenous protein on cardiac fibroblast fibrotic signaling, and its involvement in acute scar formation after MI. In vitro depletion of CCN1 reduced cardiac fibroblast senescence and proliferation. Although depletion of CCN1 decreased the expression of collagen processing and stabilization enzymes (i.e., P4HA1, PLOD1, and PLOD2), it did not inhibit myofibroblast induction or type I collagen synthesis. Alone, fibroblast-specific removal of CCN1 did not negatively impact ventricular performance or myocardial collagen content but did contribute to disorganization of collagen fibrils and increased matrix compliance. Similarly, Ccn1 ablated animals subjected to MI showed no discernible alterations in cardiac structure or function one week after permanent coronary artery ligation, but exhibited marked increases in incidence of mortality and cardiac rupture. Consistent with our findings that CCN1 depletion does not assuage myofibroblast conversion or type I collagen synthesis in vitro, Ccn1 knockout animals revealed no measurable differences in collagen scar width or mass compared to controls; however, detailed structural analyses via SHG and TEM of scar regions revealed marked alterations in their scar collagen topography-exhibiting changes in numerous macro- and micro-level collagen architectural attributes. Specifically, Ccn1 knockout mice displayed heightened ECM structural complexity in post-MI scar regions, including diminished local alignment and heightened tortuosity of collagen fibers, as well as reduced organizational coherency, packing, and size of collagen fibrils. Associated with these changes in ECM topography with the loss of CCN1 were reductions in fibroblast-matrix interactions, as evidenced by reduced fibroblast nuclear and cellular deformation in vivo and reduced focal-adhesion formation in vitro; findings that ultimately suggest CCN1's ability to influence fibroblast-led collagen alignment may in part be credited to its capacity to augment fibroblast-matrix interactions., Conclusions: These findings underscore the pivotal role of endogenous CCN1 in the scar formation process occurring after MI, directing the appropriate arrangement of the extracellular matrix's collagenous components in the maturing scar-shaping the mechanical properties that support its structural stability. While this suggests an adaptive role for CCN1 in regulating collagen structural attributes crucial for supporting scar integrity post MI, the long-term protracted expression of CCN1 holds maladaptive implications, potentially diminishing collagen structural complexity and compliance in non-infarct regions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Estimating biological sex is a crucial aspect of forensic anthropology, and is pivotal in forensic investigations. Presently, the most frequently adopted osteological sex estimation methods focus on the anterior pelvis, which is easily susceptible to postmortem damage, revealing a need for additional accurate methods. This study introduces a novel method for estimating adult sex through metric pelvic scar analysis, using a known skeletal sample (169 females; 51 males). Relationships between sex and scar dimensions were subjected to Kendall's tau-B testing, and the strongest associated measurements were further analyzed using binary logistic regression to determine their predictive capacity. The final estimation method was tested on an additional known-sex sample of 43 males and 43 females from the Spitalfields skeletal collection. All associations between biological sex and scar measurements were significant, with the preauricular sulcus and newly defined inferior interosseous cavity presenting the strongest relationships (τb 0.223-0.504). Individual regression models using the approximate volume of each feature predicted sex with over 80% accuracy, but when combined in a single regression model, the accuracy increased to an impressive 97.1%. When then applied to the validation sample, the final estimation model achieved an accuracy of 90.7%. These results highlight the high estimation accuracy achieved by simultaneously utilizing the approximate volume of the sulcus and the inferior cavity. This is not only highly accurate but also utilizes the sturdier posterior pelvis, making it a promising tool for forensic investigations and the wider field of osteology., (© 2024 The Author(s). Journal of Forensic Sciences published by Wiley Periodicals LLC on behalf of American Academy of Forensic Sciences.)

Mammals typically heal with fibrotic scars, and treatments to regenerate human skin and hair without a scar remain elusive. We discovered that mice lacking C-X-C motif chemokine receptor 2 (CXCR2 knockout [KO]) displayed robust and complete tissue regeneration across three different injury models: skin, hair follicle, and cartilage. Remarkably, wild-type mice receiving plasma from CXCR2 KO mice through parabiosis or injections healed wounds scarlessly. A comparison of circulating proteins using multiplex ELISA revealed a 24-fold higher plasma level of granulocyte colony stimulating factor (G-CSF) in CXCR2 KO blood. Local injections of G-CSF into wild-type (WT) mouse wound beds reduced scar formation and increased scarless tissue regeneration. G-CSF directly polarized macrophages into an anti-inflammatory phenotype, and both CXCR2 KO and G-CSF-treated mice recruited more anti-inflammatory macrophages into injured areas. Modulating macrophage activation states at early time points after injury promotes scarless tissue regeneration and may offer a therapeutic approach to improve healing of human skin wounds., Competing Interests: Declaration of interests A provisional patent has been filed with the US Patent and Trademark Office regarding CXCR2, G-CSF, and NETosis on reducing scar formation and promoting tissue regeneration., (Published by Elsevier Inc.)

Background and Aims: Diagnosing end-stage primary cicatricial alopecia (PCA) on routine histology is challenging since the major diagnostic feature (inflammatory infiltrate) may be minimal or absent. This study aimed to assess various staining patterns and diagnostic utility of elastic tissue staining by Verhoeff-Van Gieson (VVG) method and trichoscopy in PCA., Study Design: Cross-sectional study., Methods: Fifty-three patients clinically diagnosed with PCA underwent biopsy and trichoscopy in this cross-sectional study. Clinically active edge, if present, was biopsied. Twenty serial tissue sections were stained using H&E and VVG stain. Clinicopathological diagnoses were lichen planopilaris (LPP), discoid lupus erythematosus (DLE), folliculitis decalvans and unclassified PCA (UPCA) in 30 (56.6%), 11 (20.75%), 1 (1.9%) and 11 (20.75%) patients, respectively. Utility of VVG stain was ascertained considering clincopathological correlation (CPC) as the reference standard. Association of characteristic trichoscopic and VVG staining patterns was ascertained., Results: Diagnostic definition was achieved on VVG staining in 19/30 sections of LPP (wedge-shaped pattern) with 63.33% sensitivity; 7/11 cases of DLE (absent upper and mid dermal elastic fibres) with 63.64% sensitivity and 7/11 cases of UPCA (wedge-shaped pattern-3/7; recoil pattern-4/7). Routine histology suggested diagnosis only in 13/53 sections (24.52%). However, diagnosis on VVG staining corresponded with diagnosis on CPC in 33/53 cases (62.3%). Comparison of H&E versus VVG stain both overall and in the LPP and UPCA cohorts proved utility of VVG staining using Fisher's exact test (p<0.05). Statistical significance was also noted when trichoscopy was correlated with patterns on VVG staining (p<0.05)., Conclusion: Increased diagnostic yield is noted with trichoscopy and VVG stain in PCA especially when routine histopathology is non-diagnostic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

After cutaneous wounds successfully heal, keratinocytes that underwent the epithelial-mesenchymal transition (EMT) regain their epithelial characteristics, while in scar tissue, epidermal cells persist in a mesenchymal state. However, the regulatory mechanisms governing this reversion are poorly understood, and the impact of persistent mesenchymal-like epidermal cells in scar tissue remains unclear. In the present study, we found that during wound healing, the regulatory factor GRHL2 is highly expressed in normal epidermal cells, downregulated in EMT epidermal cells, and upregulated again during the process of mesenchymal-epithelial transition (MET). We further demonstrated that interfering with GRHL2 expression in epidermal cells can effectively induce the EMT. Conversely, the overexpression of GRHL2 in EMT epidermal cells resulted in partial reversion of the EMT to an epithelial state. To investigate the effects of failed MET in epidermal cells on skin wound healing, we interfered with GRHL2 expression in epidermal cells surrounding the cutaneous wound. The results demonstrated that the persistence of epidermal cells in the mesenchymal state promoted fibrosis in scar tissue, manifested by increased thickness of scar tissue, deposition of collagen and fibronectin, as well as the activation of myofibroblasts. Furthermore, the miR-200s/Zeb1 axis was perturbed in GRHL2 knockdown keratinocytes, and transfection with miR-200s analogs promoted the reversion of EMT in epidermal cells, which indicates that they mediate the EMT process in keratinocytes. These results suggest that restoration of the epithelial state in epidermal cells following the EMT is essential to wound healing, providing potential therapeutic targets for preventing scar formation., (© 2024. The Author(s).)

Without intervention, the natural wound healing process can often result in scarring, which can have detrimental effects on both the physical and mental well-being of patients. Therefore, it is crucial to develop biomaterials that can promote healing without scarring. Regulating the Yes-associated protein-1/PDZ-binding motif (YAP/TAZ) signaling pathway is possible to reduce excessive fibrosis of fibroblasts and proliferation of vascular endothelial cells, ultimately impacting scar formation. Arsenic trioxide (ATO), an ancient drug with medicinal and toxic properties, has shown promise in regulating this pathway. An ATO-loaded hydrogel dressing (ATO@CS/SA) was created to facilitate scarless wound healing, utilizing chitosan (CS) and sodium alginate (SA) to prevent direct contact of ATO with the wound tissue and minimize potential side effects. In vitro studies demonstrated that low concentrations of ATO did not impact cell viability and even promoted proliferation and migration. Co-culturing the hydrogel with fibroblasts and vascular endothelial cells led to decreased expression levels of YAP and TAZ. Animal studies over a 90-day period revealed significant inhibition of scar formation with this system. Histological experiments further confirmed that the decreased expression of YAP and TAZ was responsible for this outcome. In conclusion, when administered at the appropriate dose, ATO can be repurposed from a traditional poison to a therapeutic agent, effectively suppressing excessive cell fibrosis and blood vessel proliferation and offering a novel approach to scar-free treatment.

Traumatic spinal cord injuries (SCI) are debilitating injuries affecting twenty-seven million people worldwide and cause functional impairments. Despite decades of research and medical advancements, current treatment options for SCI remain limited, in part due to the complex pathophysiology of spinal cord lesions including cellular transformation and extracellular matrix (ECM) remodeling. Recent studies have increased focus on fibrotic scarring after SCI, and yet much remains unclear about the impact of fibrotic scarring on SCI lesion progression. Here, using collagen and decellularized spinal cord-based composite hydrogels, a three-dimensional (3D) cell culture model mimicking the fibrous core of spinal cord lesions was implemented to investigate its influence on the surrounding astrocytes. To mimic the fibrotic milieu, collagen fibril thickness was tuned using previously established temperature-controlled casting methods. In our platforms, astrocytes in fibro-mimetic hydrogels exhibited increased levels of activation markers such as glial fibrillary acidic protein and N-cadherin. Furthermore, astrocytes in fibro-mimetic hydrogels deposited more fibronectin and laminin, further hinting that astrocytes may also contribute to fibrotic scarring. These markers were decreased when Rho-ROCK and integrin β1 were inhibited via pharmacological inhibitors. Mechanistic analysis of Yes-associated protein reveals that blocking integrin β1 prevents mechanosensing of astrocytes, contributing to altered phenotypes in variable culture conditions. In the presence of these inhibitors, astrocytes increased the secretion of brain-derived neurotrophic factor, and a greater degree of dorsal root ganglia neurite infiltration into the underlying hydrogels was observed. Altogether, this study presents a novel tissue-engineered platform to study fibrotic scarring after SCI and may be a useful platform to advance our understanding of SCI lesion aggravation.

During the wound healing process, the activation of signal transducer and activator of transcription 3 (STAT3) is considered crucial for the migration and proliferation of epithelial cells, as well as for establishing the inflammatory environment. However, an excessive STAT3 activation aggravates scar formation. Here we show that 450 nm blue light and 630 nm red light can differentially regulate the phosphorylation of STAT3 (p-STAT3) and its downstream cytokines in keratinocytes. Further mechanistic studies reveal that red light promotes wound healing by activating the PI3 kinase p110 beta (PI3Kβ)/STAT3 signaling axis, while blue light inhibits p-STAT3 at the wound site by modulating cytochrome c-P450 (CYT-P450) activity and reactive oxygen species (ROS) generation. In a mouse scar model, skin wound healing can be significantly accelerated with red light followed by blue light to reduce scar formation. In summary, our study presents a potential strategy for regulating epithelial cell p-STAT3 through visible light to address skin scarring issues and elucidates the underlying mechanisms., (© 2024. The Author(s).)

Pathological scarring has been a challenge in skin injury repair since ancient times, and prophylactic treatment in the early stages of wound healing usually results in delayed wound healing. In this study, poly(ethylene oxide) (PEO) and chitosan (CTS) were used as carrier materials to construct multifunctional pirfenidone (PFD)/CTS/PEO (PCP) nanofiber membranes (NFMs) loaded with PFD by microfluidic blow-spinning (MBS). MBS is a good method for quickly, safely, and greenly constructing large-area manufacturing of inexpensive NFMs. PCP NFMs were uniform in external morphology, with diameters ranging from 200 to 500 nm. The encapsulation efficiency of the drug-loaded PCP NFMs was above 80%, which had a good slow release, visualization, water absorption, and biocompatibility. The inhibitory effect of PCP NFMs on normal human dermal fibroblasts was dose-dependent and inhibited the expression of the transforming growth factor-β1/SMAD family member 3 (TGF-β1/SMAD3) signaling pathway. PCP NFMs showed significant antibacterial effects against both Staphylococcus aureus and Escherichia coli . In the rabbit ear scar experiment, the wound healed about 70% on day 5 and almost completely on day 10 after PCP-3 NFMs treatment, with the thinnest scar tissue, skin color, tenderness close to normal tissue, and a Vancouver scar scale score of less than 5. PCP-3 NFMs had good effects on anti-inflammatory, wound healing, and collagen-I deposition reducing effects. In conclusion, PCP-3 NFMs can both promote wound healing and intervene to inhibit pathological scarring in advance, making them a potential multifunctional wound dressing for early prevention and treatment of pathological scarring.

After injury, mammalian spinal cords develop scars to confine the lesion and prevent further damage. However, excessive scarring can hinder neural regeneration and functional recovery 1,2 . These competing actions underscore the importance of developing therapeutic strategies to dynamically modulate scar progression. Previous research on scarring has primarily focused on astrocytes, but recent evidence has suggested that ependymal cells also participate. Ependymal cells normally form the epithelial layer encasing the central canal, but they undergo massive proliferation and differentiation into astroglia following certain injuries, becoming a core scar component 3-7 . However, the mechanisms regulating ependymal proliferation in vivo remain unclear. Here we uncover an endogenous κ-opioid signalling pathway that controls ependymal proliferation. Specifically, we detect expression of the κ-opioid receptor, OPRK1, in a functionally under-characterized cell type known as cerebrospinal fluid-contacting neuron (CSF-cN). We also discover a neighbouring cell population that expresses the cognate ligand prodynorphin (PDYN). Whereas κ-opioids are typically considered inhibitory, they excite CSF-cNs to inhibit ependymal proliferation. Systemic administration of a κ-antagonist enhances ependymal proliferation in uninjured spinal cords in a CSF-cN-dependent manner. Moreover, a κ-agonist impairs ependymal proliferation, scar formation and motor function following injury. Together, our data suggest a paracrine signalling pathway in which PDYN + cells tonically release κ-opioids to stimulate CSF-cNs and suppress ependymal proliferation, revealing an endogenous mechanism and potential pharmacological strategy for modulating scarring after spinal cord injury., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: A common treatment for large deep-to-full-thickness burns is excision and grafting with a widely meshed split-thickness skin graft (mSTSG). Due to the differential healing of the interstices and adhered split-thickness skin graft, wound patterning and delayed wound healing are common outcomes of this treatment. Delayed healing may increase infection rates and wound care requirements, while wound patterning may be psychologically and aesthetically consequential for patients. Autologous skin cell suspension (ASCS) can be used to "over spray" a meshed autograft. It was hypothesized that the use of ASCS combined with mSTSG would increase the rate of wound healing and decrease patterning in healed burn wounds., Methods: Full-thickness burns or excisional wounds (n = 8 each) were created in red Duroc pigs and received 4:1 mSTSGs after wound bed preparation. Half of the wounds received ASCS and half did not at the time of grafting. Percent re-epithelialization, patterning, rete ridge ratio, cellularity, dermal and epidermal thickness, immunofluorescent S100β staining, and melanin index were assessed for each scar., Results: Wounds that received ASCS exhibited increased rates of re-epithelialization (burn +ACSC versus burn-ASCS; day 3 (53.9 ± 3.1 versus 34.3 ± 3.3, P = 0.009): day 5 (68.1 ± 1.6 versus 40.8 ± 3.2, P < 0.001)). Excision +ASCS versus excision-ASCS; day 7 (98.1 ± 1.2 versus 86.4 ± 2.0, day 7 P = 0.022) compared to wounds not treated with ASCS. There was no difference in rete ridge ratio, cellularity, dermal thickness, epidermal thickness, S100β staining, melanin index, or patterning was measured between wounds that received ASCS and those that did not., Conclusions: The addition of ASCS to 4:1 mSTSGs leads to increased rate of wound healing but does not impact the degree of patterning in this model, suggesting that ASCS application likely robustly transfers keratinocytes but not functioning melanocytes at acute timepoints., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Cutaneous deciduosis is an extremely rare condition that clinically presents as a nodular lesion in the skin as a scar or neoplasm. Histologically, this may pose a diagnostic challenge simulating malignant epithelioid neoplasms including sarcoma. Histologically, a nodular growth pattern of large monomorphic epithelioid cells is observed. The epithelioid cells in deciduosis can appear atypical with considerable nuclear pleomorphism, mimicking a malignancy. These features can be misinterpreted as a primary cutaneous or metastatic malignancy by dermatopathologists who are not familiar with gynecologic pathology. Failure to correctly diagnose this condition may result in unnecessary diagnostic studies for the patient. In this article, we report a case of cutaneous deciduosis in a 35-year-old woman with a cesarean scar. Histological examination revealed nodular proliferation of large epithelioid cells with pale eosinophilic cytoplasm and large nuclei with prominent nucleoli. Compressed atrophic slit-like glands resembling endometrial glands were present in some areas. Histopathological features of decidual cells, along with appropriate immunohistochemical studies, help establish the diagnosis and rule out other neoplastic mimics of deciduosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Spinal cord injury (SCI) is a complex neurodegenerative pathology that consistently harbours a poor prognostic outcome. At present, there are few therapeutic strategies that can halt neuronal cell death and facilitate functional motor recovery. However, recent studies have highlighted the Wnt pathway as a key promoter of axon regeneration following central nervous system (CNS) injuries. Emerging evidence also suggests that the temporal dysregulation of Wnt may drive cell death post-SCI. A major challenge in SCI treatment resides in developing therapeutics that can effectively target inflammation and facilitate glial scar repair. Before Wnt signalling is exploited for SCI therapy, further research is needed to clarify the implications of Wnt on neuroinflammation during chronic stages of injury. In this review, an attempt is made to dissect the impact of canonical and non-canonical Wnt pathways in relation to individual aspects of glial and fibrotic scar formation. Furthermore, it is also highlighted how modulating Wnt activity at chronic time points may aid in limiting lesion expansion and promoting axonal repair., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: We present the case of a 61-year-old male patient with a history of intracranial IDH-wildtype glioblastoma with an isolated cutaneous metastasis within the previous surgical site scar. The cytomorphology of the cutaneous deposits was reminiscent of metastatic melanoma, which is a differential diagnostic pitfall. The tumor molecular characteristics are described, as these have become essential diagnostic criteria for many central nervous system tumors, along with a discussion of the role of immunohistochemical markers and potential pitfalls in the differential diagnosis of melanoma and poorly differentiated carcinoma. We discuss the biology of metastatic glioblastoma and provide a focused literature review of previous glioblastomas with tumor cell seeding within prior surgical scars., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

In goldfish, spinal cord injury triggers the formation of a fibrous scar at the injury site. Regenerating axons are able to penetrate the scar tissue, resulting in the recovery of motor function. Previous findings suggested that regenerating axons enter the scar through tubular structures surrounded by glial elements with laminin-positive basement membranes and that glial processes expressing glial fibrillary acidic protein (GFAP) are associated with axonal regeneration. How glia contribute to promoting axonal regeneration, however, is unknown. Here, we revealed that glial processes expressing vimentin or brain lipid-binding protein (BLBP) also enter the fibrous scar after spinal cord injury in goldfish. Vimentin-positive glial processes were more numerous than GFAP- or BLBP-positive glial processes in the scar tissue. Regenerating axons in the scar tissue were more closely associated with vimentin-positive glial processes than GFAP-positive glial processes. Vimentin-positive glial processes co-expressed matrix metalloproteinase (MMP)-14. Our findings suggest that vimentin-positive glial processes closely associate with regenerating axons through tubular structures entering the scar after spinal cord injury in goldfish. In intact spinal cord, ependymo-radial glial cell bodies express BLBP and their radial processes express vimentin, suggesting that vimentin-positive glial processes derive from migrating ependymo-radial glial cells. MMP-14 expressed in vimentin-positive glial cells and their processes might provide a beneficial environment for axonal regeneration., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The inflammatory response and scar formation after spinal cord injury (SCI) limit nerve regeneration and functional recovery. Our research group has previously shown that the expression of astrocyte-derived lipocalin 2 (Lcn2) is upregulated after SCI, which correlates with neuronal apoptosis and functional recovery. Therefore, we speculate that astrocyte-specific knockdown of Lcn2 after SCI may lead to a better prognosis., Methods: Tissue RNA sequencing, Western blotting, PCR, and immunofluorescence assays were conducted to assess the expression of Lcn2 following SCI in mice. Adeno-associated virus 9 (AAV9) transfection was employed to specifically reduce the expression of Lcn2 in astrocytes, and subsequent evaluations of scarring and inflammation were conducted. In vitro experiments involved treating primary astrocytes with TGF-β or an A1-induced mixture (C1q, TNF-α and IL-1α) following Lcn2 knockdown. Finally, the intrathecal injection of recombinant Lcn2 (ReLcn2) protein was conducted post-injury to further confirm the role of Lcn2 and its underlying mechanism in SCI., Results: Lcn2 expression was elevated in astrocytes after SCI at 7 dpi (days post injury). Lcn2 knockdown in astrocytes is beneficial for neuronal survival and functional recovery after SCI, and is accompanied by a reduced inflammatory response and inhibited scar formation. The inhibition of SMAD-associated signaling activation was identified as a possible mechanism, and in vitro experiments further confirmed this finding. ReLcn2 further activated SMAD-associated signaling and aggravated motor function after SCI., Conclusion: The upregulation of Lcn2 expression in astrocytes is involved in neuroinflammation and scar formation after SCI, and the activation of SMAD-associated signaling is one of the underlying mechanisms., Competing Interests: Declaration of competing interest All authors consent to this article for publication. The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Determination of infarct and scar size following myocardial infarction (MI) is commonly used to evaluate the efficacy of potential cardioprotective treatments in animal models. However, histological methods to determine morphological features in the infarcted heart have barely improved since implementation while still consuming large parts of the tissue and offering little options for parallel analyses. We aim to develop a new fluorescence technology for determining infarct area and area at risk that is comparable to 2,3,5-triphenyltetrazolium chloride (TTC) staining but allows for multiple analyses on the same heart tissue. For early and late time points following MI, we compared classical histochemical approaches with fluorescence staining methods. Reperfused MI was induced in male mice, the hearts were extracted 24 h, 7-, 21-, or 28-days later and fluorescently stained by combining Hoechst and phalloidin. This approach allowed for clear visualization of the infarct area, the area at ischemic risk and the remote area not affected by MI. The combined fluorescence staining correlated with the classic TTC/Evans Blue staining 24 h after MI (r = 0.8334). In later phases (>7 d) post-MI, wheat germ agglutinin (WGA) is equally accurate as classical Sirius Red (r = 0.9752), Masson's (r = 0.9920) and Gomori's Trichrome (r = 0.8082) staining for determination of scar size. Additionally, feasibility to co-localize fluorescence-stained immune cells in specific regions of the infarcted myocardium was demonstrated with this protocol. In conclusion, this new procedure for determination of post-MI infarct size is not inferior to classical TTC staining, yet provides substantial benefits, including the option for unbiased software-assisted analysis while sparing ample residual tissue for additional analyses. Overall, this enhances the data quality and reduces the required animal numbers consistent with the 3R concept of animal experimentation.

Traumatic brain injury (TBI) is an acquired insult to the brain caused by an external mechanical force, potentially resulting in temporary or permanent impairment. Microglia, the resident immune cells of the central nervous system, are activated in response to TBI, participating in tissue repair process. However, the underlying epigenetic mechanisms in microglia during TBI remain poorly understood. ARID1A (AT-Rich Interaction Domain 1 A), a pivotal subunit of the multi-protein SWI/SNF chromatin remodeling complex, has received little attention in microglia, especially in the context of brain injury. In this study, we generated a Arid1a cKO mouse line to investigate the potential roles of ARID1A in microglia in response to TBI. We found that glial scar formation was exacerbated due to increased microglial migration and a heightened inflammatory response in Arid1a cKO mice following TBI. Mechanistically, loss of ARID1A led to an up-regulation of the chemokine CCL5 in microglia upon the injury, while the CCL5-neutralizing antibody reduced migration and inflammatory response of LPS-stimulated Arid1a cKO microglia. Importantly, administration of auraptene (AUR), an inhibitor of CCL5, repressed the microglial migration and inflammatory response, as well as the glial scar formation after TBI. These findings suggest that ARID1A is critical for microglial response to injury and that AUR has a therapeutic potential for the treatment of TBI., (© 2024. The Author(s).)

Scar tissue formation following skin wound healing is a challenging public health problem. Skin regeneration and preventing the formation of scar tissue by currently available commercial products are largely ineffective. This study aimed to test the efficacy of a novel topical metformin lotion (ML) in inhibiting scar tissue formation during skin wound healing in rats and to determine the mechanisms of action involved. A 6% ML was prepared in our laboratory. A skin wound healing model in rats was used. The wounded rats were divided into two groups and treated daily for 10 days as follows: Group 1 received a daily application of 50 mg of control lotion, or 0% ML (totaling 100 mg of lotion per rat), and Group 2 received a daily application of 50 mg of 6% ML (totaling 100 mg of 6% ML per rat). Blood samples from the heart of each rat were analyzed for inflammatory markers, HMGB1 and IL-1β, using ELISA, and immunological and histological analyses were performed on skin tissue sections. ML decreased levels of inflammatory markers HMGB1 and IL-1β in the serum of rats and inhibited the release of HMGB1 from cell nuclei into the skin tissue matrix. Additionally, ML demonstrated anti-fibrotic properties by enhancing AMPK activity, decreasing the expression of TGF-β1, reducing the number of myofibroblasts, decreasing the production of collagen III, and increasing the expression of collagen I. ML promotes the regeneration of high-quality skin during wound healing by reducing scar tissue formation. This effect is mediated through the activation of AMPK, inhibition of TGF-β1, and a decrease in the number of myofibroblasts., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Scar tissue formation is a hallmark of wound repair in adults and can chronically affect tissue architecture and function. To understand the general phenomena, we sought to explore scar-driven imbalance in tissue homeostasis caused by a common, and standardized surgical procedure, the uterine scar due to cesarean surgery. Deep uterine scar is associated with a rapidly increasing condition in pregnant women, placenta accreta spectrum (PAS), characterized by aggressive trophoblast invasion into the uterus, frequently necessitating hysterectomy at parturition. We created a model of uterine scar, recapitulating PAS-like invasive phenotype, showing that scar matrix activates mechanosensitive ion channel, Piezo1, through glycolysis-fueled cellular contraction. Piezo1 activation increases intracellular calcium activity and Protein kinase C activation, leading to NF-κB nuclear translocation, and MafG stabilization. This inflammatory transformation of decidua leads to production of IL-8 and G-CSF, chemotactically recruiting invading trophoblasts towards scar, initiating PAS. Our study demonstrates aberrant mechanics of scar disturbs stroma-epithelia homeostasis in placentation, with implications in cancer dissemination., (© 2024. The Author(s).)

A burn is a type of injury to the skin or other tissues caused by heat, chemicals, electricity, sunlight, or radiation. Burn injuries have been proven to have the potential for long-term detrimental effects on the human body. The conventional therapeutic approaches are not able to effectively and easily heal these burn wounds completely. The main potential drawbacks of these treatments include hypertrophic scarring, contracture, infection, necrosis, allergic reactions, prolonged healing times, and unsatisfactory cosmetic results. The existence of these drawbacks and limitations in current treatment approaches necessitates the need to search for and develop better, more efficient therapies. The regenerative potential of microRNAs (miRNAs) and the exosomal miRNAs derived from various cell types, especially stem cells, offer advantages that outweigh traditional burn wound healing treatment procedures. The use of multiple types of stem cells is gaining interest due to their improved healing efficiency for various applications. Stem cells have several key distinguishing characteristics, including the ability to promote more effective and rapid healing of burn wounds, reduced inflammation levels at the wound site, and less scar tissue formation and fibrosis. In this review, we have discussed the stages of wound healing, the role of exosomes and miRNAs in improving thermal-induced wounds, and the impact of miRNAs in preventing the formation of hypertrophic scars. Research studies, pre-clinical and clinical, on the use of different cell-derived exosomal miRNAs and miRNAs for the treatment of thermal burns have been documented from the year 2000 up to the current time. Studies show that the use of different cell-derived exosomal miRNAs and miRNAs can improve the healing of burn wounds. The migration of exosomal miRNAs to the site of a wound leads to inhibition of apoptosis, induction of autophagy, re-epithelialization, granulation, regeneration of skin appendages, and angiogenesis. In conclusion, this study underscores the importance of integrating miRNA and exosome research into treatment strategies for burn injuries, paving the way for novel therapeutic approaches that could significantly improve patient outcomes and recovery times., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Excessive fibrotic scar formation during skin defect repair poses a formidable challenge, impeding the simultaneous acceleration of wound healing and prevention of scar formation and hindering the restoration of skin integrity and functionality. Drawing inspiration from the structural, compositional, and biological attributes of skin, we developed a hydrogel containing modified recombinant human collagen type III and thiolated hyaluronic acid to address the challenges of regenerating skin appendages and improving the recovery of skin functions after injury by reducing fibrotic scarring. The hydrogel displayed favorable biocompatibility, antioxidant properties, angiogenic potential, and fibroblast migration stimulation in vitro . In a rat full-layer defect model, it reduced inflammation, promoted microvascular formation, and significantly enhanced the wound healing speed and effectiveness. Additionally, by upregulating fibrosis-associated genes, such as TGFB1, it facilitated collagen accumulation and a beneficial balance between type I and type III collagen, potentially expediting skin regeneration and functional recovery. In conclusion, the utilization of rhCol III-HS demonstrated considerable potential as a wound dressing, offering a highly effective strategy for the restoration and rejuvenation of complete skin defects.

Spinal cord injury (SCI) often results in permanent loss of motor and sensory function. After SCI, the blood-spinal cord barrier (BSCB) is disrupted, causing the infiltration of neutrophils and macrophages, which secrete several kinds of cytokines, as well as matrix metalloproteinases (MMPs). MMPs are proteases capable of degrading various extracellular matrix (ECM) proteins, as well as many non-matrix substrates. The tissue inhibitor of MMPs (TIMP)-1 is significantly upregulated post-SCI and operates via MMP-dependent and MMP-independent pathways. Through the MMP-dependent pathway, TIMP-1 directly reduces inflammation and destruction of the ECM by binding and blocking the catalytic domains of MMPs. Thus, TIMP-1 helps preserve the BSCB and reduces immune cell infiltration. The MMP-independent pathway involves TIMP-1's cytokine-like functions, in which it binds specific TIMP surface receptors. Through receptor binding, TIMP-1 can stimulate the proliferation of several types of cells, including keratinocytes, aortic smooth muscle cells, skin epithelial cells, corneal epithelial cells, and astrocytes. TIMP-1 induces astrocyte proliferation, modulates microglia activation, and increases myelination and neurite extension in the central nervous system (CNS). In addition, TIMP-1 also regulates apoptosis and promotes cell survival through direct signaling. This review provides a comprehensive assessment of TIMP-1, specifically regarding its contribution to inflammation, ECM remodeling, and scar formation after SCI.

Wounds are most commonly caused by accidents, surgery and burns, and can be internal or external. Naturally, the wound healing process can take a long time and lead to scarring. In this study we present a technique to shorten wound healing time and prevent or mitigate scarring using D-mannose that is applied directly on the wound. The results showed that the healing time is almost halved compared to treatment with povidone-iodine solution which is an antiseptic widely used in surgery. D-Mannose is neither an antisepsis nor an antibiotic. We propose a posssible mechanism by which D-mannose binds to D-mannose binding lectin and immediately activates the innate immune system that ultimately phagocytizes pathogens and clears the wound of degraded cells and materials, which reduces inflammation and implicitly wound healing time. D-Mannose also intervenes in the coagulation process by binding to fibrinogen, generating a finer and denser fibrin, which visibly reduces collagen scars. Our findings show that applying D-mannose directly on the wound as a powder shortens wound healing time and visibly attenuates scarring. Apart from the unaesthetic appearance, these scars can also cause a certain tissue dysfunction, regardless of the affected organ., (© 2024. The Author(s).)

Background: Laser technology is a viable therapeutic option for treating a number of skin pathologic conditions, including pigmented lesions, vascular lesions and acne scars., Aim: In this work, through in vitro and clinical investigations we test the efficacy, the safety and the speed of treatment of high-powered laser system emitting a 675-nm in the management of various skin condition., Materials and Methods: In vitro experiments were performed irradiating adult human dermal fibroblasts cells (HDFa) with 675-nm laser for 24, 48 and 72 h with different fluences and Ki-67 + cells were counted. The confocal microscopy images of control and treated samples were acquired. Clinical skin rejuvenation/diseases treatments with 675 nm laser device were performed with different laser parameters in 11 patients with pigmented lesions, 5 patients with acne scars and 23 patients for skin rejuvenation. Data were evaluated with the validated global score using 5-point scales (GAIS) and patient's satisfaction scale., Results: The application of the high-power 675 nm laser has proven effective in stimulating cell proliferation in in vitro experiments and it led to good results for all skin pathologies. GAIS showed values between 3 and 4 points for all treated pathologies, all scores between '75%-good improvements' and '100%-excellent improvements'. The treatment time was reduced by 50% compared to the old parameters setting, resulting in a faster and good patient's satisfying technique. No serious adverse effects were recorded., Conclusion: the preclinical and clinical data confirm the efficacy and safety of this high-powered 675 nm laser for several skin condition., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Cardiac magnetic resonance imaging (CMR)-defined ventricular scar and anatomic conduction channels (CMR-CCs) offer promise in delineating ventricular tachycardia substrate. No studies have validated channels with coregistered histology, nor have they ascertained the histological characteristics of deceleration zones (DZs) within these channels. We aimed to validate CMR scar and CMR-CCs with whole-heart histology and electroanatomic mapping in a postinfarction model., Methods: Five sheep underwent anteroseptal infarction. CMR (116±20 days post infarct) was postprocessed using ADAS-3D, varying pixel intensity thresholds (5545, 6040, 6535, and 7030). DZs were identified by electroanatomic mapping (129±12 days post infarct). Explanted hearts were sectioned and stained with Picrosirius red, and whole-heart histopathologic shells were generated. Scar topography as well as percentage fibrosis, adiposity, and remaining viable myocardium within 3 mm histological biopsies and within CMR-CCs were determined., Results: Using the standard 6040 thresholding, CMR had 83.8% accuracy for identifying histological scar in the endocardium (κ, 0.666) and 61.4% in the epicardium (κ, 0.276). Thirty-seven CMR-CCs were identified by varying thresholding; 23 (62%) were unique. DZs colocalized to 19 of 23 (83%) CMR-CCs. Twenty (87%) CMR-CCs were histologically confirmed. Within-channel histological fibrosis did not differ by the presence of DZs ( P =0.242). Within-channel histological adiposity was significantly higher at sites with versus without DZs (24.1% versus 8.3%; P <0.001)., Conclusions: Postprocessed CMR-derived scars and channels were validated by histology and electroanatomic mapping. Regions of CMR-CCs at sites of DZs had higher adiposity but similar fibrosis than regions without DZs, suggesting that lipomatous metaplasia may contribute to arrhythmogenicity of postinfarction scar., Competing Interests: Dr Kumar has received research grants from Abbott Medical and Biotronik; speaker’s honoraria from Biosense Webster, Abbott Medical, Biotronik, Medtronic, and Sanofi Aventis. Dr Campbell has received speaker’s honoraria from Biosense Webster. The other authors report no conflicts.

Hair disorders, including central centrifugal cicatricial alopecia (CCCA), traction alopecia (TA), and acquired trichorrhexis nodosa (ATN), commonly occur in individuals with curly textured hair. Curly textured hair in individuals of African descent has unique properties and can present diagnostic and therapeutic challenges. CCCA has been linked to uterine leiomyoma and type 2 diabetes mellitus, as well as fibroproliferation. TA often presents with a fringe sign and can arise from high-tension hairstyles presumed to be protective. Trichoscopy is useful in establishing a diagnosis; perifollicular halos are more commonly seen than perifollicular erythema or scale in CCCA. In TA, miniaturized follicles, hair casts, and "flambeau sign" can be seen. Hairstyling practices likely contribute to TA and ATN; however, the data are mixed on the role of chemical relaxers and heat styling in CCCA. Unique considerations in the presentation of frontal fibrosing alopecia in curly textured hair have also been published recently. This review provides a comprehensive, up-to-date summary of these disorders with an emphasis on their unique properties, as well as considerations in hair care for curly textured hair., (© 2024 the International Society of Dermatology.)

Objective: To present a comprehensive flow cytometry panel for idiopathic subglottic stenosis (iSGS)., Study Design: Controlled ex vivo cohort study., Setting: Tertiary care academic hospital in a metropolitan area., Methods: Flow cytometry and single-cell RNA sequencing were performed on 9 paired normal and scar tissue samples from iSGS patients. Flow cytometry was used to assess the presence of myeloid (CD11b, CD14, CD15, Siglec8), lymphoid (CD3, CD4, CD8, gamma delta [γδ], FOXP3), endothelial (CD31), fibroblast (CD90, SMA), and epithelial (CD326, CK5) markers., Results: On flow cytometry, iSGS scar is characterized by an increased presence of myeloid, lymphoid, endothelial, and fibroblast cell types, but a decreased presence of epithelial cells. In the myeloid lineage, iSGS scar samples demonstrated increased CD11b + monocytes (P < .001), Siglec8 + eosinophils (P = .03), and CD14 + monocytes (P = .02). In the lymphoid lineage, iSGS scar demonstrated increased CD3 + T-cells (P < .001), CD4 + helper T-cells (P < .001), γδ + T-cells (P < .001), and FOXP3 + regulatory T-cells (P = .002). iSGS scar exhibited specific increases in CD90 + (P = .04) and SMA + (P < .001) fibroblasts but decreased CD326 + (E-cadherin) epithelial cells (P = .01) relative to normal samples., Conclusion: We present a comprehensive flow cytometry panel for iSGS. This flow panel may serve as a common platform among airway scientists to elucidate the cellular mechanisms underpinning iSGS and other upper airway pathologies. Scar iSGS samples demonstrate a distinct cellular profile relative to normal iSGS specimens, exhibiting increased fibroblast, endothelial, and inflammatory cell types but decreased epithelium., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Context.—: Clinical, dermoscopic, and histologic diagnostic criteria may overlap in cases with scarring and nonscarring alopecia, making diagnosis difficult for clinicians and pathologists. New histopathologic discoveries indicate that the cutaneous adnexal structural and homeostatic unit made up of the pilosebaceous unit, eccrine sweat gland coils (ESGCs), and dermal white adipose tissue may have a role in hair follicle renewal., Objective.—: To verify the presence of adipose tissue in the dermis at the level of the isthmus, infiltrating the bundles of the arrector pili muscle in biopsies from the scalp of 3 scarring alopecias: frontal fibrosing alopecia (FFA), fibrosing alopecia in a pattern distribution (FAPD), and lichen planopilaris (LPP)., Design.—: We performed a retrospective and descriptive survey of 71 female scalp biopsies from 2016 to 2022 diagnosed at the Dermatopathology Laboratory at Fluminense Federal University of Rio de Janeiro. Two pathologists reviewed and diagnosed the cases, correlating pathologic features with clinical and dermoscopic findings., Results.—: The histopathologic findings of adipose tissue infiltration in the dermis at the level of the isthmus and in the bundles of the arrector pili muscle and the displacement of ESGCs were more frequently identified in FFA, followed by FAPD and less frequently found in LPP., Conclusions.—: According to our research, adipose tissue infiltration in the dermis at the level of the isthmus and in the bundles of the arrector pili muscle and the displacement of ESGCs were observed in 3 scarring alopecias (FFA, FAPD, and LPP) and seems to be involved in the development of scarring alopecia., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Introduction: Narrow-band imaging (NBI) can improve detection of lesions in the aerodigestive tract. However, its role in benign lesions of the larynx is unclear. This study aims to determine whether NBI improves the detection of scars, sulci, and nodules compared to panchromatic lighting using objective image analysis., Methods: In total, 120 vocal folds (VFs) were analyzed with and without NBI (21 normal, 15 scars, 16 sulci, and 45 nodules). Each VF image had anterior, middle, and posterior thirds analyzed for brightness using an area morphometry software (Optimas 5.1a). The middle-third with the lesion was analyzed against surrounding VF segments for average and standard deviation (SD) in absolute grayscale., Results: The use of panchromatic light resulted in greater illumination and grayscale values than NBI. All lesions tended to be in the mid-membranous fold. Under panchromatic light, change in brightness when comparing anterior versus middle (A-M) was +6.1% for normal, versus 6.5%, 8.1%, and 7.1% for sulci, nodules, and scars, respectively. Under NBI, they were 9.0% (normal), 12.3% (sulci), 13.7% (nodules), and 13.1% (scars). A greater SD of luminescence was observed at pathology sites (p < 0.05) when using NBI. The change in absolute grayscale at all lesion sites was greater when using NBI than when using panchromatic light (p < 0.05)., Conclusion: NBI significantly enhanced the area of pathology in patients with nodules, sulci, and scars. Greater SD values in grayscale at pathologic sites were observed compared at normal sites. Thus, NBI may improve the detection of phonotraumatic lesions compared to panchromatic light., Level of Evidence: N/A Laryngoscope, 134:4066-4070, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To investigate the role of periostin (POSTN) and the transforming growth factor β (TGF-β) pathway in the formation of laryngotracheal stenosis (LTS) scar fibrosis and to explore the specific signaling mechanism of POSTN-regulated TGF-β pathway in tracheal fibroblasts., Methods: Bioinformatics analysis was performed on scar data sets from the GEO database to preliminarily analyze the involvement of POSTN and TGF-β pathways in fibrosis diseases. Expression of POSTN and TGF-β pathway-related molecules was analyzed in LTS scar tissue at the mRNA and protein levels. The effect of POSTN on the biological behavior of tracheal fibroblasts was studied using plasmid DNA overexpression and siRNA silencing techniques to regulate POSTN expression and observe the activation of TGF-β1 and the regulation of cell proliferation and migration via the TGF-β/RHOA pathway., Results: The bioinformatics analysis revealed that POSTN and the TGF-β pathway are significantly involved in fibrosis diseases. High expression of POSTN and TGF-β/RHOA pathway-related molecules (TGFβ1, RHOA, CTGF, and COL1) was observed in LTS tissue at both mRNA and protein levels. In tracheal fibroblasts, overexpression or silencing of POSTN led to the activation of TGF-β1 and regulation of cell proliferation and migration through the TGF-β/RHOA pathway., Conclusion: POSTN is a key molecule in scar formation in LTS, and it regulates the TGF-β/RHOA pathway to mediate the formation of cicatricial LTS by acting on TGF-β1. This study provides insights into the molecular mechanisms underlying LTS and suggests potential therapeutic targets for the treatment of this condition., Level of Evidence: NA Laryngoscope, 134:4078-4087, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

The unsuitable deformation stimulus, harsh urine environment, and lack of a regenerative microenvironment (RME) prevent scaffold-based urethral repair and ultimately lead to irreversible urethral scarring. The researchers clarify the optimal elastic modulus of the urethral scaffolds for urethral repair and design a multilayered PVA hydrogel scaffold for urethral scar-free healing. The inner layer of the scaffold has self-healing properties, which ensures that the wound effectively resists harsh urine erosion, even when subjected to sutures. In addition, the scaffold's outer layer has an extracellular matrix-like structure that synergizes with adipose-derived stem cells to create a favorable RME. In vivo experiments confirm successful urethral scar-free healing using the PVA multilayered hydrogel scaffold. Further mechanistic study shows that the PVA multilayer hydrogel effectively resists the urine-induced inflammatory response and accelerates the transition of urethral wound healing to the proliferative phase by regulating macrophage polarization, thus providing favorable conditions for urethral scar-free healing. This study provides mechanical criteria for the fabrication of urethral tissue-engineered scaffolds, as well as important insights into their design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Scars and stretch marks are extremely common. For scars, evidence of alterations of the dermal and hypodermic layers is known, while for stretch marks, less data are available, and they are considered purely aesthetic conditions. The intra- and inter-subject variability of the skin makes the comparison between these two particularly complex. This study presents the case of a 54-year-old man who had both stretch marks and a surgical scar on his abdomen. We performed ultrasound and elastosonographic investigations for both to analyse the structural alteration of the skin and subcutaneous layers. Their structures were also compared to the structure of intact skin. The two skin conditions appeared substantially morphologically different and different from intact skin. The alterations detected, particularly of the connective structures, allow us to state that both scars and stretch marks are alterations of both the dermis and the hypodermis and stretch marks differ from scars., (© 2024. The Author(s).)

Competing Interests: J. Rivory, L. J. Masgnaux, J. Jacques, and M. Pioche are co-founders of the ATRACT devices and co. E. De Cristofaro, T. Wallenhorst, and P. Lafeuille declare that they have no conflict of interest.

Background: Ureteral stricture (US) is a pathological stenosis in the urinary tract characterized by increased collagen synthesis and inflammation. Autophagy activation has been shown to ameliorate tissue fibrosis and protect against fibrotic diseases. Verapamil has beneficial therapeutic benefits on fibrotic disorders. The pharmacological effects of verapamil on fibroblast autophagy in US and the underlying mechanism need to be investigated further., Methods: US patients were recruited to isolate scar tissues, hematoxylin-eosin (HE) and Masson trichrome staining were performed to analyze histopathological changes. The US animal model was established and administered with verapamil (0.05 mg/kg) in the drinking water. Transforming growth factor (TGF)-β1 was adopted to facilitate collagen synthesis in fibroblasts. The mRNA and protein expressions were examined by qRT-PCR, western blot, immunofluorescence and immunohistochemistry. ELISA was adopted to measure interleukin (IL)-1β and IL-6 levels. Molecular interaction experiments like dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to analyze the interaction between signal transducers and activators of transcription 3 (STAT3) and RNA polymerase II associated factor 1 (PAF1)., Results: Herein, our results revealed that verapamil activated TGF-β1-treated fibroblast autophagy and inhibited inflammation and fibrosis by repressing Ca 2+ ⁄calmodulin-dependent protein kinase II (CaMK II) δ-mediated STAT3 activation. Our following tests revealed that STAT3 activated PAF1 transcription. PAF1 upregulation abrogated the regulatory effect of verapamil on fibroblast autophagy and fibrosis during US progression. Finally, verapamil mitigated US in vivo by activating fibroblast autophagy., Conclusion: Taken together, verapamil activated TGF-β1-treated fibroblast autophagy and inhibited fibrosis by repressing the CaMK IIδ/STAT3/PAF1 axis.

Wound rehabilitation is invariably time-consuming, scar formation further weakens therapeutic efficacy, and detailed mechanisms at the molecular level remain unclear. In this work, a Mo 4/3 B 2- x nanoscaffold was fabricated and utilized for wound healing and scar removing in a mice model, while metabolomics was used to study the metabolic reprogramming of metabolome during therapy at the molecular level. The results showed that transition metal borides, called Mo 4/3 B 2- x nanoscaffolds, could mimic superoxide dismutase and glutathione peroxidase to eliminate excess reactive oxygen species (ROS) in the wound microenvironment. During the therapeutic process, the Mo 4/3 B 2- x nanoscaffold could facilitate the regeneration of wounds and removal of scars by regulating the biosynthesis of collagen, fibers, and blood vessels at the pathological, imaging, and molecular levels. Subsequent metabolomics study revealed that the Mo 4/3 B 2- x nanoscaffold effectively ameliorated metabolic disorders in both wound and scar microenvironments through regulating ROS-related pathways including the amino acid metabolic process (including glycine and serine metabolism and glutamate metabolism) and the purine metabolic process. This study is anticipated to illuminate the potential clinical application of the Mo 4/3 B 2- x nanoscaffold as an effective therapeutic agent in traumatic diseases and provide insights into the development of analytical methodology for interrogating wound healing and scar removal-related metabolic mechanisms.

Skin scar formation following Bacille Calmette-Guérin (BCG) or smallpox (Vaccinia) vaccination is an established marker of successful vaccination and 'vaccine take'. Potent pathogen-specific (tuberculosis; smallpox) and pathogen-agnostic (protection from diseases unrelated to the intentionally targeted pathogen) effects of BCG and smallpox vaccines hold significant translational potential. Yet despite their use for centuries, how scar formation occurs and how local skin-based events relate to systemic effects that allow these two vaccines to deliver powerful health promoting effects has not yet been determined. We review here what is known about the events occurring in the skin and place this knowledge in the context of the overall impact of these two vaccines on human health with a particular focus on maternal-child health., (© 2024. The Author(s).)

Scars may represent more than a cosmetic concern for patients; they may impose functional limitations and are frequently associated with the sensation of itching or pain, thus impacting both psychological and physical well-being. From an aesthetic perspective, scars display variances in color, thickness, texture, contour, and their homogeneity, while the functional aspect encompasses considerations of functionality, pliability, and sensory perception. Scars located in critical anatomic areas have the potential to induce profound impairments, including contracture-related mobility restrictions, thereby significantly impacting daily functioning and the quality of life. Conventional approaches to scar management may suffice to a certain extent, yet there are cases where tailored interventions are warranted. Autologous fat grafting emerges as a promising therapeutic avenue in such instances. Fundamental mechanisms underlying scar formation include chronic inflammation, fibrogenesis and dysregulated wound healing, among other contributing factors. These mechanisms can potentially be alleviated through the application of adipose-derived stem cells, which represent the principal cellular component utilized in the process of lipofilling. Adipose-derived stem cells possess the capacity to secrete proangiogenic factors such as fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor, as well as neurotrophic factors, such as brain-derived neurotrophic factors. Moreover, they exhibit multipotency, remodel the extracellular matrix, act in a paracrine manner, and exert immunomodulatory effects through cytokine secretion. These molecular processes contribute to neoangiogenesis, the alleviation of chronic inflammation, and the promotion of a conducive milieu for wound healing. Beyond the obvious benefit in restoring volume, the adipose-derived stem cells and their regenerative capacities facilitate a reduction in pain, pruritus, and fibrosis. This review elucidates the regenerative potential of autologous fat grafting and its beneficial and promising effects on both functional and aesthetic outcomes when applied to scar tissue.

Vocal fold (VF) scarring, a complex problem in laryngology, results from injury and inflammation of the layered architecture of the VFs. The resultant voice hoarseness, for which successful therapeutic options are currently limited, affects the patient's quality of life. A promising strategy to reverse this disorder is the use of antifibrotic drugs. The present study proposes a novel microbead-embedded injectable hydrogel that can sustain the release of the anti-fibrotic drug pirfenidone (PFD) for vocal fold scarring. Microbeads were developed using sodium alginate and gelatin, which were further embedded into a biomimetic and tissue adhesive gellan gum (GG) hydrogel. The microbead-embedded hydrogel exhibited improved injectability, viscoelasticity, tissue adhesiveness, degradability, and swelling compared to the hydrogel without beads. Additionally, the bead-embedded hydrogel could sustain the release of the PFD for a week. In vitro studies showed that the drug-loaded hydrogel could reduce the migration and proliferation of fibroblast cells in a dose-dependent manner. In summary, this study demonstrates the potential of a PFD-loaded injectable hydrogel with enhanced viscoelastic and tissue-adhesive properties for vocal fold scarring applications.

Glial scar formation represents a fundamental response to central nervous system (CNS) injuries. It is mainly characterized by a well-defined spatial rearrangement of reactive astrocytes and microglia. The mechanisms underlying glial scar formation have been extensively studied, yet quantitative descriptors of the spatial arrangement of reactive glial cells remain limited. Here, we present a novel approach using point pattern analysis (PPA) and topological data analysis (TDA) to quantify spatial patterns of reactive glial cells after experimental ischemic stroke in mice. We provide open and reproducible tools using R and Julia to quantify spatial intensity, cell covariance and conditional distribution, cell-to-cell interactions, and short/long-scale arrangement, which collectively disentangle the arrangement patterns of the glial scar. This approach unravels a substantial divergence in the distribution of GFAP + and IBA1 + cells after injury that conventional analysis methods cannot fully characterize. PPA and TDA are valuable tools for studying the complex spatial arrangement of reactive glia and other nervous cells following CNS injuries and have potential applications for evaluating glial-targeted restorative therapies., (© 2024. The Author(s).)