Comprehensive proteomic characterization of urethral stricture disease in the Chinese population.

Background: Male urethral stricture disease (USD) is predominantly characterized by scar formation. There are few effective therapeutic drugs, and comprehensive molecular characterizations of USD formation remain undefined. Methods: The proteomic profiling of twelve scar tissues and five matched normal adjacent tissues (NATs). Proteomic analysis methods were applied to explore the molecular characterizations of USD formation, including uncovering mechanistic pathways and providing novel biomarkers for scar formation. Results: Comparative proteomic analysis showed that the extracellular matrix (ECM) and complement cascade signaling were predominant in scar tissues. COL11A1 and CD248 significantly contributed to the accumulation of ECM components. Our study presented diverse molecular mechanisms of scar formation across different ages and suggested the potential effects of PXK in Age 1 (<45) patients. Furthermore, immune infiltration studies indicated the therapeutic potential of inhibiting the complement system (C4A, C4B) in Age 2 (≥45) patients, providing a potential clinical strategy for USD. Conclusion: This study illustrated the pathogenesis of USD formation and the diverse characteristics of USD patients with different ages, enhancing our understanding of the disease's pathogenesis and providing a valuable resource for USD treatment.

SHH induces macrophage oxidative phosphorylation and efferocytosis to promote scar formation.

Excessive scar formation such as hypertrophic scars and keloids, resulting from trauma or surgical procedures, present a widespread concern for causing disfigurement, discomfort, and functional limitations. Macrophages play pivotal roles in maintaining tissue homeostasis, orchestrating tissue development, repair, and immune responses, and its transition of function and phenotype plays a critical role in regulating the balance between inflammation and tissue regeneration, which is central to cutaneous scar formation. Recent evidence suggests the involvement of Sonic Hedgehog (SHH) in the induction of anti-inflammatory M2-like macrophage phenotypes within tumor microenvironments. In our study, we observed increased SHH expression in human hypertrophic scars, prompting an investigation into its influence on macrophage polarization, efferocytosis, and cutaneous scar formation. Our findings reveal that SHH can enhance oxidative phosphorylation (OXPHOS) in macrophages, augment macrophage efferocytosis, and promote M2 polarization, finally contributing to the progression of cutaneous scar formation. Notably, targeting SHH signaling with vismodegib exhibited promising potential in mitigating scar formation by reversing the effects of enhanced OXPHOS and M2 polarization in macrophages. In conclusion, this study underscores the critical roles of macrophage metabolism, particularly OXPHOS, efferocytosis and SHH signaling in cutaneous scar formation. Understanding these mechanisms provides new avenues for potential interventions and scar prevention strategies.

Early topical mitomycin-C prevents stricture formation in children with caustic ingestion.

AIM: Stricture formation is the most common remote complication of caustic ingestion. The aim of this study was evaluation of the efficacy of early topical endoscopic application of mitomycin C (MMC) in prevention of stricture formation after corrosive ingestion in children. METHODS: We enrolled 78 children with a history of caustic ingestion within 48 h in a prospective, randomised-controlled study. Only 61 children completed the study and were classified into two groups: group A and B. After initial stabilisation, patients in group A (n = 30) received topical application of MMC within the initial 48 h while patients in group B (n = 31) only received conventional management. Follow-up endoscopic dilatation was done every 2 weeks to patients in either group until no need for further dilatation. RESULTS: The barium study, which was done on the third week, revealed that all the patients (100%) on conservative management (group B) had strictures while only nine patients (30%) in group A had strictures (P < 0.001). The median number of dilatations required for patients in group B was 26 (min. = 23 and max. = 32) while in group A, it was 0 (min. = 0 and max. = 7) (P < 0.001). The success of early MMC application was complete response in 26 patients (86.7%), partial response in 3 patients (10%) and no response in 1 patient (3.3%). On the other side, conventional therapy with endoscopic dilatation achieved complete response in 11 patients (35.5%). CONCLUSION: Early topical MMC application proved its efficacy and safety in prevention of scar and stricture formation in children following caustic ingestion.

Bioorthogonal targeted cell membrane vesicles/cell-sheet composites reduce postoperative tumor recurrence and scar formation of melanoma.

While surgical resection is the predominant clinical strategy in the treatment of melanoma, postoperative recurrence and undetectable metastasis are both pernicious drawbacks to this otherwise highly successful approach. Furthermore, the deep cavities result from tumor excision can leave long lasting wounds which are slow to heal and often leave visible scars. These unmet needs are addressed in the present work through the use of a multidimensional strategy, and also promotes wound healing and scar reduction. In the first phase, cell membrane-derived nanovesicles (NVs) are engineered to show PD-1 and dibenzocyclooctyne (DBCO). These are capable of reactivating T cells by blocking the PD-1/PD-L1 pathway. In the second phase, azido (N3) labeled mesenchymal stem cells (MSCs) are cultured into cell sheets using tissue engineering, then apply directly to surgical wounds to enhance tissue repair. Owing to the complementary association between DBCO and N3 groups, PD-1 NVs were accumulated at the site of excision. This strategy can inhibit postoperative tumor recurrence and metastasis, whilst also promoting wound healing and reducing scar formation. The results of this study set a precedent for a new and innovative multidimensional therapeutic strategy in the postoperative treatment of melanoma.

Fibroblasts and endothelial cells interplay drives hypertrophic scar formation: Insights from in vitro and in vivo models.

Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co-culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF-ß. Additionally, a suspended co-culture multicellular spheroid model revealed molecular-level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro-angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF-ß, IL-17, Wnt, Notch, PI3K-Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts-endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.

Adipose-derived stem cells enriched with therapeutic mRNA TGF-ß3 and IL-10 synergistically promote scar-less wound healing in preclinical models.

Skin wound healing often leads to scar formation, presenting physical and psychological challenges for patients. Advancements in messenger RNA (mRNA) modifications offer a potential solution for pulsatile cytokine delivery to create a favorable wound-healing microenvironment, thereby preventing cutaneous fibrosis. This study aimed to investigate the effectiveness of human adipose-derived stem cells (hADSCs) enriched with N 1-methylpseudouridine (m1ψ) modified transforming growth factor-ß3 (TGF-ß3) and interleukin-10 (IL-10) mRNA in promoting scar-free healing in preclinical models. The results demonstrated that the modified mRNA (modRNA)-loaded hADSCs efficiently and temporarily secreted TGF-ß3 and IL-10 proteins. In a dorsal injury model, hADSCs loaded with modRNA TGF-ß3 and IL-10 exhibited multidimensional therapeutic effects, including improved collagen deposition, extracellular matrix organization, and neovascularization. In vitro experiments confirmed the ability of these cells to markedly inhibit the proliferation and migration of keloid fibroblasts, and reverse the myofibroblast phenotype. Finally, collagen degradation mediated by matrix metalloproteinase upregulation was observed in an ex vivo keloid explant culture model. In conclusion, the synergistic effects of the modRNA TGF-ß3, IL-10, and hADSCs hold promise for establishing a scar-free wound-healing microenvironment, representing a robust foundation for the management of wounds in populations susceptible to scar formation.

Botulinum toxin type A inhibits M1 macrophage polarization by deactivation of JAK2/STAT1 and IκB/NFκB pathway and contributes to scar alleviation in aseptic skin wound healing.

The non-neuronal and non-muscular effects of botulinum toxin type A (BTXA) on scar reduction has been discovered. This study was designed to investigate the effects of BTXA on macrophages polarization during the early stage of skin repair. A skin defect model was established on the dorsal skin of SD rats. BTXA was intracutaneous injected into the edge of wound immediately as the model was established. Histological examinations were performed on scar samples. Raw 264.7 was selected as the cell model of recruited circulating macrophages, and was induced for M1 polarization by LPS. Identify the signaling pathways that primarily regulated M1 polarization and respond to BTXA treatment. Application of BTXA at early stage of injury significantly reduced the scar diameter without delaying wound closure. BTXA treatment improved fiber proliferation and arrangement, and inhibited angiogenesis in scar granular tissue. The number of M1 macrophages and the levels of pro-inflammation were decreased after treated with BTXA in scar tissues. LPS activated JAK2/STAT1 and IκB/NFκB pathways were downregulated by BTXA, as well as LPS induced M1 polarization. At early stage of skin wound healing, injection of BTXA effectively reduced the number of M1 macrophages and the levels of pro-inflammatory mediators which contributes to scar alleviation. BTXA resisted the M1 polarization of macrophages induced by LPS via deactivating the JAK2/STAT1 and IκB/NFκB pathways.

Qingguang'an-induced autophagy in TFs inhibits scar formation: A follow-up in vivo mechanistic investigation.

Purpose: To investigate the mechanism by which Qingguang'an inhibits scar formation in rabbits administered glaucoma filtering surgery (GFS). Methods: Combined trabeculectomy was performed in 100 rabbits diagnosed with glaucoma, which were assigned to five groups, including the no surgery, surgery only, mitomycin C (MMC; positive control), Qingguang'an (experimental) and PBS (negative control) groups. The animals were followed up at postoperative days 1-28. Ultrastructure was observed under a transmission electron microscope (TEM). Real-Time Polymerase Chain Reaction (RT-PCR), Western blot, Hematoxylin and Eosin (H&E) staining, Masson's trichrome staining and Immuno-histochemistry (IHC) were performed to assess the harvested blocks. Results: In the Qingguang'an group, intraocular pressure (IOP) on postoperative D28 was significantly lower than values in the no surgery, surgery only and PBS groups (P < 0.05). Its blebs kept better filtering function and less complications in follow-up, which be detected to have less fibroblasts and collagen deposition histologically. Compared with the PBS group, ATG5, Beclin1 and LC3-II mRNA levels were significantly increased while P62 was downregulated in the Qingguang'an group (P < 0.05). Correspondingly, ATG5 and Beclin1 protein amounts in the Qingguang'an group were increased while P62 was downregulated. The LC3-II/Ⅰ ratio tended to rise to the process of autophagy. Abundant autophagosomes were captured under TEM in this condition. Conclusions: Qingguang'an granules can inhibit scar formation in rabbits after GFS and restrain IOP increase by inducing autophagy in TFs.

Neurotropin® ameliorates chronic pain associated with scar formation in a mouse model: A gene expression analysis of the inflammatory response.

Background: Scar formation after trauma and surgery involves an inflammatory response and can lead to the development of chronic pain. Neurotropin® (NTP) is a nonprotein extract of inflamed skin of rabbits inoculated with vaccinia virus. It has been widely used for the treatment of chronic pain. However, the in vivo effects of NTP on painful scar formation have not been determined. To investigate the molecular mechanisms underlying the effects of NTP on the inflammatory response, we evaluated gene expression in the scar tissues and dorsal root ganglions (DRGs) of mice administered NTP and control mice. Methods and results: Mice injected with saline or NTP were used as controls; other mice were subjected to surgery on the left hind paw to induce painful scar formation, and then injected with saline or NTP. Hind paw pain was evaluated by measuring the threshold for mechanical stimulation using the von Frey test. The paw withdrawal threshold gradually returned to pre-operative levels over 4 weeks post-operation; NTP-treated mice showed a significantly shortened recovery time of approximately 3 weeks, suggesting that NTP exerted an analgesic effect in this mouse model. Total RNA was extracted from the scarred hind paw tissues and DRGs were collected 1 week post-operation for a microarray analysis. Gene set enrichment analysis revealed that the expression of some gene sets related to inflammatory responses was activated or inhibited following surgery and NTP administration. Quantitative real-time reverse transcription-polymerase chain reaction analysis results for several genes were consistent with the microarray results. Conclusion: The administration of NTP to the hind paws of mice with painful scar formation following surgery diminished nociceptive pain and reduced the inflammatory response. NTP inhibited the expression of some genes involved in the response to surgery-induced inflammation. Therefore, NTP is a potential therapeutic option for painful scar associated with chronic pain.

The impact of early nutritional support on postoperative wound healing in patients with complex fractures: A meta-analysis review.

Complex fractures present significant challenges in orthopaedic surgery, particularly in terms of postoperative wound healing. Nutritional status plays a crucial role in the recovery process, with early nutritional support potentially influencing wound healing outcomes. This meta-analysis aimed to assess the impact of early nutritional interventions on postoperative wound healing and scar formation in patients with complex fractures. From an initial pool of 1742 articles, 7 studies were selected for analysis. The results revealed that preoperative nutritional support significantly improved early wound healing, as indicated by lower REEDA scores (SMD = -14.06, 95% CI: [-16.79, -11.32], p < 0.01) 1 week post-surgery. Furthermore, there was a notable reduction in scar formation, as demonstrated by lower Manchester Scar Scale scores (SMD = -25.03, 95% CI: [-30.32, -19.74], p < 0.01) 3 months post-surgery. These findings highlight the importance of incorporating nutritional strategies into the management of complex fractures to optimize postoperative recovery.

PTEN hinders the formation of scars by regulating the levels of proteins in the extracellular matrix and promoting the apoptosis of dermal fibroblasts through Bcl-xL.

Hypertrophic scar (HS) is a dermatological condition characterized by an excessive accumulation of proteins in the extracellular matrix (ECM) and an elevated cell count. The development of HS is thought to be linked to the disruption of dermal fibroblast proliferation and apoptosis. The processes of cell proliferation and apoptosis are notably influenced by PTEN. However, the precise mechanisms by which PTEN regulates hypertrophic scar fibroblasts (HSFs) and its overall role in scar formation are still not fully understood. The objective of this study was to investigate the influence of PTEN on hypertrophic scars(HS) and its function in the regulation of scar formation, with the aim of identifying a pivotal molecular target for scar treatment. Our results demonstrate that the overexpression of PTEN (AdPTEN) significantly suppressed the expression of type I collagen (Col I), type III collagen (Col III), and alpha smooth muscle actin (α-SMA) in HSFs. Furthermore, it was observed that the introduction of AdPTEN resulted in the suppression of Bcl-xL expression, which consequently led to an increase in the apoptosis of HSFs. Similarly, in the inhibition of collagens expression and subsequent increase in HSF apoptosis were also observed upon silencing Bcl-xL (sibcl-xL). Additionally, the in vitro model demonstrated that both AdPTEN and sibcl-xL were effective in reducing the contraction of FPCL. The findings of our study provide validation for the role of PTEN in inhibiting the development of hypertrophic scars (HS) by modulating the expression of extracellular matrix (ECM) proteins and promoting apoptosis in hypertrophic scar fibroblasts (HSFs) via Bcl-xL. These results indicate that PTEN and Bcl-xL may hold promise as potential molecular targets for therapeutic interventions aimed at managing hypertrophic scars.

Scarring Skin: Mechanisms and Therapies.

Skin injury always results in fibrotic, non-functional scars in adults. Although multiple factors are well-known contributors to scar formation, the precise underlying mechanisms remain elusive. This review aims to elucidate the intricacies of the wound healing process, summarize the known factors driving skin cells in wounds toward a scarring fate, and particularly to discuss the impact of fibroblast heterogeneity on scar formation. To the end, we explore potential therapeutic interventions used in the treatment of scarring wounds.

Neural Stem Cells Transplanted into Rhesus Monkey Cortical Traumatic Brain Injury Can Survive and Differentiate into Neurons.

Cortical traumatic brain injury (TBI) is a major cause of cognitive impairment accompanied by motor and behavioral deficits, and there is no effective treatment strategy in the clinic. Cell transplantation is a promising therapeutic strategy, and it is necessary to verify the survival and differentiation of cells after transplantation in large animal models like rhesus monkeys. In this study, we transplanted neural stem cells (NSCs) and simultaneously injected basic fibroblast growth factor/epidermal growth factor (bFGF/EGF) into the cortex (visual and sensory cortices) of rhesus monkeys with superficial TBI. The results showed that the transplanted NSCs did not enter the cerebrospinal fluid (CSF) and were confined to the transplantation site for at least one year. The transplanted NSCs differentiated into mature neurons that formed synaptic connections with host neurons, but glial scar formation between the graft and the host tissue did not occur. This study is the first to explore the repairing effect of transplanting NSCs into the superficial cerebral cortex of rhesus monkeys after TBI, and the results show the ability of NSCs to survive long-term and differentiate into neurons, demonstrating the potential of NSC transplantation for cortical TBI.

The impact of physiotherapy interventions on enhancing wound healing post knee osteoarthritis surgery: A meta-analysis.

In knee osteoarthritis surgery, managing postoperative wound healing and minimizing scar formation are pivotal for patient recovery and satisfaction. These aspects are particularly challenging due to the nature of the surgical procedure and patient demographics. Physiotherapy interventions are increasingly recognized for their role in improving these postoperative outcomes. This meta-analysis sought to evaluate the efficacy of physiotherapy in enhancing wound healing, as measured by REEDA scores, and reducing scar formation, as indicated by Manchester Scar Scale (MSS) scores, following knee osteoarthritis surgery. Analysing data from eight studies, we found that physiotherapy significantly improved wound healing, evidenced by lower REEDA scores (SMD = -19.58, 95% CI: [-22.49, -16.66], p < 0.01), and reduced scar formation, reflected in lower MSS scores (SMD = -24.79, 95% CI: [-30.03, -19.55], p < 0.01). These findings highlight the crucial role of physiotherapy in postoperative care for knee osteoarthritis patients, emphasizing its impact on enhancing recovery and improving surgical outcomes.

Inhibition of CK2 Diminishes Fibrotic Scar Formation and Improves Outcomes After Ischemic Stroke via Reducing BRD4 Phosphorylation.

Fibrotic scars play important roles in tissue reconstruction and functional recovery in the late stage of nervous system injury. However, the mechanisms underlying fibrotic scar formation and regulation remain unclear. Casein kinase II (CK2) is a protein kinase that regulates a variety of cellular functions through the phosphorylation of proteins, including bromodomain-containing protein 4 (BRD4). CK2 and BRD4 participate in fibrosis formation in a variety of tissues. However, whether CK2 affects fibrotic scar formation remains unclear, as do the mechanisms of signal regulation after cerebral ischemic injury. In this study, we assessed whether CK2 could modulate fibrotic scar formation after cerebral ischemic injury through BRD4. Primary meningeal fibroblasts were isolated from neonatal rats and treated with transforming growth factor-ß1 (TGF-ß1), SB431542 (a TGF-ß1 receptor kinase inhibitor) or TBB (a highly potent CK2 inhibitor). Adult SD rats were intraperitoneally injected with TBB to inhibit CK2 after MCAO/R. We found that CK2 expression was increased in vitro in the TGF-ß1-induced fibrosis model and in vivo in the MCAO/R injury model. The TGF-ß1 receptor kinase inhibitor SB431542 decreased CK2 expression in fibroblasts. The CK2 inhibitor TBB reduced the increases in proliferation, migration and activation of fibroblasts caused by TGF-ß1 in vitro, and it inhibited fibrotic scar formation, ameliorated histopathological damage, protected Nissl bodies, decreased infarct volume and alleviated neurological deficits after MCAO/R injury in vivo. Furthermore, CK2 inhibition decreased BRD4 phosphorylation both in vitro and in vivo. The findings of the present study suggested that CK2 may control BRD4 phosphorylation to regulate fibrotic scar formation, to affecting outcomes after ischemic stroke.

Corrigendum: Editorial: Recent innovations to inhibit scar formation for better skin regeneration.

[This corrects the article DOI: 10.3389/fsurg.2023.1325832.].

A meta-analysis of topical Ketorolac's effect on surgical site wound healing post-cataract surgery.

This meta-analysis evaluates the impact of topical ketorolac on surgical site wound healing and scar formation after cataract surgery. A thorough literature search, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, identified eight relevant studies from 2348 articles. The selected studies were analysed for wound healing efficacy, using the redness, edema, ecchymosis, discharge and approximation (REEDA) scale, and scar formation, assessed by the Manchester scar scale (MSS). Results indicated that ketorolac significantly improved wound healing, with lower REEDA scores 1 week post-surgery (I2 = 97%; Random: standardised mean difference (SMD): -10.93, 95% CI: -13.85 to -8.00, p < 0.01), and reduced scar formation, evidenced by lower MSS scores 3 months post-surgery (I2 = 74%; Random: SMD: -9.67, 95% CI: -11.03 to -8.30, p < 0.01). The findings suggest that topical ketorolac is beneficial in post-cataract surgery care, enhancing wound healing and reducing scarring.

Comparative efficacy of silver alginate dressings versus standard gauze in enhancing wound healing post-mastectomy for triple-negative breast cancer: A systematic review and meta-analysis.

This meta-analysis evaluates the efficacy of silver alginate dressings (SAD) compared to standard gauze (SG) in enhancing wound healing and reducing scar formation post-mastectomy in patients with triple-negative breast cancer. From an initial pool of 1245 articles, five studies met the inclusion criteria. The analysis revealed that SAD significantly improve early wound healing 1 week post-mastectomy, as indicated by lower Redness, Edema, Ecchymosis, Discharge, and Approximation (REEDA) scales (I2 = 85%; Random: SMD: -7.08, 95% CI: -8.26 to -5.98, p < 0.01), compared to SG. Additionally, long-term scar outcomes measured by the Manchester Scar Scale (MSS) 5 months post-mastectomy showed a notable reduction in scar formation (I2 = 95%; Random: SMD: -12.97, 95% CI: -16.20 to -9.75, p < 0.01)) in the silver alginate group. The findings support the use of SAD in post-mastectomy care for triple-negative breast cancer patients but highlight the need for further research on long-term safety and cost-effectiveness.

Regeneration of Panniculus Carnosus Muscle in Fetal Mice Is Characterized by the Presence of Actin Cables.

Mammalian skin, including human and mouse skin, does not regenerate completely after injury; it is repaired, leaving a scar. However, it is known that skin wounds up to a certain stage of embryonic development can regenerate. The mechanism behind the transition from regeneration to scar formation is not fully understood. Panniculus carnosus muscle (PCM) is present beneath the dermal fat layer and is a very important tissue for wound contraction. In rodents, PCM is present throughout the body. In humans, on the other hand, it disappears and becomes a shallow fascia on the trunk. Fetal cutaneous wounds, including PCM made until embryonic day 13 (E13), regenerate completely, but not beyond E14. We visualized the previously uncharacterized development of PCM in the fetus and investigated the temporal and spatial changes in PCM at different developmental stages, ranging from full regeneration to non-regeneration. Furthermore, we report that E13 epidermal closure occurs through actin cables, which are bundles of actomyosin formed at wound margins. The wound healing process of PCM suggests that actin cables may also be associated with PCM. Our findings reveal that PCM regenerates through a similar mechanism.