A Network Pharmacology Study on Active Components and Targets of Citri Reticulatae Pericarpium for Treating Keloids

[Objectives]To investigate the mechanisms and pharmacologic effects of Citri Reticulatae Pericarpium against keloids by network pharmacology systematically.[Methods]TCMSP,Uniprot and BATMAN-TCM databases were used to obtain the active constituents and targets of Citri Reticulatae Pericarpium."Keloid"was used as key word to search for related therapeutic targets from Drug Bank,OMIM,TTD,and GEO databases.The Chinese medicine compound-target network was constructed by Cytoscape software.Besides,gene ontology(GO)and Kyoto Encyclopedia of genes and genome enrichment analysis were also performed.Afterward,Discovery Studio software was used to assess the interaction of key components and genes.[Results]Five active components of Citri Reticulatae Pericarpium,773 compound targets and 676 keloid treatment targets were obtained in the databases.After the intersection,there are 47 targets of Citri Reticulatae Pericarpium for treating keloids.Hub genes were identified such as MMP9,IL6,TNF,TP53,and VEGFA,which were enriched in tumor necrosis factor-α,nuclear factor kappa-B,and other signaling pathways.The molecular docking stimulation confirmed the interaction between the MMP9 and three components of Citri Reticulatae Pericarpium.[Conclusions]Citri Reticulatae Pericarpium may play an important role in treating keloids through modulating genes and signaling pathways.The present study sheds light on the mechanisms of active compounds of Citri Reticulatae Pericarpium for the treatment of keloids.

Scar-centered dilation in the treatment of large keloids

BACKGROUND Hypertrophic scars and keloid treatment is a major problem in plastic surgery.While small keloids can be treated with resection followed by radiotherapy,large keloids require treatment with a tissue expander.Conventional methods increase the need for auxiliary incisions,causing new scar hyperplasia.AIM To introduce a new method for the treatment of keloids with an expander.METHODS Between 2018 and 2021,we performed surgeries to treat large keloids in nine patients with a two-stage approach.In the first stage,an intrascar incision was made in the keloid,and a customized expander was implanted under the keloid and the surrounding normal skin.A period of 3-6 mo was allowed for skin expansion.In the second stage,after the initial incision healed,a follow-up surgery was performed to remove the expander,resect the keloid,and repair the expanded skin flap.To accomplish this,an incision was made along the scar boundary to avoid making a new surgical incision and creating new scars.Superficial radiotherapy was then performed postoperatively.RESULTS Two patients had anterior chest keloids.After treatment,the anterior chest incision was broken repeatedly and then sutured again after debridement.It healed smoothly without scar hyperplasia.Keloids were successfully removed in 7 patients without recurrence.CONCLUSION This method was performed through a keloid incision and with a custom expander embedded.After full expansion,the keloid was directly resected using a linear suture,which avoids new surgical incisions and scars and can successfully remove large-area keloids.The treatment is effective,providing new insights and strategies for the treatment of similar large-area keloid and hypertrophic scar cases in the future.

Concurrent Multi-Modality Treatment of Keloids (CMTK) Not Manageable by Conventional Postoperative Radiotherapy

Objective: To design and test a treatment regimen which is clinically responsive, readily available, cost effective, and applicable especially to children and women of child bearing age. Design Setting: A prospective cohort study. Setting: Two major postgraduate teaching hospitals: one in Tripoli, Libya and the other in Jeddah, Saudi Arabia. Participants: Fifty-seven patients with 79 keloids, referred from Plastic Surgery Units between April 1996 and January 2005. Main Outcome Measure: Degree of flattening of the keloidal lesion and symptomatic recovery. Results: Result of treatment has been analyzed using unified set criteria. Seventy-seven percent of this cohort had complete response. 19% of cases had partial response, 50% acknowledged the treatment outcome had been “satisfactory” and 44% had an “acceptable” outcome. There was no significant acute or delayed reaction. Conclusion: The technique appears universally adaptable, cost effective, and can safely be prescribed for children and women of child-bearing age. In spite of prolonged treatment course, compliance was excellent.

Androgen-related disorders and hormone therapy for patients with keloids

Keloids are a fibroproliferative disorder of the skin and can cause physical discomfort and psychological burden.Apart from local factors such as skin tension and infection,increasing evidence has suggested that systemic endocrine factors also contribute to the emergence and development of keloids.Hormone disorders have long been suspected to be a risk factor;however,previous studies have mainly focused on the role of female hormones and neglected the critical role of male hormones.As we reviewed the published literature addressing sex steroids in pathological scars,we speculated that androgens(i.e.,male hormones)could become actively involved through sebum-associated hypersensitivity reactions and acne-derived skin lesions,resulting in persistent cutaneous inflammation.This hypothesis was also supported by previous in vitro studies,in which elevated androgen levels and androgenic receptors were detected in keloid tissues.Moreover,relief of pain and pruritus has been observed in patients with keloids who accidently received anti-androgen treatment for other irrelevant indications.Thus,we propose that androgen-related disorders are critical in the pathogenesis of keloids,and systemic treatment targeting sex hormones may provide long-term benefits for predisposed patients with multiple keloids.

A Case for “Radiolysis” in Radiotherapy of Keloids

Successful treatment of keloids has eluded the medical community since their first description. Multitudes of therapeutic options are available, but none achieves satisfactory resolution of keloids. One major stumbling block is lack of understanding about their genesis. Assuming keloids are tumors, attempts have been made to treat this condition with standard radiotherapy, with dismal results. Keloidal masses are not an active biological entity. They are aggregations of cellular, hypovascular, hypoxic bundles of collagen, which are produced by atypical fibroblasts in the wounds and eventually cease production due to a hostile biological environment. Having no demonstrable inherent process of disposal of these collagen bundles, this excessive collagen tends to linger to form the bulk of keloids. The lesions eventually become symptomatic and aesthetically unacceptable, and therapeutic intervention is sought. Of all available treatments, such as post-resection radiotherapy, primary radiotherapy in selected cases and primary brachytherapy stand out above any other form of treatment. Be it brachytherapy or external beam treatment, one fundamental aspect of radiation action is the process of “radiolysis”, explaining why “radiobiological” approaches have been ineffective.

Treatment of Keloids in A Child with Surgery Alone:Clinical Application of the LBD Suturing Technique

Keloids are fibroproliferative disorders that can result from cutaneous injuries to the reticular dermis.Recurrence rates as high as 100%have been reported following surgical excision alone.Consequently,a variety of post-surgical techniques have been employed to prevent keloid recurrence,including the use of radiation.Although numerous studies have shown that post-excisional X-rays,electron beams,lasers,and brachytherapy can reduce the rate of keloid recurrence,numerous inconsistencies,including a wide range of definitions for keloid recurrence,render it difficult to compare the outcomes.The treatment of severe keloids in children is much more challenging,and there have been few previous reports.It is generally believed that children with keloids should be treated with nonsurgical treatment such as hormone injections and radiotherapy.For severe keloids,these methods require a long treatment period,and their efficacy is not ideal.Moreover,the side effects of the treatment can affect children’s health.If keloid scars are not effectively treated,they will often seriously affect the physical and mental health of children.The purpose of this review is to discuss case studies of children with severe keloids who were only treated with surgery and their postoperative recovery.In this case,the deep-embedded circular mattress suture technique(LBD,the looped,broad,and deep buried suturing technique)was used in the scar resection.After 18 months of follow-up,the surgical scar was evaluated using the Vancouver Scar Scale(VSS).The scar was stable and did not recur.The child was satisfied.This case shows that it is completely feasible to treat severe keloids with surgery alone,as long as the tension is reduced during the operation to prevent surgical scar hyperplasia.

Inhibitory Effect of Photodynamic Therapy on Keloids

Objective To investigate the inhibitory effect of photodynamic on keloid by observing the changes of various indicators of keloid under the action of different concentration of photosensitizer aminoketovaleric acid combined with laser.Methods Fifteen healthy nude mice were randomly divided into experimental group 1,experimental group 2 and control group.Keloid tissue was implanted into the back to form stable pathological scars.10%aminoketovaleric acid solution,20%aminoketovaleric acid solution,saline solution were applied to the back of the nude mice within 4,8 and 12 weeks,respectively,for half an hour,635 nm CW laser irradiation,and scar tissue was cut at 6,10 and 14 weeks for detection.Scar related indicators.Results Scar index,number of fibroblasts,number of TGF-beta 1 protein and alpha-SMA in the experimental group were lower than those in the control group,and more than 2 indexes in the experimental group were lower than those in the experimental group 1.There was significant difference among the groups.Conclusion 20%aminoketovaleric acid can produce cytotoxic effect,induce apoptosis of fibroblasts,regulate and reduce epithelial-mesenchymal transition of scar,and inhibit keloid.

Ear keloid and epidermal cyst following auricular cartilage harvest for rhinoplasty:A case report

BACKGROUND This case report highlights a rare instance of concurrent keloid and epidermal cyst development at an ear cartilage harvest site following rhinoplasty in a 25-year-old woman.Both conditions,which typically stem from skin trauma,seldom occur together,demonstrating the exceptional characteristics of this case.CASE SUMMARY The patient underwent successful surgical removal of both the keloid and the epidermal cyst.Postoperative treatment included the use of silicone sheets,gel,and oral tranilast to reduce scarring.No recurrence was observed over a 6-mo follow-up period,indicating effective management of the condition.CONCLUSION The effective management of complex skin trauma cases underscores the need for individualized treatment strategies in plastic surgery.

Radiation Therapy in Keloids Treatment： History, Strategy,Effectiveness, and Complication

Objective：Radiation therapy combined with surgical excision was considered as one of the most effective treatment plans for keloid lesions.However,there was no unanimity found over present literatures regarding the issue on optimized treatment strategy for keloids.We here provide a comprehensive review over this issue and emphasize on the influencing factors.Data Sources：The data analyzed in this review were searched from articles included in PubMed and EMBASE databases.Study Selection：The original articles and critical reviews discussing the application of radiation therapy in keloids treatment were selected for this review.Results：The application of radiation therapy has transitioned from simple superficial X-ray irradiation to brachytherapy.Furthermore,several factors including radiation type,dose,fraction,interval,and complications were reviewed,and the results revealed that these factors were significant toward clinical outcome at various levels.Conclusions：Both past and present evidence support the idea that combination therapy of radiation and surgical therapy is safe and feasible.However,the optimization of treatment strategy was based on different radiation types and should take dose,fractions,interval,and complications into consideration,which will then decrease the rate of recurrence and increase the level of satisfaction.

Role of HLA-DR and CD1a molecules in pathogenesis of hypertrophic scarring and keloids

Keyword: hypertrophic scars · keloids · HLA DR · CD1a

Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine

Background:The clinical features of keloids consist of aberrant proliferation,secretion,differentiation and apoptosis of keloid dermis-derived fibroblasts(KFBs).Notably,the apoptosis rate of KFBs is lower than the proliferation rate.Though the anti-fibrotic effect of adipose-derived stem cells(ADSCs)on keloids has become a hot topic of research,the exact anti-fibrotic mechanism of the paracrine effect remains unclear.This study aimed to find out how the conditioned medium of ADSCs(ADSC-CM)exerts an anti-fibrotic effect in KFBs.Methods:KFBs and ADSCs were extracted and cultured.Then,ADSC-CM was prepared.Whether ADSC-CM could inhibit KFB growth and induce apoptosis was verified by the use of a cell counting kit-8,an 5-Ethynyl-2-deoxyuridine(Edu)kit and flow cytometry.The expressions of cyclooxygenase-1(COX-1),COX-2,caspase 3 and B-cell lymphoma-2(Bcl-2)in ADSC-CM-cultured KFBs were tested by real-time PCR and western blotting.To clarify the role of COX-2 in ADSC-CM-induced KFB apoptosis,a specific COX-2 inhibitor,celecoxib,was applied to KFBs cultured in ADSC-CM.Moreover,we tested the production of arachidonic acid(AA)and prostaglandin E2(PGE2)by ELISA.Then,we established a keloid transplantation model in a nude mouse to validate the therapeutic effect in vivo.Results:The proliferation ability of KFBs cultured in ADSC-CM was found to be weakened and apoptosis was significantly increased.Caspase 3 expression was significantly upregulated and Bcl-2 was downregulated in ADSC-CM-cultured KFBs.Furthermore,ADSC-CM strikingly elevated COX-2 mRNA and protein expressions,but COX-1 expression was unaltered.COX-2 inhibitors reduced ADSC-CM-induced apoptosis.Additionally,COX-2 inhibition blocked the elevation of caspase 3 and reversed the decrease in Bcl-2 expression.ADSC-CM increased PGE2 levels by 1.5-fold and this effect was restrained by COX-2 inhibition.In the nude mouse model,expressions of AA,COX-2 and PGE2 were higher in the translated keloid tissues after ADSC-CM injection than in the controls.Conclusions:We showed activation of the COX-2/PGE2 cascade in KFBs in response to ADSC-CM.By employing a specific COX-2 inhibitor,COX-2/PGE2 cascade activation played a crucial role in mediating the ADSC-CM-induced KFB apoptosis and anti-proliferation effects.

Elucidating the interplay of ferroptosis-related genes in keloid formation:Insights from bioinformatics analysis

Background:Keloids are benign skin tumors characterized by fibroblast proliferation,tumor-like biological behavior,and excessive deposition of extracellular matrix in wounded skin.Ferroptosis,a type of programmed cell death,is critical in tumor pathogenesis.We aimed to investigate the role of ferroptosis in keloid formation.Methods:We downloaded public high-throughput sequencing raw count data(GSE92566),containing three normal skin and four keloid samples,from the Gene Expression Omnibus database.Ferroptosis-related genes were obtained from the Ferroptosis database website.The ferroptosis-related differentially expressed genes(FRDEGs)were obtained by merging differentially expressed genes with ferroptosis-related genes.The FRDEGs were then used for Gene Ontology,Kyoto Encyclopedia of Genes and Genomes,Gene Set Enrichment Analysis,proteinprotein interaction(PPI)network,and microRNA(miRNA)-mRNA network analysis.Finally,real-time quantitative polymerase chain reaction(RT-qPCR)was performed to validate our findings.Results:We found 25 FRDEGs,including 8 up-regulated and 17 down-regulated genes.Pathway enrichment analysis revealed that the Hippo and transforming growth factorβsignaling pathways were significantly upregulated in keloids.In contrast,regulation of the peroxisome proliferator-activated receptor signaling pathway,glutathione metabolism,and unsaturated fatty acid metabolic process were down-regulated.PPI and FRDEGs hub networks were constructed using the STRING database and Cytoscape software.Ten hub genes were identified,including PLA2G6,RARRES2,SNCA,CYP4F8,CDKN2A,ALOX12,FABP4,ALOX12B,NEDD4,and NEDD4L.We constructed a miRNA-mRNA network,which predicted hsa-mir-155-5p,hsa-let-7b-5p,hsa-mir-124-3p,hsa-mir-145-5p,hsa-mir-328-3p,hsa-mir-24-3p,and hsa-mir-10b-5p as the most connected miRNAs regulating ferroptosis in keloids.Finally,we verified the expression levels of the hub genes by RT-qPCR,which confirmed that ALOX12,ALOX12B,and CYP4F8 expression were reduced in keloids.Conclusions:This study provides novel information on ferroptosis-mediated keloid pathogenesis,underscoring the importance of further research in this area to unlock new therapeutic avenues for keloid treatment.

The Use of Triancinolone for the Treatment of Keloid Scars

Scars, when in good evolution, result in a smooth, thin and discreet tissue. Keloid scars, however, are a type of abnormal and exacerbated repair response to tissue injury, whether in surgical interventions or in various injuries, which present in a prominent and gross way. In this context, there is an excess of collagen deposition in the tissue repair process, which can lead to the formation of keloids. The diagnosis of the condition presented is made by the medical professional or by the patient himself after the surgical intervention or skin injury. Under this analysis, protruding, rough and bad-looking scars are identified. In addition, we highlight the existence of keloids similar to large tumors, described as Jorge Lobo disease. The treatment encompasses massages, compressions, corticosteroids, chemotherapy, collagenase and cryotherapy. At first, we used corticosteroid-based massages, and then we started using compressive dressings until we started intrakeloid infiltrations with injectable triamcinolone. Triamcinolone 10 mg injectable—1/10—in 0.9% saline, with syringe and fixed needle 0.3 mm × 8 mm, intralesional infiltrate, in this context, proved to be effective for its treatment when applied sequentially and linearly. In cases where the medication was applied, there was an improvement after 21 days of application and a definitive improvement 2 months after the injury. In comparison, on the other hand, patients who were not subjected to the application of the medication may improve after 4 months of the injury or worsen compared to the initial case. We have come to the conclusion that this procedure may be one of the chosen ones for the treatment of keloid scars, being one of the most recommended for cases of keloid already installed.

Advances in postoperative radiotherapy for keloids

Introduction Keloids, a type of skin lesion that presents as patho-logically excessive dermal fibrosis and aberrant wound healing, are caused by cell proliferation and hyaline degeneration of connective tissues. The specific pathogenesis of keloids is still unknown(1-2)There are multiple therapeutic strategies for keloids, including surgery, cryotherapy, laser or light-based therapy, and intralesional corticosteroid injection. However, none of these is optimal. Surgical excision combined with adjuvant radiation is considered to be a safer and more efficacious method(3)From publicly available data, the recurrence rate of keloids after simple surgical excision amounts to 45%-100%(4)Based on published reports, postoperative radiotherapy results in a control rate of 67%- 81%, and the recurrence rate decreases to 24.5%-35%(4-12)This article reviews papers related to postoperative radiotherapy treatment for keloids, and also discusses radiation types, parameters, safety and effectiveness.

Possible Mechanisms and Prospects of Stem Cell Therapy for Keloids

Introduction Keloids are a benign proliferative disease of the skin caused by abnormal healing of physiological wounds.Keloids are similar to hypertrophic scars.However,keloids extend beyond the margin of the original wound and do not spontaneously regress,while hypertrophic scars are confined to the original wound and generally maintain their shape.1 Keloids cause pain,pruritus,restricted joint activity and cosmetic problems,and negatively affect quality of life.The bioactivity of keloids is regulated by various factors,such as transforming growth factor (TGF)-β,connective tissue growth factor (CTGF),and hypoxia inducible factor (HIF).2-4 These inflammatory factors are involved in keloid fibrosis,collagen production,and the deposition of extracellular matrix.However,the pathogenesis of keloids remain unclarified,and it is still one of the most challenging diseases in clinical practice.

The radiation therapy in keloids treatment: a comprehensive review of pathomechanism, damage mechanisms and cellular response

Keloid management has always been frustrating and challenging. The combination therapy of surgical excision and radiation therapy was deemed as the last resort for decades. The authors performed a thorough and comprehensive review over the mechanisms on how radiation therapy damages the keloid cells. The keloid cells' cellular response towards damage induced by irradiation was also studied based on original and current literatures. Mechanisms of damage generated by radiation therapy on keloid cells remained partially understood. However, direct damage was identified playing dominant role, in contrast to damage involved cancer cell apoptosis. Moreover, the p53 pathway and some inflammatory factors like interleukin-6 were believed to function in cellular response to irradiation. However, the transforming growth factor beta, which was the major dysregulated pathway involved in pathogenesis of keloid formation showed no apparent correlation with cellular response to irradiation damage. These pathways could partially explain radiation resistance in some refractory keloid lesions. The scientific basis and experimental proof in this field was still inadequate, which drove us to find more evidence to identify the key regulator response to damage engendered by radiation therapy. Further pathway identification may benefit the drug development to prevent keloid recurrence.

Diagnosis and Treatment of Keloids and Hypertrophic Scars—Japan Scar Workshop Consensus Document 2018

There has been a long-standing need for guidelines on the diagnosis and treatment of keloids and hypertrophic scars that are based on an understanding of the pathomechanisms that underlie these skin fibrotic diseases.This is particularly true for clinicians who deal with Asian and African patients because these ethnicities are highly prone to these diseases.By contrast,Caucasians are less likely to develop keloids and hypertrophic scars,and if they do,the scars tend not to be severe.This ethnic disparity also means that countries vary in terms of their differential diagnostic algorithms.The lack of clear treatment guidelines also means that primary care physicians are currently applying a hotchpotch of treatments,with uneven outcomes.To overcome these issues,the Japan Scar Workshop(JSW)has created a tool that allows clinicians to objectively diagnose and distinguish between keloids,hypertrophic scars,and mature scars.This tool is called the JSW Scar Scale(JSS)and it involves scoring the risk factors of the individual patients and the affected areas.The tool is simple and easy to use.As a result,even physicians who are not accustomed to keloids and hypertrophic scars can easily diagnose them and judge their severity.The JSW has also established a committee that,in cooperation with outside experts in various fields,has prepared a Consensus Document on keloid and hypertrophic scar treatment guidelines.These guidelines are simple and will allow even inexperienced clinicians to choose the most appropriate treatment strategy.The Consensus Document is provided in this article.It describes(1)the diagnostic algorithm for pathological scars and how to differentiate them from clinically similar benign and malignant tumors,(2)the general treatment algorithms for keloids and hypertrophic scars at different medical facilities,(3)the rationale behind each treatment for keloids and hypertrophic scars,and(4)the body site-specific treatment protocols for these scars.We believe that this Consensus Document will be helpful for physicians from all over the world who treat keloids and hypertrophic scars.

The 1470 nm diode laser with an intralesional fiber device:a proposed solution for the treatment of inflamed and infected keloids

Background:Keloids are the result of abnormal wound healing and often are subject to infections and recurrent inflammation.We present a study conducted with a 1470 nm diode laser using an intralesional optical fiber device for the treatment of inflamed keloid scars.We evaluate its efficacy as a novel alternative method to decrease keloid infection and inflammation.Methods:The patients who underwent 1470 nm laser treatment from February 2016 to February 2018 at the plastic and reconstructive surgery department of the Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University with keloid accompanying serious local infection and fester were included.Patients took curative effect evaluation before and 1 year after the treatment.The test items included infection frequency in each year;pain,by visual analogue scale(VAS);itch,using VAS;quality of life(QOL),using QOL scale;and blood supply,using PeriCam PSI.Results:A total of 19 patients(mean age 35.21 years,range 11–66)with history of inflamed keloids with episodes of infection or abscess were enrolled.Patients underwent to a 1470 nm laser therapy for average of 1.16 times.After treatment,infection frequency and blood supply in keloids were reduced(p<0.001).Pain,itching,and QOL were improved(p<0.001).Conclusion:The present study shows that 1470 nm fiber laser treatment could improve inflamed keloids fairly well by decreasing inflammation,and a relative stabilization of collagen composition.Therefore,it is an effective minimally invasive scar therapy,but further studies are essential to confirm the present results.

Downregulated cytotoxic CD8^(+)T-cell identifies with the NKG2A-soluble HLA-E axis as a predictive biomarker and potential therapeutic target in keloids

Keloids are an abnormal fibroproliferative wound-healing disease with a poorly understood pathogenesis,making it difficult to predict and prevent this disease in clinical settings.Identifying disease-specific signatures at the molecular and cellular levels in both the blood circulation and primary lesions is urgently needed to develop novel biomarkers for risk assessment and therapeutic targets for recurrence-free treatment.There is mounting evidence of immune cell dysregulation in keloid scarring.In this study,we aimed to profile keloid scar tissues and blood cells and found that downregulation of cytotoxic CD8^(+)T cells is a keloid signature in the peripheral blood and keloid lesions.Single-cell RNA sequencing revealed that the NKG2A/CD94 complex was specifically upregulated,which might contribute to the significant reduction in CTLs within the scar tissue boundary.In addition,the NKG2A/CD94 complex was associated with high serum levels of soluble human leukocyte antigen-E(sHLA-E).We subsequently measured sHLA-E in our hospital-based study cohort,consisting of 104 keloid patients,512 healthy donors,and 100 patients with an interfering disease.The sensitivity and specificity of sHLA-E were 83.69%(87/104)and 92.16%(564/612),respectively,and hypertrophic scars and other unrelated diseases exhibited minimal interference with the test results.Furthermore,intralesional therapy with triamcinolone combined with 5-fluorouracil drastically decreased the sHLA-E levels in keloid patients with better prognostic outcomes,while an incomplete reduction in the sHLA-E levels in patient serum was associated with higher recurrence.sHLA-E may effectively serve as a diagnostic marker for assessing the risk of keloid formation and a prognostic marker for the clinical outcomes of intralesional treatment.

The role of macrophages in the formation of hypertrophic scars and keloids

Numerous studies have shown that macrophages can orchestrate the microenvironment from the early stage of wound healing to the later stages of scar formation.However,few reviews have highlighted the significance of macrophages during the formation of abnormal scars.The purpose of this reviewwas to outline the polarization of macrophages from early to late stage of pathological scar formation,focusing on spatiotemporal diversity of M1 and M2 macrophages.In this review,the role of macrophages in the formation of hypertrophic scars and keloids is summarized in detail.First,an increased number of M2 cells observed before injuries are significantly associated with susceptibility to abnormal scar pathogenesis.Second,decreased expression of M1 at the early stage and delayed expression of M2 at the late stage results in pathological scar formation.Third,M2 cells are highly expressed at both the margin and the superficial region,which is consistent with the invasive property of keloids.Finally,this review helps to characterize strategies for the prediction and prevention of pathological scar formation.