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Strategies to prevent hypertrophic scar formation:a review of therapeutic interventions based on molecular evidence

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Burns & Trauma 2020年第1期8卷 433-440页

作者： Eri Shirakami Sho Yamakawa Kenji Hayashida Division of Plastic and Reconstructive Surgery Shimane University Faculty of Medicine89-1 Enya-choIzumoShimane 693-8501Japan

Once scar tissues mature,it is impossible for the surrounding tissue to regenerate normal dermal ***,it is essential to understand the fundamental mechanisms and establish effective strategies to inhibit aberrant scar *** scar formation is considered a result of the imbalance between extracellular matrix synthesis and degradation during wound ***,the underlying mechanisms of hypertrophic scar development are poorly *** purpose of this review was to outline the management in the early stage after wound healing to prevent hypertrophic scar formation,focusing on strategies excluding therapeutic agents of internal *** aimed at molecular targets,including cytokines,will be future options to prevent and treat hypertrophic *** basic studies and clinical trials,including combination therapy,are required to investigate the mechanisms and prevent hypertrophic scar formation.

关键词： hypertrophic scar Therapy Intervention Cytokines

CO_(2)fractional laser-assisted transdermal delivery of silk nanofiber carriers in a rabbit ear hypertrophic scar model

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Burns & Trauma 2022年第1期10卷 142-154页

作者： Yan Yang Lutong Liu Xiaojin Wu Xue Wang Qiang Lu Zhen Zhang Department of Dermatology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011P.R.China National Engineering Laboratory for Modern Silk and Collaborative Innovation Center of Suzhou Nano Science and Technology Soochow UniversitySuzhou 215213P.R.China

Background:hypertrophic scars are skin fibrotic diseases,characterized by fibroblast hyperprolif-eration and excessive accumulation of extracellular ***,topical drug application for hypertrophic scars are *** purpose of this study was to explore the permeability of silk nanofiber hydrogels(SNFs)loaded with rhodamine 6G(R6G)and rhodamine 110(R110)mediated by CO_(2)fractional laser irradiation into hypertrophic scar ***:In this work,R6G and R110 were chosen as hydrophilic and hydrophobic model *** were loaded inside *** vivo rabbit ear hypertrophic scars were treated with CO_(2)fractional laser irradiation and then R6G/R110-laden SNFs were applied to the scars to evaluate their synergetic effect on drug penetration *** permeability was quantified by fluorescence intensity and measured by confocal laser scanning microscopy on days 1,3,5 and *** specifically,the thermal coagulation zone(CZ)and its surrounding area(peri-CZ)caused by the thermal coagulation of the laser were discussed ***:Our data indicated that the SNFs promoted the penetration of R6G but not that of R110 in the peri-CZ on day 1 when combined with laser ***,both R6G and R110 were abundant in the CZ and remained stable on days 1,3 and ***,rapid re-epithelialization hindered the long-term permeability of both ***:Combining CO_(2)fractional laser irradiation with SNF drug delivery could improve the efficiency of hydrophilic drug delivery within 24 h before total re-epithelialization.

关键词： CO_(2)fractional laser hypertrophic scar Silk nanofiber hydrogels Transdermal delivery Laser-assisted drug delivery

Control of fibrosis and hypertrophic scar formation via glycolysis regulation with IR780

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Burns & Trauma 2022年第1期10卷 452-464页

作者： Xinxian Meng Zhixi Yu Wanyu Xu Jun Chai Shuo Fang Peiru Min Yunsheng Chen Yixin Zhang Zheng Zhang Department of Plastic and Reconstructive Surgery Shanghai Ninth People’s HospitalSchool of MedicineShanghai Jiao Tong University639 Zhizaoju RdShanghai 200011China Department of Plastic and Reconstructive Surgery The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal hospitalGusu schoolNanjing Medical UniversitySuzhou 215008JiangsuChina Department of Plastic and Reconstruction First Affiliated Hospital of Naval Medical UniversityShanghai 200433China Department of Burns and Plastic Surgery Shanghai Institute of Burns ResearchRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China

Background:hypertrophic scars(HS)represent one of the most common clinical challenges due to unsatisfactory therapeutic *** formation is associated with the abnormal activation of fibroblasts and their excessive fibrotic *** dysregulation has been shown to participate in the incidence and progression of various fibrotic diseases and shows potential as a means of controlling HS *** work aimed to discuss the impact of augmented glycolysis on HS and to propose a method for controlling HS formation through glycolysis ***:Here,augmented glycolysis was confirmed together with enhanced fibrotic activity in both HS fibroblasts(HFs)and HS tissues,and the suppression of glycolysis also attenuated fibroblast *** also introduced IR780,a heptamethine cyanine dye,to regulate glycolysis for the control of HS ***:In vitro,cell studies indicated that IR780 significantly down-regulated glycolysis and suppressed the fibrotic activity of *** vivo,the intralesional injection of IR780 into rabbit HS models led to the downregulation of glycolysis and the control of HS ***,IR780 accumulated preferentially in activated fibroblasts in both in vitro and in vivo studies,and thus specifically downregulated glycolysis and efficiently controlled fibrosis by targeting activated ***:This work identified a strategy for controlling fibrosis and HS formation from the perspective of glycolysis regulation with IR780 targeting of activated fibroblasts.

关键词： hypertrophic scar Glycolysis Fibrosis IR780 Activated fibroblast

Bilayer dissolving microneedle array containing 5-fluorouracil and triamcinolone with biphasic release profile for hypertrophic scar therapy

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Bioactive Materials 2021年第8期6卷 2400-2411页

作者： Beibei Yang Yating Dong Yifeng Shen Ailin Hou Guilan Quan Xin Pan Chuanbin Wu School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou510006China College of Pharmacy Jinan UniversityGuangzhou510632China

hypertrophic scar(HS)is an undesirable skin abnormality following deep burns or *** intralesional multi-injection with the suspension of triamcinolone acetonide(TA)and 5-fluorouracil(5-Fu)has exhibited great promise to HS treatment in clinical,the difference of metabolic behavior between TA and 5-Fu remarkably compromised the treatment ***,the traditional injection with great pain is highly dependent on the skill of the experts,which results in poor ***,a bilayer dissolving microneedle(BMN)containing TA and 5-Fu(TA-5-Fu-BMN)with biphasic release profile was designed for HS *** with several micro-scale needle tips,the BMN could be self-pressed into the HS with uniform drug distribution and less *** in vitro permeation and in vivo HS retention tests revealed that TA and 5-Fu could coexist in the scar tissue for a sufficient time period due to the well-designed biphasic release ***,the rabbit ear HS model was established to assess therapeutic *** histological analysis showed that TA-5-Fu-BMN could significantly reduce abnormal fibroblast proliferation and collagen fiber *** was also found that the value of scar elevation index was ameliorated to a basal level,together with the downregulation of mRNA and protein expression of Collagen I(Col I)and transforming growth factor-β1(TGF-β1)after application of *** conclusion,the BMN with biphasic release profiles could serve as a potential strategy for HS treatment providing both convenient administrations as well as controlled drug release behavior.

关键词： hypertrophic scar Bilayer microneedle Biphasic release Triamcinolone acetonide 5-Fluorouracil

Comparative proteomic analysis of extracellular matrix proteins secreted by hypertrophic scar witb normal skin fibroblasts

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Burns & Trauma 2014年第2期2卷 76-83页

作者： Li Ma Chengjun Gan Yong Huang Ying Wang Gaoxing Luo Jun Wu Chongqing Key Laboratory for Disease Proteomics State Key Laboratory of Trauma Burns and Combined Injury Institute of Burn Research Southwest Hospital the Third Military Medical University Chongqing School of Environmental Air Security and Pollution Control Engineering Jinan University Guangzhou Chongqing Key Laboratory for Disease Proteomics State Key Laboratory of Trauma Burns and Combined Injury Institute of Burn Research Southwest Hospital the Third Military Medical University Chongqing The 421 Hospital People's Liberation Army Guangzhou China Chongqing Key Laboratory for Disease Proteomics State Key Laboratory of Trauma Burns and Combined Injury Institute of Burn Research Southwest Hospital the Third Military Medical University Chongqing

The formation of hypertrophic scars (HSs) is a fibroproliferative disorder of abnormal wound healing. HSs usually characterize excessive proliferation of fibroblasts, abnormal deposition of extracellular matrix (ECM) during wound healing, associated with cosmetic, functional, and psychological problems. Owing to the role of ECM proteins in scar formation, we comparatively analyzed matrix proteins secreted by normal skin fibroblasts (NSFs) and HS fibroblasts (HSFs). The acetone-extracted secreted proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and identified by mass spectrometry (MS). Based on Go annotation of MS data, the profiling of ECM proteins was established and scar-related proteins have been screened out. The functions of several ECM proteins identified by MS have been discussed, such as collagens I, VI, XII, fibronectin, decorin, lumican, and protein procollagen C endopeptidase enhancer 1 (PCPE-1). Among them, the MS result of PCPE-1 was supported by Western blotting that PCPE-1 from HSFs were significantly upregulated than that from NSFs. It is suggested that PCPE-1 could be a potential target for scar treatment. The exploration of scar related proteins may provide new perspectives on understanding the mechanism of scar formation and open a new way to scar treatment and prevention.

关键词： Extracellular matrix protein fibroblast proteomics hypertrophic scar

iTRAQ-based proteomic profiling reveals different protein expression between normal skin and hypertrophic scar tissue

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Burns & Trauma 2015年第2期3卷 106-113页

作者： Jianglin Tan Weifeng He Gaoxing Luo Jun Wu Institute of Burn Research State Key Laboratory of TraumaBurns and Combined InjuriesChongqing Key Laboratory for Disease ProteomicsSouthwest HospitalThird Military Medical UniversityChongqing 400038China

Background:A hypertrophic scar is a unique fibrotic disease that only exists in *** advances in burn care and rehabilitation,as well as progress in the management during these decades,the hypertrophic scar remains hard to cure following surgical methods and drugs for *** this study,we are looking forward to finding the multitude of possible traumatic mechanisms and the underlying molecular signal ways in the formation of the hypertrophic ***:We used isobaric tags for relative and absolute quantitation(iTRAQ)labeling technology,followed by high-throughput 2D LC-MS/MS,to determine relative quantitative differential proteins between the hypertrophic scar and normal skin ***:A total of 3166 proteins were identified with a high confidence(≥95%confidence).And,a total of 89 proteins were identified as the differential proteins between the hypertrophic scar and normal skin,among which 41 proteins were up-regulated and 48 proteins were down-regulated in the hypertrophic ***-Analysis indicated the up-regulated proteins were involved in extracellular matrix,whereas the down-regulated proteins were involved in dynamic junction and structural molecule ***:In our study,we demonstrate 89 proteins present differently in the hypertrophic scar compared to normal skin by iTRAQ technology,which might indicate the pathologic process of hypertrophic scar formation and guide us to propose new strategies against the hypertrophic scar.

关键词： iTRAQ hypertrophic scar Proteomics

Dynamic changes of autophagy during hypertrophic scar formation and the role of autophagy intervention

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Chinese Journal of Plastic and Reconstructive Surgery 2021年第3期3卷 113-122页

作者： Yu Liu Xiaoxia Chen Yuan Fang Yu Yan Bin He Junlin Liao Ke Cao Xi Zhang Siwei Qu Jianda Zhou Postdoctoral Research Station of Clinical Medicine&Department of Plastic Surgery The Third Xiangya HospitalCentral South UniversityChangsha 410013HunanChina Inner Mongolia Medical University Hohhot 010000Inner MongoliaChina Department of Plastic Surgery People’s Hospital of NingxiangHunan University of Chinese MedicineNingxiang 410600HunanChina Department of Plastic Surgery The Third Xiangya HospitalCentral South UniversityChangsha 410013HunanChina Department of Plastic Surgery The First Affiliated Hospital of University of South ChinaHengyang 421001HunanChina Department of Oncology The Third Xiangya HospitalCentral South UniversityChangsha 410013HunanChina Clinical Medical College of Hunan University of Chinese Medicine Changsha 410007HunanChina

Background:The role of autophagy in the formation of hypertrophic scars(HS)remains *** study aimed to explore the role and potential mechanism of autophagy during the development of ***:RNA and protein expression levels of Beclin-1,p62,and LC3II in normal skin tissues and HS specimens from different patients were *** inducers and inhibitors were used to cure established HS in rabbit ears,and the expression of Beclin-1,p62,and LC3II at the RNA and protein level was ***,the effects of autophagy inducers and inhibitors on HS development were ***:Compared to normal skin tissues,the expression of LC3II and Beclin-1 was higher(Pscar hyperplasia by enhancing autophagy。

关键词： hypertrophic scar Rabbit ear hypertrophic scar model Autophagy Beclin-1 LC3 p62

Effect of Abnormal Savda Munziq on hypertrophic scar Formation in A Rabbit Ear Model

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Chinese Journal of Integrative Medicine 2015年第7期21卷 537-541页

作者：王虎军高伟成马少林 Department of Plastic Surgery of the First Teaching Hospital Xinjiang Medical University

Objective： To investigate whether administrating Abnormal Savda Munziq （ASMq）, a traditional Uighur herbal preparation used for the prevention or treatment of diseases, affects hypertrophic scar （HTS） formation by using an established rabbit ear model. Methods： The HTS rabbit model was created by circular full- thickness skin excisions on both ears of rabbits. Twenty rabbits were randomized into four groups, with 5 rabbits and 60 wounds in each group. Group A was the control group, treated with normal saline daily. Groups B, C, and D were the treatment groups at three different doses of ASMq （400, 800, and 1200 mg/kg body weight, respectively, daily, by gastrogavage）. Twenty wounds were randomly chosen from each group on the 40th day after treatment and specimen were examined. scar elevation index （SEI） was analyzed with histological assessment, and ultrastructure analysis was analyzed with a transmission electron microscopy. Results： Groups B, C, and D demonstrated significant reductions in SEI as compared with the control group at 35.9% （P=0.0212）, 48.2% （P=0.0108）, and 52.7% （P=0.0103）, respectively in a dose-response manner. SEI was lowered in Group D compared with Group B with a significant difference （P=0.015）. However, there were no significant differences between Groups B and C, or between Groups C and D. Histological analysis showed that high- dose ASMq （1200 mg/kg） could enhance the softening of HTS of rabbit ears and increase the compliance as shown in general. Ultrastructure analysis showed that with increased ASMq dose, the fibroblasts, pro-collagen, collagen, endoplasmic reticulum and ribosomes were reduced gradually. Conclusions： Orally administered ASMq significantly reduces the severity of HTS in the rabbit ear model. The findings of this study may have clinical implications on the management of human HTS.

关键词： hypertrophic scar Abnormal Savda Munziq ultrastructure

Process of hypertrophic scar Formation： Expression of Eukaryotic Initiation Factor 6

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Chinese Medical Journal 2015年第20期128卷 2787-2791页

作者： Qing-Qing Yang Institute of Burn Research State Key Laboratory of Trauma Burn and Combined Injury Southwest Hospital The Third Military Medical University Chongqing 400038 China Chongqing Key Laboratory for Disease Proteomics The Third Military Medical University Chongqing 400038 China

Background： hypertrophic scar is one of the most common complications and often causes the disfigurement or deformity in bum or trauma patients. Therapeutic methods on hypertrophic scar treatment have limitations due to the poor understanding of mechanisms of hypertrophic scar formation. To throw light on the molecular mechanism of hypertrophic scar formation will definitely improve the outcome of the treatment. This study aimed to illustrate the negative role of eukaryotic initiation factor 6 （elF6） in the process of human hypertrophic scar tbrmation, and provide a possible indicator of hypertrophic scar treatment and a potential target molecule for hypertrophic scar. Methods： In the present study, we investigated the protein expression of elF6 in the human hypertrophic scar of different periods by immunohistochemistry and Western blot analysis. Results： In the hypertrophic scar tissue, elF6 expression was significantly decreased and absent in the basal layer of epidermis in the early period, and increased slowly and began to appear in the basal layer of epidermis by the scar formation time. Conclusions： This study confirmed that elF6 expression was significantly related to the development of hypertrophic scar, and the elF6 may be a target molecule for hypertrophic scar control or could be an indicator of the outcomes for other treatment modalities.

关键词： Eukaryotic Initiation Factor 6 hypertrophic scar Therapeutic Target