TY - JOUR T1 - THE MOLECULAR MECHANISM, TYPES AND TREATMENT OF SCAR FORMATION TT - SKAR OLUŞUMUNUN MOLEKÜLER MEKANİZMASİ, TÜRLERİ VE TEDAVİSİ AU - Tekin, Enver PY - 2024 DA - December Y2 - 2024 DO - 10.52538/iduhes.1590063 JF - Izmir Democracy University Health Sciences Journal JO - IDUHES PB - İzmir Demokrasi Üniversitesi WT - DergiPark SN - 2651-4575 SP - 223 EP - 247 VL - 7 IS - 3 LA - en AB - Wound healing and scar formation is a complex biological process that occurs as a response to injury, characterized by the deposition of extracellular matrix components and the proliferation of fibroblasts. The mechanisms underlying wound healing and following scar formation can vary significantly depending on the type of scar, such as hypertrophic scars and keloids, and are influenced by various cellular and molecular factors. Myofibroblasts, a differentiated form of fibroblasts, play a pivotal role in wound healing and scar formation due to their contractile properties and ability to produce large amounts of collagen and other extracellular matrix components. Scar formation process involves complex interactions among various cell types, including fibroblasts, macrophages, and endothelial cells, as well as the extracellular matrix components. Understanding these mechanisms is crucial for developing therapeutic strategies to minimize pathological scarring, such as hypertrophic scars and keloids. The initial phase of scar formation is dominated by inflammation, which is essential for initiating the healing process. Inflammatory cells, particularly macrophages, play a pivotal role in orchestrating the wound healing response. Fibroblasts are the primary effector cells in scar formation, responsible for synthesizing extracellular matrix components, including collagen.Scars can be classified into several types based on their characteristics, underlying mechanisms, and clinical presentations. The two most commonly discussed types of scars are hypertrophic scars and keloids, but there are also atrophic scars, contracture scars, and acne scars, each with distinct features and implications for treatment. The aim of this study is to explain the molecular mechanism, types and treatment of scar formation. KW - Wound healing KW - Scar formation KW - Fibroblast KW - Inflammation KW - keloid KW - hypertrophic scar N2 - Yara iyileşmesi ve skar oluşumu, hasara yanıt olarak hücre dışı matris bileşenlerinin birikmesi ve fibroblastların çoğalmasıyla karakterize karmaşık bir biyolojik süreçtir. Yara iyileşmesinin ve sonrasında oluşan skar oluşumunun altında yatan mekanizmaları, hipertrofik skar ve keloid gibi skar tiplerine bağlı olarak önemli ölçüde değişebilmekte ve çeşitli hücresel ve moleküler faktörlerden etkilenmektedir. Fibroblastların farklılaşmış bir formu olan miyofibroblastlar, kasılma özellikleri ve büyük miktarda kolajen ve diğer hücre dışı matris bileşenleri üretme kabiliyetleri nedeniyle yara iyileşmesinde ve skar oluşumunda önemli bir rol oynarlar.Skar oluşum süreci fibroblastlar, makrofajlar ve endotel hücreleri gibi çeşitli hücre tipleri ile hücre dışı matris bileşenleri arasındaki karmaşık etkileşimleri içerir. Bu mekanizmaların anlaşılması, hipertrofik skar ve keloid gibi patolojik skarları en aza indirmeye yönelik tedavi stratejileri geliştirmek için çok önemlidir. Skar oluşumunun ilk evresinde, iyileşme sürecinin ilk aşaması olan inflamasyon mekanizması başlar. Özellikle makrofajlar olmak üzere inflamatuar hücreler, yara iyileşmesinin düzenlenmesinde önemli bir rol oynarlar. Fibroblastlar, kollajen de dahil olmak üzere ekstraselüler matriks bileşenlerinin sentezlenmesinden sorumlu olan, skar oluşumunda birincil etkili hücrelerdir.Skarlar, özelliklerine, altta yatan mekanizmalarına ve klinik görünümlerine göre çeşitli türlere ayrılabilir. En sık tartışılan iki tür hipertrofik skar ve keloiddir, ancak atrofik skar, kontraktür skar ve akne skarı da görülebilir ve her biri tedavi için farklı özelliklere sahiptir.Bu çalışmanın amacı skar oluşumunun moleküler mekanizmasını, tiplerini ve tedavisini açıklamaktır. CR - Agarwal, N., Gupta, L., Khare, A. K., Kuldeep, C. M., Mittal, A. (2015). Therapeutic response of 70% trichloroacetic acid cross in atrophic acne scars. Dermatologic Surgery, 41(5), 597-604. https://doi.org/10.1097/dss.0000000000000355 CR - Al-Marzouqi, H., Nagy, E., Sair, M., and Mabrouk, A. (2022). The efficacy of low energy fractional carbon dioxide laser therapy in management of post-surgical hypertrophic scars. The Egyptian Journal of Plastic and Reconstructive Surgery, 46(3), 231-238. https://doi.org/10.21608/ejprs.2022.254701 CR - Aydoğmuş, S., Kelekci, K., Şengül, M., Demirel, E., Karaca, Ş., Desdicioğlu, R., Kelekci, S. (2017). Factors affecting the development of scar formation in abdominal surgery performed for gynecologic and obstetric conditions. Turkderm, 51(1), 12-17. https://doi.org/10.4274/turkderm.58751 CR - Batool, Z., Muhammad, G., Iqbal, M., Aslam, M., Raza, M., Sajjad, N., Abdullah, M., Akhtar, N., Syed, A., Elgorban, A., Al-Rejaie, S., Shafiq, Z. (2022). Hydrogel assisted synthesis of gold nanoparticles with enhanced microbicidal and in vivo wound healing potential. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-10495-3 CR - Bikash, C. and Sarkar, R. (2023). Topical management of acne scars: the uncharted terrain. Journal of Cosmetic Dermatology, 22(4), 1191-1196. https://doi.org/10.1111/jocd.15584 CR - Bitar, M. and Al-Mulla, F. (2012). ROS constitute a convergence nexus in the development of igf1 resistance and impaired wound healing in a rat model of type 2 diabetes. Disease Models and Mechanisms, 5(3), 375-388. https://doi.org/10.1242/dmm.007872 CR - Butzelaar, L., Niessen, F., Talhout, W., Schooneman, D., Ulrich, M., Beelen, R., … and Molen, A. (2017). Different properties of skin of different body sites: the root of keloid formation?. Wound Repair and Regeneration, 25(5), 758-766. https://doi.org/10.1111/wrr.12574 CR - Chanprapaph, K., Tanrattanakorn, S., Wattanakrai, P., Wongkitisophon, P., and Vachiramon, V. (2012). Effectiveness of onion extract gel on surgical scars in asians. Dermatology Research and Practice, 2012, 1-6. https://doi.org/10.1155/2012/212945 CR - Choi, J., Jun, J. H., Kim, J. H., Sung, H. J., Lee, J. H. (2014). Synergistic effect of interleukin-6 and hyaluronic acid on cell migration and erk activation in human keratinocytes. Journal of Korean Medical Science (Suppl 3), 29, 210-126. https://doi.org/10.3346/jkms.2014.29.s3.s210 CR - Choi, Y. S., Khan, G., Nam, S. M., Park, E. S. (2018). Successful treatment of post-traumatic elbow scar contracture using combined approach of surgical release & early fractional laser resurfacing. Medical Lasers, 7(1), 32-37. https://doi.org/10.25289/ml.2018.7.1.32 CR - Darby, I. and Desmoulière, A. (2020). Scar formation: cellular mechanisms., 19-26. https://doi.org/10.1007/978-3-030-44766-3_3 CR - Deng, X., Chen, Q., Qiang, L., Chi, M., Xie, N., Wu, Y., Yao, M., Zhao, D., Ma, J., Zhang, N., Xie, Y. (2018). Development of a porcine full-thickness burn hypertrophic scar model and investigation of the effects of shikonin on hypertrophic scar remediation. Frontiers in Pharmacology, 9, 1-12. https://doi.org/10.3389/fphar.2018.00590 CR - Deng, X., Zhao, F., Zhao, D., Zhang, Q., Zhu, Y., Chen, Q., Xie, Y. (2021). Oxymatrine promotes hypertrophic scar repair through reduced human scar fibroblast viability, collagen and induced apoptosis via autophagy inhibition. International Wound Journal, 19(5), 1221-1231. https://doi.org/10.1111/iwj.13717 CR - Donovan, J., Xu, S., Norman, J., Abraham, D. (2013). Platelet-derived growth factor alpha and beta receptors have overlapping functional activities towards fibroblasts. Fibrogenesis & Tissue Repair, 6(1), 1-9. https://doi.org/10.1186/1755-1536-6-10 CR - Duan, M., Zhang, Y., Zhang, H., Meng, Y., Qian, M., Zhang, G. (2020). Epidermal stem cell-derived exosomes promote skin regeneration by downregulating transforming growth factor-β1 in wound healing. Stem Cell Research & Therapy, 11(1), 1-11. https://doi.org/10.1186/s13287-020-01971-6 CR - Dwivedi, C., Pandey, H., Pandey, A., Patil, S., Ramteke, P., Laux, P., Luch, A., Singh, A. (2019). In vivo biocompatibility of electrospun biodegradable dual carrier (antibiotic + growth factor) in a mouse model—implications for rapid wound healing. Pharmaceutics, 11(4), 1-19. https://doi.org/10.3390/pharmaceutics11040180 CR - Ebrahiminaseri, A., Sadeghizadeh, M., Moshaii, A., Asgaritarghi, G., and Safari, Z. (2021). Combination treatment of dendrosomal nanocurcumin and low-level laser therapy develops proliferation and migration of mouse embryonic fibroblasts and alter tgf-β, vegf, tnf-α and il-6 expressions involved in wound healing process. Plos One, 16(5), 1-23. e0247098. https://doi.org/10.1371/journal.pone.0247098 CR - Eisendle, K., Pichler, M., Luca, J., Thuile, T. (2019). Use of self‐adherent silicone sheets in a pediatric burn patient: a case report and instructions for use. Pediatric Dermatology, 37(1), 257-260. https://doi.org/10.1111/pde.14017 CR - El‐Tahlawi, S. and Mohamed, B. (2023). Intralesional triamcinolone acetonide in the treatment of keloids and hypertrophic scars. Fayoum University Medical Journal, 11(1), 49-55. https://doi.org/10.21608/fumj.2023.278472 CR - Fabbrocini, G., Annunziata, M., D'Arco, V., Vita, V., Lodi, G., Mauriello, M., Monfrecola, G. (2010). Acne scars: pathogenesis, classification and treatment. Dermatology Research and Practice, 2010(1), 1-13. https://doi.org/10.1155/2010/893080 CR - Feng, Y., Sun, Z., Liu, S., Wu, J., Zhao, B., Lv, G., Zhou, X. (2019). Direct and indirect roles of macrophages in hypertrophic scar formation. Frontiers in Physiology, 10, 1-7. https://doi.org/10.3389/fphys.2019.01101 CR - Finnerty, C., Jeschke, M., Branski, L., Barret, J., Dziewulski, P., Herndon, D. (2016). Hypertrophic scarring: the greatest unmet challenge after burn injury. The Lancet, 388(10052), 1427-1436. https://doi.org/10.1016/s0140-6736(16)31406-4 CR - Gauglitz, G. (2013). Management of keloids and hypertrophic scars: current and emerging options. Clinical Cosmetic and Investigational Dermatology, 103. https://doi.org/10.2147/ccid.s35252 CR - Gaur, N. (2018). A comparative analysis of carbon dioxide laser technique and derma roller therapy in post-acne scars patients. International Journal of Surgery Science, 2(1), 48-50. https://doi.org/10.33545/surgery.2018.v2.i1a.888 CR - Gisquet, H., Liu, H., Blondel, W., Leroux, A., Latarche, C., Merlin, J., Guillemin, F. (2011). Intradermal tacrolimus prevent scar hypertrophy in a rabbit ear model: a clinical, histological and spectroscopical analysis. Skin Research and Technology, 17(2), 160-166. https://doi.org/10.1111/j.1600-0846.2010.00479.x CR - Guan, Y., Niu, H., Liu, Z., Dang, Y., Shen, J., Zayed, M., Ma, L., Guan, J. (2021). Sustained oxygenation accelerates diabetic wound healing by promoting epithelialization and angiogenesis and decreasing inflammation. Science Advances 7(35), 1-14. https://doi.org/10.1126/sciadv.abj0153 CR - Gurtner, G., Dauskardt, R., Wong, V., Bhatt, K., Wu, K., Vial, I., Longaker, M. (2011). Improving cutaneous scar formation by controlling the mechanical environment. Annals of Surgery Open, 254(2), 217-225. https://doi.org/10.1097/sla.0b013e318220b159 CR - Hahn, J., Glaser, K., McFarland, K., Aronow, B., Boyce, S., Supp, D. (2013). Keloid‐derived keratinocytes exhibit an abnormal gene expression profile consistent with a distinct causal role in keloid pathology. Wound Repair and Regeneration, 21(4), 530-544. https://doi.org/10.1111/wrr.12060 CR - He, T., Bai, X., Yang, L., Fan, L., Li, Y., Su, L., Gao, J., Han, S., Hu, D. (2015). Loureirin b inhibits hypertrophic scar formation via inhibition of the tgf-β1-erk/jnk pathway. Cellular Physiology and Biochemistry, 37(2), 666-676. https://doi.org/10.1159/000430385 CR - He, Y., Deng, Z., Alghamdi, M., Lü, L., Fear, M., and He, L. (2017). From genetics to epigenetics: new insights into keloid scarring. Cell Proliferation, 50(2), 1-8. https://doi.org/10.1111/cpr.12326 CR - He, J., Fang, B., Shan, S., Xie, Y., Wang, C., Zhang, Y., Zhang, X., Li, Q. (2021). Mechanical stretch promotes hypertrophic scar formation through mechanically activated cation channel piezo1. Cell Death and Disease, 12(3), 1-13. https://doi.org/10.1038/s41419-021-03481-6 CR - Hesketh, M., Sahin, K., West, Z., Murray, R. (2017). Macrophage phenotypes regulate scar formation and chronic wound healing. International Journal of Molecular Sciences, 18(7), 1-10. https://doi.org/10.3390/ijms18071545 CR - Hsiao, C., Cheng, H. W., Huang, C. M., Li, H. R., Ou, M. H., Huang, J. R., Khoo, K., Yu, W. H., Chen, Y., Wang, Y., Chiou, A., Kuo, J. (2017). Fibronectin in cell adhesion and migration via n-glycosylation. Oncotarget 8(41), 70653-70668. https://doi.org/10.18632/oncotarget.19969 CR - Hu, Z., Tang, B., Guo, D., Zhang, J., Liang, Y., Ma, D., Zhu, J. (2014). Expression of insulin‐like growth factor‐1 receptor in keloid and hypertrophic scar. Clinical and Experimental Dermatology, 39(7), 822-828. https://doi.org/10.1111/ced.12407 CR - Huang, C., Murphy, G., Akaishi, S., Ogawa, R. (2013). Keloids and hypertrophic scars. Plastic and Reconstructive Surgery Global Open, 1(4), e25. https://doi.org/10.1097/gox.0b013e31829c4597 CR - Huang, L., Chen, D., Xu, Q., Zheng, Z., Dai, X. (2020). The use of the scar cosmesis assessment and rating scale to evaluate the cosmetic outcomes of totally thoracoscopic cardiac surgery. Journal of Cardiothoracic Surgery, 15(1). https://doi.org/10.1186/s13019-020-01294-w CR - Hunasgi, S., Koneru, A., Vanishree, M., Ravikumar, S. (2013). Keloid: a case report and review of pathophysiology and differences between keloid and hypertrophic scars. Journal of Oral and Maxillofacial Pathology, 17(1), 116. https://doi.org/10.4103/0973-029x.110701 CR - Igarashi, J., Fukuda, N., Inoue, T., Nakai, S., Saito, K., Fujiwara, K., Soma, M. (2015). Preclinical study of novel gene silencer pyrrole-imidazole polyamide targeting human tgf-β1 promoter for hypertrophic scars in a common marmoset primate model. Plos One, 10(5), e0125295. https://doi.org/10.1371/journal.pone.0125295 CR - İnan, Z., Saraydın, S. (2013). Investigation of the wound healing effects of chitosan on FGFR3 and VEGF immunlocalization in experimentally diabetic rats. International Journal of Biomedical Materials Research, 1(1), 1-8. https://doi.org/10.11648/j.ijbmr.20130101.11 CR - Jin, J., Zhai, H., Jia, Z., and Luo, X. (2019). Long non-coding rna hoxa11-as induces type I collagen synthesis to stimulate keloid formation via sponging mir-124-3p and activation of smad5 signaling. Ajp Cell Physiology, 317(5), C1001-C1010. https://doi.org/10.1152/ajpcell.00319.2018 CR - Kauvar, A., Kubicki, S., Suggs, A., Friedman, P. (2019). Laser therapy of traumatic and surgical scars and an algorithm for their treatment. Lasers in Surgery and Medicine, 52(2), 125-136. https://doi.org/10.1002/lsm.23171 CR - Kieran, I., Knock, A., Bush, J., So, K., Metcalfe, A., Hobson, R., Ferguson, M. (2013). Interleukin‐10 reduces scar formation in both animal and human cutaneous wounds: results of two preclinical and phase ii randomized control studies. Wound Repair and Regeneration, 21(3), 428-436. https://doi.org/10.1111/wrr.12043 CR - Kim, D., Ryu, H., Choi, J., Ahn, H., Kye, Y., and Seo, S. (2014). A comparison of the scar prevention effect between carbon dioxide fractional laser and pulsed dye laser in surgical scars. Dermatologic Surgery, 40(9), 973-978. https://doi.org/10.1097/01.dss.0000452623.24760.9c CR - Kim, S., Lee, S., Yi, S., Jun, S., Yi, Y., Nagar, H., Oh, S. (2021). Tauroursodeoxycholic acid decreases keloid formation by reducing endoplasmic reticulum stress as implicated in the pathogenesis of keloid. International Journal of Molecular Sciences, 22(19), 10765. https://doi.org/10.3390/ijms221910765 CR - Kravvas, G. and Al‐Niaimi, F. (2017). A systematic review of treatments for acne scarring. part 1: non-energy-based techniques. Scars Burns & Healing, 3, 1-17. https://doi.org/10.1177/2059513117695312 CR - Kwak, D., Bae, T., Kim, W., Kim, H. (2016). Anti-vascular endothelial growth factor (bevacizumab) therapy reduces hypertrophic scar formation in a rabbit ear wounding model. Archives of Plastic Surgery, 43(06), 491-497. https://doi.org/10.5999/aps.2016.43.6.491 CR - Krakowski, A., Goldenberg, A., Eichenfield, L., Murray, J., Shumaker, P. (2014). Ablative fractional laser resurfacing helps treat restrictive pediatric scar contractures. Pediatrics, 134(6), e1700-e1705. https://doi.org/10.1542/peds.2014-1586 CR - Lee, S., Zheng, Z., and Roh, M. (2013). Early postoperative treatment of surgical scars using a fractional carbon dioxide laser: a split-scar, evaluator-blinded study. Dermatologic Surgery, 39(8), 1190-1196. https://doi.org/10.1111/dsu.12228 CR - Li, P., He, Q., and Luo, C. (2014). Overexpression of mir‐200b inhibits the cell proliferation and promotes apoptosis of human hypertrophic scar fibroblastsin vitro. The Journal of Dermatology, 41(10), 903-911. https://doi.org/10.1111/1346-8138.12600 CR - Li, P., Li, H., Zhong, L., Sun, Y., Liu, Y., Wu, M., Zhang, L., Kong, Q., Wang, S., Lv, C. (2015). Molecular events underlying maggot extract promoted rat in vivo and human in vitro skin wound healing. Wound Repair and Regeneration 23 (1), 65-73. https://doi.org/10.1111/wrr.12243 CR - Li, J., Chen, L., Cao, C., Yan, H., Zhou, B., Gao, Y., Li, J. (2016). The long non-coding rna lncrna8975-1 is upregulated in hypertrophic scar fibroblasts and controls collagen expression. Cellular Physiology and Biochemistry, 40(1-2), 326-334. https://doi.org/10.1159/000452548 CR - Li, X., Guo, L., Yang, X., Wang, J., Hou, Y., Zhu, S., Liu, Y. (2019). Tgf‐β1‐induced connexin43 promotes scar formation via the erk/mmp‐1/collagen iii pathway. Journal of Oral Rehabilitation, 47(S1), 99-106. https://doi.org/10.1111/joor.12829 CR - Li, K., Nicoli, F., Cui, C., Xi, W., Al-Mousawi, A., Zhang, Z., Zhang, Y. (2020). Treatment of hypertrophic scars and keloids using an intralesional 1470 nm bare-fibre diode laser: a novel efficient minimally-invasive technique. Scientific Reports, 10(1), 1-11. https://doi.org/10.1038/s41598-020-78738-9 CR - Li, S., Li, Y., Wu, Z., Wu, Z., and Fang, H. (2021). Diabetic ferroptosis plays an important role in triggering on inflammation in diabetic wound. Ajp Endocrinology and Metabolism, 321(4), E509-E520. https://doi.org/10.1152/ajpendo.00042.2021 CR - Li, M. (2023). Inhibition of proliferation, migration, and invasion of keloid fibroblasts by mir-183-5p through downregulating egr1. International Journal of Morphology, 41(6), 1610-1619. https://doi.org/10.4067/s0717-95022023000601610 CR - Limandjaja, G., Niessen, F., Scheper, R., Gibbs, S. (2020). Hypertrophic scars and keloids: overview of the evidence and practical guide for differentiating between these abnormal scars. Experimental Dermatology, 30(1), 146-161. https://doi.org/10.1111/exd.14121 CR - Ma, L., Gan, C., Huang, Y., Wang, Y., Luo, G., Wu, J. (2014). Comparative proteomic analysis of extracellular matrix proteins secreted by hypertrophic scar with normal skin fibroblasts. Burns & Trauma, 2(2), 76-83. https://doi.org/10.4103/2321-3868.130191 CR - Ma, F., Shen, J., Zhang, H., Zhang, Z., Yang, A., Xiong, J., Jiang, Y. (2022). A novel lncrna fpasl regulates fibroblast proliferation via the pi3k/akt and mapk signaling pathways in hypertrophic scar. Acta Biochimica Et Biophysica Sinica, 274-284. https://doi.org/10.3724/abbs.2022122 CR - Makwana, J., Vora, D., Soyal, V. (2022). A comparative study of efficacy of fractional co2 laser vs microdermabrasion in treatment of acne scars (total 100 patients). International Journal of Research and Review, 9(1), 34-38. https://doi.org/10.52403/ijrr.20220105 CR - Masi, E., Campos, A., Masi, F., Ratti, M., Ike, I., Masi, R. (2016). The influence of growth factors on skin wound healing in rats. Brazilian Journal of Otorhinolaryngology, 82(5), 512-521. https://doi.org/10.1016/j.bjorl.2015.09.011 CR - Medyukhina, A., Vogler, N., Latka, I., Kemper, S., Böhm, M., Dietzek, B., Popp, J. (2011). Automated classification of healthy and keloidal collagen patterns based on processing of shg images of human skin. Journal of Biophotonics, 4(9), 627-636. https://doi.org/10.1002/jbio.201100028 CR - Mohammadi, A. A., Parand, A., Kardeh, S., Janati, M., and Mohammadi, S. (2018). Efficacy of topical enalapril in treatment of hypertrophic scars. World Journal of Plastic Surgery, 7(3), 326-331. https://doi.org/10.29252/wjps.7.3.326 CR - Morris, M., Allukian, M., Herdrich, B., Caskey, R., Zgheib, C., Xu, J., Liechty, K. (2014). Modulation of the inflammatory response by increasing fetal wound size or interleukin‐10 overexpression determines wound phenotype and scar formation. Wound Repair and Regeneration, 22(3), 406-414. https://doi.org/10.1111/wrr.12180 CR - Moura, J., Sørensen, A. E., Leal, E. C., Svendsen, R. P., Carvalho, L., Willemoes, R. J., Jorgensen, P. T., Jenssen, H., Wengel, J., Dalgaard, R. T., Carvalho, E. (2019). Microrna-155 inhibition restores fibroblast growth factor 7 expression in diabetic skin and decreases wound inflammation. Scientific Reports, 9(1), 1-11. https://doi.org/10.1038/s41598-019-42309-4 CR - Natallya, F., Herwanto, N., Prakoeswa, C., Indramaya, D., Rantam, F. (2019). Effective healing of leprosy chronic plantar ulcers by application of human amniotic membrane stem cell secretome gel. Indian Journal of Dermatology, 64(3), 250. https://doi.org/10.4103/ijd.ijd_6_17 CR - Niederstätter, I., Schiefer, J., and Fuchs, P. (2021). Surgical strategies to promote cutaneous healing. Medical Sciences, 9(2), 45. https://doi.org/10.3390/medsci9020045 CR - Noh, K., Liu, X., Zhong, Z., Yang, C., Kim, Y., Lee, G., Choi, K., Kim, K. (2018). Leukocyte-poor platelet-rich plasma-derived growth factors enhance human fibroblast proliferation in vitro. Clinics in Orthopedic Surgery, 10(2), 240-247. https://doi.org/10.4055/cios.2018.10.2.240 CR - Ogawa, R., Okai, K., Tokumura, F., Mori, K., Ohmori, Y., Huang, C., Hyakusoku, H., Akaishi, S. (2012). The relationship between skin stretching/contraction and pathologic scarring: the important role of mechanical forces in keloid generation. Wound Repair and Regeneration, 20(2), 149-157. https://doi.org/10.1111/j.1524-475x.2012.00766.x CR - On, H., Lee, S., Lee, Y., Chang, H., Park, C., Roh, M. (2015). Evaluating hypertrophic thyroidectomy scar outcomes after treatment with triamcinolone injections and copper bromide laser therapy. Lasers in Surgery and Medicine, 47(6), 479-484. https://doi.org/10.1002/lsm.22375 CR - Ong, C., Khoo, Y., Mukhopadhyay, A., Masilamani, J., Do, D., Lim, I., Phan, T. (2010). Comparative proteomic analysis between normal skin and keloid scar. British Journal of Dermatology, 162(6), 1302-1315. https://doi.org/10.1111/j.1365-2133.2010.09660.x CR - Palumbo, V., Rizzuto, S., Damiano, G., Fazzotta, S., Gottardo, A., Mazzola, G., Monte, A. (2021). Use of platelet concentrate gel in second-intention wound healing: a case report. Journal of Medical Case Reports, 15(1), 1-7. https://doi.org/10.1186/s13256-020-02649-6 CR - Park, T. H., Seo, S. W., Kim, J. K., Chang, C. H. (2011). Management of chest keloids. Journal of Cardiothoracic Surgery, 6(1). https://doi.org/10.1186/1749-8090-6-49 CR - Perdanasari, A., Torresetti, M., Grassetti, L., Nicoli, F., Zhang, Y., Dashti, T., Lazzeri, D. (2015). Intralesional injection treatment of hypertrophic scars and keloids: a systematic review regarding outcomes. Burns & Trauma, 3. https://doi.org/10.1186/s41038-015-0015-7 CR - Pradhan, M. (2023). The molecular mechanisms involved in the hypertrophic scars post-burn injury. The Yale Journal of Biology and Medicine, 96(4), 549-563. https://doi.org/10.59249/rhuf5686 CR - Prakoeswa, C., Rindiastuti, Y., Wirohadidjojo, Y., Komaratih, E., Dinaryati, A., Lestari, N., Rantam, F. (2020). Resveratrol promotes secretion of wound healing related growth factors of mesenchymal stem cells originated from adult and fetal tissues. Artificial Cells Nanomedicine and Biotechnology, 48(1), 1159-1166. https://doi.org/10.1080/21691401.2020.1817057 CR - Qi, W., Yang, C., Dai, Z., Che, D., Feng, J., Mao, Y., Cheng, R., Wang, Z., He, X., Zhou, T., Gu, X., Yan, L., Yang, X., Ma, J., Gao, G. (2014). High levels of pigment epithelium–derived factor in diabetes impair wound healing through suppression of wnt signaling. Diabetes, 64(4), 1407-1419. https://doi.org/10.2337/db14-1111 CR - Qin, Song, Xie, Y., Gou, Q., Guo, X., Qian, Y., Gou, X. (2017). JAK/STAT3 and Smad3 activities are required for the wound healing properties of Periplaneta americana extracts. International Journal of Molecular Medicine, 40 (2), 465-473. https://doi.org/10.3892/ijmm.2017.3040 CR - Qiu, Y., Yang, S., Tan, J., Luo, G., Wang, H., Wu, J. (2015). Process of hypertrophic scar formation. Chinese Medical Journal, 128(20), 2787-2791. https://doi.org/10.4103/0366-6999.167359 CR - Ren, Z., Hou, Y., Ma, S., Yang, T., Li, J., Cao, H., Ji, L. (2014). Effects of ccn3 on fibroblast proliferation, apoptosis and extracellular matrix production. International Journal of Molecular Medicine, 33(6), 1607-1612. https://doi.org/10.3892/ijmm.2014.1735 CR - Rong, S., Li, C., Li, S., Wu, S., Sun, F. (2020). Genetically modified adipose‐derived stem cells with matrix metalloproteinase 3 promote scarless cutaneous repair. Dermatologic Therapy, 33(6), 1-8. https://doi.org/10.1111/dth.14112 CR - Ruthenborg, R. J., Ban, J. J., Wazir, A., Takeda, N., Kim, J. (2014). Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Molecules and Cells 37(9), 637-643. https://doi.org/10.14348/molcells.2014.0150 CR - Schouten, H., Nieuwenhuis, M., Schans, C., Niemeijer, A., Zuijlen, P. (2023). Considerations in determining the severity of burn scar contractures with focus on the knee joint. Journal of Burn Care & Research, 44(4), 810-816. https://doi.org/10.1093/jbcr/irad016 CR - Seoudy, W., Dien, S., Reheem, T., Elfangary, M., Erfan, M. (2022). Macrophages of the m1 and m2 types play a role in keloids pathogenesis. International Wound Journal, 20(1), 38-45. https://doi.org/10.1111/iwj.13834 CR - Sidgwick, G. and Bayat, A. (2011). Extracellular matrix molecules implicated in hypertrophic and keloid scarring. Journal of the European Academy of Dermatology and Venereology, 26(2), 141-152. https://doi.org/10.1111/j.1468-3083.2011.04200.x CR - Sidgwick, G. P., McGeorge, D., and Bayat, A. (2015). A comprehensive evidence-based review on the role of topicals and dressings in the management of skin scarring. Archives of Dermatological Research, 307(6), 461-477. https://doi.org/10.1007/s00403-015-1572-0 CR - Shi, H., Lin, C., Lin, B., Wang, Z., Zhang, H., Wu, F., Xiao, J. (2013). The anti-scar effects of basic fibroblast growth factor on the wound repair in vitro and in vivo. Plos One, 8(4), 1-10e59966. https://doi.org/10.1371/journal.pone.0059966 CR - Shibuya, Y., Okawa, H., Kondo, T., Khalil, D., Wang, L., Roca, Y., Jarrahy, R. (2022). Therapeutic downregulation of neuronal PAS domain 2 (npas2) promotes surgical skin wound healing. Elife, 11, 1-21. https://doi.org/10.7554/elife.71074 CR - Shin, H., Suk, S., Chae, S., Yoon, K., Kim, J. (2021). Early postoperative treatment of mastectomy scars using a fractional carbon dioxide laser: a randomized, controlled, split-scar, blinded study. Archives of Plastic Surgery, 48(4), 347-352. https://doi.org/10.5999/aps.2020.02495 CR - Shorka, D., Yemini, N., Shushan, G., Tokar, L., Benbenishty, J., and Woloski-Wruble, A. (2021). Body image and scar assessment: a longitudinal cohort analysis of cardiothoracic, neurosurgery and urology patients. Journal of Clinical Nursing, 31(17-18), 2605-2611. https://doi.org/10.1111/jocn.16083 CR - Song, H., Tan, J., Fu, Q., Huang, L., Ao, M. (2018). Comparative efficacy of intralesional triamcinolone acetonide injection during early and static stage of pathological scarring. Journal of Cosmetic Dermatology, 18(3), 874-878. https://doi.org/10.1111/jocd.12690 CR - Sun, M., He, Y., Zhou, T., Zhang, P., Gao, J., Lu, F. (2017). Adipose extracellular matrix/stromal vascular fraction gel secretes angiogenic factors and enhances skin wound healing in a murine model. Biomed Research International, 2017, 1-11. https://doi.org/10.1155/2017/3105780 CR - Surakunprapha, P., Winaikosol, K., Chowchuen, B., Punyavong, P., Jenwitheesuk, K., and Jenwitheesuk, K. (2020). A prospective randomized double-blind study of silicone gel plus herbal extracts versus placebo in pre-sternal hypertrophic scar prevention and amelioration. Heliyon, 6(5), e03883. https://doi.org/10.1016/j.heliyon.2020.e03883 CR - Suryanarayan, S., Budamakuntla, L., Khadri, S., and Sarvajnamurthy, S. (2014). Efficacy of autologous platelet-rich plasma in the treatment of chronic nonhealing leg ulcers. Plastic and Aesthetic Research, 1(2), 65-69. https://doi.org/10.4103/2347-9264.139703 CR - Süntar, İ, Çetinkaya, S., Panieri, E., Saha, S., Buttari, B., Saso, L. (2021). Regulatory role of nrf2 signaling pathway in wound healing process. Molecules 26(9), 2424. https://doi.org/10.3390/molecules26092424 CR - Takaya, K., Aramaki-Hattori, N., Sakai, S., Okabe, K., Asou, T., Kishi, K. (2022). Decorin inhibits dermal mesenchymal cell migration and induces scar formation. Plastic and Reconstructive Surgery Global Open, 10(4), e4245. https://doi.org/10.1097/gox.0000000000004245 CR - Tan, J., Zhou, J., Huang, L., Fu, Q., Ao, M., Yuan, L., Luo, G. (2020). Hypertrophic scar improvement by early intervention with ablative fractional carbon dioxide laser treatment. Lasers in Surgery and Medicine, 53(4), 450-457. https://doi.org/10.1002/lsm.23301 CR - Tan, Y., Zhang, M., Kong, Y., Zhang, F., Wang, Y., Huang, Y., Song, W., Li, Z., Hou, L., Liang, L., Guo, X., Liu, Q., Feng, Y., Zhang, C., Fu, X., Huang, S. (2023). Fibroblasts and endothelial cells interplay drives hypertrophic scar formation: insights from in vitro and in vivo models. Bioengineering & Translational Medicine, 9(2), 1-15. https://doi.org/10.1002/btm2.10630 CR - Tripathi, S., Soni, K., Agrawal, P., Gour, V., Mondal, R., Soni, V. (2020). Hypertrophic scars and keloids: a review and current treatment modalities. Biomedical Dermatology, 4(1), 1-11. https://doi.org/10.1186/s41702-020-00063-8 CR - Volk, S., Wang, Y., Mauldin, E., Liechty, K., Adams, S. (2011). Diminished type iii collagen promotes myofibroblast differentiation and increases scar deposition in cutaneous wound healing. Cells Tissues Organs, 194(1), 25-37. https://doi.org/10.1159/000322399 CR - Vukelic, S., Stojadinović, O., Pastar, I., Rabach, M., Krzyzanowska, A., Lebrun, E., Davis, S. C., Resnik, S., Brem, H., Tomic-Canic, M. (2011). Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. Journal of Biological Chemistry, 286 (12), 10265-10275. https://doi.org/10.1074/jbc.m110.188268 CR - Waibel, J., Wulkan, A., and Shumaker, P. (2013). Treatment of hypertrophic scars using laser and laser assisted corticosteroid delivery. Lasers in Surgery and Medicine, 45(3), 135-140. https://doi.org/10.1002/lsm.22120 CR - Walther, M., Vestweber, P. K., Kühn, S., Rieger, U. M., Schäfer, J., Münch, C., … and Windbergs, M. (2022). Bioactive insulin-loaded electrospun wound dressings for localized drug delivery and stimulation of protein expression associated with wound healing. Molecular Pharmaceutics, 20(1), 241-254. https://doi.org/10.1021/acs.molpharmaceut.2c00610 CR - Wang, P., Shu, B., Xu, Y., Zhu, J., Liu, J., Zhou, Z., Chen, L., Zhao, J., Liu, X., Qi, S., Xiong, K., Xie, J. (2017). Basic fibroblast growth factor reduces scar by inhibiting the differentiation of epidermal stem cells to myofibroblasts via the notch1/jagged1 pathway. Stem Cell Research & Therapy, 8(1), 1-13. https://doi.org/10.1186/s13287-017-0549-7 CR - Wang, L., Yang, J., Ran, B., Yang, X., Zheng, W., Long, Y., Jiang, X. (2017). Small molecular tgf-β1-inhibitor-loaded electrospun fibrous scaffolds for preventing hypertrophic scars. Acs Applied Materials & Interfaces, 9(38), 32545-32553. https://doi.org/10.1021/acsami.7b09796 CR - Wang, Wei, Yang, C., Wang, X. Y., Zhou, L., Lao, G., Liu, D., Wang, C., Hu, M., Zeng, T., Yan, L., Ren, M. (2018). Microrna-129 and -335 promote diabetic wound healing by inhibiting SP1-mediated MMP-9 expression. Diabetes 67 (8), 1627-1638. https://doi.org/10.2337/db17-1238 CR - Wang, H., Guo, B., Lin, S., Chang, P., Tao, K. (2019). Apigenin inhibits growth and migration of fibroblasts by suppressing fak signaling. Aging, 11(11), 3668-3678. https://doi.org/10.18632/aging.102006 CR - Wang, J., Liao, Y., Xia, J., Wang, Z., Mo, X., Feng, J., Cai, J. (2019). Mechanical micronization of lipoaspirates for the treatment of hypertrophic scars. Stem Cell Research & Therapy, 10(1). https://doi.org/10.1186/s13287-019-1140-1 CR - Wang, Z., Zhao, W., Cao, Y., Liu, Y., Sun, Q., Shi, P., Cai, J., Shen, X., Tan, W. (2020). The roles of inflammation in keloid and hypertrophic scars. Frontiers in Immunology, 11, 1-10. https://doi.org/10.3389/fimmu.2020.603187 CR - Wang, J., Wu, H., Peng, Y., Zhao, Y., Qin, Y., Zhang, Y., Xiao, Z. (2021). Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of pi3k/akt pathways. Journal of Nanobiotechnology, 19(1), 1-13. https://doi.org/10.1186/s12951-021-00942-0 CR - Fu, X., Wu, J. (2022). The clinical effectiveness and safety of using epidermal growth factor, fibroblast growth factor and granulocyte-macrophage colony stimulating factor as therapeutics in acute skin wound healing: a systematic review and meta-analysis. Burns &Amp; Trauma, 10. https://doi.org/10.1093/burnst/tkac002 CR - Wihastyoko, H. and Wuryanjono, W. (2022). The effectiveness of intradermal suture technique on hypertrophic scar prevention in rats. Jurnal Plastik Rekonstruksi, 9(1), 24-29. https://doi.org/10.14228/jprjournal.v9i1.335 CR - Williams, F., Herndon, D., Branski, L. (2014). Where we stand with human hypertrophic and keloid scar models. Experimental Dermatology, 23(11), 811-812. https://doi.org/10.1111/exd.12506 CR - Wong, V., Paterno, J., Sorkin, M., Glotzbach, J., Levi, K., Januszyk, M., Rustad, K. C., Longaker, M. D., Gurtner, G. (2011). Mechanical force prolongs acute inflammationviat‐cell‐dependent pathways during scar formation. The Faseb Journal, 25(12), 4498-4510. https://doi.org/10.1096/fj.10-178087 CR - Wong, V., Beasley, B., Zepeda, J., Dauskardt, R., Yock, P., Longaker, M., Gurtner, G. (2013). A mechanomodulatory device to minimize incisional scar formation. Advances in Wound Care, 2(4), 185-194. https://doi.org/10.1089/wound.2012.0396 CR - Wu, J., Duca, E., Espino, M., Gontzes, A., Cueto, I., Zhang, N., … and Guttman‐Yassky, E. (2020). Rna sequencing keloid transcriptome associates keloids with th2, th1, th17/th22, and jak3-skewing. Frontiers in Immunology, 11, 1-11. https://doi.org/10.3389/fimmu.2020.597741 CR - Xiao, Y., Fan, P., Lei, S., Qi, M., Yang, X. (2015). Mir‐138/peroxisome proliferator‐activated receptor β signaling regulates human hypertrophic scar fibroblast proliferation and movement in vitro. The Journal of Dermatology, 42(5), 485-495. https://doi.org/10.1111/1346-8138.12792 CR - Xiao, Y., Xu, D., Song, H., Shu, F., Pei, W., Yang, X., … and Xia, Z. (2019). Cuprous oxide nanoparticles reduces hypertrophic scarring by inducing fibroblast apoptosis. International Journal of Nanomedicine, Volume 14, 5989-6000. https://doi.org/10.2147/ijn.s196794 CR - Xu, J., Zhao, W., Fang, Q., Zhang, D., Hu, Y., Zheng, B., Tan, W. (2020). Co-transfection of hepatocyte growth factor and truncated tgf-β type ii receptor inhibit scar formation. Brazilian Journal of Medical and Biological Research, 53(1), 1-6. https://doi.org/10.1590/1414-431x20199144 CR - Yang, R., Qi, S., Shu, B., Ruan, S., Lin, Z., Yang, L., Shen, R., Zhang, F., Chen, X., Xie, J. (2016). Epidermal stem cells (escs) accelerate diabetic wound healing via the notch signalling pathway. Bioscience Reports, 36(4), 1-7. https://doi.org/10.1042/bsr20160034 CR - Yang, Bingxian, Yuxin Zheng, Binjun Yan, Hua-Li Cao, Lilla Landeck, Jiaqi Chen, Wei Li et al., 2020. "Suppressor of fused inhibits skin wound healing", Advances in Wound Care(5), 9:233-244. https://doi.org/10.1089/wound.2018.0890 CR - Yang, D., Li, M., Du, N. (2020). Effects of the circ_101238/mir 138 5p/CDK6 axis on proliferation and apoptosis keloid fibroblasts. Experimental and Therapeutic Medicine, 1995-2002. https://doi.org/10.3892/etm.2020.8917 Yannas, I., Tzeranis, D., So, P. (2017). Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation. Wound Repair and Regeneration, 25(2), 177-191. https://doi.org/10.1111/wrr.12516 CR - Yun, I., Kang, E., Ahn, H., Kim, Y., Rah, D., Roh, T., Yun, C. (2019). Effect of relaxin expression from an alginate gel-encapsulated adenovirus on scar remodeling in a pig model. Yonsei Medical Journal, 60(9), 854. https://doi.org/10.3349/ymj.2019.60.9.854 CR - Yuniati, R., Subchan, P., Riawan, W., Khrisna, M., Restiwijaya, M., Kusumaningrum, N., Nur, M. (2021). Topical ozonated virgin coconut oil improves wound healing and increases HSP90α, VEGF-A, EGF, BFGF and CD34 in diabetic ulcer mouse model of wound healing. F1000research, 9, 580. https://doi.org/10.12688/f1000research.22525.2 CR - Zhang, J., Guan, M., Xie, C., Luo, X., Zhang, Q., Xue, Y. (2014). Increased growth factors play a role in wound healing promoted by noninvasive oxygen-ozone therapy in diabetic patients with foot ulcers. Oxidative Medicine and Cellular Longevity, 2014, 1-8. https://doi.org/10.1155/2014/273475 CR - Zhang, X., Kang, X., Jin, L., Bai, J., Liu, W., and Wang, Z. (2018). Stimulation of wound healing using bioinspired hydrogels with basic fibroblast growth factor (bfgf). International Journal of Nanomedicine, Volume 13, 3897-3906. https://doi.org/10.2147/ijn.s168998 CR - Zhang, Z., Chen, J., Huang, J., Yan, W., Zhang, Y., Chen, X. (2018). Experimental study of 5-fluorouracil encapsulated ethosomes combined with co2 fractional laser to treat hypertrophic scar. Nanoscale Research Letters, 13(1), 1-12. https://doi.org/10.1186/s11671-017-2425-x CR - Zhang, Y., Liu, Y., Cai, B., Luo, C., Li, D., Wang, S., Luo, S. (2019). Improvement of surgical scars by early intervention with carbon dioxide fractional laser. Lasers in Surgery and Medicine, 52(2), 137-148. https://doi.org/10.1002/lsm.23129 CR - Zhai, X., Tang, Z., Ding, J., Lu, X. (2017). Expression of tgf-β1/mtor signaling pathway in pathological scar fibroblasts. Molecular Medicine Reports, 15(6), 3467-3472. https://doi.org/10.3892/mmr.2017.6437 CR - Zhao, W., Zhang, H., Li, R., Cui, R. (2023). Advances in immunomodulatory mechanisms of mesenchymal stem cells-derived exosome on immune cells in scar formation. International Journal of Nanomedicine, Volume 18, 3643-3662. https://doi.org/10.2147/ijn.s412717 UR - https://doi.org/10.52538/iduhes.1590063 L1 - http://dergipark.org.tr/tr/download/article-file/4388122 ER -