Skin biomechanics: a potential therapeutic intervention target to reduce scarring

Abstract

Pathological scarring imposes a major clinical and social burden worldwide. Human cutaneous wounds are responsive to mechanical forces and convert mechanical cues to biochemical signals that eventually promote scarring. To understand the mechanotransduction pathways in cutaneous scarring and develop new mechanotherapy approaches to achieve optimal scarring, the current study highlights the mechanical behavior of unwounded and scarred skin as well as intra-and extracellular mechanisms behind keloid and hypertrophic scars. Additionally, the therapeutic interventions that promote optimal scar healing by mechanical means at the molecular, cellular or tissue level are extensively reviewed. The current literature highlights the significant role of fibroblasts in wound contraction and scar formation via differentiation into myofibroblasts. Thus, understanding myofibroblasts and their responses to mechanical loading allows the development of new scar therapeutics. A review of the current clinical and preclinical studies suggests that existing treatment strategies only reduce scarring on a small scale after wound closure and result in poor functional and aesthetic outcomes. Therefore, the perspective of mechanotherapies needs to consider the application of both mechanical forces and biochemical cues to achieve optimal scarring. Moreover, early intervention is critical in wound management; thus, mechanoregulation should be conducted during the healing process to avoid scar maturation. Future studies should either consider combining mechanical loading (pressure) therapies with tension offloading approaches for scar management or developing more effective early therapies based on contraction-blocking biomaterials for the prevention of pathological scarring.

Keywords

Dermal fibrosis / Mechanotransduction / Pressure therapy / Tension therapy / Wound healing / Skin biomechanics

References

[1] Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med. 2007; 4: e234. doi: https://doi.org/10.1371/journal.pmed.0040234.

[2] Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999; 341: 738-46.

[3] Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008; 453: 314-21.

[4] Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2010; 126: 1172.

[5] Lee Y-S, Wysocki A, Warburton D, Tuan T-L. Wound healing in development. Birth Defects Res C Embryo Today: Reviews. 2012; 96: 213-22.

[6] Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle). 2015; 4: 560-82.

[7] Aarabi S, Bhatt KA, Shi Y, Paterno J, Chang EI, Loh SA, et al. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. FASEB J. 2007; 21: 3250-61.

[8] Cremers NAJ, Suttorp M, Gerritsen MM, Wong RJ, Run-van BC, van Dam GM, et al. Mechanical stress changes the complex interplay between HO-1, inflammation and fibrosis, during excisional wound repair. Front Med. 2015; 2: 86.

[9] Coolen NA, Schouten KC, Boekema BK, Middelkoop E, Ulrich MM. Wound healing in a fetal, adult, and scar tissue model: a comparative study. Wound Repair Regen. 2010; 18: 291-301.

[10] Lo DD, Zimmermann AS, Nauta A, Longaker MT, Lorenz HP. Scarless fetal skin wound healing update. Birth Defects Res C Embryo Today: Reviews. 2012; 96: 237-47.

[11] Hosseini M, Shafiee A. Engineering bioactive scaffolds for skin regeneration. Small. 2021; 17:e2101384. doi: https://doi.org/10.1002/smll.202101384.

[12] Barnes LA, Marshall CD, Leavitt T, Hu MS, Moore AL, Gonzalez JG, et al. Mechanical forces in cutaneous wound healing: emerging therapies to minimize scar formation. Adv Wound Care. 2018; 7: 47-56.

[13] Bayat A, McGrouther D, Ferguson M. Skin scarring. BMJ. 2003; 326: 88-92.

[14] Ud-Din S, Bayat A. Non-invasive objective devices for monitoring the inflammatory, proliferative and remodelling phases of cutaneous wound healing and skin scarring. Exp Dermatol. 2016; 25: 579-85.

[15] Evans ND, Oreffo RO, Healy E, Thurner PJ, Man YH. Epithelial mechanobiology, skin wound healing, and the stem cell niche. J Mech Behav Biomed Mater. 2013; 28: 397-409.

[16] Harn HI, Ogawa R, Hsu CK, Hughes MW, Tang MJ, Chuong CM. The tension biology of wound healing. Exp Dermatol. 2019; 28: 464-71.

[17] Herskovitz I, Hughes OB, Macquhae F, Rakosi A, Kirsner R. Epidermal skin grafting. Int Wound J. 2016; 3: 52-6.

[18] Ogawa R.Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis. Int J Mol Sci. 2017; 18: 606. doi: https://doi.org/10.3390/ijms18030606.

[19] Meyer M, McGrouther DA.A study relating wound tension to scar morphology in the pre-sternal scar using Langers technique. Br J Plast Surg. 1991; 44: 291-4.

[20] Wray RC. Force required for wound closure and scar appearance. Plast Reconstr Surg. 1983; 72: 380-2.

[21] Atkinson JA, McKenna KT, Barnett AG, McGrath DJ, Rudd M. A randomized, controlled trial to determine the efficacy of paper tape in preventing hypertrophic scar formation in surgical incisions that traverse Langer’s skin tension lines. Plast Reconstr Surg. 2005; 116: 1648-56.

[22] Clark JA, Cheng JC, Leung KS. Mechanical properties of normal skin and hypertrophic scars. Burns. 1996; 22: 443-6.

[23] Linares HA, Kischer CW, Dobrkovsky M, Larson DL. The histiotypic organization of the hypertrophic scar in humans. J Invest Dermatol. 1972; 59: 323-31.

[24] Agha R, Ogawa R, Pietramaggiori G, Orgill DP. A review of the role of mechanical forces in cutaneous wound healing. J Surg Res. 2011; 171: 700-8.

[25] Shafiee A, Cavalcanti AS, Saidy NT, Schneidereit D, Friedrich O, Ravichandran A, et al. Convergence of 3D printed biomimetic wound dressings and adult stem cell therapy. Biomaterials. 2021; 268: 120558. doi: https://doi.org/10.1016/j.biomaterials.2020.120558.

[26] On the anatomy and physiology of the skin. I. The cleavability of the cutis. (Translated from Langer, K. (1861). Zur Anatomie und Physiologie der haut. I. Uber die Spaltbarkeit der cutis. Sitzungsbericht der Mathematisch-naturwissenschaftlichen Classe der Kaiserlichen Academie der Wissenschaften, 44, 19.). Br J Plast Surg. 1978; 31, 1: 3:- 8.

[27] Silver FH, Siperko LM, Seehra GP. Mechanobiology of force transduction in dermal tissue. Skin Res Technol. 2003; 9: 3-23.

[28] Sidgwick GP, McGeorge D, Bayat A. A comprehensive evidence-based review on the role of topicals and dressings in the management of skin scarring. Arch Dermatol Res. 2015; 307: 461-77.

[29] Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care. 2015; 4: 119-36.

[30] Ireton JE, Unger JG, Rohrich RJ. The role of wound healing and its everyday application in plastic surgery: a practical perspective and systematic review. Plastic and Reconstructive Surgery Global Open. 2013; 1: e10-9.

[31] Papel ID. Facial plastic and reconstructive surgery. Otolaryngol Head Neck Surg. 1992; 106: 9. doi: https://doi.org/10.1177/019459989210600109.

[32] Roten SV, Bhat S, Bhawan J. Elastic fibers in scar tissue. J Cutan Pathol. 1996; 23: 37-42.

[33] Corr DT, Gallant-Behm CL, Shrive NG, Hart DA. Biomechanical behavior of scar tissue and uninjured skin in a porcine model. Wound Repair Regen. 2009; 17: 250-9.

[34] White WL, Brody GS, Glaser AA, Marangoni RD, Beckwith TG, Must JS, et al. Tensiometric studies of unwounded and wounded skin: results using a standardized testing method. Ann Surg. 1971; 173: 19-25.

[35] Thornton GM, Leask GP, Shrive NG, Frank CB. Early medial collateral ligament scars have inferior creep behaviour. J Orthop Res. 2000; 18: 238-46.

[36] Dunn MG, Silver FH, Swann DA. Mechanical analysis of hypertrophic scar tissue: structural basis for apparent increased rigidity. J Invest Dermatol. 1985; 84: 9-13.

[37] McHugh AA, Fowlkes BJ, Maevsky EI, Smith DJ, Jr, Rodriguez JL, Garner WL. Biomechanical alterations in normal skin and hypertrophic scar after thermal injury. J Burn Care Rehabil. 1997; 18: 104-8.

[38] Ogawa R, Okai K, Tokumura F, Mori K, Ohmori Y, Huang C, et al. The relationship between skin stretching/contraction and pathologic scarring: the important role of mechanical forces in keloid generation. Wound Repair Regen. 2012; 20: 149-57.

[39] Akaishi S, Akimoto M, Ogawa R, Hyakusoku H. The relationship between keloid growth pattern and stretching tension: visual analysis using the finite element method. Ann Plast Surg. 2008; 60: 445-51.

[40] Huang C, Akaishi S, Ogawa R. Mechanosignaling pathways in cutaneous scarring. Arch Dermatol Res. 2012; 304: 589-97.

[41] Dohi T, Padmanabhan J, Akaishi S, Than PA, Terashima M, Matsumoto NN, et al. The interplay of mechanical stress, strain, and stiffness at the keloid periphery correlates with increased Caveolin-1/ROCK signaling and scar progression. Plast Reconstr Surg. 2019; 144: 58e-67e. doi: https://doi.org/10.1097/PRS.0000000000005717.

[42] Knapik DM, Perera P, Nam J, Blazek AD, Rath B, Leblebicioglu B, et al. Mechanosignaling in bone health, trauma and inflammation. Antioxid Redox Signal. 2014; 20: 970-85.

[43] Marjoram RJ, Lessey EC, Burridge K. Regulation of RhoA activity by adhesion molecules and mechanotransduction. Curr Mol Med. 2014; 14: 199-208.

[44] Young SR, Gerard-O’Riley R, Kim JB, Pavalko FM. Focal adhesion kinase is important for fluid shear stress-induced mechanotransduction in osteoblasts. J Bone Miner Res. 2009; 24: 411-24.

[45] Alenghat FJ, Ingber DE. Mechanotransduction: all signals point to cytoskeleton, matrix, and integrins. Sci STKE. 2002; 12: pe6. doi: https://doi.org/10.1126/stke.2002.119.pe6.

[46] Geiger B, Spatz JP, Bershadsky AD.Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol. 2009; 10: 21-33.

[47] Sukharev S, Betanzos M, Chiang CS, Guy HR. The gating mechanism of the large mechanosensitive channel MscL. Nature. 2001; 409: 720-4.

[48] Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, et al. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol. 2006; 168: 1861-8.

[49] Chiquet M, Tunç-Civelek V, Sarasa-Renedo A. Gene regulation by mechanotransduction in fibroblasts. Appl Physiol Nutr Metab. 2007; 32: 967-73.

[50] Eckes B, Zweers MC, Zhang ZG, Hallinger R, Mauch C, Aumailley M, et al. Mechanical tension and integrin alpha 2 beta 1 regulate fibroblast functions. J Investig Dermatol Symp Proc. 2006; 11: 66-72.

[51] Kadi A, Fawzi-Grancher S, Lakisic G, Stoltz JF, Muller S. Effect of cyclic stretching and TGF-beta on the SMAD pathway in fibroblasts. Biomed Mater Eng. 2008; 18: S77-86.

[52] Khetan S, Guvendiren M, Legant WR, Cohen DM, Chen CS, Burdick JA. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat Mater. 2013; 12: 458-65.

[53] Yang C, Tibbitt MW, Basta L, Anseth KS. Mechanical memory and dosing influence stem cell fate. Nat Mater. 2014; 13: 645-52.

[54] Das T, Safferling K, Rausch S, Grabe N, Boehm H, Spatz JP. A molecular mechanotransduction pathway regulates collective migration of epithelial cells. Nat Cell Biol. 2015; 17: 276-87.

[55] Januszyk M, Wong VW, Bhatt KA, Vial IN, Paterno J, Longaker MT, et al. Mechanical offloading of incisional wounds is associated with transcriptional downregulation of inflammatory pathways in a large animal model. Organ. 2014; 10: 186-93.

[56] Kenny FN, Connelly JT. Integrin-mediated adhesion and mechano-sensing in cutaneous wound healing. Cell Tissue Res. 2015; 360: 571-82.

[57] Takada H, Furuya K, Sokabe M. Mechanosensitive ATP release from hemichannels and Ca²⁺ influx through TRPC6 accelerate wound closure in keratinocytes. J Cell Sci. 2014; 127: 4159-71.

[58] Wang J, Zhang Y, Zhang N, Wang C, Herrler T, Li Q. An updated review of mechanotransduction in skin disorders: transcriptional regulators, ion channels, and microRNAs. Cell Mol Life Sci. 2015; 72: 2091-106.

[59] Wong VW, Longaker MT, Gurtner GC. Soft tissue mechanotransduction in wound healing and fibrosis. Semin Cell Dev Biol. 2012; 23: 981-6.

[60] Wong VW, Rustad KC, Akaishi S, Sorkin M, Glotzbach JP, Januszyk M, et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med. 2011; 18: 148-52.

[61] Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci. 2017; 18: 1545. doi: https://doi.org/10.3390/ijms18071545.

[62] Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev. 2019; 99: 665-706.

[63] Schulz JN, Plomann M, Sengle G, Gullberg D, Krieg T, Eckes B. New developments on skin fibrosis-essential signals emanating from the extracellular matrix for the control of myofibroblasts. Matrix Biol. 2018; 69: 522-32.

[64] Tan J, Wu J. Current progress in understanding the molecular pathogenesis of burn scar contracture. Burns Trauma. 2017; 5: 14. https://doi.org/10.1186/s41038-017-0080-1.

[65] Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science. 2015; 348: aaa2151. doi: https://doi.org/10.1126/science.aaa2151.

[66] Mascharak S, Desjardins-Park HE, Davitt MF, Griffin M, Borrelli MR, Moore AL, et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science. 2021; 372: eaba2374. doi: https://doi.org/10.1126/science.aba2374.

[67] Panciera T, Azzolin L, Cordenonsi M, Piccolo S. Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol. 2017; 18: 758-70.

[68] Clarke DL, Carruthers AM, Mustelin T, Murray LA. Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes. Fibrogenesis Tissue Repair. 2013; 6: 1755-536.

[69] Ishise H, Larson B, Hirata Y, Fujiwara T, Nishimoto S, Kubo T, et al. Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation. Sci Rep. 2015; 5: 11620. doi: https://doi.org/10.1038/srep11620.

[70] Takahashi N, Mori Y. TRP channels as sensors and signal integrators of redox status changes. Front Pharmacol. 2011; 2: 58. doi: https://doi.org/10.3389/fphar.2011.00058.

[71] Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010; 330: 55-60.

[72] Giampaolo S, Wójcik G, Klein-Hessling S, Serfling E, Patra AK. NFAT-mediated defects in erythropoiesis cause anemia in Il2(−/−) mice. Oncotarget. 2018; 9: 9632-44.

[73] Aglialoro F, Abay A, Yagci N, Rab MAE, Kaestner L, van Wijk R, et al. Mechanical stress induces Ca2+−dependent signal transduction in erythroblasts and modulates erythropoiesis. Int J Mol Sci. 2021; 22: 955. doi: https://doi.org/10.3390/ijms22020955.

[74] He J, Fang B, Shan S, Xie Y. Mechanical stretch promotes hypertrophic scars formation through mechanically activated ion channel Piezo1. Plastic and Reconstructive Surgery Global Open. 2020; 8: 144-5.

[75] He J, Fang B, Shan S, Xie Y, Wang C, Zhang Y, et al. Mechanical stretch promotes hypertrophic scar formation through mechanically activated cation channel Piezo1. Cell Death Dis. 2021; 12: 226. doi: https://doi.org/10.1038/s41419-021-03481-6.

[76] Derderian CA, Bastidas N, Lerman OZ, Bhatt KA, Lin SE, Voss J, et al. Mechanical strain alters gene expression in an in vitro model of hypertrophic scarring. Ann Plast Surg. 2005; 55: 69-75.

[77] Santos A, Lagares D. Matrix stiffness: the conductor of organ fibrosis. Curr Rheumatol Rep. 2018; 20: 2. doi: https://doi.org/10.1007/s11926-018-0710-z.

[78] Katsumi A, Orr AW, Tzima E, Schwartz MA. Integrins in mechanotransduction. J Biol Chem. 2004; 279: 12001-4.

[79] Paterno J, Vial IN, Wong VW, Rustad KC, Sorkin M, Shi Y, et al. Akt-mediated mechanotransduction in murine fibroblasts during hypertrophic scar formation. Wound Repair Regen. 2011; 19: 49-58.

[80] Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci. 2003; 116: 1409-16.

[81] Walraven M, Hinz B. Therapeutic approaches to control tissue repair and fibrosis: extracellular matrix as a game changer. Matrix Biol. 2018; 72: 205-24.

[82] Rodrigues M, Yates CC, Nuschke A, Griffith L, Wells A. The matrikine tenascin-C protects multipotential stromal cells/mesenchymal stem cells from death cytokines such as FasL. Tissue Eng Part A. 2013; 19: 1972-83.

[83] Januszyk M, Kwon SH, Wong VW, Padmanabhan J, Maan ZN, Whittam AJ, et al. The role of focal adhesion kinase in keratinocyte fibrogenic gene expression. Int J Mol Sci. 2017; 18: 1915. doi: https://doi.org/10.3390/ijms18091915.

[84] Liu W, Ma K, Kwon SH, Garg R, Patta YR, Fujiwara T, et al. The abnormal architecture of healed diabetic ulcers is the result of FAK degradation by Calpain 1. J Invest Dermatol. 2017; 137: 1155-65.

[85] Berman B, Maderal A, Raphael B. Keloids and hypertrophic scars: pathophysiology, classification, and treatment. Dermatol Surg. 2017; 43: S3-18.

[86] Khansa I, Harrison B, Janis JE. Evidence-based scar management: how to improve results with technique and technology. Plast Reconstr Surg. 2016; 138: 165S-178S.

[87] Lichtman MK, Otero-Vinas M, Falanga V. Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis. Wound Repair Regen. 2016; 24: 215-22.

[88] Van De Water L, Varney S, Tomasek JJ. Mechanoregulation of the myofibroblast in wound contraction, scarring, and fibrosis: opportunities for new therapeutic intervention. Adv Wound Care. 2013; 2: 122-41.

[89] Shah M, Foreman DM, Ferguson MW. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci. 1995; 108: 985-1002.

[90] Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U. Skin wound healing: an update on the current knowledge and concepts. Eur Surg Res. 2017; 58: 81-94.

[91] Lü D, Li Z, Gao Y, Luo C, Zhang F, Zheng L, et al. β1 integrin signaling in asymmetric migration of keratinocytes under mechanical stretch in a co-cultured wound repair model. Biomed Eng Online. 2016; 15: 130. doi: https://doi.org/10.1186/s12938-016-0263-1.

[92] Reichelt J. Mechanotransduction of keratinocytes in culture and in the epidermis. Eur J Cell Biol. 2007; 86: 807-16.

[93] Wang J, Hori K, Ding J, Huang Y, Kwan P, Ladak A, et al. Toll-like receptors expressed by dermal fibroblasts contribute to hypertrophic scarring. J Cell Physiol. 2011; 226: 1265-73.

[94] Zhou J, Wang J, Zhang N, Zhang Y, Li Q. Identification of biomechanical force as a novel inducer of epithelial-mesenchymal transition features in mechanical stretched skin. Am J Transl Res. 2015; 7: 2187-98.

[95] Hosseini M, Brown J, Shafiee A. Strategies to induce blood vessel ingrowth into skin grafts and tissue-engineered substitutes. Tissue Eng. Part C Methods. 2022; 28: 113-26.

[96] Jones EA. Mechanical factors in the development of the vascular bed. Respir Physiol Neurobiol. 2011; 178: 59-65.

[97] Lancerotto L, Orgill DP. Mechanoregulation of angiogenesis in wound healing. Adv. Wound Care. 2014; 3: 626-34.

[98] Pietramaggiori G, Liu P, Scherer SS, Kaipainen A, Prsa MJ, Mayer H, et al. Tensile forces stimulate vascular remodeling and epidermal cell proliferation in living skin. Ann Surg. 2007; 246: 896-902.

[99] Giatsidis G, Cheng L, Facchin F, Haddad A, Lujan-Hernandez J, Lancerotto L, et al. Moderate-intensity intermittent external volume expansion optimizes the soft-tissue response in a murine model. Plast Reconstr Surg. 2017; 139: 882-90.

[100] Ogawa R, Akaishi S. Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis-keloids and hypertrophic scars may be vascular disorders. Med Hypotheses. 2016; 96: 51-60.

[101] Shojaei S, Tafazzoli-Shahdpour M, Shokrgozar MA, Haghighipour N. Effects of mechanical and chemical stimuli on differentiation of human adipose-derived stem cells into endothelial cells. Int J Artif Organs. 2013; 36: 663-73.

[102] Shoham N, Gottlieb R, Sharabani-Yosef O, Zaretsky U, Benayahu D, Gefen A.Static mechanical stretching accelerates lipid production in 3T3-L1 adipocytes by activating the MEK signaling pathway. Am J Physiol Cell Physiol. 2012; 302: C429-41. doi: https://doi.org/10.1152/ajpcell.00167.2011.

[103] Tanabe Y, Koga M, Saito M, Matsunaga Y, Nakayama K. Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated downregulation of PPARgamma2. J Cell Sci. 2004; 117: 3605-14.

[104] Verhaegen PD, Schouten HJ, Tigchelaar-Gutter W, van Marle J, van Noorden CJ, Middelkoop E, et al. Adaptation of the dermal collagen structure of human skin and scar tissue in response to stretch: an experimental study. Wound Repair Regen. 2012; 20: 658-66.

[105] Middelkoop E, Monstrey S, Teot L, Vranckx JJ. Scar management practical guidelines. Maca-Cloetens. 2011; 1-109.

[106] Mustoe TA.Evolution of silicone therapy and mechanism of action in scar management. Aesthet Plast Surg. 2008; 32: 82-92.

[107] Signorini M, Clementoni MT. Clinical evaluation of a new self-drying silicone gel in the treatment of scars: a preliminary report. Aesthet Plast Surg. 2007; 31: 183-7.

[108] Choi J, Lee EH, Park SW, Chang H. Regulation of transforming growth factor β1, platelet-derived growth factor, and basic fibroblast growth factor by silicone gel sheeting in early-stage scarring. Arch Plast Surg. 2015; 42: 20-7.

[109] Kuhn MA, Moffit MR, Smith PD, Lyle WG, Ko F, Meltzer DD, et al. Silicone sheeting decreases fibroblast activity and downregulates TGFbeta2 in hypertrophic scar model. Int J Surg Investig. 2001; 2: 467-74.

[110] Akaishi S, Akimoto M, Hyakusoku H, Ogawa R. The tensile reduction effects of silicone gel sheeting. Plast Reconstr Surg. 2010; 126: 109e-111e. doi: https://doi.org/10.1097/PRS.0b013e3181df7073.

[111] Linares HA, Larson DL, Willis-Galstaun BA. Historical notes on the use of pressure in the treatment of hypertrophic scars or keloids. Burns. 1993; 19: 17-21.

[112] Atiyeh BS. Nonsurgical management of hypertrophic scars: evidence-based therapies, standard practices, and emerging methods. Aesthet Plast Surg. 2007; 31: 468-92.

[113] Gauglitz GG.Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol. 2013; 6: 103-14.

[114] Gold MH, Berman B, Clementoni MT, Gauglitz GG, Nahai F, Murcia C. Updated international clinical recommendations on scar management: part 1-evaluating the evidence. Dermatol Surg. 2014; 40: 817-24.

[115] Nast A, Eming S, Fluhr J, Fritz K, Gauglitz G, Hohenleutner S, et al. German S2k guidelines for the therapy of pathological scars (hypertrophic scars and keloids). J Dtsch Dermatol Ges. 2012; 10: 747-62.

[116] Engrav LH, Heimbach DM, Rivara FP, Moore ML, Wang J, Carrougher GJ, et al. 12-Year within-wound study of the effectiveness of custom pressure garment therapy. Burns. 2010; 36: 975-83.

[117] Shin TM, Bordeaux JS. The role of massage in scar management: a literature review. Dermatol Surg. 2012; 38: 414-23.

[118] Smith FR. Causes of and treatment options for abnormal scar tissue. J Wound Care. 2005; 14: 49-52.

[119] Katz B. Silastic gel sheeting is found to be effective in scar therapy. Cosmet Dermatol. 1992; 6: 1-3.

[120] Puzey G. The use of pressure garments on hypertrophic scars. J Tissue Viability. 2002; 12: 11-5.

[121] Costa AM, Peyrol S, Pôrto LC, Comparin JP, Foyatier JL, Desmoulière A. Mechanical forces induce scar remodeling. Study in non-pressure-treated versus pressure-treated hypertrophic scars. Am J Pathol. 1999; 155: 1671-9.

[122] Gurtner GC, Dauskardt RH, Wong VW, Bhatt KA, Wu K, Vial IN, et al. Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies. Ann Surg. 2011; 254: 217-25.

[123] Tollefson TT, Kamangar F, Aminpour S, Lee A, Durbin-Johnson B, Tinling S. Comparison of effectiveness of silicone gel sheeting with microporous paper tape in the prevention of hypertrophic scarring in a rabbit model. Arch Facial Plast Surg. 2012; 14: 45-51.

[124] Yannas IV, Tzeranis DS. Mammals fail to regenerate organs when wound contraction drives scar formation. NPJ Regen Med. 2021; 6: 39. doi: https://doi.org/10.1038/s41536-021-00149-9.

[125] Yannas IV, Tzeranis DS, So PTC. Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation. Wound Repair Regen. 2017; 25: 177-91.

[126] Yannas IV, Lee E, Orgill DP, Skrabut EM, Murphy GF. Synthesis and characterization of a model extracellular matrix that induces partial regeneration of adult mammalian skin. Proc Natl Acad Sci U S A. 1989; 86: 933-7.

[127] Dong Y, Zheng Y, Zhang K, Yao Y, Wang L, Li X, et al. Electrospun nanofibrous materials for wound healing. Advanced Fiber Materials. 2020; 2: 212-27.

[128] Wan X, Zhao Y, Li Z, Li L. Emerging polymeric electrospun fibers: from structural diversity to application in flexible bioelectronics and tissue engineering. Exp Dermatol. 2022; 2: 20210029.

[129] Elliot D, Cory-Pearce R, Rees GM. The behaviour of presternal scars in a fair-skinned population. Ann R Coll Surg Engl. 1985; 67: 238-40.

[130] Lim AF, Weintraub J, Kaplan EN, Januszyk M, Cowley C, McLaughlin P, et al. The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial. Plast Reconstr Surg. 2014; 133: 398-405.

[131] Sommerlad B, Creasey J. The stretched scar: a clinical and histological study. Br J Plast Surg. 1978; 31: 34-45.

[132] Rosengren H, Askew DA, Heal C, Buettner PG, Humphreys WO, Semmens LA. Does taping torso scars following dermatologic surgery improve scar appearance? Dermatol Pract Concept. 2013; 3: 75-83.

[133] de Oliveira GV, Nunes TA, Magna LA, Cintra ML, Kitten GT, Zarpellon S, et al. Silicone versus nonsilicone gel dressings: a controlled trial. Dermatol Surg. 2001; 27: 721-6.

[134] Longaker MT, Rohrich RJ, Greenberg L, Furnas H, Wald R, Bansal V, et al. A randomized controlled trial of the embrace advanced scar therapy device to reduce incisional scar formation. Plast Reconstr Surg. 2014; 134: 536-46.