Clinical and Molecular Insights into Hypertrophic Scars and Keloids: A Literature Review

Main Article Content

Naina Banun Turobi
Fadel Rahman
Nathasya Fernanda
Ahmad Fawzy

Abstract

Background: Hypertrophic scars and keloids represent two distinct forms of abnormal wound healing, characterized by excessive fibrous tissue formation. Despite their prevalence, the pathophysiological mechanisms underlying their development and persistence remain incompletely understood. This literature review synthesizes current clinical and molecular insights into hypertrophic scars and keloids, aiming to highlight differences in their etiology, pathogenesis, and therapeutic responses.


Methods: A comprehensive review of the literature was conducted, focusing on articles that provided significant insights into the clinical manifestations, genetic predispositions, molecular pathways, and treatment strategies related to hypertrophic scars and keloids. Experimental studies and clinical trials were included to encompass a wide range of data sources.


Results: Hypertrophic scars are confined to the original wound boundary and may regress over time, whereas keloids extend beyond the wound margins and do not regress. Clinically, hypertrophic scars and keloids differ in their appearance, texture, and predilection sites. At the molecular level, these differences are underscored by distinct profiles of cytokine expression, growth factor activity, and extracellular matrix composition. Genetic studies have identified several predisposing factors, including specific gene mutations and polymorphisms. Treatment strategies vary; however, intralesional corticosteroids remain the first-line treatment for both conditions. Emerging therapies targeting specific molecular pathways offer potential for improved outcomes.


Conclusion: Hypertrophic scars and keloids are complex conditions with distinct clinical and molecular characteristics. Understanding these differences is crucial for developing targeted and effective therapies. Future research should focus on unraveling the genetic basis of these conditions and exploring novel therapeutic targets. Enhanced knowledge of the pathogenic mechanisms will facilitate the advancement of personalized medicine approaches in the management of hypertrophic scars and keloids.

Article Details

How to Cite
Turobi, N. B., Rahman, F., Fernanda, N., & Fawzy, A. (2024). Clinical and Molecular Insights into Hypertrophic Scars and Keloids: A Literature Review. International Journal of Medical Science and Clinical Research Studies, 4(03), 387–399. https://doi.org/10.47191/ijmscrs/v4-i03-06
Section
Articles

References

I. Jeschke MG, Wood FM, Middelkoop E, Bayat A, Teot L, Ogawa R, Gauglitz GG. Scars. Nature Reviews Disease Primers. 2023 Nov 16;9(1):64.

II. Shirakami E, Yamakawa S, Hayashida K. Strategies to prevent hypertrophic scar formation: a review of therapeutic interventions based on molecular evidence. Burns & trauma. 2020;8:tkz003

III. Shan M, Wang Y. Viewing keloids within the immune microenvironment. American Journal of Translational Research. 2022;14(2):718.

IV. Zhang M, Chen H, Qian H, Wang C. Characterization of the skin keloid microenvironment. Cell Communication and Signaling. 2023 Aug 16;21(1):207.

V. Betarbet U, et al. Keloids: A review of etiology, prevention, and treatment. Journal of Clinical Aesthetic Dermatology. 2020;13:33

VI. Yin, Q., Wolkerstorfer, A., Lapid, O., Niessen, F. B., Van Zuijlen, P. P., & Gibbs, S. (2023). The jak–stat pathway in keloid pathogenesis: A systematic review with qualitative synthesis. Experimental Dermatology, 32(5), 588–598. https://doi.org/10.1111/exd.14747

VII. Wardani FA, Peradanakusuma DS, Indramaya DM. Profile of Working-Age Patients with Keloid and Hypertrophic Scar at Dr. Soetomo General Hospital Surabaya in 2014-2017. JUXTA: Jurnal Ilmiah Mahasiswa Kedokteran Universitas Airlangga. 2021;12(2):77

VIII. Barone N, Safran T, Vorstenbosch J, Davison PG, Cugno S, Murphy AM. Current advances in hypertrophic scar and keloid management. InSeminars in Plastic Surgery 2021 Jul 15 (Vol. 35, No. 03, pp. 145-152). 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA: Thieme Medical Publishers, Inc.

IX. Mekeres GM, Voiţă-Mekereş F, Tudoran C, Buhaş CL, Tudoran M, Racoviţă M, Voiţă NC, Pop NO, Marian M. Predictors for estimating scars’ internalization in victims with post-traumatic scars versus patients with postsurgical scars. InHealthcare 2022 Mar 16 (Vol. 10, No. 3, p. 550). MDPI.

X. Liu AH, Sun XL, Liu DZ, Xu F, Feng SJ, Zhang SY, Li LZ, Zhou JL, Wang YT, Zhang L, Lin X. Epidemiological and clinical features of hypertrophic scar and keloid in Chinese college students: A university-based cross-sectional survey. Heliyon. 2023 Apr 1;9(4).

XI. Wu J, Zou J, Yang Q, Wang H, Tian H, Chen L, Ji Z, Zheng D, Li Z, Xie Y. The effects of scar in psychological disorder: A bibliometric analysis from 2003 to 2022. International Wound Journal. 2024 Jan;21(1):e14373.

XII. Limandjaja GC, Niessen FB, Scheper RJ, Gibbs S. The keloid disorder: heterogeneity, histopathology, mechanisms and models. Frontiers in cell and developmental biology. 2020 May 26;8:360.

XIII. Tripathi S, Soni K, Agrawal P, Gour V, Mondal R, Soni V. Hypertrophic scars and keloids: a review and current treatment modalities. Biomedical Dermatology. 2020 May 20;4(1):11.

XIV. Limandjaja GC, Niessen FB, Scheper RJ, Gibbs S. Hypertrophic scars and keloids: Overview of the evidence and practical guide for differentiating between these abnormal scars. Experimental Dermatology. 2021 Jan;30(1):146-61.

XV. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Molecular medicine. 2011 Jan;17(1):113-25.

XVI. Garg SP, Weissman JP, Reddy NK, Varghese J, Ellis MF, Kim JY, Galiano RD. Patient-reported Outcomes of Scar Impact: Comparing of Abdominoplasty, Breast Surgery, and Facial Surgery Patients. Plastic and Reconstructive Surgery Global Open. 2022 Oct;10(10).

XVII. Kennedy DL, Chism-Balangue T, Furniss D. Reporting of scar outcomes in the hand and wrist; a state-of-the-art literature review. BMC musculoskeletal disorders. 2023 Dec;24(1):1-1.

XVIII. Huang, C., & Ogawa, R. 2021. Keloidal pathophysiology: Current notions. Scars, Burns & Healing, 7, 205951312098032.

XIX. Delaleu, J., Charvet, E., & Petit, A. (2023). Keloid disease: Review with clinical atlas. part I: Definitions, history, epidemiology, clinics and diagnosis. Annales de Dermatologie et de Vénéréologie, 150(1), 3–15.

https://doi.org/10.1016/j.annder.2022.08.010

XX. O'Boyle CP, Shayan-Arani H, Hamada MW. Intralesional cryotherapy for hypertrophic scars and keloids: a review. Scars Burn Heal. 2017 Jan-Dec;3:2059513117702162

XXI. McGinty S, Siddiqui WJ. Keloid. 2024.StatPearls. Treasure Island (FL): StatPearls Publishing

XXII. Delaleu, J., Charvet, E., & Petit, A. (2023). Keloid disease: Review with clinical atlas. part I: Definitions, history, epidemiology, clinics and diagnosis. Annales de Dermatologie et de Vénéréologie, 150(1), 3–15.

XXIII. Fayzullin A, Ignatieva N, Zakharkina O, Tokarev M, Mudryak D, Khristidis Y, Balyasin M, Kurkov A, Churbanov S, Dyuzheva T, Timashev P. Modeling of old scars: histopathological, biochemical and thermal analysis of the scar tissue maturation. Biology. 2021 Feb 9;10(2):136.

XXIV. Yang S, Sun Y, Geng Z, Ma K, Sun X, Fu X. Abnormalities in the basement membrane structure promote basal keratinocytes in the epidermis of hypertrophic scars to adopt a proliferative phenotype. International journal of molecular medicine. 2016 May 1;37(5):1263-73.

XXV. Huang C, Murphy GF, Akaishi S, Ogawa R. Keloids and hypertrophic scars: update and future directions. Plastic and reconstructive surgery Global open. 2013 Jul;1(4).

XXVI. Zhu Z, Ding J, Tredget EE. The molecular basis of hypertrophic scars. Burns & trauma. 2016 Dec 1;4.

XXVII. Mony MP, Harmon KA, Hess R, Dorafshar AH, Shafikhani SH. An Updated Review of Hypertrophic Scarring. Cells. 2023 Feb 21;12(5):678.

XXVIII. Čoma M, Fröhlichová L, Urban L, Zajíček R, Urban T, Szabo P, Novák Š, Fetissov V, Dvořánková B, Smetana Jr K, Gál P. Molecular changes underlying hypertrophic scarring following burns involve specific deregulations at all wound healing stages (inflammation, proliferation and maturation). International Journal of Molecular Sciences. 2021 Jan 18;22(2):897.

XXIX. Amjadian S, Moradi S, Mohammadi P. The emerging therapeutic targets for scar management: Genetic and epigenetic landscapes. Skin Pharmacology and Physiology. 2022 Sep 20;35(5):247-65.

XXX. Nabai L, Pourghadiri A, Ghahary A. Hypertrophic scarring: current knowledge of predisposing factors, cellular and molecular mechanisms. Journal of Burn Care & Research. 2020 Jan 30;41(1):48-56.

XXXI. Lingzhi Z, Meirong L, Xiaobing F. Biological approaches for hypertrophic scars. International wound journal. 2020 Apr;17(2):405-18.

XXXII. Wang ZC, Zhao WY, Cao Y, Liu YQ, Sun Q, Shi P, Cai JQ, Shen XZ, Tan WQ. The roles of inflammation in keloid and hypertrophic scars. Frontiers in immunology. 2020 Dec 4;11:603187.

XXXIII. Lian N, Li T. Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications. Biomedicine & Pharmacotherapy. 2016 Dec 1;84:42-50.

XXXIV. Lee DE, Trowbridge RM, Ayoub NT, Agrawal DK. High-mobility group box protein-1, matrix metalloproteinases, and vitamin D in keloids and hypertrophic scars. Plastic and Reconstructive Surgery Global Open. 2015 Jun;3(6).

XXXV. Keskin ES, Keskin ER, Öztürk MB, Çakan D. The effect of MMP-1 on wound healing and scar formation. Aesthetic plastic surgery. 2021 Dec;45:2973-9.

XXXVI. Zhang Y, Hong WL, Li ZM, Zhang QY, Zeng K. The mechanism of miR-222 targets matrix metalloproteinase 1 in regulating fibroblast proliferation in hypertrophic scars. Aesthetic Plastic Surgery. 2021 Apr;45:749-57.

XXXVII. Limandjaja, G. C., Niessen, F. B., Scheper, R. J., & Gibbs, S. (2020). The keloid disorder: Heterogeneity, histopathology, mechanisms and models. Frontiers in Cell and Developmental Biology, https://doi.org/10.3389/fcell.2020.00360

XXXVIII. Glass, I. I. D. A. (2017). Current understanding of the genetic causes of keloid formation. J. Investig. Dermatol. Symp. Proc. 18, S50–S53.

doi: 10.1016/j.jisp.2016.10.024

XXXIX. Shih, B., and Bayat, A. (2010). Genetics of keloid scarring. Arch. Dermatol. Res. 302, 319–339. doi: 10.1007/s00403-009-1014-y

XL. Hosseini M, Brown J, Khosrotehrani K, Bayat A, Shafiee A. Skin biomechanics: a potential therapeutic intervention target to reduce scarring. Burns & trauma. 2022;10:tkac036.

XLI. Barnes LA, Marshall CD, Leavitt T, Hu MS, Moore AL, Gonzalez JG, Longaker MT, Gurtner GC. Mechanical forces in cutaneous wound healing: emerging therapies to minimize scar formation. Advances in wound care. 2018 Feb 1;7(2):47-56.

XLII. He J, Fang B, Shan S, Xie Y, Wang C, Zhang Y, Zhang X, Li Q. Mechanical stretch promotes hypertrophic scar formation through mechanically activated cation channel Piezo1. Cell death & disease. 2021 Mar 1;12(3):226.

XLIII. Wynn MO. The impact of infection on the four stages of acute wound healing: An overview. Wounds UK. 2021 Jun 9;17(2).

XLIV. Wilgus TA. Inflammation as an orchestrator of cutaneous scar formation: A review of the literature. Plastic and aesthetic research. 2020;7.

XLV. Kim EY, Hussain A, Khachemoune A. Evidence-based management of keloids and hypertrophic scars in dermatology. Archives of dermatological research. 2023 Aug;315(6):1487-95.

XLVI. Sheng M, Chen Y, Li H, Zhang Y, Zhang Z. The application of corticosteroids for pathological scar prevention and treatment: current review and update. Burns & Trauma. 2023;11:tkad009.

XLVII. Oosterhoff TC, Beekman VK, van der List JP, Niessen FB. Laser treatment of specific scar characteristics in hypertrophic scars and keloid: a systematic review. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2021 Jan 1;74(1):48-64.

XLVIII. Elazhary, E., Abd Al-Salam, F., Abd El-Hafiz, H., & Maghraby, H. (2022). Updates on Keloid Scar Pathogenesis, assessment and treatment modalities. Journal of Recent Advances in Medicine, 3(1), 75–86. https://doi.org/10.21608/jram.2021.82892.1123.

XLIX. Tian F, Jiang Q, Chen J, Liu Z. Silicone gel sheeting for treating keloid scars. Cochrane Database of Systematic Reviews 2023,Issue 1. Art. No.: CD013878.

DOI: 10.1002/14651858.CD013878.pub2.

L. Sutheno, A. 2021. Keloid after orthopedic surgery: prevention, current therapy modalities, and emerging therapies modalities. Bali Medical Journal 10(1): 225-228.

DOI: 10.15562/bmj.v10i1.2264

LI. Li K, Nicoli F, Cui C, Xi WJ, Al-Mousawi A, Zhang Z, Balzani A, Neill L, Sorge R, Tong Y, Zhang Y. Treatment of hypertrophic scars and keloids using an intralesional 1470 nm bare-fibre diode laser: a novel efficient minimally-invasive technique. Scientific Reports. 2020 Dec 10;10(1):21694.

LII. Vorstandlechner V, Laggner M, Copic D, Klas K, Direder M, Chen Y, Golabi B, Haslik W, Radtke C, Tschachler E, Hötzenecker K. The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation. Nature communications. 2021 Oct 29;12(1):6242.

LIII. Schmieder SJ, Ferrer-Bruker SJ. Hypertrophic Scarring. [Updated 2023 Sep 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls

LIV. Amini-Nik S, Yousuf Y, Jeschke MG. Scar management in burn injuries using drug delivery and molecular signaling: current treatments and future directions. Advanced drug delivery reviews. 2018 Jan 1;123:135-54.

LV. Dastagir K, Obed D, Bucher F, Hofmann T, Koyro KI, Vogt PM. Non-invasive and surgical modalities for scar management: a clinical algorithm. Journal of Personalized Medicine. 2021 Nov 29;11(12):1259.

LVI. Arno, A. I., Gauglitz, G. G., Barret, J. P., & Jeschke, M. G. (2014). Up-to-date approach to manage keloids and hypertrophic scars: A useful guide. Burns, 40(7), 1255–1266.

https://doi.org/10.1016/j.burns.2014.02.011

LVII. Lee HJ, Jang YJ. Recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids. Int J Mol Sci. 2018;19(3):1–19.