Hypertrophic Scarring and Keloids: Epidemiology, Molecular Pathogenesis, and Therapeutic Interventions

Abstract

Wound healing is a complex, multicellular process that is essential for restoring tissue integrity after injury. In a subset of individuals, however, this process becomes dysregulated, culminating in hypertrophic scars or keloids—fibroproliferative disorders marked by excessive extracellular matrix deposition and prolonged inflammation. Although these lesions differ clinically, both share overlapping molecular mechanisms involving aberrant activation of the TGF-β, Intergrin-FAK, and Wnt/β-catenin pathways. Recent insights from single-cell and multiomics technologies have revealed profound heterogeneity within scar-forming fibroblast populations and highlighted the modulatory roles of immune cells, genetic predispositions, and anatomical tension. However, despite increasing mechanistic understanding, current interventions—including surgery, corticosteroids, and laser therapy—are limited by high recurrence rates and variable efficacy. Emerging strategies now target fibroblast plasticity, inflammatory circuits, and biomechanical feedback via tools such as gene editing, immune modulation, and smart biomaterials. This review integrates advances across epidemiology, molecular signaling, and therapeutic innovation, underscoring the need for personalized, multitargeted approaches. Ultimately, transforming pathological scarring from a persistent clinical burden into a regenerative opportunity will depend on interdisciplinary collaboration and the continued translation of benchside discovery into bedside care.

Keywords

epidemiology / fibroblast dysregulation / hypertrophic scars / keloids / molecular pathogenesis / scar management

References

[1] G. C. Limandjaja, F. B. Niessen, R. J. Scheper, and S. Gibbs, “Hypertrophic Scars and Keloids: Overview of the Evidence and Practical Guide for Differentiating Between These Abnormal Scars,” Experimental Dermatology 30, no. 1 (2021): 146-161.

[2] M. G. Jeschke, F. M. Wood, E. Middelkoop, et al., “Scars,” Nature Reviews Disease Primers 9, no. 1 (2023): 64.

[3] S. K. Bharadia, L. Burnett, and V. Gabriel, “Hypertrophic Scar,” Physical Medicine and Rehabilitation Clinics of North America 34, no. 4 (2023): 783-798.

[4] R. Ogawa, “Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis,” IJMS 18, no. 3 (2017): 606.

[5] A. Burd and L. Huang, “Hypertrophic Response and Keloid Diathesis: Two Very Different Forms of Scar,” Plastic and Reconstructive Surgery 116, no. 7 (2005): 150e-157e.

[6] A. P. Trace, C. W. Enos, A. Mantel, and V. M. Harvey, “Keloids and Hypertrophic Scars: A Spectrum of Clinical Challenges,” American Journal of Clinical Dermatology 17, no. 3 (2016): 201-223.

[7] J. B. Anderson, A. Foglio, A. B. Harrant, et al., “Scoping Review of Therapeutic Strategies for Keloids and Hypertrophic Scars,” Plastic and Reconstructive Surgery - Global Open 9, no. 3 (2021): e3469.

[8] H. Lee and Y. Jang, “Recent Understandings of Biology, Prophylaxis and Treatment Strategies for Hypertrophic Scars and Keloids,” IJMS 19, no. 3 (2018): 711.

[9] J. Y. Y. Lee, C. C. Yang, S. C. Chao, and T. W. Wong, “Histopathological Differential Diagnosis of Keloid and Hypertrophic Scar,” American Journal of Dermatopathology 26, no. 5 (2004): 379-384.

[10] L. Téot, T. A. Mustoe, E. Middelkoop, and G. G. Gauglitz, Textbook on Scar Management: State of the Art Management and Emerging Technologies (Springer, 2020).

[11] P. M. De Faverney, K. Molamodi, E. Tancrede-Bohin, and M. Verschoore, “Support for Dermatological Research in Sub-Saharan Africa: Insights From African Hair and Skin Research Programs,” International Journal of Dermatology 63, no. 8 (2024): 1081-1088.

[12] C. Y. Ung, A. Warwick, A. Onoufriadis, et al., “Comorbidities of Keloid and Hypertrophic Scars Among Participants in UK Biobank,” JAMA Dermatology 159, no. 2 (2023): 172-181.

[13] G. Stanley, A. Adjei, M. Adeyemi, et al., “Prevalence, Exposure and the Public Knowledge of Keloids on Four Continents,” Journal of Plastic, Reconstructive & Aesthetic Surgery 77 (2022): 359-370.

[14] A. H. Liu, X. L. Sun, D. Z. Liu, et al., “Epidemiological and Clinical Features of Hypertrophic Scar and Keloid in Chinese College Students: A University-Based Cross-Sectional Survey,” Heliyon 9, no. 4 (2023): e15345.

[15] E. Reiche, P. R. Keller, V. Soares, et al., “Androgenic Steroids Induce Pathologic Scarring in a Preclinical Porcine Model via Dysfunctional Extracellular Matrix Deposition,” FASEB Journal 38, no. 6 (2024): e23561.

[16] A. J. James, R. A. Torres-Guzman, S. C. Chaker, et al., “Global Insights Into Keloid Formation: An International Systematic Review of Regional Genetic Risk Factors and Commonalities,” Wound Repair Regeneration 32, no. 5 (2024): 746-757.

[17] J. J. Brown and A. Bayat, “Genetic Susceptibility to Raised Dermal Scarring,” British Journal of Dermatology 161, no. 1 (2009): 8-18.

[18] C. H. Tsai and R. Ogawa, “Keloid Research: Current Status and Future Directions,” Scars, Burns & Healing 5 (2019): 2059513119868659.

[19] P. Davies, L. Cuttle, and A. Young, “A Scoping Review of the Methodology Used in Studies of Genetic Influences on the Development of Keloid or Hypertrophic Scarring in Adults and Children After Acute Wounding,” Advances in Wound Care 10, no. 10 (2021): 557-570.

[20] D. A. Mammo, K. Wai, E. Rahimy, C. K. Pan, S. K. Srivastava, and P. Mruthyunjaya, “Association of Cutaneous Keloids, Hypertrophic Scarring, and Fibrosis With Risk of Postoperative Proliferative Vitreoretinopathy,” Ophthalmology 131, no. 8 (2024): 961-966.

[21] S. Ud-Din and A. Bayat, “Controlling Inflammation Pre-Emptively or at the Time of Cutaneous Injury Optimises Outcome of Skin Scarring,” Frontiers in Immunology 13 (2022): 883239.

[22] R. Ogawa, “The Most Current Algorithms for the Treatment and Prevention of Hypertrophic Scars and Keloids: A 2020 Update of the Algorithms Published 10 Years Ago,” Plastic & Reconstructive Surgery 149, no. 1 (2022): 79e-94e.

[23] K. Chen, D. Henn, M. Januszyk, et al., “Disrupting Mechanotransduction Decreases Fibrosis and Contracture in Split-Thickness Skin Grafting,” Science Translational Medicine 14, no. 645 (2022): eabj9152.

[24] A. E. Deliaert, E. Van den Kerckhove, S. Tuinder, S. M. Noordzij, T. S. Dormaar, and R. R. van der Hulst, “Smoking and Its Effect on Scar Healing,” European Journal of Plastic Surgery 35, no. 6 (2012): 421-424.

[25] A. E. K. Deliaert, J. F. Mermans, S. J. Schop, et al., “The Effect of Smoking on Sternal Scar Healing: A Prospective Cohort Study,” Wounds 31, no. 8 (2019): 200-204.

[26] M. Y. Cho, S. G. Lee, J. E. Kim, Y. S. Lee, H. S. Chang, and M. R. Roh, “Analysis of Risk Factors to Predict Occurrence and Prognosis of Postsurgical Hypertrophic Scar Development: A Review of 4238 Cases,” Yonsei Medical Journal 64, no. 11 (2023): 687.

[27] E. A. Kouotou, J. R. Nansseu, E. Omona Guissana, et al., “Epidemiology and Clinical Features of Keloids in Black Africans: A Nested Case-Control Study From Yaoundé, Cameroon,” International Journal of Dermatology 58, no. 10 (2019): 1135-1140.

[28] R. Ogawa and S. Akaishi, “Endothelial Dysfunction May Play a Key Role in Keloid and Hypertrophic Scar Pathogenesis—Keloids and Hypertrophic Scars May Be Vascular Disorders,” Medical Hypotheses 96 (2016): 51-60.

[29] D. T. Robles and D. Berg, “Abnormal Wound Healing: Keloids,” Clinics in Dermatology 25, no. 1 (2007): 26-32.

[30] G. Grabowski, M. J. Pacana, and E. Chen, “Keloid and Hypertrophic Scar Formation, Prevention, and Management: Standard Review of Abnormal Scarring in Orthopaedic Surgery,” Journal of the American Academy of Orthopaedic Surgeons 28, no. 10 (2020): e408-e414.

[31] M. M. Kim and R. D. Goldman, “Ear-piercing Complications in Children and Adolescents,” Canadian Family Physician 68, no. 9 (2022): 661-663.

[32] F. A. Khan, N. A. Drucker, S. D. Larson, J. A. Taylor, and S. Islam, “Pediatric Earlobe Keloids: Outcomes and Patterns of Recurrence,” Journal of Pediatric Surgery 55, no. 3 (2020): 461-464.

[33] N. M. Matsumoto, W. X. Peng, M. Aoki, et al., “Histological Analysis of Hyalinised Keloidal Collagen Formation in Earlobe Keloids Over Time: Collagen Hyalinisation Starts in the Perivascular Area,” International Wound Journal 14, no. 6 (2017): 1088-1093.

[34] T. Gong, Y. Wang, S. Dong, et al., “Single-Cell RNA-Seq Reveals the Communications Between Extracellular Matrix-Related Components and Schwann Cells Contributing to the Earlobe Keloid Formation,” Frontiers in Medicine 9 (2022): 1000324.

[35] Y. Nakajima, N. Aramaki, N. Takeuchi, et al., “Mast Cells Are Activated in the Giant Earlobe Keloids: A Case Series,” International Journal of Molecular Sciences 23, no. 18 (2022): 10410.

[36] F. M. Ghazawi, R. Zargham, M. S. Gilardino, D. Sasseville, and F. Jafarian, “Insights Into the Pathophysiology of Hypertrophic Scars and Keloids: How Do They Differ?,” Advances in Skin & Wound Care 31, no. 1 (2018): 582-595.

[37] P. Chitturi and A. Leask, “The Role of Positional Information in Determining Dermal Fibroblast Diversity,” Matrix Biology 128 (2024): 31-38.

[38] L. Zhang, Y. Shang, C. Han, et al., “CD248 interacts With ECM to Promote Hypertrophic Scar Formation and Development,” Gene 927 (2024): 148730.

[39] T. Jennings, R. Duffy, M. McLarney, et al., “Acne Scarring-Pathophysiology, Diagnosis, Prevention and Education: Part I,” Journal of the American Academy of Dermatology 90, no. 6 (2024): 1123-1134.

[40] S. Qi, A. Ma, H. Lin, L. Peng, and E. Deng, “The Effect of Inflammatory Cytokines on the Risk of Hypertrophic Scar: A Mendelian Randomization Study,” Archives of Dermatological Research 316, no. 8 (2024): 551.

[41] A. S. Walter, M. Stocks, E. Akova, et al., “Keloids Are Transcriptionally Distinct From Normal and Hypertrophic Scars,” European Journal of Dermatology 33, no. 6 (2023): 604-611.

[42] J. G. Park, D. C. Lim, J. H. Park, et al., “Benzbromarone Induces Targeted Degradation of HSP47 Protein and Improves Hypertrophic Scar Formation,” Journal of Investigative Dermatology 144, no. 3 (2024): 633-644.

[43] J. Zhang, S. Li, C. Kuang, et al., “CD74⁺ fibroblasts Proliferate Upon Mechanical Stretching to Promote Angiogenesis in Keloids,” FASEB Journal 38, no. 20 (2024): e70103.

[44] D. T. Ploeger, N. A. Hosper, M. Schipper, J. A. Koerts, S. de Rond, and R. A. Bank, “Cell Plasticity in Wound Healing: Paracrine Factors of M1/M2 Polarized Macrophages Influence the Phenotypical state of Dermal Fibroblasts,” Cell Communication and Signaling 11, no. 1 (2013): 29.

[45] B. Shook, E. Xiao, Y. Kumamoto, A. Iwasaki, and V. Horsley, “CD301b⁺ Macrophages Are Essential for Effective Skin Wound Healing,” Journal of Investigative Dermatology 136 (2016): 1885-1891.

[46] Y. He, Z. Zhang, B. Yin, et al., “Identifying miRNAs Associated With the Progression of Keloid Through mRNA-miRNA Network Analysis and Validating the Targets of miR-29a-3p in Keloid Fibroblasts,” BioMed Research International 2022 (2022): 6487989.

[47] B. Y. Zhou, W. B. Wang, X. L. Wu, et al., “Nintedanib Inhibits Keloid Fibroblast Functions by Blocking the Phosphorylation of Multiple Kinases and Enhancing Receptor Internalization,” Acta Pharmacologica Sinica 41, no. 9 (2020): 1234-1245.

[48] Y. Li, M. Li, C. Qu, et al., “The Polygenic Map of Keloid Fibroblasts Reveals Fibrosis-Associated Gene Alterations in Inflammation and Immune Responses,” Frontiers in Immunology 12 (2022): 810290.

[49] J. Mao, L. Chen, S. Qian, et al., “Transcriptome Network Analysis of Inflammation and Fibrosis in Keloids,” Journal of Dermatological Science 113, no. 2 (2024): 62-73.

[50] H. Hu, G. Mao, J. Zheng, and F. Guo, “Keloid Patient Plasma-Derived Exosomal hsa_circ_0020792 Promotes Normal Skin Fibroblasts Proliferation, Migration, and Fibrogenesis via Modulating miR-193a-5p and Activating TGF-β1/Smad2/3 Signaling,” Drug Design, Development and Therapy 16 (2022): 4223-4234.

[51] Y. He, Z. Zhang, B. Yin, et al., “Identifying miRNAs Associated With the Progression of Keloid Through mRNA-miRNA Network Analysis and Validating the Targets of miR-29a-3p in Keloid Fibroblasts,” BioMed Research International 2022 (2022): 6487989.

[52] Z. Wang, C. Feng, K. Song, Z. Qi, W. Huang, and Y. Wang, “lncRNA-H19/miR-29a Axis Affected the Viability and Apoptosis of Keloid Fibroblasts Through Acting Upon COL1A1 Signaling,” Journal of Cellular Biochemistry 121, no. 11 (2020): 4364-4376.

[53] J. Milara, P. Ribera, S. Marín, P. Montero, I. Roger, and J. Cortijo, “Phosphodiesterase 4 Is Overexpressed in Keloid Epidermal Scars and Its Inhibition Reduces Keratinocyte Fibrotic Alterations,” Molecular Medicine 30, no. 1 (2024): 134.

[54] L. Guo, J. W. Mi, H. C. Zhang, et al., “Endothelial-mesenchymal Transition as a Novel Mechanism for Generating Myofibroblasts During Wound Healing and Scarring,” Journal of Cosmetic Dermatology 22, no. 2 (2023): 661-668.

[55] R. Y. Shang, J. C. Yang, W. G. Hu, et al., “Artesunate Attenuates Skin Hypertrophic Scar Formation by Inhibiting Fibroblast Activation and EndMT of Vascular Endothelial Cells,” Phytomedicine 140 (2025): 156498.

[56] H. E. Talbott, S. Mascharak, M. Griffin, D. C. Wan, and M. T. Longaker, “Wound Healing, Fibroblast Heterogeneity, and Fibrosis,” Cell Stem Cell 29, no. 8 (2022): 1161-1180.

[57] S. Abbasi, S. Sinha, E. Labit, et al., “Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts During Wound Healing,” Cell Stem Cell 27, no. 3 (2020): 396-412.e6. [Erratum in: Cell Stem Cell 28, no. 3 (2021): 581-583].

[58] M. B. Buechler, R. N. Pradhan, A. T. Krishnamurty, et al., “Cross-Tissue Organization of the Fibroblast Lineage,” Nature 593, no. 7860 (2021): 575-579.

[59] S. M. Thompson, Q. M. Phan, S. Winuthayanon, I. M. Driskell, and R. R. Driskell, “Parallel Single-Cell Multiomics Analysis of Neonatal Skin Reveals the Transitional Fibroblast States That Restrict Differentiation Into Distinct Fates,” Journal of Investigative Dermatology 142, no. 7 (2022): 1812-1823.e3.

[60] D. Correa-Gallegos, H. Ye, B. Dasgupta, et al., “CD201⁺ Fascia Progenitors Choreograph Injury Repair,” Nature 623, no. 7988 (2023): 792-802.

[61] C. F. Guerrero-Juarez, P. H. Dedhia, S. Jin, et al., “Single-Cell Analysis Reveals Fibroblast Heterogeneity and Myeloid-Derived Adipocyte Progenitors in Murine Skin Wounds,” Nature Communications 10, no. 1 (2019): 650.

[62] Q. M. Phan, G. M. Fine, L. Salz, et al., “Lef1 Expression in Fibroblasts Maintains Developmental Potential in Adult Skin to Regenerate Wounds,” Elife 9 (2020): e60066.

[63] R. S. Raktoe, M. H. Rietveld, J. J. Out-Luiting, et al., “The Effect of TGFβRI Inhibition on Fibroblast Heterogeneity in Hypertrophic Scar 2D In Vitro Models,” Burns 47, no. 7 (2021): 1563-1575.

[64] M. S. Wietecha, M. Pensalfini, M. Cangkrama, et al., “Activin-Mediated Alterations of the Fibroblast Transcriptome and Matrisome Control the Biomechanical Properties of Skin Wounds,” Nature Communications 11, no. 1 (2020): 2604.

[65] H. Zhang, C. Zang, W. Zhao, et al., “Exosome Derived From Mesenchymal Stem Cells Alleviates Hypertrophic Scar by Inhibiting the Fibroblasts via TNFSF-13/HSPG2 Signaling Pathway,” International Journal of Nanomedicine 18 (2023): 7047-7063.

[66] A. C. Zeigler, A. R. Nelson, A. S. Chandrabhatla, O. Brazhkina, J. W. Holmes, and J. J. Saucerman, “Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction,” Matrix Biology 91-92 (2020): 136-151.

[67] J. M. Peterson, J. W. Jay, Y. Wang, et al., “Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts,” IJMS 23, no. 12 (2022): 6689.

[68] N. Noskovicova, R. Schuster, S. Van Putten, et al., “Suppression of the Fibrotic Encapsulation of Silicone Implants by Inhibiting the Mechanical Activation of Pro-Fibrotic TGF-β,” Nature Biomedical Engineering 5, no. 12 (2021): 1437-1456.

[69] P. C. Tan, S. B. Zhou, M. Y. Ou, et al., “Mechanical Stretching Can Modify the Papillary Dermis Pattern and Papillary Fibroblast Characteristics During Skin Regeneration,” Journal of Investigative Dermatology 142, no. 9 (2022): 2384-2394.e8.

[70] Y. Gao, Y. Liu, D. Zheng, et al., “HDAC5-Mediated Smad7 Silencing Through MEF2A Is Critical for Fibroblast Activation and Hypertrophic Scar Formation,” International Journal of Biological Sciences 18, no. 15 (2022): 5724-5739.

[71] Y. Zhang, X. Li, Q. Yu, et al., “Using Network Pharmacology to Discover Potential Drugs for Hypertrophic Scars,” British Journal of Dermatology 191, no. 4 (2024): 592-604.

[72] Y. Zhan, X. Xu, X. Luo, et al., “Preparation of Tanshinone IIA Self-Soluble Microneedles and Its Inhibition on Proliferation of human Skin Fibroblasts,” Chinese Herbal Medicine 15, no. 2 (2023): 251-262.

[73] Y. Zhang, X. Li, W. Liu, et al., “TWEAK/Fn14 Signaling May Function as a Reactive Compensatory Mechanism Against Extracellular Matrix Accumulation in Keloid Fibroblasts,” European Journal of Cell Biology 102, no. 2 (2023): 151290.

[74] P. Li, M. Han, L. Wang, and C. Gao, “Serum Deprivation Protein Response Intervenes in the Proliferation, Motility, and Extracellular Matrix Production in Keloid Fibroblasts by Blocking the Amplification of TGF-β1/SMAD Signal Cascade via ERK1/2,” Toxicology and Applied Pharmacology 489 (2024): 117012.

[75] S. Dupont and S. A. Wickström, “Mechanical Regulation of Chromatin and Transcription,” Nature Reviews Genetics 23, no. 10 (2022): 624-643.

[76] R. Farndale, A. Sonnenberg, C. M. DiPersio, J. A. Eble, J. Heino, and D. Gullberg, “What Does It Take to Be a Collagen Receptor?” Matrix Biology 115 (2023): 128-132.

[77] R. Kolasangiani, T. C. Bidone, and M. A. Schwartz, “Integrin Conformational Dynamics and Mechanotransduction,” Cells 11, no. 22 (2022): 3584.

[78] Y. Gao, J. Zhou, Z. Xie, et al., “Mechanical Strain Promotes Skin Fibrosis Through LRG-1 Induction Mediated by ELK1 and ERK Signalling,” Communications Biology 2 (2019): 359.

[79] H. Lu, H. Wang, G. Huang, X. Wang, and X. Bu, “Therapeutic Targeting of Mechanical Stretch-Induced FAK/ERK Signaling by Fisetin in Hypertrophic Scars,” European Journal of Pharmacology 932 (2022): 175228.

[80] J. Zhao, S. Yang, Y. Xu, et al., “Mechanical Pressure-Induced Dedifferentiation of Myofibroblasts Inhibits Scarring via SMYD3/ITGBL1 Signaling,” Developmental Cell 58, no. 13 (2023): 1139-1152.e6.

[81] J. Yin, S. Zhang, C. Yang, et al., “Mechanotransduction in Skin Wound Healing and Scar Formation: Potential Therapeutic Targets for Controlling Hypertrophic Scarring,” Frontiers in Immunology 13 (2022): 1028410.

[82] Y. Zhao, X. Li, X. Xu, Z. He, L. Cui, and X. Lv, “Lumican Alleviates Hypertrophic Scarring by Suppressing Integrin-FAK Signaling,” Biochemical and Biophysical Research Communications 480, no. 2 (2016): 153-159.

[83] Y. Huang, H. Zhao, Y. Zhang, et al., “Enhancement of Zyxin Promotes Skin Fibrosis by Regulating FAK/PI3K/AKT and TGF-β Signaling Pathways via Integrins,” International Journal of Biological Sciences 19, no. 8 (2023): 2394-2408.

[84] M. Wiktorska, I. Sacewicz-Hofman, and J. Niewiarowska, “The Endothelial-to-Mesenchymal Transition Changes the Focal Adhesion Site Proteins Levels and the SLRP-Lumican Level in HMEC-1 Cell Line,” Experimental Cell Research 430, no. 1 (2023): 113692.

[85] T. Panciera, L. Azzolin, M. Cordenonsi, and S. Piccolo, “Mechanobiology of YAP and TAZ in Physiology and Disease,” Nature Reviews Molecular Cell Biology 18 (2017): 758-770.

[86] F. Liu, D. Lagares, K. M. Choi, et al., “Mechanosignaling Through YAP and TAZ Drives Fibroblast Activation and Fibrosis,” American Journal of Physiology. Lung Cellular and Molecular Physiology 308 (2015): L344-L357.

[87] Y. Xia, M. Sun, H. Huang, and W. L. Jin, “Drug Repurposing for Cancer Therapy,” Signal Transduction and Targeted Therapy 9, no. 1 (2024): 92.

[88] Z. Meng, Y. Qiu, K. C. Lin, et al., “RAP2 Mediates Mechanoresponses of the Hippo Pathway,” Nature 560, no. 7720 (2018): 655-660.

[89] T. Tu, J. Huang, M. Lin, et al., “CUDC-907 Reverses Pathological Phenotype of Keloid Fibroblasts In Vitro and In Vivo via Dual Inhibition of PI3K/Akt/mTOR Signaling and HDAC2,” International Journal of Molecular Medicine 44, no. 5 (2019): 1789-1800.

[90] Y. Teng, Y. Fan, J. Ma, et al., “The PI3K/Akt Pathway: Emerging Roles in Skin Homeostasis and a Group of Non-Malignant Skin Disorders,” Cells 10, no. 5 (2021): 1219.

[91] J. Jin, B. Pan, K. Wang, et al., “Subvacuum Environment-Enhanced Cell Migration Promotes Wound Healing Without Increasing Hypertrophic Scars Caused by Excessive Cell Proliferation,” Cell Proliferation 56, no. 11 (2023): e13493.

[92] L. Mercurio, C. Albanesi, and S. Madonna, “Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders,” Frontiers in Medicine 8 (2021): 665647.

[93] T. W. Yiu, S. R. Holman, X. Kaidonis, R. M. Graham, and S. E. Iismaa, “Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner,” IJMS 24, no. 14 (2023): 11475.

[94] S. S. Htwe, B. H. Cha, K. Yue, A. Khademhosseini, A. J. Knox, and A. M. Ghaemmaghami, “Role of Rho-Associated Coiled-Coil Forming Kinase Isoforms in Regulation of Stiffness-Induced Myofibroblast Differentiation in Lung Fibrosis,” American Journal of Respiratory Cell and Molecular Biology 56, no. 6 (2017): 772-783.

[95] J. He, B. Fang, S. Shan, et al., “Mechanical Stretch Promotes Hypertrophic Scar Formation Through Mechanically Activated Cation Channel Piezo1,” Cell Death & Disease 12, no. 3 (2021): 226.

[96] M. M. Maurice and S. Angers, “Mechanistic Insights Into Wnt-β-Catenin Pathway Activation and Signal Transduction,” Nature Reviews Molecular Cell Biology 26, no. 5 (2025): 371-388.

[97] M. Majidinia, J. Aghazadeh, R. Jahanban-Esfahlani, and B. Yousefi, “The Roles of Wnt/β-Catenin Pathway in Tissue Development and Regenerative Medicine,” Journal of Cellular Physiology 233, no. 8 (2018): 5598-5612.

[98] L. Hu, W. Chen, A. Qian, and Y. P. Li, “Wnt/β-Catenin Signaling Components and Mechanisms in Bone Formation, Homeostasis, and Disease,” Bone Research 12, no. 1 (2024): 39.

[99] D. V. N. Somanader, P. Zhao, R. E. Widdop, and C. S. Samuel, “The Involvement of the Wnt/β-Catenin Signaling Cascade in Fibrosis Progression and Its Therapeutic Targeting by Relaxin,” Biochemical Pharmacology 223 (2024): 116130.

[100] H. Clevers and R. Nusse, “Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities,” Cell 169 (2017): 985-999.

[101] Z. Dai, Y. Jiang, H. Guo, Y. Lu, W. Chen, and T. Liang, “Pirfenidone Ameliorates Hypertrophic Scar Through Inhibiting Proliferation and Migration of Fibroblasts by Regulating the Wnt/GSK-3β/β-Catenin Signaling Pathway,” Journal of Burn Care & Research ahead of print, April 8, 2025, https://doi.org/10.1093/jbcr/iraf040.

[102] T. Yamagami, P. DE, K. S. Lam, and C. J. Zhou, “Transient Activation of Wnt/β-Catenin Signaling Reporter in Fibrotic Scar Formation After Compression Spinal Cord Injury in Adult Mice,” Biochemical and Biophysical Research Communications 496, no. 4 (2018): 1302-1307.

[103] A. G. Condorelli, M. El Hachem, G. Zambruno, A. Nystrom, E. Candi, and D. Castiglia, “Notch-ing up Knowledge on Molecular Mechanisms of Skin Fibrosis: Focus on the Multifaceted Notch Signalling Pathway,” Journal of Biomedical Science 28, no. 1 (2021): 36.

[104] Y. Shi, B. Shu, R. Yang, et al., “Wnt and Notch Signaling Pathway Involved in Wound Healing by Targeting c-Myc and Hes1 Separately,” Stem Cell Research & Therapy 6, no. 1 (2015): 120.

[105] M. Tosa, Y. Abe, S. Egawa, et al., “The HEDGEHOG-GLI1 Pathway Is Important for Fibroproliferative Properties in Keloids and as a Candidate Therapeutic Target,” Communications Biology 6, no. 1 (2023): 1235.

[106] Y. Wu, W. Lv, and H. Chen, “Orthogonal Upconversion Nanocarriers for Combined Photodynamic Therapy and Precisely Triggered Gene Silencing in Combating Keloids,” Journal of Controlled Release 379 (2025): 1-13.

[107] Q. Wang, Y. Zhong, Z. Li, et al., “Multitranscriptome Analyses of Keloid Fibroblasts Reveal the Role of the HIF-1α/HOXC6/ERK Axis in Keloid Development,” Burns Trauma 10 (2022): tkac013.

[108] C. E. Yang, S. Choi, J. H. Lee, et al., “Sustained Release of Decoy Wnt Receptor (sLRP6E1E2)-Expressing Adenovirus Using Gel-Encapsulation for Scar Remodeling in Pig Model,” International Journal of Molecular Sciences 21, no. 6 (2020): 2242.

[109] M. L. Cohen, A. N. Brumwell, T. C. Ho, et al., “A Fibroblast-Dependent TGF-β1/sFRP2 Noncanonical Wnt Signaling Axis Promotes Epithelial Metaplasia in Idiopathic Pulmonary Fibrosis,” Journal of Clinical Investigation 134, no. 18 (2024): e174598.

[110] Y. Hu, Q. Wang, J. Yu, et al., “Tartrate-Resistant Acid Phosphatase 5 Promotes Pulmonary Fibrosis by Modulating β-Catenin Signaling,” Nature Communications 13, no. 1 (2022): 114.

[111] Q. Lei, Z. Yu, H. Li, J. Cheng, and Y. Wang, “Fatty Acid-Binding Protein 5 Aggravates Pulmonary Artery Fibrosis in Pulmonary Hypertension Secondary to Left Heart Disease via Activating Wnt/β-Catenin Pathway,” Journal of Advanced Research 40 (2022): 197-206.

[112] S. Huang, W. Deng, Y. Dong, et al., “Melatonin Influences the Biological Characteristics of Keloid Fibroblasts Through the Erk and Smad Signalling Pathways,” Burns Trauma 11 (2023): tkad005.

[113] S. Mascharak, H. E. Talbott, M. Januszyk, et al., “Multi-Omic Analysis Reveals Divergent Molecular Events in Scarring and Regenerative Wound Healing,” Cell Stem Cell 29, no. 2 (2022): 315-327.e6.

[114] Y. Wang, X. Wang, Z. Yuan, F. Liu, X. Luo, and J. Yang, “Identifying Potential Drug Targets for Keloid: A Mendelian Randomization Study,” Journal of Investigative Dermatology 145, no. 1 (2025): 77-84.e6.

[115] S. Zhao, J. Xie, Q. Zhang, et al., “New Anti-Fibrotic Strategies for Keloids: Insights From Single-Cell Multi-Omics,” Cell Proliferation 58, no. 6 (2025): e13818.

[116] K. Xiao, S. Wang, W. Chen, et al., “Identification of Novel Immune-Related Signatures for Keloid Diagnosis and Treatment: Insights From Integrated Bulk RNA-seq and scRNA-seq Analysis,” Human Genomics 18, no. 1 (2024): 80.

[117] Y. K. Hong, Y. C. Lin, T. L. Cheng, et al., “TEM1/Endosialin/CD248 Promotes Pathologic Scarring and TGF-β Activity Through Its Receptor Stability in Dermal Fibroblasts,” Journal of Biomedical Science 31, no. 1 (2024): 12.

[118] Y. K. Hong, Y. H. Chang, Y. C. Lin, B. Chen, B. E. K. Guevara, and C. K. Hsu, “Inflammation in Wound Healing and Pathological Scarring,” Advances in Wound Care 12, no. 5 (2023): 288.

[119] M. Bhattacharya and P. Ramachandran, “Immunology of Human Fibrosis,” Nature Immunology 24, no. 9 (2023): 1423-1433.

[120] Y. Feng, Z. L. Sun, S. Y. Liu, et al., “Direct and Indirect Roles of Macrophages in Hypertrophic Scar Formation,” Frontiers in Physiology 10 (2019): 1101.

[121] Z. C. Wang, W. Y. Zhao, Y. Cao, et al., “The Roles of Inflammation in Keloid and Hypertrophic Scars,” Frontiers in Immunology 11 (2020): 603187.

[122] T. A. Wynn and T. R. Ramalingam, “Mechanisms of Fibrosis: Therapeutic Translation for Fibrotic Disease,” Nature Medicine 18, no. 7 (2012): 1028-1040.

[123] W. D. Short, X. Wang, and S. G. Keswani, “The Role of T Lymphocytes in Cutaneous Scarring,” Advances in Wound Care 11, no. 3 (2022): 121-131.

[124] X. Wang, S. Balaji, E. H. Steen, et al., “T Lymphocytes Attenuate Dermal Scarring by Regulating Inflammation, Neovascularization, and Extracellular Matrix Remodeling,” Advances in Wound Care 8, no. 11 (2019): 527-537.

[125] Y. Chen, N. Liao, F. Lu, H. Peng, and J. Gao, “The Role of Duffy Antigen Receptor for Chemokines in Keloids,” Gene 570, no. 1 (2015): 44-49.

[126] B. Berman, A. Maderal, and B. Raphael, “Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment,” Dermatologic Surgery 43, no. S1 (2017): S3-S18.

[127] T. Zhang, X. F. Wang, Z. C. Wang, et al., “Current Potential Therapeutic Strategies Targeting the TGF-β/Smad Signaling Pathway to Attenuate Keloid and Hypertrophic Scar Formation,” Biomedicine & Pharmacotherapy 129 (2020): 110287.

[128] C. Huang and R. Ogawa, “Role of Inflammasomes in Keloids and Hypertrophic Scars—Lessons Learned From Chronic Diabetic Wounds and Skin Fibrosis,” International Journal of Molecular Sciences 23, no. 12 (2022): 6820.

[129] I. G. Petrou, S. Nikou, S. Madduri, M. Nifora, V. Bravou, and D. F. Kalbermatten, “The Role of Hippo Signaling Pathway and ILK in the Pathophysiology of Human Hypertrophic Scars and Keloids: An Immunohistochemical Investigation,” Cells 11, no. 21 (2022): 3426.

[130] R. Ogawa, T. Dohi, M. Tosa, M. Aoki, and S. Akaishi, “The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol,” Journal of Nippon Medical School 88, no. 1 (2021): 2-9.

[131] H. J. Kim and Y. H. Kim, “Comprehensive Insights Into Keloid Pathogenesis and Advanced Therapeutic Strategies,” International Journal of Molecular Sciences 25, no. 16 (2024): 8776.

[132] T. Tsuge, M. Aoki, S. Akaishi, T. Dohi, H. Yamamoto, and R. Ogawa, “Geometric Modeling and a Retrospective Cohort Study on the Usefulness of Fascial Tensile Reductions in Severe Keloid Surgery,” Surgery 167, no. 2 (2020): 504-509.

[133] D. Correa-Gallegos, D. Jiang, S. Christ, et al., “Patch Repair of Deep Wounds by Mobilized Fascia,” Nature 576, no. 7786 (2019): 287-292.

[134] D. Jiang and Y. Rinkevich, “Furnishing Wound Repair by the Subcutaneous Fascia,” International Journal of Molecular Sciences 22, no. 16 (2021): 9006.

[135] A. Szabó, I. De Decker, S. Semey, et al., “Photo-Crosslinkable Polyester Microneedles as Sustained Drug Release Systems Toward Hypertrophic Scar Treatment,” Drug Delivery 31, no. 1 (2024): 2305818.

[136] B. Yang, Y. Dong, Y. Shen, et al., “Bilayer Dissolving Microneedle Array Containing 5-Fluorouracil and Triamcinolone With Biphasic Release Profile for Hypertrophic Scar Therapy,” Bioactive Materials 6, no. 8 (2021): 2400-2411.

[137] Q. Zhang, L. Shi, H. He, et al., “Down-Regulating Scar Formation by Microneedles Directly via a Mechanical Communication Pathway,” ACS Nano 16, no. 7 (2022): 10163-10178.

[138] S. Lin, G. Quan, A. Hou, et al., “Strategy for Hypertrophic Scar Therapy: Improved Delivery of Triamcinolone Acetonide Using Mechanically Robust Tip-Concentrated Dissolving Microneedle Array,” Journal of Controlled Release 306 (2019): 69-82.

[139] Z. R. Yang, H. Suo, J. W. Fan, et al., “Endogenous Stimuli-Responsive Separating Microneedles to Inhibit Hypertrophic Scar Through Remodeling the Pathological Microenvironment,” Nature Communications 15, no. 1 (2024): 2038.

[140] S. Mascharak, H. E. desJardins-Park, M. F. Davitt, et al., “Preventing Engrailed-1 Activation in Fibroblasts Yields Wound Regeneration Without Scarring,” Science 372, no. 6540 (2021): eaba2374.

[141] Y. Zhang, S. Wang, Y. Yang, et al., “Scarless Wound Healing Programmed by Core-Shell Microneedles,” Nature Communications 14, no. 1 (2023): 3431.

[142] A. Aliu and M. Aust, “Minimal Invasive Technologies for Treatment of HTS and Keloids: Medical Needling,” in Textbook on Scar Management: State of the Art Management and Emerging Technologies, ed. L. Téot, T. A. Mustoe, E. Middelkoop, G. G. Gauglitz (Springer, 2020), 287-298.

[143] W. Disphanurat, N. Sivapornpan, B. Srisantithum, and J. Leelawattanachai, “Efficacy of a Triamcinolone Acetonide-Loaded Dissolving Microneedle Patch for the Treatment of Hypertrophic Scars and Keloids: A Randomized, Double-Blinded, Placebo-Controlled Split-Scar Study,” Archives of Dermatological Research 315, no. 4 (2023): 989-997.

[144] Z. Haghani-Dogahe, R. Hadadi, M. Esmailzadeh, and M. Mobayen, “Comparing Intralesional Triamcinolone and Verapamil-Triamcinolone Injections in Keloids: A Single-Blinded Randomised Clinical Trial,” International Wound Journal 20, no. 10 (2023): 4166-4174.

[145] Y. Xia, Y. Wang, Y. Hao, et al., “Deciphering the Single-Cell Transcriptome Network in Keloids With Intra-Lesional Injection of Triamcinolone Acetonide Combined With 5-Fluorouracil,” Frontiers in Immunology 14 (2023): 1106289.

[146] K. E. Hietanen, T. A. Järvinen, H. Huhtala, T. T. Tolonen, H. O. Kuokkanen, and I. S. Kaartinen, “Treatment of Keloid Scars With Intralesional Triamcinolone and 5-Fluorouracil Injections—A Randomized Controlled Trial,” Journal of Plastic, Reconstructive & Aesthetic Surgery 72, no. 1 (2019): 4-11.

[147] Y. Chen, K. Chen, S. Zhong, et al., “Transdermal Transfersome Nanogels Control Hypertrophic Scar Formation via Synergy of Macrophage Phenotype-Switching and Anti-Fibrosis Effect,” Advanced Science 11, no. 7 (2024): 2305468.

[148] Y. Zhao, Y. Zou, H. Chen, Y. Rao, and X. Lin, “Erbium: YAG Laser Treatment Efficacy and Association With Histologic Features for Giant Congenital Melanocytic Nevi Management,” Lasers in Surgery and Medicine 56, no. 4 (2024): 361-370.

[149] L. A. Walsh, E. Wu, D. Pontes, et al., “Keloid Treatments: An Evidence-Based Systematic Review of Recent Advances,” Systematic Reviews 12, no. 1 (2023): 42.

[150] M. K. Kivi, A. Jafarzadeh, F. S. Hosseini-Baharanchi, S. Salehi, and A. Goodarzi, “The Efficacy, Satisfaction, and Safety of Carbon Dioxide (CO₂) Fractional Laser in Combination With Pulsed Dye Laser (PDL) Versus Each One Alone in the Treatment of Hypertrophic Burn Scars: A Single-Blinded Randomized Controlled Trial,” Lasers in Medical Science 39, no. 1 (2024): 69.

[151] J. Wen, Z. Li, W. Liu, N. Yu, and X. Wang, “Dual-Wavelength Dye Laser Combined With Betamethasone Injection for Treatment of Keloids: Protocol of a Randomised Controlled Trial,” BMJ Open 14, no. 7 (2024): e084939.

[152] X. J. Liu, Y. Lei, M. H. Gold, and J. Tan, “Efficacy of Pulsed Dye Laser Combined With Fractional CO₂ Laser in the Treatment of Pediatric Burn Scars,” Lasers in Surgery and Medicine 55, no. 5 (2023): 464-470.

[153] D. A. Hashemi, J. Tao, J. V. Wang, and R. G. Geronemus, “The 595-nm Wavelength Pulsed Dye Laser for Pediatric Port-Wine Birthmarks and Infantile Hemangiomas: A Systematic Review,” Lasers in Surgery and Medicine 57, no. 1 (2025): 27-36.

[154] Z. Yin, X. H. Zhang, Y. Y. He, et al., “Combination Therapy of Pulsed Dye Laser and Ablative Fractional Carbon Dioxide Laser for the Treatment of Pediatric Postburn Scar: A Systematic Review,” Lasers in Medical Science 40, no. 1 (2025): 77.

[155] D. Seidel, M. Storck, H. Lawall, et al., “Negative Pressure Wound Therapy Compared With Standard Moist Wound Care on Diabetic Foot Ulcers in Real-Life Clinical Practice: Results of the German DiaFu-RCT,” BMJ Open 10, no. 3 (2020): e026345.

[156] P. Wei, L. Wu, H. Xie, Z. Chen, R. Tan, and Z. Xu, “Application of a Meshed Artificial Dermal Scaffold and Negative-Pressure Wound Therapy in the Treatment of Full-Thickness Skin Defects: A Prospective in Vivo Study,” Biomaterials Science 12, no. 7 (2024): 1914-1923.

[157] E. Lumsden, R. Kimble, C. McMillan, K. Storey, R. S. Ware, and B. Griffin, “The Feasibility of Negative Pressure Wound Therapy Versus Standard Dressings in Paediatric Hand and Foot Burns Protocol: A Pilot, Single-Centre, Randomised Control Trial,” Pilot and Feasibility Studies 9, no. 1 (2023): 90.

[158] M. Wu, D. Y. Matar, Z. Yu, et al., “Continuous NPWT Regulates Fibrosis in Murine Diabetic Wound Healing,” Pharmaceutics 14, no. 10 (2022): 2125.

[159] Y. B. Meng, J. Lei, H. R. Zhang, Z. M. Hao, P. Y. Bai, and P. Duan, “Clinical Effects of In Situ Perforation of Preserved Split Scar Matrix in Combination With Scalp Transplantation and Vacuum Sealing Drainage in the Treatment of Hypertrophic Scar in Non-Functional Sites After Burns” [in Chinese], Zhonghua Shao Shang Yu Chuang Mian Xiu Fu Za Zhi 2022; 38(3): 251-255.

[160] C. C. Hsu, W. C. Tsai, C. P. Chen, Y. M. Lu, and J. S. Wang, “Effects of Negative Pressures on Epithelial Tight Junctions and Migration in Wound Healing,” American Journal of Physiology. Cell Physiology 299, no. 2 (2010): C528-C534.

[161] T. R. Lin, F. H. Chou, H. H. Wang, and R. H. Wang, “Effects of Scar Massage on Burn Scars: A Systematic Review and Meta-analysis,” Journal of Clinical Nursing 32, no. 13-14 (2023): 3144-3154.

[162] T. Koller, “Mechanosensitive Aspects of Cell Biology in Manual Scar Therapy for Deep Dermal Defects,” IJMS 21, no. 6 (2020): 2055.

[163] B. Bordoni, A. R. Escher, G. T. Girgenti, F. Tobbi, and R. Bonanzinga, “Osteopathic Approach for Keloids and Hypertrophic Scars,” Cureus 15, no. 9 (2023): e44815.

[164] A. Lubczyńska, A. Garncarczyk, and D. Wcisło-Dziadecka, “Effectiveness of Various Methods of Manual Scar Therapy,” Skin Research and Technology 29, no. 3 (2023): e13272.

[165] A. Klingenstein, A. Garip-Kuebler, D. R. Muth, and C. Hintschich, “A Prospective Randomized Pilot Study Evaluating the Scar Outcome After Gluteal Dermis Fat Graft With and Without Kinesiotaping,” International Ophthalmology 42, no. 8 (2022): 2563-2571.

[166] L. Zhuang, J. Su, J. Jiao, and H. Li, “Utilizing Magnetic Discs Combined With Thin Silicone Gel Sheets for Pressure Therapy in Earlobe Keloid Postexcision,” Journal of the American Academy of Dermatology 92, no. 2 (2025): e35-e36.

[167] S. Napavichayanun, A. Vasuratna, S. Santibenchakul, S. Cherdchom, and P. Aramwit, “Evaluating Efficacy and Safety of the Topical Silicone Gel Containing Onion Extract in the Treatment of Post-Cesarean Surgical Scars,” Journal of Cosmetic Dermatology 21, no. 7 (2022): 2908-2915.

[168] N. Barone, T. Safran, J. Vorstenbosch, P. G. Davison, S. Cugno, and A. M. Murphy, “Current Advances in Hypertrophic Scar and Keloid Management,” Seminars in Plastic Surgery 35, no. 03 (2021): 145-152.

[169] I. De Decker, H. Hoeksema, E. Vanlerberghe, et al., “Occlusion and Hydration of Scars: Moisturizers Versus Silicone Gels,” Burns 49, no. 2 (2023): 365-379.

[170] R. Ogawa, S. Akita, S. Akaishi, et al., “Diagnosis and Treatment of Keloids and Hypertrophic Scars—Japan Scar Workshop Consensus Document 2018,” Burns Trauma 7 (2019): 39.

[171] J. Wiseman, M. Simons, R. Kimble, R. S. Ware, S. M. McPhail, and Z. Tyack, “Effectiveness of Topical Silicone Gel and Pressure Garment Therapy for Burn Scar Prevention and Management in Children 12-Months Postburn: A Parallel Group Randomised Controlled Trial,” Clinical Rehabilitation 35, no. 8 (2021): 1126-1141.

[172] K. C. Hsu and C. W. Luan, “Review of Silicone Gel Sheeting and Silicone Gel for the Prevention of Hypertrophic Scars and Keloids,” Wounds 29, no. 5 (2017): 154-158.

[173] E. E. M. Mohamed, H. L. Abd-Elaleem, and S. A. A. Zahran, “Silicone Gel Versus Combination of Silicone Gel and a 577-nm Diode Laser in the Treatment of Post-Surgery Hypertrophic Scar (Comparative Study),” Archives of Dermatological Research 317, no. 1 (2025): 324.

[174] F. Tian, Q. Jiang, J. Chen, and Z. Liu, “Silicone Gel Sheeting for Treating Keloid Scars,” Cochrane Database of Systematic Reviews (Online) 1, no. 1 (2023): CD013878.

[175] H. M. Powell and B. Nedelec, “Mechanomodulation of Burn Scarring via Pressure Therapy,” Advances in Wound Care 11, no. 4 (2022): 179-191.

[176] N. Obaidi, C. Keenan, and R. K. Chan, “Burn Scar Management and Reconstructive Surgery,” Surgical Clinics of North America 103, no. 3 (2023): 515-527.

[177] S. J. Hwang, J. Seo, J. Y. Cha, et al., “Utility of Customized 3D Compression Mask With Pressure Sensors on Facial Burn Scars: A Single-Blinded, Randomized Controlled Trial,” Burns 50, no. 7 (2024): 1885-1897.

[178] C. H. Santuzzi, F. M. Gonçalves Liberato, N. F. Fachini de Oliveira, A. Sgrancio do Nascimento, and L. R. Nascimento, “Massage, Laser and Shockwave Therapy Improve Pain and Scar Pruritus After Burns: A Systematic Review,” Journal of Physiotherapy 70, no. 1 (2024): 8-15.

[179] I. M. Harris, K. C. Lee, J. J. Deeks, D. J. Moore, N. S. Moiemen, and J. Dretzke, “Pressure-Garment Therapy for Preventing Hypertrophic Scarring After Burn Injury,” Cochrane Database of Systematic Reviews (Online) 1, no. 1 (2024): CD013530.

[180] I. De Decker, A. Beeckman, H. Hoeksema, et al., “Pressure Therapy for Scars: Myth or Reality? A Systematic Review,” Burns 49, no. 4 (2023): 741-756.

[181] E. Crofton, P. Meredith, P. Gray, S. O'Reilly, and J. Strong, “Non-Adherence With Compression Garment Wear in Adult Burns Patients: A Systematic Review and Meta-Ethnography,” Burns 46, no. 2 (2020): 472-482.

[182] S. Meng, Q. Wei, S. Chen, et al., “MiR-141-3p-Functionalized Exosomes Loaded in Dissolvable Microneedle Arrays for Hypertrophic Scar Treatment,” Small 20, no. 8 (2024): e2305374.

[183] T. Li, M. Zhang, Y. Li, et al., “Twist-Related Protein 1 Promotes Transforming Growth Factor β Receptor 1 in Keloid Fibroblasts via Regulating the Stability of Myocyte Enhancer Factor 2A,” Burns Trauma 12 (2024): tkae024.

[184] J. M. Hahn, K. A. Combs, C. M. Phillips, et al., “CYP24A1 is Overexpressed in Keloid Keratinocytes and Its Inhibition Alters Profibrotic Gene Expression,” Burns Trauma 13 (2025): tkae063.

[185] X. Zhou and S. Lin, “HOXC10 Promotes Hypertrophic Scar Fibroblast Fibrosis Through the Regulation of STMN2 and the TGF-β/Smad Signaling Pathway,” Histochemistry and Cell Biology 162, no. 5 (2024): 403-413.

[186] H. Cai, X. Liu, D. Liu, and B. Liu, “GEO Data Mining Identifies Potential Immune-Related Genes in Hypertrophic Scar and Verities in a Rabbit Model,” Heliyon 9, no. 7 (2023): e17266.

[187] B. Song, Y. Zhu, Y. Zhao, et al., “Machine Learning and Single-Cell Transcriptome Profiling Reveal Regulation of Fibroblast Activation Through THBS2/TGFβ1/P-Smad2/3 Signalling Pathway in Hypertrophic Scar,” International Wound Journal 21, no. 3 (2024): e14481.

[188] C. Liu, L. Khairullina, Y. Qin, Y. Zhang, and Z. Xiao, “Adipose Stem Cell Exosomes Promote Mitochondrial Autophagy Through the PI3K/AKT/mTOR Pathway to Alleviate Keloids,” Stem Cell Research & Therapy 15, no. 1 (2024): 305.

[189] J. Li, Y. Yin, J. Zou, et al., “The Adipose-Derived Stem Cell Peptide ADSCP2 Alleviates Hypertrophic Scar Fibrosis via Binding With Pyruvate Carboxylase and Remodeling the Metabolic Landscape,” Acta Physiologica 238, no. 4 (2023): e14010.

[190] Z. Ebrahimi, Y. Alimohamadi, M. Janani, P. Hejazi, M. Kamali, and A. Goodarzi, “Platelet-Rich Plasma in the Treatment of Scars, to Suggest or Not to Suggest? A Systematic Review and Meta-analysis,” Journal of Tissue Engineering and Regenerative Medicine 16, no. 10 (2022): 875-899.

[191] H. Qian, L. Zhang, C. Wang, M. Zhang, L. Wen, and W. Zhao, “Chlorpheniramine Maleate Exerts an Anti-Keloid Activity by Regulation of IL-6/JAK1/STAT3 Signaling Pathway,” International Immunopharmacology 148 (2025): 114181.

[192] I. Correia-Sá, P. Serrão, M. Marques, and M. A. Vieira-Coelho, “Hypertrophic Scars: Are Vitamins and Inflammatory Biomarkers Related With the Pathophysiology of Wound Healing?” Obesity Surgery 27, no. 12 (2017): 3170-3178.

[193] S. H. Kim, J. M. Oh, H. Roh, K. W. Lee, J. H. Lee, and W. J. Lee, “Zinc-Alpha-2-Glycoprotein Peptide Downregulates Type I and III Collagen Expression via Suppression of TGF-β and p-Smad 2/3 Pathway in Keloid Fibroblasts and Rat Incisional Model,” Tissue Engineering and Regenerative Medicine 21, no. 7 (2024): 1079-1092.

[194] B. Yuan, Z. Upton, D. Leavesley, C. Fan, and X. Q. Wang, “Vascular and Collagen Target: A Rational Approach to Hypertrophic Scar Management,” Advances in Wound Care 12, no. 1 (2023): 38-55.

[195] H. Shucheng, J. Li, Y. L. Liu, X. Chen, and X. Jiang, “Causal Relationship Between Gut Microbiota and Pathological Scars: A Two-Sample Mendelian Randomization Study,” Frontiers in Medicine 11 (2024): 1405097.

[196] Q. Sun, W. Chen, R. Wu, et al., “Serine Protease Inhibitor, SerpinA3n, Regulates Cardiac Remodelling After Myocardial Infarction,” Cardiovascular Research 120, no. 8 (2024): 943-953.

[197] R. Xie, C. Li, J. Yun, et al., “Identifying the Pattern Characteristics of Anoikis-Related Genes in Keloid,” Advances in Wound Care 14, no. 5 (2025): 223-237.

[198] N. Atefi, Z. P. Yeganeh, A. S. Bazargan, et al., “Evaluation of the Efficacy, Safety, and Satisfaction Rate of Topical Latanoprost in Patients With Hypopigmented Burn Scars Treated With Fractional CO₂ Laser: A Double-Blind Randomized Controlled Clinical Trial,” Lasers in Medical Science 40, no. 1 (2025): 14.

[199] C. Zhou, B. Zhang, Y. Yang, et al., “Stem Cell-Derived Exosomes: Emerging Therapeutic Opportunities for Wound Healing,” Stem Cell Research & Therapy 14, no. 1 (2023): 107.

[200] L. A. Walsh, E. Wu, D. Pontes, et al., “Keloid Treatments: An Evidence-Based Systematic Review of Recent Advances,” Systematic Reviews 12, no. 1 (2023): 42.

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