PROBLEMS OF HEALING SOFT TISSUE INJURIES

Authors

DOI:

https://doi.org/10.21272/eumj.2025;13(1):1-13

Keywords:

skin and muscle injuries, wound healing, reparative processes, chronic wounds

Abstract

Introduction. Wound healing is one of the key physiological processes that ensure human survival, and at the same time, it is an urgent medical problem. This literature review presents modern ideas on the repair of soft tissue injuries in normal and in various pathological conditions.

Methods. The literature review was based on published scientific studies using the information retrieval systems PubMed, Web of Science, Scopus, Google Scholar, and ResearchGate. We mainly reviewed the studies that were published in the last 5 years. 77 scientific papers were selected for the article.

Results. The structure and cellular composition, the role of stem cells of the skin and muscle tissue in the regenerative aspect were analyzed. The histological characteristics of the stages of healing, as well as the effect of some pro-inflammatory and anti-inflammatory interleukins, growth factors, are given. Scientific data indicate that repairing acute wounds is a strictly coordinated process in time and space of the interaction of various cell pools and bioactive molecules. Analysis of experimental and clinical studies also reflects the sensitivity of the healing process to the action of both local and systemic factors. The influence of such factors leads to the transition of acute wounds into chronic ones. Mechanisms of disorders arising from excessive inflammation and synthesis of the extracellular matrix, delay of re-epithelialization are given in the review. The influence of infection, hypoxia, hormonal and dietary disorders, hyperglycemia, venous hypertension, kidney diseases, and tissue compression is highlighted.

Conclusions. The skin and underlying muscles are often exposed to injuries and have significant regenerative and repair capabilities. Acute wounds go through a series of successive stages in their healing process, which ensure the restoration of the morphological and functional properties of tissues. Under the influence of various factors acute soft tissue injuries can turn into chronic, long-term wounds. Such wounds are characterized by disturbances in the sequence and duration of healing stages, intercellular and cell-matrix interactions, and the dynamics of regulatory cytokines. Further scientific research on the pathogenesis of chronic wounds will contribute to their more successful treatment.

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References

Krishtafor DA, Klygunenko OM, Krishtafor AA. Comparative characteristics of civilian and military multiple trauma in a level III hospital. Emergency Medicine (Ukraine). 2019;3(98):127–33.[Ukrainian]. https://doi.org/10.22141/2224-0586.3.98.2019.165490

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(1-2):81-94. https://doi.org/10.1159/000454919

Babenko NM, Litvinova OB, Pavlov SB, Kumechko MV, Komarchuk VV. Problems of healing chronic wounds. Modern Medical Technology. 2023;58(3):66–70. https://doi.org/10.34287/MMT.3(58).2023.10

Prince N, Penatzer JA, Dietz MJ, Boyd JW. Impact of Cytokines and Phosphoproteins in Response to Chronic Joint Infection. Biology (Basel). 2020;9(7): 167. https://doi.org/ https://doi.org/10.3390%2Fbiology9070167

Gonzales AK, Fuchs E. Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche. Dev Cell. 2017;43(4):387-401. https://doi.org/10.1016/j.devcel.2017.10.001

Jang H, Jo Y, Lee JH, Choi S. Aging of hair follicle stem cells and their niches. BMB Rep. 2023;56(1):2-9. doi: 10.5483/BMBRep.2022-0183.

Page ME, Lombard P, Ng F, Gottgens B, Jensen KB. The epidermis comprises autonomous compartments maintained by distinct stem cell populations. Cell Stem Cell. 2013;13:471-82. https://doi.org/10.1016/j.stem.2013.07.010

Vietri Rudan M, Watt FM. Mammalian Epidermis: A Compendium of Lipid Functionality. Front Physiol. 2022;12:804824. https://doi.org/10.3389/fphys.2021.804824

Gaur M, Dobke M, Lunyak VV. Mesenchymal Stem Cells from Adipose Tissue in Clinical Applications for Dermatological Indications and Skin Aging. Int J Mol Sci. 2017;18(1):208. https://doi.org/10.3390/ijms18010208

Lefèvre-Utile A, Braun C, Haftek M, Aubin F. Five Functional Aspects of the Epidermal Barrier. Int J Mol Sci. 2021;22(21):11676. https://doi.org/10.3390%2Fijms222111676

Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG. Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics. Cells. 2020;9(5):1313. https://doi.org/10.3390/cells9051313

Niu P, Smagul A, Wang L, Sadvakas A, Ying S, Pérez LM, Nussupbekova A, Amirbekov A, Akanov AA, Gálvez BG, Jordan IK, Lunyak VV. Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence. Oncotarget. 2015;6(20):17938-57. https://doi.org/10.18632/oncotarget.4852

Roh NK, Kim MJ, Lee YW, Choe YB, Ahn KJ. A Split-Face Study of the Effects of a Stabilized Hyaluronic Acid-Based Gel of Nonanimal Origin for Facial Skin Rejuvenation Using a Stamp-Type Multineedle Injector: A Randomized Clinical Trial. Plast Reconstr Surg. 2016;137:809–16. https://doi.org/10.1097/01.prs.0000480686.68275.60

Naderi N, Combellack EJ, Griffin M, Sedaghati T, Javed M, Findlay MW, Wallace CG, Mosahebi A, Butler PE, Seifalian AM. The regenerative role of adipose-derived stem cells (adsc) in plastic and reconstructive surgery. Int Wound J. 2017;14:112–24. https://doi.org/10.1111/iwj.12569

Li Y, Long J, Zhang Z, Yin W. Insights into the unique roles of dermal white adipose tissue (dWAT) in wound healing. Front Physiol. 2024;15:1346612. https://doi.org/10.3389/fphys.2024.1346612

Kaczmarek A, Kaczmarek M, Ciałowicz M, Clemente FM, Wolański P, Badicu G, Murawska-Ciałowicz E. The Role of Satellite Cells in Skeletal Muscle Regeneration-The Effect of Exercise and Age. Biology (Basel). 2021;10(10):1056. https://doi.org/10.3390/biology10101056

Comai G, Tajbakhsh S. Molecular and cellular regulation of skeletal myogenesis. Curr Top Dev Biol. 2014;110:1-73. https://doi.org/10.1016/B978-0-12-405943-6.00001-4

Godo S, Shimokawa H. Endothelial Functions. Arterioscler Thromb Vasc Biol. 2017;37(9):e108-e114. https://doi.org/10.1161/ATVBAHA.117.309813

Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound Healing: A Cellular Perspective. Physiol Rev. 2019;99(1):665-706. https://doi.org/10.1152/physrev.00067.2017

Li X, Sim MMS, Wood JP. Recent Insights Into the Regulation of Coagulation and Thrombosis. Arterioscler Thromb Vasc Biol. 2020;40(5):e119-e125. https://doi.org/10.1161/ATVBAHA.120.312674

Reinke JM, Sorg H. (). Wound repair and regeneration. Eur Surg Res. 2012;49(1):35-43. https://doi.org/10.1159/000339613

Gonzalez A, Costa T, Andrade Z, Medrado A. Wound healing - A literature review. An Bras Dermatol. 2016;91(5):614-60. https://doi.org/10.1590/abd1806-4841.20164741

Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci Transl Med. 2014;265:265sr6. https://doi.org/10.1126/scitranslmed.3009337

Sharifiaghdam M, Shaabani E, Faridi-Majidi R, De Smedt SC, Braeckmans K, Fraire J. Macrophages as a therapeutic target to promote diabetic wound healing. Mol Ther. 2022;30(9):2891-2908. https://doi.org/10.1016/j.ymthe.2022.07.016

Hassanshahi A, Moradzad M, Ghalamkari S, Fadaei M, Cowin A, Hassanshahi M. Macrophage-Mediated Inflammation in Skin Wound Healing. Cells. 2022;11(19):2953. https://doi.org/10.3390/cells11192953

Brancato SK, Albina JE. Wound macrophages as key regulators of repair: origin, phenotype, and function. Am J Pathol. 2011;178(1):19-25. https://doi.org/10.1016/j.ajpath.2010.08.003

Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, Bhasker V, Gordillo GM, Sen CK, Roy S. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PloS One. 2010;5(3):e9539. https://doi.org/10.1371/journal.pone.0009539

Meszaros AJ, Reichner JS, Albina JE. Macrophage-induced neutrophil apoptosis. J Immunol. 2000;165(1):435-41. https://doi.org/10.4049/jimmunol.165.1.435

Joorabloo A, Liu T. Recent advances in nanomedicines for regulation of macrophages in wound healing. J Nanobiotechnology. 2022;20(1):407. https://doi.org/10.1186/s12951-022-01616-1

Rittié L. Cellular mechanisms of skin repair in humans and other mammals. J Cell Commun Signal. 2016;10(2):103-20. https://doi.org/10.1007/s12079-016-0330-1

Wilkinson HN, Hardman MJ. Wound healing: cellular mechanisms and pathological outcomes. Open Biol. 2020;10(9):200223. https://doi.org/10.1098/rsob.200223

Jacinto A, Martinez-Arias A, Martin P. Mechanisms of epithelial fusion and repair. Nat Cell Biol. 2001;3(5):E117–E123. https://doi.org/10.1038/35074643

Ashraf JV, Ayman AZ. Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis. Int J Mol Sci. 2021;22(19):10585. https://doi.org/10.3390/ijms221910585

Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–21. https://doi.org/10.1038/nature07039

Barker TH. The role of ECM proteins and protein fragments in guiding cell behavior in regenerative medicine. Biomaterials. 2011;32:4211–14. https://doi.org/10.1016/j.biomaterials.2011.02.027

Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol. 2007;127(3):526-37. https://doi.org/10.1038/sj.jid.5700613

Tziotzios C, Profyris C, Sterling J. Cutaneous scarring: pathophysiology, molecular mechanisms, and scar reduction therapeutics. J Am Acad Dermatol. 2012;66:13–24. https://doi.org/10.1016/j.jaad.2011.05.055

Gardner T, Kenter K, Li Y. Fibrosis following Acute Skeletal Muscle Injury: Mitigation and Reversal Potential in the Clinic. J Sports Med (Hindawi Publ Corp). 2020; 2020:7059057. https://doi.org/10.1155/2020/7059057

Yang W, Hu P. Skeletal muscle regeneration is modulated by inflammation. J Orthop Translat. 2018; 13:25-32. https://doi.org/10.1016/j.jot.2018.01.002

Forcina L, Miano C, Scicchitano B, Musarò A. Signals from the niche: insights into the role of IGF-1 and IL-6 in modulating skeletal muscle fibrosis. Cells. 2019;8(3):232. https://doi.org/10.3390%2Fcells8030232

Serra MB, Barroso WA, da Silva NN, Silva SDN, Borges ACR, Abreu IC, Borges M. From Inflammation to Current and Alternative Therapies Involved in Wound Healing. Int J Inflam. 2017; 2017:3406215. https://doi.org/10.1155/2017/3406215

Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33(3):127–48. https://doi.org/10.1093/intimm/dxaa078

Narazaki M, Kishimoto T. The two-faced cytokine il-6 in host defense and diseases. Int J Mol Sci. 2018;19(11):3528. https://doi.org/10.3390/ijms19113528

Steen-Louws C, Hartgring SAY, Popov-Celeketic J, Lopes AP, de Smet MBM, Eijkelkamp N, Lafeber FPJG, Hack CE, van Roon JAG. IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin-4 and interleukin-10. Clin Exp Immunol. 2019;195(1):1–9. https://doi.org/10.1111/cei.13224

Zhu ZX, Sun CC, Ting ZY, Wang Y, Wang T, Chi LS, Cai WH, Zheng JY, Zhou X, Cong WT, Li XK, Jin LT. Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration. Exp Cell Res. 2017;355(2): 83–94. https://doi.org/10.1016/j.yexcr.2017.03.054

Matsumine H, Niimi Y. Basic fibroblast growth factor-impregnated collagen gelatin sponge completes formation of dermis-like tissue within 2 weeks: A prospective cohort study. Regen Ther. 2022;21:210-5. https://doi.org/10.1016/j.reth.2022.07.007

Wilgus T.A. Vascular Endothelial Growth Factor and Cutaneous Scarring. Adv Wound Care (New Rochelle). 2019;8(12):671–8. https://doi.org/10.1089/wound.2018.0796

Kisacik ÖG, Güneş Ü, Yaprakçi MV, Altunbaş K. Effectiveness of bitter melon extract in the treatment of ischemic wounds in rats. Turk J Biol. 2018;42(6): 506–16. https://doi.org/10.3906/biy-1804-36

Zhao R, Liang H, Clarke E, Jackson C, Xue M. Inflammation in chronic wounds. Int J Mol Sci. 2016;17(12):2085. https://doi.org/10.3390/ijms17122085

Waheed TO, Hahn O, Sridharan K, Mörke C, Kamp G, Peters K. Oxidative Stress Response in Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells. Int J Mol Sci. 2022;23(21):13435. https://doi.org/10.3390/ijms232113435

Rössler S, Nischwitz SP, Luze H, Holzer-Geissler JCJ, Zrim R, Kamolz LP. In Vivo Models for Hypertrophic Scars-A Systematic Review. Medicina (Kaunas). 2022:58(6):736. https://doi.org/10.3390/medicina58060736

Ogawa R. Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis. Int J Mol Sci. 2017;18(3):606. https://doi.org/10.3390/ijms18030606

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. Exp Dermatol. 2021;30(1):146-61. https://doi.org/10.1111/exd.14121

Xue M, Jackson CJ. Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring. Adv Wound Care (New Rochelle). 2015;4(3):119–36. https://doi.org/10.1089/wound.2013.0485

Huang C, Ogawa R. The vascular involvement in soft tissue fibrosis-lessons learned from pathological scarring. Int J Mol Sci. 2020;21:2542. https://doi.org/10.3390%2Fijms21072542

Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, Merchant A, Galiano RD, Tomic-Canic M. Molecular Pathogenesis of Chronic Wounds—The role of b-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol. 2005;167:59–69. https://doi.org/10.1016/S0002-9440(10)62953-7

Gushiken LFS, Beserra FP, Bastos JK, Jackson CJ, Pellizzon CH. Cutaneous Wound Healing: An Update from Physiopathology to Current Therapies. Life (Basel). 2021;11(7):665. https://doi.org/10.3390/life11070665

Tottoli EM, Dorati R, Genta I, Chiesa E, Pisani S, Conti B. Skin Wound Healing Process and New Emerging Technologies for Skin Wound Care and Regeneration. Pharmaceutics. 2020;12(8):735. https://doi.org/10.3390/pharmaceutics12080735

Ružička J, Dejmek J, Bolek L, Beneš J, Kuncová J. Hyperbaric oxygen influences chronic wound healing - a cellular level review. Physiol Res. 2021;70(S3):S261-S273. https://doi.org/10.33549/physiolres.934822

Beyene RT, Derryberry JSL, Barbul A. The effect of comorbidities on wound healing. Surg Clin North Am. 2020;100(4):695–705. https://doi.org/10.1016/j.suc.2020.05.002

Wild T, Rahbarnia A, Kellner M, Sobotka L, Eberlein T. Basics in nutrition and wound healing. Nutrition. 2010;26(9):862-6. https://doi.org/10.1016/j.nut.2010.05.008

Takahashi A, Flanigan ME, McEwen BS, Russo SJ. Aggression, Social Stress, and the Immune System in Humans and Animal Models. Front Behav Neurosci. 2018;12:56. https://doi.org/10.3389/fnbeh.2018.00056

Horng HC, Chang WH, Yeh CC, Huang BS, Chang CP, Chen YJ, Tsui KH, Wang PH. Estrogen Effects on Wound Healing. Int J Mol Sci. 2017;18(11):2325. https://doi.org/10.3390/ijms18112325

Gilliver SC, Ashworth JJ, Ashcroft GS. The hormonal regulation of cutaneous wound healing. Clin Dermatol. 2007;25(1):56-62. https://doi.org/10.1016/j.clindermatol.2006.09.012

Pavlov S, Babenko N, Kumetchko M, Litvinova O, Mikhaylusov R. Features of Metabolism in Chronic Wound Remodelling. Scr Med (Banja Luka). 2024; 55(1):53–61. https://doi.org/10.5937/scriptamed55-48179

Golovakha M, Klyatsky Yu, Kozhemyaka M, Maslennikov S, Kosylo V. Justification of the complex treatment of purulous complications of foot injuries in patients with diabetes mellitus. East Ukr Med J. 2024;12(2):359-368. https://doi.org/10.21272/eumj.2024;12(2):359-368

Maksymova OS, German SM, Moskalenko PO, Yasenok VO, Gortynska OM, Hortynskyi KM, Tkach GF. Features of skin wounds healing under chronic hyperglycemia and improvement of their treatment methods. Wiad Lek. 2021;74(5):1174-9. https://doi.org/10.36740/WLek202105124

Zhou W, Duan Z, Zhao J, Fu R, Zhu C, Fan D. Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing. Bioact Mater. 2022;17:1-17. https://doi.org/10.1016/j.bioactmat.2022.01.004

Yu T, Gao M, Yang P, Liu D, Wang D, Song F, Zhang X, Liu Y. Insulin promotes macrophage phenotype transition through PI3K/Akt and PPAR-γ signaling during diabetic wound healing. J Cell Physiol. 2019;234(4):4217-31. https://doi.org/10.1002/jcp.27185

Azar J, Rao Amit, Oropallo A. Chronic venous insufficiency: a comprehensive review of management. J Wound Care. 2022;31(6):510-9. https://doi.org/10.12968/jowc.2022.31.6.510

Querfeld U, Mak RH, Pries AR. Microvascular disease in chronic kidney disease: the base of the iceberg in cardiovascular comorbidity. Clin Sci (Lond). 2020;134(12):1333–56. https://doi.org/10.1042/CS20200279

Robles-Mendez JC, Vazquez-Martinez O, Ocampo-Candiani J. Skin manifestations of chronic kidney disease. Actas Dermosifiliogr (Engl Ed). 2015;106(8):609–22. https://doi.org/10.1016/j.ad.2015.05.007

Webster J, Liu Z, Norman G, Dumville JC, Chiverton L, Scuffham P, Stankiewicz M, Chaboyer WP. Negative pressure wound therapy for surgical wounds healing by primary closure. Cochrane Database Syst Rev. 2019;3(3): CD009261. https://doi.org/10.1002/14651858.CD009261.pub4

Connolly, M., Ibrahim, Z.R. & Johnson, O.N. Changing paradigms in lower extremity reconstruction in war-related injuries. Military Med Res. 2016;3:9. https://doi.org/10.1186/s40779-016-0080-7

Pavlov S, Litvinova O, Mikhaylusov R, Negoduyko V, Kumetchko M, Semko N. Healing features of experimental injuries of soft tissues that contain foreign bodies in the form of fragments of military personnel uniforms. BMJ Mil Health. 2021;169(e1):e59-e63. https://doi.org/10.1136/bmjmilitary-2020-001666

Weber B, Lackner I, Haffner-Luntzer M, Palmer A, Pressmar J, Scharffetter-Kochanek K, Knöll B, Schrezenemeier H, Relja B, Kalbitz M. Modeling trauma in rats: similarities to humans and potential pitfalls to consider. J Transl Med. 2019;17(1):305.https://doi.org/10.1186/s12967-019-2052-7

Martin P, Nunan R. Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol. 2015;173(2):370-8. https://doi.org/10.1111/bjd.13954

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Published

2025-03-29

How to Cite

Litvinova, O. ., Kumetchko, M. ., Pavlov, S. ., Babenko, N. ., & Kolisnyk, I. . (2025). PROBLEMS OF HEALING SOFT TISSUE INJURIES. Eastern Ukrainian Medical Journal, 13(1), 1–13. https://doi.org/10.21272/eumj.2025;13(1):1-13

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LITERATURE REVIEW. SURGERY