Severe traumatic wounds and burns have a high chance of mortality and can leave survivors with many functional disabilities and cosmetic problems, including scars. The healing process requires a harmonious interplay of various cells and growth factors. Different structures of the skin house numerous cells, matrix components and growth factors. Any disturbance in the balance between these components can impair the healing process. The function of cells and growth factors can be manipulated and facilitated to aid tissue repair. In the current review, the authors focus on the importance of the skin microenvironment, the pathophysiology of various types of burns, mechanisms and factors involved in skin repair and wound healing and regeneration of the skin using tissue engineering approaches.

Plain language summary

Wounds and ulcers, especially burn wounds, are major causes of morbidity and mortality and pose a significant burden for individuals and societies. The skin has numerous structures that play important roles in wound healing via cells and growth factors. Tissue engineering and regenerative medicine represent a rather new field that focuses on manipulating cells and growth factors, aiming to facilitate repair and regeneration of injured tissues and organs. This review focuses on different burn injuries that can result in nonhealing wounds, provides an overview of several cells and growth factors that are involved in the healing process of the skin and introduces various strategies practiced in tissue engineering with regard to cutaneous wound healing.

Graphical abstract

Keywords:

Papers of special note have been highlighted as: • of interest

References

1. Dissanaike S. Editorial on trends in burn injury. Ann. Surg. 270(6), 954 (2019).
MedlineGoogle Scholar
2. Bhattacharya Sameek. Burns: Etiology and classification. In: Principles and Practice of Burn Care. Sarabahi STVGoel A (Eds). Jaypee Publishers, New Delhi, India, 25–36 (2010).
Google Scholar
3. Tiwari V. Burn wound: how it differs from other wounds? Indian J. Plast. Surg. 45(2), 364–373 (2012).
Medline CASGoogle Scholar
4. Brandão C, Vaz M, Brito IM et al. Electrical burns: a retrospective analysis over a 10-year period. Ann. Burns Fire Disasters 30(4), 268–271 (2017).
Medline CASGoogle Scholar
5. WHO. Burns. www.who.int/news-room/fact-sheets/detail/burns
Google Scholar
6. Kaddoura I, Abu-Sittah G, Ibrahim A, Karamanoukian R, Papazian N. Burn injury: review of pathophysiology and therapeutic modalities in major burns. Ann. Burns Fire Disasters 30(2), 95 (2017).
Medline CASGoogle Scholar
7. Yousef H, Alhajj M, Sharma S. Anatomy, Skin (Integument), Epidermis. In: StatPearls [Internet]. StatPearls Publishing, Treasure Island, FL, USA (2022). [Updated 2021 Nov 19]. Available from: www.ncbi.nlm.nih.gov/books/NBK470464/
Google Scholar
8. Williams AE. Immunology of the Skin. In: Immunology. Williams AE. (Ed.). (2011). https://doi.org/10.1002/9781119998648.ch10
Google Scholar
9. Hashmi S, Marinkovich MP. Molecular organization of the basement membrane zone. Clin. Dermatol. 29(4), 398–411 (2011).
MedlineGoogle Scholar
10. Walker NJ, King KC. Acute and Chronic Thermal Burn Evaluation and Management. In: StatPearls [Internet]. StatPearls Publishing, Treasure sland, FL, USA (2022). [Updated 2021 Jul 21]. Available from: www.ncbi.nlm.nih.gov/books/NBK430730/
Google Scholar
11. Brans T, Dutrieux R, Hoekstra M, Kreis R, Du Pont J. Histopathological evaluation of scalds and contact burns in the pig model. Burns 20, S48–S51 (1994).
MedlineGoogle Scholar
12. Button B, Baker RD, Vertrees RA, Allen SE, Brodwick MS, Kramer GC. Quantitative assessment of a circulating depolarizing factor in shock. Shock 15(3), 239–244 (2001).
Medline CASGoogle Scholar
13. Evans JA, Darlington DN, Gann DS. A circulating factor (s) mediates cell depolarization in hemorrhagic shock. Ann. Surg. 213(6), 549 (1991).
Medline CASGoogle Scholar
14. Trunkey DD, Illner H, Arango A, Holiday R, Shires GT. Changes in cell membrane function following shock and cross-perfusion. Surgical forum. 25(0), 1–3 (1974).
MedlineGoogle Scholar
15. Friedstat J, Brown DA, Levi B. Chemical, electrical, and radiation injuries. Clin. Plast. Surg. 44(3), 657 (2017).
MedlineGoogle Scholar
16. Bounds EJ, Khan M, Kok SJ. Electrical Burns. In: StatPearls [Internet]. StatPearls Publishing, FL, USA (2022). [Updated 2021 May 4]. Available from: www.ncbi.nlm.nih.gov/books/NBK519514/
Google Scholar
17. Vučenović S, Šetrajčić JP, Vojnović M, Šetrajčić-Tomić AJ, Džambas LD. Physiological processes when an electrical current passes through the tissues and organs. Presented at: Fifth International Conference on radiation and applications in various fields of research. Budva, Montenegro (12.6 - 16/6 2017).
Google Scholar
18. Grimnes S. Dielectric breakdown of human skin in vivo. Med. Biol. Eng. Comput. 21(3), 379–381 (1983).
Medline CASGoogle Scholar
19. Waghmare CM. Radiation burn – from mechanism to management. Burns 39(2), 212–219 (2013).
MedlineGoogle Scholar
20. Koenig TR, Wolff D, Mettler FA, Wagner LK. Skin injuries from fluoroscopically guided procedures: part 1, characteristics of radiation injury. AJR Am. J. Roentgenol. 177(1), 3–11 (2001).
Medline CASGoogle Scholar
21. Palao R, Monge I, Ruiz M, Barret JP. Chemical burns: pathophysiology and treatment. Burns 36(3), 295–304 (2010).
Medline CASGoogle Scholar
22. Seth R, Chester D, Moiemen N. A review of chemical burns. Trauma 9(2), 81–94 (2007).
Google Scholar
23. Robson MC. Plastic Surgery: Principles and Practice. Jurkiewicz EA (Ed.). CV Mosby, MO, USA, 1355–1410 (1990).
Google Scholar
24. Williams FN, Lee JO. Chemical burns. In: Total Burn Care (5th Edition). Herndon DN (Ed.). Elsevier, 408–413.e401 (2018). eBook ISBN: 9780323497428
Google Scholar
25. Dinis-Oliveira RJ, Carvalho F, Moreira R et al. Clinical and forensic signs related to chemical burns: a mechanistic approach. Burns 41(4), 658–679 (2015).
MedlineGoogle Scholar
26. Matshes EW, Taylor KA, Rao VJ. Sulfuric acid injury. Am. J. Forensic Med. Pathol. 29(4), 340–345 (2008).
MedlineGoogle Scholar
27. Jelenko C 3rd. Chemicals that ‘burn.’ J. Trauma 14(1), 65–72 (1974).
Medline CASGoogle Scholar
28. Thorne CH, Gosain AK, Gurtner GC, Mehrara BJ, Rubin JP, Spear Sl. Grabb and Smith's Plastic Surgery (7th Edition). Lippincott Wiliams & Wilkins, London, UK(2014).
Google Scholar
29. Scalise A, Bianchi A, Tartaglione C et al. Microenvironment and microbiology of skin wounds: the role of bacterial biofilms and related factors. Semin. Vasc. Surg. 28(3), 151–159 (2015).
Medline CASGoogle Scholar
30. Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin. Dermatol. 25(1), 9–18 (2007).
Medline CASGoogle Scholar
31. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 453(7193), 314–321 (2008).
Medline CASGoogle Scholar
32. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92(8), 827–839 (2003).
Medline CASGoogle Scholar
33. Tizard IR. Immunity at body surfaces. In: Veterinary Immunology. Tizard IR (Ed.). Saunders, PA, USA, 222–234 (2000).
Google Scholar
34. Kubo T, Sugimoto K, Kojima T, Sawada N, Sato N, Ichimiya S. Tight junction protein claudin-4 is modulated via Δnp63 in human keratinocytes. Biochem. Biophys. Res. Commun. 455(3–4), 205–211 (2014).
Medline CASGoogle Scholar
35. Raja SK, Garcia MS, Isseroff RR. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front. Biosci. 12(3), 2849–2868 (2007).
Medline CASGoogle Scholar
36. Gasque P, Jaffar-Bandjee MC. The immunology and inflammatory responses of human melanocytes in infectious diseases. J. Infect. 71(4), 413–421 (2015).
MedlineGoogle Scholar
37. Plonka PM, Passeron T, Brenner M et al. What are melanocytes really doing all day long…? Exp. Dermatol. 18(9), 799–819 (2009).
Medline CASGoogle Scholar
38. Rognoni E, Watt FM. Skin cell heterogeneity in development, wound healing, and cancer. Trends Cell Biol. 28(9), 709–722 (2018).
MedlineGoogle Scholar
39. Brown TM, Krishnamurthy K. Histology, Dermis. [Updated 2021 Nov 19]. In: StatPearls [Internet]. StatPearls Publishing, FL, USA (2022) Available from: www.ncbi.nlm.nih.gov/books/NBK535346/
Google Scholar
40. Stunova A, Vistejnova L. Dermal fibroblasts – a heterogeneous population with regulatory function in wound healing. Cytokine Growth Factor Rev. 39, 137–150 (2018).
Medline CASGoogle Scholar
41. Darby IA, Zakuan N, Billet F, Desmouliere A. The myofibroblast, a key cell in normal and pathological tissue repair. Cell. Mol. Life Sci. 73(6), 1145–1157 (2016).
Medline CASGoogle Scholar
42. Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. International review of cytology. International review of cytology 257, 143–179 (2007).
Medline CASGoogle Scholar
43. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol. Med. 17(1), 113–125 (2011).
Medline CASGoogle Scholar
44. Li Z, Maitz P. Cell therapy for severe burn wound healing. Burns Trauma 6, 13 (2018).
MedlineGoogle Scholar
45. Nanba D. Human keratinocyte stem cells: from cell biology to cell therapy. J. Dermatol. Sci. 96(2), 66–72 (2019).
Medline CASGoogle Scholar
46. Spichkina OG, Kalmykova NV, Kukhareva LV, Voronkina IV, Blinova MI, Pinaev GP. Isolation of human basal keratinocytes by selective adhesion to extracellular matrix proteins. Tsitologiia 48(10), 841–847 (2006).
Medline CASGoogle Scholar
47. Hasebe Y, Hasegawa S, Hashimoto N et al. Analysis of cell characterization using cell surface markers in the dermis. J. Dermatol. Sci. 62(2), 98–106 (2011).
Medline CASGoogle Scholar
48. Iwata Y, Akamatsu H, Hasebe Y, Hasegawa S, Sugiura K. Skin-resident stem cells and wound healing. Nihon Rinsho Meneki Gakkai Kaishi 40(1), 1–11 (2017).
Medline CASGoogle Scholar
49. Iwata Y, Akamatsu H, Hasegawa S et al. The epidermal integrin beta-1 and p75^NTR positive cells proliferating and migrating during wound healing produce various growth factors, while the expression of p75^NTR is decreased in patients with chronic skin ulcers. J. Dermatol. Sci. 71(2), 122–129 (2013).
Medline CASGoogle Scholar
50. Hasebe Y, Hasegawa S, Hashimoto N et al. Analysis of cell characterization using cell surface markers in the dermis. J. Dermatol. Sci. 62(2), 98–106 (2011).
Medline CASGoogle Scholar
51. Iwata Y, Hasebe Y, Hasegawa S et al. Dermal CD271+ cells are closely associated with regeneration of the dermis in the wound healing process. Acta Derm. Venereol. 97(5), 593–600 (2017).
Medline CASGoogle Scholar
52. Hynds RE, Bonfanti P, Janes SM. Regenerating human epithelia with cultured stem cells: feeder cells, organoids and beyond. EMBO molecular medicine 10(2), 139–150 (2018).
Medline CASGoogle Scholar
53. Unger C, Gao S, Cohen M et al. Immortalized human skin fibroblast feeder cells support growth and maintenance of both human embryonic and induced pluripotent stem cells. Human reproduction (Oxford, England) 24(10), 2567–2581 (2009).
Medline CASGoogle Scholar
54. Werner S, Krieg T, Smola H. Keratinocyte–fibroblast interactions in wound healing. J. Invest. Dermatol. 127(5), 998–1008 (2007).
Medline CASGoogle Scholar
55. Maas-Szabowski N, Shimotoyodome A, Fusenig NE. Keratinocyte growth regulation in fibroblast cocultures via a double paracrine mechanism. J. Cell Sci. 112(12), 1843–1853 (1999).
MedlineGoogle Scholar
56. Waelti ER, Inaebnit SP, Rast HP et al. Co-culture of human keratinocytes on post-mitotic human dermal fibroblast feeder cells: production of large amounts of interleukin 6. J. Invest. Dermatol. 98(5), 805–808 (1992).
Medline CASGoogle Scholar
57. Smola H, Thiekötter G, Fusenig NE. Mutual induction of growth factor gene expression by epidermal–dermal cell interaction. J. Cell Biol. 122(2), 417–429 (1993).
Medline CASGoogle Scholar
58. Boxman IL, Ruwhof C, Boerman OC, Löwik CW, Ponec M. Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1. Arch. Dermatol. Res. 288(7), 391–398 (1996).
Medline CASGoogle Scholar
59. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr. Opin. Cell Biol. 9(2), 240–246 (1997).
Medline CASGoogle Scholar
60. Szabowski A, Maas-Szabowski N, Andrecht S et al. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal–epidermal interaction in skin. Cell 103(5), 745–755 (2000).
Medline CASGoogle Scholar
61. Florin L, Maas-Szabowski N, Werner S, Szabowski A, Angel P. Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts. J. Cell Sci. 118(9), 1981–1989 (2005).
Medline CASGoogle Scholar
62. Brazil JC, Quiros M, Nusrat A, Parkos CA. Innate immune cell–epithelial crosstalk during wound repair. J. Clin. Invest. 129(8), 2983–2993 (2019).
MedlineGoogle Scholar
63. Brinkmann V, Reichard U, Goosmann C et al. Neutrophil extracellular traps kill bacteria. Science 303(5663), 1532–1535 (2004).
Medline CASGoogle Scholar
64. Feiken E, Rømer J, Eriksen J, Lund LR. Neutrophils express tumor necrosis factor-alpha during mouse skin wound healing. J. Invest. Dermatol. 105(1), 120–123 (1995).
Medline CASGoogle Scholar
65. Campbell EL, Bruyninckx WJ, Kelly CJ et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40(1), 66–77 (2014).
Medline CASGoogle Scholar
66. Chen F, Yang W, Huang X et al. Neutrophils promote amphiregulin production in intestinal epithelial cells through TGF-β and contribute to intestinal homeostasis. J. Immunol. 201(8), 2492–2501 (2018).
Medline CASGoogle Scholar
67. Ramirez H, Patel SB, Pastar I. The role of TGFβ signaling in wound epithelialization. Adv. Wound Care (New Rochelle) 3(7), 482–491 (2014).
MedlineGoogle Scholar
68. Cox DA, Kunz S, Cerletti N, McMaster GK, Burk RR. Wound healing in aged animals – effects of locally applied transforming growth factor beta 2 in different model systems. EXS 61, 287–295 (1992).
Medline CASGoogle Scholar
69. Gharaee-Kermani M, Phan SH. Role of cytokines and cytokine therapy in wound healing and fibrotic diseases. Curr. Pharm. Des. 7(11), 1083–1103 (2001).
Medline CASGoogle Scholar
70. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 83(3), 835–870 (2003).
Medline CASGoogle Scholar
71. Beer HD, Longaker MT, Werner S. Reduced expression of PDGF and PDGF receptors during impaired wound healing. J. Invest. Dermatol. 109(2), 132–138 (1997).
Medline CASGoogle Scholar
72. Pierce GF, Tarpley JE, Tseng J et al. Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds. J. Clin. Invest. 96(3), 1336–1350 (1995).
Medline CASGoogle Scholar
73. Beer HD, Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam. Horm. 59, 217–239 (2000).
Medline CASGoogle Scholar
74. Niessen FB, Andriessen MP, Schalkwijk J, Visser L, Timens W. Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars. J. Pathol. 194(2), 207–216 (2001).
Medline CASGoogle Scholar
75. Haisa M, Okochi H, Grotendorst GR. Elevated levels of PDGF alpha receptors in keloid fibroblasts contribute to an enhanced response to PDGF. J. Invest. Dermatol. 103(4), 560–563 (1994).
Medline CASGoogle Scholar
76. Clark RA. Regulation of fibroplasia in cutaneous wound repair. Am. J. Med. Sci. 306(1), 42–48 (1993).
Medline CASGoogle Scholar
77. Seppä H, Grotendorst G, Seppä S, Schiffmann E, Martin GR. Platelet-derived growth factor in chemotactic for fibroblasts. J. Cell Biol. 92(2), 584–588 (1982).
Medline CASGoogle Scholar
78. Deuel TF, Senior RM, Huang J, Griffin G. Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J. Clin. Invest. 69(4), 1046–1049 (1982).
Medline CASGoogle Scholar
79. Risau W, Drexler H, Mironov V et al. Platelet-derived growth factor is angiogenic in vivo. Growth Factors 7(4), 261–266 (1992).
Medline CASGoogle Scholar
80. Nicosia RF, Nicosia S, Smith M. Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am. J. Pathol. 145(5), 1023 (1994).
Medline CASGoogle Scholar
81. Yun YR, Won JE, Jeon E et al. Fibroblast growth factors: biology, function, and application for tissue regeneration. J. Tissue Eng. 2010, 218142 (2010).
MedlineGoogle Scholar
82. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 103(2), 211–225 (2000).
Medline CASGoogle Scholar
83. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract (review). Int. J. Oncol. 29(1), 163–168 (2006).
Medline CASGoogle Scholar
84. Kolkova K, Novitskaya V, Pedersen N, Berezin V, Bock E. Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway. J. Neurosci. 20(6), 2238–2246 (2000).
Medline CASGoogle Scholar
85. Werner S, Breeden M, Hübner G, Greenhalgh DG, Longaker MT. Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse. J. Invest. Dermatol. 103(4), 469–473 (1994).
Medline CASGoogle Scholar
86. Shukla A, Dubey M, Srivastava R, Srivastava BS. Differential expression of proteins during healing of cutaneous wounds in experimental normal and chronic models. Biochem. Biophys. Res. Commun. 244(2), 434–439 (1998).
Medline CASGoogle Scholar
87. Swift ME, Kleinman HK, Dipietro LA. Impaired wound repair and delayed angiogenesis in aged mice. Lab. Invest. 79(12), 1479–1487 (1999).
Medline CASGoogle Scholar
88. Broadley K, Aquino A, Woodward S et al. Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. Lab. Invest. 61(5), 571–575 (1989).
Medline CASGoogle Scholar
89. Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C. Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc. Natl Acad. Sci. U. S. A. 95(10), 5672–5677 (1998).
Medline CASGoogle Scholar
90. Werner S, Smola H, Liao X et al. The function of KGF in epithelial morphogenesis and wound reepithelialization. Science 266, 819–822 (1994).
Medline CASGoogle Scholar
91. Igarashi M, Finch PW, Aaronson SA. Characterization of recombinant human fibroblast growth factor (FGF)-10 reveals functional similarities with keratinocyte growth factor (FGF-7). J. Biol. Chem. 273(21), 13230–13235 (1998).
Medline CASGoogle Scholar
92. Ornitz DM, Xu J, Colvin JS et al. Receptor specificity of the fibroblast growth factor family. J. Biol. Chem. 271(25), 15292–15297 (1996).
Medline CASGoogle Scholar
93. Guo L, Degenstein L, Fuchs E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev. 10(2), 165–175 (1996).
Medline CASGoogle Scholar
94. Schneider MR, Werner S, Paus R, Wolf E. Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology. Am. J. Pathol. 173(1), 14–24 (2008).
Medline CASGoogle Scholar
95. Cook PW, Pittelkow MR, Keeble WW, Graves-Deal R, Coffey RJ, Shipley GD. Amphiregulin messenger RNA is elevated in psoriatic epidermis and gastrointestinal carcinomas. Cancer Res. 52(11), 3224–3227 (1992).
Medline CASGoogle Scholar
96. Piepkorn M. Overexpression of amphiregulin, a major autocrine growth factor for cultured human keratinocytes, in hyperproliferative skin diseases. Am. J. Dermatopathol. 18(2), 165–171 (1996).
Medline CASGoogle Scholar
97. Rittié L, Kansra S, Stoll SW et al. Differential ErbB1 signaling in squamous cell versus basal cell carcinoma of the skin. Am. J. Pathol. 170(6), 2089–2099 (2007).
Medline CASGoogle Scholar
98. Dahlhoff M, Schneider MR. Transgenic mouse lines help decipher the roles of EGFR ligands in the skin. Exp. Dermatol. 25(3), 185–186 (2016).
Medline CASGoogle Scholar
99. Schneider MR, Antsiferova M, Feldmeyer L et al. Betacellulin regulates hair follicle development and hair cycle induction and enhances angiogenesis in wounded skin. J. Invest. Dermatol. 128(5), 1256–1265 (2008).
Medline CASGoogle Scholar
100. Shirakata Y, Kimura R, Nanba D et al. Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing. J. Cell Sci. 118(11), 2363–2370 (2005).
Medline CASGoogle Scholar
101. Yamazaki S, Iwamoto R, Saeki K et al. Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities. J. Cell Biol. 163(3), 469–475 (2003).
Medline CASGoogle Scholar
102. Su Y, Richmond A. Chemokine regulation of neutrophil infiltration of skin wounds. Adv. Wound Care (New Rochelle) 4(11), 631–640 (2015).
MedlineGoogle Scholar
103. Bryant VL, Slade CA. Chemokines, their receptors and human disease: the good, the bad and the itchy. Immunol. Cell Biol. 93(4), 364–371 (2015).
Medline CASGoogle Scholar
104. Baggiolini M. Chemokines in pathology and medicine. J. Intern. Med. 250(2), 91–104 (2001).
Medline CASGoogle Scholar
105. Drechsler M, Duchene J, Soehnlein O. Chemokines control mobilization, recruitment, and fate of monocytes in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 35(5), 1050–1055 (2015).
Medline CASGoogle Scholar
106. Bodnar RJ. Chemokine regulation of angiogenesis during wound healing. Adv. Wound Care (New Rochelle) 4(11), 641–650 (2015).
MedlineGoogle Scholar
107. Christopherson K, Hromas R. Chemokine regulation of normal and pathologic immune responses. Stem Cells 19(5), 388–396 (2001).
Medline CASGoogle Scholar
108. Dipietro LA, Polverini PJ, Rahbe SM, Kovacs EJ. Modulation of JE/MCP-1 expression in dermal wound repair. Am. J. Pathol. 146(4), 868 (1995).
Medline CASGoogle Scholar
109. Jackman SH, Yoak MB, Keerthy S, Beaver BL. Differential expression of chemokines in a mouse model of wound healing. Ann. Clin. Lab. Sci. 30(2), 201–207 (2000).
Medline CASGoogle Scholar
110. Wetzler C, Kämpfer H, Stallmeyer B, Pfeilschifter J, Frank S. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J. Invest. Dermatol. 115(2), 245–253 (2000).
Medline CASGoogle Scholar
111. Engelhardt E, Toksoy A, Goebeler M, Debus S, Bröcker EB, Gillitzer R. Chemokines IL-8, GROα, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am. J. Pathol. 153(6), 1849–1860 (1998).
Medline CASGoogle Scholar
112. Dipietro LA, Burdick M, Low QE, Kunkel SL, Strieter RM. MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. J. Clin. Invest. 101(8), 1693–1698 (1998).
Medline CASGoogle Scholar
113. Low QE, Drugea IA, Duffner LA et al. Wound healing in MIP-1α-/- and MCP-1-/- mice. Am. J. Pathol. 159(2), 457–463 (2001).
Medline CASGoogle Scholar
114. Ding J, Tredget EE. The role of chemokines in fibrotic wound healing. Adv. Wound Care (New Rochelle) 4(11), 673–686 (2015).
MedlineGoogle Scholar
115. Martins-Green M, Petreaca M, Wang L. Chemokines and their receptors are key players in the orchestra that regulates wound healing. Adv. Wound Care (New Rochelle) 2(7), 327–347 (2013).
MedlineGoogle Scholar
116. Rennekampff HO, Hansbrough JF, Woods V Jr, Doré C, Kiessig V, Schröder JM. Role of melanoma growth stimulatory activity (MGSA/gro) on keratinocyte function in wound healing. Arch. Dermatol. Res. 289(4), 204–212 (1997).
Medline CASGoogle Scholar
117. Jones SA, Wolf M, Qin S, Mackay CR, Baggiolini M. Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2. Proc. Natl Acad. Sci. U. S. A. 93(13), 6682–6686 (1996).
Medline CASGoogle Scholar
118. Rennekampff HO, Hansbrough JF, Kiessig V, Doré C, Sticherling M, Schröder JM. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J. Surg. Res. 93(1), 41–54 (2000).
Medline CASGoogle Scholar
119. Iocono JA, Colleran KR, Remick DG, Gillespie BW, Ehrlich HP, Garner WL. Interleukin-8 levels and activity in delayed-healing human thermal wounds. Wound Repair Regen. 8(3), 216–225 (2000).
Medline CASGoogle Scholar
120. Puapatanakul P, Chansritrakul S, Susantitaphong P et al. Interferon-inducible protein 10 and disease activity in systemic lupus erythematosus and lupus nephritis: a systematic review and meta-analysis. Int. J. Mol. Sci. 20(19), 4954 (2019).
CASGoogle Scholar
121. Luster AD, Cardiff RD, Maclean JA, Crowe K, Granstein RD. Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine. Proc. Assoc. Am. Physicians 110(3), 183–196 (1998).
Medline CASGoogle Scholar
122. Belperio JA, Keane MP, Arenberg DA et al. CXC chemokines in angiogenesis. J. Leukoc. Biol. 68(1), 1–8 (2000).
Medline CASGoogle Scholar
123. Luster AD, Greenberg SM, Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J. Exp. Med. 182(1), 219–231 (1995).
Medline CASGoogle Scholar
124. Singer AJ, Quinn JV, Clark RE, Hollander JE, Group TS. Closure of lacerations and incisions with octylcyanoacrylate: a multicenter randomized controlled trial. Surgery 131(3), 270–276 (2002).
MedlineGoogle Scholar
125. Kim H, Kim W, Kang GH et al. Comparison of Leukosan SkinLink with surgical suture for traumatic laceration repair: a randomized controlled trial. Medicine (Baltimore) 97(25), e10918 (2018).
MedlineGoogle Scholar
126. Stone RC, Stojadinovic O, Rosa AM et al. A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers. Sci. Transl. Med. 9(371), eaaf8611 (2017).
MedlineGoogle Scholar
127. Cogliati B, Vinken M, Silva TC et al. Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice. J. Dermatol. Sci. 79(1), 50–56 (2015).
Medline CASGoogle Scholar
128. Rhett JM, Jourdan J, Gourdie RG. Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol. Biol. Cell 22(9), 1516–1528 (2011).
Medline CASGoogle Scholar
129. Grek CL, Prasad G, Viswanathan V, Armstrong DG, Gourdie RG, Ghatnekar GS. Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: a multicenter, randomized trial. Wound Repair Regen. 23(2), 203–212 (2015).
MedlineGoogle Scholar
130. Ghatnekar GS, Grek CL, Armstrong DG, Desai SC, Gourdie RG. The effect of a connexin43-based peptide on the healing of chronic venous leg ulcers: a multicenter, randomized trial. J. Invest. Dermatol. 135(1), 289–298 (2015).
Medline CASGoogle Scholar
131. Ghatnekar GS, O'Quinn MP, Jourdan LJ, Gurjarpadhye AA, Draughn RL, Gourdie RG. Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regen. Med. 4(2), 205–223 (2009).
CASGoogle Scholar
132. Shi A, Li J, Qiu X et al. TGF-β loaded exosome enhances ischemic wound healing in vitro and in vivo. Theranostics 11(13), 6616–6631 (2021). • Introduces a rather novel process and an interesting new product.
Medline CASGoogle Scholar
133. Atiyeh BS, Costagliola M. Cultured epithelial autograft (CEA) in burn treatment: three decades later. Burns 33(4), 405–413 (2007).
MedlineGoogle Scholar
134. Karlsson M, Steinvall I, Olofsson P et al. Sprayed cultured autologous keratinocytes in the treatment of severe burns: a retrospective matched cohort study. Ann. Burns Fire Disasters 33(2), 134 (2020).
Medline CASGoogle Scholar
135. Yim H, Yang HT, Cho YS et al. Clinical study of cultured epithelial autografts in liquid suspension in severe burn patients. Burns 37(6), 1067–1071 (2011).
MedlineGoogle Scholar
136. Schlabe J, Johnen C, Schwartlander R et al. Isolation and culture of different epidermal and dermal cell types from human scalp suitable for the development of a therapeutical cell spray. Burns 34(3), 376–384 (2008).
MedlineGoogle Scholar
137. Esteban-Vives R, Young MT, Zhu T et al. Calculations for reproducible autologous skin cell-spray grafting. Burns 42(8), 1756–1765 (2016).
MedlineGoogle Scholar
138. Gerlach JC, Johnen C, Ottomann C et al. Method for autologous single skin cell isolation for regenerative cell spray transplantation with non-cultured cells. Int. J. Artif. Organs 34(3), 271–279 (2011).
MedlineGoogle Scholar
139. Matsumura H, Gondo M, Imai R, Shibata D, Watanabe K. Chronological histological findings of cultured epidermal autograft over bilayer artificial dermis. Burns 39(4), 705–713 (2013).
MedlineGoogle Scholar
140. Jeong JH. Adipose stem cells and skin repair. Curr. Stem Cell Res. Ther. 5(2), 137–140 (2010).
Medline CASGoogle Scholar
141. Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen. 14(3), 325–335 (2006).
MedlineGoogle Scholar
142. Mao HS, Wang YP, Wang Q et al. Prospective randomized controlled study on clinical effects of autologous skin paste in repairing medium-thickness skin donor site wounds. Zhonghua Shao Shang Za Zhi 37(3), 232–236 (2021).
Medline CASGoogle Scholar
143. Leung A, Balaji S, Keswani SG. Biology and function of fetal and pediatric skin. Facial Plast. Surg. Clin. North Am. 21(1), 1 (2013).
MedlineGoogle Scholar
144. Guo SA, Dipietro LA. Factors affecting wound healing. J. Dent. Res. 89(3), 219–229 (2010).
Medline CASGoogle Scholar
145. Holmes JHT, Schurr MJ, King BT et al. An open-label, prospective, randomized, controlled, multicenter, phase 1b study of StrataGraft skin tissue versus autografting in patients with deep partial-thickness thermal burns. Burns 45(8), 1749–1758 (2019).
MedlineGoogle Scholar
146. Gholian S, Pishgahi A, Shakouri SK et al. Use of autologous conditioned serum dressings in hard-to-heal wounds: a randomised prospective clinical trial. J. Wound Care 31(1), 68–77 (2022). • Examines autologous conditioned serum as a dressing for nonhealing wounds; autologous serum collection and conditioning have been shown to be effective and rather easy to perform.
MedlineGoogle Scholar
147. Tissue-Engineered Skin Graft Repair of Autologous Scar Dermal Scaffolds. https://clinicaltrials.gov/show/NCT04389164
Google Scholar
148. Autologous Keratinocyte Suspension Versus Adipose-Derived Stem Cell–Keratinocyte Suspension for Post-Burn Raw Area. https://clinicaltrials.gov/show/NCT03686449
Google Scholar
149. Study With an Autologous Dermo-epidermal Skin Substitute for the Treatment of Full-Thickness Skin Defects in Adults and Children. https://clinicaltrials.gov/show/NCT03394612
Google Scholar
150. Controlled Comparison of a Traditional Dressing Versus a Biologic Dressing Composed of Fetal Fibroblasts and Keratinocytes in Association With a Collagen Matrix on Skin Donor Sites (CICAFAST). https://clinicaltrials.gov/show/NCT03334656
Google Scholar
151. Efficacy and Safety of Heberprot-P^® in Patients With Advanced Diabetic Foot Ulcer in Dasman Diabetes Institute.. https://clinicaltrials.gov/show/NCT03239457
Google Scholar
152. Study With an Autologous Dermo-epidermal Skin Substitute for the Treatment of Burns in Children. https://clinicaltrials.gov/ct2/show/NCT03229564
Google Scholar
153. Study With an Autologous Dermo-epidermal Skin Substitute for the Treatment of Burns in Adults. https://clinicaltrials.gov/show/NCT03227146
Google Scholar
154. Allogeneic ADSCs and Platelet-Poor Plasma Fibrin Hydrogel to Treat the Patients With Burn Wounds (ADSCs-BWs) (ADSCs-BWs). https://clinicaltrials.gov/show/NCT03113747
Google Scholar
155. StrataGraft^® Skin Tissue in the Promotion of Autologous Skin Regeneration of Complex Skin Defects Due to Thermal Burns That Contain Intact Dermal Elements. https://clinicaltrials.gov/show/NCT03005106
Google Scholar
156. The Activity of Tissue Engineering Skin Substitutes (MSCs). https://clinicaltrials.gov/show/NCT02668042
Google Scholar
157. ExpressGraft-C9T1 Skin Tissue as a Treatment of Diabetic Foot Ulcers. https://clinicaltrials.gov/show/NCT02657876
Google Scholar
158. EktoTherix^™ Regenerative Tissue Scaffold for Repair of Surgical Excision Wounds. https://clinicaltrials.gov/show/NCT02409628
Google Scholar
159. Phase I Study for Autologous Dermal Substitutes and Dermo-epidermal Skin Substitutes for Treatment of Skin Defects. https://clinicaltrials.gov/show/NCT02145130
Google Scholar
160. Feasibility Study for Fibroblast Autologous Skin Grafts. https://clinicaltrials.gov/show/NCT01964859
Google Scholar
161. A Comparative Efficacy Study: Treatment for Non-healing Diabetic Foot Ulcers. https://clinicaltrials.gov/show/NCT01858545
Google Scholar
162. Study Investigating the Safety and Efficacy of HP802-247 in the Treatment of Venous Leg Ulcers >12 cm² to ≤36 cm². https://clinicaltrials.gov/show/NCT01737762
Google Scholar
163. Study Investigating the Safety and Efficacy of HP802-247 in the Treatment of Venous Leg Ulcers. https://clinicaltrials.gov/show/NCT01656889
Google Scholar
164. Effect of Platelet Rich Plasma and Keratinocyte Suspensions on Wound Healing. https://clinicaltrials.gov/show/NCT00856934
Google Scholar
165. Application of Cultured Autologous Keratinocytes for Burn Wound Healing (KC). https://clinicaltrials.gov/show/NCT00832156
Google Scholar
166. Clinical Application of Autologous Three-Cellular Cultured Skin Substitutes (CSS). https://clinicaltrials.gov/show/NCT00718978
Google Scholar
167. Efficacy and Safety Study of DERMAGEN^® vs Conventional Treatment to Treat Diabetic Neuropathic Foot Ulcer (DERMAGEN^®). https://clinicaltrials.gov/show/NCT00521937
Google Scholar
168. Evaluation of Safety and Activity of Celaderm in Healing Venous Leg Ulcers. https://clinicaltrials.gov/show/NCT00399308
Google Scholar

Vol. 17, No. 6

Metrics

Downloaded 201 times

History

Received 24 February 2022

Accepted 1 April 2022

Published online 12 May 2022

Published in print June 2022

Information

Keywords

Author contributions

PM Yeganeh and S Tahmasebi contributed to gathering data, writing the primary draft of the manuscript and designing figures and tables. A Esmaeilzadeh is the corresponding author and contributed to the hypothesis, corresponding, scientific and structural editing and verification of the manuscript before submission.

Acknowledgments

The authors would like to acknowledge our professor, A Esmaeilzadeh, for his valuable guidance and motivation and for encouraging us to complete this article. The authors would also like to thank our friend MH Khatibi for his much appreciated help in revising and editing the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

PDF download