КОЖНЫЕ РАНЫ И ИХ МОДЕЛИРОВАНИЕ В ЭКСПЕРИМЕНТЕ

Заживление кожных ран представляет собой сложный процесс с участием многих типов клеток и медиаторов. Изучение механизмов регенерации кожи требует создания экспериментальных моделей, позволяющих анализировать динамику раневого процесса, выявлять влияющие на него факторы и разрабатывать новые методы лечения. Цель исследования – обобщение имеющихся в мировой литературе сведений о патогенезе раневого процесса и экспериментальных моделях механического повреждения кожи. Материал и методы исследования - статьи, опубликованные в научных изданиях и доступные для поиска в сети Интернет (базы данных eLibrary и PubMed). Поиск осуществлялся по следующим ключевым словам: кожные раны, реге-нерация кожи, заживление ран, ссадины, линейные раны, инцизионные раны, эксцизионные раны, skin wounds, skin regeneration, wound healing, abrations, linear wound, incisional wound, excisional wound. В результате анализа усыновлено, что процесс репаративной регенерации кожи включает три взаимосвязанных этапа: гемостаз и воспаление, пролиферацию клеток и восстановление тканей и ремоделирование. Несмотря на то, что некоторые аспекты заживления ран могут быть изучены in vitro, воспроизведение регенеративного процесса в условиях целостного организма требует использования лабораторных животных. Как правило, кожные раны моделируют на крысах и мышах, реже используют более крупных животных (кроликов, свиней, овец). Модели механического повреждения кожи используют для оценки терапевтического эффекта ранозаживляющих средств, перевязочных материалов, физиотерапевтических методов воздействия на регенеративный процесс, таких, как фототерапия лазерным излучением и электромеханическая стимуляция. Состояние поврежденной кожи анализируют морфометрическими, гистологическими, иммуногистохимическими и молекулярно-генетическими методами. Наиболее распространенные модели механического повреждения кожи – это ссадины, полнослойные линейные и эксцизионные раны. Они могут служить основой для воспроизведения хронических ран, заживление которых затруднено нарушениями метаболизма или иммунного статуса, дисциркуляторными расстройствами, инфекциями или другими причинами. При изучении повреждений кожи следует помнить о неполном соответствии характера и процессов ее регенерации у животных и человека, в связи с чем результаты моделирования требуют подтверждения в соответствующих клинических исследованиях.

1. Robson MC, Steed DL, Franz MG. Wound healing: biologic features and approaches to maximize healing traectories. Curr Probl Surg. 2001;38(2):72-140. https://doi.org/10.1067/msg.2001.111167

2. Maksimova NV, Lyundup AV, Lyubimov RO i dr. Patofiziologicheskie aspekty protsessa zazhivleniya ran v norme i pri sindrome diabeticheskoy stopy. Vestnik Rossiyskoy akademii meditsinskikh nauk. 2014;69(11-12):110-117. In Russian

3. Sorg H, Sorg CGG. Skin wound healing: Of players, patterns, and processes. Eur Surg Res. 2023;64(2):141-157. https://doi.org/10.1159/000528271

4. Mahdavian Delavary B, van der Veer WM et al. Macrophages in skin injury and repair. Immunobiology. 2011;216(7):753-762. https://doi.org/10.1016/j.imbio.2011.01.001

5. Scully D, Sfyri P, Wilkinson HN et al. Optimising platelet secretomes to deliver robust tissue-specific regeneration. J Tissue Eng Regen Med. 2020;14(1):82-98. https://doi.org/10.1002/term.2965

6. Kingsley K, Huff JL, Rust WL et al. ERK1/2 mediates PDGF-BB stimulated vascular smooth muscle cell proliferation and migration on laminin-5. Biochem Biophys Res Commun. 2002;293(3):1000-1006. https://doi.org/10.1016/S0006-291X(02)00331-5

7. Ebermeyer T, Cognasse F, Berthelot P et al. Platelet innate immune receptors and TLRs: A double-edged sword. Int J Mol Sci. 2021;22(15):7894. https://doi.org/10.3390/ijms22157894

8. Wang PH, Huang BS, Horng HC et al. Wound healing. J Chin Med Assoc. 2018;81(2):94-101. https://doi.org/10.1016/j.jcma.2017.11.002

9. 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

10. Larouche J, Sheoran S, Maruyama K, Martino MM. Immune regulation of skin wound healing: Mechanisms and novel therapeutic targets. Adv Wound Care (New Rochelle). 2018;7(7):209-231. https://doi.org/10.1089/wound.2017.0761

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

12. Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci. 2016;73(20):3861-3885. https://doi.org/10.1007/s00018-016-2268-0

13. Hassanshahi A, Moradzad M, Ghalamkari S. Macrophage-mediated inflammation in skin wound healing. Cells. 2022;11(19):2953. https://doi.org/10.3390/cells11192953

14. Shaw TJ, Martin P. Wound repair: a showcase for cell plasticity and migration. Curr Opin Cell Biol. 2016;42:29-37. https://doi.org/10.1016/j.ceb.2016.04.001

15. Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol. 2007;25(1):9-18. https://doi.org/10.1016/j.clindermatol.2006.09.007.

16. Santoro MM, Gaudino G. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Exp Cell Res. 2005;304(1):274-286. https://doi.org/10.1016/j.yexcr.2004.10.033

17. Baum CL, Arpey CJ. Normal cutaneous wound healing: clinical correlation with cellular and molecular events. Dermatol Surg. 2005;31(6):674-686. https://doi.org/10.1111/j.1524-4725.2005.31612

18. Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle). 2015;4(3):119-136. https://doi.org/10.1089/wound.2013.0485

19. Huang SP, Wu MS, Shun CT, et al. Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma. J Biomed Sci. 2005;12(1):229-241. https://doi.org/10.1007/s11373-004-8177-5

20. Rennert RC, Sorkin M, Garg RK, Gurtner GC. Stem cell recruitment after injury: lessons for regenerative medicine. Regen Med. 2012;7(6):833-850. https://doi.org/10.2217/rme.12.82

21. Niehues H, Bouwstra JA, Ghalbzouri A et al. 3D skin models for 3R research: The potential of 3D reconstructed skin models to study skin barrier function. Exp Dermatol. 2018;27(5):501-511. https://doi.org/10.1111/exd.13531

22. Stamm A, Reimers K, Strauß S et al. In vitro wound healing assays - State of the art. BioNanoMat. 2016;17(1-2):79-87. https://doi.org/10.1515/bnm-2016-0002

23. Hofmann E, Fink J, Pignet AL et al. Human in vitro skin models for wound healing and wound healing disorders. Biomedicines. 2023;11(4):1056. https://doi.org/10.3390/biomedicines11041056

24. Masson-Meyers DS, Andrade TAM, Caetano GF et al. Experimental models and methods for cutaneous wound healing assessment. Int J Exp Pathol. 2020;101(1-2):21-37. https://doi.org/10.1111/iep.12346

25. Elliot S, Wikramanayake TC, Jozic I et al. A modeling conundrum: murine models for cutaneous wound healing. J Invest Dermatol. 2018;138(4):736-740. https://doi.org/10.1016/j.jid.2017.12.001

26. Grada A, Mervis J, Falanga V. Research techniques made simple: Animal models of wound healing. J Invest Dermatol. 2018;138(10):2095-2105.e1. https://doi.org/10.1016/j.jid.2018.08.005

27. Reid RR, Said HK, Mogford E et al. The future of wound healing: pursuing surgical models in transgenic and knockout mice. J Am Coll Surg. 2004;199(4):578-585. https://doi.org/10.1016/j.jamcollsurg.2004.05.262

28. Shrimanker M, Patel N, Modi H et al. A review: screening models for wound healing activity in animals. Am J Pharm Tech Res. 2013;3(3):237-251

29. Warner RL, Bhagavathula N, Nerusu K et al. MDI 301, a nonirritating retinoid, improves abrasion wound healing in damaged/atrophic skin. Wound Repair Regen. 2008;16(1):117-124. https://doi.org/10.1111/j.1524-475X.2007.00338.x

30. Stupin VA, Smirnova GO, Manturova NE i dr. Sravnitel'ny analiz protsessov zazhivleniya khirurgicheskikh ran pri ispol'zovanii razlichnykh vidov radiochastotnykh rezhushchikh ustroystv i metallicheskogo skal'pelya. Chelovek i ego zdorov'e. 2010;4:9-14. In Russian

31. Pavlyut' TO, Melik-Kasumov TB, Zhavoronok IP i dr. Vliyanie N-pal'mitoiletanolamina i N-stearoiletanolamina v liposomal'noy forme na zazhivlenie eksperimental'nykh ran kozhi. Novosti khirurgii. 2016;24(5):425-435. In Russian. https://doi.org/10.18484/2305-0047.2016.5.425

32. Obraztsova AE, Nozdrevatykh AA. Morfofunktsional'nye osobennosti reparativnogo protsessa pri zazhivlenii kozhnykh ran s uchetom vozmozhnykh rubtsovykh deformatsiy (obzor literatury). Vestnik novykh meditsinskikh tekhnologiy. Elektronnoe izdanie. 2021;15(1). In Russian. https://doi.org/10.24412/2075-4094-2021-1-3-3

33. Payushina OV, Butorina NN, Sheveleva ON i dr. Vliyanie mezenkhimal'nykh stromal'nykh kletok i konditsionirovannoy sredy na zazhivlenie kozhnykh ran. 2018;165:572–575. In Russian

34. Medhora M, Gasperetti T, Schamerhorn A et al. Wound trauma exacerbates acute, but not delayed, effects of radiation in rats: Mitigation by Lisinopril. Int J Mol Sci. 2020;21(11):3908. https://doi.org/10.3390/ijms21113908

35. Silina EV, Stupin VA, Suzdaltseva YG et al. Application of polymer drugs with cerium dioxide nanomolecules and mesenchymal stem cells for the treatment of skin wounds in aged rats. Polymers (Basel). 2021;13(9):1467. https://doi.org/10.3390/polym13091467

36. Gulyaev AE, Shul'gau ZT, Sergazy ShD i dr. Ranozazhivlyayushchee i protivovospalitel'noe deystvie rekombinantnogo angiogenina cheloveka. Biopreparaty. Profilaktika, diagnostika, lechenie. 2022;22(3):293-307. In Russian. https://doi.org/10.30895/2221-996X-2022-22-3-293-307

37. Yao G, Mo X, Yin C et al. A programmable and skin temperature-activated electromechanical synergistic dressing for effective wound healing. Sci Adv. 2022;8(4):eabl8379. https://doi.org/10.1126/sciadv.abl8379

38. Ren H, Zhang Z, Cheng X et al. Inectable, self-healing hydrogel adhesives with firm tissue adhesion and on-demand biodegradation for sutureless wound closure. Sci Adv. 2023;9(33):eadh4327. https://doi.org/10.1126/sciadv.adh4327

39. Zhang Z, Chen T, Liu W et al. Paeonol accelerates skin wound healing by regulating macrophage polarization and inflammation in diabetic rats. Korean J Physiol Pharmacol. 2023;27(5):437-448. https://doi.org/10.4196/kjpp.2023.27.5.437

40. Gopee NV, Roberts DW, Webb P et al. Quantitative determination of skin penetration of PEG-coated CdSe quantum dots in dermabraded but not intact SKH-1 hairless mouse skin. Toxicol Sci. 2009;111(1):37-48. https://doi.org/10.1093/toxsci/kfp139

41. Dai T, Tegos GP, Zhiyentayev T et al. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model. Lasers Surg Med. 2010;42(1):38-44. https://doi.org/10.1002/lsm.20887

42. Dunn L, Prosser HC, Tan JT et al. Murine model of wound healing. J Vis Exp. 2013;(75):e50265. https://doi.org/10.3791/50265

43. Gupta A, Dai T, Hamblin MR. Effect of red and near-infrared wavelengths on low-level laser (light) therapy-induced healing of partial-thickness dermal abrasion in mice. Lasers Med Sci. 2014;29(1):257-265. https://doi.org/10.1007/s10103-013-1319-0

44. Li Y, Xu T, Tu Z et al. Bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with high angiogenesis for promoting diabetic wound healing and skin repair. Theranostics. 2020;10(11):4929-4943. https://doi.org/10.7150/thno.41839

45. Chen Z, Zhang B, Shu J et al. Human decellularized adipose matrix derived hydrogel assists mesenchymal stem cells delivery and accelerates chronic wound healing. J Biomed Mater Res A. 2021;109(8):1418-1428. https://doi.org/10.1002/jbm.a.37133

46. Rhea L, Dunnwald M. Murine excisional wound healing model and histological morphometric wound analysis. J Vis Exp. 2020;(162):10.3791/61616. https://doi.org/10.3791/61616

47. Shidin VA, Aptekar' IA, Akhmatov AV i dr. Morfogenez kozhnogo regenerata i lokal’nye faktory ego regulyatsii. Ul'yanovskiy mediko-biologicheskiy zhurnal. 2023;(4):153-168. In Russian. https://doi.org/10.34014/2227-1848-2023-4-153-168

48. Dovnar RI. Modelirovanie kozhnykh ran v eksperimente. Novosti khirurgii. 2021;29(4):480-489. In Russian. https://doi.org/10.18484/2305-0047.2021.4.480

49. Xu X, Cui N, Wang E. Application of an acellular dermal matrix to a rabbit model of oral mucosal defects. Experimental and therapeutic medicine. 2018;15(3):2450-2456

50. Gerasimenko AY, Morozova EA, Ryabkin DI et al. Reconstruction of soft biological tissues using laser soldering technology with temperature control and biopolymer nanocomposites. Bioengineering (Basel). 2022;9(6):238. https://doi.org/10.3390/bioengineering9060238

51. Martinello T, Gomiero C, Perazzi A et al. Allogeneic mesenchymal stem cells improve the wound healing process of sheep skin. BMC Vet Res. 2018;14(1):202. https://doi.org/10.1186/s12917-018-1527-8

52. Zaruby J, Gingras K, Taylor J, Maul D. An in vivo comparison of barbed suture devices and conventional monofilament sutures for cosmetic skin closure: biomechanical wound strength and histology. Aesthet Surg J. 2011;31(2):232-240. https://doi.org/10.1177/1090820X10395010

53. Mauskar NA, Sood S, Travis TE et al. Donor site healing dynamics: molecular, histological, and noninvasive imaging assessment in a porcine model. J Burn Care Res. 2013;34(5):549-562. https://doi.org/10.1097/BCR.0b013e3182839aca

54. Swindle MM, Makin A, Herron AJ et al. Swine as models in biomedical research and toxicology testing. Vet Pathol. 2012;49(2):344-356. https://doi.org/10.1177/0300985811402846

55. Wong VW, Sorkin M, Glotzbach JP et al. Surgical approaches to create murine models of human wound healing. J Biomed Biotechnol. 2011;2011:969618. https://doi.org/10.1155/2011/969618

56. Tamrazova OB. Reparativnaya terapiya «malykh» ran s pozitsii dermatologa i kosmetologa. Allergologiya i immunologiya v pediatrii. 2019;2(57):4-12. In Russian. https://doi.org/10.24411/2500-1175-2019-00006

57. Shrestha R, Krishan K, Ishaq H, Kanchan T. Abrasion. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. App. Date is 06/06/2024. URL: https://www.ncbi.nlm.nih.gov/books/NBK554465

58. Domaratskaya EI, Payushina OV. Perspektivy ispol’zovaniya mezenkhimnykh stromal’nykh kletok dlya regeneratsii povrezhdennoy kozhi. Uspekhi sovremennoy biologii. 2017;137(1):56-69. In Russian