cfpdБюллетень физиологии и патологии дыханияBulletin Physiology and Pathology of Respiration1998-5029Дальневосточный научный центр физиологии и патологии дыхания10.36604/1998-5029-2020-77-117-124cfpd-827Research ArticleОБЗОРЫREVIEWSКлеточная терапия в лечении ожогов кожиCell therapy in treatment of skin burnsЯценкоА. А.YatsenkoA. A.

Антон Андреевич Яценко, врач-патологоанатом, аспирант

Anton A. Yatsenko, MD, Pathologist, Postgraduate Student

mdyatsenko@gmail.comБаранниковС. В.BarannikovS. V.

Сергей Владимирович Баранников, студент 6 курса лечебного факультета

Sergey V. Barannikov, 6 th year Student of Medical Faculty

barannikovsv97@gmail.comМакаровИ. Ю.MakarovI. Yu.

Игорь Юрьевич Макаров, д-р мед. наук, профессор, зав. кафедрой патологической анатомии с курсом судебной медицины

Igor Yu. Makarov, MD, PhD, D.Sc. (Med.), Professor, Head of Department of Pathology

prorektoragma@mail.ruБороздаИ. В.BorozdaI. V.

Иван Викторович Борозда, д-р мед. наук, профессор, зав. кафедрой травматологии с курсом медицины катастроф

Ivan V. Borozda, MD, PhD, D.Sc. (Med.), Professor, Head of Department of Traumatology

bivdok@mail.ruСпиринаЮ. А.SpirinaYu. A.

Юлия Алексеевна Спирина, студентка 3 курса лечебного факультета

Yulia A. Spirina, 3rd year Student of Medical Faculty

julia_spirina99@mail.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Амурская государственная медицинская академия» Министерства здравоохранения Российской Федерации; Общество с ограниченной ответственностью «Ай Кью Биофабрик»Amur State Medical Academy; Scientific Research Center “IQ Biofabric"Федеральное государственное бюджетное образовательное учреждение высшего образования «Амурская государственная медицинская академия» Министерства здравоохранения Российской ФедерацииAmur State Medical Academy202027092020077117124Copyright © Яценко А.А., Баранников С.В., Макаров И.Ю., Борозда И.В., Спирина Ю.А., 20202020Яценко А.А., Баранников С.В., Макаров И.Ю., Борозда И.В., Спирина Ю.А.Yatsenko A.A., Barannikov S.V., Makarov I.Y., Borozda I.V., Spirina Y.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cfpd.elpub.ru/jour/article/view/827

В обзоре обобщены результаты современных исследований в области клеточной терапии ожогов кожи. Описана актуальность проведения данных исследований, как в России, так и в мире. Обозначены методики воздействия на регенерацию кожи после ожогов помимо клеточной терапии. Дана историческая справка о развитии методов клеточной терапии ожоговых повреждений кожи. Приведены документы, регламентирующие проведение клеточной терапии в России. Описаны преимущества и недостатки клеточных технологий с использованием кератиноцитов. Проанализированы методы клеточной терапии ожогов кожи с применением фибробластов. Описана роль в регенерации кожи трехмерных тканеинженерных конструкций – скаффолдов. Дана их классификация по продолжительности покрытия раны (постоянные, полупостоянные и временные), по составу (клеточные, бесклеточные), по виду материала (синтетические, биологические, которые в свою очередь делятся на аллогенные и аутологичные). Описаны основные представители каждой группы, используемые в исследованиях в качестве терапии в лечении ожогов кожи: Biobrane, Integra, Dermagraft, TransCyte, Hyalograft 3D, эпидермальный заменитель Laser skin, система аутотрансплантата TissueTech. Приведены данные по экспериментальному тестированию каждого из представителей. Также затронут вопрос улучшения васкуляризации тканеинженерных конструкций с применением биореакторов. По результатам обзора сделан вывод о том, что использование трехмерных конструкций в лечении ожоговых повреждений кожи показывает наибольшую среди проанализированных вариантов клеточной терапии эффективность и безопасность при применении в клинической практике. В то же время существующие недостатки проанализированных образцов требуют дальнейших изучения и анализа.

The review summarizes the results of modern research in the field of cell therapy for skin burns. The relevance of conducting these studies both in Russia and in the world is described. The methods of influence on the skin regeneration after burns in addition to cell therapy are indicated. A history reference on the development of cell therapy for burn skin lesions is given. The documents governing the conduct of cell therapy in Russia are presented. The advantages and disadvantages of cell technology using keratinocytes are described. The methods of cell therapy for skin burns using fibroblasts are analyzed. The role of three-dimensional tissue-engineered structures – scaffolds in the regeneration of the skin is described. Their classification is given by the duration of wound coverage (permanent, semi-permanent and temporary), by composition (cellular, acellular), by type of material (synthetic, biological, which are divided into allogeneic and autologous). The main representatives of each group that are used in research as therapy in the treatment of skin burns are described: Biobrane, Integra, Dermagraft, TransCyte, Hyalograft 3D, Laser skin epidermal replacement, TissueTech autograft system. The data on the experimental testing of each of the representatives are presented. The issue of improving vascularization of tissue-engineering structures using bioreactors was also raised. According to the results of the review, it was concluded that the use of three-dimensional structures in the treatment of burn skin lesions shows the greatest efficacy and safety among pronounced cell therapy options in clinical practice. At the same time, the existing drawbacks of the analyzed samples require further study and analysis.

клеточная терапияожоги кожискаффолдыcell therapyskin burnsscaffoldsReferencesЕвдокимов В.И., Коуров А.С. Генезис научных исследований по ожоговой травме (анализ отечественных журнальных статей в 2005–2017 гг.) // Медико-биологические и социально-психологические проблемы безопасности в чрезвычайных ситуациях. 2018. №4. С.108–120. https://doi.org/10.25016/2541-7487-2018-0-4-108-120Evdokimov V.I., Kourov A.S. Genesis of research on burn injury (analysis of domestic articles in 2005–2017). Mediko-biologičeskie i socialʹno-psihologičeskie problemy bezopasnosti v črezvyčajnyh situaciâh = Medicо-Biological and Socio-Psychological Problems of Safety in Emergency Situations 2018; (4):108–120 (in Russian).Олифирова О.С., Козка А.А. Способ оптимизации лечения ран различного генеза // Тихоокеанский медицинский журнал. 2019. №2. С.80–83. https://doi.org/10.17238/PmJ1609-1175.2019.2.80-83https://doi.org/10.25016/2541-7487-2018-0-4-108-120Olifirova O.S., Kozka A.A., Volosenkova E.A. Possibilities of therapy optimization of patients with superficial burning wounds // Амурский медицинский журнал. 2017. №3(19). С.140–141. doi: 10.22448/AMJ.2017.3.140-141Olifirova O.S., Kozka A.A. Optimization techniques to treat injuries of different genesis. Pacific Medical Journal 2019; (2):80–83 (in Russian). https://doi.org/10.17238/PmJ1609-1175.2019.2.80-83Metcalfe AD, Ferguson MWJ. Bioengineering skin using mechanisms of regeneration and repair // Biomaterials. 2007. Vol.28, Iss.34. Р.5100–5113. doi: 10.1016/j.biomaterials.2007.07.031.Olifirova O.S., Kozka A.A., Volosenkova E.A. Possibilities of therapy optimization of patients with superficial burning wounds. Аmurskiy meditsinskiy zhurnal = Amur Medical Journal 2017; (3):140–141. doi: 10.22448/AMJ.2017.3.140-141Groeber F., Holeiter M., Hampel M., Hinderer S., Schenke-Layland K. Skin tissue engineering – in vivo and in vitro applications // Adv. Drug Deliv. Rev. 2011. Vol.63, Iss.4-5. P.352–366. doi: 10.1016/j.addr.2011.01.005Metcalfe A.D., Ferguson M.W.J. Bioengineering skin using mechanisms of regeneration and repair. Biomaterials 2007; 28(34):5100–5113. doi: 10.1016/j.biomaterials.2007.07.031Gantwerker E.A., Hom D.B. Skin: histology and physiology of wound healing // Clin. Plast. Surg. 2012. Vol.39. Iss.1. Р.85–97. doi: 10.1016/j.cps.2011.09.005Groeber F., Holeiter M., Hampel M., Hinderer S., Schenke-Layland K. Skin tissue engineering – in vivo and in vitro applications. Adv. Drug Deliv. Rev. 2011; 63(4-5):352–366. doi: 10.1016/j.addr.2011.01.005Gallico G.G.3rd, O'Connor N.E, Compton C.C., Kehinde O., Green H. Permanent coverage of large burn wounds with autologous cultured human epithelium // New Engl. J. Med. 1984. Vol.311, Iss.7. P.448–451. doi: 10.1056/NEJM198408163110706Gantwerker E.A., Hom D.B. Skin: histology and physiology of wound healing. Clin. Plast. Surg. 2012; 39(1):85–97. doi: 10.1016/j.cps.2011.09.005Potten C.S., Booth C. Keratinocyte stem cells: a commentary // J. Invest. Dermatol. 2002. Vol.119, №4. Р.888–899. doi: https://doi.org/10.1046/j.1523-1747.2002.00020.xGallico G.G.3rd, O'Connor N.E, Compton C.C., Kehinde O., Green H. Permanent coverage of large burn wounds with autologous cultured human epithelium. New Engl. J. Med. 1984; 311(7):448–451. doi:10.1056/NEJM198408163110706Ronfard V., Rives J.M., Neveux Y., Carsin H., Barrandon Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix // Transplantation. 2000; Vol.70. №11. Р.1588–1598. doi: 10.1097/00007890-200012150-00009Potten C.S, Booth C. Keratinocyte stem cells: a commentary. J. Invest. Dermatol. 2002; 119(4):888–899. doi: https://doi.org/10.1046/j.1523-1747.2002.00020.xSood R., Roggy D., Zieger M., Balledux J., Chaudhari S., Koumanis D.J., Mir H.S., Cohen A., Knipe C., Gabehart K., Coleman J.J. Cultured epithelial autografts for coverage of large burn wounds in eighty-eight patients: the Indiana University experience // J. Burn Care Res. 2010; Vol.31. №4. Р.559–568. doi: 10.1097/BCR.0b013e3181e4ca29Ronfard V., Rives J.M., Neveux Y., Carsin H., Barrandon Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation 2000; 70(11):1588–1598. doi: 10.1097/00007890-200012150-00009Billingham R.E., Reynolds J. Transplantation studies on sheets of pure epidermal epithelium and on epidermal cell suspensions // Br. J. Plast. Surg. 1952. Vol.5, №1. Р.25–36. doi: 10.1016/s0007-1226(52)80004-9Sood R., Roggy D., Zieger M., Balledux J., Chaudhari S., Koumanis D.J., Mir H.S., Cohen A., Knipe C., Gabehart K., Coleman J.J. Cultured epithelial autografts for coverage of large burn wounds in eighty-eight patients: the Indiana University experience. J. Burn Care Res. 2010; 31(4):559–568. doi: 10.1097/BCR.0b013e3181e4ca29Schlabe J., Johnen C., Schwartlander R., Moser V., Hartmann B., Gerlach J.C., Küntscher M.V. Isolation and culture of different epidermal and dermal cell types from human scalp suitable for the development of a therapeutical cell spray // Burns. 2008. Vol.34, №3. Р.376–384. doi: 10.1016/j.burns.2007.04.005Billingham R.E., Reynolds J. Transplantation studies on sheets of pure epidermal epithelium and on epidermal cell suspensions. Br. J. Plast. Surg. 1952; 5(1):25–36. doi: 10.1016/s0007-1226(52)80004-9Svensjö T., Yao F., Pomahac B., Eriksson E. Autologous keratinocyte suspensions accelerate epidermal wound healing in pigs // J. Surg. Res. 2001. Vol.99, №2. Р.211–221. doi: 10.1006/jsre.2001.6197Schlabe J., Johnen C., Schwartlander R., Moser V., Hartmann B., Gerlach J.C., Küntscher M.V. Isolation and culture of different epidermal and dermal cell types from human scalp suitable for the development of a therapeutical cell spray. Burns 2008; 34(3):376–384. doi: 10.1016/j.burns.2007.04.005Kopp J., Jeschke M.G., Bach A.D., Kneser U., Horch R.E. Applied tissue engineering in the closure of severe burns and chronic wounds using cultured human autologous keratinocytes in a natural fibrin matrix // Cell Tissue Bank. 2004. Vol.5. №2. Р.89–96. doi: 10.1023/B:CATB.0000034082.29214.3dSvensjö T., Yao F., Pomahac B., Eriksson E. Autologous keratinocyte suspensions accelerate epidermal wound healing in pigs. J. Surg. Res. 2001; 99(2):211–221. doi: 10.1006/jsre.2001.6197Eldardiri M., Martin Y., Roxburgh J., Lawrence-Watt D.J., Sharpe J.R. Wound contraction is significantly reduced by the use of microcarriers to deliver keratinocytes and fibroblasts in an in vivo pig model of wound repair and regeneration // Tissue Eng. Part A. 2012. Vol.18, №5-6. Р.587–597. doi: 10.1089/ten.TEA.2011.0258Kopp J., Jeschke M.G., Bach A.D., Kneser U., Horch R.E. Applied tissue engineering in the closure of severe burns and chronic wounds using cultured human autologous keratinocytes in a natural fibrin matrix. Cell Tissue Bank. 2004; 5(2):89–96. doi: 10.1023/B:CATB.0000034082.29214.3dNolte S.V., Xu W., Rennekampff H.O., Rodemann H.P. Diversity of Fibroblasts – A Review on Implications for Skin Tissue Engineering // Cells Tissues Organs. 2008. Vol.187, №3. Р.165–176. doi: 10.1159/000111805Eldardiri M., Martin Y., Roxburgh J., Lawrence-Watt D.J., Sharpe J.R. Wound contraction is significantly reduced by the use of microcarriers to deliver keratinocytes and fibroblasts in an in vivo pig model of wound repair and regeneration. Tissue Eng. Part A 2012; 18(5-6):587–597. doi: 10.1089/ten.TEA.2011.0258Wong T., McGrath J.A., Navsaria H. The Role of Fibroblasts in Tissue Engineering and Regeneration // Br. J. Dermatol. 2007. Vol.56, №6. Р.1149–1155. doi: 10.1111/j.1365-2133.2007.07914.xNolte S.V., Xu W., Rennekampff H.O., Rodemann H.P. Diversity of Fibroblasts – A Review on Implications for Skin Tissue Engineering. Cells Tissues Organs 2008 187(3):165–176. doi: 10.1159/000111805Spiekstra S.W., Breetveld M., Rustemeyer T., Scheper R.J., Gibbs S. Wound-healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes // Wound Repair Regen. 2007. Vol.15. №5. Р.708–717. doi: 10.1111/j.1524-475X.2007.00280.xWong T., McGrath J.A., Navsaria H. The Role of Fibroblasts in Tissue Engineering and Regeneration. Br. J. Dermatol. 2007; 56(6):1149–1155. doi: 10.1111/j.1365-2133.2007.07914.xYamakawa S., Hayashida K. Advances in surgical applications of growth factors for wound healing // Burns Trauma. 2019. Vol.7. Р.10. doi: 10.1186/s41038-019-0148-1Spiekstra S.W., Breetveld M., Rustemeyer T., Scheper R.J., Gibbs S. Wound-healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes. Wound Repair Regen. 2007; 15(5):708–717. doi: 10.1111/j.1524-475X.2007.00280.xФедоров В.Д., Саркисов Д.С., Алексеев А.А., Туманов В.П., Серов Г.Г. Применение культивированных фибробластов при ожогах кожи // Врач. 1999. №11. С.26–28.Yamakawa S., Hayashida K. Advances in surgical applications of growth factors for wound healing. Burns Trauma 2019; 7:10. doi: 10.1186/s41038-019-0148-1Воздвиженский С.И., Будкевич Л.И., Шурова Л.В. Организация этапной медицинской помощи детям раннего возраста с термической травмой // Материалы VII Всероссийской научно-практической конференции по проблеме термических поражений. Челябинск, 1999. С.20.Fedorov V.D., Sarkisov D.S., Аlekseev А.А., Тumanov V.P., Serov G.G. The use of cultured fibroblasts for skin burns. Vrach 1999; 11:26–28 (in Russian).Horst B., Chouhan G., Moiemen N.S., Grover L.M. Advances in keratinocyte delivery in burn wound care // Adv. Drug Deliv. Rev. 2018. Vol.123. Р.18–32. doi: 10.1016/j.addr.2017.06.012Vozdvizhensky V.I., Budkevich L.I., Shurova L.V. Organization of staged medical care for young children with thermal injury. Proceedings of the VII All-Russian Scientific and Practical Conference on the Problem of Thermal Damage. Chelyabinsk; 1999 (in Russian).Вагнер Д.О, Зиновьев Е.В. Крылов К.М., Крылов П.К., Солошенко В.В., Костяков Д.В., Юркевич Ю.В., Енукашвили Н.И., Блинова М.И., Александрова О.И., Михайлова Н.А. Опыт клинического применения аллогенных фибробластов у пострадавших с обширными ожогами кожи // Вестник Северо-Западного государственного медицинского университета им. И.И.Мечникова. 2018. Т.10, №3. С.65–72. doi: 10.17816/mechnikov201810365-72Horst B., Chouhan G., Moiemen N.S., Grover L.M. Advances in keratinocyte delivery in burn wound care. Adv. Drug Deliv. Rev. 2018; 123:18–32. doi: 10.1016/j.addr.2017.06.012Lykov A.P., Poveshchenko O.V., Bondarenko N.A., Surovtseva M.A. Therapeutic potential of fibroblast combined with platelet-rich plasma on burn skin wound healing // J. Biol. Today's World. 2019. Vol.8, №1. Р.1–5. doi: 10.15412/J.JBTW.01070201Wagner D.O., Zinoviev E.V., Krylov K.M., Krylov P.K., Soloshenko V.V., Kostyakov D.V., Yurkevich Yu.V., Enukashvily N.I., Blinova M.I., Aleksandrova O.I., Mikhailova N.A. Experience in the clinical use of allogeneic fibroblasts in patients with severe burns. Herald of North-Western State Medical University named after I.I. Mechnikov. 2018; 10(3):65–72 (in Russian). doi: 10.17816/mechnikov201810365-72Shevchenko R.V., James S.L., James S.E. A review of tissue-engineered skin bioconstructs available for skin reconstruction // J. R. Soc. Interface. 2010. Vol.7. P.229–258. doi: 10.1098/rsif.2009.0403Lykov A.P., Poveshchenko O.V., Bondarenko N.A., Surovtseva M.A. Therapeutic potential of fibroblast combined with platelet-rich plasma on burn skin wound healing. J. Biol. Today's World 2019; 8(1):1–5 doi: 10.15412/J.JBTW.01070201Shakespeare P.G. The role of skin substitutes in the treatment of burn injuries // Clin. Dermatol. 2005. Vol.23, №4. Р.413–418. doi: 10.1016/j.clindermatol.2004.07.015Shevchenko R.V., James S.L., James S.E. A review of tissue-engineered skin bioconstructs available for skin reconstruction. J. R. Soc. Interface 2010; 7(43):229–258. doi: 10.1098/rsif.2009.0403Melkun E.T., Few J.W. The use of biosynthetic skin substitute (Biobrane) for axillary reconstruction after surgical excision for hidradenitis suppurative // Plast. Reconstr. Surg. 2005, Vol.115, №5. Р.1385–1388. doi: 10.1097/01.prs.0000157013.40191.91Shakespeare P.G. The role of skin substitutes in the treatment of burn injuries. Clin. Dermatol. 2005; 23(4):413–418. doi: 10.1016/j.clindermatol.2004.07.015Supp D.M., Boyce S.T. Engineered skin substitutes: practices and potentials // Clin. Dermatol. 2005, Vol.23, №4. Р.403–412. doi: 10.1016/j.clindermatol.2004.07.023Melkun E.T., Few J.W. The use of biosynthetic skin substitute (Biobrane) for axillary reconstruction after surgical excision for hidradenitis suppurativa. Plast. Reconstr. Surg. 2005; 115(5):1385–1388. doi: 10.1097/01.prs.0000157013.40191.91Bello Y.M., Falabella A.F., Eaglstein W.H. Tissue-engineered skin. Current status in wound healing // Am. J. Clin. Dermatol. 2001. Vol.2, №5 Р.305–313. doi: 10.2174/1381612823666170526094606Supp D.M., Boyce S.T. Engineered skin substitutes: practices and potentials. Clin. Dermatol. 2005; 23(4):403–412. doi: 10.1016/j.clindermatol.2004.07.023Dodson B.P., Levine A.D. Challenges in the translation and commercialization of cell therapies // BMC Biotechnol. 2015. Vol.15. Р.70. doi: 10.1186/s12896-015-0190-4Bello Y.M., Falabella A.F., Eaglstein W.H. Tissue-engineered skin. Current status in wound healing. Am. J. Clin. Dermatol. 2001; 2(5):305–313. doi: 10.2174/1381612823666170526094606Dickinson L.E., Gerecht S. Engineered biopolymeric scaffolds for chronic wound healing // Front. Physiol. 2016. Vol.7. Р.341. doi: 10.3389/fphys.2016.00341Dodson B.P., Levine A.D. Challenges in the translation and commercialization of cell therapies. BMC Biotechnol. 2015; 15:70. doi: 10.1186/s12896-015-0190-4Raguse J.D., Gath H.J. The buccal fad pad lined with a metabolic active dermal replacement (dermagraft) for treatment of defects of the buccal plane // Br. J. Plast. Surg. 2004. Vol.57, №8. Р.764–768. doi: 10.1016/j.bjps.2004.05.003Dickinson L.E., Gerecht S. Engineered biopolymeric scaffolds for chronic wound healing. Front. Physiol. 2016; 7:341. doi: 10.3389/fphys.2016.00341Lovett M., Lee K., Edwards A., Kaplan D.L. Vascularization strategies for tissue engineering // Tissue Eng. Part B, Rev. 2009. Vol.15, №3. Р.353–370. doi: 10.1089/ten.TEB.2009.0085Raguse J.D., Gath H.J. The buccal fad pad lined with a metabolic active dermal replacement (dermagraft) for treatment of defects of the buccal plane. Br. J. Plast. Surg. 2004; 57(8):764–768. doi: 10.1016/j.bjps.2004.05.003Limova M. Active wound coverings: bioengineered skin and dermal substitutes // Surg. Clin. North Am. 2010. Vol.90, №6. Р.1237–1255. doi: 10.1016/j.suc.2010.08.004Lovett M., Lee K., Edwards A., Kaplan D.L. Vascularization strategies for tissue engineering. Tissue Eng. Part B Rev. 2009; 15(3):353–370. doi: 10.1089/ten.TEB.2009.0085Uccioli L. A clinical investigation on the characteristics and outcomes of treating chronic lower extremity wounds using the tissuetech autograft system // Int. J. Low. Extrem. Wounds. 2003. Vol.2, №3. Р.140–151. doi: 10.1177/1534734603258480Limova M. Active wound coverings: bioengineered skin and dermal substitutes. Surg. Clin. North Am. 2010; 90(6):1237–1255. doi: 10.1016/j.suc.2010.08.004MacNeil S. Progress and opportunities for tissue-engineered skin // Nature. 2007. Vol.445, №7130. Р.874–880.doi: 10.1038/nature05664Uccioli L. A clinical investigation on the characteristics and outcomes of treating chronic lower extremity wounds using the tissuetech autograft system. Int. J. Low. Extrem. Wounds 2003; 2(3):140–151. doi: 10.1177/1534734603258480MacNeil S. Progress and opportunities for tissue-engineered skin. Nature 2007; 445(7130):874–880. doi: 10.1038/nature05664MacNeil S. Progress and opportunities for tissue-engineered skin. Nature 2007; 445(7130):874–880. doi: 10.1038/nature05664

The authors declare that there are no conflicts of interest present.