biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Productsbiopreparat-95Research ArticleОБЗОРЫREVIEWSДизайн доклинических исследований биомедицинских клеточных продуктов: особенности, ключевые принципы и требованияDesign of preclinical studies of biomedical cell products: characteristics, key principles and requirementsМельниковаЕ. В.MelnikovaE. V.

Ведущий эксперт лаборатории биомедицинских клеточных продуктов Испытательного центра экспертизы качества лекарственных средств, канд. биол. наук

Leading expert of the Laboratory of Biomedical Cell Products of the Testing Centre for Evaluation of Medicinal Products’ Quality. Candidate of Biological Sciences

noemail@neicon.ruМеркуловаО. В.MerkulovaO. V.

Ведущий эксперт лаборатории биомедицинских клеточных продуктов Испытательного центра экспертизы качества лекарственных средств, канд. мед. наук

Leading expert of the Laboratory of Biomedical Cell Products of the Testing Centre for Evaluation of Medicinal Products’ Quality. Candidate of Medical Sciences

noemail@neicon.ruЧапленкоА. А.ChaplenkoA. A.

Эксперт 2 категории лаборатории биомедицинских клеточных продуктов Испытательного центра экспертизы качества лекарственных средств

2nd professional category expert of the Laboratory of Biomedical Cell Products of the Testing Centre for Evaluation of Medicinal Products’ Quality

Chaplenko@expmed.ruМеркуловВ. А.MerkulovV. A.

Заместитель генерального директора по экспертизе лекарственных средств, д-р мед. наук, профессор

Deputy Director-General for Medicinal Products’ Evaluation. Doctor of Medical Sciences, professor

noemail@neicon.ruНаучный центр экспертизы средств медицинского примененияРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation201720022018173133144Copyright © Мельникова Е.В., Меркулова О.В., Чапленко А.А., Меркулов В.А., 20182018Мельникова Е.В., Меркулова О.В., Чапленко А.А., Меркулов В.А.Melnikova E.V., Merkulova O.V., Chaplenko A.A., Merkulov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/95

В соответствии с Федеральным законом «О биомедицинских клеточных продуктах», доклинические исследования (ДКИ) являются неотъемлемой частью разработки биомедицинского клеточного продукта (БМКП). В настоящей статье отражены основные принципы реализации требований, представленных в Правилах доклинических исследований БМКП. Основная цель проведения ДКИ БМКП - оценка эффективности, безопасности и биораспределения клеточного продукта. Для достоверной идентификации фармакодинамического действия БМКП в организме хозяина должны применяться должным образом обоснованные маркеры биологической активности. Оценка безопасности БМКП должна быть комплексной для осуществления идентификации, характеризации и количественного анализа потенциальной локальной и системной токсичности, оценки начала ее возникновения, возможности снижения токсичности, а также влияния определенной дозы препарата на результаты исследований токсичности. Конечной целью доклинических токсикологических исследований является получение данных, достаточных для определения возможности и риска проведения клинических исследований БМКП. Ключевыми принципами дизайна ДКИ БМКП являются рациональный подход и обоснование всех принятых в ходе проведения исследования решений. Результаты ДКИ, проведенных в соответствии с требованиями нормативно-правовых актов, могут быть включены в состав досье на БМКП и рассмотрены в процессе регистрации экспертным учреждением Минздрава.

According to the Federal Law «On Biomedical Cell Products», preclinical trials are an integral part of biomedical cell product (BCP) development. This article describes the basic principles of fulfilling requirements laid down in the Rules for conducting preclinical trials of BCPs. The main objective of preclinical trials is evaluation of efficacy, safety and biodistribution of cell products. Properly justified markers of biological activity must be used for reliable identification of BCP pharmacodynamic action in the host organism. BCP safety assessment must be comprehensive and include identification, characterization and quantitative evaluation of potential local and systemic toxicity, estimation of the onset of toxicity and possibility of its reduction, and the effect of a particular drug dose on the results of toxicity studies. The ultimate goal of preclinical toxicity studies is to obtain data sufficient for making a conclusion on the possibility of conducting clinical trials of BCP and determining associated risks. The key principles of preclinical trials design are a rational approach and justification of all decisions made during the study. The results of preclinical trials that were conducted in compliance with the law, can be included in the BCP dossier and considered during the product authorization by the expert institution of the Ministry of Health.

доклинические исследованиябиомедицинские клеточные продуктырелевантные моделимодели заболеванийэффективностьоптимальная дозабиораспределениетоксикологические исследованияpreclinical studiesbiomedical cell productsrelevant modelsdisease modelsefficacyoptimal dosebiodistributiontoxicity studiesReferencesПриказ Министерства здравоохранения и социального развития РФ от 31 декабря 2004 г. № 346 «Об организации выдачи разрешений на применение медицинских технологий» (утратил силу).Order of the Ministry of Health and Social Development of the Russian Federation of December 31, 2004 ¹ 346 «On the procedure for issuing permits for the application of medical technologies» (repealed) (in Russian).Доработанный текст проекта Приказа Министерства здравоохранения Российской Федерации «Об утверждении правил надлежащей практики по работе с биомедицинскими клеточными продуктами» (подготовлен Минздравом России 30.10.2016).Revised draft of Order of the Ministry of Health of the Russian Federation «On approval of rules of good practice for working with biomedical cell products» (prepared by the Ministry of Health of the Russian Federation on October 30, 2016) (in Russian).Guideline on human cell-based medicinal products (London, 21 May 2008. EMEA/CHMP/410869/2006). Available from: https://goo.gl/VNLa48.Guideline on human cell-based medicinal products (London, 21 May 2008. EMEA/CHMP/410869/2006). Available from: https://goo.gl/VNLa48.Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products (U. S. Food and Drug Administration, November 2013). Available from: https://goo.gl/32h9MY.Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products (U. S. Food and Drug Administration, November 2013). Available from: https://goo.gl/ 32h9MY.Миронов АН, ред. Руководство по проведению доклинических исследований лекарственных средств. Ч. I, II. М.: Гриф и К, 2013.Mironov AN, ed. Manual on expertise of medicines. Vol. I, II. M.: Grif and K, 2013 (in Russian).Бурова ЕД, Ходько СВ, Гущина СВ, Макарова МН, Макаров ВГ. Управление рисками для обеспечения качества доклинических исследований лекарственных средств. Ведомости Научного центра экспертизы средств медицинского применения 2017; 7(1): 25-32.Burova ED, Khodko SV, Gushchina SV, Makarova MN, Makarov VG. Risk management for quality assurance of preclinical research. The Bulletin of the Scientific for Expert Evaluation of Medicinal Products 2017; 7(1): 25–32 (in Russian).Reflection paper on in-vitro cultured chondrocyte containing products for cartilage repair of the knee (London, 08 April 2010. EMA/CAT/CPWP/568181/2009). Available from: https://goo.gl/32b8wa.Reflection paper on in-vitro cultured chondrocyte containing products for cartilage repair of the knee (London, 08 April 2010. EMA/CAT/CPWP/568181/2009). Available from: https://goo.gl/ 32b8wa.Report from CAT-Interested Parties Focus Groups (CAT-IPs FG) on non-clinical development of ATMPs (18 March 2011. EMA/CAT/134694/2011). Available from: https://goo.gl/QFDMT9.Report from CAT-Interested Parties Focus Groups (CAT-IPs FG) on non-clinical development of ATMPs (18 March 2011. EMA/CAT/134694/2011). Available from: https://goo.gl/QFDMT9.Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nature reviews. Nat Rev Immunol. 2007; 7(2): 118-30.Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007; 7(2): 118–30.Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 2002; 100(9): 3175-82.Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 2002; 100(9): 3175–82.Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 2004; 304(5667): 104-7.Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 2004; 304(5667): 104–7.Astashkina A, Mann B, Grainger DW. A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol Ther. 2012; 134(1): 82-106.Astashkina A, Mann B, Grainger DW. A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol Ther. 2012; 134(1): 82–106.Hester RE, Harrison RM, eds. Alternatives to animal testing. Issues in Environmental Science and Technology, Vol. 23. Cambridge: The Royal Society of Chemistry; 2006.Hester RE, Harrison RM, eds. Alternatives to animal testing. Issues in Environmental Science and Technology, Vol. 23. Cambridge: The Royal Society of Chemistry; 2006.Shankar G, Bader R, Lodge PA. The COSTIM bioassay: a novel potency test for dendritic cells. J Immunol Methods 2004; 285(2): 293-9.Shankar G, Bader R, Lodge PA. The COSTIM bioassay: a novel potency test for dendritic cells. J Immunol Methods 2004; 285(2): 293–9.Shankar G, Fourrier MS, Grevenkamp MA, Lodge PA. Validation of the COSTIM bioassay for dendritic cell potency. J Pharm Biomed Anal. 2004; 36(2): 285-94.Shankar G, Fourrier MS, Grevenkamp MA, Lodge PA. Validation of the COSTIM bioassay for dendritic cell potency. J Pharm Biomed Anal. 2004; 36(2):285–94.Hinz T, Buchholz CJ, van der Stappen T, Cichutek K, Kalinke U. Manufacturing and quality control of cell-based tumor vaccines: a scientific and a regulatory perspective. J Immunother. 2006; 29(5): 472-6.Hinz T, Buchholz CJ, van der Stappen T, Cichutek K, Kalinke U. Manufacturing and quality control of cell-based tumor vaccines: a scientific and a regulatory perspective. J Immunother. 2006; 29(5): 472–6.Buchholz M, Knauer J, Lehmann J, Hass M, Gargosky S. Qualification of the COSTIM assay to determine potency and use in clinical trials. Cytotherapy 2013; 15(4): S51.Buchholz M, Knauer J, Lehmann J, Hass M, Gargosky S. Qualification of the COSTIM assay to determine potency and use in clinical trials. Cytotherapy 2013; 15(4): S51.Schneider CK, Salmikangas P, Jilma B, Flamion B, Todorova LR, Paphitou A, et al. Challenges with advanced therapy medicinal products and how to meet them. Nat Rev Drug Discov. 2010; 9(3): 195-201.Schneider CK, Salmikangas P, Jilma B, Flamion B, Todorova LR, Paphitou A, et al. Challenges with advanced therapy medicinal products and how to meet them. Nat Rev Drug Discov. 2010; 9(3): 195–201.Басок ЮБ, Севастьянов ВИ. Технологии тканевой инженерии и регенеративной медицины в лечении дефектов хрящевой ткани суставов. Вестник трансплантологии и искусственных органов 2016; 18(4): 102-22.Basok YuB, Sevastianov VI. Tissue engineering and regenerative medicine technologies in the treatment of articular cartilage defects. Russian Journal of Transplantology and Artificial Organs 2016; 18(4):102–22 (in Russian).New advanced therapy to repair cartilage defects in the knee (19 May 2017. EMA/CHMP/315817/2017). Available from: https://goo.gl/zGVBR9.New advanced therapy to repair cartilage defects in the knee (19 May 2017. EMA/CHMP/315817/2017). Available from: https://goo.gl/zGVBR9.Amer LD, Mahoney MJ, Bryant SJ. Tissue engineering approaches to cell-based type 1 diabetes therapy. Tissue Eng Part B Rev. 2014; 20(5): 455-67.Amer LD, Mahoney MJ, Bryant SJ. Tissue engineering approaches to cell-based type 1 diabetes therapy. Tissue Eng Part B Rev. 2014; 20(5): 455–67.Daoud JT, Petropavlovskaia MS, Patapas JM, Degrandpré CE, Diraddo RW, Rosenberg L, Tabrizian M. Long-term in vitro human pancreatic islet culture using three-dimensional microfabricated scaffolds. Biomaterials 2011; 32(6): 1536-42.Daoud JT, Petropavlovskaia MS, Patapas JM, Degrandpré CE, Diraddo RW, Rosenberg L, Tabrizian M. Long-term in vitro human pancreatic islet culture using three-dimensional microfabricated scaffolds. Biomaterials 2011; 32(6): 1536–42.Скалецкая ГН, Скалецкий НН, Севастьянов ВИ. Перспективы применения тканеинженерных конструкций поджелудочной железы в лечении сахарного диабета 1-го типа. Вестник трансплантологии и искусственных органов 2016; 18(4): 133-45.Skaletskaya GN, Skaletskiy NN, Sevastianov VI. Prospects of application of tissue-engineered pancreatic constructs in the treatment of type 1 diabetes. Russian Journal of Transplantology and Artificial Organs 2016; 18(4): 133–45 (in Russian).Зорин В, Зорина А, Черкасов В, Копнин П, Деев Р, Исаев А и др. Применение аутологичных дермальных фибробластов для коррекции возрастных изменений кожи лица. Результаты годичных исследований. Эстетическая медицина 2012; 11(2): 171-82.Zorin V, Zorina A, Cherkasov V, Kopnin P, Deev P, Isaev A, et al. The use of autologous dermal fibroblasts for the correction of age-related changes in the facial skin. The results of a year’s research. Aesthetic medicine 2012; 11(2): 171–82 (in Russian).Алейник ДЯ, Зорин ВЛ, Еремин ИИ, Корсаков ИН, Чарыкова ИН. Использование клеточных технологий для восстановления повреждений кожи при ожоговой травме. Современные проблемы науки и образования 2015; (4). Available from: https://goo.gl/3aW9Ug.Aleynik DYa, Zorin VL, Eremin II, Korsakov IN, Charykova IN. Use of cell technologies for skin damage recovery in burn injuries. Modern problems of science and education 2015; (4). Available from: https://goo.gl/3aW9Ug (in Russian).Ковалев ГА, Введенский БП, Сандомирский БП. Технология моделирования остеоартроза крупных суставов. Biotechnologia Acta 2010; 3(4): 37-43.Koval’ov GA, Vvedenskyy BP, Sandomirskiy BP. Technology of modeling of large joints osteoarthrosis. BIOTECHNOLOGIA ACTA 2010; 3(4): 37–43 (in Russian).Макушин ВД, Степанов МА, Ступина ТА. Экспериментальное моделирование остеоартроза коленного сустава у собак. Биомедицина 2012; (3): 108-15.Makushin VD, Stepanov MA, Stupina TA. Experimental modeling of the knee joint osteoarthrosis in dogs. Biomedicine 2012; (3): 108–15 (in Russian).Yoo SA, Park BH, Yoon HJ, Lee JY, Song JH, Kim HA, et al. Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis. Arthritis Rheum. 2007; 56(7): 2299-311.Yoo SA, Park BH, Yoon HJ, Lee JY, Song JH, Kim HA, et al. Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis. Arthritis Rheum. 2007; 56(7): 2299–311.Baragi VM, Becher G, Bendele AM, Biesinger R, Bluhm H, Boer J, et al. A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum. 2009; 60(7): 2008-18.Baragi VM, Becher G, Bendele AM, Biesinger R, Bluhm H, Boer J, et al. A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum. 2009; 60(7): 2008–18.Методы экспериментального моделирования остеоартрозов у мелких экспериментальных животных. Available from: https://goo.gl/n6jd3t.Methods of experimental modeling of osteoarthritis in experimental small animals. Available from: https://goo.gl/n6jd3t (in Russian).Ozkan FU, Ozkan K, Ramadan S, Guven Z. Chondroprotective effect of N-acetylglucosamine and hyaluronate in early stages of osteoarthritis - an experimental study in rabbits. Bull NYU Hosp Jt Dis. 2009; 67(4): 352-7.Ozkan FU, Ozkan K, Ramadan S, Guven Z. Chondroprotective effect of N-acetylglucosamine and hyaluronate in early stages of osteoarthritis — an experimental study in rabbits. Bull NYU Hosp Jt Dis. 2009; 67(4): 352–7.Jean YH, Wen ZH, Chang YC, Hsieh SP, Tang CC, Wang YH, Wong CS. Intraarticular injection of the cyclooxygenase-2 inhibitor parecoxib attenuates osteoarthritis progression in anterior cruciate ligament-transected knee in rats: role of excitatory amino acids. Osteoarthritis Cartilage 2007; 15(6): 638-45.Jean YH, Wen ZH, Chang YC, Hsieh SP, Tang CC, Wang YH, Wong CS. Intraarticular injection of the cyclooxygenase-2 inhibitor parecoxib attenuates osteoarthritis progression in anterior cruciate ligament-transected knee in rats: role of excitatory amino acids. Osteoarthritis Cartilage 2007; 15(6): 638 – 45.Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004; 50(4): 1193-206.Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004; 50(4): 1193–206.Janusz MJ, Bendele AM, Brown KK, Taiwo YO, Hsieh L, Heitmeyer SA. Induction of osteoarthritis in the rat by surgical tear of the meniscus: Inhibition of joint damage by a matrix metalloproteinase inhibitor. Osteoarthritis Cartilage 2002; 10(10): 785-91.Janusz MJ, Bendele AM, Brown KK, Taiwo YO, Hsieh L, Heitmeyer SA. Induction of osteoarthritis in the rat by surgical tear of the meniscus: Inhibition of joint damage by a matrix metalloproteinase inhibitor. Osteoarthritis Cartilage 2002; 10(10): 785–91.Dai G, Wang S, Li J, Liu C, Liu Q. The validity of osteoarthritis model induced by bilateral ovariectomy in guinea pig. J Huazhong Univ Sci Technolog Med Sci. 2006; 26(6): 716-9.Dai G, Wang S, Li J, Liu C, Liu Q. The validity of osteoarthritis model induced by bilateral ovariectomy in guinea pig. J Huazhong Univ Sci Technolog Med Sci. 2006; 26(6): 716–9.Bendele AM, Hulman JF. Spontaneous cartilage degeneration in guinea pigs. Arthritis Rheum. 1988; 31(4): 561-5.Bendele AM, Hulman JF. Spontaneous cartilage degeneration in guinea pigs. Arthritis Rheum. 1988; 31(4): 561–5.Bendele AM. Animal models of osteoarthritis in an era of molecular biology. J Musculoskelet Neuronal Interact. 2002; 2(6): 501-3.Bendele AM. Animal models of osteoarthritis in an era of molecular biology. J Musculoskelet Neuronal Interact. 2002; 2(6): 501–3.Uchida K, Urabe K, Naruse K, Ogawa Z, Mabuchi K, Itoman M. Hyperlipidemia and hyperinsulinemia in the spontaneous osteoarthritis mouse model, STR/Ort. Exp Anim. 2009; 58(2): 181-7.Uchida K, Urabe K, Naruse K, Ogawa Z, Mabuchi K, Itoman M. Hyperlipidemia and hyperinsulinemia in the spontaneous osteoarthritis mouse model, STR/Ort. Exp Anim. 2009; 58(2): 181–7.Vallon R, Freuler F, Desta-Tsedu N, Robeva A, Dawson J, Wenner P, et al. Serum amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases. J Immunol. 2001; 166(4): 2801-7.Vallon R, Freuler F, Desta-Tsedu N, Robeva A, Dawson J, Wenner P, et al. Serum amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases. J Immunol. 2001; 166(4): 2801–7.Шиманский ВА, Кушнир ВА, Фролов ВИ, Крашенинников МЕ, Баранова ОВ, Онищенко НА. Применение аутологичных клеток костного мозга для торможения разрушения структуры хряща при остеоартрозе коленных суставов. В кн.: Шумакова ВИ, Онищенко НА, ред. Биологические резервы клеток костного мозга и коррекция органных дисфункции. М.: ЛАВР, 2009. С. 213-24.Shimansky VA, Kushnir VA, Frolov VI, Krasheninnikov IU, Baranova S, Onishchenko NA. The use of autologous bone marrow cells for inhibition of the destruction of the structure of cartilage in osteoarthritis of the knee. In: Shumakov VI, Onishchenko NA, eds. Biological reserves bone marrow cells and correction of organ dysfunction. M.: LAVR, 2009. P. 213–24 (in Russian).Hedlund P, Matsumoto K, Andersson KE. Animal models of erectile dysfunction. Curr Protoc Pharmacol. 2005; Chapter 5: Unit 5.41.Hedlund P, Matsumoto K, Andersson KE. Animal models of erectile dysfunction. Curr Protoc Pharmacol. 2005; Chapter 5: Unit 5.41.Полянских ЛС, Петросян МА, Жесткова НВ, Балашова НН. Экспериментальные модели патологии печени. Экспериментальная и клиническая фармакология 2017; 80(2): 39-44.Polyanskikh LS, Petrosyan MA, Zhestkova NV, Balashova NN. Experimental Models of Liver Disorders (Review). Russian Journal of Experimental and Clinical Pharmacology 2017; 80(2): 39–44 (in Russian).Мышкин ВА, Ибатуллина РБ, Волкова ЕС, Савлуков АИ, Симонова НИ. Способ моделирования токсической гепатопатии. Патент Российской Федерации, № 2188457; 2002.Myshkin VA, Ibatullina RB, Volkova ES, Savlukov AI, Simonova NI. The method of modeling toxic hepatopathy. Patent RF 2188457; 2002 (in Russian).Мышкин ВА, Ибатуллина РБ, Савлуков АИ, Симонова НИ, Бакиров АБ. Способ моделирования цирроза печени. Патент Российской Федерации, № 2197018; 2003.Myshkin VA, Ibatullina RB, Savlukov AI, Simonova NI, Bakirov AB. The method of modeling liver cirrhosis. Patent RF 2197018; 2003 (in Russian).Рыкало НА, Гуминская ОЮ. Закономерности и особенности репаративной регенерации печени неполовозрелых крыс на фоне хронического медикаментозного гепатита в эксперименте. Журнал анатомии и гистопатологии 2014; 3(1): 37-9.Rykalo NA, Guminskaya OYu. The regularities and peculiarities of liver reparative regeneration in immature rats on the background of experimental chronic drug-induced hepatitis. Journal of Anatomy and Histopathology 2014; 3(1): 37–9 (in Russian).Хабриев РУ, ред. Руководство по проведению клинических исследований новых лекарственных средств. М., 2005. C. 360.Khabriev RU, ed. Guidelines for conducting clinical trials of new drugs. M., 2005. C. 360. (in Russian).Венгеровский АИ, Коваленко МЮ, Арбузов АГ, Головина ЕЛ, Чучалин ВС, Соснина НВ и др. Влияние гепатопротекторов растительного происхождения на эффекты преднизолона при экспериментальном токсическом гепатите. Растительные ресурсы 1998; 34(3): 91-6.Vengerovsky AI, Kovalenko MJ, Arbuzov AG, Golovina EL, Chuchalin VS, Sosnina NV, et al. Influence of hepatoprotectors of vegetable origin on the effects of prednisolone in experimental toxic hepatitis. Plant resources 1998; 34(3): 91–6 (in Russian).Грицай ДВ, Лебединский АС, Оченашко ОВ, Рогульская ЕЮ, Петренко ЮА, Лозинский ВИ и др. Трансплантация криоконсервированных клеток фетальной печени, заселенных в макропористые альгинат-желатиновые матрицы, крысам с печеночной недостаточностью. Вестник трансплантологии и искусственных органов 2015; 17(3): 50-7.Grizay DV, Lebedinsky AS, Ochenashko OV, Rogulska OY, Petrenko YA, Lozinsky VI, et al. Transplantation of cryopreserved fetal liver cells seeded into macroporous alginate-gelatin scaffolds in rats with liver failure. Russian Journal of Transplantology and Artificial Organs 2015; 17(3): 50–7 (in Russian).Itoh A, Isoda K, Kondoh M, Kawase M, Watari A, Kobayashi M, et al. Hepatoprotective effect of syringic acid and vanillic acid on CCl4-induced liver injury. Biol Pharm Bull. 2010; 33(6): 983-7.Itoh A, Isoda K, Kondoh M, Kawase M, Watari A, Kobayashi M, et al. Hepatoprotective effect of syringic acid and vanillic acid on CCl4-induced liver injury. Biol Pharm Bull. 2010; 33(6): 983–7.Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 2007; 117(9): 2553-61.Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 2007; 117(9): 2553–61.Cardinal JW, Allan DJ, Cameron DP. Poly(ADP-ribose)polymerase activation determines strain sensitivity to stpretrozotocin-induced beta cell death in inbred mice. J Mol Endocrinol. 1999; 22(1): 65-70.Cardinal JW, Allan DJ, Cameron DP. Poly(ADP-ribose)polymerase activation determines strain sensitivity to stpretrozotocin-induced beta cell death in inbred mice. J Mol Endocrinol. 1999; 22(1): 65–70.Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001; 50(6): 537-46.Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001; 50(6): 537–46.Toyoda H, Formby B. Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model. Bioessays 1998; 20(9): 750-7.Toyoda H, Formby B. Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model. Bioessays 1998; 20(9): 750–7.Green EA, Flavell RA. Tumor necrosis factor-alpha and the progression of diabetes in non-obese diabetic mice. Immunol Rev. 1999; 169: 11-22.Green EA, Flavell RA. Tumor necrosis factor-alpha and the progression of diabetes in non-obese diabetic mice. Immunol Rev. 1999; 169: 11–22.Zornoff LA, Paiva SA, Minicucci MF, Spadaro J. Experimental myocardium infarction in rats: analysis of the model. Arq Bras Cardiol. 2009; 93(4): 434-40, 426-32.Zornoff LA, Paiva SA, Minicucci MF, Spadaro J. Experimental myocardium infarction in rats: analysis of the model. Arq Bras Cardiol. 2009; 93(4): 434–40, 426–32.Chimenti S, Carlo E, Masson S, Bai A, Latini R. Myocardial infarction: animal models. Methods Mol Med. 2004; 98: 217-26.Chimenti S, Carlo E, Masson S, Bai A, Latini R. Myocardial infarction: animal models. Methods Mol Med. 2004; 98: 217–26.Limbourg A, Korff T, Napp LC, Schaper W, Drexler H, Limbourg FP. Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Nat Protoc. 2009; 4(12): 1737-46.Limbourg A, Korff T, Napp LC, Schaper W, Drexler H, Limbourg FP. Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Nat Protoc. 2009; 4(12): 1737–46.Lotfi S, Patel AS, Mattock K, Egginton S, Smith A, Modarai B. Towards a more relevant hind limb model of muscle ischaemia. Atherosclerosis 2013; 227(1): 1-8.Lotfi S, Patel AS, Mattock K, Egginton S, Smith A, Modarai B. Towards a more relevant hind limb model of muscle ischaemia. Atherosclerosis 2013; 227(1): 1–8.Shevchenko EK, Makarevich PI, Tsokolaeva ZI, Boldyreva MA, Sysoeva VY, Tkachuk VA, Parfyonova YV. Transplantation of modified human adipose derived stromal cells expressing VEGF165 results in more efficient angiogenic response in ischemic skeletal muscle. J Transl Med. 2013; 11: 138.Shevchenko EK, Makarevich PI, Tsokolaeva ZI, Boldyreva MA, Sysoeva VY, Tkachuk VA, Parfyonova YV. Transplantation of modified human adipose derived stromal cells expressing VEGF165 results in more efficient angiogenic response in ischemic skeletal muscle. J Transl Med. 2013; 11: 138.Traktuev DO, Prater DN, Merfeld-Clauss S, Sanjeevaiah AR, Saadatzadeh MR, Murphy M, et al. Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. Circ Res. 2009; 104(12): 1410-20.Traktuev DO, Prater DN, Merfeld-Clauss S, Sanjeevaiah AR, Saadatzadeh MR, Murphy M, et al. Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. Circ Res. 2009; 104(12): 1410–20.Xie Y, Zhu KQ, Deubner H, Emerson DA, Carrougher GJ, Gibran NS, Engrav LH. The microvasculature in cutaneous wound healing in the female red Duroc pig is similar to that in human hypertrophic scars and different from that in the female Yorkshire pig. J Burn Care Res. 2007; 28(3): 500-6.Xie Y, Zhu KQ, Deubner H, Emerson DA, Carrougher GJ, Gibran NS, Engrav LH. The microvasculature in cutaneous wound healing in the female red Duroc pig is similar to that in human hypertrophic scars and different from that in the female Yorkshire pig. J Burn Care Res. 2007; 28(3): 500–6.Zhu KQ, Carrougher GJ, Gibran NS, Isik FF, Engrav LH. Review of the female Duroc/Yorkshire pig model of human fibroproliferative scarring. Wound Repair Regen. 2007; 15 Suppl 1: S32-9.Zhu KQ, Carrougher GJ, Gibran NS, Isik FF, Engrav LH. Review of the female Duroc/Yorkshire pig model of human fibroproliferative scarring. Wound Repair Regen. 2007; 15 Suppl 1: S32–9.Porter RM. Mouse models for human hair loss disorders. J Anat. 2003; 202(1): 125-31.Porter RM. Mouse models for human hair loss disorders. J Anat. 2003; 202(1): 125–31.Azzi L, El-Alfy M, Martel C, Labrie F. Gender differences in mouse skin morphology and specific effects of sex steroids and dehydroepiandrosterone. J Invest Dermatol. 2005; 124(1): 22-7.Azzi L, El-Alfy M, Martel C, Labrie F. Gender differences in mouse skin morphology and specific effects of sex steroids and dehydroepiandrosterone. J Invest Dermatol. 2005; 124(1): 22–7.Chen JS, Longaker MT, Gurtner GC. Murine models of human wound healing. Methods Mol Biol. 2013; 1037: 265-74.Chen JS, Longaker MT, Gurtner GC. Murine models of human wound healing. Methods Mol Biol. 2013; 1037: 265–74.Lindblad WJ. Considerations for selecting the correct animal model for dermal wound-healing studies. J Biomater Sci Polym Ed. 2008; 19(8): 1087-96.Lindblad WJ. Considerations for selecting the correct animal model for dermal wound-healing studies. J Biomater Sci Polym Ed. 2008; 19(8): 1087–96.Ansell DM, Campbell L, Thomason HA, Brass A, Hardman MJ. A statistical analysis of murine incisional and excisional acute wound models. Wound Repair Regen. 2014; 22(2): 281-7.Ansell DM, Campbell L, Thomason HA, Brass A, Hardman MJ. A statistical analysis of murine incisional and excisional acute wound models. Wound Repair Regen. 2014; 22(2): 281–7.Naumova AV, Modo M, Moore A, Murry CE, Frank JA. Clinical imaging in regenerative medicine. Nat Biotechnol. 2014; 32(8): 804-18.Naumova AV, Modo M, Moore A, Murry CE, Frank JA. Clinical imaging in regenerative medicine. Nat Biotechnol. 2014; 32(8): 804–18.Daar AS, Greenwood HL. A proposed definition of regenerative medicine. J Tissue Eng Regen Med. 2007; 1(3): 179-84.Daar AS, Greenwood HL. A proposed definition of regenerative medicine. J Tissue Eng Regen Med. 2007; 1(3): 179–84.Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009; 18(5): 683-92.Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009; 18(5): 683–92.Harting MT, Jimenez F, Xue H, Fischer UM, Baumgartner J, Dash PK, Cox CS. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J Neurosurg. 2009; 110(6): 1189-97.Harting MT, Jimenez F, Xue H, Fischer UM, Baumgartner J, Dash PK, Cox CS. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J Neurosurg. 2009; 110(6): 1189–97.Everaert BR, Bergwerf I, De Vocht N, Ponsaerts P, Van Der Linden A, Timmermans JP, Vrints CJ. Multimodal in vivo imaging reveals limited allograft survival, intrapulmonary cell trapping and minimal evidence for ischemia-directed BMSC homing. BMC Biotechnol. 2012; 12: 93.Everaert BR, Bergwerf I, De Vocht N, Ponsaerts P, Van Der Linden A, Timmermans JP, Vrints CJ. Multimodal in vivo imaging reveals limited allograft survival, intrapulmonary cell trapping and minimal evidence for ischemia-directed BMSC homing. BMC Biotechnol. 2012; 12: 93.Ramsden CM, Powner MB, Carr AJ, Smart MJ, da Cruz L, Coffey PJ. Stem cells in retinal regeneration: past, present and future. Development 2013; 140(12): 2576-85.Ramsden CM, Powner MB, Carr AJ, Smart MJ, da Cruz L, Coffey PJ. Stem cells in retinal regeneration: past, present and future. Development 2013; 140(12): 2576–85.Husser O, Monmeneu JV, Bonanad C, Gomez C, Chaustre F, Nunez J, et al. Head-to-head comparison of 1 week versus 6 months CMR-derived infarct size for prediction of late events after STEMI. Int J Cardiovasc Imaging 2013; 29(7): 1499-509.Husser O, Monmeneu JV, Bonanad C, Gomez C, Chaustre F, Nunez J, et al. Head-to-head comparison of 1 week versus 6 months CMR-derived infarct size for prediction of late events after STEMI. Int J Cardiovasc Imaging 2013; 29(7): 1499–509.Kumar R, Nguyen HD, Ogren JA, Macey PM, Thompson PM, Fonarow GC, et al. Global and regional putamen volume loss in patients with heart failure. Eur J Heart Fail. 2011; 13(6): 651-5.Kumar R, Nguyen HD, Ogren JA, Macey PM, Thompson PM, Fonarow GC, et al. Global and regional putamen volume loss in patients with heart failure. Eur J Heart Fail. 2011; 13(6): 651–5.Шаманская ТВ, Осипова ЕЮ, Пурбуева ББ, Устюгов АЮ, Астрелина ТА, Яковлева МВ, Румянцев СА. Культивирование мезенхимальных стволовых клеток ex vivo в различных питательных средах (обзор литературы и собственный опыт). Онкогематология 2010; 3: 65-71.Shamanskaya TV, Osipova YeYu, Purbueva BB, Ustyugov AYu, Astrelina TA, Yakovleva MV, Rumyantsev SA. Ex vivo expansion of mesenchymal stem cells in different culture conditions (the literature review and own experience). Oncohematology 2010; 3: 65–71 (in Russian).Correa PL, Mesquita CT, Felix RM, Azevedo JC, Barbirato GB, Falcгo CH, et al. Assessment of intra-arterial injected autologous bone marrow mononuclear cell distribution by radioactive labeling in acute ischemic stroke. Clin Nucl Med. 2007; 32(11): 839-41.Correa PL, Mesquita CT, Felix RM, Azevedo JC, Barbirato GB, Falcão CH, et al. Assessment of intra-arterial injected autologous bone marrow mononuclear cell distribution by radioactive labeling in acute ischemic stroke. Clin Nucl Med. 2007; 32(11): 839–41.Daadi MM, Li Z, Arac A, Grueter BA, Sofilos M, Malenka RC, et al. Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol Ther. 2009; 17(7): 1282-91.Daadi MM, Li Z, Arac A, Grueter BA, Sofilos M, Malenka RC, et al. Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol Ther. 2009; 17(7): 1282–91.Australian Public Assessment Report for Remestemcel-L, ex vivo adult human mesenchymal stem cells. Prochymal® (Osiris). Available from: https://goo.gl/YEKuWf.Australian Public Assessment Report for Remestemcel-L, ex vivo adult human mesenchymal stem cells. Prochymal® (Osiris). Available from: https://goo.gl/YEKuWf.Assessment report. Holoclar (18 December 2014. EMA/25273/2015). Available from: https://goo.gl/ns68Yq.Assessment report. Holoclar (18 December 2014. EMA/25273/ 2015). Available from: https://goo.gl/ns68Yq.

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