vtioВестник трансплантологии и искусственных органовRussian Journal of Transplantology and Artificial Organs1995-1191Academician V.I.Shumakov National Medical Research Center of Transplantology and Artificial Organs", Ministry of Health of the Russian Federation10.15825/1995-1191-2017-3-53-64vtio-781Research ArticleРегенеративная медицина и клеточные технологииRegenerative Medicine and Cell TechnologiesСшиваемые in situ гидрогели для создания клеточного микроокруженияIn situ crosslinkable hydrogels for engineered cellular microenvironmentsПаркКун МинParkKyung Min

Отделение биоинженерии, Колледж наук о жизни и биоинженерии

Инчеон, 22012, Республика Корея

Division of Bioengineering, College of Life Sciences and Bioengineering

Incheon 22012, Republic of Korea

ПаркКи ДонгParkKi Dong

Факультет молекулярной науки и технологии

Сувон 443-749, Республика Корея

Department of Molecular Science and Technology

Suwon 443-749, Republic of Korea

kdp@ajou.ac.krСевастьяновВ. И.SevastianovV. I.НемецЕ. А.NemetzE. A.ВасилецВ. Н.VasiletsV. N.Национальный университет ИнчеонаЮжная КореяIncheon National UniversityKorea, Republic ofУниверситет АжонЮжная КореяAjou UniversityKorea, Republic ofФГБУ «Национальный медицинский исследовательский центр трансплантологии и искусственных органов имени академика В.И. Шумакова» Минздрава РоссииРоссияV.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Ministry of Healthcare of the Russian FederationRussian Federation2017160920171935364Copyright © Парк К.М., Парк К.Д., Севастьянов В.И., Немец Е.А., Василец В.Н., 20172017Парк К.М., Парк К.Д., Севастьянов В.И., Немец Е.А., Василец В.Н.Park K.M., Park K.D., Sevastianov V.I., Nemetz E.A., Vasilets V.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.transpl.ru/vtio/article/view/781

Формируемые (сшиваемые) in situ гидрогели широко применяются в качестве терапевтических имплантатов и систем доставки для различных биомедицинских технологий, включая тканевую инженерию, регенеративную медицину и фармакологию, благодаря биосовместимости гидрогелей и простоте инкорпорирования в них лекарственных веществ, клеток или сигнальных молекул в процессе образования сетчатой структуры. В последнее время гидрогелевые материалы часто используются в качестве искусственного внеклеточного матрикса из-за их структурного сходства с нативным внеклеточным матриксом человека, а также из-за возможности регулировать их многообразные свойства. В качестве клеточной микросреды (матриксов, носителей) на основе различных технологий сшивки был разработан ряд синтетических, природных и полусинтетических гидрогелей. В данном обзоре обсуждаются вопросы создания формируемых in situ гидрогелей с регулируемыми физическими, химическими и биологическими свойствами. Будет сделан также анализ новых методов применения инновационных гидрогелевых материалов для создания клеточной микросреды как матриксов для биомедицинских тканевых продуктов, так и систем доставки клеток и лекарственных веществ.

In situ crosslinkable hydrogels have been widely used as therapeutic implants and vehicles for a broad range of biomedical applications including tissue regenerative medicine because of their biocompatibility and easiness of encapsulation of cells or signaling molecules during hydrogel formation. Recently, these hydrogel materials have been widely utilized as an artificial extracellular matrix (aECM) because of its structural similarity with the native extracellular matrix (ECM) of the human body and its multi-tunable properties. Various synthetic, natural, and semisynthetic hydrogels have been developed as engineered cellular microenvironments by using various crosslinking strategies. In this review, we discuss how in situ forming hydrogels are being created with tunable physical, chemical, and biological properties. In particular, we focus on emerging techniques to apply advanced hydrogel materials for engineered cellular microenvironments.

полимерный гидрогельформируемый гидрогельсшивкатканевая инженериярегенеративная медицинаклеточная микросредаимплантатносительpolymeric hydrogelin situ forming hydrogelcrosslinkable hydrogeltissue engineeringregenerative medicineengineered cellular microenvironmentsimplantcarrierReferencesKopecek J. Hydrogel biomaterials: a smart future? Biomaterials. 2007; 28: 5185–5192.Kopecek J. Hydrogel biomaterials: a smart future? Biomaterials. 2007; 28: 5185–5192.Peppas NA, Hilt JZ, Khademhosseini A, Langer R. Hydrogels in biology and medicine: From molecular principles to bionanotechnology. Advanced materials. 2006; 18: 1345– 1360.Peppas NA, Hilt JZ, Khademhosseini A, Langer R. Hydrogels in biology and medicine: From molecular principles to bionanotechnology. Advanced materials. 2006; 18: 1345– 1360.Surguchenko VA, Ponomareva AS, Kirsanova LA, Skaleckij NN, Sevastianov VI. The cell- engineered construct of cartilage on the basis of biopolymer hydrogel matrix and human adipose tissue-derived mesenchymal stromal cells (in vitro study). J. Biomed. Mater. Res. Part A. 2015; 103A (2): 463–470.Surguchenko VA, Ponomareva AS, Kirsanova LA, Skaleckij NN, Sevastianov VI. The cell- engineered construct of cartilage on the basis of biopolymer hydrogel matrix and human adipose tissue-derived mesenchymal stromal cells (in vitro study). J. Biomed. Mater. Res. Part A. 2015; 103A (2): 463–470.Sevastianov VI, Dukhina GA, Ponomareva AS, Kirsanova LA, Perova NV, Skaletskiy NN. A Biomedical Cell Product for the Regeneration of Articular Cartilage: Biocompatible and Histomorphological Properties (an Experimental Model of Subcutaneous Implantation). Inorganic Materials: Applied Research. 2015; 6 (2): 162–170.Sevastianov VI, Dukhina GA, Ponomareva AS, Kirsanova LA, Perova NV, Skaletskiy NN. A Biomedical Cell Product for the Regeneration of Articular Cartilage: Biocompatible and Histomorphological Properties (an Experimental Model of Subcutaneous Implantation). Inorganic Materials: Applied Research. 2015; 6 (2): 162–170.Sivashanmugam A, Kumar RA, Priya MV, Nair SV, Jayakumar R. An overview of injectable polymeric hydrogels for tissue engineerin. European Polymer Journal. 2015; 72: 543–565.Sivashanmugam A, Kumar RA, Priya MV, Nair SV, Jayakumar R. An overview of injectable polymeric hydrogels for tissue engineerin. European Polymer Journal. 2015; 72: 543–565.Alexander AA, Khan J, Saraf S, Saraf S. Thermosensitive polymers for controlled delivery of hormones. J. Control Release. 2013; 172: 715–729.Alexander AA, Khan J, Saraf S, Saraf S. Thermosensitive polymers for controlled delivery of hormones. J. Control Release. 2013; 172: 715–729.Bae KH, Wang L-S, Kurisawa M. Injectable biodegradable hydrogels: progress and challenges. J. Mater. Chem. B. 2013; 1: 5371–5388.Bae KH, Wang L-S, Kurisawa M. Injectable biodegradable hydrogels: progress and challenges. J. Mater. Chem. B. 2013; 1: 5371–5388.Yang J-A, Yeom J, Hwang BW, Hoffman AS, Hahn SK. N-succinyl chitosan preparation, characterization, properties and biomedical applications: a state of the art review. Prog Polym Sci. 2014; 39: 1973–1986.Yang J-A, Yeom J, Hwang BW, Hoffman AS, Hahn SK. N-succinyl chitosan preparation, characterization, properties and biomedical applications: a state of the art review. Prog Polym Sci. 2014; 39: 1973–1986.Atala A, Cima LG, Kim W, Paige KT, Vacanti JP, Retik AB, Vacanti CA. Injectable alginate seeded with chondrocytes as a potential treatment for vesicoureteral reux. J. Urol. 1993; 150: 745–747.Atala A, Cima LG, Kim W, Paige KT, Vacanti JP, Retik AB, Vacanti CA. Injectable alginate seeded with chondrocytes as a potential treatment for vesicoureteral reux. J. Urol. 1993; 150: 745–747.Zhao L, Weir MD, Xu HH. An injectable calcium phosphate-alginate hydrogel- umbilical cord mesenchymal stem cell paste for bone tissue engineering. Biomaterials. 2010; 31: 6502–6510.Zhao L, Weir MD, Xu HH. An injectable calcium phosphate-alginate hydrogel- umbilical cord mesenchymal stem cell paste for bone tissue engineering. Biomaterials. 2010; 31: 6502–6510.Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 2007; 32: 762–798.Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 2007; 32: 762–798.Sun J-Y, Zhao X, Illeperuma WR, Chaudhuri O, Oh KH, Mooney DJ, Vlassak JJ, Suo Z. Highly stretchable and tough hydrogels. Nature. 2012; 489: 133–136.Sun J-Y, Zhao X, Illeperuma WR, Chaudhuri O, Oh KH, Mooney DJ, Vlassak JJ, Suo Z. Highly stretchable and tough hydrogels. Nature. 2012; 489: 133–136.Tseng TC, Tao L, Hsieh FY, Wei Y, Chiu IM, Hsu SH. An Injectable, Self-Healing Hydrogel to Repair the Central Nervous System. Advanced materials. 2015; 27: 3518– 3524.Tseng TC, Tao L, Hsieh FY, Wei Y, Chiu IM, Hsu SH. An Injectable, Self-Healing Hydrogel to Repair the Central Nervous System. Advanced materials. 2015; 27: 3518– 3524.Hunt NC, Hallam D, Karimi A, Mellough CB, Chen J, Steel DH, Lako M. 3D culture of human pluripotent stem cells in RGD-alginate hydrogel improves retinal tissue development. Acta biomaterialia. 2017; 49: 329–343.Hunt NC, Hallam D, Karimi A, Mellough CB, Chen J, Steel DH, Lako M. 3D culture of human pluripotent stem cells in RGD-alginate hydrogel improves retinal tissue development. Acta biomaterialia. 2017; 49: 329–343.Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and futur. Nat. Rev. Drug Discovery. 2004; 3: 1023–1035.Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and futur. Nat. Rev. Drug Discovery. 2004; 3: 1023–1035.Li J. Self-assembled supramolecular hydrogels based on polymer – cyclodextrin inclusion complexes for drug delivery. NPG Asia Materials. 2010; 2: 112–118.Li J. Self-assembled supramolecular hydrogels based on polymer – cyclodextrin inclusion complexes for drug delivery. NPG Asia Materials. 2010; 2: 112–118.Kretschmann O, Choi SW, Miyauchi M, Tomatsu I, Harada A, RitterH. Switchable Hydrogels Obtained by Supramolecular Cross-Linking of Adamantyl-Containing LCST Copolymers with Cyclodextrin Dimers. Angewandte Chemie International Edition. 2006; 45: 4361– 4365.Kretschmann O, Choi SW, Miyauchi M, Tomatsu I, Harada A, RitterH. Switchable Hydrogels Obtained by Supramolecular Cross-Linking of Adamantyl-Containing LCST Copolymers with Cyclodextrin Dimers. Angewandte Chemie International Edition. 2006; 45: 4361– 4365.Manakker F, Pot M, Vermonden T, Nostrum CF, Hennink WE. Self-assembling hydrogels based on β-cyclodextrin/cholesterol inclusion complexes. Macromolecules. 2008; 41 (5): 1766–1773.Manakker F, Pot M, Vermonden T, Nostrum CF, Hennink WE. Self-assembling hydrogels based on β-cyclodextrin/cholesterol inclusion complexes. Macromolecules. 2008; 41 (5): 1766–1773.Rodell CB, Kaminski AL, Burdick JA. Sequential crosslinking to control cellular spreading in 3-dimensional hydrogels. Biomacromolecules. 2013; 14 (11): 4125–4134.Rodell CB, Kaminski AL, Burdick JA. Sequential crosslinking to control cellular spreading in 3-dimensional hydrogels. Biomacromolecules. 2013; 14 (11): 4125–4134.Elisseeff J, Anseth K, Sims D, McIntosh W, Randolph M, Langer R. Transdermal photopolymerization of poly(ethylene oxide)-based injectable hydrogels for tissue- engineered cartilage. Proceedings of the National Academy of Sciences. 1999; 96: 3104–3107.Elisseeff J, Anseth K, Sims D, McIntosh W, Randolph M, Langer R. Transdermal photopolymerization of poly(ethylene oxide)-based injectable hydrogels for tissue- engineered cartilage. Proceedings of the National Academy of Sciences. 1999; 96: 3104–3107.Kramer N, Lohbauer U, García-Godoy F, Frankenberger R. Light curing of resin-based composites in the LED era. Am. J. Dent. 21 (3): 135–142.Kramer N, Lohbauer U, García-Godoy F, Frankenberger R. Light curing of resin-based composites in the LED era. Am. J. Dent. 21 (3): 135–142.Ifkovits JL, Burdick JA. Engineered microenvironments for controlled stem cell differentiation. Tissue engineering. 2007; 13 (10): 2369–2385.Ifkovits JL, Burdick JA. Engineered microenvironments for controlled stem cell differentiation. Tissue engineering. 2007; 13 (10): 2369–2385.Nichol JW, Koshy ST, Bae H, Hwang CM, Yamanlar S, Khademhosseini A. Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials. 2010; 31 (21): 5536– 5544.Nichol JW, Koshy ST, Bae H, Hwang CM, Yamanlar S, Khademhosseini A. Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials. 2010; 31 (21): 5536– 5544.Binder WH, Sachsenhofer R. Click’ chemistry in polymer and materials science. Macromol Rapid Comm. 2007: 28: 15–54.Binder WH, Sachsenhofer R. Click’ chemistry in polymer and materials science. Macromol Rapid Comm. 2007: 28: 15–54.Moses JE, Moorhouse AD. The growing applications of click chemistry. Chem. Soc. Rev. 2007; 36: 1249–1262.Moses JE, Moorhouse AD. The growing applications of click chemistry. Chem. Soc. Rev. 2007; 36: 1249–1262.Horne WS, Yadav MK, Stout CD, Ghadiri MR. Heterocyclic Peptide Backbone Modifications in an α-Helical Coiled Coil. J. Am. Chem. Soc. 2004; 126 (47): 15366– 15367.Horne WS, Yadav MK, Stout CD, Ghadiri MR. Heterocyclic Peptide Backbone Modifications in an α-Helical Coiled Coil. J. Am. Chem. Soc. 2004; 126 (47): 15366– 15367.Angelo NG, Arora PS. Nonpeptidic Foldamers from Amino Acids: Synthesis and Characterization of 1,3-Substituted Triazole Oligomers. J. Am. Chem. Soc. 2005; 127 (49): 17134–17135.Angelo NG, Arora PS. Nonpeptidic Foldamers from Amino Acids: Synthesis and Characterization of 1,3-Substituted Triazole Oligomers. J. Am. Chem. Soc. 2005; 127 (49): 17134–17135.Alge DL, Azagarsamy MA, Donohue DF, Anseth KS. Synthetically tractable click hydrogels for three-dimensional cell culture formed using tetrazine-norbornene chemistry. Biomacromolecules. 2013; 14: 949–953.Alge DL, Azagarsamy MA, Donohue DF, Anseth KS. Synthetically tractable click hydrogels for three-dimensional cell culture formed using tetrazine-norbornene chemistry. Biomacromolecules. 2013; 14: 949–953.Hu J, Zhang G, Liu S. Highly selective fluorogenic multianalyte biosensors constructed via enzyme-catalyzed coupling and aggregation-induced emission. Chem. Soc. Rev. 2012; 41 (18): 5933–5949.Hu J, Zhang G, Liu S. Highly selective fluorogenic multianalyte biosensors constructed via enzyme-catalyzed coupling and aggregation-induced emission. Chem. Soc. Rev. 2012; 41 (18): 5933–5949.Jin R, Hiemstra C, Zhong Z, Feijen J. Enzyme-mediated fast in situ formation of hydrogels from dextran-tyramine conjugates. Biomaterials. 2007; 28: 2791–2800.Jin R, Hiemstra C, Zhong Z, Feijen J. Enzyme-mediated fast in situ formation of hydrogels from dextran-tyramine conjugates. Biomaterials. 2007; 28: 2791–2800.Park KM, Shin YM, Joun YK, Shin H, Park KD. In situ forming hydrogels based on tyramine conjugated 4-Arm- PPO-PEO via enzymatic oxidative reaction. Biomacromolecules. 2010; 11: 706–712.Park KM, Shin YM, Joun YK, Shin H, Park KD. In situ forming hydrogels based on tyramine conjugated 4-Arm- PPO-PEO via enzymatic oxidative reaction. Biomacromolecules. 2010; 11: 706–712.Kurisawa M, Chung JE, Yang YY, Gao SJ, Uyama H. Chem Commun. Injectable biodegradable hydrogels composed of hyaluronic acid – tyramine conjugates for drug delivery and tissue engineering. Chem. Commun. 2005; 34: 4312–4314.Kurisawa M, Chung JE, Yang YY, Gao SJ, Uyama H. Chem Commun. Injectable biodegradable hydrogels composed of hyaluronic acid – tyramine conjugates for drug delivery and tissue engineering. Chem. Commun. 2005; 34: 4312–4314.Park KM, Ko KS, Joung YK, Shin H, Park KD. In situ cross-linkable gelatin- poly(ethylene glycol)-tyramine hydrogel via enzyme-mediated reaction for tissue regenerative medicine. J. Mater. Chem. 2011; 21: 13180– 13187.Park KM, Ko KS, Joung YK, Shin H, Park KD. In situ cross-linkable gelatin- poly(ethylene glycol)-tyramine hydrogel via enzyme-mediated reaction for tissue regenerative medicine. J. Mater. Chem. 2011; 21: 13180– 13187.Park KM, Gerecht S. Hypoxia-inducible hydrogels. Nature communications. 2014; 5: 4075.Park KM, Gerecht S. Hypoxia-inducible hydrogels. Nature communications. 2014; 5: 4075.Park S, Park KM. Engineered Polymeric Hydrogels for 3D Tissue Models. Polymers. 2016; 8 (1): 23.Park S, Park KM. Engineered Polymeric Hydrogels for 3D Tissue Models. Polymers. 2016; 8 (1): 23.Park KM, Gerecht S. Polymeric hydrogels as artificial extracellular microenvironments for cancer research. Eur. Polym. J. 2015; 72: 507–513.Park KM, Gerecht S. Polymeric hydrogels as artificial extracellular microenvironments for cancer research. Eur. Polym. J. 2015; 72: 507–513.Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nature medicine. 2013; 19: 1423–1437.Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nature medicine. 2013; 19: 1423–1437.Junttila MR, de Sauvage FJ. Influence of tumour microenvironment heterogeneity on therapeutic response. Nature. 2013; 501 (7467): 346–354.Junttila MR, de Sauvage FJ. Influence of tumour microenvironment heterogeneity on therapeutic response. Nature. 2013; 501 (7467): 346–354.Rizki A, Weaver VM, Lee SY, Rozenberg GI, Chin K, Myers CA et al. A human breast cell model of preinvasive to invasive transition. Cancer Res. 2008 Mar 1; 68 (5): 1378– 1387. Cancer research. 2008; 68: 1378–1387.Rizki A, Weaver VM, Lee SY, Rozenberg GI, Chin K, Myers CA et al. A human breast cell model of preinvasive to invasive transition. Cancer Res. 2008 Mar 1; 68 (5): 1378– 1387. Cancer research. 2008; 68: 1378–1387.Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat. Rev. Cancer. 2008; 8: 967–975.Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat. Rev. Cancer. 2008; 8: 967–975.

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