Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press125410.17650/1726-9784-2021-20-2-19-30REVIEWSОБЗОРЫ ЛИТЕРАТУРЫVIRAL DELIVERY USING SCAFFOLDSСКАФФОЛД КАК СПОСОБ ДОСТАВКИ ВИРУСНЫХ ВЕКТОРОВLaevskayaA. A.ЛаевскаяА. А.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

KosenchukV. V.КосенчукВ. В.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

YakushovS. I.ЯкушовС. И.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

https://orcid.org/0000-0001-7773-2435TimashevP. S.ТимашевП. С.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

https://orcid.org/0000-0002-0818-0363UlasovI. V.УласовИ. В.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

Илья Валентинович Уласов

119991 Москва, ул. Трубецкая, 8, стр. 2

ulasov_i_v@staff.sechenov.ruI. M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of RussiaФГАОУ ВО Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава России (Сеченовский Университет)1407202120219301307202113072021https://bioterapevt.abvpress.ru/jour/article/view/1254

In experimental oncology there are multiple approaches have been developed to target tumor cells. Many of them are based on scaffolds, a 3D models that mimics the structure of tissue in normal and pathophysiological state. It  is known that to deliver a viral load to target cells, cells-carriers undergo limited differentiation, and premature aging. Since viral agents require cells to be in specific proliferative state, the delivery of the virus to the target cell is the main goal of the functional framework such as scaffold. Over decade, multiple studies demonstrate the production of scaffolds using matrigel, polyalacinic acid, poly-lactide-co-glycolide, vinyl stilbens, or bioactive polymers. Our review will describe the potential benefits of delivering the viral vector using 3D scaffolds for virus-mediated expression of biologically active substances that prevent angiogenesis, neoplasm proliferation, or, conversely, stimulate wound healing. 3D materials such as hydrogels and scaffolds are among the key innovations in the field of material chemistry. Moreover, viral vectors provide specific delivery of genes to target cells. However, the immunogenicity of a viral capsid consisting of viral proteins hinders the clinical use of such vectors widely. These limitations can be surmounted by using scaffolds. Therefore, our review might interest researchers working in the fields of chemistry, materials science and natural sciences, as well as in the field of bioengineering and medical technologies.

Для экспериментальной терапии опухолей разрабатываются и применяются многочисленные подходы. Среди них особое значение приобрело получение скаффолдов – трехмерных (3D) моделей, которые имитируют структуру тканей человека и животных в физиологическом и патологическом состояниях. Как правило, клетки, используемые для доставки вирусов, подвергаются частичной дифференцировке и преждевременному старению. Учитывая, что для обеспечения эффективного инфицирования различными вирусными векторами необходимо определенное состояние клеток, доставка вируса в клетку-мишень является основной функцией скаффолда. За последние годы разработаны подходы к получению скаффолдов на основе различных материалов, в числе которых матригель, полиалациновая кислота, полилактид-ко-гликолид, винил-стилбены и биоактивные полимеры. В нашем обзоре описаны потенциальные преимущества доставки вирусного вектора в ткани с помощью 3D-скаффолдов в целях получения противовоспалительного и регенеративного эффектов, а также достижения вирус-опосредованной экспрессии биологически активных веществ, препятствующих ангиогенезу и пролиферации малигнизированных клеток или, наоборот, стимулирующих заживление ран. 3D-материалы, такие как гидрогели и  скаффолды, являются одними из  наиболее перспективных инноваций в  области биоматериалов. Вирусные векторы обеспечивают уникальную специфичность и эффективность доставки генов в клетки-мишени. Из всех вирусных агентов векторы на основе аденовирусов человека серотипов 2/5 получили наиболее широкое применение в онколитической виротерапии для доставки терапевтических генов. Однако широкому применению таких векторов в клинической практике препятствует иммуногенность белкового вирусного капсида. Эти ограничения могут быть преодолены посредством использования скаффолдов с вирусными векторами для безопасной и устойчивой доставки целевых генов в потенциальные мишени. Согласно данным литературы, использование скаффолдов значительно снижает иммунный ответ организма на чужеродный агент. Наш обзор будет интересен исследователям, работающим в области производства биоматериалов и заинтересованным в создании скаффолдов, одновременно обеспечивающих эффективную доставку генов в клетки-мишени и обладающих низкой иммуногенностью.

scaffoldviral vectorscellsвирусный векторскаффолдклетки1. Vardell E. Global Health Observatory Data Repository. Med Ref Serv 2020;39(1):67–74. DOI: 10.1080/02763869.2019.1693231.Vardell E. Global Health Observatory Data Repository. Med Ref Serv 2020;39(1):67–74. DOI: 10.1080/02763869.2019.1693231.2. Lang F.F., Conrad C., GomezManzano C. et al. Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol 2018;36(14):1419–27. DOI: 10.1200/JCO.2017.75.8219.Lang F.F., Conrad C., GomezManzano C. et al. Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol 2018;36(14):1419–27. DOI: 10.1200/JCO.2017.75.8219.3. Streby K.A., Geller J.I., Currier M.A. et al. Intratumoral injection of HSV1716, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients. Clin Cancer Res 2017;23(14):3566–74. DOI: 10.1158/1078-0432.CCR-16-2900.Streby K.A., Geller J.I., Currier M.A. et al. Intratumoral injection of HSV1716, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients. Clin Cancer Res 2017;23(14):3566–74. DOI: 10.1158/1078-0432.CCR-16-2900.4. Draganov D.D., Santidrian A.F., Minev I. et al. Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers. J Transl Med 2019;17(1):100. DOI: 10.1186/s12967-019-1829-z.Draganov D.D., Santidrian A.F., Minev I. et al. Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers. J Transl Med 2019;17(1):100. DOI: 10.1186/s12967-019-1829-z.5. Kazimirsky G., Jiang W., Slavin S. et al. Mesenchymal stem cells enhance the oncolytic effect of Newcastle disease virus in glioma cells and glioma stem cells via the secretion of TRAIL. Stem Cell Res Ther 2016;7(1): 149. DOI: 10.1186/s13287-016-0414-0.Kazimirsky G., Jiang W., Slavin S. et al. Mesenchymal stem cells enhance the oncolytic effect of Newcastle disease virus in glioma cells and glioma stem cells via the secretion of TRAIL. Stem Cell Res Ther 2016;7(1): 149. DOI: 10.1186/s13287-016-0414-0.6. Mooney R., Majid A.A., Batalla-Covello J. et al. Enhanced Delivery of Oncolytic Adenovirus by Neural Stem Cells for Treatment of Metastatic Ovarian Cancer. Mol Ther Oncolytics 2020;17:508. DOI: 10.1016/j.omto.2020.05.005.Mooney R., Majid A.A., Batalla-Covello J. et al. Enhanced Delivery of Oncolytic Adenovirus by Neural Stem Cells for Treatment of Metastatic Ovarian Cancer. Mol Ther Oncolytics 2020;17:508. DOI: 10.1016/j.omto.2020.05.005.7. Pannier A.K., Shea L.D. Controlled release systems for DNA delivery. Mol Ther 2004;10(1):19–26. DOI: 10.1016/j.ymthe.2004.03.020.Pannier A.K., Shea L.D. Controlled release systems for DNA delivery. Mol Ther 2004;10(1):19–26. DOI: 10.1016/j.ymthe.2004.03.020.8. Dang J.M., Leong K.W. Natural polymers for gene delivery and tissue engineering. Adv Drug Deliv Rev 2006;58(4):487–99. DOI: 10.1016/j.addr.2006.03.001.Dang J.M., Leong K.W. Natural polymers for gene delivery and tissue engineering. Adv Drug Deliv Rev 2006;58(4):487–99. DOI: 10.1016/j.addr.2006.03.001.9. Zhang Y., Cheng X., Wang J. et al. Novel chitosan/collagen scaffold containing transforming growth factor-β1 DNA for periodontal tissue engineering. Biochem Biophys Res Commun 2006;344(1):362–9. DOI: 10.1016/j.bbrc.2006.03.106.Zhang Y., Cheng X., Wang J. et al. Novel chitosan/collagen scaffold containing transforming growth factor-β1 DNA for periodontal tissue engineering. Biochem Biophys Res Commun 2006;344(1):362–9. DOI: 10.1016/j.bbrc.2006.03.106.10. Perea-Gil I., Prat-Vidal C., Bayes-Genis A. In vivo experience with natural scaffolds for myocardial infarction: the times they are a-changin’. Stem Cell Res Ther 2015;6:248. DOI: 10.1186/s13287-015-0237-4.Perea-Gil I., Prat-Vidal C., Bayes-Genis A. In vivo experience with natural scaffolds for myocardial infarction: the times they are a-changin’. Stem Cell Res Ther 2015;6:248. DOI: 10.1186/s13287-015-0237-4.11. Brown B.N., Londono R., Tottey S. et al. Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater 2012;8(3):978–87. DOI: 10.1016/j.actbio.2011.11.031.Brown B.N., Londono R., Tottey S. et al. Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater 2012;8(3):978–87. DOI: 10.1016/j.actbio.2011.11.031.12. Rowland C.R., Glass K.A., Ettyreddy A.R. et al. Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs. Biomaterials 2018;177:161–75. DOI: 10.1016/j.biomaterials.2018.04.049.Rowland C.R., Glass K.A., Ettyreddy A.R. et al. Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs. Biomaterials 2018;177:161–75. DOI: 10.1016/j.biomaterials.2018.04.049.13. Reyes R., Delgado A., Solis R. et al. Cartilage repair by local delivery of transforming growth factor-β1 or bone morphogenetic protein-2 from a novel, segmented polyurethane/polylactic-coglycolic bilayered scaffold. J Biomed Mater Res A 2014;102(4):1110–20. DOI: 10.1002/jbma.34769.Reyes R., Delgado A., Solis R. et al. Cartilage repair by local delivery of transforming growth factor-β1 or bone morphogenetic protein-2 from a novel, segmented polyurethane/polylactic-coglycolic bilayered scaffold. J Biomed Mater Res A 2014;102(4):1110–20. DOI: 10.1002/jbma.34769.14. Shao X., Goh J.C.H., Hutmacher D.W. et al. Repair of large articular osteochondral defects using hybrid scaffolds and bone marrow-derived mesenchymal stem cells in a rabbit model. Tissue Eng 2006;12(6):1539–51. DOI: 10.1089/ten.2006.12.1539.Shao X., Goh J.C.H., Hutmacher D.W. et al. Repair of large articular osteochondral defects using hybrid scaffolds and bone marrow-derived mesenchymal stem cells in a rabbit model. Tissue Eng 2006;12(6):1539–51. DOI: 10.1089/ten.2006.12.1539.15. Asawa Y., Sakamoto T., Komura M. et al. Early stage foreign body reaction against biodegradable polymer scaffolds affects tissue regeneration during the autologous transplantation of tissue-engineered cartilage in the canine model. Cell Transplant 2012;21(7):1431–42. DOI: 10.3727/096368912X640574.Asawa Y., Sakamoto T., Komura M. et al. Early stage foreign body reaction against biodegradable polymer scaffolds affects tissue regeneration during the autologous transplantation of tissue-engineered cartilage in the canine model. Cell Transplant 2012;21(7):1431–42. DOI: 10.3727/096368912X640574.16. Shin S., Salvay D.M., Shea L.D. Lentivirus delivery by adsorption to tissue engineering scaffolds. J Biomed Mater Res A 2010;93(4):1252–9. DOI: 10.1002/jbm.a.32619.Shin S., Salvay D.M., Shea L.D. Lentivirus delivery by adsorption to tissue engineering scaffolds. J Biomed Mater Res A 2010;93(4):1252–9. DOI: 10.1002/jbm.a.32619.17. Lee S., Kim J.S., Chu H.S. et al. Electrospun nanofibrous scaffolds for controlled release of adeno-associated viral vectors. Acta Biomater 2011;7(11):3868–76. DOI: 10.1016/j.actbio.2011.06.035.Lee S., Kim J.S., Chu H.S. et al. Electrospun nanofibrous scaffolds for controlled release of adeno-associated viral vectors. Acta Biomater 2011;7(11):3868–76. DOI: 10.1016/j.actbio.2011.06.035.18. Howard D., Buttery L.D., Shakesheff K.M., Roberts S.J. Tissue engineering: Strategies, stem cells and scaffolds. J Anat 2008;213(1):66–72. DOI: 10.1111/j.1469-7580.2008.00878.x.Howard D., Buttery L.D., Shakesheff K.M., Roberts S.J. Tissue engineering: Strategies, stem cells and scaffolds. J Anat 2008;213(1):66–72. DOI: 10.1111/j.1469-7580.2008.00878.x.19. Willerth S.M., Sakiyama-Elbert S.E. Combining Stem Cells and Biomaterial Scaffolds for Constructing Tissues and cell delivery. In: StemBook. Cambridge (MA): Harvard Stem Cell Institute. 2008. DOI: 10.3824/stembook.1.1.1.Willerth S.M., Sakiyama-Elbert S.E. Combining Stem Cells and Biomaterial Scaffolds for Constructing Tissues and cell delivery. In: StemBook. Cambridge (MA): Harvard Stem Cell Institute. 2008. DOI: 10.3824/stembook.1.1.1.20. Bhati R.S., Mukherjee D.P., McCarthy K.J. et al. The growth of chondrocytes into a fibronectincoated biodegradable scaffold. J Biomed Mater Res 2001;56(1):74–82. DOI: 10.1002/1097-4636(200107)56:1<74::aid-jbm1070>3.0.co;2-m.Bhati R.S., Mukherjee D.P., McCarthy K.J. et al. The growth of chondrocytes into a fibronectincoated biodegradable scaffold. J Biomed Mater Res 2001;56(1):74–82. DOI: 10.1002/1097-4636(200107)56:1<74::aid-jbm1070>3.0.co;2-m.21. Mohamadyar-Toupkanlou F., Vasheghani-Farahani E., HanaeeAhvaz H. et al. Osteogenic Differentiation of MSCs on Fibronectin-Coated and nHA-Modified Scaffolds. ASAIO J 2017;63(5):684–91. DOI: 10.1097/MAT.0000000000000551.Mohamadyar-Toupkanlou F., Vasheghani-Farahani E., HanaeeAhvaz H. et al. Osteogenic Differentiation of MSCs on Fibronectin-Coated and nHA-Modified Scaffolds. ASAIO J 2017;63(5):684–91. DOI: 10.1097/MAT.0000000000000551.22. Glass K.A., Link J.M., Brunger J.M. et al. Tissue-engineered cartilage with inducible and tunable immunomodulatory properties. Biomaterials 2014;35(22):5921–31. DOI: 10.1016/j.biomaterials.2014. 03.073.Glass K.A., Link J.M., Brunger J.M. et al. Tissue-engineered cartilage with inducible and tunable immunomodulatory properties. Biomaterials 2014;35(22):5921–31. DOI: 10.1016/j.biomaterials.2014. 03.073.23. Cam C., Segura T. Matrix-based gene delivery for tissue repair. Curr Opin Biotechnol 2013;24(5):855–63. DOI: 10.1016/j.copbio.2013.04.007.Cam C., Segura T. Matrix-based gene delivery for tissue repair. Curr Opin Biotechnol 2013;24(5):855–63. DOI: 10.1016/j.copbio.2013.04.007.24. Qi K., Li N., Zhang Z., Melino G. Tissue regeneration: The crosstalk between mesenchymal stem cells and immune response. Cell Immunol 2018;326:86–93. DOI: 10.1016/j.cellimm.2017.11.010.Qi K., Li N., Zhang Z., Melino G. Tissue regeneration: The crosstalk between mesenchymal stem cells and immune response. Cell Immunol 2018;326:86–93. DOI: 10.1016/j.cellimm.2017.11.010.25. Guo X., Zheng Q., Kulbatski I. et al. Bone Regeneration With Active Angiogenesis by Basic Fibroblast Growth Factor Gene Transfected Mesenchymal Stem Cells Seeded on Porous beta-TCP Ceramic Scaffolds. Biomed Mater 2006;1(3):93–9. DOI: 10.1088/1748-6041/1/3/001.Guo X., Zheng Q., Kulbatski I. et al. Bone Regeneration With Active Angiogenesis by Basic Fibroblast Growth Factor Gene Transfected Mesenchymal Stem Cells Seeded on Porous beta-TCP Ceramic Scaffolds. Biomed Mater 2006;1(3):93–9. DOI: 10.1088/1748-6041/1/3/001.26. Richardson S.M., Curran J.M., Chen R. et al. The differentiation of bone marrow mesenchymal stem cells into chondrocyte-like cells on poly-l-lactic acid (PLLA) scaffolds. Biomaterials 2006;27(22):4069–78. DOI: 10.1016/j.biomaterials.2006.03.017.Richardson S.M., Curran J.M., Chen R. et al. The differentiation of bone marrow mesenchymal stem cells into chondrocyte-like cells on poly-l-lactic acid (PLLA) scaffolds. Biomaterials 2006;27(22):4069–78. DOI: 10.1016/j.biomaterials.2006.03.017.27. Hu W.W., Wang Z., Hollister S.J., Krebsbach P.H. Localized viral vector delivery to enhance in situ regenerative gene therapy. Gene Ther 2007;14(11): 891–901. DOI: 10.1038/sj.gt.3302940.Hu W.W., Wang Z., Hollister S.J., Krebsbach P.H. Localized viral vector delivery to enhance in situ regenerative gene therapy. Gene Ther 2007;14(11): 891–901. DOI: 10.1038/sj.gt.3302940.28. Brunger J.M., Huynh N.P., Guenther C.M. et al. Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc Natl Acad Sci U S A 2014;111(9):E798–806. DOI: 10.1073/pnas.1321744111.Brunger J.M., Huynh N.P., Guenther C.M. et al. Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc Natl Acad Sci U S A 2014;111(9):E798–806. DOI: 10.1073/pnas.1321744111.29. Phillips J.E., Burns K.L., Le Doux J.M. et al. Engineering graded tissue interfaces. Proc Natl Acad Sci U S A 2008;105(34):12170–5. DOI: 10.1073/pnas.0801988105.Phillips J.E., Burns K.L., Le Doux J.M. et al. Engineering graded tissue interfaces. Proc Natl Acad Sci U S A 2008;105(34):12170–5. DOI: 10.1073/pnas.0801988105.30. Stojanov S., Berlec A. Electrospun Nanofibers as Carriers of Microorganisms, Stem Cells, Proteins, and Nucleic Acids in Therapeutic and Other Applications. Front Bioeng Biotechnol 2020; 8:130. DOI: 10.3389/fbioe.2020.00130.Stojanov S., Berlec A. Electrospun Nanofibers as Carriers of Microorganisms, Stem Cells, Proteins, and Nucleic Acids in Therapeutic and Other Applications. Front Bioeng Biotechnol 2020; 8:130. DOI: 10.3389/fbioe.2020.00130.31. Maurmann N., Sperling L.E., Pranke P. Electrospun and Electrosprayed Scaffolds for Tissue Engineering. Adv Exp Med Biol 2018;1078:79–100. DOI: 10.1007/978-981-13-0950-2_5.Maurmann N., Sperling L.E., Pranke P. Electrospun and Electrosprayed Scaffolds for Tissue Engineering. Adv Exp Med Biol 2018;1078:79–100. DOI: 10.1007/978-981-13-0950-2_5.32. Zdechlik A.C., He Y., Aird E.J. et al. Programmable Assembly of AdenoAssociated Virus-Antibody Composites for Receptor-Mediated Gene Delivery. Bioconjug Chem 2020;31(4):1093–106. DOI: 10.1021/acs.bioconjchem.9b00790.Zdechlik A.C., He Y., Aird E.J. et al. Programmable Assembly of AdenoAssociated Virus-Antibody Composites for Receptor-Mediated Gene Delivery. Bioconjug Chem 2020;31(4):1093–106. DOI: 10.1021/acs.bioconjchem.9b00790.33. Hu W.W., Lang M.W., Krebsbach P.H. Development of adenovirus immobilization strategies for in situ gene therapy. J Gene Med 2008;10(10):1102–12. DOI: 10.1002/jgm.1233.Hu W.W., Lang M.W., Krebsbach P.H. Development of adenovirus immobilization strategies for in situ gene therapy. J Gene Med 2008;10(10):1102–12. DOI: 10.1002/jgm.1233.34. Hu W.W., Wang Z., Krebsbach P.H. Virus immobilization on biomaterial scaffolds through biotin-avidin interaction for improving bone regeneration. J Tissue Eng Regen Med 2016;10(2):E63–72. DOI: 10.1002/term.1774.Hu W.W., Wang Z., Krebsbach P.H. Virus immobilization on biomaterial scaffolds through biotin-avidin interaction for improving bone regeneration. J Tissue Eng Regen Med 2016;10(2):E63–72. DOI: 10.1002/term.1774.35. Huynh N.P.T., Brunger J.M., Gloss C.C. et al. Genetic Engineering of Mesenchymal Stem Cells for Differential Matrix Deposition on 3D Woven Scaffolds. Tissue Eng Part A 2018;24(19–20): 1531–44. DOI: 10.1089/ten.TEA.2017.0510.Huynh N.P.T., Brunger J.M., Gloss C.C. et al. Genetic Engineering of Mesenchymal Stem Cells for Differential Matrix Deposition on 3D Woven Scaffolds. Tissue Eng Part A 2018;24(19–20): 1531–44. DOI: 10.1089/ten.TEA.2017.0510.36. Dreifke M.B., Ebraheim N.A., Jayasuriya A.C. Investigation of potential injectable polymeric biomaterials for bone regeneration. J Biomed Mater Res A 2013;101(8):2436–47. DOI: 10.1002/jbm.a.34521.Dreifke M.B., Ebraheim N.A., Jayasuriya A.C. Investigation of potential injectable polymeric biomaterials for bone regeneration. J Biomed Mater Res A 2013;101(8):2436–47. DOI: 10.1002/jbm.a.34521.37. Chang B., Ahuja N., Ma C., Liu X. Injectable scaffolds: Preparation and application in dental and craniofacial regeneration. Mater Sci Eng R Rep 2017;111:1–26. DOI: 10.1016/j.mser.2016.11.001.Chang B., Ahuja N., Ma C., Liu X. Injectable scaffolds: Preparation and application in dental and craniofacial regeneration. Mater Sci Eng R Rep 2017;111:1–26. DOI: 10.1016/j.mser.2016.11.001.38. Ueda N., Atsuta I., Ayukawa Y. et al. Novel application method for mesenchymal stem cell therapy utilizing its attractant-responsive accumulation property. Appl Sci 2019;9(22):4908. DOI: 10.3390/app9224908.Ueda N., Atsuta I., Ayukawa Y. et al. Novel application method for mesenchymal stem cell therapy utilizing its attractant-responsive accumulation property. Appl Sci 2019;9(22):4908. DOI: 10.3390/app9224908.39. Ercan H., Durkut S., Koc-Demir A. et al. Clinical Applications of Injectable Biomaterials. Adv Exp Med Biol 2018;1077:163–82. DOI: 10.1007/978-981-13-0947-2_10.Ercan H., Durkut S., Koc-Demir A. et al. Clinical Applications of Injectable Biomaterials. Adv Exp Med Biol 2018;1077:163–82. DOI: 10.1007/978-981-13-0947-2_10.40. Ehtesham M., Yuan X., Kabos P. et al. Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 2004;6(3):287–93. DOI: 10.1593/neo.3427.Ehtesham M., Yuan X., Kabos P. et al. Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 2004;6(3):287–93. DOI: 10.1593/neo.3427.41. Kim S.U. Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 2004;24(3):159–71.DOI: 10.1111/j.1440-1789.2004.00552.x.Kim S.U. Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 2004;24(3):159–71.DOI: 10.1111/j.1440-1789.2004.00552.x.42. Kim K., Lam J., Lu S. et al. Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model. J Control Release 2013;168(2):166–78. DOI: 10.1016/j.jconrel.2013.03.013.Kim K., Lam J., Lu S. et al. Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model. J Control Release 2013;168(2):166–78. DOI: 10.1016/j.jconrel.2013.03.013.43. Sun H., Mei L., Song C. et al. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials 2006;27(9):1735–40. DOI: 10.1016/j.biomaterials.2005.09.019.Sun H., Mei L., Song C. et al. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials 2006;27(9):1735–40. DOI: 10.1016/j.biomaterials.2005.09.019.44. Moutos F.T., Glass K.A., Compton S.A. et al. Anatomically shaped tissueengineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. Proc Natl Acad Sci U S A 2016;113(31):E4513–22. DOI: 10.1073/pnas.1601639113.Moutos F.T., Glass K.A., Compton S.A. et al. Anatomically shaped tissueengineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. Proc Natl Acad Sci U S A 2016;113(31):E4513–22. DOI: 10.1073/pnas.1601639113.45. Lu S., Lam J., Trachtenberg J.E. et al. Dual growth factor delivery from bilayered, biodegradable hydrogel composites for spatially-guided osteochondral tissue repair. Biomaterials 2014;35(31):8829–39. DOI: 10.1016/j.biomaterials.2014.07.006.Lu S., Lam J., Trachtenberg J.E. et al. Dual growth factor delivery from bilayered, biodegradable hydrogel composites for spatially-guided osteochondral tissue repair. Biomaterials 2014;35(31):8829–39. DOI: 10.1016/j.biomaterials.2014.07.006.46. Zhang Y., Fan W., Nothdurft L. et al. In vitro and in vivo evaluation of adenovirus combined silk fibroin scaffolds for bone morphogenetic protein-7 gene delivery. Tissue Eng Part C Methods 2011;17(8):789–97. DOI: 10.1089/ten.tec.2010.0453.Zhang Y., Fan W., Nothdurft L. et al. In vitro and in vivo evaluation of adenovirus combined silk fibroin scaffolds for bone morphogenetic protein-7 gene delivery. Tissue Eng Part C Methods 2011;17(8):789–97. DOI: 10.1089/ten.tec.2010.0453.47. Yang C., Blum N.T., Lin J. et al. Biomaterial scaffold-based local drug delivery systems for cancer immunotherapy. Scince Bul 2020;65(17):1489–504. DOI: 10.1016/j.scib.2020.04.012.Yang C., Blum N.T., Lin J. et al. Biomaterial scaffold-based local drug delivery systems for cancer immunotherapy. Scince Bul 2020;65(17):1489–504. DOI: 10.1016/j.scib.2020.04.012.48. Khorshidi S., Karhaneh R. A review on gradient hydrogel/fiber scaffolds for osteochondral regeneration. J Tissue Eng Regen Med 2018;12(4):e1974-e1990. DOI: 10.1002/term.2628.Khorshidi S., Karhaneh R. A review on gradient hydrogel/fiber scaffolds for osteochondral regeneration. J Tissue Eng Regen Med 2018;12(4):e1974-e1990. DOI: 10.1002/term.2628.49. Okino H., Manabe T., Tanaka M., Matsuda T. Novel therapeutic strategy for prevention of malignant tumor recurrence after surgery: Local delivery and prolonged release of adenovirus immobilized in photocured, tissue-adhesive gelatinous matrix. J Biomed Mater Res A 2003;66(3):643–51. DOI: 10.1002/jbm.a.10016.Okino H., Manabe T., Tanaka M., Matsuda T. Novel therapeutic strategy for prevention of malignant tumor recurrence after surgery: Local delivery and prolonged release of adenovirus immobilized in photocured, tissue-adhesive gelatinous matrix. J Biomed Mater Res A 2003;66(3):643–51. DOI: 10.1002/jbm.a.10016.50. Rowland C.R., Colucci L.A., Guilak F. Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds. Biomaterials 2016;91:57–72. DOI: 10.1016/j.biomaterials.2016.03.012.Rowland C.R., Colucci L.A., Guilak F. Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds. Biomaterials 2016;91:57–72. DOI: 10.1016/j.biomaterials.2016.03.012.51. Pinheiro A., Cooley A., Liao J. et al. Comparison of natural crosslinking agents for the stabilization of xenogenic articular cartilage. J Orthop Res 2016;34(6):1037–46. DOI: 10.1002/jor.23121.Pinheiro A., Cooley A., Liao J. et al. Comparison of natural crosslinking agents for the stabilization of xenogenic articular cartilage. J Orthop Res 2016;34(6):1037–46. DOI: 10.1002/jor.23121.52. Elder S., Pinheiro A., Young C. et al. Evaluation of genipin for stabilization of decellularized porcine cartilage. J Orthop Res 2017;35(9):1949–57. DOI: 10.1002/jor.23483.Elder S., Pinheiro A., Young C. et al. Evaluation of genipin for stabilization of decellularized porcine cartilage. J Orthop Res 2017;35(9):1949–57. DOI: 10.1002/jor.23483.53. Burnsed O.A., Schwartz Z., Marchand K.O. et al. Hydrogels derived from cartilage matrices promote induction of human mesenchymal stem cell chondrogenic differentiation. Acta Biomater 2016;43:139–49. DOI: 10.1016/j.actbio.2016.07.034.Burnsed O.A., Schwartz Z., Marchand K.O. et al. Hydrogels derived from cartilage matrices promote induction of human mesenchymal stem cell chondrogenic differentiation. Acta Biomater 2016;43:139–49. DOI: 10.1016/j.actbio.2016.07.034.54. Raisin S., Belamie E., Morille M. Non-viral gene activated matrices for mesenchymal stem cells based tissue engineering of bone and cartilage. Biomaterials 2016;104:223–37. DOI: 10.1016/j.biomaterials.2016.07.017.Raisin S., Belamie E., Morille M. Non-viral gene activated matrices for mesenchymal stem cells based tissue engineering of bone and cartilage. Biomaterials 2016;104:223–37. DOI: 10.1016/j.biomaterials.2016.07.017.55. Madrigal J.L., Stilhano R., Silva E.A. Biomaterial-guided gene delivery for musculoskeletal tissue repair. Tissue Eng Part B Rev 2017;23(4):347–61. DOI: 10.1089/ten.TEB.2016.0462.Madrigal J.L., Stilhano R., Silva E.A. Biomaterial-guided gene delivery for musculoskeletal tissue repair. Tissue Eng Part B Rev 2017;23(4):347–61. DOI: 10.1089/ten.TEB.2016.0462.56. Carter B., Burstein H., Peluso R. Adenoassociated Virus and AAV Vectors for Gene Delivery. In: Gene and Cell Therapy. CRC Press, 2003. P. 71–101. DOI: 10.1201/9780824758608.ch5.Carter B., Burstein H., Peluso R. Adenoassociated Virus and AAV Vectors for Gene Delivery. In: Gene and Cell Therapy. CRC Press, 2003. P. 71–101. DOI: 10.1201/9780824758608.ch5.57. Li L., Liu S., Han D. et al. Delivery and Biosafety of Oncolytic Virotherapy. Front Oncol 2020;10:475. DOI: 10.3389/fonc.2020.00475.Li L., Liu S., Han D. et al. Delivery and Biosafety of Oncolytic Virotherapy. Front Oncol 2020;10:475. DOI: 10.3389/fonc.2020.00475.58. Marchini A., Scott E.M., Rommelaere J. Overcoming barriers in oncolytic virotherapy with HDAC inhibitors and immune checkpoint blockade. Viruses 2016;8(1):9. DOI: 10.3390/v8010009.Marchini A., Scott E.M., Rommelaere J. Overcoming barriers in oncolytic virotherapy with HDAC inhibitors and immune checkpoint blockade. Viruses 2016;8(1):9. DOI: 10.3390/v8010009.59. Merchan J., Toro Bejarano M. Targeting tumor vasculature through oncolytic virotherapy: recent advances. Oncolytic Virother 2015;4:169–81. DOI: 10.2147/OV.S66045.Merchan J., Toro Bejarano M. Targeting tumor vasculature through oncolytic virotherapy: recent advances. Oncolytic Virother 2015;4:169–81. DOI: 10.2147/OV.S66045.60. Kaufman H.L., Kohlhapp F.J., Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov 2016;15(9):660. DOI: 10.1038/nrd.2016.178.Kaufman H.L., Kohlhapp F.J., Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov 2016;15(9):660. DOI: 10.1038/nrd.2016.178.61. Valkenburg K.C., De Groot A.E., Pienta K.J. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol 2018;15(6):366–81. DOI: 10.1038/s41571-018-0007-1.Valkenburg K.C., De Groot A.E., Pienta K.J. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol 2018;15(6):366–81. DOI: 10.1038/s41571-018-0007-1.62. Khan Z., Marshall J.F. The role of integrins in TGFβ activation in the tumour stroma. Cell Tissue Res 2016;365(3):657–73. DOI: 10.1007/s00441-016-2474-y.Khan Z., Marshall J.F. The role of integrins in TGFβ activation in the tumour stroma. Cell Tissue Res 2016;365(3):657–73. DOI: 10.1007/s00441-016-2474-y.63. Bougnaud S., Golebiewska A., Oudin A. et al. Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget 2016;7:31955–71. DOI: 10.18632/oncotarget.7454.Bougnaud S., Golebiewska A., Oudin A. et al. Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget 2016;7:31955–71. DOI: 10.18632/oncotarget.7454.64. Kolb A.D., Bussard K.M. The bone extracellular matrix as an ideal milieu for cancer cell metastases. Cancers 2019;11(7):1020. DOI: 10.3390/cancers11071020.Kolb A.D., Bussard K.M. The bone extracellular matrix as an ideal milieu for cancer cell metastases. Cancers 2019;11(7):1020. DOI: 10.3390/cancers11071020.65. Filipe E.C., Chitty J.L., Cox T.R. Charting the unexplored extracellular matrix in cancer. Int J Exp Pathol 2018;99:58–76. DOI: 10.1111/iep.12269. 66. Juurikka K., Butler G.S., Salo T. et al. The role of MMP8 in cancer: A systematic review. Int J Mol Sci 2019;20(18):4506. DOI: 10.3390/ijms20184506.Filipe E.C., Chitty J.L., Cox T.R. Charting the unexplored extracellular matrix in cancer. Int J Exp Pathol 2018;99:58–76. DOI: 10.1111/iep.12269. 66. Juurikka K., Butler G.S., Salo T. et al. The role of MMP8 in cancer: A systematic review. Int J Mol Sci 2019;20(18):4506. DOI: 10.3390/ijms20184506.67. Gao Y., Bado I., Wang H. et al. Metastasis Organotropism: Redefining the Congenial Soil. Developmental Cell 2019;49:375–91. DOI: 10.1016/j.devcel.2019.04.012.Gao Y., Bado I., Wang H. et al. Metastasis Organotropism: Redefining the Congenial Soil. Developmental Cell 2019;49:375–91. DOI: 10.1016/j.devcel.2019.04.012.68. Seyfried T.N., Huysentruyt L.C. On the origin of cancer metastasis. Crit Rev Oncog 2013;18:43–73. DOI: 10.1615/critrevoncog.v18.i1-2.40.Seyfried T.N., Huysentruyt L.C. On the origin of cancer metastasis. Crit Rev Oncog 2013;18:43–73. DOI: 10.1615/critrevoncog.v18.i1-2.40.