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Gene therapy for bone tissue engineering

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Gene therapy holds a great promise and has been extensively investigated to improve bone formation and regeneration therapies in bone tissue engineering. A variety of osteogenic genes can be delivered by combining different vectors (viral or non-viral), scaffolds and delivery methodologies. Ex vivo & in vivo gene enhanced tissue engineering approaches have led to successful osteogenic differentiation and bone formation. In this article, we review recent advances of gene therapy-based bone tissue engineering discussing strengths and weaknesses of various strategies as well as general overview of gene therapy.

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References

  1. Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 2008;87:107–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lind M. Growth factors: possible new clinical tools. A review. Acta Orthop Scand 1996;67:407–417.

    Article  CAS  PubMed  Google Scholar 

  3. Urist MR. Bone: formation by autoinduction. Science 1965;150:893–899.

    Article  CAS  PubMed  Google Scholar 

  4. Sartori R, Sandri M. BMPs and the muscle-bone connection. Bone 2015;80:37–42.

    Article  CAS  PubMed  Google Scholar 

  5. Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001;83-A Suppl 1(Pt 2):S151–S158.

    PubMed  Google Scholar 

  6. Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 2002;84-A:2123–2134.

    PubMed  Google Scholar 

  7. Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976) 2000;25:376–381.

    CAS  Google Scholar 

  8. Talwar R, Di Silvio L, Hughes FJ, King GN. Effects of carrier release kinetics on bone morphogenetic protein-2-induced periodontal regeneration in vivo. J Clin Periodontol 2001;28:340–347.

    Article  CAS  PubMed  Google Scholar 

  9. Uludag H, Gao T, Porter TJ, Friess W, Wozney JM. Delivery systems for BMPs: factors contributing to protein retention at an application site. J Bone Joint Surg Am 2001;83-A Suppl 1(Pt 2):S128–S135.

    PubMed  Google Scholar 

  10. Ylä-Herttuala S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol Ther 2012;20:1831–1832.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Melchiorri D, Pani L, Gasparini P, Cossu G, Ancans J, Borg JJ, et al. Regulatory evaluation of Glybera in Europe -two committees, one mission. Nat Rev Drug Discov 2013;12:719.

    Article  CAS  PubMed  Google Scholar 

  12. Solheim E. Growth factors in bone. Int Orthop 1998;22:410–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barba M, Cicione C, Bernardini C, Campana V, Pagano E, Michetti F, et al. Spinal fusion in the next generation: gene and cell therapy approaches. ScientificWorldJournal 2014;2014:406159.

    PubMed  PubMed Central  Google Scholar 

  14. Evans CH, Robbins PD. Possible orthopaedic applications of gene therapy. J Bone Joint Surg Am 1995;77:1103–1114.

    CAS  PubMed  Google Scholar 

  15. Betz VM, Betz OB, Harris MB, Vrahas MS, Evans CH. Bone tissue engineering and repair by gene therapy. Front Biosci 2008;13:833–841.

    Article  CAS  PubMed  Google Scholar 

  16. Makarov SS, Olsen JC, Johnston WN, Anderle SK, Brown RR, Baldwin AS Jr, et al. Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc Natl Acad Sci U S A 1996;93: 402-406.

    Google Scholar 

  17. Shea LD, Smiley E, Bonadio J, Mooney DJ. DNA delivery from polymer matrices for tissue engineering. Nat Biotechnol 1999;17:551–554.

    Article  CAS  PubMed  Google Scholar 

  18. Kumar S, Ponnazhagan S. Gene therapy for osteoinduction. Curr Gene Ther 2004;4:287–296.

    Article  CAS  PubMed  Google Scholar 

  19. Scaduto AA, Lieberman JR. Gene therapy for osteoinduction. Orthop Clin North Am 1999;30:625–633.

    Article  CAS  PubMed  Google Scholar 

  20. Wegman F, Oner FC, Dhert WJ, Alblas J. Non-viral gene therapy for bone tissue engineering. Biotechnol Genet Eng Rev 2013;29:206–220.

    Article  CAS  PubMed  Google Scholar 

  21. Verma IM, Somia N. Gene therapy —promises, problems and prospects. Nature 1997;389:239–242.

    Article  CAS  PubMed  Google Scholar 

  22. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012-an update. J Gene Med 2013;15:65–77.

    Article  CAS  PubMed  Google Scholar 

  23. Oligino TJ, Yao Q, Ghivizzani SC, Robbins P. Vector systems for gene transfer to joints. Clin Orthop Relat Res 2000;(379 Suppl):S17–S30.

    Article  PubMed  Google Scholar 

  24. Musgrave DS, Bosch P, Ghivizzani S, Robbins PD, Evans CH, Huard J. Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone 1999;24:541–547.

    Article  CAS  PubMed  Google Scholar 

  25. Betz OB, Betz VM, Nazarian A, Pilapil CG, Vrahas MS, Bouxsein ML, et al. Direct percutaneous gene delivery to enhance healing of segmental bone defects. J Bone Joint Surg Am 2006;88:355–365.

    Article  PubMed  Google Scholar 

  26. Lieberman JR, Daluiski A, Stevenson S, Wu L, McAllister P, Lee YP, et al. The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral defects in rats. J Bone Joint Surg Am 1999;81:905–917.

    CAS  PubMed  Google Scholar 

  27. Cao H, Koehler DR, Hu J. Adenoviral vectors for gene replacement therapy. Viral Immunol 2004;17:327–333.

    Article  CAS  PubMed  Google Scholar 

  28. Sugiyama O, An DS, Kung SP, Feeley BT, Gamradt S, Liu NQ, et al. Lentivirus-mediated gene transfer induces long-term transgene expression of BMP-2 in vitro and new bone formation in vivo. Mol Ther 2005;11:390–398.

    Article  CAS  PubMed  Google Scholar 

  29. Peng H, Usas A, Gearhart B, Young B, Olshanski A, Huard J. Development of a self-inactivating tet-on retroviral vector expressing bone morphogenetic protein 4 to achieve regulated bone formation. Mol Ther 2004;9:885–894.

    Article  CAS  PubMed  Google Scholar 

  30. Gafni Y, Pelled G, Zilberman Y, Turgeman G, Apparailly F, Yotvat H, et al. Gene therapy platform for bone regeneration using an exogenously regulated, AAV-2-based gene expression system. Mol Ther 2004;9:587–595.

    Article  CAS  PubMed  Google Scholar 

  31. Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med 2001;7:33–40.

    Article  CAS  PubMed  Google Scholar 

  32. Salmon F, Grosios K, Petry H. Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®). Expert Rev Clin Pharmacol 2014;7:53–65.

    Article  CAS  PubMed  Google Scholar 

  33. Morrison C. $1-million price tag set for Glybera gene therapy. Nat Biotechnol 2015;33:217–278.

    Article  CAS  PubMed  Google Scholar 

  34. Mintzer MA, Simanek EE. Nonviral vectors for gene delivery. Chem Rev 2009;109:259–302.

    Article  CAS  PubMed  Google Scholar 

  35. Gill DR, Pringle IA, Hyde SC. Progress and prospects: the design and production of plasmid vectors. Gene Ther 2009;16:165–171.

    Article  CAS  PubMed  Google Scholar 

  36. Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene delivery. Nat Rev Drug Discov 2005;4:581–593.

    Article  CAS  PubMed  Google Scholar 

  37. Dang JM, Leong KW. Natural polymers for gene delivery and tissue engineering. Adv Drug Deliv Rev 2006;58:487–499.

    Article  CAS  PubMed  Google Scholar 

  38. Jiang HL, Kim YK, Arote R, Nah JW, Cho MH, Choi YJ, et al. Chitosangraft-polyethylenimine as a gene carrier. J Control Release 2007;117:273–280.

    Article  CAS  PubMed  Google Scholar 

  39. Kim TH, Jiang HL, Jere D, Park IK, Cho MH, Nah JW, et al. Chemical modification of chitosan as a gene carrier in vitro and in vivo. Proc Polym Sci 2007;32:726–753.

    Article  CAS  Google Scholar 

  40. Jiang HL, Kim TH, Kim YK, Park IY, Cho MH, Cho CS. Efficient gene delivery using chitosan-polyethylenimine hybrid systems. Biomed Mater 2008;3:025013.

    Article  PubMed  CAS  Google Scholar 

  41. Kumar MNR. A review of chitin and chitosan applications. React Func Polym 2000;46:1–27.

    Article  CAS  Google Scholar 

  42. Kim TH, Ihm JE, Choi YJ, Nah JW, Cho CS. Efficient gene delivery by urocanic acid-modified chitosan. J Control Release 2003;93:389–402.

    Article  CAS  PubMed  Google Scholar 

  43. Kim TH, Park IK, Nah JW, Choi YJ, Cho CS. Galactosylated chitosan/ DNA nanoparticles prepared using water-soluble chitosan as a gene carrier. Biomaterials 2004;25:3783–3792.

    Article  CAS  PubMed  Google Scholar 

  44. Jiang HL, Kwon JT, Kim EM, Kim YK, Arote R, Jere D, et al. Galactosylated poly(ethylene glycol)-chitosan-graft-polyethylenimine as a gene carrier for hepatocyte-targeting. J Control Release 2008;131:150–157.

    Article  CAS  PubMed  Google Scholar 

  45. Park IK, Park YH, Shin BA, Choi ES, Kim YR, Akaike T, et al. Galactosylated chitosan-graft-dextran as hepatocyte-targeting DNA carrier. J Control Release 2000;69:97–108.

    Article  CAS  PubMed  Google Scholar 

  46. Jiang HL, Xu CX, Kim YK, Arote R, Jere D, Lim HT, et al. The suppression of lung tumorigenesis by aerosol-delivered folate-chitosan-graftpolyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway. Biomaterials 2009;30:5844–5852.

    Article  CAS  PubMed  Google Scholar 

  47. Kim TH, Nah JW, Cho MH, Park TG, Cho CS. Receptor-mediated gene delivery into antigen presenting cells using mannosylated chitosan/ DNA nanoparticles. J Nanosci Nanotechnol 2006;6:2796–2803.

    Article  CAS  PubMed  Google Scholar 

  48. Jiang HL, Kim YK, Arote R, Jere D, Quan JS, Yu JH, et al. Mannosylated chitosan-graft-polyethylenimine as a gene carrier for Raw 264.7 cell targeting. Int J Pharm 2009;375:133–139.

    Article  CAS  PubMed  Google Scholar 

  49. Jiang HL, Lim HT, Kim YK, Arote R, Shin JY, Kwon JT, et al. Chitosangraft-spermine as a gene carrier in vitro and in vivo. Eur J Pharm Biopharm 2011;77:36–42.

    Article  CAS  PubMed  Google Scholar 

  50. Kim TH, Kim SI, Akaike T, Cho CS. Synergistic effect of poly(ethylenimine) on the transfection efficiency of galactosylated chitosan/DNA complexes. J Control Release 2005;105:354–366.

    Article  CAS  PubMed  Google Scholar 

  51. Jiang G, Min SH, Oh EJ, Hahn SK. DNA/PEI/Alginate polyplex as an efficient in vivo gene delivery system. Biotechnol Bioprocess Engineer 2007;12:684–689.

    Article  CAS  Google Scholar 

  52. Kong HJ, Kim ES, Huang YC, Mooney DJ. Design of biodegradable hydrogel for the local and sustained delivery of angiogenic plasmid DNA. Pharm Res 2008;25:1230–1238.

    Article  CAS  PubMed  Google Scholar 

  53. Krebs MD, Salter E, Chen E, Sutter KA, Alsberg E. Calcium phosphate-DNA nanoparticle gene delivery from alginate hydrogels induces in vivo osteogenesis. J Biomed Mater Res A 2010;92:1131–1138.

    PubMed  Google Scholar 

  54. Wegman F, Bijenhof A, Schuijff L, Oner FC, Dhert WJ, Alblas J. Osteogenic differentiation as a result of BMP-2 plasmid DNA based gene therapy in vitro and in vivo. Eur Cell Mater 2011;21:230–242; discussion242.

    CAS  PubMed  Google Scholar 

  55. Wegman F, Geuze RE, van der Helm YJ, Cumhur Öner F, Dhert WJ, Alblas J. Gene delivery of bone morphogenetic protein-2 plasmid DNA promotes bone formation in a large animal model. J Tissue Eng Regen Med 2014;8:763–770.

    Article  CAS  PubMed  Google Scholar 

  56. Kasper FK, Kushibiki T, Kimura Y, Mikos AG, Tabata Y. In vivo release of plasmid DNA from composites of oligo(poly(ethylene glycol)fumarate) and cationized gelatin microspheres. J Control Release 2005;107:547–561.

    Article  CAS  PubMed  Google Scholar 

  57. Kasper FK, Young S, Tanahashi K, Barry MA, Tabata Y, Jansen JA, et al. Evaluation of bone regeneration by DNA release from composites of oligo(poly(ethylene glycol) fumarate) and cationized gelatin microspheres in a critical-sized calvarial defect. J Biomed Mater Res A 2006;78:335–342.

    Article  PubMed  CAS  Google Scholar 

  58. Chew SA, Kretlow JD, Spicer PP, Edwards AW, Baggett LS, Tabata Y, et al. Delivery of plasmid DNA encoding bone morphogenetic protein-2 with a biodegradable branched polycationic polymer in a critical-size rat cranial defect model. Tissue Eng Part A 2011;17:751–763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Boussif O, Lezoualc’h F, Zanta MA, Mergny MD, Scherman D, Demeneix B, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci U S A 1995;92:7297–7301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jere D, Jiang HL, Arote R, Kim YK, Choi YJ, Cho MH, et al. Degradable polyethylenimines as DNA and small interfering RNA carriers. Expert Opin Drug Deliv 2009;6:827–834.

    Article  CAS  PubMed  Google Scholar 

  61. Chollet P, Favrot MC, Hurbin A, Coll JL. Side-effects of a systemic injection of linear polyethylenimine-DNA complexes. J Gene Med 2002;4:84–91.

    Article  PubMed  Google Scholar 

  62. Abdallah B, Hassan A, Benoist C, Goula D, Behr JP, Demeneix BA. A powerful nonviral vector for in vivo gene transfer into the adult mammalian brain: polyethylenimine. Hum Gene Ther 1996;7:1947–1954.

    Article  CAS  PubMed  Google Scholar 

  63. Boletta A, Benigni A, Lutz J, Remuzzi G, Soria MR, Monaco L. Nonviral gene delivery to the rat kidney with polyethylenimine. Hum Gene Ther 1997;8:1243–1251.

    Article  CAS  PubMed  Google Scholar 

  64. Goula D, Benoist C, Mantero S, Merlo G, Levi G, Demeneix BA. Polyethylenimine-based intravenous delivery of transgenes to mouse lung. Gene Ther 1998;5:1291–1295.

    Article  CAS  PubMed  Google Scholar 

  65. Coll JL, Chollet P, Brambilla E, Desplanques D, Behr JP, Favrot M. In vivo delivery to tumors of DNA complexed with linear polyethylenimine. Hum Gene Ther 1999;10:1659–1666.

    Article  CAS  PubMed  Google Scholar 

  66. Islam MA, Shin JY, Firdous J, Park TE, Choi YJ, Cho MH, et al. The role of osmotic polysorbitol-based transporter in RNAi silencing via caveolaemediated endocytosis and COX-2 expression. Biomaterials 2012;33:8868–8880.

    Article  CAS  PubMed  Google Scholar 

  67. Muthiah M, Islam MA, Cho CS, Hwang JE, Chung IJ, Park IK. Substrate-mediated delivery of microRNA-145 through a polysorbitolbased osmotically active transporter suppresses smooth muscle cell proliferation: implications for restenosis treatment. J Biomed Nanotechnol 2014;10:571–579.

    Article  CAS  PubMed  Google Scholar 

  68. Muthiah M, Islam MA, Lee HJ, Moon MJ, Cho CS, Park IK. MicroRNA delivery with osmotic polysorbitol-based transporter suppresses breast cancer cell proliferation. Int J Biol Macromol 2015;72:1237–1243.

    Article  CAS  PubMed  Google Scholar 

  69. Nguyen KC, Muthiah M, Islam MA, Kalash RS, Cho CS, Park H, et al. Selective transfection with osmotically active sorbitol modified PEI nanoparticles for enhanced anti-cancer gene therapy. Colloids Surf B Biointerfaces 2014;119:126–136.

    Article  CAS  PubMed  Google Scholar 

  70. Islam MA, Shin JY, Yun CH, Cho CS, Seo HW, Chae C, et al. The effect of RNAi silencing of p62 using an osmotic polysorbitol transporter on autophagy and tumorigenesis in lungs of K-rasLA1 mice. Biomaterials 2014;35:1584–1596.

    Article  CAS  PubMed  Google Scholar 

  71. Islam MA, Yun CH, Choi YJ, Shin JY, Arote R, Jiang HL, et al. Accelerated gene transfer through a polysorbitol-based transporter mechanism. Biomaterials 2011;32:9908–9924.

    Article  CAS  PubMed  Google Scholar 

  72. Park TE, Kang B, Kim YK, Zhang Q, Lee WS, Islam MA, et al. Selective stimulation of caveolae-mediated endocytosis by an osmotic polymannitol-based gene transporter. Biomaterials 2012;33:7272–7281.

    Article  CAS  PubMed  Google Scholar 

  73. Garg P, Pandey S, Kang B, Lim KT, Kim J, Cho MH, et al. Highly efficient gene transfection by a hyperosmotic polymannitol based gene tranporter through regulation of caveolae and COX-2 induced endocytosis. J Mater Chem B 2014;2:2666–2679.

    Article  CAS  Google Scholar 

  74. Park TE, Singh B, Li H, Lee JY, Kang SK, Choi YJ, et al. Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer’s disease. Biomaterials 2015;38:61–71.

    Article  CAS  PubMed  Google Scholar 

  75. Lee WS, Kim YK, Zhang Q, Park TE, Kang SK, Kim DW, et al. Polyxylitol-based gene carrier improves the efficiency of gene transfer through enhanced endosomal osmolysis. Nanomedicine 2014;10:525–534.

    CAS  PubMed  Google Scholar 

  76. Garg P, Pandey S, Seonwoo H, Yeom S, Choung YH, Cho CS, et al. Hyperosmotic polydixylitol for crossing the blood brain barrier and efficient nucleic acid delivery. Chem Commun (Camb) 2015;51:3645–3648.

    Article  CAS  Google Scholar 

  77. Jiang HL, Hong SH, Kim YK, Islam MA, Kim HJ, Choi YJ, et al. Aerosol delivery of spermine-based poly(amino ester)/Akt1 shRNA complexes for lung cancer gene therapy. Int J Pharm 2011;420:256–265.

    Article  CAS  PubMed  Google Scholar 

  78. Xu CX, Jere D, Jin H, Chang SH, Chung YS, Shin JY, et al. Poly(ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. Am J Respir Crit Care Med 2008;178:60–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yang J, Zhang Q, Chang H, Cheng Y. Surface-engineered dendrimers in gene delivery. Chem Rev 2015;115:5274–5300.

    Article  CAS  PubMed  Google Scholar 

  80. Akhtar S, Chandrasekhar B, Attur S, Yousif MH, Benter IF. On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFRERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells. Int J Pharm 2013;448:239–246.

    Article  CAS  PubMed  Google Scholar 

  81. Duncan R, Izzo L. Dendrimer biocompatibility and toxicity. Adv Drug Deliv Rev 2005;57:2215–2237.

    Article  CAS  PubMed  Google Scholar 

  82. Ortiz Mellet C, García Fernández JM, Benito JM. Cyclodextrin-based gene delivery systems. Chem Soc Rev 2011;40:1586–1608.

    Article  PubMed  Google Scholar 

  83. Croyle MA, Roessler BJ, Hsu CP, Sun R, Amidon GL. Beta cyclodextrins enhance adenoviral-mediated gene delivery to the intestine. Pharm Res 1998;15:1348–1355.

    Article  CAS  PubMed  Google Scholar 

  84. Croyle MA, Cheng X, Wilson JM. Development of formulations that enhance physical stability of viral vectors for gene therapy. Gene Ther 2001;8:1281–1290.

    Article  CAS  PubMed  Google Scholar 

  85. Gonzalez H, Hwang SJ, Davis ME. New class of polymers for the delivery of macromolecular therapeutics. Bioconjug Chem 1999;10:1068–1074.

    Article  CAS  PubMed  Google Scholar 

  86. Dunn CA, Jin Q, Taba M Jr, Franceschi RT, Bruce Rutherford R, Giannobile WV. BMP gene delivery for alveolar bone engineering at dental implant defects. Mol Ther 2005;11:294–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dai J, Rabie AB. VEGF: an essential mediator of both angiogenesis and endochondral ossification. J Dent Res 2007;86:937–950.

    Article  CAS  PubMed  Google Scholar 

  88. Weinzierl K, Halama D, Burkhardt JK, Gaunitz F, Frerich B. Intraindividual comparison of the osteogenic differentiation potential of mesenchyml progenitor cells drived from adult adipose tissue and bone marrow. Cytotherapy 2006;8 Suppl 2:38.

    Google Scholar 

  89. Zhao Z, Zhao M, Xiao G, Franceschi RT. Gene transfer of the Runx2 transcription factor enhances osteogenic activity of bone marrow stromal cells in vitro and in vivo. Mol Ther 2005;12:247–253.

    Article  CAS  PubMed  Google Scholar 

  90. Lee JS, Lee JM, Im GI. Electroporation-mediated transfer of Runx2 and Osterix genes to enhance osteogenesis of adipose stem cells. Biomaterials 2011;32:760–768.

    Article  CAS  PubMed  Google Scholar 

  91. Zhou X, Zhang Z, Feng JQ, Dusevich VM, Sinha K, Zhang H, et al. Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice. Proc Natl Acad Sci U S A 2010;107:12919–12924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kishimoto KN, Watanabe Y, Nakamura H, Kokubun S. Ectopic bone formation by electroporatic transfer of bone morphogenetic protein-4 gene. Bone 2002;31:340–347.

    Article  CAS  PubMed  Google Scholar 

  93. Kotajima S, Kishimoto KN, Watanuki M, Hatori M, Kokubun S. Gene expression analysis of ectopic bone formation induced by electroporatic gene transfer of BMP4. Ups J Med Sci 2006;111:231–241.

    Article  PubMed  Google Scholar 

  94. Kimelman-Bleich N, Pelled G, Zilberman Y, Kallai I, Mizrahi O, Tawackoli W, et al. Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair. Mol Ther 2011;19:53–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Feichtinger GA, Hofmann AT, Slezak P, Schuetzenberger S, Kaipel M, Schwartz E, et al. Sonoporation increases therapeutic efficacy of inducible and constitutive BMP2/7 in vivo gene delivery. Hum Gene Ther Methods 2014;25:57–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee ET, Lim KT, Kim JH, Im AL, Son HM, Seonwoo H, et al. Effects of low intensity ultrasound stimulation on the proliferation of alveolar bone marrow stem cell. Tissue Eng Regen Med 2008;5:572–580.

    Google Scholar 

  97. Sheyn D, Kimelman-Bleich N, Pelled G, Zilberman Y, Gazit D, Gazit Z. Ultrasound-based nonviral gene delivery induces bone formation in vivo. Gene The 2008;15:257–266.

    CAS  Google Scholar 

  98. Pelled G, Ben-Arav A, Hock C, Reynolds DG, Yazici C, Zilberman Y, et al. Direct gene therapy for bone regeneration: gene delivery, animal models, and outcome measures. Tissue Eng Part B Rev 2010;16:13–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bonadio J, Smiley E, Patil P, Goldstein S. Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med 1999;5:753–759.

    Article  CAS  PubMed  Google Scholar 

  100. Geiger F, Bertram H, Berger I, Lorenz H, Wall O, Eckhardt C, et al. Vascular endothelial growth factor gene-activated matrix (VEGF165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects. J Bone Miner Res 2005;20:2028–2035.

    Article  CAS  PubMed  Google Scholar 

  101. Santos JL, Pandita D, Rodrigues J, Pêgo AP, Granja PL, Tomás H. Nonviral gene delivery to mesenchymal stem cells: methods, strategies and application in bone tissue engineering and regeneration. Curr Gene Ther 2011;11:46–57.

    Article  PubMed  Google Scholar 

  102. Kim IY, Chung JH, Choi YJ, Cho CS. Protein and gene delivery in tissue engineering. Tissue Eng Regen Med 2008;5:671–677.

    Google Scholar 

  103. Yamamoto K, Igawa K, Sugimoto K, Yoshizawa Y, Yanagiguchi K, Ikeda T, et al. Biological safety of fish (tilapia) collagen. Biomed Res Int 2014;2014:630757.

    PubMed  PubMed Central  Google Scholar 

  104. Oliveira SM, Ringshia RA, Legeros RZ, Clark E, Yost MJ, Terracio L, et al. An improved collagen scaffold for skeletal regeneration. J Biomed Mater Res A 2010;94:371–379.

    PubMed  PubMed Central  Google Scholar 

  105. Endo M, Kuroda S, Kondo H, Maruoka Y, Ohya K, Kasugai S. Bone regeneration by modified gene-activated matrix: effectiveness in segmental tibial defects in rats. Tissue Eng 2006;12:489–497.

    Article  CAS  PubMed  Google Scholar 

  106. Kuroda S, Kondo H, Ohya K, Kasugai S. A new technique with calcium phosphate precipitate enhances efficiency of in vivo plasmid DNA gene transfer. J Pharmacol Sci 2005;97:227–233.

    Article  CAS  PubMed  Google Scholar 

  107. Zhang Y, Wang Y, Shi B, Cheng X. A platelet-derived growth factor releasing chitosan/coral composite scaffold for periodontal tissue engineering. Biomaterials 2007;28:1515–1522.

    Article  CAS  PubMed  Google Scholar 

  108. Zhang Y, Shi B, Li C, Wang Y, Chen Y, Zhang W, et al. The synergetic bone-forming effects of combinations of growth factors expressed by adenovirus vectors on chitosan/collagen scaffolds. J Control Release 2009;136:172–178.

    Article  CAS  PubMed  Google Scholar 

  109. Luo T, Zhang W, Shi B, Cheng X, Zhang Y. Enhanced bone regeneration around dental implant with bone morphogenetic protein 2 gene and vascular endothelial growth factor protein delivery. Clin Oral Implants Res 2012;23:467–473.

    Article  PubMed  Google Scholar 

  110. Correia C, Bhumiratana S, Yan LP, Oliveira AL, Gimble JM, Rockwood D, et al. Development of silk-based scaffolds for tissue engineering of bone from human adipose-derived stem cells. Acta Biomater 2012;8:2483–2492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang Y, Fan W, Nothdurft L, Wu C, Zhou Y, Crawford R, 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;17:789–797.

    Article  CAS  PubMed  Google Scholar 

  112. Dhandayuthapani B, Yoshida Y, Maekawa T, Kumar DS. Polymeric scaffolds in tissue engineering application: a review. Int J Polymer Sci 2011; 2011:19.

    Article  Google Scholar 

  113. Huang YC, Simmons C, Kaigler D, Rice KG, Mooney DJ. Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4). Gene Ther 2005;12:418–426.

    Article  CAS  PubMed  Google Scholar 

  114. Chew SA, Kretlow JD, Spicer PP, Edwards AW, Baggett LS, Tabata Y, et al. Delivery of plasmid DNA encoding bone morphogenetic protein-2 with a biodegradable branched polycationic polymer in a critical-size rat cranial defect model. Tissue Eng Part A 2011;17:751–763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chung JH, Kim JH, Cho CS, Choung YH, Lim KT, Son HM, et al. Mechanical stimulation of mesenchymal stem cells for tissue engineering. Tissue Eng Regen Med 2009;6:199–206.

    Google Scholar 

  116. Kumar S, Wan C, Ramaswamy G, Clemens TL, Ponnazhagan S. Mesenchymal stem cells expressing osteogenic and angiogenic factors synergistically enhance bone formation in a mouse model of segmental bone defect. Mol Ther 2010;18:1026–1034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001;169:12–20.

    Article  CAS  PubMed  Google Scholar 

  118. Dawson JI, Kanczler J, Tare R, Kassem M, Oreffo RO. Concise review: bridging the gap: bone regeneration using skeletal stem cell-based strategies -where are we now? Stem Cells 2014;32:35–44.

    Article  CAS  PubMed  Google Scholar 

  119. Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin 2013;34:747–754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lu CH, Chang YH, Lin SY, Li KC, Hu YC. Recent progresses in gene delivery-based bone tissue engineering. Biotechnol Adv 2013;31:1695–1706.

    Article  CAS  PubMed  Google Scholar 

  121. Kumar S, Ponnazhagan S. Bone homing of mesenchymal stem cells by ectopic alpha 4 integrin expression. FASEB J 2007;21:3917–3927.

    Article  CAS  PubMed  Google Scholar 

  122. Guan M, Yao W, Liu R, Lam KS, Nolta J, Jia J, et al. Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat Med 2012;18:456–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zwingenberger S, Yao Z, Jacobi A, Vater C, Valladares RD, Li C, et al. Enhancement of BMP-2 induced bone regeneration by SDF-1a mediated stem cell recruitment. Tissue Eng Part A 2014;20:810–818.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Byers BA, Guldberg RE, Hutmacher DW, García AJ. Effects of Runx2 genetic engineering and in vitro maturation of tissue-engineered constructs on the repair of critical size bone defects. J Biomed Mater Res A 2006;76:646–655.

    Article  PubMed  CAS  Google Scholar 

  125. Xu XL, Tang T, Dai K, Zhu Z, Guo XE, Yu C, et al. Immune response and effect of adenovirus-mediated human BMP-2 gene transfer on the repair of segmental tibial bone defects in goats. Acta Orthop 2005;76:637–646.

    Article  PubMed  Google Scholar 

  126. Lin CY, Chang YH, Lin KJ, Yen TC, Tai CL, Chen CY, et al. The healing of critical-sized femoral segmental bone defects in rabbits using baculovirusengineered mesenchymal stem cells. Biomaterials 2010;31:3222–3230.

    Article  CAS  PubMed  Google Scholar 

  127. He X, Dziak R, Mao K, Genco R, Swihart M, Li C, et al. Integration of a novel injectable nano calcium sulfate/alginate scaffold and BMP2 genemodified mesenchymal stem cells for bone regeneration. Tissue Eng Part A 2013;19:508–518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zou D, Zhang Z, Ye D, Tang A, Deng L, Han W, et al. Repair of criticalsized rat calvarial defects using genetically engineered bone marrow-derived mesenchymal stem cells overexpressing hypoxia-inducible factor-1a. Stem Cells 2011;29:1380–1390.

    CAS  PubMed  Google Scholar 

  129. Ding H, Gao YS, Hu C, Wang Y, Wang CG, Yin JM, et al. HIF-1a transgenic bone marrow cells can promote tissue repair in cases of corticosteroid-induced osteonecrosis of the femoral head in rabbits. PLoS One 2013;8:e63628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li Y, Fan L, Liu S, Liu W, Zhang H, Zhou T, et al. The promotion of bone regeneration through positive regulation of angiogenic-osteogenic coupling using microRNA-26a. Biomaterials 2013;34:5048–5058.

    Article  CAS  PubMed  Google Scholar 

  131. Shum KT, Chan C, Leung CM, Tanner JA. Identification of a DNA aptamer that inhibits sclerostin’s antagonistic effect on Wnt signalling. Biochem J 2011;434:493–501.

    Article  CAS  PubMed  Google Scholar 

  132. van Wijnen AJ, van de Peppel J, van Leeuwen JP, Lian JB, Stein GS, Westendorf JJ, et al. MicroRNA functions in osteogenesis and dysfunctions in osteoporosis. Curr Osteoporos Rep 2013;11:72–82.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Deng Y, Bi X, Zhou H, You Z, Wang Y, Gu P, et al. Repair of critical-sized bone defects with anti-miR-31-expressing bone marrow stromal stem cells and poly(glycerol sebacate) scaffolds. Eur Cell Mater 2014;27:13–24; discussion 24-25.

    CAS  PubMed  Google Scholar 

  134. Jia S, Yang X, Song W, Wang L, Fang K, Hu Z, et al. Incorporation of osteogenic and angiogenic small interfering RNAs into chitosan sponge for bone tissue engineering. Int J Nanomedicine 2014;9:5307–5316.

    PubMed  PubMed Central  Google Scholar 

  135. Ramamoorth M, Narvekar A. Non viral vectors in gene therapy-an overview. J Clin Diagn Res 2015;9:GE01–GE06.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Islam MA, Park TE, Singh B, Maharjan S, Firdous J, Cho MH, et al. Major degradable polycations as carriers for DNA and siRNA. J Control Release 2014;193:74–89.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Genetics, School of Dentistry, Seoul National University, Seoul, Korea

    Young-Dong Kim & Rohidas Arote

  2. Department of Chemical Engineering, Institute of Chemical Technology, Mumbai, India

    Prasad Pofali & Ratnesh Jain

  3. Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, Korea

    Tae-Eun Park, Bijay Singh, Kihyun Cho, Sushila Maharjan, Yun-Jaie Choi & Chong-Su Cho

  4. Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India

    Prajakta Dandekar

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  1. Young-Dong Kim
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Correspondence to Chong-Su Cho.

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These authors contributed equally to this work.

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Kim, YD., Pofali, P., Park, TE. et al. Gene therapy for bone tissue engineering. Tissue Eng Regen Med 13, 111–125 (2016). https://doi.org/10.1007/s13770-016-9063-8

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