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. 2016 Apr 5;13(2):111–125. doi: 10.1007/s13770-016-9063-8

Gene therapy for bone tissue engineering

Young-Dong Kim 1, Prasad Pofali 2, Tae-Eun Park 3, Bijay Singh 3, Kihyun Cho 3, Sushila Maharjan 3, Prajakta Dandekar 4, Ratnesh Jain 2, Yun-Jaie Choi 3, Rohidas Arote 1, Chong-Su Cho 3,✉
PMCID: PMC6170855  PMID: 30603391

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.

Key Words: Gene therapy, Viral vector, Non-viral vector, Bone tissue engineering, Bone morphogenetic protein

Footnotes

These authors contributed equally to this work.

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. doi: 10.1177/154405910808700215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Lind M. Growth factors: possible new clinical tools. A review. Acta Orthop Scand. 1996;67:407–417. doi: 10.3109/17453679609002342. [DOI] [PubMed] [Google Scholar]
  • 3.Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–899. doi: 10.1126/science.150.3698.893. [DOI] [PubMed] [Google Scholar]
  • 4.Sartori R, Sandri M. BMPs and the muscle-bone connection. Bone. 2015;80:37–42. doi: 10.1016/j.bone.2015.05.023. [DOI] [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(1):S151–S158. [PMC free article] [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. doi: 10.2106/00004623-200212000-00001. [DOI] [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. doi: 10.1097/00007632-200002010-00020. [DOI] [PubMed] [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. doi: 10.1034/j.1600-051x.2001.028004340.x. [DOI] [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(1):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. doi: 10.1038/mt.2012.194. [DOI] [PMC free article] [PubMed] [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. doi: 10.1038/nrd3835-c1. [DOI] [PubMed] [Google Scholar]
  • 12.Solheim E. Growth factors in bone. Int Orthop. 1998;22:410–416. doi: 10.1007/s002640050290. [DOI] [PMC free article] [PubMed] [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. doi: 10.1155/2014/406159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Evans CH, Robbins PD. Possible orthopaedic applications of gene therapy. J Bone Joint Surg Am. 1995;77:1103–1114. doi: 10.2106/00004623-199507000-00021. [DOI] [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. doi: 10.2741/2724. [DOI] [PubMed] [Google Scholar]
  • 16.Proc Natl Acad Sci U S A. 1996.
  • 17.Shea LD, Smiley E, Bonadio J, Mooney DJ. DNA delivery from polymer matrices for tissue engineering. Nat Biotechnol. 1999;17:551–554. doi: 10.1038/9853. [DOI] [PubMed] [Google Scholar]
  • 18.Kumar S, Ponnazhagan S. Gene therapy for osteoinduction. Curr Gene Ther. 2004;4:287–296. doi: 10.2174/1566523043346219. [DOI] [PubMed] [Google Scholar]
  • 19.Scaduto AA, Lieberman JR. Gene therapy for osteoinduction. Orthop Clin North Am. 1999;30:625–633. doi: 10.1016/S0030-5898(05)70115-2. [DOI] [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. doi: 10.1080/02648725.2013.801227. [DOI] [PubMed] [Google Scholar]
  • 21.Verma IM, Somia N. Gene therapy —promises, problems and prospects. Nature. 1997;389:239–242. doi: 10.1038/38410. [DOI] [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. doi: 10.1002/jgm.2698. [DOI] [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:S17–S30. doi: 10.1097/00003086-200010001-00004. [DOI] [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. doi: 10.1016/S8756-3282(99)00086-1. [DOI] [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. doi: 10.2106/JBJS.E.00464. [DOI] [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. doi: 10.2106/00004623-199907000-00002. [DOI] [PubMed] [Google Scholar]
  • 27.Cao H, Koehler DR, Hu J. Adenoviral vectors for gene replacement therapy. Viral Immunol. 2004;17:327–333. doi: 10.1089/vim.2004.17.327. [DOI] [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. doi: 10.1016/j.ymthe.2004.10.019. [DOI] [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. doi: 10.1016/j.ymthe.2004.02.023. [DOI] [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. doi: 10.1016/j.ymthe.2003.12.009. [DOI] [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. doi: 10.1038/83324. [DOI] [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. doi: 10.1586/17512433.2014.852065. [DOI] [PubMed] [Google Scholar]
  • 33.Morrison C. $1-million price tag set for Glybera gene therapy. Nat Biotechnol. 2015;33:217–278. doi: 10.1038/nbt0315-217. [DOI] [PubMed] [Google Scholar]
  • 34.Mintzer MA, Simanek EE. Nonviral vectors for gene delivery. Chem Rev. 2009;109:259–302. doi: 10.1021/cr800409e. [DOI] [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. doi: 10.1038/gt.2008.183. [DOI] [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. doi: 10.1038/nrd1775. [DOI] [PubMed] [Google Scholar]
  • 37.Dang JM, Leong KW. Natural polymers for gene delivery and tissue engineering. Adv Drug Deliv Rev. 2006;58:487–499. doi: 10.1016/j.addr.2006.03.001. [DOI] [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. doi: 10.1016/j.jconrel.2006.10.025. [DOI] [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. doi: 10.1016/j.progpolymsci.2007.05.001. [DOI] [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. doi: 10.1088/1748-6041/3/2/025013. [DOI] [PubMed] [Google Scholar]
  • 41.Kumar MNR. A review of chitin and chitosan applications. React Func Polym. 2000;46:1–27. doi: 10.1016/S1381-5148(00)00038-9. [DOI] [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. doi: 10.1016/j.jconrel.2003.08.017. [DOI] [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. doi: 10.1016/j.biomaterials.2003.10.063. [DOI] [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. doi: 10.1016/j.jconrel.2008.07.029. [DOI] [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. doi: 10.1016/S0168-3659(00)00298-4. [DOI] [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. doi: 10.1016/j.biomaterials.2009.07.017. [DOI] [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. doi: 10.1166/jnn.2006.434. [DOI] [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. doi: 10.1016/j.ijpharm.2009.03.033. [DOI] [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. doi: 10.1016/j.ejpb.2010.09.014. [DOI] [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. doi: 10.1016/j.jconrel.2005.03.024. [DOI] [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. doi: 10.1007/BF02931086. [DOI] [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. doi: 10.1007/s11095-007-9526-7. [DOI] [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. doi: 10.1002/jbm.a.32441. [DOI] [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. doi: 10.22203/ecm.v021a18. [DOI] [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. doi: 10.1002/term.1571. [DOI] [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. doi: 10.1016/j.jconrel.2005.07.005. [DOI] [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. doi: 10.1002/jbm.a.30698. [DOI] [PubMed] [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. doi: 10.1089/ten.tea.2010.0496. [DOI] [PMC free article] [PubMed] [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. doi: 10.1073/pnas.92.16.7297. [DOI] [PMC free article] [PubMed] [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. doi: 10.1517/17425240903029183. [DOI] [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. doi: 10.1002/jgm.237. [DOI] [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. doi: 10.1089/hum.1996.7.16-1947. [DOI] [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. doi: 10.1089/hum.1997.8.10-1243. [DOI] [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. doi: 10.1038/sj.gt.3300717. [DOI] [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. doi: 10.1089/10430349950017662. [DOI] [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. doi: 10.1016/j.biomaterials.2012.08.049. [DOI] [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. doi: 10.1166/jbn.2014.1737. [DOI] [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. doi: 10.1016/j.ijbiomac.2014.10.041. [DOI] [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. doi: 10.1016/j.colsurfb.2014.05.003. [DOI] [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. doi: 10.1016/j.biomaterials.2013.11.010. [DOI] [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. doi: 10.1016/j.biomaterials.2011.09.013. [DOI] [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. doi: 10.1016/j.biomaterials.2012.06.037. [DOI] [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. doi: 10.1039/c3tb21831g. [DOI] [PubMed] [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. doi: 10.1016/j.biomaterials.2014.10.068. [DOI] [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. doi: 10.1016/j.nano.2013.10.005. [DOI] [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. doi: 10.1039/C4CC09871D. [DOI] [PubMed] [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. doi: 10.1016/j.ijpharm.2011.08.045. [DOI] [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. doi: 10.1164/rccm.200707-1022OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Yang J, Zhang Q, Chang H, Cheng Y. Surface-engineered dendrimers in gene delivery. Chem Rev. 2015;115:5274–5300. doi: 10.1021/cr500542t. [DOI] [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. doi: 10.1016/j.ijpharm.2013.03.039. [DOI] [PubMed] [Google Scholar]
  • 81.Duncan R, Izzo L. Dendrimer biocompatibility and toxicity. Adv Drug Deliv Rev. 2005;57:2215–2237. doi: 10.1016/j.addr.2005.09.019. [DOI] [PubMed] [Google Scholar]
  • 82.Ortiz Mellet C, García Fernández JM, Benito JM. Cyclodextrin-based gene delivery systems. Chem Soc Rev. 2011;40:1586–1608. doi: 10.1039/C0CS00019A. [DOI] [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. doi: 10.1023/A:1011985101580. [DOI] [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. doi: 10.1038/sj.gt.3301527. [DOI] [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. doi: 10.1021/bc990072j. [DOI] [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. doi: 10.1016/j.ymthe.2004.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Dai J, Rabie AB. VEGF: an essential mediator of both angiogenesis and endochondral ossification. J Dent Res. 2007;86:937–950. doi: 10.1177/154405910708601006. [DOI] [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(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. doi: 10.1016/j.ymthe.2005.03.009. [DOI] [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. doi: 10.1016/j.biomaterials.2010.09.042. [DOI] [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. doi: 10.1073/pnas.0912855107. [DOI] [PMC free article] [PubMed] [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. doi: 10.1016/S8756-3282(02)00825-6. [DOI] [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. doi: 10.3109/2000-1967-044. [DOI] [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. doi: 10.1038/mt.2010.190. [DOI] [PMC free article] [PubMed] [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. doi: 10.1089/hgtb.2013.113. [DOI] [PMC free article] [PubMed] [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. doi: 10.1038/sj.gt.3303070. [DOI] [PubMed] [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. doi: 10.1089/ten.teb.2009.0156. [DOI] [PMC free article] [PubMed] [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. doi: 10.1038/10473. [DOI] [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. doi: 10.1359/JBMR.050701. [DOI] [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. doi: 10.2174/156652311794520102. [DOI] [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. doi: 10.1155/2014/630757. [DOI] [PMC free article] [PubMed] [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. doi: 10.1002/jbm.a.32694. [DOI] [PMC free article] [PubMed] [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. doi: 10.1089/ten.2006.12.489. [DOI] [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. doi: 10.1254/jphs.FP0040504. [DOI] [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. doi: 10.1016/j.biomaterials.2006.11.040. [DOI] [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. doi: 10.1016/j.jconrel.2009.02.016. [DOI] [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. doi: 10.1111/j.1600-0501.2011.02164.x. [DOI] [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. doi: 10.1016/j.actbio.2012.03.019. [DOI] [PMC free article] [PubMed] [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. doi: 10.1089/ten.tec.2010.0453. [DOI] [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. doi: 10.1155/2011/290602. [DOI] [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. doi: 10.1038/sj.gt.3302439. [DOI] [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. doi: 10.1089/ten.tea.2010.0496. [DOI] [PMC free article] [PubMed] [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. doi: 10.1038/mt.2009.315. [DOI] [PMC free article] [PubMed] [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. doi: 10.1159/000047856. [DOI] [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. doi: 10.1002/stem.1559. [DOI] [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. doi: 10.1038/aps.2013.50. [DOI] [PMC free article] [PubMed] [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. doi: 10.1016/j.biotechadv.2013.08.015. [DOI] [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. doi: 10.1096/fj.07-8275com. [DOI] [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. doi: 10.1038/nm.2665. [DOI] [PMC free article] [PubMed] [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. doi: 10.1089/ten.tea.2013.0222. [DOI] [PMC free article] [PubMed] [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. doi: 10.1002/jbm.a.30549. [DOI] [PubMed] [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. doi: 10.1080/17453670510041709. [DOI] [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. doi: 10.1016/j.biomaterials.2010.01.030. [DOI] [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. doi: 10.1089/ten.tea.2012.0244. [DOI] [PMC free article] [PubMed] [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. doi: 10.1002/stem.693. [DOI] [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. doi: 10.1371/journal.pone.0063628. [DOI] [PMC free article] [PubMed] [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. doi: 10.1016/j.biomaterials.2013.03.052. [DOI] [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. doi: 10.1042/BJ20101096. [DOI] [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. doi: 10.1007/s11914-013-0143-6. [DOI] [PMC free article] [PubMed] [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. doi: 10.22203/ecm.v027a02. [DOI] [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. doi: 10.2147/IJN.S70457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135.Ramamoorth M, Narvekar A. Non viral vectors in gene therapy-an overview. J Clin Diagn Res. 2015;9:GE01–GE06. doi: 10.7860/JCDR/2015/10443.5394. [DOI] [PMC free article] [PubMed] [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. doi: 10.1016/j.jconrel.2014.05.055. [DOI] [PubMed] [Google Scholar]

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