Current Trends in Viral Gene Therapy for Human Orthopaedic Regenerative Medicine

  • Jagadeesh Kumar Venkatesan
  • Ana Rey-Rico
  • Magali CucchiariniEmail author
Review Article
Part of the following topical collections:
  1. Cartilage regeneration



Viral vector-based therapeutic gene therapy is a potent strategy to enhance the intrinsic reparative abilities of human orthopaedic tissues. However, clinical application of viral gene transfer remains hindered by detrimental responses in the host against such vectors (immunogenic responses, vector dissemination to nontarget locations). Combining viral gene therapy techniques with tissue engineering procedures may offer strong tools to improve the current systems for applications in vivo.


The goal of this work is to provide an overview of the most recent systems exploiting biomaterial technologies and therapeutic viral gene transfer in human orthopaedic regenerative medicine.


Integration of tissue engineering platforms with viral gene vectors is an active area of research in orthopaedics as a means to overcome the obstacles precluding effective viral gene therapy.


In light of promising preclinical data that may rapidly expand in a close future, biomaterial-guided viral gene therapy has a strong potential for translation in the field of human orthopaedic regenerative medicine.


Viral vectors Biomaterials Orthopaedic regenerative medicine Gene therapy 



This work was supported by a Grant from the Deutsche Forschungsgemeinschaft (DFG VE 1099/1-1 to JKV and MC).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical statement

There are no animal experiments carried out for this article.


  1. 1.
    Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213:626–34.CrossRefPubMedGoogle Scholar
  2. 2.
    Madry H, Grün UW, Knutsen G. Cartilage repair and joint preservation: medical and surgical treatment options. Dtsch Arztebl Int. 2011;108:669–77.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Tuan RS, Chen AF, Klatt BA. Cartilage regeneration. J Am Acad Orthop Surg. 2013;21:303–11.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grøntvedt T, Solheim E, et al. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am. 2004;86-A:455–64.CrossRefPubMedGoogle Scholar
  6. 6.
    Einhorn TA. Enhancement of fracture-healing. J Bone Joint Surg Am. 1995;77:940–56.CrossRefPubMedGoogle Scholar
  7. 7.
    Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11:45–54.CrossRefPubMedGoogle Scholar
  8. 8.
    Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma. 1989;3:192–5.CrossRefGoogle Scholar
  9. 9.
    McDermott I. Meniscal tears, repairs and replacement: their relevance to osteoarthritis of the knee. Br J Sports Med. 2011;45:292–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Verdonk R, Madry H, Shabshin N, Dirisamer F, Peretti GM, Pujol N, et al. The role of meniscal tissue in joint protection in early osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2016;24:1763–74.CrossRefPubMedGoogle Scholar
  11. 11.
    Hildebrand KA, Frank CB. Scar formation and ligament healing. Can J Surg. 1998;41:425–9.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Woo SL, Vogrin TM, Abramowitch SD. Healing and repair of ligament injuries in the knee. J Am Acad Orthop Surg. 2000;8:364–72.CrossRefPubMedGoogle Scholar
  13. 13.
    Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science. 2018. Scholar
  14. 14.
    Lieberman JR, Ghivizzani SC, Evans CH. Gene transfer approaches to the healing of bone and cartilage. Mol Ther. 2002;6:141–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Wu D, Razzano P, Grande DA. Gene therapy and tissue engineering in repair of the musculoskeletal system. J Cell Biochem. 2003;88:467–81.CrossRefPubMedGoogle Scholar
  16. 16.
    Nixon AJ, Watts AE, Schnabel LV. Cell- and gene-based approaches to tendon regeneration. J Shoulder Elbow Surg. 2012;21:278–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol. 2015;11:234–42.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cucchiarini M, McNulty AL, Mauck RL, Setton LA, Guilak F, Madry H. Advances in combining gene therapy with cell and tissue engineering-based approaches to enhance healing of the meniscus. Osteoarthritis Cartilage. 2016;24:1330–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Im GI. Gene transfer strategies to promote chondrogenesis and cartilage regeneration. Tissue Eng Part B Rev. 2016;22:136–48.CrossRefPubMedGoogle Scholar
  20. 20.
    Grol MW, Lee BH. Gene therapy for repair and regeneration of bone and cartilage. Curr Opin Pharmacol. 2018;40:59–66.CrossRefPubMedGoogle Scholar
  21. 21.
    Al-Dosari MS, Gao X. Nonviral gene delivery: principle, limitations, and recent progress. AAPS J. 2009;11:671–81.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Im GI. Nonviral gene transfer strategies to promote bone regeneration. J Biomed Mater Res A. 2013;101:3009–18.CrossRefPubMedGoogle Scholar
  23. 23.
    Giacca M, Zacchigna S. Virus-mediated gene delivery for human gene therapy. J Control Release. 2012;161:377–88.CrossRefPubMedGoogle Scholar
  24. 24.
    Appaiahgari MB, Vrati S. Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls. Expert Opin Biol Ther. 2015;15:337–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Glorioso JC. Herpes simplex viral vectors: late bloomers with big potential. Hum Gene Ther. 2014;25:83–91.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Miller AD, Jolly DJ, Friedmann T, Verma IM. A transmissible retrovirus expressing human hypoxanthine phosphoribosyltransferase (HPRT): gene transfer into cells obtained from humans deficient in HPRT. Proc Natl Acad Sci U S A. 1983;80:4709–13.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272:263–7.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Berns KI, Giraud C. Adenovirus and adeno-associated virus as vectors for gene therapy. Ann N Y Acad Sci. 1995;772:95–104.CrossRefPubMedGoogle Scholar
  29. 29.
    Grieger JC, Samulski RJ. Adeno-associated virus vectorology, manufacturing, and clinical applications. Methods Enzymol. 2012;507:229–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet. 2014;15:445–51.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Marshall E. Gene therapy death prompts review of adenovirus vector. Science. 1999;286:2244–5.CrossRefGoogle Scholar
  32. 32.
    Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118:3132–42.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Xiao X, Li J, Samulski RJ. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol. 1996;70:8098–108.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Madry H, Cucchiarini M, Terwilliger EF, Trippel SB. Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum Gene Ther. 2003;14:393–402.CrossRefPubMedGoogle Scholar
  35. 35.
    Nault JC, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015;47:1187–93.CrossRefPubMedGoogle Scholar
  36. 36.
    Gil-Farina I, Fronza R, Kaeppel C, Lopez-Franco E, Ferreira V, D’Avola D, et al. Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol Ther. 2016;24:1100–5.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Morisset S, Frisbie DD, Robbins PD, Nixon AJ, McIllwraith CW. IL-1ra/IGF-1 gene therapy modulates repair of microfractured chondral defects. Clin Orthop Relat Res. 2007;462:221–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Cucchiarini M, Madry H, Ma C, Thurn T, Zurakowski D, Menger MD, et al. Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol Ther. 2005;12:229–38.CrossRefPubMedGoogle Scholar
  39. 39.
    Hiraide A, Yokoo N, Xin KQ, Okuda K, Mizukami H, Ozawa K, et al. Repair of articular cartilage defect by intraarticular administration of basic fibroblast growth factor gene, using adeno-associated virus vector. Hum Gene Ther. 2005;16:1413–21.CrossRefPubMedGoogle Scholar
  40. 40.
    Cucchiarini M, Orth P, Madry H. Direct rAAV SOX9 administration for durable articular cartilage repair with delayed terminal differentiation and hypertrophy in vivo. J Mol Med (Berl). 2013;91:625–36.CrossRefGoogle Scholar
  41. 41.
    Cucchiarini M, Madry H. Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo. Gene Ther. 2014;21:811–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Cucchiarini M, Asen AK, Goebel L, Venkatesan JK, Schmitt G, Zurakowski D, et al. Effects of TGF-β overexpression via rAAV gene transfer on the early repair processes in an osteochondral defect model in minipigs. Am J Sports Med. 2018;46:1987–96.CrossRefPubMedGoogle Scholar
  43. 43.
    Baltzer AW, Lattermann C, Whalen JD, Wooley P, Weiss K, Grimm M, et al. Genetic enhancement of fracture repair: healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Ther. 2000;7:734–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Tarkka T, Sipola A, Jämsä T, Soini Y, Ylä-Herttuala S, Tuukkanen J, et al. Adenoviral VEGF-A gene transfer induces angiogenesis and promotes bone formation in healing osseous tissues. J Gene Med. 2003;5:560–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Southwood LL, Frisbie DD, Kawcak CE, Ghivizzani SC, Evans CH, McIlwraith CW. Evaluation of Ad-BMP-2 for enhancing fracture healing in an infected defect fracture rabbit model. J Orthop Res. 2004;22:66–72.CrossRefPubMedGoogle Scholar
  46. 46.
    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;88:355–65.CrossRefPubMedGoogle Scholar
  47. 47.
    Egermann M, Lill CA, Griesbeck K, Evans CH, Robbins PD, Schneider E, et al. Effect of BMP-2 gene transfer on bone healing in sheep. Gene Ther. 2006;13:1290–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Betz OB, Betz VM, Nazarian A, Egermann M, Gerstenfeld LC, Einhorn TA, et al. Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects. Gene Ther. 2007;14:1039–44.CrossRefPubMedGoogle Scholar
  49. 49.
    Ishihara A, Shields KM, Litsky AS, Mattoon JS, Weisbrode SE, Bartlett JS, et al. Osteogenic gene regulation and relative acceleration of healing by adenoviral-mediated transfer of human BMP-2 or -6 in equine osteotomy and ostectomy models. J Orthop Res. 2008;26:764–71.CrossRefPubMedGoogle Scholar
  50. 50.
    Rundle CH, Miyakoshi N, Kasukawa Y, Chen ST, Sheng MH, Wergedal JE, et al. In vivo bone formation in fracture repair induced by direct retroviral-based gene therapy with bone morphogenetic protein-4. Bone. 2003;32:591–601.CrossRefPubMedGoogle Scholar
  51. 51.
    Rundle CH, Strong DD, Chen ST, Linkhart TA, Sheng MH, Wergedal JE, et al. Retroviral-based gene therapy with cyclooxygenase-2 promotes the union of bony callus tissues and accelerates fracture healing in the rat. J Gene Med. 2008;10:229–41.CrossRefPubMedGoogle Scholar
  52. 52.
    Strohbach CA, Rundle CH, Wergedal JE, Chen ST, Linkhart TA, Lau KH, et al. LMP-1 retroviral gene therapy influences osteoblast differentiation and fracture repair: a preliminary study. Calcif Tissue Int. 2008;83:202–11.CrossRefPubMedGoogle Scholar
  53. 53.
    Cucchiarini M, Schetting S, Terwilliger EF, Kohn D, Madry H. rAAV-mediated overexpression of FGF-2 promotes cell proliferation, survival, and alpha-SMA expression in human meniscal lesions. Gene Ther. 2009;16:1363–72.CrossRefPubMedGoogle Scholar
  54. 54.
    Cucchiarini M, Schmidt K, Frisch J, Kohn D, Madry H. Overexpression of TGF-β via rAAV-mediated gene transfer promotes the healing of human meniscal lesions ex vivo on explanted menisci. Am J Sports Med. 2015;43:1197–205.CrossRefPubMedGoogle Scholar
  55. 55.
    Madry H, Kohn D, Cucchiarini M. Direct FGF-2 gene transfer via recombinant adeno-associated virus vectors stimulates cell proliferation, collagen production, and the repair of experimental lesions in the human ACL. Am J Sports Med. 2013;41:194–202.CrossRefPubMedGoogle Scholar
  56. 56.
    Tang JB, Chen CH, Zhou YL, McKeever C, Liu PY. Regulatory effects of introduction of an exogenous FGF2 gene on other growth factor genes in a healing tendon. Wound Repair Regen. 2014;22:111–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Tang JB, Wu YF, Cao Y, Chen CH, Zhou YL, Avanessian B, et al. Basic FGF or VEGF gene therapy corrects insufficiency in the intrinsic healing capacity of tendons. Sci Rep. 2016;6:20643.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gelse K, von der Mark K, Aigner T, Park J, Schneider H. Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells. Arthritis Rheum. 2003;48:430–41.CrossRefPubMedGoogle Scholar
  59. 59.
    Kuroda R, Usas A, Kubo S, Corsi K, Peng H, Rose T, et al. Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells. Arthritis Rheum. 2006;54:433–42.CrossRefPubMedGoogle Scholar
  60. 60.
    Park J, Gelse K, Frank S, von der Mark K, Aigner T, Schneider H. Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells. J Gene Med. 2006;8:112–25.CrossRefPubMedGoogle Scholar
  61. 61.
    Pagnotto MR, Wang Z, Karpie JC, Ferretti M, Xiao X, Chu CR. Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Gene Ther. 2007;14:804–13.CrossRefPubMedGoogle Scholar
  62. 62.
    Kubo S, Cooper GM, Matsumoto T, Phillippi JA, Corsi KA, Usas A, et al. Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis Rheum. 2009;60:155–65.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Matsumoto T, Cooper GM, Gharaibeh B, Meszaros LB, Li G, Usas A, et al. Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt-1. Arthritis Rheum. 2009;60:1390–405.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Liu TM, Guo XM, Tan HS, Hui JH, Lim B, Lee EH. Zinc-finger protein 145, acting as an upstream regulator of SOX9, improves the differentiation potential of human mesenchymal stem cells for cartilage regeneration and repair. Arthritis Rheum. 2011;63:2711–20.CrossRefPubMedGoogle Scholar
  65. 65.
    Lee JM, Im GI. SOX trio-co-transduced adipose stem cells in fibrin gel to enhance cartilage repair and delay the progression of osteoarthritis in the rat. Biomaterials. 2012;33:2016–24.CrossRefPubMedGoogle Scholar
  66. 66.
    Hidaka C, Goodrich LR, Chen CT, Warren RF, Crystal RG, Nixon AJ. Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res. 2003;21:573–83.CrossRefPubMedGoogle Scholar
  67. 67.
    Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ. Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Joint Surg Br. 2007;89:672–85.CrossRefPubMedGoogle Scholar
  68. 68.
    Ortved KF, Begum L, Mohammed HO, Nixon AJ. Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. Mol Ther. 2015;23:363–73.CrossRefPubMedGoogle Scholar
  69. 69.
    Ivkovic A, Pascher A, Hudetz D, Maticic D, Jelic M, Dickinson S, et al. Articular cartilage repair by genetically modified bone marrow aspirate in sheep. Gene Ther. 2010;17:779–89.CrossRefPubMedGoogle Scholar
  70. 70.
    Sieker JT, Kunz M, Weißenberger M, Gilbert F, Frey S, Rudert M, et al. Direct bone morphogenetic protein 2 and Indian hedgehog gene transfer for articular cartilage repair using bone marrow coagulates. Osteoarthritis Cartilage. 2015;23:433–42.CrossRefPubMedGoogle Scholar
  71. 71.
    Evans CH, Liu FJ, Glatt V, Hoyland JA, Kirker-Head C, Walsh A, et al. Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage. Eur Cell Mater. 2009;18:96–111.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Betz VM, Keller A, Foehr P, Thirion C, Salomon M, Rammelt S, et al. BMP-2 gene activated muscle tissue fragments for osteochondral defect regeneration in the rabbit knee. J Gene Med. 2017;19:e2972.CrossRefGoogle Scholar
  73. 73.
    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;81:905–17.CrossRefPubMedGoogle Scholar
  74. 74.
    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;18:1026–34.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J, et al. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med. 2005;11:291–7.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Koefoed M, Ito H, Gromov K, Reynolds DG, Awad HA, Rubery PT, et al. Biological effects of rAAV-caAlk2 coating on structural allograft healing. Mol Ther. 2005;12:212–8.CrossRefPubMedGoogle Scholar
  77. 77.
    Betz OB, Betz VM, Abdulazim A, Penzkofer R, Schmitt B, Schröder C, et al. Healing of large segmental bone defects induced by expedited bone morphogenetic protein-2 gene-activated, syngeneic muscle grafts. Hum Gene Ther. 2009;20:1589–96.CrossRefPubMedGoogle Scholar
  78. 78.
    Yazici C, Takahata M, Reynolds DG, Xie C, Samulski RJ, Samulski J, et al. Self-complementary AAV2.5-BMP2-coated femoral allografts mediated superior bone healing versus live autografts in mice with equivalent biomechanics to unfractured femur. Mol Ther. 2011;19:1416–25.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Betz VM, Betz OB, Rosin T, Keller A, Thirion C, Salomon M, et al. The effect of BMP-7 gene activated muscle tissue implants on the repair of large segmental bone defects. Injury. 2015;46:2351–8.CrossRefPubMedGoogle Scholar
  80. 80.
    Liu F, Ferreira E, Porter RM, Glatt V, Schinhan M, Shen Z, et al. Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. Eur Cell Mater. 2015;30:118–30.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Betz VM, Betz OB, Rosin T, Keller A, Thirion C, Salomon M, et al. An expedited approach for sustained delivery of bone morphogenetic protein-7 to bone defects using gene activated fragments of subcutaneous fat. J Gene Med. 2016;18:199–207.CrossRefPubMedGoogle Scholar
  82. 82.
    Hou Y, Mao Z, Wei X, Lin L, Chen L, Wang H, et al. Effects of transforming growth factor-beta1 and vascular endothelial growth factor 165 gene transfer on Achilles tendon healing. Matrix Biol. 2009;28:324–35.CrossRefPubMedGoogle Scholar
  83. 83.
    Basile P, Dadali T, Jacobson J, Hasslund S, Ulrich-Vinther M, Søballe K, et al. Freeze-dried tendon allografts as tissue-engineering scaffolds for Gdf5 gene delivery. Mol Ther. 2008;16:466–73.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Majewski M, Betz O, Ochsner PE, Liu F, Porter RM, Evans CH. Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model. Gene Ther. 2008;15:1139–46.CrossRefPubMedGoogle Scholar
  85. 85.
    Schnabel LV, Lynch ME, van der Meulen MC, Yeager AE, Kornatowski MA, Nixon AJ. Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons. J Orthop Res. 2009;27:1392–8.CrossRefPubMedGoogle Scholar
  86. 86.
    Majewski M, Porter RM, Betz OB, Betz VM, Clahsen H, Flückiger R, et al. Improvement of tendon repair using muscle grafts transduced with TGF-β1 cDNA. Eur Cell Mater. 2012;23:94–101.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Hasslund S, Dadali T, Ulrich-Vinther M, Søballe K, Schwarz EM, Awad HA. Freeze-dried allograft-mediated gene or protein delivery of growth and differentiation factor 5 reduces reconstructed murine flexor tendon adhesions. J Tissue Eng. 2014;5:2041731414528736.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Tan C, Lui PP, Lee YW, Wong YM. Scx-transduced tendon-derived stem cells (tdscs) promoted better tendon repair compared to mock-transduced cells in a rat patellar tendon window injury model. PLoS One. 2014;9:e97453.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Ghivizzani SC, Lechman ER, Kang R, Tio C, Kolls J, Evans CH, et al. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci U S A. 1998;95:4613–8.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Lechman ER, Jaffurs D, Ghivizzani SC, Gambotto A, Kovesdi I, Mi Z, Evans CH, et al. Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. J Immunol. 1999;163:2202–8.PubMedGoogle Scholar
  91. 91.
    Chan JM, Villarreal G, Jin WW, Stepan T, Burstein H, Wahl SM. Intraarticular gene transfer of TNFR: Fc suppresses experimental arthritis with reduced systemic distribution of the gene product. Mol Ther. 2002;6:727–36.CrossRefPubMedGoogle Scholar
  92. 92.
    Zhou X, Shen L, Liu L, Wang C, Qi W, Zhao A, et al. Preclinical safety evaluation of recombinant adeno-associated virus 2 vector encoding human tumor necrosis factor receptor-immunoglobulin Fc fusion gene. Hum Vaccin Immunother. 2016;12:732–9.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Bellavia D, Veronesi F, Carina V, Costa V, Raimondi L, De Luca A, et al. Gene therapy for chondral and osteochondral regeneration: is the future now? Cell Mol Life Sci. 2018;75:649–67.CrossRefPubMedGoogle Scholar
  94. 94.
    Cottard V, Valvason C, Falgarone G, Lutomski D, Boissier MC, Bessis N. Immune response against gene therapy vectors: influence of synovial fluid on adeno-associated virus mediated gene transfer to chondrocytes. J Clin Immunol. 2004;24:162–9.CrossRefPubMedGoogle Scholar
  95. 95.
    Mangeat B, Trono D. Lentiviral vectors and antiretroviral intrinsic immunity. Hum Gene Ther. 2005;16:913–20.CrossRefPubMedGoogle Scholar
  96. 96.
    Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009;199:381–90.CrossRefPubMedGoogle Scholar
  97. 97.
    Nayak S, Herzog RW. Progress and prospects: immune responses to viral vectors. Gene Ther. 2010;17:295–304.CrossRefPubMedGoogle Scholar
  98. 98.
    Fausther-Bovendo H, Kobinger GP. Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, what’s important? Hum Vaccin Immunother. 2014;10:2875–84.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Schuettrumpf J, Zou J, Zhang Y, Schlachterman A, Liu YL, Edmonson S, et al. The inhibitory effects of anticoagulation on in vivo gene transfer by adeno-associated viral or adenoviral vectors. Mol Ther. 2006;13:88–97.CrossRefPubMedGoogle Scholar
  100. 100.
    Robbins PD, Tahara H, Ghivizzani SC. Viral vectors for gene therapy. Trends Biotechnol. 1998;16:35–40.CrossRefPubMedGoogle Scholar
  101. 101.
    Campbell EM, Hope TJ. Gene therapy progress and prospects: viral trafficking during infection. Gene Ther. 2005;12:1353–9.CrossRefPubMedGoogle Scholar
  102. 102.
    Langer RS, Peppas NA. Present and future applications of biomaterials in controlled drug delivery systems. Biomaterials. 1981;2:201–14.CrossRefPubMedGoogle Scholar
  103. 103.
    Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–6.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Freed LE, Guilak F, Guo XE, Gray ML, Tranquillo R, Holmes JW, et al. Advanced tools for tissue engineering: scaffolds, bioreactors, and signaling. Tissue Eng. 2006;12:3285–305.CrossRefPubMedGoogle Scholar
  105. 105.
    Mikos AG, Herring SW, Ochareon P, Elisseeff J, Lu HH, Kandel R, et al. Engineering complex tissues. Tissue Eng. 2006;12:3307–39.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Johnstone B, Alini M, Cucchiarini M, Dodge GR, Eglin D, Guilak F, et al. Tissue engineering for articular cartilage repair—the state of the art. Eur Cell Mater. 2013;25:248–67.CrossRefPubMedGoogle Scholar
  107. 107.
    Smith BD, Grande DA. The current state of scaffolds for musculoskeletal regenerative applications. Nat Rev Rheumatol. 2015;11:213–22.CrossRefPubMedGoogle Scholar
  108. 108.
    Tatara AM, Mikos AG. Tissue engineering in orthopaedics. J Bone Joint Surg Am. 2016;98:1132–9.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Verrier S, Alini M, Alsberg E, Buchman SR, Kelly D, Laschke MW, et al. Tissue engineering and regenerative approaches to improving the healing of large bone defects. Eur Cell Mater. 2016;32:87–110.CrossRefPubMedGoogle Scholar
  110. 110.
    Armiento AR, Stoddart MJ, Alini M, Eglin D. Biomaterials for articular cartilage tissue engineering: Learning from biology. Acta Biomater. 2018;65:1–20.CrossRefPubMedGoogle Scholar
  111. 111.
    Kim BS, Cho CS. Injectable hydrogels for regenerative medicine. Tissue Eng Regen Med. 2018;15:511–2.CrossRefPubMedGoogle Scholar
  112. 112.
    Oh HJ, Kim SH, Cho JH, Park SH, Min BH. Mechanically reinforced extracellular matrix scaffold for the application of cartilage tissue engineering. Tissue Eng Regen Med. 2018;15:287–99.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Patel M, Park S, Lee HJ, Jeong B. Polypeptide thermogels as three-dimensional scaffolds for cells. Tissue Eng Regen Med. 2018;15:521–30.CrossRefPubMedGoogle Scholar
  114. 114.
    Mason JM, Breitbart AS, Barcia M, Porti D, Pergolizzi RG, Grande DA. Cartilage and bone regeneration using gene-enhanced tissue engineering. Clin Orthop Relat Res. 2000;379:S171–8.CrossRefGoogle Scholar
  115. 115.
    Grande DA, Mason J, Light E, Dines D. Stem cells as platforms for delivery of genes to enhance cartilage repair. J Bone Joint Surg Am. 2003;85-A Suppl 2:111–6.CrossRefGoogle Scholar
  116. 116.
    Yokoo N, Saito T, Uesugi M, Kobayashi N, Xin KQ, Okuda K, et al. Repair of articular cartilage defect by autologous transplantation of basic fibroblast growth factor gene-transduced chondrocytes with adeno-associated virus vector. Arthritis Rheum. 2005;52:164–70.CrossRefPubMedGoogle Scholar
  117. 117.
    Cao L, Yang F, Liu G, Yu D, Li H, Fan Q, et al. The promotion of cartilage defect repair using adenovirus mediated Sox9 gene transfer of rabbit bone marrow mesenchymal stem cells. Biomaterials. 2011;32:3910–20.CrossRefPubMedGoogle Scholar
  118. 118.
    Klinger P, Surmann-Schmitt C, Brem M, Swoboda B, Distler JH, Carl HD, et al. Chondromodulin 1 stabilizes the chondrocyte phenotype and inhibits endochondral ossification of porcine cartilage repair tissue. Arthritis Rheum. 2011;63:2721–31.CrossRefPubMedGoogle Scholar
  119. 119.
    Qi BW, Yu AX, Zhu SB, Zhou M, Wu G. Chiotosan/poly(vinyl alcohol) hydrogel combined with Ad-hTGF-β1 transfected mesenchymal stem cells to repair rabbit articular cartilage defects. Exp Biol Med (Maywood). 2013;238:23–30.CrossRefGoogle Scholar
  120. 120.
    Rose T, Peng H, Shen HC, Usas A, Kuroda R, Lill H, et al. The role of cell type in bone healing mediated by ex vivo gene therapy. Langenbecks Arch Surg. 2003;388:347–55.CrossRefPubMedGoogle Scholar
  121. 121.
    Shen HC, Peng H, Usas A, Gearhart B, Fu FH, Huard J. Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4. J Gene Med. 2004;6:984–91.CrossRefPubMedGoogle Scholar
  122. 122.
    Peterson B, Zhang J, Iglesias R, Kabo M, Hedrick M, Benhaim P, et al. Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue. Tissue Eng. 2005;11:120–9.CrossRefPubMedGoogle Scholar
  123. 123.
    Hsu WK, Sugiyama O, Park SH, Conduah A, Feeley BT, Liu NQ, et al. Lentiviral-mediated BMP-2 gene transfer enhances healing of segmental femoral defects in rats. Bone. 2007;40:931–8.CrossRefPubMedGoogle Scholar
  124. 124.
    Virk MS, Conduah A, Park SH, Liu N, Sugiyama O, Cuomo A, et al. Influence of short-term adenoviral vector and prolonged lentiviral vector mediated bone morphogenetic protein-2 expression on the quality of bone repair in a rat femoral defect model. Bone. 2008;42:921–31.CrossRefPubMedGoogle Scholar
  125. 125.
    Wojtowicz AM, Templeman KL, Hutmacher DW, Guldberg RE, García AJ. Runx2 overexpression in bone marrow stromal cells accelerates bone formation in critical-sized femoral defects. Tissue Eng Part A. 2010;16:2795–808.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Li J, Zhao Q, Wang E, Zhang C, Wang G, Yuan Q. Transplantation of Cbfa1-overexpressing adipose stem cells together with vascularized periosteal flaps repair segmental bone defects. J Surg Res. 2012;176:e13–20.CrossRefPubMedGoogle Scholar
  127. 127.
    Sonnet C, Simpson CL, Olabisi RM, Sullivan K, Lazard Z, Gugala Z, et al. Rapid healing of femoral defects in rats with low dose sustained BMP2 expression from PEGDA hydrogel microspheres. J Orthop Res. 2013;31:1597–604.CrossRefPubMedGoogle Scholar
  128. 128.
    Duan C, Liu J, Yuan Z, Meng G, Yang X, Jia S, et al. Adenovirus-mediated transfer of VEGF into marrow stromal cells combined with PLGA/TCP scaffold increases vascularization and promotes bone repair in vivo. Arch Med Sci. 2014;10:174–81.CrossRefPubMedGoogle Scholar
  129. 129.
    Ho CY, Sanghani A, Hua J, Coathup M, Kalia P, Blunn G. Mesenchymal stem cells with increased stromal cell-derived factor 1 expression enhanced fracture healing. Tissue Eng Part A. 2015;21:594–602.CrossRefPubMedGoogle Scholar
  130. 130.
    Yin C, Chen J, Chen Z, Zeng Z, Qiu J. hBMP-2 and hTGF-β1 expressed in implanted BMSCs synergistically promote the repairing of segmental bone defects. J Orthop Sci. 2015;20:717–27.CrossRefPubMedGoogle Scholar
  131. 131.
    Bougioukli S, Jain A, Sugiyama O, Tinsley BA, Tang AH, Tan MH, et al. Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect. Bone. 2016;84:93–103.CrossRefPubMedGoogle Scholar
  132. 132.
    Yan X, Zhou Z, Guo L, Zeng Z, Guo Z, Shao Q, et al. BMP7-overexpressing bone marrow-derived mesenchymal stem cells (BMSCs) are more effective than wild-type BMSCs in healing fractures. Exp Ther Med. 2018;16:1381–8.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Otabe K, Nakahara H, Hasegawa A, Matsukawa T, Ayabe F, Onizuka N, et al. Transcription factor Mohawk controls tenogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo. J Orthop Res. 2015;33:1–8.CrossRefPubMedGoogle Scholar
  134. 134.
    Xu K, Sun Y, Kh Al-Ani M, Wang C, Sha Y, Sung KP, et al. Synergistic promoting effects of bone morphogenetic protein 12/connective tissue growth factor on functional differentiation of tendon derived stem cells and patellar tendon window defect regeneration. J Biomech. 2018;66:95–102.CrossRefPubMedGoogle Scholar
  135. 135.
    Fang J, Zhu YY, Smiley E, Bonadio J, Rouleau JP, Goldstein SA, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A. 1996;93:5753–8.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    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;5:753–9.CrossRefPubMedGoogle Scholar
  137. 137.
    Bonadio J. Tissue engineering via local gene delivery: update and future prospects for enhancing the technology. Adv Drug Deliv Rev. 2000;44:185–94.CrossRefPubMedGoogle Scholar
  138. 138.
    Im GI, Kim HJ, Lee JH. Chondrogenesis of adipose stem cells in a porous PLGA scaffold impregnated with plasmid DNA containing SOX trio (SOX-5,-6 and -9) genes. Biomaterials. 2011;32:4385–92.CrossRefPubMedGoogle Scholar
  139. 139.
    Pannier AK, Shea LD. Controlled release systems for DNA delivery. Mol Ther. 2004;10:19–26.CrossRefPubMedGoogle Scholar
  140. 140.
    Gower RM, Shea LD. Biomaterial scaffolds for controlled, localized gene delivery of regenerative factors. Adv Wound Care (New Rochelle). 2013;2:100–6.CrossRefGoogle Scholar
  141. 141.
    Jang JH, Schaffer DV, Shea LD. Engineering biomaterial systems to enhance viral vector gene delivery. Mol Ther. 2011;19:1407–15.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Cucchiarini M. Human gene therapy: novel approaches to improve the current gene delivery systems. Discov Med. 2016;21:495–506.PubMedGoogle Scholar
  143. 143.
    Rey-Rico A, Cucchiarini M. Controlled release strategies for rAAV-mediated gene delivery. Acta Biomater. 2016;29:1–10.CrossRefPubMedGoogle Scholar
  144. 144.
    Raftery RM, Walsh DP, Castaño IM, Heise A, Duffy GP, Cryan SA, et al. Delivering nucleic-acid based nanomedicines on biomaterial scaffolds for orthopedic tissue repair: challenges, progress and future perspectives. Adv Mater. 2016;28:5447–69.CrossRefPubMedGoogle Scholar
  145. 145.
    Rey-Rico A, Cucchiarini M. Recent tissue engineering-based advances for effective rAAV-mediated gene transfer in the musculoskeletal system. Bioengineered. 2016;7:175–88.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Rey-Rico A, Cucchiarini M, Madry H. Hydrogels for precision meniscus tissue engineering: a comprehensive review. Connect Tissue Res. 2017;58:317–28.CrossRefPubMedGoogle Scholar
  147. 147.
    Venkatesan JK, Falentin-Daudré C, Leroux A, Migonney V, Cucchiarini M. Controlled release of gene therapy constructs from solid scaffolds for therapeutic applications in orthopedics. Discov Med. 2018;25:195–203.PubMedGoogle Scholar
  148. 148.
    Díaz-Rodríguez P, Rey-Rico A, Madry H, Landin M, Cucchiarini M. Effective genetic modification and differentiation of hMSCs upon controlled release of rAAV vectors using alginate/poloxamer composite systems. Int J Pharm. 2015;496:614–26.CrossRefPubMedGoogle Scholar
  149. 149.
    Rey-Rico A, Venkatesan JK, Frisch J, Rial-Hermida I, Schmitt G, Concheiro A, et al. PEO–PPO–PEO micelles as effective rAAV-mediated gene delivery systems to target human mesenchymal stem cells without altering their differentiation potency. Acta Biomater. 2015;27:42–52.CrossRefPubMedGoogle Scholar
  150. 150.
    Rey-Rico A, Venkatesan JK, Frisch J, Schmitt G, Monge-Marcet A, Lopez-Chicon P, et al. Effective and durable genetic modification of human mesenchymal stem cells via controlled release of rAAV vectors from self-assembling peptide hydrogels with a maintained differentiation potency. Acta Biomater. 2015;18:118–27.CrossRefPubMedGoogle Scholar
  151. 151.
    Rey-Rico A, Frisch J, Venkatesan JK, Schmitt G, Rial-Hermida I, Taboada P, et al. PEO–PPO–PEO carriers for rAAV-mediated transduction of human articular chondrocytes in vitro and in a human osteochondral defect model. ACS Appl Mater Interfaces. 2016;8:20600–13.CrossRefPubMedGoogle Scholar
  152. 152.
    Rey-Rico A, Babicz H, Madry H, Concheiro A, Alvarez-Lorenzo C, Cucchiarini M. Supramolecular polypseudorotaxane gels for controlled delivery of rAAV vectors in human mesenchymal stem cells for regenerative medicine. Int J Pharm. 2017;531:492–503.CrossRefPubMedGoogle Scholar
  153. 153.
    Rey-Rico A, Venkatesan JK, Schmitt G, Concheiro A, Madry H, Alvarez-Lorenzo C, et al. rAAV-mediated overexpression of TGF-β via vector delivery in polymeric micelles stimulates the biological and reparative activities of human articular chondrocytes in vitro and in a human osteochondral defect model. Int J Nanomedicine. 2017;12:6985–96.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Rey-Rico A, Venkatesan JK, Schmitt G, Speicher-Mentges S, Madry H, Cucchiarini M. Effective remodelling of human osteoarthritic cartilage by sox9 gene transfer and overexpression upon delivery of rAAV vectors in polymeric micelles. Mol Pharm. 2018;15:2816–26.CrossRefPubMedGoogle Scholar
  155. 155.
    Brunger JM, Huynh NP, Guenther CM, Perez-Pinera P, Moutos FT, Sanchez-Adams J, et al. Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc Natl Acad Sci U S A. 2014;111:E798–806.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Glass KA, Link JM, Brunger JM, Moutos FT, Gersbach CA, Guilak F. Tissue-engineered cartilage with inducible and tunable immunomodulatory properties. Biomaterials. 2014;35:5921–31.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Moutos FT, Glass KA, Compton SA, Ross AK, Gersbach CA, Guilak F, et al. Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. Proc Natl Acad Sci U S A. 2016;113:E4513–22.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Rowland CR, Glass KA, Ettyreddy AR, Gloss CC, Matthews JRL, Huynh NPT, et al. Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs. Biomaterials. 2018;177:161–75.CrossRefPubMedGoogle Scholar
  159. 159.
    Uemura T, Kojima H. Bone formation in vivo induced by Cbfa1-carrying adenoviral vectors released from a biodegradable porous β-tricalcium phosphate (β-TCP) material. Sci Technol Adv Mater. 2011;12:034405.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Nasu T, Ito H, Tsutsumi R, Kitaori T, Takemoto M, Schwarz EM, et al. Biological activation of bone-related biomaterials by recombinant adeno-associated virus vector. J Orthop Res. 2009;27:1162–8.CrossRefPubMedGoogle Scholar
  161. 161.
    Dupont KM, Boerckel JD, Stevens HY, Diab T, Kolambkar YM, Takahata M, et al. Synthetic scaffold coating with adeno-associated virus encoding BMP2 to promote endogenous bone repair. Cell Tissue Res. 2012;347:575–88.CrossRefPubMedGoogle Scholar
  162. 162.
    Xue J, Lin H, Bean A, Tang Y, Tan J, Tuan RS, et al. One-step fabrication of bone morphogenetic protein-2 gene-activated porous poly-l-lactide scaffold for bone induction. Mol Ther Methods Clin Dev. 2017;7:50–9.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy is becoming a reality. Nat Rev Rheumatol. 2018;14:381–2.CrossRefPubMedGoogle Scholar
  164. 164.
    Cherian JJ, Parvizi J, Bramlet D, Lee KH, Romness DW, Mont MA. Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-β1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthritis Cartilage. 2015;23:2109–18.CrossRefPubMedGoogle Scholar
  165. 165.
    Ha CW, Cho JJ, Elmallah RK, Cherian JJ, Kim TW, Lee MC, et al. A multicenter, single-blind, phase IIa clinical trial to evaluate the efficacy and safety of a cell-mediated gene therapy in degenerative knee arthritis patients. Hum Gene Ther Clin Dev. 2015;26:125–30.CrossRefPubMedGoogle Scholar
  166. 166.
    Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2017: an update. J Gene Med. 2018;20:e3015.CrossRefPubMedGoogle Scholar
  167. 167.
    Bozo IY, Deev RV, Drobyshev AY, Isaev AA, Eremin II. World’s first clinical case of gene-activated bone substitute application. Case Rep Dent. 2016;2016:8648949.PubMedPubMedCentralGoogle Scholar
  168. 168.
    Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol. 2014;32:773–85.CrossRefPubMedGoogle Scholar
  169. 169.
    Cunniffe GM, Gonzalez-Fernandez T, Daly A, Sathy BN, Jeon O, Alsberg E, et al. Three-dimensional bioprinting of polycaprolactone reinforced gene activated bioinks for bone tissue engineering. Tissue Eng Part A. 2017;23:891–900.CrossRefPubMedGoogle Scholar
  170. 170.
    Daly AC, Freeman FE, Gonzalez-Fernandez T, Critchley SE, Nulty J, Kelly DJ. 3D bioprinting for cartilage and osteochondral tissue engineering. Adv Healthc Mater. 2017;6:1700298.CrossRefGoogle Scholar
  171. 171.
    Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346:1258096.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Adkar SS, Brunger JM, Willard VP, Wu CL, Gersbach CA, Guilak F. Genome engineering for personalized arthritis therapeutics. Trends Mol Med. 2017;23:917–31.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Almarza D, Cucchiarini M, Loughlin J. Genome editing for human osteoarthritis—a perspective. Osteoarthritis Cartilage. 2017;25:1195–8.CrossRefPubMedGoogle Scholar
  174. 174.
    Kim M, Yun HW, Park DY, Choi BH, Min BH. Three-dimensional spheroid culture increases exosome secretion from mesenchymal stem cells. Tissue Eng Regen Med. 2018;15:427–36.CrossRefPubMedGoogle Scholar

Copyright information

© The Korean Tissue Engineering and Regenerative Medicine Society and Springer Nature B.V. 2019

Authors and Affiliations

  • Jagadeesh Kumar Venkatesan
    • 1
  • Ana Rey-Rico
    • 1
    • 2
  • Magali Cucchiarini
    • 1
    Email author
  1. 1.Center of Experimental OrthopaedicsSaarland University Medical CenterHomburg/SaarGermany
  2. 2.Cell Therapy and Regenerative Medicine Unit, Centro de Investigacións Científicas Avanzadas (CICA)Universidade da CoruñaA CoruñaSpain

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