Review Article | Published:

Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair

Nature Reviews Rheumatologyvolume 15pages1829 (2019) | Download Citation


Articular cartilage defects are prevalent and are potentially involved in the initiation of osteoarthritis, yet the lack of efficient therapeutic options to treat cartilage defects represents a substantial challenge. Molecular treatments that require the delivery of therapeutic gene vectors are often less effective that specific, targeted approaches, and the scientific evidence for acellular biomaterial-assisted procedures is limited. Controlled delivery of gene vectors using biocompatible materials is emerging as a novel strategy for the sustained and tuneable release of gene therapies in a spatiotemporally precise manner, thereby reducing intra-articular vector spread and possible loss of the therapeutic gene product. Controlled, biomaterial-guided delivery of gene vectors could be used to enhance intrinsic mechanisms of cartilage repair while affording protection against potentially damaging host immune responses that might counteract the gene therapy component. This Review provides an overview of advances in gene vector-loaded biomaterials for articular cartilage repair. Such systems enable the sustained release of gene therapies while maintaining transduction efficacy. Strategies that harness these properties are likely to result in improved in situ cartilage tissue regeneration that could be safely translated into clinical applications in the near future.

Key points

  • Articular cartilage has a limited capacity for self-repair in terms of strength and sustainability.

  • None of the current pharmacological or surgical options for cartilage repair can completely restore damaged articular cartilage to its original structure and function.

  • Gene therapy holds promise for the treatment of articular cartilage lesions by providing reparative gene sequences at sites of tissue injury.

  • Tissue engineering approaches provide adapted scaffolding matrices that can support the mechanisms of cartilage repair.

  • Host physiological barriers preclude the optimal use of gene therapy or tissue engineering procedures for translational applications to treat articular cartilage injuries.

  • Combining gene therapy and scaffold-mediated approaches might enable the safe, effective and durable regeneration of articular cartilage at lesion sites in patients with osteoarthritis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Guermazi, A. et al. Brief report: partial- and full-thickness focal cartilage defects contribute equally to development of new cartilage damage in knee osteoarthritis: the multicenter osteoarthritis study. Arthritis Rheumatol. 69, 560–564 (2017).

  2. 2.

    Sanders, T. L. et al. High rate of osteoarthritis after osteochondritis dissecans fragment excision compared with surgical restoration at a mean 16-year follow-up. Am. J. Sports Med. 45, 1799–1805 (2017).

  3. 3.

    Hunziker, E. B., Lippuner, K., Keel, M. J. & Shintani, N. An educational review of cartilage repair: precepts & practice — myths & misconceptions — progress & prospects. Osteoarthritis Cartilage 23, 334–350 (2015).

  4. 4.

    Makris, E. A., Gomoll, A. H., Malizos, K. N., Hu, J. C. & Athanasiou, K. A. Repair and tissue engineering techniques for articular cartilage. Nat. Rev. Rheumatol. 11, 21–34 (2015).

  5. 5.

    Mundi, R. et al. Cartilage restoration of the knee: a systematic review and meta-analysis of level 1 studies. Am. J. Sports Med. 44, 1888–1895 (2016).

  6. 6.

    Hunziker, E. B. Articular cartilage repair: basic science and clinical progress. A review of the current state and prospects. Osteoarthritis Cartilage 10, 432–463 (2002).

  7. 7.

    Evans, C. H. & Huard, J. Gene therapy approaches to regenerating the musculoskeletal system. Nat. Rev. Rheumatol. 11, 234–242 (2015).

  8. 8.

    Nita, I. et al. Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo. Arthritis Rheum. 39, 820–828 (1996).

  9. 9.

    Madry, H., Gao, L., Eichler, H., Orth, P. & Cucchiarini, M. Bone marrow aspirate concentrate-enhanced marrow stimulation of chondral defects. Stem Cells Int. 2017, 1609685 (2017).

  10. 10.

    Brittberg, M. et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Engl. J. Med. 331, 889–895 (1994).

  11. 11.

    Mistry, H. et al. Autologous chondrocyte implantation in the knee: systematic review and economic evaluation. Health Technol. Assess. 21, 1–294 (2017).

  12. 12.

    Knutsen, G. et al. A randomized multicenter trial comparing autologous chondrocyte implantation with microfracture: long-term follow-up at 14 to 15 years. J. Bone Joint Surg. Am. 98, 1332–1339 (2016).

  13. 13.

    Gao, L., Orth, P., Cucchiarini, M. & Madry, H. Autologous matrix-induced chondrogenesis: a systematic review of the clinical evidence. Am. J. Sports Med. (2017).

  14. 14.

    Pareek, A. et al. Osteochondral autograft transfer versus microfracture in the knee: a meta-analysis of prospective comparative studies at midterm. Arthroscopy 32, 2118–2130 (2016).

  15. 15.

    Gracitelli, G. C. et al. Fresh osteochondral allografts in the knee: comparison of primary transplantation versus transplantation after failure of previous subchondral marrow stimulation. Am. J. Sports Med. 43, 885–891 (2015).

  16. 16.

    Lohmander, S. et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 66, 1820–1831 (2014).

  17. 17.

    Adkar, S. S. et al. Genome engineering for personalized arthritis therapeutics. Trends Mol. Med. 23, 917–931 (2017).

  18. 18.

    Chen, X. & Goncalves, M. A. Engineered viruses as genome editing devices. Mol. Ther. 24, 447–457 (2016).

  19. 19.

    Cucchiarini, M. & Madry, H. Gene therapy for cartilage defects. J. Gene Med. 7, 1495–1509 (2005).

  20. 20.

    Evans, C. H. et al. Using gene therapy to protect and restore cartilage. Clin. Orthop. Relat. Res. 379, S214–S219 (2000).

  21. 21.

    Maeder, M. L. & Gersbach, C. A. Genome-editing technologies for gene and cell therapy. Mol. Ther. 24, 430–446 (2016).

  22. 22.

    Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

  23. 23.

    Cucchiarini, M. Human gene therapy: novel approaches to improve the current gene delivery systems. Discov. Med. 21, 495–506 (2016).

  24. 24.

    Cucchiarini, M. et al. Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol. Ther 12, 229–238 (2005).

  25. 25.

    Hiraide, A. et al. Repair of articular cartilage defect by intraarticular administration of basic fibroblast growth factor gene, using adeno-associated virus vector. Hum. Gene Ther. 16, 1413–1421 (2005).

  26. 26.

    Menendez, M. I. et al. Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. Osteoarthritis Cartilage 19, 1066–1075 (2011).

  27. 27.

    Morisset, S., Frisbie, D. D., Robbins, P. D., Nixon, A. J. & McIlwraith, C. W. IL-1ra/IGF-1 gene therapy modulates repair of microfractured chondral defects. Clin. Orthop. Relat. Res. 462, 221–228 (2007).

  28. 28.

    Evans, C. H. et al. Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage. Eur. Cell. Mater. 18, 96–111 (2009).

  29. 29.

    Ivkovic, A. et al. Articular cartilage repair by genetically modified bone marrow aspirate in sheep. Gene Ther. 17, 779–789 (2010).

  30. 30.

    Liu, T. M. et al. 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. 63, 2711–2720 (2011).

  31. 31.

    Sieker, J. T. et al. Direct bone morphogenetic protein 2 and Indian hedgehog gene transfer for articular cartilage repair using bone marrow coagulates. Osteoarthritis Cartilage 23, 433–442 (2015).

  32. 32.

    Berns, K. I. & Linden, R. M. The cryptic life style of adeno-associated virus. Bioessays 17, 237–245 (1995).

  33. 33.

    Samulski, R. J., Berns, K. I., Tan, M. & Muzyczka, N. Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc. Natl Acad. Sci. USA 79, 2077–2081 (1982).

  34. 34.

    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. 91, 625–636 (2013).

  35. 35.

    Madry, H. et al. Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I). Gene Ther. 12, 1171–1179 (2005).

  36. 36.

    Wehling, P. et al. Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. Hum. Gene Ther. 20, 97–101 (2009).

  37. 37.

    Dunbar, C. E. et al. Gene therapy comes of age. Science 359, eaan4672 (2018).

  38. 38.

    Kim, M. K. et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum. Gene Ther. Clin. Dev. 29, 48–59 (2018).

  39. 39.

    Evans, C. H., Ghivizzani, S. C. & Robbins, P. D. Arthritis gene therapy is becoming a reality. Nat. Rev. Rheumatol. 14, 381–382 (2018).

  40. 40.

    Madry, H., Cucchiarini, M., Terwilliger, E. F. & Trippel, S. B. Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum. Gene Ther. 14, 393–402 (2003).

  41. 41.

    Schuettrumpf, J. et al. The inhibitory effects of anticoagulation on in vivo gene transfer by adeno-associated viral or adenoviral vectors. Mol. Ther 13, 88–97 (2006).

  42. 42.

    Anderson, J. L. & Hope, T. J. Intracellular trafficking of retroviral vectors: obstacles and advances. Gene Ther. 12, 1667–1678 (2005).

  43. 43.

    Glover, D. J. Artificial viruses: exploiting viral trafficking for therapeutics. Infect. Disord. Drug Targets 12, 68–80 (2012).

  44. 44.

    Lam, A. P. & Dean, D. A. Progress and prospects: nuclear import of nonviral vectors. Gene Ther. 17, 439–447 (2010).

  45. 45.

    Wu, P. et al. Non-viral gene delivery systems for tissue repair and regeneration. J. Transl Med. 16, 29 (2018).

  46. 46.

    Lundstrom, K. Viral vectors in gene therapy. Diseases 6, 42 (2018).

  47. 47.

    Appaiahgari, M. B. & Vrati, S. Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls. Expert Opin. Biol. Ther. 15, 337–351 (2015).

  48. 48.

    Goins, W. F., Hall, B., Cohen, J. B. & Glorioso, J. C. Retargeting of herpes simplex virus (HSV) vectors. Curr. Opin. Virol. 21, 93–101 (2016).

  49. 49.

    Crystal, R. G. Adenovirus: the first effective in vivo gene delivery vector. Hum. Gene Ther. 25, 3–11 (2014).

  50. 50.

    Marshall, E. Gene therapy death prompts review of adenovirus vector. Science 286, 2244–2245 (1999).

  51. 51.

    Raper, S. E. et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab. 80, 148–158 (2003).

  52. 52.

    Vandamme, C., Adjali, O. & Mingozzi, F. Unraveling the complex story of immune responses to AAV vectors trial after trial. Hum. Gene Ther. 28, 1061–1074 (2017).

  53. 53.

    Felgner, P. L. et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc. Natl Acad. Sci. USA 84, 7413–7417 (1987).

  54. 54.

    Goodwin, T. & Huang, L. Nonviral vectors: we have come a long way. Adv. Genet. 88, 1–12 (2014).

  55. 55.

    Schmeer, M., Buchholz, T. & Schleef, M. Plasmid DNA manufacturing for indirect and direct clinical applications. Hum. Gene Ther. 28, 856–861 (2017).

  56. 56.

    Romano, G. Current development of nonviral-mediated gene transfer. Drug News Perspect. 20, 227–231 (2007).

  57. 57.

    Halbert, C. L. et al. Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J. Virol. 74, 1524–1532 (2000).

  58. 58.

    Smith, R. H. Adeno-associated virus integration: virus versus vector. Gene Ther. 15, 817–822 (2008).

  59. 59.

    Flotte, T. R. et al. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc. Natl Acad. Sci. USA 90, 10613–10617 (1993).

  60. 60.

    Flotte, T. R., Afione, S. A. & Zeitlin, P. L. Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am. J. Respir. Cell. Mol. Biol. 11, 517–521 (1994).

  61. 61.

    Ofri, R. et al. Six years and counting: restoration of photopic retinal function and visual behavior following gene augmentation therapy in a sheep model of CNGA3 achromatopsia. Hum. Gene Ther. (2018).

  62. 62.

    Yan, Z., Zhang, Y., Duan, D. & Engelhardt, J. F. Trans-splicing vectors expand the utility of adeno-associated virus for gene therapy. Proc. Natl Acad. Sci. USA 97, 6716–6721 (2000).

  63. 63.

    Hermonat, P. L., Quirk, J. G., Bishop, B. M. & Han, L. The packaging capacity of adeno-associated virus (AAV) and the potential for wild-type-plus AAV gene therapy vectors. FEBS Lett. 407, 78–84 (1997).

  64. 64.

    Duan, D., Yue, Y., Yan, Z. & Engelhardt, J. F. A new dual-vector approach to enhance recombinant adeno-associated virus-mediated gene expression through intermolecular cis activation. Nat. Med. 6, 595–598 (2000).

  65. 65.

    Ferrari, F. K., Samulski, T., Shenk, T. & Samulski, R. J. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J. Virol. 70, 3227–3234 (1996).

  66. 66.

    Fisher, K. J. et al. Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. J. Virol. 70, 520–532 (1996).

  67. 67.

    McCarty, D. M., Monahan, P. E. & Samulski, R. J. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 8, 1248–1254 (2001).

  68. 68.

    Halbert, C. L. et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum. Gene Ther. 17, 440–447 (2006).

  69. 69.

    Colella, P., Ronzitti, G. & Mingozzi, F. Emerging issues in AAV-mediated in vivo gene therapy. Mol. Ther. Methods Clin. Dev. 8, 87–104 (2018).

  70. 70.

    Cottard, V. et al. Immune response against gene therapy vectors: influence of synovial fluid on adeno-associated virus mediated gene transfer to chondrocytes. J. Clin. Immunol. 24, 162–169 (2004).

  71. 71.

    Mingozzi, F. et al. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci. Transl Med. 5, 194ra92 (2013).

  72. 72.

    Nayak, S. & Herzog, R. W. Progress and prospects: immune responses to viral vectors. Gene Ther. 17, 295–304 (2010).

  73. 73.

    Calceo, R. & Wilson, J. M. Humoral immune response to AAV. Front. Immunol. 4, 341 (2013).

  74. 74.

    Wu, T. L. & Ertl, H. C. Immune barriers to successful gene therapy. Trends Mol. Med. 15, 32–39 (2009).

  75. 75.

    Goater, J. et al. Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis. J. Rheumatol. 27, 983–989 (2000).

  76. 76.

    Kaufmann, K. B., Buning, H., Galy, A., Schambach, A. & Grez, M. Gene therapy on the move. EMBO Mol. Med. 5, 1642–1661 (2013).

  77. 77.

    Mi, Z. et al. Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees. Arthritis Res. Ther. 5, R132–R139 (2003).

  78. 78.

    Hacein-Bey-Abina, S. et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 118, 3132–3142 (2008).

  79. 79.

    Howe, S. J. et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J. Clin. Invest. 118, 3143–3150 (2008).

  80. 80.

    Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

  81. 81.

    Poeschla, E., Corbeau, P. & Wong-Staal, F. Development of HIV vectors for anti-HIV gene therapy. Proc. Natl Acad. Sci. USA 93, 11395–11399 (1996).

  82. 82.

    Nault, J. C. et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 47, 1187–1193 (2015).

  83. 83.

    Gil-Farina, I. et al. Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol. Ther. 24, 1100–1105 (2016).

  84. 84.

    Srivastava, A. & Carter, B. J. AAV infection: protection from cancer. Hum. Gene Ther. 28, 323–327 (2017).

  85. 85.

    Food and Drug Administration. Guidance for industry: preparation of IDEs and INDs for products intended to repair or replace knee cartilage. (2011).

  86. 86.

    European Commission. Good manufacturing practice for advanced therapy medicinal products. (2017).

  87. 87.

    Baragi, V. M. et al. Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo. Osteoarthritis Cartilage 5, 275–282 (1997).

  88. 88.

    Madry, H. & Trippel, S. B. Efficient lipid-mediated gene transfer to articular chondrocytes. Gene Ther. 7, 286–291 (2000).

  89. 89.

    Rey-Rico, A. et al. Determination of effective rAAV-mediated gene transfer conditions to support chondrogenic differentiation processes in human primary bone marrow aspirates. Gene Ther. 22, 50–57 (2015).

  90. 90.

    Halbert, C. L., Standaert, T. A., Wilson, C. B. & Miller, A. D. Successful readministration of adeno-associated virus vectors to the mouse lung requires transient immunosuppression during the initial exposure. J. Virol. 72, 9795–9805 (1998).

  91. 91.

    Selot, R. S., Hareendran, S. & Jayandharan, G. R. Developing immunologically inert adeno-associated virus (AAV) vectors for gene therapy: possibilities and limitations. Curr. Pharm. Biotechnol. 14, 1072–1082 (2014).

  92. 92.

    Buchholz, C. J., Friedel, T. & Buning, H. Surface-engineered viral vectors for selective and cell type-specific gene delivery. Trends Biotechnol. 33, 777–790 (2015).

  93. 93.

    Buning, H., Huber, A., Zhang, L., Meumann, N. & Hacker, U. Engineering the AAV capsid to optimize vector-host-interactions. Curr. Opin. Pharmacol. 24, 94–104 (2015).

  94. 94.

    Mingozzi, F. & High, K. A. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 122, 23–36 (2013).

  95. 95.

    Mitchell, A. M., Nicolson, S. C., Warischalk, J. K. & Samulski, R. J. AAV’s anatomy: roadmap for optimizing vectors for translational success. Curr. Gene Ther. 10, 319–340 (2010).

  96. 96.

    Vandenberghe, L. H., Wilson, J. M. & Gao, G. Tailoring the AAV vector capsid for gene therapy. Gene Ther. 16, 311–319 (2009).

  97. 97.

    Freed, L. E., Martin, I. & Vunjak-Novakovic, G. Frontiers in tissue engineering. In vitro modulation of chondrogenesis. Clin. Orthop. Relat. Res. 367, S46–S58 (1999).

  98. 98.

    Kon, E., Filardo, G., Perdisa, F., Venieri, G. & Marcacci, M. Clinical results of multilayered biomaterials for osteochondral regeneration. J. Exp. Orthop. 1, 10 (2014).

  99. 99.

    Kon, E., Roffi, A., Filardo, G., Tesei, G. & Marcacci, M. Scaffold-based cartilage treatments: with or without cells? A systematic review of preclinical and clinical evidence. Arthroscopy 31, 767–775 (2015).

  100. 100.

    Armiento, A. R., Stoddart, M. J., Alini, M. & Eglin, D. Biomaterials for articular cartilage tissue engineering: learning from biology. Acta Biomater. 65, 1–20 (2018).

  101. 101.

    Cucchiarini, M. et al. A vision on the future of articular cartilage repair. Eur. Cell. Mater. 27, 12–16 (2014).

  102. 102.

    Johnstone, B. et al. Tissue engineering for articular cartilage repair — the state of the art. Eur. Cell. Mater. 25, 248–267 (2013).

  103. 103.

    Lopa, S. & Madry, H. Bioinspired scaffolds for osteochondral regeneration. Tissue Eng. Part A 20, 2052–2076 (2014).

  104. 104.

    Nukavarapu, S. P. & Dorcemus, D. L. Osteochondral tissue engineering: current strategies and challenges. Biotechnol. Adv. 31, 706–721 (2013).

  105. 105.

    Smith, B. D. & Grande, D. A. The current state of scaffolds for musculoskeletal regenerative applications. Nat. Rev. Rheumatol. 11, 213–222 (2015).

  106. 106.

    Serban, M. A. Translational biomaterials-the journey from the bench to the market-think ‘product’. Curr. Opin. Biotechnol. 40, 31–34 (2016).

  107. 107.

    Brittberg, M. Cell carriers as the next generation of cell therapy for cartilage repair: a review of the matrix-induced autologous chondrocyte implantation procedure. Am. J. Sports Med. 38, 1259–1271 (2010).

  108. 108.

    Athanasiou, K. A., Niederauer, G. G. & Agrawal, C. M. Sterilization, toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers. Biomaterials 17, 93–102 (1996).

  109. 109.

    Madry, H., Kaul, G., Zurakowski, D., Vunjak-Novakovic, G. & Cucchiarini, M. Cartilage constructs engineered from chondrocytes overexpressing IGF-I improve the repair of osteochondral defects in a rabbit model. Eur. Cell. Mater. 25, 229–247 (2013).

  110. 110.

    Hinckel, B. B. & Gomoll, A. H. Autologous chondrocytes and next-generation matrix-based autologous chondrocyte implantation. Clin. Sports Med. 36, 525–548 (2017).

  111. 111.

    Gao, L., Orth, P., Cucchiarini, M. & Madry, H. Effects of solid acellular type-I/III collagen biomaterials on in vitro and in vivo chondrogenesis of mesenchymal stem cells. Expert Rev. Med. Devices 14, 717–732 (2017).

  112. 112.

    Benya, P. D. & Shaffer, J. D. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30, 215–224 (1982).

  113. 113.

    Vega, S. L., Kwon, M. Y. & Burdick, J. A. Recent advances in hydrogels for cartilage tissue engineering. Eur. Cell. Mater. 33, 59–75 (2017).

  114. 114.

    Filardo, G., Kon, E., Roffi, A., Di Martino, A. & Marcacci, M. Scaffold-based repair for cartilage healing: a systematic review and technical note. Arthroscopy 29, 174–186 (2013).

  115. 115.

    Girotto, D. et al. Tissue-specific gene expression in chondrocytes grown on three-dimensional hyaluronic acid scaffolds. Biomaterials 24, 3265–3275 (2003).

  116. 116.

    Jha, A. K. et al. Matrix metalloproteinase-13 mediated degradation of hyaluronic acid-based matrices orchestrates stem cell engraftment through vascular integration. Biomaterials 89, 136–147 (2016).

  117. 117.

    Kandil, A. & Safran, M. R. Hip arthroscopy: a brief history. Clin. Sports Med. 35, 321–329 (2016).

  118. 118.

    Seol, D. et al. Biocompatibility and preclinical feasibility tests of a temperature-sensitive hydrogel for the purpose of surgical wound pain control and cartilage repair. J. Biomed. Mater. Res. B Appl. Biomater. 101, 1508–1515 (2013).

  119. 119.

    Bartnikowski, M., Bartnikowski, N. J., Woodruff, M. A., Schrobback, K. & Klein, T. J. Protective effects of reactive functional groups on chondrocytes in photocrosslinkable hydrogel systems. Acta Biomater. 27, 66–76 (2015).

  120. 120.

    Almqvist, K. F. et al. Treatment of cartilage defects in the knee using alginate beads containing human mature allogenic chondrocytes. Am. J. Sports Med. 37, 1920–1929 (2009).

  121. 121.

    Kim, Y. S. et al. Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis. Am. J. Sports Med. 43, 2738–2746 (2015).

  122. 122.

    Sofu, H. et al. Clinical and radiographic outcomes of chitosan-glycerol phosphate/blood implant are similar with hyaluronic acid-based cell-free scaffold in the treatment of focal osteochondral lesions of the knee joint. Knee Surg. Sports Traumatol. Arthrosc. (2018).

  123. 123.

    Thier, S., Baumann, F., Weiss, C. & Fickert, S. Feasibility of arthroscopic autologous chondrocyte implantation in the hip using an injectable hydrogel. Hip. Int. 28, 442–449 (2017).

  124. 124.

    Mason, J. M. et al. Cartilage and bone regeneration using gene-enhanced tissue engineering. Clin. Orthop. Relat. Res. 379, S171–S178 (2000).

  125. 125.

    Goodrich, L. R., Hidaka, C., Robbins, P. D., Evans, C. H. & Nixon, A. J. Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J. Bone Joint Surg. Br. 89, 672–685 (2007).

  126. 126.

    Grande, D. A., Mason, J., Light, E. & Dines, D. Stem cells as platforms for delivery of genes to enhance cartilage repair. J. Bone Joint Surg. Am. 85-A, 111–116 (2003).

  127. 127.

    Cao, L. et al. The promotion of cartilage defect repair using adenovirus mediated Sox9 gene transfer of rabbit bone marrow mesenchymal stem cells. Biomaterials 32, 3910–3920 (2011).

  128. 128.

    Lam, J., Lu, S., Kasper, F. K. & Mikos, A. G. Strategies for controlled delivery of biologics for cartilage repair. Adv. Drug Deliv. Rev. 84, 123–134 (2015).

  129. 129.

    Lee, S. J. Cytokine delivery and tissue engineering. Yonsei Med. J. 41, 704–719 (2000).

  130. 130.

    Pannier, A. K. & Shea, L. D. Controlled release systems for DNA delivery. Mol. Ther. 10, 19–26 (2004).

  131. 131.

    Rey-Rico, A. 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 8, 20600–20613 (2016).

  132. 132.

    Dupont, K. M. et al. Synthetic scaffold coating with adeno-associated virus encoding BMP2 to promote endogenous bone repair. Cell Tissue Res. 347, 575–588 (2012).

  133. 133.

    Fang, J. et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc. Natl Acad. Sci. USA 93, 5753–5758 (1996).

  134. 134.

    Brunger, J. M. et al. Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc. Natl Acad. Sci. USA 111, E798–E806 (2014).

  135. 135.

    Glass, K. A. et al. Tissue-engineered cartilage with inducible and tunable immunomodulatory properties. Biomaterials 35, 5921–5931 (2014).

  136. 136.

    Moutos, F. T. et al. Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. Proc. Natl Acad. Sci. USA 113, E4513–E4522 (2016).

  137. 137.

    Diaz-Rodriguez, 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. 496, 614–626 (2015).

  138. 138.

    Lee, H. H. et al. Release of bioactive adeno-associated virus from fibrin scaffolds: effects of fibrin glue concentrations. Tissue Eng. Part A 17, 1969–1978 (2011).

  139. 139.

    Rey-Rico, A. 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. 18, 118–127 (2015).

  140. 140.

    Rey-Rico, A. et al. rAAV-mediated overexpression of TGF-beta 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. Nanomed. 12, 6985–6996 (2017).

  141. 141.

    Rey-Rico, 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. 27, 42–52 (2015).

  142. 142.

    Rey-Rico, A. et al. Supramolecular polypseudorotaxane gels for controlled delivery of rAAV vectors in human mesenchymal stem cells for regenerative medicine. Int. J. Pharm. 531, 492–503 (2017).

  143. 143.

    Singh, M. et al. Cationic microparticles: a potent delivery system for DNA vaccines. Proc. Natl Acad. Sci. USA 97, 811–816 (2000).

  144. 144.

    Zhao, R., Peng, X., Li, Q. & Song, W. Effects of phosphorylatable short peptide-conjugated chitosan-mediated IL-1Ra and IGF-1 gene transfer on articular cartilage defects in rabbits. PLoS ONE 9, e112284 (2014).

  145. 145.

    Li, B. et al. Fabrication of poly(lactide-co-glycolide) scaffold filled with fibrin gel, mesenchymal stem cells, and poly(ethylene oxide)-b-poly(L-lysine)/TGF-beta1 plasmid DNA complexes for cartilage restoration in vivo. J. Biomed. Mater. Res. A 101, 3097–3108 (2013).

  146. 146.

    Li, B. et al. Poly(lactide-co-glycolide)/fibrin gel construct as a 3D model to evaluate gene therapy of cartilage in vivo. Mol. Pharm 11, 2062–2070 (2014).

  147. 147.

    Wang, W. et al. In vivo restoration of full-thickness cartilage defects by poly(lactide-co-glycolide) sponges filled with fibrin gel, bone marrow mesenchymal stem cells and DNA complexes. Biomaterials 31, 5953–5965 (2010).

  148. 148.

    Almarza, D., Cucchiarini, M. & Loughlin, J. Genome editing for human osteoarthritis - a perspective. Osteoarthritis Cartilage 25, 1195–1198 (2017).

  149. 149.

    Brunger, J. M., Zutshi, A., Willard, V. P., Gersbach, C. A. & Guilak, F. CRISPR/Cas9 editing of murine induced pluripotent stem cells for engineering inflammation-resistant tissues. Arthritis Rheumatol. 69, 1111–1121 (2017).

  150. 150.

    Brunger, J. M., Zutshi, A., Willard, V. P., Gersbach, C. A. & Guilak, F. Genome engineering of stem cells for autonomously regulated, closed-loop delivery of biologic drugs. Stem Cell Rep. 8, 1202–1213 (2017).

  151. 151.

    Farhang, N. et al. CRISPR-based epigenome editing of cytokine receptors for the promotion of cell survival and tissue deposition in inflammatory environments. Tissue Eng. Part A 23, 738–749 (2017).

  152. 152.

    van der Kraan, P. M. The changing role of TGFβ in healthy, ageing and osteoarthritic joints. Nat. Rev. Rheumatol. 13, 155–163 (2017).

  153. 153.

    Madry, H. & Cucchiarini, M. Gene therapy for human osteoarthritis: principles and clinical translation. Expert Opin. Biol. Ther. 16, 331–346 (2016).

  154. 154.

    Nixon, A. J. et al. Matrix-induced autologous chondrocyte implantation (MACI) using a cell-seeded collagen membrane improves cartilage healing in the equine model. J. Bone Joint Surg. Am. 99, 1987–1998 (2017).

  155. 155.

    Schmidt-Bleek, K., Willie, B. M., Schwabe, P., Seemann, P. & Duda, G. N. BMPs in bone regeneration: less is more effective, a paradigm-shift. Cytokine Growth Factor Rev. 27, 141–148 (2016).

  156. 156.

    Eglitis, M. A., Kohn, D. B., Moen, R. C., Blaese, R. M. & Anderson, W. F. Infection of human hematopoietic progenitor cells using a retroviral vector with a xenotropic pseudotype. Biochem. Biophys. Res. Commun. 151, 201–206 (1988).

  157. 157.

    Miller, A. D., Jolly, D. J., Friedmann, T. & Verma, I. M. A transmissible retrovirus expressing human hypoxanthine phosphoribosyltransferase (HPRT): gene transfer into cells obtained from humans deficient in HPRT. Proc. Natl Acad. Sci. USA 80, 4709–4713 (1983).

  158. 158.

    Xiao, X., Li, J. & Samulski, R. J. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol. 70, 8098–8108 (1996).

  159. 159.

    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. 21, 811–819 (2014).

  160. 160.

    Pagnotto, M. R. et al. Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Gene Ther. 14, 804–813 (2007).

  161. 161.

    Park, J. et al. Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells. J. Gene Med. 8, 112–125 (2006).

  162. 162.

    Kubo, S. et al. Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis Rheum. 60, 155–165 (2009).

  163. 163.

    Matsumoto, T. et al. The influence of sex on the chondrogenic potential of muscle-derived stem cells: implications for cartilage regeneration and repair. Arthritis Rheum. 58, 3809–3819 (2008).

  164. 164.

    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. 48, 430–441 (2003).

  165. 165.

    Che, J. H. et al. Application of tissue-engineered cartilage with BMP-7 gene to repair knee joint cartilage injury in rabbits. Knee Surg. Sports Traumatol. Arthrosc. 18, 496–503 (2010).

  166. 166.

    Kaul, G. et al. Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo. J. Gene Med. 8, 100–111 (2006).

  167. 167.

    Orth, P. et al. Transplanted articular chondrocytes co-overexpressing IGF-I and FGF-2 stimulate cartilage repair in vivo. Knee Surg. Sports Traumatol. Arthrosc. 19, 2119–2130 (2011).

  168. 168.

    Yokoo, N. 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. 52, 164–170 (2005).

  169. 169.

    Xia, X. et al. Matrigel scaffold combined with Ad-hBMP7-transfected chondrocytes improves the repair of rabbit cartilage defect. Exp. Ther. Med. 13, 542–550 (2017).

  170. 170.

    Qi, B. W., Yu, A. X., Zhu, S. B., Zhou, M. & Wu, G. Chitosan/poly(vinyl alcohol) hydrogel combined with Ad-hTGF-beta1 transfected mesenchymal stem cells to repair rabbit articular cartilage defects. Exp. Biol. Med. 238, 23–30 (2013).

  171. 171.

    Zhu, S. et al. Combined effects of connective tissue growth factor-modified bone marrow-derived mesenchymal stem cells and NaOH-treated PLGA scaffolds on the repair of articular cartilage defect in rabbits. Cell Transplant. 23, 715–727 (2014).

  172. 172.

    Hu, B. et al. Enhanced treatment of articular cartilage defect of the knee by intra-articular injection of Bcl-xL-engineered mesenchymal stem cells in rabbit model. J. Tissue Eng. Regen. Med. 4, 105–114 (2010).

  173. 173.

    Katayama, R. et al. Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal cells derived from bone marrow. Rheumatology 43, 980–985 (2004).

  174. 174.

    Guo, X. et al. Repair of full-thickness articular cartilage defects by cultured mesenchymal stem cells transfected with the transforming growth factor beta1 gene. Biomed. Mater. 1, 206–215 (2006).

  175. 175.

    Shi, J. et al. Nanoparticle delivery of the bone morphogenetic protein 4 gene to adipose-derived stem cells promotes articular cartilage repair in vitro and in vivo. Arthroscopy 29, 2001–2011 (2013).

  176. 176.

    Gelse, K. et al. Chondrogenic differentiation of growth factor-stimulated precursor cells in cartilage repair tissue is associated with increased HIF-1alpha activity. Osteoarthritis Cartilage 16, 1457–1465 (2008).

  177. 177.

    Hidaka, C. et al. Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J. Orthop. Res. 21, 573–583 (2003).

  178. 178.

    Griffin, D. J., Ortved, K. F., Nixon, A. J. & Bonassar, L. J. Mechanical properties and structure-function relationships in articular cartilage repaired using IGF-I gene-enhanced chondrocytes. J. Orthop. Res. 34, 149–153 (2016).

  179. 179.

    Ortved, K. F., Begum, L., Mohammed, H. O. & Nixon, A. J. Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. Mol. Ther. 23, 363–373 (2015).

  180. 180.

    Andree, C. et al. Plasmid gene delivery to human keratinocytes through a fibrin-mediated transfection system. Tissue Eng. 7, 757–766 (2001).

  181. 181.

    Bielinska, A. U. et al. Application of membrane-based dendrimer/DNA complexes for solid phase transfection in vitro and in vivo. Biomaterials 21, 877–887 (2000).

  182. 182.

    Lee, C. R., Grodzinsky, A. J., Hsu, H. P. & Spector, M. Effects of a cultured autologous chondrocyte-seeded type II collagen scaffold on the healing of a chondral defect in a canine model. J. Orthop. Res. 21, 272–281 (2003).

  183. 183.

    Li, Z. et al. Controlled gene delivery system based on thermosensitive biodegradable hydrogel. Pharm. Res. 20, 884–888 (2003).

  184. 184.

    Shin, S. & Shea, L. D. Lentivirus immobilization to nanoparticles for enhanced and localized delivery from hydrogels. Mol. Ther. 18, 700–706 (2010).

  185. 185.

    Shin, S., Tuinstra, H. M., Salvay, D. M. & Shea, L. D. Phosphatidylserine immobilization of lentivirus for localized gene transfer. Biomaterials 31, 4353–4359 (2010).

  186. 186.

    Cohen-Sacks, H. et al. Delivery and expression of pDNA embedded in collagen matrices. J. Control. Release 95, 309–320 (2004).

  187. 187.

    Doukas, J. et al. Delivery of FGF genes to wound repair cells enhances arteriogenesis and myogenesis in skeletal muscle. Mol. Ther. 5, 517–527 (2002).

  188. 188.

    Ochiya, T. et al. New delivery system for plasmid DNA in vivo using atelocollagen as a carrier material: the Minipellet. Nat. Med 5, 707–710 (1999).

  189. 189.

    Fukunaka, Y., Iwanaga, K., Morimoto, K., Kakemi, M. & Tabata, Y. Controlled release of plasmid DNA from cationized gelatin hydrogels based on hydrogel degradation. J. Control. Release 80, 333–343 (2002).

  190. 190.

    Kushibiki, T., Tomoshige, R., Fukunaka, Y., Kakemi, M. & Tabata, Y. In vivo release and gene expression of plasmid DNA by hydrogels of gelatin with different cationization extents. J. Control. Release 90, 207–216 (2003).

  191. 191.

    Garcia del Barrio, G., Hendry, J., Renedo, M. J., Irache, J. M. & Novo, F. J. In vivo sustained release of adenoviral vectors from poly(D,L-lactic-co-glycolic) acid microparticles prepared by TROMS. J. Control. Release 94, 229–235 (2004).

  192. 192.

    Schek, R. M., Hollister, S. J. & Krebsbach, P. H. Delivery and protection of adenoviruses using biocompatible hydrogels for localized gene therapy. Mol. Ther. 9, 130–138 (2004).

  193. 193.

    Thomas, A. M., Palma, J. L. & Shea, L. D. Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries. J. Control. Release 204, 1–10 (2015).

  194. 194.

    Thomas, A. M. & Shea, L. D. Polysaccharide-modified scaffolds for controlled lentivirus delivery in vitro and after spinal cord injury. J. Control. Release 170, 421–429 (2013).

  195. 195.

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

  196. 196.

    Huang, Y. C., Simmons, C., Kaigler, D., Rice, K. G. & Mooney, D. J. Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4). Gene Ther. 12, 418–426 (2005).

  197. 197.

    Hu, W. W., Wang, Z., Hollister, S. J. & Krebsbach, P. H. Localized viral vector delivery to enhance in situ regenerative gene therapy. Gene Ther. 14, 891–901 (2007).

Download references

Reviewer information

Nature Reviews Rheumatology thanks A. Hollander and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Centre of Experimental Orthopaedics, Saarland University Medical Centre and Saarland University, Homburg, Germany

    • Magali Cucchiarini
    •  & Henning Madry
  2. Department of Orthopaedic Surgery, Saarland University Medical Centre and Saarland University, Homburg, Germany

    • Henning Madry


  1. Search for Magali Cucchiarini in:

  2. Search for Henning Madry in:


Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Magali Cucchiarini.

About this article

Publication history


Issue Date