Large Animal Models for Osteochondral Regeneration

  • Isabel R. DiasEmail author
  • Carlos A. Viegas
  • Pedro P. Carvalho
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1059)


Namely, in the last two decades, large animal models – small ruminants (sheep and goats), pigs, dogs and horses – have been used to study the physiopathology and to develop new therapeutic procedures to treat human clinical osteoarthritis. For that purpose, cartilage and/or osteochondral defects are generally performed in the stifle joint of selected large animal models at the condylar and trochlear femoral areas where spontaneous regeneration should be excluded. Experimental animal care and protection legislation and guideline documents of the US Food and Drug Administration, the American Society for Testing and Materials and the International Cartilage Repair Society should be followed, and also the specificities of the animal species used for these studies must be taken into account, such as the cartilage thickness of the selected defect localization, the defined cartilage critical size defect and the joint anatomy in view of the post-operative techniques to be performed to evaluate the chondral/osteochondral repair. In particular, in the articular cartilage regeneration and repair studies with animal models, the subchondral bone plate should always be taken into consideration. Pilot studies for chondral and osteochondral bone tissue engineering could apply short observational periods for evaluation of the cartilage regeneration up to 12 weeks post-operatively, but generally a 6- to 12-month follow-up period is used for these types of studies.


Large animal models Osteochondral tissue Tissue engineering Translational studies 


  1. 1.
    Boushell MK, Hung CT, Hunziker EB, Strauss EJ, Lu HH (2016) Current strategies for integrative cartilage repair. Connect Tissue Res 6:1–14Google Scholar
  2. 2.
    Chahla J, LaPrade RF, Mardones R, Huard J, Philippon MJ, Nho S, Mei-Dan O, Pascual-Garrido C (2016) Biological therapies for cartilage lesions in the hip: a new horizon. Orthopedics 39(4):e715–e723PubMedCrossRefGoogle Scholar
  3. 3.
    Richter DL, Schenck RC Jr, Wascher DC, Treme G (2016) Knee articular cartilage repair and restoration techniques: a review of the literature. Sports Health 8(2):153–160PubMedCrossRefGoogle Scholar
  4. 4.
    Frehner F, Benthien JP (2017) Microfracture: state of the art in cartilage surgery? Cartilage.
  5. 5.
    Tan AR, Hung CT (2017) Concise review: mesenchymal stem cells for functional cartilage tissue engineering: taking cues from chondrocyte-based constructs. Stem Cells Transl Med 6(4):1295–1303PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Grässel S, Lorenz J (2014) Tissue-engineering strategies to repair chondral and osteochondral tissue in osteoarthritis: use of mesenchymal stem cells. Curr Rheumatol Rep 16(10):452PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Shen Y, Fu Y, Wang J, Li G, Zhang X, Xu Y, Lin Y (2014) Biomaterial and mesenchymal stem cell for articular cartilage reconstruction. Curr Stem Cell Res Ther 9(3):254–267PubMedCrossRefGoogle Scholar
  8. 8.
    Kon E, Roffi A, Filardo G, Tesei G, Marcacci M (2015) Scaffold-based cartilage treatments: with or without cells? A systematic review of preclinical and clinical evidence. Arthroscopy 31(4):767–775PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kumar R, Griffin M, Butler PE (2016) A review of current regenerative medicine strategies that utilize nanotechnology to treat cartilage damage. Open Orthop J 10:862–876PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    López-Ruiz E, Jiménez G, García MÁ, Antich C, Boulaiz H, Marchal JA, Perán M (2016) Polymers, scaffolds and bioactive molecules with therapeutic properties in osteochondral pathologies: What's new? Expert Opin Ther Pat 26(8):877–890PubMedCrossRefGoogle Scholar
  11. 11.
    Driessen BJ, Logie C, Vonk LA (2017) Cellular reprogramming for clinical cartilage repair. Cell Biol Toxicol 33(4):329–349. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hinckel BB, Gomoll AH (2017) Autologous chondrocytes and next-generation matrix-based autologous chondrocyte implantation. Clin Sports Med 36(3):525–548PubMedCrossRefGoogle Scholar
  13. 13.
    Goldberg A, Mitchell K, Soans J, Kim L, Zaidi R (2017) The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. J Orthop Surg Res 12(1):39PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Huang K, Li Q, Li Y, Yao Z, Luo D, Rao P, Xiao J (2017) Cartilage tissue regeneration: the roles of cells, stimulating factors and scaffolds. Curr Stem Cell Res Ther.
  15. 15.
    Lolli A, Penolazzi L, Narcisi R, van Osch GJVM, Piva R (2017) Emerging potential of gene silencing approaches targeting anti-chondrogenic factors for cell-based cartilage repair. Cell Mol Life Sci 74(19):3451–3465. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Monibi FA, Cook JL (2017) Tissue-derived extracellular matrix bioscaffolds: emerging applications in cartilage and meniscus repair. Tissue Eng Part B Rev 23(4):386–398. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rai V, Dilisio MF, Dietz NE, Agrawal DK (2017) Recent strategies in cartilage repair: a systemic review of the scaffold development and tissue engineering. J Biomed Mater Res A 105(8):2343–2354. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Vega SL, Kwon MY, Burdick JA (2017) Recent advances in hydrogels for cartilage tissue engineering. Eur Cell Mater 33:59–75PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Yang J, Zhang YS, Yue K, Khademhosseini A (2017) Cell-laden hydrogels for osteochondral and cartilage tissue engineering. Acta Biomater 57:1–25. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ahern BJ, Parvizi J, Boston R, Schaer TP (2009) Preclinical animal models in single site cartilage defect testing: a systematic review. Osteoarthr Cartil 17(6):705–713PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    An YA, Friedman RJ (1999) Animal models of articular cartilage defect. In: An YA, Friedman RJ (eds) Animal models in orthopaedic research. CRC Press, Boca Raton, pp 309–325Google Scholar
  22. 22.
    Chu CR, Szczodry M, Bruno S (2010) Animal models for cartilage regeneration and repair. Tissue Eng Part B 16(1):105–115CrossRefGoogle Scholar
  23. 23.
    Schneider-Wald B, von Thaden AK, Schwarz MLR (2013) Defect models for the regeneration of articular cartilage in large animals. Orthopade 42(4):242–253PubMedCrossRefGoogle Scholar
  24. 24.
    Eitel F, Klapp F, Jacobson W, Schweiberer L (1981) Bone regeneration in animals and man. Arch Orthop Traumat Surg 99(1):59–64CrossRefGoogle Scholar
  25. 25.
    Aerssens J, Boonen S, Lowet G, Dequeker J (1998) Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research. Endocrinology 139(2):663–670PubMedCrossRefGoogle Scholar
  26. 26.
    An YA, Draughn RA (1999) Mechanical properties and testing methods of bone. In: An YA, Friedman RJ (eds) Animal models in orthopaedic research. CRC Press, Boca Raton, pp 139–163Google Scholar
  27. 27.
    An YA, Friedman RJ (1999) Animal selection in orthopaedic research. In: An YA, Friedman RJ (eds) Animal models in orthopaedic research. CRC Press, Boca Raton, pp 39–57Google Scholar
  28. 28.
    Hillier ML, Bell LS (2006) Differentiating human bone from animal bone: a review of histological methods. J Forensic Sci 52(2):249–263CrossRefGoogle Scholar
  29. 29.
    Martiniaková M, Grosskopf B, Omelka R, Vondráková M, Bauerová M (2006) Differences among species in compact bone tissue microstructure of mammalian skeleton: use of a discriminant function analysis for species identification. J Forensic Sci 51(6):1235–1239PubMedCrossRefGoogle Scholar
  30. 30.
    Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG (2007) Animal models for implant biomaterial research in bone: a review. Eur Cell Mater 13:1–10PubMedCrossRefGoogle Scholar
  31. 31.
    Chevrier A, Kouao AS, Picard G, Hurtig MB, Buschmann MD (2015) Interspecies comparison of subchondral bone properties important for cartilage repair. J Orthop Res 33(1):63–70PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Jainudeen MR, Wahid H, Hafez ESE (2000) Sheep and goats. In: Hafez B, Hafez ESE (eds) Reproduction in farm animals, 7th edn. Lippincott Williams & Wilkins, Baltimore, pp 172–181Google Scholar
  33. 33.
    Smith AC, Swindle MM (2006) Preparation of swine for the laboratory. ILAR J 47(4):358–363PubMedCrossRefGoogle Scholar
  34. 34.
    Laber KE, Whary MT, Bingel SA, Goodrich JA, Smith AC, Swindle MM (2002) Biology and disease in swine. In: Fox JG, Anderson LC, Loew FM, Quimby FW (eds) Laboratory animals medicine, 2nd edn. Academic, San Diego, pp 615–673CrossRefGoogle Scholar
  35. 35.
    Bradshaw JWS (2006) The evolutionary basis for the feeding behavior of domestic dogs (Canis familiaris) and cats (Felis catus). J Nutr 136(Suppl 7):1927S–1931SPubMedCrossRefGoogle Scholar
  36. 36.
    Concannon PW (2011) Reproductive cycles of the domestic bitch. Anim Reprod Sci 124(3–4):200–210PubMedCrossRefGoogle Scholar
  37. 37.
    Simon VA (2010) Nutritional adaptations. In: Simon VA (ed) Adaptations in the animal kingdom. Xlibris corporation, Bloomington, pp 19–28Google Scholar
  38. 38.
    Aurich C (2011) Reproductive cycles of horses. Anim Reprod Sci 124(3–4):220–228PubMedCrossRefGoogle Scholar
  39. 39.
    Li Y, Chen SK, Li L, Qin L, Wang XL, Lai YX (2015) Bone defect animal models for testing efficacy of bone substitute biomaterials. J Orthop Translat 3(3):95–104CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hunziker EB (1999) Biologic repair of articular cartilage. Defect models in experimental animals and matrix requirements. Clin Orthop Relat Res (367 Suppl):S135– S146CrossRefGoogle Scholar
  41. 41.
    Hjelle K, Solheim E, Strand T, Muri R, Brittberg M (2002) Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy 18(7):730–734PubMedCrossRefGoogle Scholar
  42. 42.
    Orth P, Madry H (2015) Advancement of the subchondral bone plate in translational models of osteochondral repair: implications for tissue engineering approaches. Tissue Eng Part B Rev 21(6):504–520PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Bouwmeester PS, Kuijer R, Homminga GN, Bulstra SK, Geesink RG (2002) A retrospective analysis of two independent prospective cartilage repair studies: autogenous perichondrial grafting versus subchondral drilling 10 years post-surgery. J Orthop Res 20(2):267–273PubMedCrossRefGoogle Scholar
  44. 44.
    Hunziker EB (2002) Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthr Cartil 10(6):432–463PubMedCrossRefGoogle Scholar
  45. 45.
    Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, Jobanputra P, Waugh N. (2005) Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation. Health Technol Assess 9(47):iii–iv, ix–x, 1–82Google Scholar
  46. 46.
    Frisbie DD, Cross MW, McIlwraith CWA (2006) Comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee. Vet Comp Orthop Traumatol 19(3):142–146PubMedCrossRefGoogle Scholar
  47. 47.
    Martino F, Ettorre GC, Patella V, Macarini L, Moretti B, Pesce V, Resta L (1993) Articular cartilage echography as a criterion of the evolution of osteoarthritis of the knee. Int J Clin Pharmacol Res 13(Suppl):35–42PubMedPubMedCentralGoogle Scholar
  48. 48.
    Malda J, de Grauw JC, Benders KE, Kik MJ, van de Lest CH, Creemers LB, Dhert WJ, van Weeren PR (2013) Of mice, men and elephants: the relation between articular cartilage thickness and body mass. PLoS One 8(2):e57683PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Pineda S, Pollack A, Stevenson S, Goldberg V, Caplan A (1992) A semiquantitative scale for histologic grading of articular cartilage repair. Acta Anat (Basel) 143(4):335–340CrossRefGoogle Scholar
  50. 50.
    Aigner T, Cook JL, Gerwin N, Glasson SS, Laverty S, Little CB, McIlwraith W, Kraus VB (2010) Histopathology atlas of animal model systems – overview of guiding principles. Osteoarthr Cartil 18(Suppl 3):S2–S6PubMedCrossRefGoogle Scholar
  51. 51.
    Mainil-Varlet P, Van Damme B, Nesic D, Knutsen G, Kandel R, Roberts S (2010) A new histology scoring system for the assessment of the quality of human cartilage repair: ICRS II. Am J Sports Med 38(5):880–890PubMedCrossRefGoogle Scholar
  52. 52.
    Heir S, Årøen A, Løken S, Sulheim S, Engebretsen L, Reinholt FP (2010) Intraarticular location predicts cartilage filling and subchondral bone changes in a chondral defect. Acta Orthop 81(5):619–627PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hoemann C, Kandel R, Roberts S, Saris DB, Creemers L, Mainil-Varlet P, Méthot S, Hollander AP, Buschmann MD (2011) International cartilage repair society (ICRS) recommended guidelines for histological endpoints for cartilage repair studies in animal models and clinical trials. Cartilage 2(2):153–172PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Hurtig MB, Buschmann MD, Fortier LA, Hoemann CD, Hunziker EB, Jurvelin JS, Mainil-Varlet P, McIlwraith CW, Sah RL, Whiteside RA (2011) Preclinical studies for cartilage repair: recommendations from the international cartilage repair society. Cartilage 2(2):137–152PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Fortier LA, Cole BJ, Science MICW (2012) Animal models of marrow stimulation for cartilage repair. J Knee Surg 25(1):3–8PubMedCrossRefGoogle Scholar
  56. 56.
    Cook JL, Hung CT, Kuroki K, Stoker AM, Cook CR, Pfeiffer FM, Sherman SL, Stannard JP (2014) Animal models of cartilage repair. Bone Joint Res 3(4):89–94PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    American Society for Testing and Materials (2010) ASTM F2451–05 Standard Guide for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage. (date last Accessed 20 June 2017)
  58. 58.
    International Cartilage Repair Society (ICRS) (2011) Preclinical studies for cartilage repair: recommendation from the international cartilage repair society; ICRS recommendation papers. Cartilage 2(2):137–152CrossRefGoogle Scholar
  59. 59.
    Hoemann C, Kandel R, Roberts S, Saris DB, Creemers L, Mainil-Varlet P, Méthot S, Hollander AP, Buschmann MD (2011) International cartilage repair society (ICRS) recommended guidelines for histological endpoints for cartilage repair studies in animal models and clinical trials. Cartilage 2(2):153–172PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Food and Drug Administration: Guidance for industry: Preparation of IDEs and INDs for products intended to repair or replace knee cartilage.!home (date last Accessed 20 June 2017)
  61. 61.
    Luther JK, Cook CR, Cook JL (2009) Meniscal release in cruciate ligament intact stifles causes lameness and medial compartment cartilage pathology in dogs 12 weeks post operatively. Vet Surg 38(4):520–529PubMedCrossRefGoogle Scholar
  62. 62.
    Garner BC, Stoker AM, Kuroki K, Evans R, Cook CR, Cook JL (2011) Using animal models in osteoarthritis biomarker research. J Knee Surg 24(4):251–264PubMedCrossRefGoogle Scholar
  63. 63.
    Kuroki K, Cook CR, Cook JL (2011) Subchondral bone changes in three different canine models of osteoarthritis. Osteoarthr Cartil 19(9):1142–1149PubMedCrossRefGoogle Scholar
  64. 64.
    O’Connell GD, Lima EG, Liming B, Chahine NO, Albro MB, Cook JL, Ateshian GA, Hung CT (2012) Toward engineering a biological joint replacement. J Knee Surg 25(3):187–196PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Simon WH (1970) Scale effects in animal joints. I. Articular cartilage thickness and compressive stress. Arthritis Rheum 13(3):244–256PubMedCrossRefGoogle Scholar
  66. 66.
    Lu Y, Hayashi K, Hecht P, Fanton GS, Thabit G 3rd, Cooley AJ, Edwards RB, Markel MD (2000) The effect of monopolar radiofrequency energy on partial-thickness defects of articular cartilage. Arthroscopy 16(5):527–536PubMedCrossRefGoogle Scholar
  67. 67.
    Cellular, Tissue and Gene Therapies Advisory Committee. Cellular Products for Joint Surface Repair – Briefing Document. Meeting 38, US Food and Drug Administration, 3–4 March 2005Google Scholar
  68. 68.
    Archibald M, Runciman J, Dickey J, Hurtig M Do animal models approximate the subchondral bone and cartilage characteristics of humans? In 4th International Cartilage Repair Society, June 2002, Toronto, CanadaGoogle Scholar
  69. 69.
    Homminga GN, Bulstra SK, Kuijer R, van der Linden AJ (1991) Repair of sheep articular cartilage defects with a rabbit costal perichondrial graft. Acta Orthop Scand 62(5):415–418PubMedCrossRefGoogle Scholar
  70. 70.
    Hurtig MB, Novak K, McPherson R, McFadden S, McGann LE, Mul drew K, Schachar NS (1998) Osteochondral dowel transplantation for repair of focal defects in the knee: an outcome study using an ovine model. Vet Surg 27(1):5–16PubMedCrossRefGoogle Scholar
  71. 71.
    Pearce SG, Hurtig MB, Clarnette R, Kalra M, Cowan B, Miniaci A (2001) An investigation of 2 techniques for optimizing joint surface congruency using multiple cylindrical osteochondral autografts. Arthroscopy 17(1):50–55PubMedCrossRefGoogle Scholar
  72. 72.
    Siebert CH, Miltner O, Weber M, Sopka S, Koch S, Niedhart C (2003) Healing of osteochondral grafts in an ovine model under the influence of bFGF. Arthroscopy 19(2):182–187PubMedCrossRefGoogle Scholar
  73. 73.
    von Rechenberg B, Akens MK, Nadler D, Bittmann P, Zlinszky K, Kutter A, Poole AR, Auer JA (2003) Changes in subchondral bone in cartilage resurfacing – an experimental study in sheep using different types of osteochondral grafts. Osteoarthr Cartil 11(4):265–277CrossRefGoogle Scholar
  74. 74.
    Guo X, Wang C, Duan C, Descamps M, Zhao Q, Dong L, Lü S, Anselme K, Lu J, Song YQ (2004) Repair of osteochondral defects with autologous chondrocytes seeded onto bioceramic scaffold in sheep. Tissue Eng 10(11–12):1830–1840PubMedCrossRefGoogle Scholar
  75. 75.
    Tibesku CO, Szuwart T, Kleffner TO, Schlegel PM, Jahn UR, Van Aken H, Fuchs S (2004) Hyaline cartilage degenerates after autologous osteochondral transplantation. J Orthop Res 22(6):1210–1214PubMedCrossRefGoogle Scholar
  76. 76.
    Dorotka R, Windberger U, Macfelda K, Bindreiter U, Toma C, Nehrer S (2005) Repair of articular cartilage defects treated by microfracture and a three-dimensional collagen matrix. Biomaterials 26(17):3617–3629PubMedCrossRefGoogle Scholar
  77. 77.
    Hoemann CD, Hurtig M, Rossomacha E, Sun J, Chevrier A, Shive MS, Buschmann MD (2005) Chitosan-glycerol phosphate/blood implants improve hyaline cartilage repair in ovine microfracture defects. J Bone Joint Surg Am 87(12):2671–2686PubMedCrossRefGoogle Scholar
  78. 78.
    Russlies M, Behrens P, Ehlers EM, Bröhl C, Vindigni C, Spector M, Kurz B (2005) Periosteum stimulates subchondral bone densification in autologous chondrocyte transplantation in a sheep model. Cell Tissue Res 319(1):133–142PubMedCrossRefGoogle Scholar
  79. 79.
    Tytherleigh-Strong G, Hurtig M, Miniaci A (2005) Intra-articular hyaluronan following autogenous osteochondral grafting of the knee. Arthroscopy 21(8):999–1005PubMedCrossRefGoogle Scholar
  80. 80.
    Burks RT, Greis PE, Arnoczky SP, Scher C (2006) The use of a single osteochondral autograft plug in the treatment of a large osteochondral lesion in the femoral condyle: an experimental study in sheep. Am J Sports Med 34(2):247–255PubMedCrossRefGoogle Scholar
  81. 81.
    Frosch KH, Drengk A, Krause P, Viereck V, Miosge N, Werner C, Schild D, Stürmer EK, Stürmer KM (2006) Stem cell-coated titanium implants for the partial joint resurfacing of the knee. Biomaterials 27(12):2542–2549PubMedCrossRefGoogle Scholar
  82. 82.
    Kandel RA, Grynpas M, Pilliar R, Lee J, Wang J, Waldman S, Zalzal P, Hurtig M (2006) CIHR-bioengineering of skeletal tissues team. Repair of osteochondral defects with biphasic cartilage-calcium polyphosphate constructs in a sheep model. Biomaterials 27(22):4120–4131PubMedCrossRefGoogle Scholar
  83. 83.
    Siebert CH, Schneider U, Sopka S, Wahner T, Miltner O, Niedhart C (2006) Ingrowth of osteochondral grafts under the influence of growth factors: 6-month results of an animal study. Arch Orthop Trauma Surg 126(4):247–252PubMedCrossRefGoogle Scholar
  84. 84.
    Jones CW, Willers C, Keogh A, Smolinski D, Fick D, Yates PJ, Kirk TB, Zheng MH (2008) Matrix-induced autologous chondrocyte implantation in sheep: objective assessments including confocal arthroscopy. J Orthop Res 26(3):292–303PubMedCrossRefGoogle Scholar
  85. 85.
    Jubel A, Andermahr J, Schiffer G, Fischer J, Rehm KE, Stoddart MJ, Häuselmann HJ (2008) Transplantation of de novo scaffold-free cartilage implants into sheep knee chondral defects. Am J Sports Med 36(8):1555–1564PubMedCrossRefGoogle Scholar
  86. 86.
    Schlichting K, Schell H, Kleemann RU, Schill A, Weiler A, Duda GN, Epari DR (2008) Influence of scaffold stiffness on subchondral bone and subsequent cartilage regeneration in an ovine model of osteochondral defect healing. Am J Sports Med 36(12):2379–2391PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Schagemann JC, Erggelet C, Chung HW, Lahm A, Kurz H, Mrosek EH (2009) Cell-laden and cell-free biopolymer hydrogel for the treatment of osteochondral defects in a sheep model. Tissue Eng Part A 15(1):75–82PubMedCrossRefGoogle Scholar
  88. 88.
    Streitparth F, Schöttle P, Schlichting K, Schell H, Fischbach F, Denecke T, Duda GN, Schröder RJ (2009) Osteochondral defect repair after implantation of biodegradable scaffolds: indirect magnetic resonance arthrography and histopathologic correlation. Acta Radiol 50(7):765–774PubMedCrossRefGoogle Scholar
  89. 89.
    Wegener B, Schrimpf FM, Pietschmann MF, Milz S, Berger-Lohr M, Bergschmidt P, Jansson V, Müller PE (2009) Matrix-guided cartilage regeneration in chondral defects. Biotechnol Appl Biochem 53(Pt 1):63–70PubMedCrossRefGoogle Scholar
  90. 90.
    Gille J, Kunow J, Boisch L, Behrens P, Bos I, Hoffmann C, Köller W, Russlies M, Kurz B (2010) Cell-laden and cell-free matrix-induced chondrogenesis versus microfracture for the treatment of articular cartilage defects: a histological and biomechanical study in sheep. Cartilage 1(1):29–42PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kon E, Delcogliano M, Filardo G, Fini M, Giavaresi G, Francioli S, Martin I, Pressato D, Arcangeli E, Quarto R, Sandri M, Marcacci M (2010) Orderly osteochondral regeneration in a sheep model using a novel nano-composite multilayered biomaterial. J Orthop Res 28(1):116–124PubMedPubMedCentralGoogle Scholar
  92. 92.
    Kon E, Filardo G, Delcogliano M, Fini M, Salamanna F, Giavaresi G, Martin I, Marcacci M (2010) Platelet autologous growth factors decrease the osteochondral regeneration capability of a collagen-hydroxyapatite scaffold in a sheep model. BMC Musculoskelet Disord 11:220PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Getgood A, Henson F, Skelton C, Herrera E, Brooks R, Fortier LA, Rushton N (2012) The augmentation of a collagen/glycosaminoglycan biphasic osteochondral scaffold with platelet-rich plasma and concentrated bone marrow aspirate for osteochondral defect repair in sheep: a pilot study. Cartilage 3(4):351–363PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Milano G, Deriu L, Sanna Passino E, Masala G, Manunta A, Postacchini R, Saccomanno MF, Fabbriciani C (2012) Repeated platelet concentrate injections enhance reparative response of microfractures in the treatment of chondral defects of the knee: an experimental study in an animal model. Arthroscopy 28(5):688–701PubMedCrossRefGoogle Scholar
  95. 95.
    Bell AD, Lascau-Coman V, Sun J, Chen G, Lowerison MW, Hurtig MB, Hoemann CD (2013) Bone-induced chondroinduction in sheep jamshidi biopsy defects with and without treatment by subchondral chitosan-blood implant: 1-day, 3-week, and 3-month repair. Cartilage 4(2):131–143PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Bernstein A, Niemeyer P, Salzmann G, Südkamp NP, Hube R, Klehm J, Menzel M, von Eisenhart-Rothe R, Bohner M, Görz L, Mayr HO (2013) Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: histological results. Acta Biomater 9(7):7490–7505PubMedCrossRefGoogle Scholar
  97. 97.
    Carneiro MO, Barbieri CH, Neto JB (2013) Platelet-rich plasma gel promotes regeneration of articular cartilage in knees of sheep. Acta Ortop Bras 21(2):80–86PubMedCentralCrossRefGoogle Scholar
  98. 98.
    Fan W, Wu C, Miao X, Liu G, Saifzadeh S, Sugiyama S, Afara I, Crawford R, Xiao Y (2013) Biomaterial scaffolds in cartilage-subchondral bone defects influencing the repair of autologous articular cartilage transplants. J Biomater Appl 27(8):979–989PubMedCrossRefGoogle Scholar
  99. 99.
    Kunz M, Devlin SM, Hurtig MB, Waldman SD, Rudan JF, Bardana DD, Stewart AJ (2013) Image-guided techniques improve the short-term outcome of autologous osteochondral cartilage repair surgeries: an animal trial. Cartilage 4(2):153–164PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Martinez-Carranza N, Berg HE, Hultenby K, Nurmi-Sandh H, Ryd L, Lagerstedt AS (2013) Focal knee resurfacing and effects of surgical precision on opposing cartilage. A pilot study on 12 sheep. Osteoarthr Cartil 21(5):739–745PubMedCrossRefGoogle Scholar
  101. 101.
    Mayr HO, Klehm J, Schwan S, Hube R, Südkamp NP, Niemeyer P, Salzmann G, von Eisenhardt-Rothe R, Heilmann A, Bohner M, Bernstein A (2013) Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: biomechanical results. Acta Biomater 9(1):4845–4855PubMedCrossRefGoogle Scholar
  102. 102.
    Schinhan M, Gruber M, Dorotka R, Pilz M, Stelzeneder D, Chiari C, Rössler N, Windhager R, Nehrer S (2013) Matrix-associated autologous chondrocyte transplantation in a compartmentalized early stage of osteoarthritis. Osteoarthr Cartil 21(1):217–225PubMedCrossRefGoogle Scholar
  103. 103.
    Schleicher I, Lips KS, Sommer U, Schappat I, Martin AP, Szalay G, Hartmann S, Schnettler R (2013) Biphasic scaffolds for repair of deep osteochondral defects in a sheep model. J Surg Res 183(1):184–192PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Schleicher I, Lips KS, Sommer U, Schappat I, Martin AP, Szalay G, Schnettler R (2013) Allogenous bone with collagen for repair of deep osteochondral defects. J Surg Res 185(2):667–675PubMedCrossRefGoogle Scholar
  105. 105.
    Caminal M, Moll X, Codina D, Rabanal RM, Morist A, Barrachina J, Garcia F, Pla A, Vives J (2014) Transitory improvement of articular cartilage characteristics after implantation of polylactide:polyglycolic acid (PLGA) scaffolds seeded with autologous mesenchymal stromal cells in a sheep model of critical-sized chondral defect. Biotechnol Lett 36(10):2143–2153PubMedCrossRefGoogle Scholar
  106. 106.
    Eldracher M, Orth P, Cucchiarini M, Pape D, Madry H (2014) Small subchondral drill holes improve marrow stimulation of articular cartilage defects. Am J Sports Med 42(11):2741–2750PubMedCrossRefGoogle Scholar
  107. 107.
    Fonseca C, Caminal M, Peris D, Barrachina J, Fàbregas PJ, Garcia F, Cairó JJ, Gòdia F, Pla A, Vives J (2014) An arthroscopic approach for the treatment of osteochondral focal defects with cell-free and cell-loaded PLGA scaffolds in sheep. Cytotechnology 66(2):345–354PubMedCrossRefGoogle Scholar
  108. 108.
    Guillén-García P, Rodríguez-Iñigo E, Guillén-Vicente I, Caballero-Santos R, Guillén-Vicente M, Abelow S, Giménez-Gallego G, López-Alcorocho JM (2014) Increasing the dose of autologous chondrocytes improves articular cartilage repair: histological and molecular study in the sheep animal model. Cartilage 5(2):114–122PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Martinez-Carranza N, Berg HE, Lagerstedt AS, Nurmi-Sandh H, Schupbach P, Ryd L (2014) Fixation of a double-coated titanium-hydroxyapatite focal knee resurfacing implant: a 12-month study in sheep. Osteoarthr Cartil 22(6):836–844PubMedCrossRefGoogle Scholar
  110. 110.
    Pilichi S, Rocca S, Pool RR, Dattena M, Masala G, Mara L, Sanna D, Casu S, Manunta ML, Manunta A, Passino ES (2014) Treatment with embryonic stem-like cells into osteochondral defects in sheep femoral condyles. BMC Vet Res 10:301PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Power J, Hernandez P, Guehring H, Getgood A, Henson F (2014) Intra-articular injection of rhFGF-18 improves the healing in microfracture treated chondral defects in an ovine model. J Orthop Res 32(5):669–676PubMedCrossRefGoogle Scholar
  112. 112.
    Sanz-Ramos P, Duart J, Rodríguez-Goñi MV, Vicente-Pascual M, Dotor J, Mora G, Izal-Azcárate I (2014) Improved chondrogenic capacity of collagen hydrogel-expanded chondrocytes: in vitro and in vivo analyses. J Bone Joint Surg Am 96(13):1109–1117PubMedCrossRefGoogle Scholar
  113. 113.
    Garcia D, Longo UG, Vaquero J, Forriol F, Loppini M, Khan WS, Denaro V (2015) Amniotic membrane transplant for articular cartilage repair: an experimental study in sheep. Curr Stem Cell Res Ther 10(1):77–83PubMedCrossRefGoogle Scholar
  114. 114.
    Gelse K, Riedel D, Pachowsky M, Hennig FF, Trattnig S, Welsch GH (2015) Limited integrative repair capacity of native cartilage autografts within cartilage defects in a sheep model. J Orthop Res 33(3):390–397PubMedCrossRefGoogle Scholar
  115. 115.
    Hopper N, Wardale J, Brooks R, Power J, Rushton N, Henson F (2015) Peripheral blood mononuclear cells enhance cartilage repair in in vivo osteochondral defect model. PLoS One 10(8):e0133937PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Howard D, Wardale J, Guehring H, Henson F (2015) Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model. J Orthop Res 33(8):1120–1127PubMedCrossRefGoogle Scholar
  117. 117.
    Mohan N, Gupta V, Sridharan BP, Mellott AJ, Easley JT, Palmer RH, Galbraith RA, Key VH, Berkland CJ, Detamore MS (2015) Microsphere-based gradient implants for osteochondral regeneration: a long-term study in sheep. Regen Med 10(6):709–728PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Zorzi AR, Amstalden EM, Plepis AM, Martins VC, Ferretti M, Antonioli E, Duarte AS, Luzo AC, Miranda JB (2015) Effect of human adipose tissue mesenchymal stem cells on the regeneration of ovine articular cartilage. Int J Mol Sci 16(11):26813–26831PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Caminal M, Peris D, Fonseca C, Barrachina J, Codina D, Rabanal RM, Moll X, Morist A, García F, Cairó JJ, Gòdia F, Pla A, Vives J (2016) Cartilage resurfacing potential of PLGA scaffolds loaded with autologous cells from cartilage, fat, and bone marrow in an ovine model of osteochondral focal defect. Cytotechnology 68(4):907–919PubMedCrossRefGoogle Scholar
  120. 120.
    de Barros CN, Miluzzi Yamada AL, Junior RS, Barraviera B, Hussni CA, de Souza JB, Watanabe MJ, Rodrigues CA, Garcia Alves AL (2016) A new heterologous fibrin sealant as a scaffold to cartilage repair-experimental study and preliminary results. Exp Biol Med (Maywood) 241(13):1410–1415CrossRefGoogle Scholar
  121. 121.
    Hindle P, Baily J, Khan N, Biant LC, Simpson AH, Péault B (2016) Perivascular mesenchymal stem cells in sheep: characterization and autologous transplantation in a model of articular cartilage repair. Stem Cells Dev 25(21):1659–1669PubMedCrossRefGoogle Scholar
  122. 122.
    Kitamura N, Yokota M, Kurokawa T, Gong JP, Yasuda K (2016) In vivo cartilage regeneration induced by a double-network hydrogel: evaluation of a novel therapeutic strategy for femoral articular cartilage defects in a sheep model. J Biomed Mater Res A 104(9):2159–2165PubMedCrossRefGoogle Scholar
  123. 123.
    Mrosek EH, Chung HW, Fitzsimmons JS, O'Driscoll SW, Reinholz GG, Schagemann JC (2016) Porous tantalum biocomposites for osteochondral defect repair: a follow-up study in a sheep model. Bone Joint Res 5(9):403–411PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Schagemann JC, Rudert N, Taylor ME, Sim S, Quenneville E, Garon M, Klinger M, Buschmann MD, Mittelstaedt H (2016) Bilayer implants: electromechanical assessment of regenerated articular cartilage in a sheep model. Cartilage 7(4):346–360PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Yucekul A, Ozdil D, Kutlu NH, Erdemli E, Aydin HM, Doral MN (2017) Tri-layered composite plug for the repair of osteochondral defects: in vivo study in sheep. J Tissue Eng.
  126. 126.
    Vahedi P, Soleimanirad J, Roshangar L, Shafaei H, Jarolmasjed S, Nozad Charoudeh H (2016) Advantages of sheep infrapatellar fat pad adipose tissue derived stem cells in tissue engineering. Adv Pharm Bull 6(1):105–110PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Al Faqeh H, Nor Hamdan BM, Chen HC, Aminuddin BS, Ruszymah BH (2012) The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol 47(6):458–464PubMedCrossRefGoogle Scholar
  128. 128.
    Ude CC, Sulaiman SB, Min-Hwei N, Hui-Cheng C, Ahmad J, Yahaya NM, Saim AB, Idrus RB (2014) Cartilage regeneration by chondrogenic induced adult stem cells in osteoarthritic sheep model. PLoS One 9(6):e98770PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Song F, Tang J, Geng R, Hu H, Zhu C, Cui W, Fan W (2014) Comparison of the efficacy of bone marrow mononuclear cells and bone mesenchymal stem cells in the treatment of osteoarthritis in a sheep model. Int J Clin Exp Pathol 7(4):1415–1426PubMedPubMedCentralGoogle Scholar
  130. 130.
    Desando G, Giavaresi G, Cavallo C, Bartolotti I, Sartoni F, Nicoli Aldini N, Martini L, Parrilli A, Mariani E, Fini M, Grigolo B (2016) Autologous bone marrow concentrate in a sheep model of osteoarthritis: new perspectives for cartilage and meniscus repair. Tissue Eng Part C Methods 22(6):608–619PubMedCrossRefGoogle Scholar
  131. 131.
    Schinhan M, Gruber M, Vavken P, Dorotka R, Samouh L, Chiari C, Gruebl-Barabas R, Nehrer S (2012) Critical-size defect induces unicompartmental osteoarthritis in a stable ovine knee. J Orthop Res 30(2):214–220PubMedCrossRefGoogle Scholar
  132. 132.
    Beck A, Murphy DJ, Carey-Smith R, Wood DJ, Zheng MH (2016) Treatment of articular cartilage defects with microfracture and autologous matrix-induced chondrogenesis leads to extensive subchondral bone cyst formation in a sheep model. Am J Sports Med 44(10):2629–2643PubMedCrossRefGoogle Scholar
  133. 133.
    Vikingsson L, Sancho-Tello M, Ruiz-Saurí A, Martínez Díaz S, Gómez-Tejedor JA, Gallego Ferrer G, Carda C, Monllau JC, Gómez Ribelles JL (2015) Implantation of a polycaprolactone scaffold with subchondral bone anchoring ameliorates nodules formation and other tissue alterations. Int J Artif Organs 38(12):659–666PubMedCrossRefGoogle Scholar
  134. 134.
    Brehm W, Aklin B, Yamashita T, Rieser F, Trüb T, Jakob RP, Mainil-Varlet P (2006) Repair of superficial osteochondral defects with an autologous scaffold-free cartilage construct in a caprine model: implantation method and short-term results. Osteoarthr Cartil 14(12):1214–1226PubMedCrossRefGoogle Scholar
  135. 135.
    Shahgaldi BF, Amis AA, Heatley FW, McDowell J, Bentley G (1991) Repair of cartilage lesions using biological implants. A comparative histological and biomechanical study in goats. J Bone Joint Surg Br 73(1):57–64PubMedCrossRefGoogle Scholar
  136. 136.
    Butnariu-Ephrat M, Robinson D, Mendes DG, Halperin N, Nevo Z (1996) Resurfacing of goat articular cartilage by chondrocytes derived from bone marrow. Clin Orthop Relat Res 330:234–243CrossRefGoogle Scholar
  137. 137.
    Jackson DW, Halbrecht J, Proctor C, Van Sickle D, Simon TM (1996) Assessment of donor cell and matrix survival in fresh articular cartilage allografts in a goat model. J Orthop Res 14(2):255–264PubMedCrossRefGoogle Scholar
  138. 138.
    van Susante JL, Buma P, Schuman L, Homminga GN, van den Berg WB, Veth RP (1999) Resurfacing potential of heterologous chondrocytes suspended in fibrin glue in large full-thickness defects of femoral articular cartilage: an experimental study in the goat. Biomaterials 20(13):1167–1175PubMedCrossRefGoogle Scholar
  139. 139.
    Louwerse RT, Heyligers IC, Klein-Nulend J, Sugihara S, van Kampen GP, Semeins CM, Goei SW, de Koning MH, Wuisman PI, Burger EH (2000) Use of recombinant human osteogenic protein-1 for the repair of subchondral defects in articular cartilage in goats. J Biomed Mater Res 49(4):506–516PubMedCrossRefGoogle Scholar
  140. 140.
    Niederauer GG, Slivka MA, Leatherbury NC, Korvick DL, Harroff HH, Ehler WC, Dunn CJ, Kieswetter K (2000) Evaluation of multiphase implants for repair of focal osteochondral defects in goats. Biomaterials 21(24):2561–2574PubMedCrossRefGoogle Scholar
  141. 141.
    Lane JG, Tontz WL Jr, Ball ST, Massie JB, Chen AC, Bae WC, Amiel ME, Sah RL, Amiel D (2001) A morphologic, biochemical, and biomechanical assessment of short-term effects of osteochondral autograft plug transfer in an animal model. Arthroscopy 17(8):856–863PubMedCrossRefGoogle Scholar
  142. 142.
    Quintavalla J, Uziel-Fusi S, Yin J, Boehnlein E, Pastor G, Blancuzzi V, Singh HN, Kraus KH, O'Byrne E, Pellas TC (2002) Fluorescently labeled mesenchymal stem cells (MSCs) maintain multilineage potential and can be detected following implantation into articular cartilage defects. Biomaterials 23(1):109–119PubMedCrossRefGoogle Scholar
  143. 143.
    Welch RD, Berry BH, Crawford K, Zhang H, Zobitz M, Bronson D, Krishnan S (2002) Subchondral defects in caprine femora augmented with in situ setting hydroxyapatite cement, polymethylmethacrylate, or autogenous bone graft: biomechanical and histomorphological analysis after two-years. J Orthop Res 20(3):464–472PubMedCrossRefGoogle Scholar
  144. 144.
    Dell'Accio F, Vanlauwe J, Bellemans J, Neys J, De Bari C, Luyten FP (2003) Expanded phenotypically stable chondrocytes persist in the repair tissue and contribute to cartilage matrix formation and structural integration in a goat model of autologous chondrocyte implantation. J Orthop Res 21(1):123–131PubMedCrossRefGoogle Scholar
  145. 145.
    Lane JG, Massie JB, Ball ST, Amiel ME, Chen AC, Bae WC, Sah RL, Amiel D (2004) Follow-up of osteochondral plug transfers in a goat model: a 6-month study. Am J Sports Med 32(6):1440–1450PubMedCrossRefGoogle Scholar
  146. 146.
    Vasara AI, Hyttinen MM, Lammi MJ, Lammi PE, Långsjö TK, Lindahl A, Peterson L, Kellomäki M, Konttinen YT, Helminen HJ, Kiviranta I (2004) Subchondral bone reaction associated with chondral defect and attempted cartilage repair in goats. Calcif Tissue Int 74(1):107–114PubMedCrossRefGoogle Scholar
  147. 147.
    Kirker-Head CA, Van Sickle DC, Ek SW, McCool JC (2006) Safety of, and biological and functional response to, a novel metallic implant for the management of focal full-thickness cartilage defects: preliminary assessment in an animal model out to 1 year. J Orthop Res 24(5):1095–1108PubMedCrossRefGoogle Scholar
  148. 148.
    Hunziker EB, Stähli A (2008) Surgical suturing of articular cartilage induces osteoarthritis-like changes. Osteoarthr Cartil 16(9):1067–1073PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Lind M, Larsen A (2008) Equal cartilage repair response between autologous chondrocytes in a collagen scaffold and minced cartilage under a collagen scaffold: an in vivo study in goats. Connect Tissue Res 49(6):437–442PubMedCrossRefGoogle Scholar
  150. 150.
    Lind M, Larsen A, Clausen C, Osther K, Everland H (2008) Cartilage repair with chondrocytes in fibrin hydrogel and MPEG polylactide scaffold: an in vivo study in goats. Knee Surg Sports Traumatol Arthrosc 16(7):690–698PubMedCrossRefGoogle Scholar
  151. 151.
    Custers RJ, Saris DB, Dhert WJ, Verbout AJ, van Rijen MH, Mastbergen SC, Lafeber FP, Creemers LB (2009) Articular cartilage degeneration following the treatment of focal cartilage defects with ceramic metal implants and compared with microfracture. J Bone Joint Surg Am 91(4):900–910PubMedCrossRefGoogle Scholar
  152. 152.
    Lane JG, Healey RM, Chen AC, Sah RL, Amiel D (2010) Can osteochondral grafting be augmented with microfracture in an extended-size lesion of articular cartilage? Am J Sports Med 38(7):1316–1323PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Miot S, Brehm W, Dickinson S, Sims T, Wixmerten A, Longinotti C, Hollander AP, Mainil-Varlet P, Martin I (2012) Influence of in vitro maturation of engineered cartilage on the outcome of osteochondral repair in a goat model. Eur Cell Mater 23:222–236PubMedCrossRefGoogle Scholar
  154. 154.
    Bekkers JE, Creemers LB, Tsuchida AI, van Rijen MH, Custers RJ, Dhert WJ, Saris DB (2013) One-stage focal cartilage defect treatment with bone marrow mononuclear cells and chondrocytes leads to better macroscopic cartilage regeneration compared to microfracture in goats. Osteoarthr Cartil 21(7):950–956PubMedCrossRefGoogle Scholar
  155. 155.
    Kon E, Filardo G, Robinson D, Eisman JA, Levy A, Zaslav K, Shani J, Altschuler N (2014) Osteochondral regeneration using a novel aragonite-hyaluronate bi-phasic scaffold in a goat model. Knee Surg Sports Traumatol Arthrosc 22(6):1452–1464PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Pei Y, Fan JJ, Zhang XQ, Zhang ZY, Repairing YM (2014) The osteochondral defect in goat with the tissue-engineered osteochondral graft preconstructed in a double-chamber stirring bioreactor. Biomed Res Int 2014:21e9203Google Scholar
  157. 157.
    Geraghty S, Kuang JQ, Yoo D, LeRoux-Williams M, Vangsness CT Jr, Danilkovitch A (2015) A novel, cryopreserved, viable osteochondral allograft designed to augment marrow stimulation for articular cartilage repair. J Orthop Surg Res 10:66PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Kon E, Filardo G, Shani J, Altschuler N, Levy A, Zaslav K, Eisman JE, Robinson D (2015) Osteochondral regeneration with a novel aragonite-hyaluronate biphasic scaffold: up to 12-month follow-up study in a goat model. J Orthop Surg Res 10:81PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Mumme M, Steinitz A, Nuss KM, Klein K, Feliciano S, Kronen P, Jakob M, von Rechenberg B, Martin I, Barbero A, Pelttari K. Regenerative potential of tissue-engineered nasal chondrocytes in goat articular cartilage defects. Tissue Eng Part A 2016;22(21–22):1286–1295PubMedCrossRefGoogle Scholar
  160. 160.
    Sun J, Hou XK, Zheng YX (2016) Restore a 9 mm diameter osteochondral defect with gene enhanced tissue engineering followed mosaicplasty in a goat model. Acta Orthop Traumatol Turc 50(4):464–469PubMedCrossRefGoogle Scholar
  161. 161.
    Wang F, Sun Y, He D, Wang L (2017) Effect of concentrated growth factors on the repair of the goat temporomandibular joint. J Oral Maxillofac Surg 75(3):498–507PubMedCrossRefGoogle Scholar
  162. 162.
    Shahgaldi BF (1998) Repair of large osteochondral defects: load bearing and structural properties of osteochondral repair tissue. Knee 5:111–117CrossRefGoogle Scholar
  163. 163.
    Jackson DW, Lalor PA, Aberman HM, Simon TM (2001) Spontaneous repair of full-thickness defects of articular cartilage in a goat model. A preliminary study. J Bone Joint Surg Am 83-A(1):53–64PubMedCrossRefGoogle Scholar
  164. 164.
    Simon TM, Aberman HM (2010) Cartilage regeneration and repair testing in a surrogate large animal model. Tissue Eng Part B Rev 16(1):65–79PubMedCrossRefGoogle Scholar
  165. 165.
    Murphy JM, Fink DJ, Hunziker EB, Barry FP (2003) Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 48(12):3464–3474PubMedCrossRefGoogle Scholar
  166. 166.
    Ko JY, Lee J, Lee J, Im GI (2017) Intra-articular xenotransplantation of adipose-derived stromal cells to treat osteoarthritis in goat model. Tissue Eng Regen Med 14(1):65–71CrossRefGoogle Scholar
  167. 167.
    Kangarlu A, Gahunia HK (2006) Magnetic resonance imaging characterization of osteochondral defect repair in a goat model at 8 T. Osteoarthr Cartil 14(1):52–62PubMedCrossRefGoogle Scholar
  168. 168.
    Watanabe A, Boesch C, Anderson SE, Brehm W, Mainil Varlet P (2009) Ability of dGEMRIC and T2 mapping to evaluate cartilage repair after microfracture: a goat study. Osteoarthr Cartil 17(10):1341–1349PubMedCrossRefGoogle Scholar
  169. 169.
    Søndergaard LV, Dagnæs-Hansen F, Herskin MS (2011) Welfare assessment in porcine biomedical research – suggestion for an operational tool. Res Vet Sci 91(3):e1–e9PubMedCrossRefGoogle Scholar
  170. 170.
    Reiland S (1978) Growth and skeletal development of the pig. Acta Radiol Suppl 358:15–22PubMedPubMedCentralGoogle Scholar
  171. 171.
    Gotterbarm T, Breusch SJ, Schneider U, Jung M (2008) The minipig model for experimental chondral and osteochondral defect repair in tissue engineering: retrospective analysis of 180 defects. Lab Anim 42(1):71–82PubMedCrossRefGoogle Scholar
  172. 172.
    Kaab MJ, Gwynn JA, Notzli HP (1998) Collagen fibre arrangement in the tibial plateau articular cartilage of man and other mammalian species. J Anat 193(Pt 1):23–34PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Pan Y, Li Z, Xie T, Chu CR (2003) Hand-held arthroscopic optical coherence tomography for in vivo high-resolution imaging of articular cartilage. J Biomed Opt 8(4):648–654PubMedCrossRefGoogle Scholar
  174. 174.
    Zelle S, Zantop T, Schanz S, Petersen W (2007) Arthroscopic techniques for the fixation of a three-dimensional scaffold for autologous chondrocyte transplantation: structural properties in an in vitro model. Arthroscopy 23(10):1073–1078PubMedCrossRefGoogle Scholar
  175. 175.
    Vasara AI, Hyttinen MM, Pulliainen O, Lammi MJ, Jurvelin JS, Peterson L, Lindahl A, Helminen HJ, Kiviranta I (2006) Immature porcine knee cartilage lesions show good healing with or without autologous chondrocyte transplantation. Osteoarthr Cartil 14(10):1066–1074PubMedCrossRefGoogle Scholar
  176. 176.
    Hembry RM, Dyce J, Driesang I, Hunziker EB, Fosang AJ, Tyler JA, Murphy G (2001) Immunolocalization of matrix metalloproteinases in partial-thickness defects in pig articular cartilage. A preliminary report. J Bone Joint Surg Am 83-A(6):826–838PubMedCrossRefGoogle Scholar
  177. 177.
    Chiang H, Kuo TF, Tsai CC, Lin MC, She BR, Huang YY, Lee HS, Shieh CS, Chen MH, Ramshaw JA, Werkmeister JA, Tuan RS, Jiang CC (2005) Repair of porcine articular cartilage defect with autologous chondrocyte transplantation. J Orthop Res 23(3):584–593PubMedCrossRefGoogle Scholar
  178. 178.
    Shimomura K, Ando W, Tateishi K, Nansai R, Fujie H, Hart DA, Kohda H, Kita K, Kanamoto T, Mae T, Nakata K, Shino K, Yoshikawa H, Nakamura N (2010) The influence of skeletal maturity on allogenic synovial mesenchymal stem cell-based repair of cartilage in a large animal model. Biomaterials 31(31):8004–8011PubMedCrossRefGoogle Scholar
  179. 179.
    Hunziker EB, Rosenberg LC (1996) Repair of partial-thickness defects in articular cartilage: cell recruitment from the synovial membrane. J Bone Joint Surg Am 78(5):721–733PubMedCrossRefGoogle Scholar
  180. 180.
    Mainil-Varlet P, Rieser F, Grogan S, Mueller W, Saager C, Jakob RP (2001) Articular cartilage repair using a tissue-engineered cartilage-like implant: an animal study. Osteoarthr Cartil 9(Suppl A):S6–15PubMedCrossRefGoogle Scholar
  181. 181.
    Gal P, Necas A, Adler J, Teyschl O, Fabian P, Bibrova S (2002) Transplantation of the autogenous chondrocyte graft to physeal defects: an experimental study in pigs. Acta Vet Brno 71(3):327–332CrossRefGoogle Scholar
  182. 182.
    Liu Y, Chen F, Liu W, Cui L, Shang Q, Xia W, Wang J, Cui Y, Yang G, Liu D, Wu J, Xu R, Buonocore SD, Cao Y (2002) Repairing large porcine full-thickness defects of articular cartilage using autologous chondrocyte-engineered cartilage. Tissue Eng 8(4):709–721PubMedCrossRefGoogle Scholar
  183. 183.
    Jung M, Gotterbarm T, Gruettgen A, Vilei SB, Breusch S, Richter W (2005) Molecular characterization of spontaneous and growth-factor-augmented chondrogenesis in periosteum-bone tissue transferred into a joint. Histochem Cell Biol 123(4–5):447–456PubMedCrossRefGoogle Scholar
  184. 184.
    Chang CH, Kuo TF, Lin CC, Chou CH, Chen KH, Lin FH, Liu HC (2006) Tissue engineering-based cartilage repair with allogenous chondrocytes and gelatin-chondroitin-hyaluronan tri-copolymer scaffold: a porcine model assessed at 18, 24, and 36 weeks. Biomaterials 27(9):1876–1888PubMedCrossRefGoogle Scholar
  185. 185.
    Harman BD, Weeden SH, Lichota DK, Brindley GW (2006) Osteochondral autograft transplantation in the porcine knee. Am J Sports Med 34(6):913–918PubMedCrossRefGoogle Scholar
  186. 186.
    Ando W, Tateishi K, Hart DA, Katakai D, Tanaka Y, Nakata K, Hashimoto J, Fujie H, Shino K, Yoshikawa H, Nakamura N (2007) Cartilage repair using an in vitro generated scaffold-free tissue-engineered construct derived from porcine synovial mesenchymal stem cells. Biomaterials 28(36):5462–5470PubMedCrossRefGoogle Scholar
  187. 187.
    Filová E, Rampichová M, Handl M, Lytvynets A, Halouzka R, Usvald D, Hlucilová J, Procházka R, Dezortová M, Rolencová E, Kostáková E, Trc T, Stastný E, Kolácná L, Hájek M, Motlík J, Amler E (2007) Composite hyaluronate-type I collagen-fibrin scaffold in the therapy of osteochondral defects in miniature pigs. Physiol Res 56(Suppl 1):S5–16PubMedPubMedCentralGoogle Scholar
  188. 188.
    Jiang CC, Chiang H, Liao CJ, Lin YJ, Kuo TF, Shieh CS, Huang YY, Tuan RS (2007) Repair of porcine articular cartilage defect with a biphasic osteochondral composite. J Orthop Res 25(10):1277–1290PubMedCrossRefGoogle Scholar
  189. 189.
    Baumbach K, Petersen JP, Ueblacker P, Schröder J, Göpfert C, Stork A, Rueger JM, Amling M, Meenen NM (2008) The fate of osteochondral grafts after autologous osteochondral transplantation: a one-year follow-up study in a minipig model. Arch Orthop Trauma Surg 128(11):1255–1263PubMedCrossRefGoogle Scholar
  190. 190.
    Petersen JP, Ueblacker P, Goepfert C, Adamietz P, Baumbach K, Stork A, Rueger JM, Poertner R, Amling M, Meenen NM (2008) Long term results after implantation of tissue engineered cartilage for the treatment of osteochondral lesions in a minipig model. J Mater Sci Mater Med 19(5):2029–2038PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Blanke M, Carl HD, Klinger P, Swoboda B, Hennig F, Gelse K (2009) Transplanted chondrocytes inhibit endochondral ossification within cartilage repair tissue. Calcif Tissue Int 85(5):421–433PubMedCrossRefGoogle Scholar
  192. 192.
    Jung M, Kaszap B, Redöhl A, Steck E, Breusch S, Richter W, Gotterbarm T (2009) Enhanced early tissue regeneration after matrix-assisted autologous mesenchymal stem cell transplantation in full thickness chondral defects in a minipig model. Cell Transplant 18(8):923–932PubMedCrossRefGoogle Scholar
  193. 193.
    Li WJ, Chiang H, Kuo TF, Lee HS, Jiang CC, Tuan RS (2009) Evaluation of articular cartilage repair using biodegradable nanofibrous scaffolds in a swine model: a pilot study. J Tissue Eng Regen Med 3(1):1–10PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Steck E, Fischer J, Lorenz H, Gotterbarm T, Jung M, Richter W (2009) Mesenchymal stem cell differentiation in an experimental cartilage defect: restriction of hypertrophy to bone-close neocartilage. Stem Cells Dev 18(7):969–978PubMedCrossRefGoogle Scholar
  195. 195.
    Ho ST, Hutmacher DW, Ekaputra AK, Hitendra D, Hui JH (2010) The evaluation of a biphasic osteochondral implant coupled with an electrospun membrane in a large animal model. Tissue Eng Part A 16(4):1123–1141PubMedCrossRefGoogle Scholar
  196. 196.
    Schneider U, Schmidt-Rohlfing B, Gavenis K, Maus U, Mueller-Rath R, Andereya S (2011) A comparative study of 3 different cartilage repair techniques. Knee Surg Sports Traumatol Arthrosc 19(12):2145–2152PubMedCrossRefGoogle Scholar
  197. 197.
    Ebihara G, Sato M, Yamato M, Mitani G, Kutsuna T, Nagai T, Ito S, Ukai T, Kobayashi M, Kokubo M, Okano T, Mochida J (2012) Cartilage repair in transplanted scaffold-free chondrocyte sheets using a minipig model. Biomaterials 33(15):3846–3851PubMedCrossRefGoogle Scholar
  198. 198.
    Nakamura T, Sekiya I, Muneta T, Hatsushika D, Horie M, Tsuji K, Kawarasaki T, Watanabe A, Hishikawa S, Fujimoto Y, Tanaka H, Kobayashi E (2012) Arthroscopic, histological and MRI analyses of cartilage repair after a minimally invasive method of transplantation of allogeneic synovial mesenchymal stromal cells into cartilage defects in pigs. Cytotherapy 14(3):327–338PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Betsch M, Schneppendahl J, Thuns S, Herten M, Sager M, Jungbluth P, Hakimi M, Wild M (2013) Bone marrow aspiration concentrate and platelet rich plasma for osteochondral repair in a porcine osteochondral defect model. PLoS One 8(8):e71602PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Filová E, Rampichová M, Litvinec A, Držík M, Míčková A, Buzgo M, Košťáková E, Martinová L, Usvald D, Prosecká E, Uhlík J, Motlík J, Vajner L, Amler E (2013) A cell-free nanofiber composite scaffold regenerated osteochondral defects in miniature pigs. Int J Pharm 447(1–2):139–149PubMedCrossRefGoogle Scholar
  201. 201.
    Moriguchi Y, Tateishi K, Ando W, Shimomura K, Yonetani Y, Tanaka Y, Kita K, Hart DA, Gobbi A, Shino K, Yoshikawa H, Nakamura N (2013) Repair of meniscal lesions using a scaffold-free tissue-engineered construct derived from allogenic synovial MSCs in a miniature swine model. Biomaterials 34(9):2185–2193PubMedCrossRefGoogle Scholar
  202. 202.
    Jagodzinski M, Liu C, Guenther D, Burssens A, Petri M, Abedian R, Willbold E, Krettek C, Haasper C, Witte F (2014) Bone marrow-derived cell concentrates have limited effects on osteochondral reconstructions in the mini pig. Tissue Eng Part C Methods 20(3):215–226PubMedCrossRefGoogle Scholar
  203. 203.
    Wang X, Li Y, Han R, He C, Wang G, Wang J, Zheng J, Pei M, Wei L (2014) Demineralized bone matrix combined bone marrow mesenchymal stem cells, bone morphogenetic protein-2 and transforming growth factor-β3 gene promoted pig cartilage defect repair. PLoS One 9(12):e116061PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Ha CW, Park YB, Chung JY, Park YG (2015) Cartilage repair using composites of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel in a minipig model. Stem Cells Transl Med 4(9):1044–1051PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Matsuo T, Kita K, Mae T, Yonetani Y, Miyamoto S, Yoshikawa H, Nakata K (2015) Bone substitutes and implantation depths for subchondral bone repair in osteochondral defects of porcine knee joints. Knee Surg Sports Traumatol Arthrosc 23(5):1401–1409PubMedCrossRefGoogle Scholar
  206. 206.
    Peck Y, He P, Chilla GS, Poh CL, Wang DA (2015) A preclinical evaluation of an autologous living hyaline-like cartilaginous graft for articular cartilage repair: a pilot study. Sci Rep 5:16225PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Sosio C, Di Giancamillo A, Deponti D, Gervaso F, Scalera F, Melato M, Campagnol M, Boschetti F, Nonis A, Domeneghini C, Sannino A, Peretti GM (2015) Osteochondral repair by a novel interconnecting collagen-hydroxyapatite substitute: a large-animal study. Tissue Eng Part A 21(3–4):704–715PubMedCrossRefGoogle Scholar
  208. 208.
    Ding J, Chen B, Lv T, Liu X, Fu X, Wang Q, Yan L, Kang N, Cao Y, Xiao R (2016) Bone marrow mesenchymal stem cell-based engineered cartilage ameliorates polyglycolic acid/polylactic acid scaffold-induced inflammation through M2 polarization of macrophages in a pig model. Stem Cells Transl Med 5(8):1079–1089PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Fisher MB, Belkin NS, Milby AH, Henning EA, Söegaard N, Kim M, Pfeifer C, Saxena V, Dodge GR, Burdick JA, Schaer TP, Steinberg DR, Mauck RL (2016) Effects of mesenchymal stem cell and growth factor delivery on cartilage repair in a mini-pig model. Cartilage 7(2):174–184PubMedCrossRefGoogle Scholar
  210. 210.
    Muhonen V, Salonius E, Haaparanta AM, Järvinen E, Paatela T, Meller A, Hannula M, Björkman M, Pyhältö T, Ellä V, Vasara A, Töyräs J, Kellomäki M, Kiviranta I (2016) Articular cartilage repair with recombinant human type II collagen/polylactide scaffold in a preliminary porcine study. J Orthop Res 34(5):745–753PubMedCrossRefGoogle Scholar
  211. 211.
    Zuo Q, Cui W, Liu F, Wang Q, Chen Z, Fan W (2016) Utilizing tissue-engineered cartilage or BMNC-PLGA composites to fill empty spaces during autologous osteochondral mosaicplasty in porcine knees. J Tissue Eng Regen Med 10(11):916–926PubMedCrossRefGoogle Scholar
  212. 212.
    Lin H, Zhou J, Cao L, Wang HR, Dong J, Chen ZR (2017) Tissue-engineered cartilage constructed by a biotin-conjugated anti-CD44 avidin binding technique for the repairing of cartilage defects in the weight-bearing area of knee joints in pigs. Bone Joint Res 6(5):284–295PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Duda GN, Maldonado ZM, Klein P, Heller MO, Burns J, Bail H (2005) On the influence of mechanical conditions in osteochondral defect healing. J Biomech 38(4):843–851PubMedCrossRefGoogle Scholar
  214. 214.
    Shortkroff S, Barone L, Hsu HP, Wrenn C, Gagne T, Chi T, Breinan H, Minas T, Sledge CB, Tubo R, Spector M (1996) Healing of chondral and osteochondral defects in a canine model: the role of cultured chondrocytes in regeneration of articular cartilage. Biomaterials 17(2):147–154PubMedCrossRefGoogle Scholar
  215. 215.
    Vainio O (2012) Translational animal models using veterinary patients – an example of canine osteoarthritis (OA). Scand J Pain 3(2):84–89CrossRefPubMedGoogle Scholar
  216. 216.
    Campbell CJ, Ishida H, Takahashi H, Kelly F (1963) The transplantation of articular cartilage. An experimental study in dogs. J Bone Joint Surg Am 45A:1579–1592CrossRefGoogle Scholar
  217. 217.
    Engkvist O (1979) Reconstruction of patellar articular cartilage with free autologous perichondrial grafts. An experimental study in dogs. Scand J Plast Reconstr Surg 13(3):361–369PubMedCrossRefGoogle Scholar
  218. 218.
    Stevenson S, Dannucci GA, Sharkey NA, Pool RR (1989) The fate of articular cartilage after transplantation of fresh and cryopreserved tissue-antigen-matched and mismatched osteochondral allografts in dogs. J Bone Joint Surg Am 71A(9):1297–1307CrossRefGoogle Scholar
  219. 219.
    Klompmaker J, Jansen HW, Veth RP, Nielsen HK, de Groot JH, Pennings AJ (1992) Porous polymer implants for repair of full-thickness defects of articular cartilage: an experimental study in rabbit and dog. Biomaterials 13(9):625–634PubMedCrossRefGoogle Scholar
  220. 220.
    Oates KM, Chen AC, Young EP, Kwan MK, Amiel D, Convery FR (1995) Effect of tissue culture storage on the in vivo survival of canine osteochondral allografts. J Orthop Res 13(4):562–569PubMedCrossRefGoogle Scholar
  221. 221.
    Breinan HA, Minas T, Hsu HP, Nehrer S, Sledge CB, Spector M (1997) Effect of cultured autologous chondrocytes on repair of chondral defects in a canine model. J Bone Joint Surg Am 79(10):1439–1451PubMedCrossRefGoogle Scholar
  222. 222.
    Nehrer S, Breinan HA, Ramappa A, Hsu HP, Minas T, Shortkroff S, Sledge CB, Yannas IV, Spector M (1998) Chondrocyte-seeded collagen matrices implanted in a chondral defect in a canine model. Biomaterials 19(24):2313–2328PubMedCrossRefGoogle Scholar
  223. 223.
    van Dyk GE, Dejardin LM, Flo G, Johnson LL (1998) Cancellous bone grafting of large osteochondral defects: an experimental study in dogs. Arthroscopy 14(3):311–320PubMedCrossRefGoogle Scholar
  224. 224.
    Breinan HA, Martin SD, Hsu HP, Spector M (2000) Healing of canine articular cartilage defects treated with microfracture, a type-II collagen matrix, or cultured autologous chondrocytes. J Orthop Res 18(5):781–789PubMedCrossRefGoogle Scholar
  225. 225.
    Breinan HA, Minas T, Hsu HP, Nehrer S, Shortkroff S, Spector M (2001) Autologous chondrocyte implantation in a canine model: change in composition of reparative tissue with time. J Orthop Res 19(3):482–492PubMedCrossRefGoogle Scholar
  226. 226.
    Cook SD, Patron LP, Salkeld SL, Rueger DC (2003) Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs. J Bone Joint Surg Am 85-A(Suppl 3):116–123CrossRefGoogle Scholar
  227. 227.
    Feczkó P, Hangody L, Varga J, Bartha L, Diószegi Z, Bodó G, Kendik Z, Módis L (2003) Experimental results of donor site filling for autologous osteochondral mosaicplasty. Arthroscopy 19(7):755–761PubMedCrossRefGoogle Scholar
  228. 228.
    Lee CR, Grodzinsky AJ, Hsu HP, Spector M (2003) 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(2):272–281PubMedCrossRefGoogle Scholar
  229. 229.
    Chen G, Sato T, Tanaka J, Tateishi T (2006) Preparation of a biphasic scaffold for osteochondral tissue engineering. Mater Sci Eng 26(1):118–123CrossRefGoogle Scholar
  230. 230.
    Glenn RE Jr, McCarty EC, Potter HG, Juliao SF, Gordon JD, Spindler KP (2006) Comparison of fresh osteochondral autografts and allografts: a canine model. Am J Sports Med 34(7):1084–1093PubMedCrossRefGoogle Scholar
  231. 231.
    Yamazoe K, Mishima H, Torigoe K, Iijima H, Watanabe K, Sakai H, Kudo T (2007) Effects of atelocollagen gel containing bone marrow-derived stromal cells on repair of osteochondral defect in a dog. J Vet Med Sci 69(8):835–839PubMedCrossRefGoogle Scholar
  232. 232.
    Choi HJ, Kwon E, Lee JI (2009) Safety and efficacy assessment of mesenchymal stem cells from canine adipose tissue or umbilical cord blood in a canine osteochondral defect model. Tissue Eng. Regen Med 6(14):1381–1390Google Scholar
  233. 233.
    Sagliyan A, Karabulut E, Unsaldi E, Yaman Y (2009) Evaluation of the activity of intraarticular hyaluronic acid in the repair of experimentally induced osteochondral defects of the stifle joint in dogs. Vet Med-Czech 54(1):33–40CrossRefGoogle Scholar
  234. 234.
    Ng KW, Lima EG, Bian L, O'Conor CJ, Jayabalan PS, Stoker AM, Kuroki K, Cook CR, Ateshian GA, Cook JL, Hung CT (2010) Passaged adult chondrocytes can form engineered cartilage with functional mechanical properties: a canine model. Tissue Eng Part A 16(3):1041–1051PubMedCrossRefGoogle Scholar
  235. 235.
    Mokbel A, El-Tookhy O, Shamaa AA, Sabry D, Rashed L, Mostafa A (2011) Homing and efficacy of intra-articular injection of autologous mesenchymal stem cells in experimental chondral defects in dogs. Clin Exp Rheumatol 29(2):275–284PubMedPubMedCentralGoogle Scholar
  236. 236.
    Sun S, Ren Q, Wang D, Zhang L, Wu S, Sun XT (2011) Repairing cartilage defects using chondrocyte and osteoblast composites developed using a bioreactor. Chin Med J 124(5):758–763PubMedPubMedCentralGoogle Scholar
  237. 237.
    Igarashi T, Iwasaki N, Kawamura D, Kasahara Y, Tsukuda Y, Ohzawa N, Ito M, Izumisawa Y, Minami A (2012) Repair of articular cartilage defects with a novel injectable in situ forming material in a canine model. J Biomed Mater Res A 100(1):180–187PubMedCrossRefGoogle Scholar
  238. 238.
    Zhang Y, Wang J, Wang P, Fan X, Li X, Fu J, Li S, Fan H, Guo Z (2013) Low elastic modulus contributes to the osteointegration of titanium alloy plug. J Biomed Mater Res B Appl Biomater 101((4):584–590CrossRefGoogle Scholar
  239. 239.
    Kazemi D, Fakhrjou A, Dizaji VM, Alishahi MK (2014) Effect of autologous platelet rich fibrin on the healing of experimental articular cartilage defects of the knee in an animal model. Biomed Res Int 2014:486436PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Lv YM, Yu QS (2015) Repair of articular osteochondral defects of the knee joint using a composite lamellar scaffold. Bone Joint Res 4(4):56–64PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Cook JL, Stannard JP, Stoker AM, Bozynski CC, Kuroki K, Cook CR, Pfeiffer FM (2016) Importance of donor chondrocyte viability for osteochondral allografts. Am J Sports Med 44(5):1260–1268PubMedCrossRefGoogle Scholar
  242. 242.
    McCarty EC, Fader RR, Mitchell JJ, Glenn RE Jr, Potter HG, Spindler KP (2016) Fresh osteochondral allograft versus autograft: twelve-month results in isolated canine knee defects. Am J Sports Med 44(9):2354–2365PubMedCrossRefGoogle Scholar
  243. 243.
    Kazemi D, Shams Asenjan K, Dehdilani N, Parsa H (2017) Canine articular cartilage regeneration using mesenchymal stem cells seeded on platelet rich fibrin: macroscopic and histological assessments. Bone Joint Res 6(2):98–107PubMedPubMedCentralCrossRefGoogle Scholar
  244. 244.
    Calandruccio RA, Gilmer WS (1962) Proliferation regeneration, and repair of articular cartilage of immature animals. J Bone Joint Surg 44A:431–455CrossRefGoogle Scholar
  245. 245.
    Hale JE, Rudert MJ, Brown TD (1993) Indentation assessment of biphasic mechanical property deficits in size-dependent osteochondral defect repair. J Biomech 26(11):1319–1325PubMedCrossRefGoogle Scholar
  246. 246.
    Convery FR, Akeson WH, Keown GH (1972) The repair of large osteochondral defects. An experimental study in horses. Clin Orthop Relat Res 82:253–262PubMedCrossRefGoogle Scholar
  247. 247.
    Koch TG, Betts DH (2007) Stem cell therapy for joint problems using the horse as a clinically relevant animal model. Expert Opin Biol Ther 7(11):1621–1626PubMedCrossRefGoogle Scholar
  248. 248.
    Dzierzecka M, Wasowski A, Kobryn H (2005) Time-span of the ossification of the distal epiphysis in thoroughbred horses as a criterion of skeleton maturity. Med Weter 61(10):1190–1192Google Scholar
  249. 249.
    Pasolini MP, Meomartino L, Testa A, Fatone G, Potena A, Di Rosa G, Lamagna E (2007) Radiographic assessment of skeletal maturity in the racehorse: statistical validation and correlation with orthopaedic injuries in the standardbred. Ippologia 18(3):15–19Google Scholar
  250. 250.
    Pasolini MP, Santoro P, Lamagna F, Greco M, Labriola S, Orefice R, Meomartino L (2007) Use of two biochemical markers of bone metabolism, bone alkaline phosphatase (B-ALP) and cross linked c-telopeptide of type I collagen (ICTP), in the assessment of skeletal maturity in the standardbred horse. Ippologia 18(3):11–14Google Scholar
  251. 251.
    Luszczynski J, Pieszka M, Kosiniak-Kamysz K (2011) Effect of horse breed and sex in growth rate and radiographic closure time of distal radial metaphyseal growth plate. Livest Sci 141(2–3):252–258CrossRefGoogle Scholar
  252. 252.
    Shamis LD, Bramlage LR, Gabel AA, Weisbrode S (1989) Effect of subchondral drilling on repair of partial-thickness cartilage defects of third carpal bones in horses. Am J Vet Res 50(2):290–295PubMedPubMedCentralGoogle Scholar
  253. 253.
    Vachon AM, McIlwraith CW, Keeley FW (1991) Biochemical study of repair of induced osteochondral defects of the distal portion of the radial carpal bone in horses by use of periosteal autografts. Am J Vet Res 52(2):328–332PubMedPubMedCentralGoogle Scholar
  254. 254.
    Vachon AM, McIlwraith CW, Powers BE, McFadden PR, Amiel D (1992) Morphologic and biochemical study of sternal cartilage autografts for resurfacing induced osteochondral defects in horses. Am J Vet Res 53(6):1038–1047PubMedPubMedCentralGoogle Scholar
  255. 255.
    Hendrickson DA, Nixon AJ, Grande DA, Todhunter RJ, Minor RM, Erb H, Lust G (1994) Chondrocyte-fibrin matrix transplants for resurfacing extensive articular cartilage defects. J Orthop Res 12(4):485–497PubMedCrossRefGoogle Scholar
  256. 256.
    Howard RD, McIlwraith CW, Trotter GW, Powers BE, McFadden PR, Harwood FL, Amiel D (1994) Long-term fate and effects of exercise on sternal cartilage autografts used for repair of large osteochondral defects in horses. Am J Vet Res 55(8):1158–1167PubMedPubMedCentralGoogle Scholar
  257. 257.
    Sams AE, Nixon AJ (1995) Chondrocyte-laden collagen scaffolds for resurfacing extensive articular cartilage defects. Osteoarthr Cartil 3(1):47–59PubMedCrossRefGoogle Scholar
  258. 258.
    Frisbie DD, Trotter GW, Powers BE, Rodkey WG, Steadman JR, Howard RD, Park RD, McIlwraith CW (1999) Arthroscopic subchondral bone plate microfracture technique augments healing of large chondral defects in the radial carpal bone and medial femoral condyle of horses. Vet Surg 28(4):242–255PubMedCrossRefGoogle Scholar
  259. 259.
    Nixon AJ, Fortier LA, Williams J, Mohammed H (1999) Enhanced repair of extensive articular defects by insulin-like growth factor-I-laden fibrin composites. J Orthop Res 17(4):475–487PubMedCrossRefGoogle Scholar
  260. 260.
    Fortier LA, Mohammed HO, Lust G, Nixon AJ (2002) Insulin-like growth factor-I enhances cell-based repair of articular cartilage. J Bone Joint Surg Br 84(2):276–288PubMedCrossRefGoogle Scholar
  261. 261.
    Hidaka C, Goodrich LR, Chen CT, Warren RF, Crystal RG, Nixon AJ (2003) Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res 21(4):573–583PubMedCrossRefGoogle Scholar
  262. 262.
    Litzke LF, Wagner E, Baumgaertner W, Hetzel U, Josimovic-Alasevic O, Libera J (2004) Repair of extensive articular cartilage defects in horses by autologous chondrocyte transplantation. Ann Biomed Eng 32(1):57–69PubMedCrossRefGoogle Scholar
  263. 263.
    Strauss EJ, Goodrich LR, Chen CT, Hidaka C, Nixon AJ (2005) Biochemical and biomechanical properties of lesion and adjacent articular cartilage after chondral defect repair in an equine model. Am J Sports Med 33(11):1647–1653PubMedCrossRefGoogle Scholar
  264. 264.
    Barnewitz D, Endres M, Krüger I, Becker A, Zimmermann J, Wilke I, Ringe J, Sittinger M, Kaps C (2006) Treatment of articular cartilage defects in horses with polymer-based cartilage tissue engineering grafts. Biomaterials 27(14):2882–2889PubMedCrossRefGoogle Scholar
  265. 265.
    Gratz KR, Wong VW, Chen AC, Fortier LA, Nixon AJ, Sah RL (2006) Biomechanical assessment of tissue retrieved after in vivo cartilage defect repair: tensile modulus of repair tissue and integration with host cartilage. J Biomech 39(1):138–146PubMedCrossRefGoogle Scholar
  266. 266.
    Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ (2007) Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Joint Surg Br 89(5):672–685PubMedCrossRefGoogle Scholar
  267. 267.
    Morisset S, Frisbie DD, Robbins PD, Nixon AJ, McIlwraith CW (2007) IL-1ra/IGF-1 gene therapy modulates repair of microfractured chondral defects. Clin Orthop Rel Res 462:221–228CrossRefGoogle Scholar
  268. 268.
    Wilke MM, Nydam DV, Nixon AJ (2007) Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model. J Orthop Res 25(7):913–925PubMedCrossRefGoogle Scholar
  269. 269.
    Frisbie DD, Bowman SM, Colhoun HA, DiCarlo EF, Kawcak CE, McIlwraith CW (2008) Evaluation of autologous chondrocyte transplantation via a collagen membrane in equine articular defects: results at 12 and 18 months. Osteoarthr Cartil 16(6):667–679PubMedCrossRefGoogle Scholar
  270. 270.
    Frisbie DD, Lu Y, Kawcak CE, DiCarlo EF, Binette F, McIlwraith CW (2009) In vivo evaluation of autologous cartilage fragment-loaded scaffolds implanted into equine articular defects and compared with autologous chondrocyte implantation. Am J Sports Med 37(Suppl 1):S71–S80CrossRefGoogle Scholar
  271. 271.
    Fortier LA, Potter HG, Rickey EJ, Schnabel LV, Foo LF, Chong LR, Stokol T, Cheetham J, Nixon AJ (2010) Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model. J Bone Joint Surg Am 92(10):1927–1937PubMedCrossRefGoogle Scholar
  272. 272.
    Kon E, Mutini A, Arcangeli E, Delcogliano M, Filardo G, Nicoli Aldini N, Pressato D, Quarto R, Zaffagnini S, Marcacci M (2010) Novel nanostructured scaffold for osteochondral regeneration: pilot study in horses. J Tissue Eng Regen Med 4(4):300–308PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    McIlwraith CW, Frisbie DD, Rodkey WG, Kisiday JD, Werpy NM, Kawcak CE, Steadman JR (2011) Evaluation of intra-articular mesenchymal stem cells to augment healing of microfractured chondral defects. Arthroscopy 27(11):1552–1561PubMedCrossRefGoogle Scholar
  274. 274.
    Nixon AJ, Begum L, Mohammed HO, Huibregtse B, O'Callaghan MM, Matthews GL (2011) Autologous chondrocyte implantation drives early chondrogenesis and organized repair in extensive full- and partial-thickness cartilage defects in an equine model. J Orthop Res 29(7):1121–1130PubMedCrossRefGoogle Scholar
  275. 275.
    Seo JP, Tanabe T, Tsuzuki N, Haneda S, Yamada K, Furuoka H, Tabata Y, Sasaki N (2013) Effects of bilayer gelatin/β-tricalcium phosphate sponges loaded with mesenchymal stem cells, chondrocytes, bone morphogenetic protein-2, and platelet rich plasma on osteochondral defects of the talus in horses. Res Vet Sci 95(3):1210–1216PubMedCrossRefGoogle Scholar
  276. 276.
    Miller RE, Grodzinsky AJ, Barrett MF, Hung HH, Frank EH, Werpy NM, McIlwraith CW, Frisbie DD (2014) Effects of the combination of microfracture and self-assembling peptide filling on the repair of a clinically relevant trochlear defect in an equine model. J Bone Joint Surg Am 96(19):1601–1609PubMedPubMedCentralCrossRefGoogle Scholar
  277. 277.
    Tsuzuki N, Oshita N, Seo JP, Yamada K, Haneda S, Furuoka H, Tabata Y, Sasaki N (2014) Effect of platelet-rich plasma-incorporated gelatin hydrogel microspheres and subchondral drilling on equine cartilage defects. J Equine Vet Sci 34(6):820–824CrossRefGoogle Scholar
  278. 278.
    Frisbie DD, McCarthy HE, Archer CW, Barrett MF, McIlwraith CW (2015) Evaluation of articular cartilage progenitor cells for the repair of articular defects in an equine model. J Bone Joint Surg Am 97A(6):484–493CrossRefGoogle Scholar
  279. 279.
    Nixon AJ, Rickey E, Butler TJ, Scimeca MS, Moran N, Matthews GL (2015) A chondrocyte infiltrated collagen type I/III membrane (MACI® implant) improves cartilage healing in the equine patellofemoral joint model. Osteoarthr Cartil 23(4):648–660PubMedCrossRefGoogle Scholar
  280. 280.
    Ortved KF, Begum L, Mohammed HO, Nixon AJ (2015) Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. Mol Ther 23(2):363–373PubMedCrossRefGoogle Scholar
  281. 281.
    Seo JP, Kambayashi Y, Itho M, Haneda S, Yamada K, Furuoka H, Tabata Y, Sasaki N (2015) Effects of a synovial flap and gelatin/β-tricalcium phosphate sponges loaded with mesenchymal stem cells, bone morphogenetic protein-2, and platelet rich plasma on equine osteochondral defects. Res Vet Sci 101:140–143PubMedCrossRefGoogle Scholar
  282. 282.
    Fortier LA, Chapman HS, Pownder SL, Roller BL, Cross JA, Cook JL, Cole BJ (2016) Biocartilage improves cartilage repair compared with microfracture alone in an equine model of full-thickness cartilage loss. Am J Sports Med 44(9):2366–2374PubMedCrossRefGoogle Scholar
  283. 283.
    Rocha Júnior SS, Mendes HMF, Beier SL, Paz CFR, Azevedo DSD, Lacerda IGO, Correa MG, Faleiros RR (2016) Macroscopic and histological evaluations of equine joint cartilage repair treated with microperforation of the subchondral bone associated or not with intra-articular kartogenin. Pesq Vet Bras 36(4):272–278CrossRefGoogle Scholar
  284. 284.
    Yamada ALM, Alvarenga ML, Brandão JS, Watanabe MJ, Rodrigues CA, Hussni CA, Alves ALG (2016) PRP gel scaffold associated with mesenchymal stem cells. Use in experimental chondral defect of equine models. Pesq Vet Bras 36(6):461–467CrossRefGoogle Scholar
  285. 285.
    McIlwraith CW, Fortier LA, Frisbie DD, Nixon AJ (2011) Equine models of articular cartilage repair. Cartilage 2(4):317–326PubMedPubMedCentralCrossRefGoogle Scholar
  286. 286.
    Cokelaere S, Malda J, van Weeren R (2016) Cartilage defect repair in horses: current strategies and recent developments in regenerative medicine of the equine joint with emphasis on the surgical approach. Vet J 214:61–71PubMedPubMedCentralCrossRefGoogle Scholar
  287. 287.
    Johnson SA, Frisbie DD (2016) Cartilage therapy and repair in equine athletes. Oper Tech Orthop 26(3):155–165CrossRefGoogle Scholar
  288. 288.
    Ortved KF, Nixon AJ (2016) Cell-based cartilage repair strategies in the horse. Vet J 208:1–12PubMedCrossRefGoogle Scholar
  289. 289.
    Vidal MA, Robinson SO, Lopez MJ, Paulsen DB, Borkhsenious O, Johnson JR, Moore RM, Gimble JM (2008) Comparison of chondrogenic potential in equine mesenchymal stromal cells derived from adipose tissue and bone marrow. Vet Surg 37(8):713–724PubMedPubMedCentralCrossRefGoogle Scholar
  290. 290.
    Henson FMD, Getgood AMJ, Caborn DM, McIlwraith CW, Rushton N (2012) Effect of a solution of hyaluronic acid-chondroitin sulfate-H-acetyl glucosamine on the repair response of cartilage to single impact load damage. Am J Vet Res 73(2):306–312PubMedCrossRefGoogle Scholar
  291. 291.
    Shoemaker RS, Bertone AL, Martin GS, McIlwraith CW, Roberts ED, Pechman R, Kearney MT (1992) Effects of intra-articular administration of methylprednisolone acetate on normal articular cartilage and on healing of experimentally induced osteochondral defects in horses. Am J Vet Res 53(8):1446–1453PubMedPubMedCentralGoogle Scholar
  292. 292.
    Todhunter RJ, Minor RR, Wootton JA, Krook L, Burton-Wurster N, Lust G (1993) Effects of exercise and polysulfated glycosaminoglycan on repair of articular cartilage defects in the equine carpus. J Orthop Res 11(6):782–795PubMedCrossRefGoogle Scholar
  293. 293.
    Bertone AL, Bramlage LR, McIlwraith CW, Malemud CJ (2005) Comparison of proteoglycan and collagen in articular cartilage of horses with naturally developing osteochondrosis and healing osteochondral fragments of experimentally induced fractures. Am J Vet Res 66(11):1881–1890PubMedCrossRefGoogle Scholar
  294. 294.
    Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the Protection of Animals Used for Scientific Purposes. Official Journal of the European Union.
  295. 295.
    Rehbinder C, Baneux P, Forbes D, van Herck H, Nicklas W, Rugaya Z, Winkler G (1998) FELASA recommendations for the health monitoring of breeding colonies and experimental units of cats, dogs and pigs. Report of the Federation of European Laboratory Animal Science Associations (FELASA) working group on animal health. Lab Anim 32(1):1–17PubMedCrossRefGoogle Scholar
  296. 296.
    Rehbinder C, Alenius S, Bures J, de las Heras ML, Greko C, Kroon PS, Gutzwiller A (2000) FELASA recommendations for the health monitoring of experimental units of calves, sheep and goats report of the federation of European Laboratory Animal Science Associations (FELASA) Working Group on Animal Health. Lab Anim 34(4):329–350PubMedCrossRefGoogle Scholar
  297. 297.
    Mähler Convenor M, Berard M, Feinstein R, Gallagher A, Illgen-Wilcke B, Pritchett-Corning K, Raspa M (2014) FELASA recommendations for the health monitoring of mouse, rat, hamster, Guinea pig and rabbit colonies in breeding and experimental units. Lab Anim 48(3):178–192PubMedCrossRefGoogle Scholar
  298. 298.
    Balls M (1994) Replacement of animal procedures: alternatives in research, education and testing. Lab Anim 28(3):193–211PubMedCrossRefGoogle Scholar
  299. 299.
    Auer JA, Goodship A, Arnoczky S, Pearce S, Price J, Claes L, von Rechenberg B, Hofmann-Amtenbrinck M, Schneider E, Müller-Terpitz R, Thiele F, Rippe KP, Grainger DW (2007) Refining animal models in fracture research: seeking consensus in optimising both animal welfare and scientific validity for appropriate biomedical use. BMC Musculoskelet Disord 8:72PubMedPubMedCentralCrossRefGoogle Scholar
  300. 300.
    van Gaalen SM, Kruyt MC, Geuze RE, de Bruijn JD, Alblas J, Dhert WJ (2010) Use of fluorochrome labels in in vivo bone tissue engineering research. Tissue Eng Part B Rev 16(2):209–217PubMedCrossRefGoogle Scholar
  301. 301.
    Franco NH, Olsson IA (2014) Scientists and the 3Rs: attitudes to animal use in biomedical research and the effect of mandatory training in laboratory animal science. Lab Anim 48(1):50–60PubMedCrossRefGoogle Scholar
  302. 302.
    Hurtig M1, Chubinskaya S, Dickey J, Rueger D (2009) BMP-7 protects against progression of cartilage degeneration after impact injury. J Orthop Res 27(5):602–11PubMedCrossRefGoogle Scholar
  303. 303.
    Ishimaru J, Goss AN (1992) A model for osteoarthritis of the temporomandibular joint. J Oral Maxillofac Surg. 50(11):1191–5PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Isabel R. Dias
    • 1
    • 2
    • 3
    Email author
  • Carlos A. Viegas
    • 1
    • 2
    • 3
  • Pedro P. Carvalho
    • 5
    • 4
  1. 1.Department of Veterinary Sciences, Agricultural and Veterinary Sciences SchoolUniversity of Trás-os-Montes e Alto Douro (UTAD)Vila RealPortugal
  2. 2.3B’s Research Group – Biomaterials, Biodegradables and BiomimeticsBarco - GuimarãesPortugal
  3. 3.Department of Veterinary Medicine, ICVS/3B’s – PT Government Associate LaboratoryBraga/GuimarãesPortugal
  4. 4.Department of Veterinary MedicineUniversity School Vasco da GamaCoimbraPortugal
  5. 5.CIVG - Vasco da Gama Research CenterUniversity School Vasco da GamaCoimbraPortugal

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