Advertisement

Biological Treatment in Cartilage Injuries

  • Elizaveta Kon
  • Berardo Di Matteo
  • Francesco Iacono
  • Filippo Vandenbulcke
  • Nicolò Danilo Vitale
  • Maurilio Marcacci
Chapter

Abstract

In occidental societies, a great number of people practice sport regularly at all ages. In this context, cartilage injury incidences have become higher and higher. They are frequently diagnosed during knee arthroscopy even in asymptomatic patients. However, patients commonly present with pain, recurrent effusion, and loss of function. Concomitantly with the increasing incidence, the expectations of patients about function restore have risen as well. Since articular cartilage is characterized by a poor intrinsic regenerative capacity, treatment of these lesions is particularly challenging.

Orthopedic surgeons should face this pathology not only because it is symptomatic but also for the risk of more extensive joint damage and further degeneration of the whole articular compartment.

Several therapeutic strategies have been developed, both conservative and surgical. In this chapter we will focus on infiltrative therapies, such as platelet-rich plasma (PRP), mesenchymal stem cells (MSCs), and bioengineered osteochondral scaffolds.

Platelet-rich plasma (PRP) is a concentrate obtained from autologous blood containing high concentrations of human platelets and platelet-derived growth factors. They are capable of modulating the early healing response and influencing inflammation, angiogenesis, and cell migration. PRP is a safe procedure, and clinical outcome is encouraging, even if it is difficult to establish PRP efficacy because authors have used different PRP formulations, with a large inter-product variability.

Another powerful tool for cartilage repair emerging in recent years is mesenchymal stem cells (MSC). Their regenerative effects are due to their immunomodulatory and anti-inflammatory action but above all to their structural contribution to tissue repair. They have a capacity for self-renewal, stemness maintenance, and the marked ability to differentiate into a variety of connective tissues. MSCs can be isolated from human sources other than the bone marrow, such as adipose tissue. Studies available suggest a potential for these cell-based treatments to be developed and to represent a promising new approach with preliminary interesting findings. Nevertheless, many aspects remain to be clarified and optimized.

The awareness of the involvement of the subchondral bone in many of these lesions resulted in the need to develop cell-free treatment strategies focused on the entire osteochondral unit. Therefore, surgical techniques move on from autologous chondrocyte implantation (ACI) and autograft or allograft osteochondral implantation to new bioengineered scaffolds.

Ideally, a scaffold should have the following characteristics:
  • Three-dimensional and highly porous with an interconnected pore network for cell growth and flow transport of nutrients and metabolic waste.

  • Biocompatible and bioresorbable with a controllable degradation and resorption rate to match cell/tissue growth in vitro and/or in vivo.

  • Suitable surface chemistry for cell attachment, proliferation, and differentiation and mechanical properties to match those of the tissues at the site of implantation.

Among them MaioRegen® and, more recently, Agili-C® have shown some of the most promising results.

Keywords

Biological treatment Cartilage injuries Osteochondral scaffold Infiltrative therapies MSC PRP 

References

  1. 1.
    Marcacci M, Filardo G, Kon E. Treatment of cartilage lesions: what works and why? Injury. 2013;44(Suppl 1):S11–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Widuchowski W, Widuchowski J, Trzaska T. Articular cartilage defects: study of 25,124 knee arthroscopies. Knee. 2007;14(3):177–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Arøen A, Løken S, Heir S, et al. Articular cartilage lesions in 993 consecutive knee arthroscopies. Am J Sports Med. 2004;32(1):211–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Hjelle K, Solheim E, Strand T, et al. Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy. 2002;18(7):730–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Noyes FR, Bassett RW, Grood ES, Butler DL. Arthroscopy in acute traumatic hemarthrosis of the knee: incidence of anterior cruciate tears and other injuries. J Bone Joint Surg Am. 1980;62:687–95.PubMedCrossRefGoogle Scholar
  6. 6.
    Buckwalter JA, Mankin HJ. Articular cartilage: tissue design and chondrocyte–matrix interactions. Instr Course Lect. 1998;47:477–86.PubMedGoogle Scholar
  7. 7.
    Buckwalter JA. Articular cartilage: injuries and potential for healing. J Orthop Sports Phys Ther. 1998;28(4):192–202.PubMedCrossRefGoogle Scholar
  8. 8.
    Gratz KR, Wong BL, Bae WC, Sah RL. The effects of focal articular defects on intra-tissue strains in the surrounding and opposing cartilage. Biorheology. 2008;45(3–4):193–207.PubMedGoogle Scholar
  9. 9.
    Schinhan M, Gruber M, Vavken P, et al. Critical-size defect induces unicompartmental osteoarthritis in a stable ovine knee. J Orthop Res. 2012;30(2):214–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Andia I, Abate M. Platelet-rich plasma: underlying biology and clinical correlates. Regen Med. 2013;8:645–58.PubMedCrossRefGoogle Scholar
  11. 11.
    Andia I, Sanchez M, Maffulli N. Tendon healing and platelet-rich plasma therapies. Expert Opin Biol Ther. 2010;10:1415–26.PubMedCrossRefGoogle Scholar
  12. 12.
    Bosch G, Moleman M, Barneveld A, van Weeren PR, van Schie HT. The effect of platelet-rich plasma on the neovascularization of surgically created equine superficial digital flexor tendon lesions. Scand J Med Sci Sports. 2011;21:554–61.PubMedCrossRefGoogle Scholar
  13. 13.
    Lyras D, Kazakos K, Verettas D, Polychronidis A, Simopoulos C, Botaitis S, Agrogiannis G, Kokka A, Patsouris E. Immunohistochemical study of angiogenesis after local administration of platelet-rich plasma in a patellar tendon defect. Int Orthop. 2010;34:143–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Lyras DN, Kazakos K, Verettas D, Polychronidis A, Tryfonidis M, Botaitis S, Agrogiannis G, Simopoulos C, Kokka A, Patsouris E. The influence of platelet-rich plasma on angiogenesis during the early phase of tendon healing. Foot Ankle Int. 2009;30:1101–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Alvarez P, Green PG, Levine JD. Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat. Pain. 2014;155:1161–7.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Andia I, Rubio-Azpeitia E, Maffulli N. Platelet-rich plasma modulates the secretion of inflammatory/angiogenic proteins by inflamed tenocytes. Clin Orthop Relat Res. 2015;473(5):1624–34.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost. 1999;82:165–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Xie X, Wang Y, Zhao C, Guo S, Liu S, Jia W, Tuan RS, Zhang C. Comparative evaluation of MSCs from bone marrow and adipose tissue seeded in PRP-derived scaffold for cartilage regeneration. Biomaterials. 2012;33:7008–18.PubMedCrossRefGoogle Scholar
  19. 19.
    Akeda K, An HS, Okuma M, Attawia M, Miyamoto K, Thonar EJ, Lenz ME, Sah RL, Masuda K. Platelet-rich plasma stimulates porcine articular chondrocyte proliferation and matrix biosynthesis. Osteoarthr Cartil. 2006;14:1272–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Chien CS, Ho HO, Liang YC, Ko PH, Sheu MT, Chen CH. Incorporation of exudates of human platelet-rich fibrin gel in biodegradable fibrin scaffolds for tissue engineering of cartilage. J Biomed Mater Res B Appl Biomater. 2012;100:948–55.PubMedCrossRefGoogle Scholar
  21. 21.
    Spreafico A, Chellini F, Frediani B, Bernardini G, Niccolini S, Serchi T, Collodel G, Paffetti A, Fossombroni V, Galeazzi M, Marcolongo R, Santucci A. Biochemical investigation of the effects of human platelet releasates on human articular chondrocytes. J Cell Biochem. 2009;108:1153–65.PubMedCrossRefGoogle Scholar
  22. 22.
    Kaps C, Loch A, Haisch A, Smolian H, Burmester GR, Haupl T, Sittinger M. Human platelet supernatant promotes proliferation but not differentiation of articular chondrocytes. Med Biol Eng Comput. 2002;40:485–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Gaissmaier C, Fritz J, Krackhardt T, Flesch I, Aicher WK, Ashammakhi N. Effect of human platelet supernatant on proliferation and matrix synthesis of human articular chondrocytes in monolayer and three-dimensional alginate cultures. Biomaterials. 2005;26:1953–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Drengk A, Zapf A, Sturmer EK, Sturmer KM, Frosch KH. Influence of platelet-rich plasma on chondrogenic differentiation and proliferation of chondrocytes and mesenchymal stem cells. Cells Tissues Organs. 2009;189:317–26.PubMedCrossRefGoogle Scholar
  25. 25.
    Kon E, Filardo G, Di Matteo B, Marcacci M. PRP for the treatment of cartilage pathology. Open Orthop J. 2013;7:120–8.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Marx R. Platelet rich plasma (PRP): what is PRP and what is not PRP? Implant Dent. 2001;10:225–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Dohan Ehrenfest DM, Rasmuson L, Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (LPRF). Trends Biotechnol. 2009;27(3):158–67.PubMedCrossRefGoogle Scholar
  28. 28.
    Tschon M, Fini M, Giardino R, et al. Lights and shadows concerning platelet products for musculoskeletal regeneration. Front Biosci. 2011;3:96–107.Google Scholar
  29. 29.
    Torricelli P, Fini M, Filardo G, et al. Regenerative medicine for the treatment of musculoskeletal overuse injuries in competition horses. Int Orthop. 2011;35(10):1569–76.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Boswell SG, Cole BJ, Sundman EA, Karas V, Fortier LA. Platelet-rich plasma: a milieu of bioactive factors. Arthroscopy. 2012;28(3):429–39.PubMedCrossRefGoogle Scholar
  31. 31.
    Wasterlain A, Braun HJ, Dragoo JL. Contents and formulations of platelet-rich plasma. Oper Tech Orthop. 2012;22(1):33–42.CrossRefGoogle Scholar
  32. 32.
    Arnoczky S, Delos D, Rodeo S. What is platelet-rich plasma? Oper Tech Sports Med. 2011;19(3):142–8.CrossRefGoogle Scholar
  33. 33.
    Giannini S, Buda R, Vannini F, Cavallo M, Grigolo B. One-step bone marrow-derived cell transplantation in talar osteochondral lesions. Clin Orthop Relat Res. 2009;467(12):3307–20.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Giannini S, Buda R, Cavallo M, et al. Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury. 2010;41(11):1196–203.PubMedCrossRefGoogle Scholar
  35. 35.
    Buda R, Vannini F, Cavallo M, Grigolo B, Cenacchi A, Giannini S. Osteochondral lesions of the knee: a new one-step repair technique with bone-marrow-derived cells. J Bone Joint Surg Am. 2010;92(Suppl 2):2–11.PubMedCrossRefGoogle Scholar
  36. 36.
    Dhollander AA, De Neve F, Almqvist KF, et al. Autologous matrix-induced chondrogenesis combined with platelet-rich plasma gel technical description and a five pilot patients report. Knee Surg Sports Traumatol Arthrosc. 2011;19(4):536–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Siclari A, Mascaro G, Gentili C, Cancedda R, Boux E. A cell-free scaffold-based cartilage repair provides improved function hyaline-like repair at one year. Clin Orthop Relat Res. 2012;470(3):910–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Mei-Dan O, Carmont MR, Laver L, Mann G, Maffulli N, Nyska M. Platelet-rich plasma or hyaluronate in the management of osteochondral lesions of the talus. Am J Sports Med. 2012;40(3):534–41.CrossRefGoogle Scholar
  39. 39.
    Filardo G, Kon E, Pereira Ruiz MT, et al. Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double-spinning approach. Knee Surg Sports Traumatol Arthrosc. 2012;20(10):2082–91.PubMedCrossRefGoogle Scholar
  40. 40.
    Spaková T, Rosocha J, Lacko M, Harvanová D, Gharaibeh A. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil. 2012;91(5):411–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Sánchez M, Fiz N, Azofra J, et al. A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy. 2012;28(8):1070–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1717–29.PubMedCrossRefGoogle Scholar
  43. 43.
    Caplan AI. Mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng. 2005;11(7–8):1198–211.PubMedCrossRefGoogle Scholar
  44. 44.
    Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol. 2011;6:457–78.PubMedCrossRefGoogle Scholar
  45. 45.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Dj P, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;6(3):381–90.Google Scholar
  47. 47.
    Caplan AI, Koutroupas S. The control of muscle and cartilage development in the chick limb: the role of differential vascularization. J Embryol Exp Morphol. 1973;29(3):571–83.PubMedGoogle Scholar
  48. 48.
    Spencer ND, Gimble JM, Lopez MJ. Mesenchymal stromal cells: past, present, and future. Vet Surg. 2011;40(2):129–39.PubMedCrossRefGoogle Scholar
  49. 49.
    Wakitani S, Goto T, Pineda SJ, Young RG, Mansour JM, Caplan AI, Goldberg VM. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage. J Bone Joint Surg Am. 1994;76(4):579–92.PubMedCrossRefGoogle Scholar
  50. 50.
    Quarto R, Mastrogiacomo M, Cancedda R, Kutepov SM, Mukhachev V, Lavroukov A, Kon E, Marcacci M. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med. 2011;344(5):385–6.CrossRefGoogle Scholar
  51. 51.
    Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res. 2011;30:9.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011;14(2):211–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Chang CH, Kuo TF, Lin FH, Wang JH, Hsu YM, Huang HT, Loo ST, Fang HW, Liu HC, Wang WC. Tissue engineering based cartilage repair with mesenchymal stem cells in a porcine model. J Orthop Res. 2011;29(12):1874–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Saw KY, Anz A, Merican S, Tay YG, Ragavanaidu K, Jee CSY, McGuire DA. Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: a report of 5 cases with histology. Arthroscopy. 2011;27(4):493–506.PubMedCrossRefGoogle Scholar
  55. 55.
    Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, Fries JW, Tiemann K, Bohlen H, Hescheler J, Welz A, Bloch W, Jacobsen SE, Fleischmann BK. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007;110(4):1362–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Wakitani S, Okabe T, Horibe S, Mitsuoka T, Saito M, Koyama T, Nawata M, Tensho K, Kato H, Uematsu K, Kuroda R, Kurosaka M, Yoshiya S, Hattori K, Ohgushi H. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. 2011;5(2):146–50.PubMedCrossRefGoogle Scholar
  57. 57.
    Keeney M, Pandit A. The osteochondral junction and its repair via bi-phasic tissue engineering scaffolds. Tissue Eng Part B Rev. 2009;15(1):55–73.PubMedCrossRefGoogle Scholar
  58. 58.
    Kocher MS, Tucker R, Ganley TJ, Flynn JM. Management of osteochondritis dissecans of the knee: current concepts review. Am J Sports Med. 2006;34(7):1181–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Pape D, Filardo G, Kon E, Van Dijk CN, Madry H. Disease-specific clinical problems associated with the subchondral bone. Knee Surg Sports Traumatol Arthrosc. 2010;18(4):448–62.PubMedCrossRefGoogle Scholar
  60. 60.
    Gomoll AH, Madry H. The subchondral bone in articular cartilage repair : current problems in the surgical management. Knee Surg Sports Traumatol Arthrosc. 2010;18(4):434–47.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Gratz KR, Wong BL, Bae WC, Sah RL. The effects of focal articular defects on cartilage contact mechanics. J Orthop Res. 2009;27(5):584–92.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Wong BL, Kim SHC, Antonacci JM, Mcilwraith CW, Sah RL. Cartilage shear dynamics during tibio-femoral articulation: effect of acute joint injury and tribosupplementation on synovial fluid lubrication. Osteoarthr Cartil. 2010;18(3):464–71.PubMedCrossRefGoogle Scholar
  63. 63.
    Von Der Mark K, Gauss V, Von Der Marl H, Muller P. Relationship between cell shape and type of collagen synthesised as chondrocytes lose their cartilage phenotype in culture. Nature. 1977;267(5611):531–2.PubMedCrossRefGoogle Scholar
  64. 64.
    Freed L, Marquis J, Nohria A. Neocartilage formation in vitro and in vivo using cells cultured on synthetic biodegradable polymers. J Biomed Mater Res. 1993;27(1):11–23.PubMedCrossRefGoogle Scholar
  65. 65.
    Gricolo B, Lisignoli G, Piacentini A, Fiorini M, Gobbi P, Mazzotti G, Duca M, Pavesio A, Facchini A. Evidence for redifferentiation of human chondrocytes grown on a hyaluronan-based biomaterial (HYAFF11): melocular, immunohistochemical and ultrastructural analysis. Biomaterials. 2002;23(4):1187–95.CrossRefGoogle Scholar
  66. 66.
    Caterson EJ, Nesti LJ, Li WJ, Danielson KG, Albert TJ, Vaccaro AR, Tuan RS. Three-dimensional cartilage formation by bone marrow-derived cells seed in polyactide/alginate amalgam. J Biomed Mater Res. 2001;57(3):394–403.PubMedCrossRefGoogle Scholar
  67. 67.
    Marcacci M, Kon E, Zaffagnini S, Filardo G, Delcogliano M, Neri MP, Iacono F, Hollander AP. Arthroscopic second generation autologous chondrocyte implantation. Knee Surg Sports Traumatol Arthrosc. 2007;15(5):610–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Filardo G, Kon E, Di Martino A, Iacono F, Marcacci M. Arthroscopic second-generation autologous chondrocyte implantation: a prospective 7-year follow-up study. Am J Sports Med. 2011;39(10):2153–60.PubMedCrossRefGoogle Scholar
  69. 69.
    Podskubka A, Povysil C, Kubes R, Sprindrich J, Sedlacek R. Treatment of deep cartilage defects of the knee with autologous chondrocyte transplantation on a hyaluronic acid ester scaffolds (Hyalograft C). Acta Chir Orthop Traumatol Cech. 2006;73(4):251–63.PubMedGoogle Scholar
  70. 70.
    Hollander AP, Dickinson SC, Sims TJ, Brun P, Cortivo R, Kon E, Marcacci M, Zanasi S, Borrione A, De Luca C, Pavesio A, Soranzo C, Abatangelo G. Maturation of tissue engineered cartilage implanted in injured and osteoarthritic human knees. Tissue Eng. 2006;12(7):1787–98.PubMedCrossRefGoogle Scholar
  71. 71.
    Kon E, Di Martino A, Filardo G, Tetta C, Busacca M, Iacono F, Delcogliano M, Albisinni U, Marcacci M. Second-generation autologous chondrocyte transplantation: MRI findings and clinical correlations at a minimum 5-year follow-up. Eur J Radiol. 2011;79(3):382–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Lu Y, Dhanaraj S, Wang Z, et al. Minced cartilage without cell culture serves as an effective cell source for cartilage repair. J Orthop Res. 2006;24(6):1261–70.PubMedCrossRefGoogle Scholar
  73. 73.
    Kon E, Robinson D, Verdonk P, Drobnic M, Patrascu J, Dulic O. A novel aragonite-based scaffold for osteochondral regeneration: early experience on human implants and technical developments. Injury. 2016;47(Suppl 6):S27–32.PubMedCrossRefGoogle Scholar
  74. 74.
    Wang X, Grogan SP, Rieser F, Winkelmann V, Maquet V, La Berge M. Tissue engineering of biphasic cartilage constructs using various biodegradable scaffolds: an in vitro study. Biomaterials. 2004;25(17):3681–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Woodfield TB, Malda J, De Wijn J, Peters F, Riesle J, Van Blitterswijk CA. Design of porous scaffolds for cartilage tissue engineering using a three-dimensional fiber-deposition technique. Biomaterials. 2004;25(18):4149–61.PubMedCrossRefGoogle Scholar
  76. 76.
    Kon E, Delcogliano M, Filardo G, et al. A novel nano-composite multi-layered biomaterial for treatment of osteochondral lesions: technique note and an early stability pilot clinical trial. Injury. 2010;41(7):693–701.PubMedCrossRefGoogle Scholar
  77. 77.
    Kon E, Delcogliano M, Filardo G, et al. Orderly osteochondral regeneration in a sheep model using a novel nano-composite multilayered biomaterial. J Orthop Res. 2010;28(1):116–24.PubMedGoogle Scholar
  78. 78.
    Kon E, Delcogliano M, Filardo G, Busacca M, Di Martino A, Marcacci M. Novel nano-composite multilayered biomaterial for osteochondral regeneration a pilot clinical trial. Am J Sports Med. 2011;39(6):1180–90.PubMedCrossRefGoogle Scholar
  79. 79.
    Demers C, Hamdy C, Corsi K, Chellat F, Tabrizian M, Yahia L. Natural coral exoskeleton as a bone graft substitute: a review. Biomed Mater Eng. 2002;12(1):15–35.PubMedGoogle Scholar
  80. 80.
    Kon E, Filardo G, Shani J, Altschuler N, Levy A, Zaslav K, Eisman JE, Robinson D. Osteochondral regeneration with a novel aragonite-hyaluronate biphasic scaffold: up to 12-month follow-up study in a goat model. J Orthop Surg Res. 2015;10:81.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Kon E, Robinson D, Verdonk P, Drobnic M, Patrascu JM, Dulic O, Gavrilovic G, Filardo G. A novel aragonite-based scaffold for osteochondral regeneration: early experience on human implants and technical developments. Injury. 2016;47(Suppl 6):S27–32.PubMedCrossRefGoogle Scholar

Copyright information

© ISAKOS 2019

Authors and Affiliations

  • Elizaveta Kon
    • 1
    • 2
  • Berardo Di Matteo
    • 1
    • 2
  • Francesco Iacono
    • 1
    • 2
  • Filippo Vandenbulcke
    • 1
    • 2
  • Nicolò Danilo Vitale
    • 1
    • 2
  • Maurilio Marcacci
    • 1
    • 2
  1. 1.Department of Biomedical SciencesHumanitas UniversityMilanItaly
  2. 2.Humanitas Clinical and Research CenterMilanItaly

Personalised recommendations