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Spatiotemporal Focal Delivery of Dual Regenerating Factors for Osteochondral Defect Repair

Part of the Advances in Delivery Science and Technology book series (ADST)

Abstract

The design of focal spatiotemporal delivery systems for multiple regeneration-inducing factors represents a crucial step in the development of effective therapies for osteochondral injuries, osteoarthritis, and other pathologies of cartilage and bone. While endogenous bone regeneration is an established process, cartilage has very limited intrinsic regeneration ability. Thus, cartilage defects progressively affect subchondral bone and alter osteochondral interface homeostasis, leading to pain and disability. Spatiotemporal delivery of osteo- and chondroinductive factors by biomaterial-based systems represents an attractive therapeutic strategy for the currently available clinical therapies that still cannot provide a superior functional replacement for the damaged or lost tissue. This chapter offers an up-to-date review of the acellular biomaterial-based strategies, aimed at simultaneous regeneration of bone and cartilage by the controlled focal delivery of the appropriate factors. It describes the various factors and delivery systems (microspheres, hydrogels, and macroporous scaffolds) developed and tested in animals and presents a novel biomaterial approach, developed by our group, for the affinity binding of TGF-β1 and BMP-4 in two separate layers, which promoted the regeneration of osteochondral interface in rabbits with osteochondral defects.

Keywords

  • Articular Cartilage
  • Subchondral Bone
  • Cartilage Repair
  • Chondrogenic Differentiation
  • Autologous Chondrocyte Implantation

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Klein TJ, Malda J, Sah RL, Hutmacher DW (2009) Tissue engineering of articular cartilage with biomimetic zones. Tissue Eng Part B Rev 15:143–157

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  2. Swieszkowski W, Tuan BH, Kurzydlowski KJ, Hutmacher DW (2007) Repair and regeneration of osteochondral defects in the articular joints. Biomol Eng 24:489–495

    CAS  PubMed  CrossRef  Google Scholar 

  3. Chung C, Burdick JA (2008) Engineering cartilage tissue. Adv Drug Deliv Rev 60:243–262

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  4. Yang PJ, Temenoff JS (2009) Engineering orthopedic tissue interfaces. Tissue Eng Part B Rev 15:127–141

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  5. Onyekwelu I, Goldring MB, Hidaka C (2009) Chondrogenesis, joint formation, and articular cartilage regeneration. J Cell Biochem 107:383–392

    CAS  PubMed  CrossRef  Google Scholar 

  6. Clouet J, Vinatier C, Merceron C, Pot-vaucel M, Maugars Y, Weiss P et al (2009) From osteoarthritis treatments to future regenerative therapies for cartilage. Drug Discov Today 14:913–925

    CAS  PubMed  CrossRef  Google Scholar 

  7. Keeney M, Pandit A (2009) The osteochondral junction and its repair via bi-phasic tissue engineering scaffolds. Tissue Eng Part B Rev 15:55–73

    CAS  PubMed  CrossRef  Google Scholar 

  8. O’Shea TM, Miao X (2008) Bilayered scaffolds for osteochondral tissue engineering. Tissue Eng Part B Rev 14:447–464

    PubMed  CrossRef  Google Scholar 

  9. Mano JF, Reis RL (2007) Osteochondral defects: present situation and tissue engineering approaches. J Tissue Eng Regen Med 1:261–273

    CAS  PubMed  CrossRef  Google Scholar 

  10. Gomoll AH, Madry H, Knutsen G, van Dijk N, Seil R, Brittberg M et al (2010) The subchondral bone in articular cartilage repair: current problems in the surgical management. Knee Surg Sports Traumatol Arthrosc 18:434–447

    PubMed Central  PubMed  CrossRef  Google Scholar 

  11. Madry H, Grun UW, Knutsen G (2011) Cartilage repair and joint preservation: medical and surgical treatment options. Dtsch Arztebl Int 108:669–677

    PubMed Central  PubMed  Google Scholar 

  12. Rodrigues MT, Gomes ME, Reis RL (2011) Current strategies for osteochondral regeneration: from stem cells to pre-clinical approaches. Curr Opin Biotechnol 22:726–733

    CAS  PubMed  CrossRef  Google Scholar 

  13. Ahmed TA, Hincke MT (2010) Strategies for articular cartilage lesion repair and functional restoration. Tissue Eng Part B Rev 16:305–329

    CAS  PubMed  CrossRef  Google Scholar 

  14. Versier G, Dubrana F (2011) Treatment of knee cartilage defect in 2010. Orthop Traumatol Surg Res 97:S140–S153

    CAS  PubMed  CrossRef  Google Scholar 

  15. Perera JR, Gikas PD, Bentley G (2012) The present state of treatments for articular cartilage defects in the knee. Ann R Coll Surg Engl 94:381–387

    CAS  PubMed  CrossRef  Google Scholar 

  16. Panseri S, Russo A, Cunha C, Bondi A, Di Martino A, Patella S et al (2012) Osteochondral tissue engineering approaches for articular cartilage and subchondral bone regeneration. Knee Surg Sports Traumatol Arthrosc 20:1182–1191

    PubMed  CrossRef  Google Scholar 

  17. Kock L, van Donkelaar CC, Ito K (2012) Tissue engineering of functional articular cartilage: the current status. Cell Tissue Res 347:613–627

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  18. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR (2009) Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med 37:2053–2063

    PubMed  CrossRef  Google Scholar 

  19. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889–895

    CAS  PubMed  CrossRef  Google Scholar 

  20. Peterson L, Brittberg M, Kiviranta I, Akerlund EL, Lindahl A (2002) Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med 30:2–12

    PubMed  Google Scholar 

  21. Peterson L, Minas T, Brittberg M, Lindahl A (2003) Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation: results at two to ten years. J Bone Joint Surg Am 85-A(Suppl 2):17–24

    PubMed  Google Scholar 

  22. Gooding CR, Bartlett W, Bentley G, Skinner JA, Carrington R, Flanagan A (2006) A prospective, randomised study comparing two techniques of autologous chondrocyte implantation for osteochondral defects in the knee: periosteum covered versus type I/III collagen covered. Knee 13:203–210

    CAS  PubMed  CrossRef  Google Scholar 

  23. Kalson NS, Gikas PD, Briggs TW (2010) Current strategies for knee cartilage repair. Int J Clin Pract 64:1444–1452

    CAS  PubMed  CrossRef  Google Scholar 

  24. Kon E, Filardo G, Di Martino A, Marcacci M (2012) ACI and MACI. J knee surg 25:17–22

    PubMed  CrossRef  Google Scholar 

  25. Rodriguez-Merchan EC (2012) The treatment of cartilage defects in the knee joint: microfracture, mosaicplasty, and autologous chondrocyte implantation. Am J Orthop (Belle Mead NJ) 41:236–239

    Google Scholar 

  26. Seong JM, Kim BC, Park JH, Kwon IK, Mantalaris A, Hwang YS (2010) Stem cells in bone tissue engineering. Biomed Mater 5:062001

    PubMed  CrossRef  Google Scholar 

  27. Marolt D, Knezevic M, Novakovic GV (2010) Bone tissue engineering with human stem cells. Stem Cell Res ther 1:10

    PubMed  CrossRef  Google Scholar 

  28. Oldershaw RA (2012) Cell sources for the regeneration of articular cartilage: the past, the horizon and the future. Int J Exp Pathol 93:389–400

    CAS  PubMed Central  PubMed  Google Scholar 

  29. van Osch GJ, Brittberg M, Dennis JE, Bastiaansen-Jenniskens YM, Erben RG, Konttinen YT et al (2009) Cartilage repair: past and future–lessons for regenerative medicine. J Cell Mol Med 13:792–810

    PubMed  CrossRef  Google Scholar 

  30. Grayson WL, Chao PH, Marolt D, Kaplan DL, Vunjak-Novakovic G (2008) Engineering custom-designed osteochondral tissue grafts. Trends Biotechnol 26:181–189

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  31. Mahmoudifar N, Doran PM (2012) Chondrogenesis and cartilage tissue engineering: the longer road to technology development. Trends Biotechnol 30:166–176

    CAS  PubMed  CrossRef  Google Scholar 

  32. Freyria AM, Mallein-Gerin F (2012) Chondrocytes or adult stem cells for cartilage repair: the indisputable role of growth factors. Injury 43:259–265

    PubMed  CrossRef  Google Scholar 

  33. Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH (2010) Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med 38:1110–1116

    PubMed  CrossRef  Google Scholar 

  34. Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y, Horibe S (2004) Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant 13:595–600

    PubMed  CrossRef  Google Scholar 

  35. Kuroda R, Ishida K, Matsumoto T, Akisue T, Fujioka H, Mizuno K et al (2007) Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthritis Cartilage 15:226–231

    CAS  PubMed  CrossRef  Google Scholar 

  36. Vinatier C, Mrugala D, Jorgensen C, Guicheux J, Noel D (2009) Cartilage engineering: a crucial combination of cells, biomaterials and biofactors. Trends Biotechnol 27:307–314

    CAS  PubMed  CrossRef  Google Scholar 

  37. Danisovic L, Varga I, Polak S (2012) Growth factors and chondrogenic differentiation of mesenchymal stem cells. Tissue Cell 44:69–73

    CAS  PubMed  CrossRef  Google Scholar 

  38. Fortier LA, Barker JU, Strauss EJ, McCarrel TM, Cole BJ (2011) The role of growth factors in cartilage repair. Clin Orthop Relat Res 469:2706–2715

    PubMed  CrossRef  Google Scholar 

  39. Bessa PC, Casal M, Reis RL (2008) Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts). J Tissue Eng Regen Med 2:1–13

    CAS  PubMed  CrossRef  Google Scholar 

  40. Tamai N, Myoui A, Hirao M, Kaito T, Ochi T, Tanaka J et al (2005) A new biotechnology for articular cartilage repair: subchondral implantation of a composite of interconnected porous hydroxyapatite, synthetic polymer (PLA-PEG), and bone morphogenetic protein-2 (rhBMP-2). Osteoarthritis Cartilage 13:405–417

    PubMed  CrossRef  Google Scholar 

  41. Huang X, Yang D, Yan W, Shi Z, Feng J, Gao Y et al (2007) Osteochondral repair using the combination of fibroblast growth factor and amorphous calcium phosphate/poly(l-lactic acid) hybrid materials. Biomaterials 28:3091–3100

    CAS  PubMed  CrossRef  Google Scholar 

  42. Lee SH, Shin H (2007) Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering. Adv Drug Deliv Rev 59:339–359

    CAS  PubMed  CrossRef  Google Scholar 

  43. Vo TN, Kasper FK, Mikos AG (2012) Strategies for controlled delivery of growth factors and cells for bone regeneration. Adv Drug Deliv Rev 64:1292–1309

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  44. Mehta M, Schmidt-Bleek K, Duda GN, Mooney DJ (2012) Biomaterial delivery of morphogens to mimic the natural healing cascade in bone. Adv Drug Deliv Rev 64:1257–1276

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  45. Porter JR, Ruckh TT, Popat KC (2009) Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnol Prog 25:1539–1560

    CAS  PubMed  Google Scholar 

  46. De Biase P, Capanna R (2005) Clinical applications of BMPs. Injury 36(Suppl 3):S43–S46

    PubMed  CrossRef  Google Scholar 

  47. Khan Y, Yaszemski MJ, Mikos AG, Laurencin CT (2008) Tissue engineering of bone: material and matrix considerations. J Bone Joint Surg Am 90(Suppl 1):36–42

    PubMed  CrossRef  Google Scholar 

  48. Spiller KL, Maher SA, Lowman AM (2011) Hydrogels for the repair of articular cartilage defects. Tissue Eng Part B Rev 17:281–299

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  49. Balakrishnan B, Banerjee R (2011) Biopolymer-based hydrogels for cartilage tissue engineering. Chem Rev 111:4453–4474

    CAS  PubMed  CrossRef  Google Scholar 

  50. Akhyari P, Kamiya H, Haverich A, Karck M, Lichtenberg A (2008) Myocardial tissue engineering: the extracellular matrix. Eur J Cardiothorac Surg 34:229–241

    PubMed  CrossRef  Google Scholar 

  51. Al-Shamkhani A, Duncan R (1995) Radioiodination of alginate via covalently-bound tyrosinamide allows monitoring of its fate in vivo. J Bioact Compat Polym 10:4–13

    CAS  Google Scholar 

  52. Prestwich GD, Kuo JW (2008) Chemically-modified HA for therapy and regenerative medicine. Curr Pharm Biotechnol 9:242–245

    CAS  PubMed  CrossRef  Google Scholar 

  53. Prestwich GD (2011) Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine. J Control Release 155:193–199

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  54. Sellers RS, Peluso D, Morris EA (1997) The effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the healing of full-thickness defects of articular cartilage. J Bone Joint Surg Am 79:1452–1463

    CAS  PubMed  Google Scholar 

  55. Tokuhara Y, Wakitani S, Imai Y, Kawaguchi A, Fukunaga K, Kim M et al (2010) Repair of experimentally induced large osteochondral defects in rabbit knee with various concentrations of Escherichia coli-derived recombinant human bone morphogenetic protein-2. Int Orthop 34:761–767

    PubMed Central  PubMed  CrossRef  Google Scholar 

  56. Maehara H, Sotome S, Yoshii T, Torigoe I, Kawasaki Y, Sugata Y et al (2010) Repair of large osteochondral defects in rabbits using porous hydroxyapatite/collagen (HAp/Col) and fibroblast growth factor-2 (FGF-2). J Orthop Res 28:677–686

    CAS  PubMed  Google Scholar 

  57. Reyes R, Delgado A, Sanchez E, Fernandez A, Hernandez A, Evora C (2012) Repair of an osteochondral defect by sustained delivery of BMP-2 or TGFbeta1 from a bilayered alginate-PLGA scaffold. J Tissue Eng Regen Med. doi:10.1002/term.1549

  58. Mohan N, Dormer NH, Caldwell KL, Key VH, Berkland CJ, Detamore MS (2011) Continuous gradients of material composition and growth factors for effective regeneration of the osteochondral interface. Tissue Eng Part A 17:2845–2855

    CAS  PubMed  CrossRef  Google Scholar 

  59. Holland TA, Bodde EW, Cuijpers VM, Baggett LS, Tabata Y, Mikos AG et al (2007) Degradable hydrogel scaffolds for in vivo delivery of single and dual growth factors in cartilage repair. Osteoarthritis Cartilage 15:187–197

    CAS  PubMed  CrossRef  Google Scholar 

  60. Sukegawa A, Iwasaki N, Kasahara Y, Onodera T, Igarashi T, Minami A (2012) Repair of rabbit osteochondral defects by an acellular technique with an ultrapurified alginate gel containing stromal cell-derived factor-1. Tissue Eng Part A 18:934–945

    CAS  PubMed  CrossRef  Google Scholar 

  61. Lopiz-Morales Y, Abarrategi A, Ramos V, Moreno-Vicente C, Lopez-Duran L, Lopez-Lacomba JL et al (2010) In vivo comparison of the effects of rhBMP-2 and rhBMP-4 in osteochondral tissue regeneration. Eur Cell Mater 20:367–378

    CAS  PubMed  Google Scholar 

  62. Liu XW, Hu J, Man C, Zhang B, Ma YQ, Zhu SS (2011) Insulin-like growth factor-1 suspended in hyaluronan improves cartilage and subchondral cancellous bone repair in osteoarthritis of temporomandibular joint. Int J Oral Maxillofac Surg 40:184–190

    PubMed  CrossRef  Google Scholar 

  63. Miyakoshi N, Kobayashi M, Nozaka K, Okada K, Shimada Y, Itoi E (2005) Effects of intraarticular administration of basic fibroblast growth factor with hyaluronic acid on osteochondral defects of the knee in rabbits. Arch Orthop Trauma Surg 125:683–692

    PubMed  CrossRef  Google Scholar 

  64. Miller RE, Grodzinsky AJ, Vanderploeg EJ, Lee C, Ferris DJ, Barrett MF et al (2010) Effect of self-assembling peptide, chondrogenic factors, and bone marrow-derived stromal cells on osteochondral repair. Osteoarthritis Cartilage 18:1608–1619

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  65. Re’em T, Witte F, Willbold E, Ruvinov E, Cohen S (2012) Simultaneous regeneration of articular cartilage and subchondral bone induced by spatially presented TGF-beta and BMP-4 in a bilayer affinity binding system. Acta Biomater 8:3283–3293

    PubMed  CrossRef  Google Scholar 

  66. Freeman I, Kedem A, Cohen S (2008) The effect of sulfation of alginate hydrogels on the specific binding and controlled release of heparin-binding proteins. Biomaterials 29:3260–3268

    CAS  PubMed  CrossRef  Google Scholar 

  67. Freeman I, Cohen S (2009) The influence of the sequential delivery of angiogenic factors from affinity-binding alginate scaffolds on vascularization. Biomaterials 30:2122–2131

    CAS  PubMed  CrossRef  Google Scholar 

  68. Re’em T, Kaminer-Israeli Y, Ruvinov E, Cohen S (2012) Chondrogenesis of hMSC in affinity-bound TGF-beta scaffolds. Biomaterials 33:751–761

    PubMed  CrossRef  Google Scholar 

  69. Goldring MB, Tsuchimochi K, Ijiri K (2006) The control of chondrogenesis. J Cell Biochem 97:33–44

    CAS  PubMed  CrossRef  Google Scholar 

  70. Petersen W, Tsokos M, Pufe T (2002) Expression of VEGF121 and VEGF165 in hypertrophic chondrocytes of the human growth plate and epiphyseal cartilage. J Anat 201:153–157

    CAS  PubMed  CrossRef  Google Scholar 

  71. Tuli R, Tuli S, Nandi S, Huang X, Manner PA, Hozack WJ et al (2003) Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. J Biol Chem 278:41227–41236

    CAS  PubMed  CrossRef  Google Scholar 

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Correspondence to Smadar Cohen .

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Ruvinov, E., Cohen, S. (2014). Spatiotemporal Focal Delivery of Dual Regenerating Factors for Osteochondral Defect Repair. In: Domb, A., Khan, W. (eds) Focal Controlled Drug Delivery. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-9434-8_22

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