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BioDrugs

, Volume 17, Issue 5, pp 301–314 | Cite as

Biotherapeutics in Orthopaedic Medicine

Accelerating the Healing Process?
Drug Development

Abstract

Musculoskeletal injuries have a significant human and financial impact on society. In particular, fractures that lead to delayed union or even nonunion represent a serious clinical challenge for which few treatment options are available. The multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life. Biotechnological advances have made possible a host of potential treatments for enhancing and accelerating the repair of bone. By stimulating the body’s own healing mechanisms, clinical outcomes may be improved while also containing procedural costs. Biotherapeutics may take the form of proteins, genes or cells that can be used to treat the injury. Protein biotherapeutics have received the greatest attention. Using recombinant DNA techniques, growth factors that play important roles in bone development and repair are being produced. By delivering exogenous growth factors to the site of injury in an appropriate manner, bone formation can be stimulated. Although individual proteins have been the primary focus of investigation, combinations of biomolecules can have additive, and perhaps synergistic, effects. Alternatively, genes coding for osteotropic growth factors can be delivered to the site of injury. Expression of the gene effectively results in localised delivery of the growth factor. Delivery of cells having osteogenic potential can also result in bone formation. Furthermore, it may be possible to obtain additional benefits by combining biotherapeutic approaches, such as by introducing cells genetically modified to overexpress therapeutic proteins of interest. Although biotherapeutics have great potential for stimulating bone repair, only a limited number of treatments have been approved by governmental regulatory agencies for clinical use. Bone morphogenetic activity was initially described in 1965, but not until 2001 and 2002 did two protein biotherapeutics, utilising bone morphogenetic proteins 2 and 7, receive approval for commercial distribution. Gene-and cell-based therapies are in a comparatively early stage of development.

Keywords

Bone Formation Bone Morphogenetic Protein Osteoblastic Cell Bone Repair Demineralised Bone Matrix 
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.

Notes

Acknowledgments

The author gratefully acknowledges the support of the Whitaker Foundation, Kentucky Science and Engineering Foundation (KSEF-148-502-03-67), and the National Institutes of Health (AR048700). The author has no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Praemer A, Furner S, Rice DP. Musculoskeletal conditions in the United States. Rosemont (IL): American Academy of Orthopaedic Surgeons, 1999Google Scholar
  2. 2.
    Einhorn TA. Enhancement of fracture-healing. J Bone Joint Surg Am 1995 Jun; 77(6): 940–56PubMedGoogle Scholar
  3. 3.
    Lind M. Growth factors: possible new clinical tools. A review. Acta Orthop Scand 1996 Aug; 67(4): 407–17PubMedCrossRefGoogle Scholar
  4. 4.
    Mohan S, Baylink DJ. Bone growth factors. Clin Orthop 1991 Feb; 263: 30–48PubMedGoogle Scholar
  5. 5.
    Lind M. Growth factor stimulation of bone healing: effects on osteoblasts, osteomies, and implants fixation. Acta Orthop Scand Suppl 1998 Oct; 283: 2–37PubMedGoogle Scholar
  6. 6.
    Iwata H, Sakano S, Itoh T, et al. Demineralized bone matrix and native bone morphogenetic protein in orthopaedic surgery. Clin Orthop 2002 Feb; 395: 99–109PubMedCrossRefGoogle Scholar
  7. 7.
    Li H, Pujic Z, Xiao Y, et al. Identification of bone morphogenetic proteins 2 and 4 in commercial demineralized freeze-dried bone allograft preparations: pilot study. Clin Implant Dent Relat Res 2000; 2(2): 110–7PubMedCrossRefGoogle Scholar
  8. 8.
    Takikawa S, Bauer TW, Kambic H, et al. Comparative evaluation of the osteoinductivity of two formulations of human demineralized bone matrix. J Biomed Mater Res 2003 Apr 1; 65A(1): 37–42CrossRefGoogle Scholar
  9. 9.
    Lucas PA, Syftestad GT, Goldberg VM, et al. Ectopic induction of cartilage and bone by water-soluble proteins from bovine bone using a collagenous delivery vehicle. J Biomed Mater Res 1989 Apr; 23(A1 Suppl.): 23–39PubMedCrossRefGoogle Scholar
  10. 10.
    Nielsen HM, Andreassen TT, Ledet T, et al. Local injection of TGF-beta increases the strength of tibial fractures in the rat. Acta Orthop Scand 1994 Feb; 65(1): 37–41PubMedCrossRefGoogle Scholar
  11. 11.
    Kato T, Kawaguchi H, Hanada K, et al. Single local injection of recombinant fibroblast growth factor-2 stimulates healing of segmental bone defects in rabbits. J Orthop Res 1998 Nov; 16(6): 654–9PubMedCrossRefGoogle Scholar
  12. 12.
    Giannobile WV, Finkelman RD, Lynch SE. Comparison of canine and non-human primate animal models for periodontal regenerative therapy: results following a single administration of PDGF/IGF-I. J Periodontol 1994 Dec; 65(12): 1158–68PubMedCrossRefGoogle Scholar
  13. 13.
    Govender S, Csimma C, Genant HK, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 2002 Dec; 84-A(12): 2123–34PubMedGoogle Scholar
  14. 14.
    Ma Q, Mao T, Liu B, et al. Vascular osteomuscular autograft prefabrication using coral, type I collagen and recombinant human bone morphogenetic protein-2. Br J Oral Maxillofac Surg 2000 Oct; 38(5): 561–4PubMedCrossRefGoogle Scholar
  15. 15.
    Peter SJ, Lu L, Kim DJ, et al. Effects of transforming growth factor betal released from biodegradable polymer microparticles on marrow stromal osteoblasts cultured on poly(propylene fumarate) substrates. J Biomed Mater Res 2000 Jun; 50(3): 452–62PubMedCrossRefGoogle Scholar
  16. 16.
    Urist MR. Bone: formation by autoinduction. Science 1965 Nov 12; 150(698): 893–9PubMedCrossRefGoogle Scholar
  17. 17.
    Urist MR, Strates BS. Bone morphogenetic protein. J Dent Res 1971 Nov–Dec; 50(6): 1392–406PubMedCrossRefGoogle Scholar
  18. 18.
    Wozney JM, Rosen V. Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop 1998 Jan; 346: 26–37PubMedGoogle Scholar
  19. 19.
    Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev 2002 Dec; 23(6): 787–823PubMedCrossRefGoogle Scholar
  20. 20.
    Bostrom MP, Lane JM, Berberian WS, et al. Immunolocalization and expression of bone morphogenetic proteins 2 and 4 in fracture healing. J Orthop Res 1995 May; 13(3): 357–67PubMedCrossRefGoogle Scholar
  21. 21.
    Yu Y, Yang JL, Chapman-Sheath PJ, et al. TGF-beta, BMPs, and their signal transducing mediators, Smads, in rat fracture healing. J Biomed Mater Res 2002 Jun; 60(3): 392–7PubMedCrossRefGoogle Scholar
  22. 22.
    Wang EA, Rosen V, Cordes P, et al. Purification and characterization of other distinct bone-inducing factors. Proc Natl Acad Sci U S A 1988 Dec; 85(24): 9484–8PubMedCrossRefGoogle Scholar
  23. 23.
    Wang EA, Rosen V, D’Alessandro JS, et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci U S A 1990 Mar; 87(6): 2220–4PubMedCrossRefGoogle Scholar
  24. 24.
    Khan SN, Sandhu HS, Lane JM, et al. Bone morphogenetic proteins: relevance in spine surgery. Orthop Clin North Am 2002 Apr; 33(2): 447–63PubMedCrossRefGoogle Scholar
  25. 25.
    Bouxsein ML, Turek TJ, Blake CA, et al. Recombinant human bone morphogenetic protein-2 accelerates healing in a rabbit ulnar osteotomy model. J Bone Joint Surg Am 2001 Aug; 83-A(8): 1219–30PubMedGoogle Scholar
  26. 26.
    Sciadini MF, Johnson KD. Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res 2000 Mar; 18(2): 289–302PubMedCrossRefGoogle Scholar
  27. 27.
    Gerhart TN, Kirker-Head CA, Kriz MJ, et al. Healing segmental femoral defects in sheep using recombinant human bone morphogenetic protein. Clin Orthop 1993 Aug; 293: 317–26PubMedGoogle Scholar
  28. 28.
    Kusumoto K, Bessho K, Fujimura K, et al. Osteoinduction by recombinant human bone morphogenetic protein-2 in muscles of non-human primates. J Int Med Res 2002 May–Jun; 30(3): 251–9PubMedGoogle Scholar
  29. 29.
    Sampath TK, Maliakal JC, Hauschka PV, et al. Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem 1992 Oct; 267(28): 20352–62PubMedGoogle Scholar
  30. 30.
    Cook SD, Baffes GC, Wolfe MW, et al. The effect of recombinant human osteogenic protein-1 on healing of large segmental bone defects. J Bone Joint Surg Am 1994 Jun; 76(6): 827–38PubMedGoogle Scholar
  31. 31.
    Cook SD, Baffes GC, Wolfe MW, et al. Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin Orthop 1994 Apr; 301: 302–12PubMedGoogle Scholar
  32. 32.
    Cook SD, Wolfe MW, Salkeld SL, et al. Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates. J Bone Joint Surg Am 1995 May; 77(5): 734–50PubMedGoogle Scholar
  33. 33.
    Friedlaender GE, Perry CR, Cole JD, et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001; 83-ASuppl. 1 (Pt 2): S151–8PubMedGoogle Scholar
  34. 34.
    Jeppsson C, Bostrom M, Aspenberg P. Intraosseous BMP implants in rabbits: inhibitory effect on bone formation. Acta Orthop Scand 1999 Feb; 70(1): 77–83PubMedCrossRefGoogle Scholar
  35. 35.
    Kujala S, Raatikainen T, Ryhanen J, et al. Composite implant of native bovine bone morphogenetic protein (BMP) and biocoral in the treatment of scaphoid nonunions: a preliminary study. Scand J Surg 2002; 91(2): 186–90PubMedGoogle Scholar
  36. 36.
    Wurzler KK, DeWeese TL, Sebald W, et al. Radiation-induced impairment of bone healing can be overcome by recombinant human bone morphogenetic protein-2. J Craniofac Surg 1998 Mar; 9(2): 131–7PubMedCrossRefGoogle Scholar
  37. 37.
    Luppen CA, Blake CA, Ammirati KM, et al. Recombinant human bone morphogenetic protein-2 enhances osteotomy healing in glucocorticoid-treated rabbits. J Bone Miner Res 2002 Feb; 17(2): 301–10PubMedCrossRefGoogle Scholar
  38. 38.
    Chen X, Kidder LS, Lew WD. Osteogenic protein-1 induced bone formation in an infected segmental defect in the rat femur. J Orthop Res 2002 Jan; 20(1): 142–50PubMedCrossRefGoogle Scholar
  39. 39.
    Solheim E. Growth factors in bone. Int Orthop 1998; 22(6): 410–6PubMedCrossRefGoogle Scholar
  40. 40.
    Bonewald LF, Mundy GR. Role of transforming growth factor-beta in bone remodeling. Clin Orthop 1990 Jan; 250: 261–76PubMedGoogle Scholar
  41. 41.
    Joyce ME, Jingushi S, Bolander ME. Transforming growth factor-beta in the regulation of fracture repair. Orthop Clin North Am 1990 Jan; 21(1): 199–209PubMedGoogle Scholar
  42. 42.
    Bourque WT, Gross M, Hall BK. Expression of four growth factors during fracture repair. Int J Dev Biol 1993 Dec; 37(4): 573–9PubMedGoogle Scholar
  43. 43.
    Kasperk CH, Wergedal JE, Mohan S, et al. Interactions of growth factors present in bone matrix with bone cells: effects on DNA synthesis and alkaline phosphatase. Growth Factors 1990; 3(2): 147–58PubMedCrossRefGoogle Scholar
  44. 44.
    Noda M, Rodan GA. Type-beta transforming growth factor inhibits proliferation and expression of alkaline phosphatase in murine osteoblast-like cells. Biochem Biophys Res Commun 1986 Oct 15; 140(1): 56–65PubMedCrossRefGoogle Scholar
  45. 45.
    Iba K, Sawada N, Nuka S, et al. Phase-dependent effects of transforming growth factor beta 1 on osteoblastic markers of human osteoblastic cell line sV-HFO during mineralization. Bone 1996 Oct; 19(4): 363–9PubMedCrossRefGoogle Scholar
  46. 46.
    Zellin G, Beck S, Hardwick R, et al. Opposite effects of recombinant human transforming growth factor-betal on bone regeneration in vivo: effects of exclusion of periosteal cells by microporous membrane. Bone 1998 Jun; 22(6): 613–20PubMedCrossRefGoogle Scholar
  47. 47.
    Beck LS, Deguzman L, Lee WP, et al. TGF-beta 1 induces bone closure of skull defects. J Bone Miner Res 1991 Nov; 6(11): 1257–65PubMedCrossRefGoogle Scholar
  48. 48.
    Sumner DR, Turner TM, Purchio AF, et al. Enhancement of bone ingrowth by transforming growth factor-beta. J Bone Joint Surg Am 1995 Aug; 77(8): 1135–47PubMedGoogle Scholar
  49. 49.
    Lind M, Overgaard S, Nguyen T, et al. Transforming growth factor-beta stimulates bone ongrowth: hydroxyapatite-coated implants studied in dogs. Acta Orthop Scand 1996 Dec; 67(6): 611–6PubMedCrossRefGoogle Scholar
  50. 50.
    Sumner DR, Turner TM, Urban RM, et al. Locally delivered rhTGF-β2 enhances bone ingrowth and bone regeneration at local and remote sites of skeletal injury. J Orthop Res 2001 Jan; 19(1): 85–94PubMedCrossRefGoogle Scholar
  51. 51.
    Ripamonti U, Duneas N, Van Den Heever B, et al. Recombinant transforming growth factor-betal induces endochondral bone in the baboon and synergizes with recombinant osteogenic protein-1 (bone morphogenetic protein-7) to initiate rapid bone formation. J Bone Miner Res 1997 Oct; 12(10): 1584–95PubMedCrossRefGoogle Scholar
  52. 52.
    Lind M, Schumacker B, Soballe K, et al. Transforming growth factor-beta enhances fracture healing in rabbit tibiae. Acta Orthop Scand 1993 Oct; 64(5): 553–6PubMedCrossRefGoogle Scholar
  53. 53.
    Critchlow MA, Bland YS, Ashhurst DE. The effect of exogenous transforming growth factor-beta 2 on healing fractures in the rabbit. Bone 1995 May; 16(5): 521–7PubMedCrossRefGoogle Scholar
  54. 54.
    Heckman JD, Ehler W, Brooks BP, et al. Bone morphogenetic protein but not transforming growth factor-beta enhances bone formation in canine diaphyseal nonunions implanted with a biodegradable composite polymer. J Bone Joint Surg Am 1999 Dec; 81(12): 1717–29PubMedGoogle Scholar
  55. 55.
    Finkelman RD, Mohan S, Jennings JC, et al. Quantitation of growth factors IGF-I, SGF/IGF-II, and TGF-beta in human dentin. J Bone Miner Res 1990 Jul; 5(7): 717–23PubMedCrossRefGoogle Scholar
  56. 56.
    Mohan S, Baylink DJ. IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol 2002 Oct; 175(1): 19–31PubMedCrossRefGoogle Scholar
  57. 57.
    Andrew JG, Hoyland J, Freemont AJ, et al. Insulin-like growth factor gene expression in human fracture callus. Calcif Tissue Int 1993 Aug; 53(2): 97–102PubMedCrossRefGoogle Scholar
  58. 58.
    Scheven BA, Hamilton NJ, Fakkeldij TM, et al. Effects of recombinant human insulin-like growth factor I and II (IGF-I/-II) and growth hormone (GH) on the growth of normal adult human osteoblast-like cells and human osteogenic sarcoma cells. Growth Regul 1991 Dec; 1(4): 160–7PubMedGoogle Scholar
  59. 59.
    Pfeilschifter J, Oechsner M, Naumann A, et al. Stimulation of bone matrix apposition in vitro by local growth factors: a comparison between insulin-like growth factor I, platelet-derived growth factor, and transforming growth factor beta. Endocrinology 1990 Jul; 127(1): 69–75PubMedCrossRefGoogle Scholar
  60. 60.
    McCarthy TL, Centrella M, Canalis E. Regulatory effects of insulin-like growth factors I and II on bone collagen synthesis in rat calvarial cultures. Endocrinology 1989 Jan; 124(1): 301–9PubMedCrossRefGoogle Scholar
  61. 61.
    Spencer EM, Liu CC, Si EC, et al. In vivo actions of insulin-like growth factor-I (IGF-I) on bone formation and resorption in rats. Bone 1991; 12(1): 21–6PubMedCrossRefGoogle Scholar
  62. 62.
    Aspenberg P, Albrektsson T, Thorngren KG. Local application of growth-factor IGF-1 to healing bone: experiments with a titanium chamber in rabbits. Acta Orthop Scand 1989 Oct; 60(5): 607–10PubMedCrossRefGoogle Scholar
  63. 63.
    Thaller SR, Lee TJ, Armstrong M, et al. Effect of insulin-like growth factor type 1 on critical-size defects in diabetic rats. J Craniofac Surg 1995 May; 6(3): 218–23PubMedCrossRefGoogle Scholar
  64. 64.
    Thaller SR, Salzhauer MA, Rubinstein AJ, et al. Effect of insulin-like growth factor type I on critical size calvarial bone defects in irradiated rats. J Craniofac Surg 1998 Mar; 9(2): 138–41PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang L, Leeman E, Carnes DC, et al. Human osteoblasts synthesize and respond to platelet-derived growth factor. Am J Physiol 1991 Aug; 261: C348–54PubMedGoogle Scholar
  66. 66.
    Centrella M, McCarthy TL, Kusmik WF, et al. Relative binding and biochemical effects of heterodimeric and homodimeric isoforms of platelet-derived growth factor in osteoblast-enriched cultures from fetal rat bone. J Cell Physiol 1991 Jun; 147(3): 420–6PubMedCrossRefGoogle Scholar
  67. 67.
    Andrew JG, Hoyland JA, Freemont AJ, et al. Platelet-derived growth factor expression in normally healing human fractures. Bone 1995 Apr; 16(4): 455–60PubMedGoogle Scholar
  68. 68.
    Hughes FJ, Aubin JE, Heersche JN. Differential chemotactic responses of different populations of fetal rat calvaria cells to platelet-derived growth factor and transforming growth factor beta. Bone Miner 1992 Oct; 19(1): 63–74PubMedCrossRefGoogle Scholar
  69. 69.
    Canalis E, Varghese S, McCarthy TL, et al. Role of platelet derived growth factor in bone cell function. Growth Regul 1992 Dec; 2(4): 151–5PubMedGoogle Scholar
  70. 70.
    Canalis E, McCarthy TL, Centrella M. Effects of platelet-derived growth factor on bone formation in vitro. J Cell Physiol 1989 Sep; 140(3): 530–7PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang Z, Chen J, Jin D. Platelet-derived growth factor (PDGF)-BB stimulates osteoclastic bone resorption directly: the role of receptor beta. Biochem Biophys Res Commun 1998 Oct 9; 251(1): 190–4PubMedCrossRefGoogle Scholar
  72. 72.
    Nash TJ, Howlett CR, Martin C, et al. Effect of platelet-derived growth factor on tibial osteotomies in rabbits. Bone 1994 Mar–Apr; 15(2): 203–8PubMedCrossRefGoogle Scholar
  73. 73.
    Vikjaer D, Blom S, Hjorting-Hansen E, et al. Effect of platelet-derived growth factor-BB on bone formation in calvarial defects: an experimental study in rabbits. Eur J Oral Sci 1997 Feb; 105(1): 59–66PubMedCrossRefGoogle Scholar
  74. 74.
    Arm DM, Tencer AF, Bain SD, et al. Effect of controlled release of platelet-derived growth factor from a porous hydroxyapatite implant on bone ingrowth. Biomaterials 1996 Apr; 17(7): 703–9PubMedCrossRefGoogle Scholar
  75. 75.
    Ornitz DM. FGFs, heparan sulfate and FGFRs: complex interactions essential for development. Bioessays 2000 Feb; 22(2): 108–12PubMedCrossRefGoogle Scholar
  76. 76.
    McCarthy TL, Centrella M, Canalis E. Effects of fibroblast growth factors on deoxyribonucleic acid and collagen synthesis in rat parietal bone cells. Endocrinology 1989 Oct; 125(4): 2118–26PubMedCrossRefGoogle Scholar
  77. 77.
    Nakamura T, Hara Y, Tagawa M, et al. Recombinant human basic fibroblast growth factor accelerates fracture healing by enhancing callus remodeling in experimental dog tibial fracture. J Bone Miner Res 1998 Jun; 13(6): 942–9PubMedCrossRefGoogle Scholar
  78. 78.
    Radomsky ML, Aufdemorte TB, Swain LD, et al. Novel formulation of fibroblast growth factor-2 in a hyaluronan gel accelerates fracture healing in nonhuman primates. J Orthop Res 1999 Jul; 17(4): 607–14PubMedCrossRefGoogle Scholar
  79. 79.
    Kawaguchi H, Nakamura K, Tabata Y, et al. Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2. J Clin Endocrinol Metab 2001 Feb; 86(2): 875–80PubMedCrossRefGoogle Scholar
  80. 80.
    Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 1999 Jun; 14(6): 960–8PubMedCrossRefGoogle Scholar
  81. 81.
    Holzer G, Majeska RJ, Lundy MW, et al. Parathyroid hormone enhances fracture healing: a preliminary report. Clin Orthop 1999 Sep; 366: 258–63PubMedCrossRefGoogle Scholar
  82. 82.
    Andreassen TT, Fledelius C, Ejersted C, et al. Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 2001 Jun; 72(3): 304–7PubMedCrossRefGoogle Scholar
  83. 83.
    Jahng JS, Kim HW. Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 2000 Oct; 23(10): 1089–94PubMedGoogle Scholar
  84. 84.
    Crandall C. Parathyroid hormone for treatment of osteoporosis. Arch Intern Med 2002 Nov 11; 162(20): 2297–309PubMedCrossRefGoogle Scholar
  85. 85.
    Howell TH, Fiorellini JP, Paquette DW, et al. A phase I/II clinical trial to evaluate a combination of recombinant human platelet-derived growth factor-BB and recombinant human insulin-like growth factor-I in patients with periodontal disease. J Periodontol 1997 Dec; 68(12): 1186–93PubMedCrossRefGoogle Scholar
  86. 86.
    Takita H, Tsuruga E, Ono I, et al. Enhancement by bFGF of osteogenesis induced by rhBMP-2 in rats. Eur J Oral Sci 1997 Dec; 105(6): 588–92PubMedCrossRefGoogle Scholar
  87. 87.
    Schmidmaier G, Wildemann B, Bail H, et al. Local application of growth factors (insulin-like growth factor-1 and transforming growth factor-betal) from a biodegradable poly(D,L-lactide) coating of osteosynthetic implants accelerates fracture healing in rats. Bone 2001 Apr; 28(4): 341–50PubMedCrossRefGoogle Scholar
  88. 88.
    Raschke M, Wildemann B, Inden P, et al. Insulin-like growth factor-1 and transforming growth factor-betal accelerates osteotomy healing using polylactide-coated implants as a delivery system: a biomechanical and histological study in minipigs. Bone 2002 Jan; 30(1): 144–51PubMedCrossRefGoogle Scholar
  89. 89.
    Blumenfeld I, Srouji S, Lanir Y, et al. Enhancement of bone defect healing in old rats by TGF-beta and IGF-1. Exp Gerontol 2002 Apr; 37(4): 553–65PubMedCrossRefGoogle Scholar
  90. 90.
    Marden LJ, Fan RS, Pierce GF, et al. Platelet-derived growth factor inhibits bone regeneration induced by osteogenin, a bone morphogenetic protein, in rat craniotomy defects. J Clin Invest 1993 Dec; 92(6): 2897–905PubMedCrossRefGoogle Scholar
  91. 91.
    Agha-Mohammadi S, Lotze MT. Regulatable systems: applications in gene therapy and replicating viruses. J Clin Invest 2000 May; 105(9): 1177–83PubMedCrossRefGoogle Scholar
  92. 92.
    Musgrave DS, Bosch P, Ghivizzani S, et al. Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone 1999 Jun; 24(6): 541–7PubMedCrossRefGoogle Scholar
  93. 93.
    Okubo Y, Bessho K, Fujimura K, et al. The time course study of osteoinduction by bone morphogenetic protein-2 via adenoviral vector. Life Sci 2001 Dec 7; 70(3): 325–36PubMedCrossRefGoogle Scholar
  94. 94.
    Franceschi RT, Wang D, Krebsbach PH, et al. Gene therapy for bone formation: in vitro and in vivo osteogenic activity of an adenovirus expressing BMP7. J Cell Biochem 2000 Jun 6; 78(3): 476–86PubMedCrossRefGoogle Scholar
  95. 95.
    Niyibizi C, Baltzer A, Lattermann C, et al. Potential role for gene therapy in the enhancement of fracture healing. Clin Orthop 1998 Oct; 355 Suppl.: S148–53PubMedGoogle Scholar
  96. 96.
    van Griensven M, Lobenhoffer P, Barke A, et al. Adenoviral gene transfer in a rat fracture model. Lab Anim 2002 Oct; 36(4): 455–61PubMedCrossRefGoogle Scholar
  97. 97.
    Baltzer AW, Lattermann C, Whalen JD, et al. Potential role of direct adenoviral gene transfer in enhancing fracture repair. Clin Orthop 2000 Oct; 379 Suppl.: S120–5PubMedCrossRefGoogle Scholar
  98. 98.
    Fang J, Zhu YY, Smiley E, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A 1996 Jun; 93(12): 5753–8PubMedCrossRefGoogle Scholar
  99. 99.
    Bonadio J, Smiley E, Patil P, et al. Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med 1999 Jul; 5(7): 753–9PubMedCrossRefGoogle Scholar
  100. 100.
    Fibbe WE. Mesenchymal stem cells: a potential source for skeletal repair. Ann Rheum Dis 2002 Nov; 61 Suppl. 2: ii29–31Google Scholar
  101. 101.
    Muschler GF, Nitto H, Boehm CA, et al. Age-and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res 2001 Jan; 19(1): 117–25PubMedCrossRefGoogle Scholar
  102. 102.
    Caplan AI. The mesengenic process. Clin Plast Surg 1994 Jul; 21(3): 429–35PubMedGoogle Scholar
  103. 103.
    Bosch P, Musgrave DS, Lee JY, et al. Osteoprogenitor cells within skeletal muscle. J Orthop Res 2000 Nov; 18(6): 933–44PubMedCrossRefGoogle Scholar
  104. 104.
    Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002 Dec; 13(12): 4279–95PubMedCrossRefGoogle Scholar
  105. 105.
    Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000 Apr; 109(1): 235–42PubMedCrossRefGoogle Scholar
  106. 106.
    Connolly JF, Guse R, Tiedeman J, et al. Autologous marrow injection as a substitute for operative grafting of tibial nonunions. Clin Orthop 1991 May; 266: 259–70PubMedGoogle Scholar
  107. 107.
    Connolly J, Guse R, Lippiello L, et al. Development of an osteogenic bone-marrow preparation. J Bone Joint Surg Am 1989 Jun; 71(5): 684–91PubMedGoogle Scholar
  108. 108.
    Bruder SP, Jaiswal N, Haynesworth SE. Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J Cell Biochem 1997 Feb; 64(2): 278–94PubMedCrossRefGoogle Scholar
  109. 109.
    Caplan AI, Bruder SP. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med 2001 Jun; 7(6): 259–64PubMedCrossRefGoogle Scholar
  110. 110.
    Ishaug-Riley SL, Crane GM, Gurlek A, et al. Ectopic bone formation by marrow stromal osteoblast transplantation using poly(DL-lactic-co-glycolic acid) foams implanted into the rat mesentery. J Biomed Mater Res 1997 Jul; 36(1): 1–8PubMedCrossRefGoogle Scholar
  111. 111.
    Solchaga LA, Dennis JE, Goldberg VM, et al. Hyaluronic acid-based polymers as cell carriers for tissue-engineered repair of bone and cartilage. J Orthop Res 1999 Mar; 17(2): 205–13PubMedCrossRefGoogle Scholar
  112. 112.
    Boo JS, Yamada Y, Okazaki Y, et al. Tissue-engineered bone using mesenchymal stem cells and a biodegradable scaffold. J Craniofac Surg 2002 Mar; 13(2): 231–9PubMedCrossRefGoogle Scholar
  113. 113.
    Burdick JA, Anseth KS. Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. Biomaterials 2002 Nov; 23(22): 4315–23PubMedCrossRefGoogle Scholar
  114. 114.
    Payne RG, Yaszemski MJ, Yasko AW, et al. Development of an injectable, in situ crosslinkable, degradable polymeric carrier for osteogenic cell populations. Part 1: encapsulation of marrow stromal osteoblasts in surface crosslinked gelatin microparticles. Biomaterials 2002 Nov; 23(22): 4359–71PubMedCrossRefGoogle Scholar
  115. 115.
    Lieberman JR, Le LQ, Wu L, et al. Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res 1998 May; 16(3): 330–9PubMedCrossRefGoogle Scholar
  116. 116.
    Turgeman G, Pittman DD, Muller R, et al. Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med 2001 May–Jun; 3(3): 240–51PubMedCrossRefGoogle Scholar
  117. 117.
    Wright V, Peng H, Usas A, et al. BMP4-expressing muscle-derived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice. Mol Ther 2002 Aug; 6(2): 169–78PubMedCrossRefGoogle Scholar
  118. 118.
    Rutherford RB, Moalli M, Franceschi RT, et al. Bone morphogenetic protein-transduced human fibroblasts convert to osteoblasts and form bone in vivo. Tissue Eng 2002 Jul; 8(3): 441–52PubMedCrossRefGoogle Scholar
  119. 119.
    Boden SD, Titus L, Hair G, et al. Lumbar spine fusion by local gene therapy with a cDNA encoding a novel osteoinductive protein (LMP-1). Spine 1998 Dec 1; 23(23): 2486–92PubMedCrossRefGoogle Scholar
  120. 120.
    Peng H, Wright V, Usas A, et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest 2002 Sep; 110(6): 751–9PubMedGoogle Scholar
  121. 121.
    Johnson EE, Urist MR, Finerman GA. Repair of segmentai defects of the tibia with cancellous bone grafts augmented with human bone morphogenetic protein: a preliminary report. Clin Orthop 1988 Nov; 236: 249–57PubMedGoogle Scholar
  122. 122.
    Johnson EE, Urist MR, Finerman GA. Distal metaphyseal tibial non-union: deformity and bone loss treated by open reduction, internal fixation, and human bone morphogenetic protein (hBMP). Clin Orthop 1990 Jan; 250: 234–40PubMedGoogle Scholar
  123. 123.
    Johnson EE, Urist MR, Finerman GA. Resistant nonunions and partial or complete segmental defects of long bones: treatment with implants of a composite of human bone morphogenetic protein (BMP) and autolyzed, antigen-extracted, allogeneic (AAA) bone. Clin Orthop 1992 Apr; 277: 229–37PubMedGoogle Scholar
  124. 124.
    McKay B, Sandhu HS. Use of recombinant human bone morphogenetic protein-2 in spinal fusion applications. Spine 2002 Aug 15; 27(16 Suppl. 1): S66–85PubMedCrossRefGoogle Scholar
  125. 125.
    Li RH, Wozney JM. Delivering on the promise of bone morphogenetic proteins. Trends Biotechnol 2001 Jul; 19(7): 255–65PubMedCrossRefGoogle Scholar
  126. 126.
    Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988 Dec 16; 242(4885): 1528–34PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Wenner-Gren Lab, Center for Biomedical EngineeringUniversity of KentuckyLexingtonUSA

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