A review of preclinical program development for evaluating injectable carriers for osteogenic factors

Journal of Bone and Joint Surgery

Volumn 85, Issue SUPPL. 3, 2003, Pages 96-108

  Seeherman, Howard ^a   Li, Rebecca ^b   Wozney, John ^b  

^a PFIZER INC   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

BONE CEMENT; BONE MORPHOGENETIC PROTEIN; BUFFER; CALCIUM PHOSPHATE; DRUG CARRIER; GELFOAM; HYALURONIC ACID; MACROGOL DERIVATIVE; RECOMBINANT BONE MORPHOGENETIC PROTEIN 2; SYNVISC HYLAN G F 20;

BONE REMODELING; CONFERENCE PAPER; DIAPHYSIS; DRUG DELIVERY SYSTEM; DRUG FORMULATION; DRUG SCREENING; FRACTURE; INJECTION; NONHUMAN; OSTEOTOMY; PRIORITY JOURNAL; RABBIT;

EID: 0042626174     PISSN: 00219355     EISSN: None     Source Type: Journal    
DOI: 10.2106/00004623-200300003-00016     Document Type: Conference Paper

References (95)

1. BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Börner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Rüter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T. 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;84:2123-34.
2. Valentin-Opran A, Wozney J, Csimma C, Lilly L, Riedel GE. Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop. 2002;395:110-20.
3. Friedlaender GE, Perry CR, Cole JD, Cook SD, Clerny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83 Suppl 1 (Pt 2):S151-8.
4. Praemer A, Furner S, Rice DP. Musculoskeletal conditions in the United States. Rosemont, IL: American Academy of Orthopaedic Surgeons; 1999.
5. Einhorn TA. Enhancement of fracture-healing. J Bone Joint Surg Am. 1995;77:940-56.
6. Trippel SB, Coutts RD, Einhorn TA, Mundy GR, Rosenfeld RG. Growth factors as therapeutic agents. J Bone Joint Surg Am. 1996;78:1272-86.
7. Einhorn TA, Trippel SB. Growth factor treatment of fractures. Instr Course Lect. 1997;46:483-6.
8. Barnes GL, Kostenuik PJ, Gerstenfeld LC, Einhorn TA. Growth factor regulation of fracture repair. J Bone Miner Res. 1999;14:1805-15.
9. Rosen V, Wozney J. Bone morphogenetic proteins. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. 2nd ed. San Diego: Academic Press; 2002. p 919-28.
10. Sakou T. Bone morphogenetic proteins: from basic studies to clinical approaches. Bone. 1998;22:591-603.
11. Schmitt JM, Hwang K, Winn SR, Hollinger JO. Bone morphogenetic proteins: an update on basic biology and clinical relevance. J Orthop Res. 1999;17:269-78.
12. Bosch P, Musgrave DS, Lee JY, Cummins J, Shuler T, Ghivizzani TC, Evans T, Robbins TD, Huard J. Osteoprogenitor cells within skeletal muscle. J Orthop Res. 2000;18:933-44.
13. Levy MM, Joyner CJ, Virdi AS, Reed A, Triffitt JT, Simpson AH, Kenwright J, Stein H, Francis MJ. Osteoprogenitor cells of mature human skeletal muscle tissue: an in vitro study. Bone. 2001;29:317-22.
14. Musgrave DS, Pruchnic R, Wright V, Bosch P, Ghivizzani SC, Robbins PD, Huard J. The effect of bone morphogenetic protein-2 expression on the early fate of skeletal muscle-derived cells. Bone. 2001;28:499-506.
15. Einhorn TA, Majeska RJ, Mohaideen A, Kagel EM, Bouxsein ML, Turek TJ, Wozney JM. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Joint Surg Am. 2003;85:1425-35.
16. Bouxsein M, D'Augusta D, Blake C, Ammirati KA, Luppen CA, Seeherman HJ, Wozney JM. A single injection of rhBMP-2 enhances fracture healing in a rabbit ulnar osteotomy model. Trans Orthop Res Soc. 2000;25:280.
17. Popich LS, Salkeld SL, Rueger DC, Tucker M, Cook SD. Critical and noncritical size defect healing with osteogenic protein-1. Trans Orthop Res Soc. 1997;22:600.
18. Blokhuis TJ, den Boer FC, Bramer JA, Jenner JM, Bakker FC, Patka P, Haarman HJ. Biomechanical and histological aspects of fracture healing, stimulated with osteogenic protein-1. Biomaterials. 2001;22:725-30.
19. den Boer FC, Bramer JA, Blokhuis TJ, Van Soest FJ, Jenner JM, Patka P, Bakker FC, Burger EH, Haarman HJ. Effect of recombinant human osteogenic protein-1 on the healing of a freshly closed diaphyseal fracture. Bone. 2002;31:158-64.
20. Li RH, Wozney JM. Delivering on the promise of bone morphogenetic proteins. Trends Biotechnol. 2001;19:255-65.
21. Seeherman H, Wozney J, Li R. Bone morphogenetic protein delivery systems. Spine. 2002;27 (16 Suppl 1):S16-23.
22. Cook SD, Salkeld SL, Patron LP, Sargent MC, Rueger DC. Healing course of primate ulna segmental defects treated with osteogenic protein-1. J Invest Surg. 2002;15:69-79.
23. Salkeld SL, Patron LP, Barrack RL, Cook SD. The effect of osteogenic protein-1 on the healing of segmental bone defects treated with autograft or allograft bone. J Bone Joint Surg Am. 2001;83:803-16.
24. Cook SD. Preclinical and clinical evaluation of osteogenic protein-1 (BMP-7) in bony sites. Orthopedics. 1999;22:669-71.
25. den Boer FC, Wippermann BW, Blokhuis TJ, Patka P, Bakker FC, Haarman HJ. Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow. J Orthop Res. 2003;21:521-8.
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;18:289-302.
27. Bouxsein ML, Turek TJ, Blake CA, D'Augusta D, Li X, Stevens M, Seeherman HJ, Wozney JM. Recombinant human bone morphogenetic protein-2 accelerates healing in a rabbit ulnar osteotomy model. J Bone Joint Surg Am. 2001;83:1219-30.
28. Pluhar GE, Manley PA, Heiner JP, Vanderby R Jr, Seeherman HJ, Markel MD. The effect of recombinant human bone morphogenetic protein-2 on femoral reconstruction with an intercalary allograft in a dog model. J Orthop Res. 2001;19:308-17.
29. Welch RD, Jones AL, Bucholz RW, Reinert CM, Tjia JS, Pierce WA, Wozney JM, Li XJ. Effect of recombinant human bone morphogenetic protein-2 on fracture healing in a goat tibial fracture model. J Bone Miner Res. 1998;13:1483-90.
30. Seeherman H. The influence of delivery vehicles and their properties on the repair of segmental defects and fractures with osteogenic factors. J Bone Joint Surg Am. 2001;83 (Suppl 1):S79-81.
31. Nunamaker DM. Experimental models of fracture repair. Clin Orthop. 1998;355 Suppl:S56-65.
32. An YH, Friedman RJ. Animal models in orthopaedic research. Boca Raton, FL: CRC Press; 1999.
33. Tieline L, Puolakkainen P, Pohjonen T, Rautavuori J, Tormala P, Rokkanen P. The effect of transforming growth factor-beta1, released from a bioabsorbable self-reinforced polylactide pin, on a bone defect. Biomaterials. 2002;23:3817-23.
34. Schmidmaler G, Wildemann B, Heeger J, Gabelein T, Flyvbjerg A, Ball HJ, Raschke M. Improvement of fracture healing by systemic administration of growth hormone and local application of insulin-like growth factor-1 and transforming growth factor-beta1. Bone. 2002;31:165-72.
35. Schmidmaler G, Wildemann B, Cromme F, Kandziora F, Haas NP, Raschke M. Bone morphogenetic protein-2 coating of titanium implants increases biomechanical strength and accelerates bone remodeling in fracture treatment: a biomechanical and histological study in rats. Bone. 2002;30:816-22.
36. Lee FY, Storer S, Hazan EJ, Gebhardt MC, Mankin HJ. Repair of bone allograft fracture using bone morphogenetic protein-2. Clin Orthop. 2002;397:119-26.
37. Ohura K, Hamanishi C, Tanaka S, Matsuda N. Healing of segmental bone defects in rats induced by a beta-TCP-MCPM cement combined with rhBMP-2. J Biomed Mater Res. 1999;44:168-75.
38. Gebhart M, Lane J. A radiographical and biomechanical study of demineralized bone matrix implanted into a bone defect of rat femurs with and without bone marrow. Acta Orthop Belg. 1991;57:130-43.
39. Einhorn TA, Lane JM, Burstein AH, Kopman CR, Vigorita VJ. The healing of segmental bone defects induced by demineralized bone matrix. A radiographic and biomechanical study. J Bone Joint Surg Am. 1984;66:274-9.
40. Luppen CA, Blake CA, Ammirati KM, Stevens ML, Seeherman HJ, Wozney JM, Bouxsein ML. Recombinant human bone morphogenetic protein-2 enhances osteotomy healing in glucocorticoid-treated rabbits. J Bone Miner Res. 2002;17:301-10.
41. Martin GJ Jr, Boden SD, Titus L. Recombinant human bone morphogenetic protein-2 overcomes the inhibitory effect of ketorolac, a nonsteroidal antiinflammatory drug (NSAID), on posterolateral lumbar intertransverse process spine fusion. Spine. 1999;24:2188-93.
42. Bostrom M, Lane JM, Tomin E, Browne M, Barbarian W, Turek T, Smith J, Wozney J, Schildhauer T. Use of bone morphogenetic protein-2 in the rabbit ulnar nonunion model. Clin Orthop. 1996;327:272-82.
43. Bax BE, Wozney JM, Ashhurst DE. Bone morphogenetic protein-2 increases the rate of callus formation after fracture of the rabbit tibia. Calcif Tissue Int. 1999;65:83-9.
44. Kato T, Kawaguchi H, Hanada K, Aoyama I, Hiyama Y, Nakamura T, Kuzutani K, Tamura M, Kurokawa T, Nakamura K. Single local injection of recombinant fibroblast growth factor-2 stimulates healing of segmental bone defects in rabbits. J Orthop Res. 1998;16:654-9.
45. Inui K, Maeda M, Sano A, Fujioka K, Yutani Y, Sakawa A, Yamano Y, Kato Y, Kolke T. Local application of basic fibroblast growth factor minipellet induces the healing of segmental bony defects in rabbits. Calcif Tissue Int. 1998;63:490-5.
46. Cook SD, Baffes GC, Wolfe MW, Sampath TK, Rueger DC, Whitecloud TS 3rd. The effect of recombinant human osteogenic protein-1 on healing of Large segmental bone defects. J Bone Joint Surg Am. 1994;76:827-38.
47. Bonnarens F, Einhorn TA. Production of a standard closed fracture in laboratory animal bone. J Orthop Res. 1984;2:97-101.
48. Zabka AG, Pluhar GE, Edwards RB 3rd, Manley PA, Hayashi K, Heiner JP, Kaischeur VL, Seeherman HJ, Markel M. Histomorphometric description of allograft bone remodeling and union in a canine segmental femoral defect model: a comparison of rhBMP-2, cancellous bone graft, and absorbable collagen sponge. J Orthop Res. 2001;19:318-27.
49. Toriumi DM, Kotler HS, Luxenberg DP, Holtrop ME, Wang EA. Mandibular reconstruction with a recombinant bone-inducing factor. Functional, histologic, and biomechanical evaluation. Arch Otolaryngol Head Neck Surg. 1991;117:1101-12.
50. Heckman JD, Ehler W, Brooks BP, Aufdemorte TB, Lohmann CH, Morgan T, Boyan BD. 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;81:1717-29.
51. Gerhart TN, Kirker-Head CA, Kriz MJ, Holtrop ME, Hennig GE, Hipp J, Schelling SH, Wang E. Healing segmental femoral defects in sheep using recombinant human bone morphogenetic protein. Clin Orthop. 1993;293:317-26.
52. Zdeblick TA, Ghanayem AJ, Rapoff AJ, Swain C, Bassett T, Cooke ME, Markel M. Cervical interbody fusion cages. An animal model with and without bone morphogenetic protein. Spine. 1998;23:758-66.
53. Edwards RB 3rd, Zabka A, Hayashi K, Bogdanske J, Devitt J, Kaischeur V, Vanderby R Jr, Alolova M, Seeherman HJ, Markel M. Accelerated fracture healing by percutaneous injection of rhBMP-2 and alpha-BSM. Trans Orthop Res Soc. 2000;25:850.
54. Edwards RB 3rd, Seeherman H, Bogdanske JJ, Devitt J, Vanderby R Jr, Markel MD. Percutaneous injection of recombinant bone morphogenetic protein-2 in a rapidly resorbable calcium phosphate paste accelerates healing of a canine tibial osteotomy. Unpublished data.
55. Cavagna GA, Heglund NC, Taylor CR. Mechanical work in terrestrial locomotion: two basic mechanisms for minimizing energy expenditure. Am J Physiol. 1977;233:R243-61.
56. Alexander RM. Energy-saving mechanisms in walking and running. J Exp Biol. 1991;160:55-69.
57. Turner AS. The sheep as a model for osteoporosis in humans. Vet J. 2002;163:232-9.
58. Newman E, Turner AS, Wark JD. The potential of sheep for the study of osteopenia: current status and comparison with other animal models. Bone. 1995;16 (4 Suppl):277-84S.
59. Wippermann B, den Boer F, Schratt H, Donow C, Haarman H, Tscherne H. The resorbable calcium phosphate cement alpha BSM in a sheep tibia segmental defect. Trans Orthop Res Soc. 1999;24:525.
60. Aro HT, Wahner HT, Chao EY. Healing patterns of transverse and oblique osteotomies in the canine tibia under external fixation. J Orthop Trauma. 1991;5:351-64.
61. Aro HT, Chao EY. Bone-healing patterns affected by loading, fracture fragment stability, fracture type, and fracture site compression. Clin Orthop. 1993;293:8-17.
62. Bouvy BM, Markel MD, Chelikani S, Egger EL, Plermattel DL, Vanderby R Jr. Ex vivo biomechanics of Kirschner-Ehmer external skeletal fixation applied to canine tibiae. Vet Surg. 1993;22:194-207.
63. Hanson PD, Warner C, Kofroth R, Osmond C, Bogdanske JJ, Kaischeur VL, Frassica FJ, Markel MD. Effect of intramedullary polymethylmethacrylate and autogenous cancellous bone on healing of frozen segmental allografts. J Orthop Res. 1998;16:285-92.
64. Hara Y, Nakamura T, Fukuda H, Harada Y, Nezu Y, Tagawa M. Changes of biomechanical characteristics of the bone in experimental tibial osteotomy model in the dog. J Vet Med Sci. 2003;65:103-7.
65. Johnson AL, Kneller SK, Weigel RM. Radial and tibial fracture repair with external skeletal fixation. Effects of fracture type, reduction, and complications on healing. Vet Surg. 1989;18:367-72.
66. Lewallen DG, Chao EY, Kasman RA, Kelly PJ. Comparison of the effects of compression plates and external fixators on early bone-healing. J Bone Joint Surg Am. 1984;66:1084-91.
67. Markel MD, Wlkenhelser MA, Chao EY. A study of fracture callus material properties: relationship to the torsional strength of bone. J Orthop Res. 1990;8:843-50.
68. Markel MD, Bogdanske JJ. The effect of increasing gap width on localized densitometric changes within tibial ostectomies in a canine model. Calcif Tissue Int. 1994;54:155-9.
69. O'Sullivan ME, Bronk JT, Chao EY, Kelly PJ. Experimental study of the effect of weight bearing on fracture healing in the canine tibia. Clin Orthop. 1994;302:273-83.
70. Wu JJ, Shyr HS, Chao EY, Kelly PJ. Comparison of osteotomy healing under external fixation devices with different stiffness characteristics. J Bone Joint Surg Am. 1984;66:1258-64.
71. Fischgrund JS, James SB, Chabot MC, Hankin R, Herkowitz HN, Wozney JM, Shirkhoda A. Augmentation of autograft using rhBMP-2 and different carrier media in the canine spinal fusion model. J Spinal Disord. 1997;10:467-72.
72. Markel MD. The effect of rhBMP-2/ACS on the union of femoral allograft-host bone junctions in a canine model. Cambridge: Genetics Institute; 1999.
73. Wang X, Mabrey JD, Agrawal CM. An interspecies comparison of bone fracture properties. Biomed Mater Eng. 1998:1-9.
74. Aerssens J, Boonen S, Lowet G, Dequeker J. Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research. Endocrinology. 1998;139:663-70.
75. Sheehan JP, Sheehan JM, Seeberman H, Quigg M, Heim GA. The safety and utility of recombinant human bone morphogenetic protein-2 for cranial procedures in a nonhuman primate model. J Neurosurg. 2003;98:125-30.
76. Kawaguchi H, Nakamura K, Tabata Y, Ikada Y, Aoyama I, Anzal J, Nakamura T, Hiyama Y, Tamura M. Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2. J Clin Endocrinol Metab. 2001;86:875-80.
77. Radomsky ML, Aufdemorte TB, Swain LD, Fox WC, Spiro RC, Poser JW. Novel formulation of fibroblast growth factor-2 in a hyaluronan gel accelerates fracture healing in nonhuman primates. J Orthop Res. 1999;17:607-14.
78. Seeherman H, Alolova M, Bouxseln M, Wozney J. A single injection of rhBMP-2/calcium phosphate paste accelerates healing in a nonhuman primate osteotomy model. Trans Orthop Res Soc. 2001;26:251.
79. Seeherman H, Li R, Blake C, Bouxseln ML, Cooper J, Gavin D, Li J, Wozney J. A single injection of rhBMP-2/calcium phosphate paste given one week after surgery accelerates healing by 50% in a non-human primate fibula osteotomy model. Trans Orthop Res Soc. 2002;27:237.
80. Park SH, O'Connor K, Sung R, McKellop H, Sarmiento A. Comparison of healing process in open osteotomy model and closed fracture model. J Orthop Trauma. 1999;13:114-20.
81. Iwabu S, Augat P, Claes L. The revascularization and bone healing following fracture with severe soft tissue injury: a new closed fracture model in the rat. Read at the International Society for Fracture Repair, Hong Kong; 2000; Hong Kong, China.
82. Blokhuis TJ, den Boer FC, Bramer JA, van Lingen A, Roos JC, Bakker FC, Patka P, Haarman HJ. Evaluation of strength of healing fractures with dual energy Xray absorptiometry. Clin Orthop. 2000;380:260-8.
83. Schlegel U, Eckhardt CH, Wieling R, Bouxsein ML, Seeherman HJ, Schneider E. Temporal in vivo monitoring of fracture healing in sheep tibiae. In: Transactions of the Sixth World Biomaterials Congress; 2000 May 15-20; Kamuela, HI; Society for Biomaterials; 2000. p 1261.
84. Blokhuis TJ, de Bruine JH, Bramer JA, den Boer FC, Bakker FC, Patka P, Haarman HJ, Manollu RA. The reliability of plain radiography in experimental fracture healing. Skeletal Radiol. 2001;30:151-6.
85. Aro HT, Kelly PJ, Lewallen DG, Chao EY. The effects of physiologic dynamic compression on bone healing under external fixation. Clin Orthop. 1990;256:260-73.
86. Inoue N, Ohnishi I, Chen D, Deltz LW, Schwardt JD, Chao EY. Effect of pulsed electromagnetic fields (PEMF) on late-phase osteotomy gap healing in a canine tibial model. J Orthop Res. 2002;20:1106-14.
87. Gaston P, Will E, Elton RA, McQueen MM, Court-Brown CM. Fractures of the tibia. Can their outcome be predicted? J Bone Joint Surg Br. 1999;81:71-6.
88. Bohner M. Calcium orthophosphates in medicine: from ceramics to calcium phosphate cements. Injury. 2000;31 Suppl 4:37-47.
89. Wang EA, Rosen V, D'Alessandro JS, Bauduy M, Cordes P, Harada T, Israel DI, Hewick RM, Kerns KM, LaPan P, Luxenberg DH, McQuaid D, Moutsatsos IK, Nove J, Wozney JM. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci USA. 1990;87:2220-4.
90. Li R, Bouxsein M, Blake C, D'Augusta D, Kim H, Li XJ, Wozney JM, Seeherman HJ. RhBMP-2 injected in a calcium-phosphate paste (alpha-BSM) accelerated healing in the rabbit ulnar osteotomy model. J Orthop Res; in press.
91. Kim HD, D'Augusta DA, Li RH. Formulation of hyaluronic acid ester-based injectable carriers for the delivery of rhBMP-2. In: Transactions of the Sixth World Biomaterials Congress; 2000 May 15-20; Kamuela, HI; Society for Biomaterials; 2000. p 626.
92. Kim HD, Li R, D'Augusta DA, Bouxsein M, Blake C, Luppen C, Seeherman H, Wozney JM. Injectable hyaluronic adid/tricalcium phosphate composites for the delivery of rhBMP-2. In: Proceedings of the 27th International Symposium on Controlled Release of Bioactive Molecules; 2000 July 7-13; Paris, France; Controlled Release Society; 2000. p 978.
93. Li RH, Seeherman H, Bouxsein M, D'Augusta D, Blake C, Ammirati C, Luppen C, Stevens M, Li J, Kim H, Wozney J. Acceleration of fracture healing with rhBMP-2 delivered in an injectable gelfoam delivery system. In: Transactions of the Sixth World Biomaterials Congress; 2000 May 15-20; Kamuela, HI; Society for Biomaterials; 2000. p 560.
94. Li R, Seeherman H, Bouxsein M, Kim H, D'Augusta D, Blake C, Luppen C, Stevens M, Williams D, Li J, Wozney J. rhBMP-2 release characteristics and efficacy in gelatin/ceramic composite carriers. In: Proceedings of the 27th International Symposium on Controlled Release of Bioactive Molecules; 2000 July 7-13; Paris, France; Controlled Release Society; 2000. p 261.
95. Li R, D'Augusta D, Blake C, Bouxsein M, Wozney J, Li J, Stevens M, Kim H, Seeherman H. rhBMP-2 delivery and efficacy in an injectable calcium-phosphate based matrix. In: Proceedings of the 28th International Symposium on Controlled Release of Bioactive Molecules; 2001 June 23-27; San Diego, CA; Controlled Release Society; 2001. p 870.