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• W2106573856 abstract "The Journal of Bone and Joint Surgery. British volumeVol. 88-B, No. 6 Review ArticleFree AccessThe role of growth factors and related agents in accelerating fracture healingA. H. R. W. Simpson, L. Mills, B. NobleA. H. R. W. SimpsonProfessor of Orthopaedics and TraumaThe Musculoskeletal Tissue Engineering Consortium, Room SU304, University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.Search for more papers by this author, L. MillsSpecialist Registrar in Orthopaedics and TraumaThe Musculoskeletal Tissue Engineering Consortium, Room SU304, University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.Search for more papers by this author, B. NobleDirector of The Musculoskeletal Tissue Engineering ConsortiumThe Musculoskeletal Tissue Engineering Consortium, Room SU304, University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.Search for more papers by this authorPublished Online:1 Jun 2006https://doi.org/10.1302/0301-620X.88B6.17524AboutSectionsPDF/EPUB ToolsDownload CitationsTrack CitationsPermissionsAdd to Favourites ShareShare onFacebookTwitterLinked InRedditEmail In vivo studies have shown that bone morphogenetic proteins (BMPs), transforming growth factor (TGF) beta, insulin-like growth factor (IGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are all present during normal healing of fractures.1–8 They are all naturally-occurring agents, each of which has a range of molecular variants which have been identified in vivo.7,9,10The BMPs are members of the larger TGF-beta super family. To date, over 20 different BMPs have been isolated, but only some have the potential to induce formation of new bone.11,12 TGF-beta, another of the TGF-beta super family, has five isoforms and is found in many types of tissue.9 Animal studies have demonstrated varying results in its influence on the healing of fractures.3,13–15 The IGF family consists of two polypeptide members; IGF-II is the most abundant in bone, but IGF-I has the greater osteogenic potency.9In vitro, IGF-I has been shown to stimulate chemotaxis and activity of osteoblasts, whilst in vivo, increased bone formation has been observed in bone-repair models in animals. IGF-I is of greatest effect when used in combination with TGF-beta.16,17 To date, nine members of the FGF family have been identified, the most abundant in human tissue being FGF-1 (alpha) and FGF-2 (beta).9 The former has been shown to promote an osteogenic response in progenitor cells by providing cytotoxic resistance to inflammatory oxidants,18–20 and the latter has been found to accelerate fracture healing directly.21–23 VEGF is stored and secreted by osteoblasts and endothelium and has an important role in angiogenesis during repair of fractures.24–27 The role of PDGF in the healing of fractures has not been clarified. It is released from platelets during the formation of haematoma9 and has been shown to stimulate the migration of osteoblasts28 and mesenchymal progenitor cells.29In addition to these agents, various hormones such as growth hormone and parathyroid hormone (PTH) have an effect on the repair of fractures.30–33 Growth hormone (GH) has been shown to increase the ultimate load, stiffness and callus in a model of fracture repair,30,34 while PTH was found to increase the bone mineral content, density and strength in a model of repair in long bones and to accelerate healing.32,33Agents such as the statins, PTH-related peptide (PTH-rP), TP508 (a thrombin-derived peptide) and pleiotrophin may also have the potential to affect the healing of fractures. Statins have been shown to induce BMP-2 and VEGF, inducing earlier bone formation in repair models.35–37 PTH-rP is a hormone which acts on the same receptors as PTH and was found to improve fracture repair greatly in a model of delayed healing.5,38 TP508 is a synthetic peptide with a similar amino-acid sequence to thrombin, and accelerates fracture repair and bone formation.39–41 Pleiotrophin is an extracellular matrix-associated protein which has recently been found to have a role in osteoblastic recruitment, motility and proliferation.42Clinical situationsThere are a number of clinical situations for which the application of therapeutic agents should be considered. These include:simple closed fractures;delayed healing (open-fracture/high-velocity injuries and older osteoporotic fractures);nonunion; andsegmental defects.These different situations almost certainly lead to the recruitment of different cells, growth factors and growth-factor inhibitors within the site of the fracture. Receptor expression may also be influenced. Models of non-unions have demonstrated the influence of growth factors on their receptors and blood vessels which are present in varying degrees in the fracture gap, but not necessarily in the correct temporal and spatial arrangement.43,44 The endogenous levels of the various growth factors and the receptiveness of the cells are likely to vary under these different circumstances.4 This needs to be kept in mind when considering the experimental evidence and the studies carried out with the various growth factors on patients, since it may not be possible to extrapolate from one situation to another.Time of deliveryThe type of cells present within the site of the fracture varies at the different stages of healing.5,45–47 The growth receptors on the cells also vary in number at different stages.2,8,44,48,49 It is therefore possible that if a growth factor is given at an early stage of attempted repair, it may have less influence or be completely ineffective than when given at a later stage when receptive cells are present. The surrounding environment of the cells, particularly the degree of vascularity and their mechanical stability, will also have an effect on whether the growth factor can initiate an improvement in healing.24,40,50 Impairment in vascularity at the outset may result in specific factors missing their ‘window of opportunity’ in the healing cascade.51Mode of deliveryThe options to be considered are:open insertion versus injection;suspension in a carrier or buffer vehicle;local application versus systemic treatment; andpeptide versus gene treatment.The major advantage of a carrier over a buffer is that it can release the active agent in the exact area required, delivering it over a sustained period of time. The carrier also prevents the growth factor leeching away from the site into the surrounding tissues.52–54 Collagen is a popular choice of carrier since it is biocompatible, degradable and osteoconductive.55–58 It has been used in sponge and particle forms in human trials with BMP.59–61 The disadvantage of collagen sponge is that it requires an open procedure for insertion and is a xenogeneic material. Various synthetic biodegradable polymers have been created and tested17 and recently, injectable forms have been investigated. Hyaluronic-based gels, gelatin gels and calcium-phosphate pastes have also been tested.21–24,62–65 In a small animal study, retention of recombinant human BMP-2 (rhBMP-2) at the site of an osteotomy was determined after injection of nine different carriers and buffer. There was a vast difference in local retention of BMP-2 between products, but despite the diverse range of concentrations of BMP-2, seven of the nine carriers produced statistically significant acceleration of healing.66 Studies using injection of growth factor alone or in a buffer have shown significant enhancement of healing in both large and small animal models even when given as a single injection.40,67,68 This may indicate that the growth factors have the potential to direct uncommitted cells down the osteogenic lineage to produce a beneficial effect over an extended period of time.Most therapeutic agents, in particular BMPs, are delivered locally to the site of the fracture.22–24,69 The effect of systemic subcutaneous injection has also been tested using growth hormone, PTH and PTH-rP, with acceleration of bone healing.31–33 Although injections are simple to administer, they are required daily or three times per week for several weeks.An alternative method of delivery which is currently under investigation is gene therapy. Here the complementary DNA sequence of a particular growth factor is delivered to cells at the site of the fracture. Once the cells have incorporated this DNA into their own they can produce the desired growth factor. There are two types of vector for delivery of the DNA into the cell; viral, using an adenovirus or retrovirus; and non-viral, liposomes or polypeptides. The vector can be administered directly to cells at the defect or fracture site, or may be transferred to cells ex vivo, and these are subsequently delivered to the site. Each method has its own advantages and disadvantages.49,70–72Gene therapy has the following potential advantages:a prolonged expression of the protein;high local concentrations;greater effectiveness;low cost of manufacture;reduced systemic effects; andlonger shelf life and easier storage.There are, however, some potential disadvantages:a host immune response, which may require suppression;immunosensitisation;non-specific inflammatory response;variation of gene expression;the potential to revert to the wildtype virus;ectopic bone formation; andexcess growth of bone.In vivo studies of gene therapy are still in their infancy. Delivery of TGF-beta, BMP-2, BMP-6 and BMP-7 into osteotomy models by adenovirus have been shown to produce accelerated healing.73–75 Cells genetically engineered to express BMP ex vivo have been administered to segmental and other defects resulting in osseous repair.72,76,77 The ability to manipulate expression of cellular genes has opened up the possibility of engineering hybrid cells ex vivo to express multiple types of BMP.78,79 IGF-1-modified cells administered systemically were found to localise at the site of the fracture and enhance repair.80 Percutaneous delivery of a marker gene into a model of avascular atrophic non-union showed sustained local expression of the adenoviral vector for over four weeks. This could potentially overcome the problems of leeching of growth factor, molecular degradation and protein delivery in an avascular defect.81 However, these methods of delivery by gene therapy have yet to be fully explored. There is a limited amount of research available comparing the different forms of gene delivery.82Current levels of researchOver the last 20 years there has been an immense rise in the number of publications on the osteogenic potential of growth factors. There are now over 3000 articles in the literature on BMPs. Evaluation of the agents tends to go through several stages. These are:the effect on cell culture;the effect in small animal experiments;the effect in large animal experiments;observations on uncontrolled series of patients; andrandomised, controlled trials in patients.All the growth factors discussed have been tested in small animal trials.5,25,32,39,41,42,83 GH, IGF, TGF-beta, and FGF are further on, and have been studied in large animal experiments.14,16,22,31,34 The gold standard is patient randomised control trials; however, only BMP-2 and BMP-7 have reached this level of scrutiny.59,60,83 Even at this stage, there is considerable variation in their assessment. BMP-2 was evaluated in open fractures,59 whereas the effect of BMP-7 was examined in nonunion60,84 and open fractures of the tibia.83 Variation is also a factor in the animal models that have been used. IGF, TGF, FGF and TP508 have all been assessed in fracture and defect models whereas PTH and PTH-rP have only been tested in simple fracture models. Models of nonunion have only been utilised for studies with VEGF and BMP.Clinical studiesThe best clinical evidence for BMP’s we have to date is derived from randomised, controlled trials. Two large trials have been undertaken which tested rhBMP-7, otherwise known as osteogenic protein 1 (OP1). One trial, by Friedlaender et al,60 studied 122 patients with 124 established nonunions of the tibia. All the patients had an intramedullary nail and were then randomised to receive either fresh autograft or rhBMP-7 in a type-1 collagen carrier. After nine months, 81% of the rhBMP-7 group and 85% of the autograft group had achieved clinical union and 75% of the rhBMP-7 group and 84% of the autograft group were considered to have united radiologically. At two years there was no statistical difference between the control and treatment groups. The authors concluded that rhBMP-7 was equivalent to autograft in the management of nonunion, but noted that 20% of the autograft group had chronic pain at the donor site.The other trial using rhBMP-7 was carried out by McKee et al.83 Only the preliminary results are available. They studied the effect of rhBMP-7 applied without a collagen carrier in fresh open fractures of the tibia. All 124 patients had debridement, irrigation and intramedullary nailing. The treatment group (n = 62) also received rhBMP-7. They found that at six months the treatment group had a significantly lower rate of secondary intervention and had an improved functional outcome as assessed by pain and the ability to fully weight-bear.A prospective pilot study by McKee et al84 evaluated the administration of rhBMP-7 in 15 patients with established complex nonunion of a long bone with a mean of 2.8 previous unsuccessful operations. Within three months 87% had healed.Treatment with BMP-2 was studied in 450 patients with open fractures of the tibia.59 This was a randomised, prospective trial stratified for the grade of open fracture. The patients were managed by irrigation and debridement of the wound, initial reduction of the fracture within 24 hours and final closure of the wound and reduction of the fracture within 14 days. The patients were stabilised within 24 hours. In addition to a control group of 250 patients, there were two further groups who had a collagen sponge impregnated with BMP-2 placed at the fracture site. One received a low dose of BMP (0.75 mg/ml) and the other a high dose (1.5 mg/ml). The baseline profile for the type of fracture and the characteristics of stabilisation were similar. At 12 months 94% of the patients were followed up. Those treated with high-dose BMP-2 had statistically significant (p = 0.0022) acclerated healing, fewer invasive interventions and a lower rate of nonunion than the control group.There has been a rhBMP-7 clinical trial in the United States with 653 cases.85 There was an 82% success rate with rhBMP. However, it was observational, non-randomised and incorporated a wide variety of clinical scenarios and anatomical differences.Cost-effectivenessBefore these agents come into active clinical practice, we need to be clear as to whether we are using them to try to accelerate healing or to reduce the rate of nonunion. In the former case we need to consider by how many weeks we have to reduce the healing time to justify the cost of treatment. In the case of BMP, when delivered as a protein the cost may be £1000 or more, but the use of thrombin peptide may be considerably less. However, it may be simpler to justify the use of the more expensive therapies in the treatment of nonunion, as the cost of the current management of such patients can be in excess of £10 000. With the development of gene therapy, which is potentially much cheaper to produce than BMP, the application of growth factors in the management of high-risk or even common fractures may become economically advantageous.ConclusionWe now have agents including BMP-2 and BMP-7 which have been demonstrated to have a beneficial effect on the healing of fractures and nonunions in randomised, controlled trials. However, caution must be used in extrapolating these results. Other agents, such as GH, FGF and PTH-rP have shown promise in experiments on large animals, and others, including PTH and VEGF, in small animals. Further studies are needed to evaluate the range of agents available and to determine the optimum time and means of delivery to achieve success.References1 Bostrom MP. Expression of bone morphogenetic proteins in fracture healing. Clin Orthop 1998;355(Suppl):116–23. Google Scholar2 Bourque WT, Gross M, Hall BK. Expression of four growth factors during fracture repair. Int J Dev Biol 1993;37:573–9. Medline, ISI, Google Scholar3 Joyce ME, Jingushi S, Bolander ME. Transforming growth factor-beta in the regulation of fracture repair. Orthop Clin North Am 1990;21:199–209. Crossref, Medline, ISI, Google Scholar4 Zimmermann G, Henle P, Kusswetter M, et al. TGF-beta 1 as a marker of delayed fracture healing. Bone 2005;36:779–85. Crossref, Medline, ISI, Google Scholar5 Okazaki K, Jingushi S, Ikenoue T, et al. Expression of parathyroid hormone-related peptide and insulin-like growth factor I during rat fracture healing. J Orthop Res 2003;21:511–20. Crossref, Medline, ISI, Google Scholar6 Andrew JG, Hoyland JA, Freemont AJ, Marsh DR. Platelet-derived growth factor expression in normally healing human fractures. Bone 1995;16:455–60. Medline, ISI, Google Scholar7 Mayer H, Bertram H, Lindenmaier W, et al. Vascular endothelial growth factor (VEGF-A) expression in human mesenchymal stem cells: autocrine and paracrine role on osteoblastic and endothelial differentiation. J Cell Biochem 2005;95:827–39. Crossref, Medline, ISI, Google Scholar8 Kloen P, Di Paola M, Borens O, et al. BMP signalling components are expressed in human fracture callus. Bone 2003;33:362–71. Crossref, Medline, ISI, Google Scholar9 Lieberman JR, Daluiski A, Einhorn TA. The role of growth factors in the repair of bone: biology and clinical applications. J Bone Joint Surg [Am] 2002;84-A:1032–44. Google Scholar10 Baylink DJ, Finkelman RD, Mohan S. Growth factors to stimulate bone formation. J Bone Miner Res 1993;8(Suppl 2):565–72. Google Scholar11 ten Dijke P, Fu J, Schaap P, Roelen BA. Signal transduction of bone morphogenetic proteins in osteoblast differentiation. J Bone Joint Surg [Am] 2003;85-A (Suppl):34–8. Google Scholar12 Wozney JM, Rosen V. Bone morphogenetic protein and bone morphogenetic protein family in bone formation and repair. Clin Orthop 1998;346:26–37. Google Scholar13 Nielsen HM, Andreassen TT, Ledet T, Oxlund H. Local injection of TGF-beta increases the strength of tibial fractures in the rat. Acta Orthop Scand 1994;65:37–41. Crossref, Medline, Google Scholar14 Broderick E, Infanger S, Turner TM, Sumner DR. Depressed bone mineralisation following high dose TGF-beta-1 application in an orthopaedic implant model. Calcif Tissue Int 2005;76:379–84. Crossref, Medline, ISI, Google Scholar15 Lind M, Schumacker B, Soballe K, et al. Transforming growth factor-beta enhances fracture healing in rabbit tibiae. Acta Orthop Scand 1993;64:553–6. Crossref, Medline, Google Scholar16 Schmidmaier G, Wildemann B, Gabelein T, et al. Synergistic effect of IGF-I and TGF-beta 1 on fracture healing in rats: single versus combined application of IGF-I and TGF-beta 1. Acta Orthop Scand 2003;74:604–10. Crossref, Medline, Google Scholar17 Meinel L, Zoidis E, Zapf J, Hassa P, et al. Localised insulin-like growth factor I delivery to enhance new bone formation. Bone 2003;33:660–72. Crossref, Medline, ISI, Google Scholar18 Chen WJ, Jingushi S, Aoyama I, et al. Effects of FGF-2 on metaphyseal fracture repair in rabbit tibiae. J Bone Miner Metab 2004;22:303–9. Medline, ISI, Google Scholar19 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;86: 875–80. Crossref, Medline, ISI, Google Scholar20 Radomsky ML, Aufdemorte TB, Swain LD, et al. Novel formulation of fibroblast growth factor-2 in a hyaluron gel accelerates fracture healing in nonhuman primates. J Orthop Res 1999;17:607–14. Crossref, Medline, ISI, Google Scholar21 Kelpke SS, Reiff D, Prince CW, Thompson JA. Acidic fibroblast factor signaling inhibits peroxynitrite-induced death of osteoblasts and osteoblast precursors. J Bone Min Res 2001;16:1917–25. Crossref, Medline, ISI, Google Scholar22 Kelpke SS, Zinn KR, Rue LW, Thompson JA. Site specfic delivery of acidic fibroblast growth factor stimulates angiogenic and osteogenic responses in vivo. J Biomed Mater Res A 2004;71:316–25. Medline, ISI, Google Scholar23 Reiff DA, Kelpke S, Rue L 3rd, Thompson JA. Acidic fibroblast growth factor attenuates the cytotoxic effects of peroxynitrite in primary human osteoblast precursors. J Trauma 2001;50:433–8. Crossref, Medline, Google Scholar24 Eckhardt H, Ding M, Lind M, et al. Recombinant human vascular endothelial growth factor enhances bone healing in an experimental nonunion model. J Bone Joint Surg [Br] 2005;87-B:1434–8. Link, Google Scholar25 Deckers MM, van Bezooijen RL, van der Horst G, et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology 2002;143:1545–53. Crossref, Medline, ISI, Google Scholar26 Li G, Cui Y, McIlmurray L, Allen WE, Wang H. RhBMP-2, rhVEGF165, rhPTN and thrombin-related peptide, TP508 induce chemotaxis of human osteoblasts and microvascular endothelial cells. J Orthop Res 2005;23:680–5. Crossref, Medline, ISI, Google Scholar27 Street JT, Wang JH, Wu QD, et al. The angiogenic response to skeletal injury is preserved in the elderly. J Orthop Res 2001;19:1057–66. Crossref, Medline, ISI, Google Scholar28 Mehrotra M, Krane SM, Walters K, Pilbeam C. Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells. J Cell Biochem 2004;93:741–52. Crossref, Medline, ISI, Google Scholar29 Fiedler J, Etzel N, Brenner RE. To go or not to go: migration of human mesenchymal progenitor cells stimulated by isoforms of PDGF. J Cell Biochem 2004;93:990–8. Crossref, Medline, ISI, Google Scholar30 Andreassen TT, Oxlund H. Local anabolic effects of growth hormone on intact bone and healing fractures in rats. Calcif Tissue Int 2003;73:258–64. Crossref, Medline, ISI, Google Scholar31 Bail HJ, Kolbeck S, Krummrey G, et al. Systemic application of growth hormone for enhancement of secondary and intramembranous fracture healing. Horm Res 2002;58(Suppl 3):39–42. Google Scholar32 Alkhiary YM, Gerstenfeld C, Krall E, et al. Enhancement of experimental fracture-healing by systemic admistration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg [Am] 2005;87-A:731–41. Google Scholar33 Komatsubara S, Mori S, Mashiba T, et al. Human parathyroid hormone (1–34) accelerates the fracture healing process of woven to lamellar bone replacement and new cortical shell formation in rat femora. Bone 2005;36:678–87. Crossref, Medline, ISI, Google Scholar34 Kolbeck S, Bail H, Schmidmaier G, et al. Homologous growth hormone accelerates bone healing: a biomechanical and histological study. Bone 2003;33:628–37. Crossref, Medline, ISI, Google Scholar35 Mundy G, Garret R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999;286:1946–9. Crossref, Medline, ISI, Google Scholar36 Wong RW, Rabie AB. Early healing pattern of statin-induced osteogenesis. Br J Oral Maxillofac Surg 2005;43:46–50. Crossref, Medline, ISI, Google Scholar37 Hatano H, Maruo A, Bolander ME, Sarkar G. Statin stimulates bone morphogenetic protein-2, aggrecan, and type 2 collagen gene expression and proteoglycan synthesis in rat chondrocytes. J Orthop Sci 2003;8:842–8. Crossref, Medline, Google Scholar38 Martin TJ. Osteoblast-derived PTHrP is a physiological regulator of bone formation. J Clin Invest 2005;115:2322–4. Crossref, Medline, ISI, Google Scholar39 Sheller MR, Crowther RS, Kinney JH, et al. Repair of rabbit segmental defects with the thrombin peptide, TP508. J Orthop Res 2004;22:1094–9. Crossref, Medline, ISI, Google Scholar40 Wang H, Li X, Tomin E, et al. Thrombin peptide (TP508) promotes fracture repair by up-regulating inflammatory mediators, early growth factors and increasing angiogenesis. J Orthop Res 2005;23:671–9. Crossref, Medline, ISI, Google Scholar41 Li G, Ryaby JT, Carney DH, Wang H. Bone formation is enhanced by thrombin-related peptide TP508 during distraction osteogenesis. J Orthop Res 2005;23: 196–202. Crossref, Medline, ISI, Google Scholar42 Li G, Bunn JR, Mushipe MT, He Q, Chen X. Effects of pleiotrophin (PTN) over-expression on mouse long bone development, fracture healing and bone repair. Calcif Tissue Int 2005;76:299–306. Crossref, Medline, ISI, Google Scholar43 Kloen P, Doty SB, Gordon E, et al. Expression and activation of the BMP-signaling components in human fracture nonunions. J Bone Joint Surg [Am] 2002;84-A: 1909–18. Google Scholar44 Brownlow HC, Reed A, Simpson AH. Growth factor expression during the development of atrophic non-union. Injury 2001;32:519–24. Crossref, Medline, ISI, Google Scholar45 Tatsuyama K, Maezawa Y, Baba H, Imamura Y, Fukuda M. Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone. Eur J Histochem 2000;44:269–78. Medline, ISI, Google Scholar46 Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 2002;17:513–20. Crossref, Medline, ISI, Google Scholar47 Phillips AM. Overview of the fracture healing cascade. Injury 2005;36(Suppl 3):5–7. Crossref, ISI, Google Scholar48 Kuroda S, Virdi AS, Dai Y, Shott S, Sumner DR. Patterns and localisation of gene expression during intramembranous bone regeneration in the rat femoral marrow ablation model. Calcif Tissue Int 2005;77:212–25. Crossref, Medline, ISI, Google Scholar49 Southwood LL, Frisbie DD, Kawcak CE, McIlwraith CW. Delivery of growth factors using gene therapy to enhance bone healing. Vet Surg 2004;33:565–78. Crossref, Medline, ISI, Google Scholar50 Klein P, Schell H, Streitparth F, et al. The initial phase of fracture healing is specifically sensitive to mechanical conditions. J Orthop Res 2003;21:662–9. Crossref, Medline, ISI, Google Scholar51 Brownlow HC, Reed A, Simpson AH. The vascularity of atrophic non-unions. Injury 2002;33:145–50. Crossref, Medline, ISI, Google Scholar52 Winn SR, Uludag H, Hollinger JO. Carrier systems for bone morphogenetic proteins. Clin Orthop 1999;367(Suppl):95–106. Crossref, Google Scholar53 Hollinger JO, Uludag H, Win SR. Sustained release emphasizing recombinant human bone morphogenetic protein-2. Adv Drug Deliv Rev 1998;31:303–18. Crossref, Medline, ISI, Google Scholar54 Keskin DS, Texcaner A, Korkusuz P, Korkusuz F, Hasirci V. Collagen-chondroitin sulfate-based PLLA-SAIB-coated rhBMP-2 delivery system for bone repair. Biomaterials 2005;26:4023–34. Crossref, Medline, ISI, Google Scholar55 Ueda H, Hong L, Yamamoto M, et al. Use of collagen sponge incorporating transforming growth factor-beta 1 to promote bone repair in skull defects in rabbits. Biomaterials 2002;23:1003–10. Crossref, Medline, ISI, Google Scholar56 Yasko AW, Lane JM, Fellinger EJ, et al. The healing of segmental bone defects, induced by recombinant human bone morphogenetic protein (rhBMP-2): a radiographic, histological, and biomechanical study in rats. J Bone Joint Surg [Am] 1992; 74-A:659–70. ISI, Google Scholar57 Welch RD, Jones AL, Bucholz RW, Reinert CM, et al. 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. Crossref, Medline, ISI, Google Scholar58 Termaat MF, Den Boer FC, Bakker FC, Patka P, Haarman HJ. Bone morphogenetic proteins: development and clinical efficacy in the treatment of fractures and bone defects. J Bone Joint Surg [Am] 2005;87-A:1367–78. Google Scholar59 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;84-A: 2123–34. Crossref, Medline, ISI, Google Scholar60 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-A(Suppl 1):151–8. Google Scholar61 Geesink RC, Hoefnagels NH, Bulstra SK. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg [Br] 1999; 81-B:710–18. Link, Google Scholar62 Seerherman HJ, Bouxsein M, Kim H, et al. Recombinant human bone morphogenetic protein-2 delivered in an injectable calcium phosphate paste accelerates osteotomy-site healing in a nonhuman primate model. J Bone Joint Surg [Am] 2004; 86-A:1961–72. Google Scholar63 Ruje PQ, Boerman OC, Russel FG, et al. Controlled release of rhBMP-2 loaded poly (dl-lactic-co-glycolic acid)/calcium phosphate cement composites in vivo. J Control Release 2005;106:162–71. Crossref, Medline, ISI, Google Scholar64 Edwards RB 3rd, Seerherman HJ, Bogdanske JJ, et al. Percutaneous injection of recombinant human bone morphogenetic protein-2 in a calcium phosphate paste accelerates healing of a canine tibial osteotomy. J Bone Joint Surg [Am] 2004;86-A:1425–38. Google Scholar65 Li RH, Bouxsein ML, Blake CA, et al. rhBMP-2 injected in a calcium phosphate paste (alpha-BSM) accelerates healing in the rabbit ulnar osteotomy model. J Orthop Res 2003;21:997–1004. Crossref, Medline, ISI, Google Scholar66 Seerherman H, Li R, Wozney J. A review of preclinical program development for evaluating injectable carriers for osteogenic factors. J Bone Joint Surg [Am] 2003; 85-A(Suppl 3):96–108. Google Scholar67 Einhorn TA, Majeska RJ, Mohaideen A, et al. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Joint Surg [Am] 2003;85-A:1425–35. Google Scholar68 Blokhuis" @default.
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• W2106573856 title "The role of growth factors and related agents in accelerating fracture healing" @default.
• W2106573856 cites W188165332 @default.
• W2106573856 cites W1920277048 @default.
• W2106573856 cites W1962377023 @default.
• W2106573856 cites W1963564766 @default.
• W2106573856 cites W1969230308 @default.
• W2106573856 cites W1971797678 @default.
• W2106573856 cites W1972856924 @default.
• W2106573856 cites W1978844120 @default.
• W2106573856 cites W1979615651 @default.
• W2106573856 cites W1981875126 @default.
• W2106573856 cites W1982696638 @default.
• W2106573856 cites W1991742354 @default.
• W2106573856 cites W1993527272 @default.
• W2106573856 cites W1998912363 @default.
• W2106573856 cites W2005865470 @default.
• W2106573856 cites W2006729920 @default.
• W2106573856 cites W2014410963 @default.
• W2106573856 cites W2015668670 @default.
• W2106573856 cites W2018922394 @default.
• W2106573856 cites W2020364703 @default.
• W2106573856 cites W2022409816 @default.
• W2106573856 cites W2030140856 @default.
• W2106573856 cites W2030748676 @default.
• W2106573856 cites W2030913739 @default.
• W2106573856 cites W2034301129 @default.
• W2106573856 cites W2034614189 @default.
• W2106573856 cites W2036291368 @default.
• W2106573856 cites W2037897781 @default.
• W2106573856 cites W2037923118 @default.
• W2106573856 cites W2044417136 @default.
• W2106573856 cites W2044760997 @default.
• W2106573856 cites W2045072633 @default.
• W2106573856 cites W2046778891 @default.
• W2106573856 cites W2047974221 @default.
• W2106573856 cites W2049348171 @default.
• W2106573856 cites W2049550331 @default.
• W2106573856 cites W2050563961 @default.
• W2106573856 cites W2054180787 @default.
• W2106573856 cites W2055208639 @default.
• W2106573856 cites W2057797464 @default.
• W2106573856 cites W2057896668 @default.
• W2106573856 cites W2067498263 @default.
• W2106573856 cites W2075196631 @default.
• W2106573856 cites W2075527797 @default.
• W2106573856 cites W2079933080 @default.
• W2106573856 cites W2083407704 @default.
• W2106573856 cites W2085173237 @default.
• W2106573856 cites W2086564192 @default.
• W2106573856 cites W2089797394 @default.
• W2106573856 cites W2090254613 @default.
• W2106573856 cites W2090346665 @default.
• W2106573856 cites W2090399106 @default.
• W2106573856 cites W2091311058 @default.
• W2106573856 cites W2091678835 @default.
• W2106573856 cites W2093579735 @default.
• W2106573856 cites W2094321766 @default.
• W2106573856 cites W2101367251 @default.
• W2106573856 cites W2102618636 @default.
• W2106573856 cites W2104813930 @default.
• W2106573856 cites W2111100707 @default.
• W2106573856 cites W2115384001 @default.
• W2106573856 cites W2117115638 @default.
• W2106573856 cites W2119369991 @default.
• W2106573856 cites W2126928203 @default.
• W2106573856 cites W2133997977 @default.
• W2106573856 cites W2134154222 @default.
• W2106573856 cites W2146749461 @default.
• W2106573856 cites W2148468644 @default.
• W2106573856 cites W2153643845 @default.
• W2106573856 cites W2154015205 @default.
• W2106573856 cites W2156682347 @default.
• W2106573856 cites W2157023674 @default.
• W2106573856 cites W2161716085 @default.
• W2106573856 cites W2182467042 @default.
• W2106573856 cites W2260043331 @default.
• W2106573856 cites W2284393334 @default.
• W2106573856 cites W2293758038 @default.
• W2106573856 cites W3000473592 @default.
• W2106573856 cites W4233641026 @default.
• W2106573856 cites W4240863455 @default.
• W2106573856 cites W4319688072 @default.
• W2106573856 cites W4376848429 @default.
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