- Email: [email protected]
Bone morphogenetic proteins in critical-size bone defects: what are the options?
Injury, Int. J. Care Injured 40 (2009) S3, S39–S43
Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Bone morphogenetic proteins in critical-size bone defects: what are the options? Gerald Schmidmaiera, *, Rodolpho Capannab , Britt Wildemannc , Thierry Bequed , David Lowenberge a Center
for Musculoskeletal Surgery, Charit´e Universit¨ atsmedizin Berlin, Berlin, Germany of Orthopaedic Oncology and Reconstructive Surgery, Centro Traumatologico Ortopedico, Azienda Ospedaliera-Universitaria Careggi, Florence, Italy c Julius Wolff Institut, Berlin-Brandenburg Center for Regenerative Therapies, Charit´ e-Universit¨ atsmedizin Berlin, Berlin, Germany d Service d’Orthop´ edie-Traumatologie, Hˆ opital Avicenne, Bobigny, France e Department of Orthopedic Surgery, California Pacific Medical Center, San Francisco, CA, USA b Division
article info
abstract
Keywords: Critical-size defect BMPs Healing Bone grafting
The recent development of new orthopaedic devices and advanced techniques for softtissue reconstruction have clearly improved the outcome in trauma and orthopaedic surgery. Nevertheless, large bone defects are still difficult to treat and require a careful analysis of the situation. Individual planning of the reconstructive strategy is desirable. Bone morphogenetic proteins (BMPs) have successfully been applied in the clinical setting for the treatment of spinal fusion, fracture healing and delayed and non-unions. Following the ‘diamond concept’, surgeons have begun using BMPs for treatment of critical-size defects also – in most cases, ‘off label’; different treatment strategies are currently being evaluated. BMPs are often used in combination with autogenic, allogenic, xenogenic or synthetic grafting materials and even with mesenchymal stem cells. In addition, gene therapy approaches present an attractive option. Experimental studies and first clinical results are promising in the use of BMPs for treatment of critical-size defects; however, there is obvious need for further controlled studies to define strategies. © 2009 Elsevier Ltd. All rights reserved.
Introduction Segmental defects in bone remain an ongoing challenge in musculoskeletal care. For the most part, they represent the quintessential picture of a non-union, as with few exceptions they will not spontaneously heal. In segmental defects, the problem involves both absolute and relative size. Their absolute size can be easily measured and is clear. What is less clear is the impact of the relative size of defects in a bone segment. For instance, a 2 cm defect in the ulna would be viewed quite differently from a 2 cm defect in a femur. When bone morphogenetic proteins (BMPs) were introduced into clinical practice, surgeons began in the late 1990s to discuss whether these biologically active proteins could be used to fill segmental defects of bone. The discussions then focused on what size of defect could be healed using a BMP with or without allograft supplementation, primarily at the site of the tibial diaphysis. The term ‘critical-size defect’ was adopted to describe the limit of a defect (in length) which, if exceeded, might no longer heal without the addition of a bone graft or appropriate substitute. Early work by Cook et al.10,11 and Salkeld et al.41 helped pave the way to describing the efficacy of a BMP in critical-size long-bone defects in animal * Corresponding author. Center for Musculoskeletal Surgery, Charite´ Universitatsmedizin ¨ Berlin, Charite´ Platz 1, D-10117 Berlin, Germany. Tel.: +49 30 450 515 223; fax: +49 30 450 515 923. E-mail address: [email protected] (G. Schmidmaier). 0020-1383/ $ – see front matter © 2009 Elsevier Ltd. All rights reserved.
models. Geesink et al.24 then contributed to the early demonstration of its efficacy in human models. Following acceptance of the definition of a critical-size defect in a model, implications for the same term in clinical care expanded to describe the maximum-size defect that could be treated effectively with a BMP substitute. Retrospectively, ambiguity in the use of BMPs in clinical practice apparently began at this point. The qualification of critical-size defects, as measuring 2 cm in length and being effectively managed with placement of a BMP, soon became popular. This number was in fact extrapolated mainly from animal data in which controlled segmental defects were created surgically with minimal trauma to the soft-tissue envelope. There are no reliable data to confirm universal acceptance of this in clinical practice. It has now become clear that clinically numerous factors contribute to what a critical-size defect implies. Most surgeons accept that the use of a BMP for treatment of a segmental defect must be tailored to the individual circumstance. Certainly the bone involved has a bearing on the acceptable value for a critical-size defect. Some long bones heal more readily than others. With comparable stable fixation, the femur clearly is more likely to heal a defect than the tibia. The site on the affected bone can have a bearing on the acceptable segmental defect as well. Some clinicians would argue that the acceptable critical size of a segmental defect at the distal tibial diaphysis (the ‘watershed zone’) would be very limited. What may further confuse the issue is the spontaneous ossification of a bone defect with stable fixation. This is more
S40
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
commonly seen at the distal femoral shaft and seems to be due to preservation of a portion of the periosteal envelope. In these conditions, a 6 or 8 cm defect can spontaneously heal. Hence, a critical-size defect in the distal femur could easily be 8 cm in selected cases. This is in strict contrast to the distal tibial diaphysis, where the acceptable critical-size defect in a severely traumatised limb can be nil. It has therefore become quite clear that the bone segment involved, and often the actual site on the affected bone, have a direct effect on the ability of a defect to heal either on its own or with the isolated addition of a BMP. This fact alone has probably been one of the greatest obstacles in researching and comparing the efficacy of BMPs in the treatment of long-bone non-unions. Equally important in the calculation of an acceptable defect size for a particular limb segment are the amounts of acute and cumulative trauma the affected limb segment has sustained. This would mean that a limb that has sustained a grade 3B open fracture with five subsequent surgeries and a segmental defect would have a much smaller acceptable critical-size defect for treatment with a BMP than would a limb that has sustained a grade 2 open fracture and has undergone a single operative intervention to gain stable fixation and a healed soft-tissue envelope. Options for treatment of bone defects The treatment of bone defects is still a challenge in reconstructive surgery. Different options are available, with differing advantages and disadvantages. The choice of the right procedure depends on many factors and its formulation has changed over recent decades. There is no one strategy to be recommended for all conditions – in every case it is an individual decision and requires a careful analysis of the situation.16 The following aspects have to be considered: (1) The condition of the patient should be noted, including social situation, age, body weight, general state of health including comorbidities (e.g. diabetes), drugs and consumption of alcohol and nicotine. (2) Patient compliance is also important, as the duration of treatment may be prolonged, for example in distraction osteogenesis. (3) It has to be determined whether the defect has a critical size, is loaded or unloaded at the lower or upper extremity in the metaphyseal or diaphyseal part of the bone and whether the situation is stable or unstable. The vascularisation and softtissue coverage impact upon the outcome of every treatment strategy. (4) The history of the defect is of enormous importance. Factors such as the cause of the defect (e.g. trauma or tumour resection), number of previous interventions and particularly infection status have to be considered. In every case a possible infection has to be treated first, including radical debridement of the infected tissue.47,51 Careful analysis leads to diverse treatment options, such as soft-tissue conditioning including vacuum therapy,31 and various flap techniques34 that allow the reconstruction of soft tissue. Bone reconstruction can be achieved by a number of techniques, which for example in the tibia include distraction osteogenesis,38,39 free vascularised fibula grafts23 or fibula-pro-tibia transfer,21 use of autogenic, allogenic or xenogenic materials or de-mineralised bone matrix (DBM),25 and other synthetic bone substitutes and scaffolds.5,33,46,48 For treatment of critical-size defects, platelet-rich plasma43 and growth factors (BMPs)30,52 have been used, as well for osteoinduction. Often a combination of these methods is necessary to achieve bone defect and soft-tissue reconstruction with a good functional outcome. Tissue engineering, mesenchymal stem
cells and gene therapy approaches are newer techniques with or without combination with BMPs and have shown promising early results.37,49,58 Larger bone defects are still treated successfully using distraction osteogenesis. This method allows the in-vivo regeneration of new bone. Even in situations with critical-size bone defects and large soft-tissue defects, distraction osteogenesis in combination with free muscle flap grafts have achieved good results.35 However, the procedure is often very time consuming and side effects such as pin infections have been described in some cases.1,45 Furthermore, the docking site after successful distraction can produce a non-union and require the local application of autologous bone graft with or without application of a BMP.7 With the advances in biotechnology today, larger bone defects can be treated with BMPs in combination with synthetic carriers or graft materials and tissue engineering approaches.40 The ‘diamond concept’26 was successfully introduced to analyse and treat non-union situations. The treatment of atrophic nonunions caused by biological factors is very challenging and often requires re-operation with debridement of the atrophic tissue, re-stabilisation and use of biological techniques, such as local application of BMPs. The principles of the diamond concept can also be used for treatment of bone defect, i.e. mechanical stabilisation, osteoconduction by scaffolds, osteoinduction by growth factors, and osteogenesis by cells and vascularisation.27 After debridement and infection treatment, an adequate mechanical stabilisation is the precondition for successful bone-defect healing.13 Role of grafting materials in bone-defect treatment The treatment of bone defects often requires the use of grafting material. Ideally the graft provides an osteoconductive structure containing osteoinductive growth factors and osteogenic cells. The material must be biocompatible and, if required, should be biodegradable and provide stability.25 At present, it is believed that only autogenic bone meets most of these requirements and this is still considered the gold standard.53 The disadvantages of the use of autogenic material are the additional surgical intervention and the morbidity associated with the harvesting procedure, including donor-site pain, local infection and paraesthesia; additionally, the amount of bone available for autografting is limited.44,54,55 This has led to increased interest in bone-graft substitutes such as allogenic or xenogenic grafts, DBM and various other synthetic materials.13,19,20,42 Osteoinductive factors can be applied exogenously to these materials. Beside autografts, allografts and synthetic materials, DBM is used for bone-defect filling and treatment of non-unions. Different DBM formulations have been introduced into clinical practice in past years. However, not only have differences between the various products been identified with respect to total protein content and the absolute growth factor values, but also considerable variability between successive lots has been observed.61 Another source of bone graft material might be the cuttings produced during intramedullary reaming. The bony reaming debris is a rich source of growth factors comparable with that from iliac crest.50 Platelet-rich plasma (PRP) is in clinical use for bone-defect healing. Most applications described have been in maxillofacial surgery. The components of the autologous growth factors in PRP are promising. However, the total concentration is low compared with that in reaming debris or iliac crest.50 Role of BMPs in bone-defect treatment BMPs, as members of the TGF-b superfamily, are well known to be osteo- and chondroinductive.62 After the landmark study in 1965 by Urist, who discovered that de-mineralised bone induces ectopic
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
bone formation,57 it took 23 years to isolate the DNA and express the proteins which were named BMPs.62 These have been extensively investigated and have shown a strong osteoinductive effect in many experiments.32 Various studies have also been performed to investigate the effect of BMPs on bone-defect healing. Donati et al.15 showed the effect of BMP-7 on allograft integration in a long-bone critical-size defect sheep model, with faster callus formation and bone remodelling being demonstrated in the BMP-7 group. Azad et al.3 evaluated the effect of BMP-2 in a diabetic rat segmental defect model and found an increased area of new bone formation, higher mechanical stability and faster consolidation compared with control. However, studying a chronically infected segmental defect in the rat femur, Chen et al.8 reported significantly more mineralised callus in the BMP-7 group compared with control. BMP-2 and BMP-7 have received approval for restricted clinical use. Besides spinal applications,4,36 BMP-2 is approved for the treatment of open tibial fractures28 and BMP-7 for the treatment of tibial non-unions22,30 and, with limited indications, for spinal fusion. Nevertheless, both growth factors are often used ‘off label’ to stimulate bone and defect healing, not only in the upper and lower extremities6,14,17,60 but also in craniofacial surgery.56 BMPs still represent an expensive treatment option. However, studies clearly demonstrate that the total treatment costs for non-unions using BMP-7 are lower compared with standard treatment.12 BMPs have been investigated in the treatment of critical-size defects but, to date, the studies are not comparable and do not allow clear conclusions as to indications and strategies. Geesink et al.24 performed a prospective, randomised, double-blind study among 24 people undergoing high tibial osteotomy with a criticalsize defect, and found no bony changes in the untreated group but formation of new bone in the BMP-7-group. Other authors found no benefit in the use of BMP-7 compared with autologous bone graft in the healing of metaphyseal defects in the distal radius.18 Jones et al.29 showed, in a randomised controlled trial among people with a diaphyseal tibia fracture with cortical defects, that BMP-2 in combination with allograft was safe and as effective as autologous bone grafting. Clokie et al.9 successfully treated people with a major mandibular defect, following resection of biopsyproven ameloblastoma lesions or osteomyelitis, with a bio-implant containing BMP-7 in a DBM. Warnke et al.59 reported the growth and transplantation of a custom-vascularised bone graft in a man with an extended mandibular defect. In this case a titanium mesh cage was filled with bone mineral blocks and infiltrated with BMP-7. Thus prepared, the transplant was implanted into the latissimus dorsi muscle and, 7 weeks later, was transplanted as a free bone– muscle flap to repair the mandibular defect. Axelrad et al.2 recently reported on the occurrence of heterotopic ossification in limbs treated for a non-union with the commercially available exogenous BMPs. It is interesting to note that all cases in their experience occurred in a location with a well-vascularised muscle envelope circumferentially and all involved the humerus. We have never seen a case of heterotopic ossification to any degree at a level below the tibial plateau, despite the fact that the tibial shaft and distal tibia are the sites at which these exogenous BMPs have been most commonly used. Metaphyseal and diaphyseal critical-size defects One issue of particular importance in evaluating the treatment options for defects is their location in the bone. It is widely accepted that epiphsysio-metaphyseal defects and metaphyseal defects of long bones, with preserved cortical integrity, respond excellently to simple allografting or bone-void substitute filling of the confined defect. There is generally a good vascular supply, and these locations remodel well. We have all had success also with exogenous BMP applied to the proximal tibial metaphysis in selected cases where
S41
simpler methods have failed and there is a well-vascularised softtissue envelope of muscle in direct continuity with the confined bone. The remodelling ability at a diaphyseal level is less clear. Whereas bone graft substitutes do incorporate in partial structural defects of long bones, they do not remodel to the degree seen at the metaphyseal level. It has become quite apparent in clinical practice that the diaphysis of a previously traumatised limb does not represent a suitable source, at least in number, of stem cells to be activated upon by an exogenous BMP implant. For treating criticalsize defects in the diaphyseal region without bone stability, the choice of therapy is distinctly different from what it would be if there were an intact cortical rim and bone stability. Provided that good bone stabilisation can be achieved and there is a healthy muscle envelope in contact with the area of the critical-size defect, the addition of a BMP could potentially provide benefit, possibly in conjunction with a bone-void expander. Authors’ experience with the use of BMPs in bone defects The authors follow the ‘diamond concept’ for treatment of bone defects in special cases. After critical analyses of the patient and defect situations and exclusion of an ongoing infection, all necrotic material undergoes radical debridement; the defect zone needs a good blood supply, or the defect will fail to heal. The next step is adequate stabilisation with internal or external fixation. The use of angular stable implants allows soft-tissue closure and respects the periosteal blood supply important for bone healing and remodelling. The grafting material is then prepared. Depending on the size of the defect, the authors use 3.3–6.6 mg BMP-7 (Osigraft® , StrykerBiotec, West Lebanon, NH) for osteoinduction in combination with resorbable tricalciumphosphate (TCP) as the scaffold necessary for three-dimensional cell orientation (osteoconduction). Depending on the vitality of the defect in some cases, vital cells should be applied in addition (osteogenesis). BMPs stimulate vital cells, and treatment will fail if the osteoinductive growth factor is applied in necrotic situations without sufficient blood supply. Bone aspirate from iliac crest, reaming debris or mesenchymal stem cells (MSCs) can be the source of vital cells. After osteosynthesis, the defect then is filled with the ‘biological cocktail’. The surrounding soft tissue should be protected with, for example, a collagen sponge or polylactide membrane to reduce the risk of ectopic bone formation (Figures 1 and 2). Other workers use a two-step technique. After debridement, the defect is filled with bone cement which forms a membrane surrounding the defect. After a few weeks, the cement is removed and the defect filled with BMP-7 and grafting materials.5 The osteoinductive potential of BMPs may be beneficial for bonedefect treatment, but adequate osteosynthetic stabilisation is fundamental. Users have to realise that BMPs stimulate bone formation and do not compensate for inadequate stabilisation. The initial results are promising but, because of the variability of the treatment strategies, a comparison of the studies is difficult and there is substantial need for prospective investigations to define a clear indication, the right timing of application, the correct dosage and the best application technique. Therefore, most authors still recommend bone transportation and use of autografts as standard therapy for critical-size defect treatment.35 Conclusion BMPs play an increasing role in orthopaedic surgery and have been successfully used for spinal fusion, fracture healing and treatment of delayed or non-unions. Many in-vitro and in-vivo studies and clinical trials clearly show a strong osteoinductive effect of BMPs.
S42
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
Fig. 1. Case report of a critical-size defect treated with bone morphogenetic protein (BMP). (a–d) Infected non-union in a 42-year-old man after a 3º open femur fracture and multiple revision surgeries. (e, f) Segment resection start of distraction osteogenesis. (g, h) Failure of the procedure without any callus formation 5 months later. (i, j) Reaming and bone grafting of the contralateral femur. (k–m) Debridement of the defect – soft-tissue protection with a membrane and defect filling with BMP and reaming aspirate.
Fig. 2. Follow-up over 52 weeks of the BMP-treated critical-size defect. (a, b) At 6 weeks after bone defect filling. (c, d) At 10 weeks after bone defect filling: removal of the fixator and intramedullary nailing with a PDLLA–gentamicin-coated femur nail. (e, f) At 12 weeks after bone defect filling. (g, h) At 16 weeks after bone defect filling: full weight bearing. (i, j) At 24 weeks after bone defect filling. (k, l) Situation 52 weeks from bone filling. PDLLA: poly(D,L-lactide).
However, the standard therapies for critical-size defects are still distraction osteogenesis and autografting. There might be an indication for BMP use in the treatment of critical-size defects in combination or as an alternative to established therapies, such as distraction ostoegenesis. So far, the techniques described have been variable. There is pressing need for further experimental and clinical studies to define clear indications and treatment strategies. Competing interests: The authors declare no conflict of interest. References 1. Antoci V, Ono CM, Antoci V, Jr, Raney EM. Pin-tract infection during limb lengthening using external fixation. Am J Orthop 2008;37:E150–4. 2. Axelrad TW, Steen B, Lowenberg DW, et al. Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients. J Bone Joint Surg Br 2008;90:1617–22. 3. Azad V, Breitbart E, Al Zube L, et al. rhBMP-2 enhances the bone healing response in a diabetic rat segmental defect model. J Orthop Trauma 2009;23:267–76. 4. Benglis D, Wang MY, Levi AD. A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery 2008;62:ONS423–31. 5. Biau DJ, Pannier S, Masquelet AC, Glorion C. Case report: reconstruction of a 16-cm diaphyseal defect after Ewing’s resection in a child. Clin Orthop 2009; 467:572–7. 6. Bishop GB, Einhorn TA. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop 2007;31: 721–7.
7. Burkhart KJ, Rommens PM. Intramedullary application of bone morphogenetic protein in the management of a major bone defect after an Ilizarov procedure. J Bone Joint Surg Br 2008;90:806–9. 8. Chen X, Schmidt AH, Tsukayama DT, et al. Recombinant human osteogenic protein-1 induces bone formation in a chronically infected, internally stabilized segmental defect in the rat femur. J Bone Joint Surg.Am 2006;88:1510–23. 9. Clokie CM, Sandor GK. Reconstruction of 10 major mandibular defects using bioimplants containing BMP-7. J Can Dent Assoc 2008;74:67–72. 10. 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;76:827–38. 11. Cook SD, Wolfe MW, Salkeld SL, Rueger DC. Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates. J Bone Joint Surg Am 1995;77:734–50. 12. Dahabreh Z, Dimitriou R, Giannoudis PV. Health economics: a cost analysis of treatment of persistent fracture non-unions using bone morphogenetic protein-7. Injury 2007;38:371–7. 13. DeLong WG, Jr, Einhorn TA, Koval K, et al. Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis. J Bone Joint Surg Am 2007; 89:649–58. 14. Dimitriou R, Dahabreh Z, Katsoulis E, et al. Application of recombinant BMP-7 on persistent upper and lower limb non-unions. Injury 2005;36(Suppl 4):S51–9. 15. Donati D, Di Bella C, Lucarelli E, et al. OP-1 application in bone allograft integration: preliminary results in sheep experimental surgery. Injury 2008; 39(Suppl 2):S65–72. 16. Drosse I, Volkmer E, Capanna R, et al. Tissue engineering for bone defect healing: an update on a multi-component approach. Injury 2008;39(Suppl 2):S9–20. 17. 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;85:1425–35. 18. Ekrol I, Hajducka C, Court-Brown C, McQueen MM. A comparison of RhBMP-7
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
19.
20. 21.
22.
23.
24.
25. 26. 27. 28.
29.
30. 31.
32. 33. 34. 35. 36.
37. 38. 39.
(OP-1) and autogenous graft for metaphyseal defects after osteotomy of the distal radius. Injury 2008;39(Suppl 2):S73–82. Eppley BL, Pietrzak WS, Blanton MW. Allograft and alloplastic bone substitutes: a review of science and technology for the craniomaxillofacial surgeon. J Craniofac Surg 2005;16:981–9. Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am 2002;84:454–64. Fohn M, Bannasch H, Stark GB. Single step fibula-pro-tibia transfer and soft tissue coverage with free myocutaneous latissimus dorsi flap after extensive osteomyelitis and soft tissue necrosis – a 3 year follow up. J Plast Reconstr Aesthet Surg 2008, in press. Friedlaender GE, Perry CR, Cole JD, et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions: a prospective, randomized clinical trial comparing rhOP-1 with fresh bone autograft. J Bone Joint Surg Am 2001;83:S151. Friedrich JB, Moran SL, Bishop AT, Shin AY. Free vascularized fibula grafts for salvage of failed oncologic long bone reconstruction and pathologic fractures. Microsurgery 2009. Geesink RG, 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;81:710–8. Giannoudis PV, Dinopoulos H, Tsiridis E. Bone substitutes: an update. Injury 2005;36S:S20–7. Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury 2007;38(Suppl 4):S3–6. Giannoudis PV, Einhorn TA, Schmidmaier G, Marsh D. The diamond concept – open questions. Injury 2008;39(Suppl 2):S5–8. 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;84:2123–4. Jones AL, Bucholz RW, Bosse MJ, et al. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am 2006;88:1431–41. Kanakaris NK, Calori GM, Verdonk R, et al. Application of BMP-7 to tibial nonunions: a 3-year multicenter experience. Injury 2008;39(Suppl 2):S83–90. Kanakaris NK, Thanasas C, Keramaris N, et al. The efficacy of negative pressure wound therapy in the management of lower extremity trauma: review of clinical evidence. Injury 2007;38(Suppl 5):S9–18. Lane JM. Bone morphogenic protein science and studies. J Orthop.Trauma 2005; 19:S17–22. Laurencin C, Khan Y, El Amin SF. Bone graft substitutes. Expert Rev Med Devices 2006;3:49–57. Levin LS. Principles of definitive soft tissue coverage with flaps. J Orthop Trauma 2008;22:S161–6. Lowenberg DW, Feibel RJ, Louie KW, Eshima I. Combined muscle flap and Ilizarov reconstruction for bone and soft tissue defects. Clin Orthop 1996;332:37–51. Papakostidis C, Kontakis G, Bhandari M, Giannoudis PV. Efficacy of autologous iliac crest bone graft and bone morphogenetic proteins for posterolateral fusion of lumbar spine: a meta-analysis of the results. Spine 2008;33:E680–92. Petite H, Viateau V, Bensaid W, et al. Tissue-engineered bone regeneration. Nat Biotechnol 2000;18:959–63. Raschke M, Ficke J, Freileben C, et al. Posttraumatic segmental and soft tissue defects of the tibia treated with the Ilizarov method. Injury 1993;24:45–53. Raschke M, Oedekoven G, Ficke J, Claudi B. The monorail method for segment bone transport. Injury 1993;24:54–61.
S43
40. Regauer M, Jurgens I, Kotsianos D, et al. [New-bone formation by osteogenic protein-1 and autogenic bone marrow in a critical tibial defect model in sheep.] Zentralbl Chir 2005;130:338–45. 41. 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. 42. Sammarco VJ, Chang L. Modern issues in bone graft substitutes and advances in bone tissue technology. Foot Ankle Clin 2002;7:19–41. 43. Sammartino G, Tia M, Marenzi G, et al. Use of autologous platelet-rich plasma (PRP) in periodontal defect treatment after extraction of impacted mandibular third molars. J Oral Maxillofac Surg 2005;63:766–70. 44. Sasso RC, Lehuec JC, Shaffrey C. Iliac crest bone graft donor site pain after anterior lumbar interbody fusion: a prospective patient satisfaction outcome assessment. J Spinal Disord Tech 2005;18:S77–81. 45. Saulacic N, Zix J, Iizuka T. Complication rates and associated factors in alveolar distraction osteogenesis: a comprehensive review. Int J Oral Maxillofac Surg 2009;38:210–7. 46. Schieker M, Heiss C, Mutschler W. [Bone substitutes.] Unfallchirurg 2008;111: 613–20. 47. Schieker M, Mutschler W. [Bridging posttraumatic bony defects. Established and new methods.] Unfallchirurg 2006;109:715–32. 48. Schieker M, Seitz H, Drosse I, et al. Biomaterials as scaffold for bone tissue engineering. European Journal of Trauma and Emergency Surgery 2006;32:114–24. 49. Schillinger U, Wexel G, Hacker C, et al. A fibrin glue composition as carrier for nucleic acid vectors. Pharm Res 2008;25:2946–62. 50. Schmidmaier G, Herrmann S, Green J, et al. Quantitative assessment of growth factors in reaming aspirate, iliac crest, and platelet preparation. Bone 2006;39: 1156–63. 51. Schmidmaier G, Lucke M, Wildemann B, et al. Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury 2006; 37(Suppl 2):S105–12. 52. Schmidmaier G, Schwabe P, Wildemann B, Haas NP. Use of bone morphogenetic proteins for treatment of non-unions and future perspectives. Injury 2007; 38(Suppl 4):S35–41. 53. Sen MK, Miclau T. Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions? Injury 2007;38(Suppl 1):S75–80. 54. Silber JS, Anderson DG, Daffner SD, et al. Donor site morbidity after anterior iliac crest bone harvest for single-level anterior cervical discectomy and fusion. Spine 2003;28:134–9. 55. Skaggs DL, Samuelson MA, Hale JM, et al. Complications of posterior iliac crest bone grafting in spine surgery in children. Spine 2000;25:2400–2. 56. Smith DM, Cooper GM, Mooney MP, et al. Bone morphogenetic protein 2 therapy for craniofacial surgery. J Craniofac Surg 2008;19:1244–59. 57. Urist MR. Bone: formation by autoinduction. Science 1965;150:893–9. 58. Vacanti CA, Bonassar LJ, Vacanti MP, Shufflebarger J. Replacement of an avulsed phalanx with tissue-engineered bone. N Engl J Med 2001;344:1511–4. 59. Warnke PH, Springer IN, Wiltfang J, et al. Growth and transplantation of a custom vascularised bone graft in a man. Lancet 2004;364:766–70. 60. White AP, Vaccaro AR, Hall JA, et al. Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion. Int Orthop 2007;31:735–41. 61. Wildemann B, Kadow-Romacker A, Haas NP, Schmidmaier G. Quantification of various growth factors in different demineralized bone matrix preparations. J Biomed Mater Res A 2007;81:437–42. 62. Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988;242:1528–34.
Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Bone morphogenetic proteins in critical-size bone defects: what are the options? Gerald Schmidmaiera, *, Rodolpho Capannab , Britt Wildemannc , Thierry Bequed , David Lowenberge a Center
for Musculoskeletal Surgery, Charit´e Universit¨ atsmedizin Berlin, Berlin, Germany of Orthopaedic Oncology and Reconstructive Surgery, Centro Traumatologico Ortopedico, Azienda Ospedaliera-Universitaria Careggi, Florence, Italy c Julius Wolff Institut, Berlin-Brandenburg Center for Regenerative Therapies, Charit´ e-Universit¨ atsmedizin Berlin, Berlin, Germany d Service d’Orthop´ edie-Traumatologie, Hˆ opital Avicenne, Bobigny, France e Department of Orthopedic Surgery, California Pacific Medical Center, San Francisco, CA, USA b Division
article info
abstract
Keywords: Critical-size defect BMPs Healing Bone grafting
The recent development of new orthopaedic devices and advanced techniques for softtissue reconstruction have clearly improved the outcome in trauma and orthopaedic surgery. Nevertheless, large bone defects are still difficult to treat and require a careful analysis of the situation. Individual planning of the reconstructive strategy is desirable. Bone morphogenetic proteins (BMPs) have successfully been applied in the clinical setting for the treatment of spinal fusion, fracture healing and delayed and non-unions. Following the ‘diamond concept’, surgeons have begun using BMPs for treatment of critical-size defects also – in most cases, ‘off label’; different treatment strategies are currently being evaluated. BMPs are often used in combination with autogenic, allogenic, xenogenic or synthetic grafting materials and even with mesenchymal stem cells. In addition, gene therapy approaches present an attractive option. Experimental studies and first clinical results are promising in the use of BMPs for treatment of critical-size defects; however, there is obvious need for further controlled studies to define strategies. © 2009 Elsevier Ltd. All rights reserved.
Introduction Segmental defects in bone remain an ongoing challenge in musculoskeletal care. For the most part, they represent the quintessential picture of a non-union, as with few exceptions they will not spontaneously heal. In segmental defects, the problem involves both absolute and relative size. Their absolute size can be easily measured and is clear. What is less clear is the impact of the relative size of defects in a bone segment. For instance, a 2 cm defect in the ulna would be viewed quite differently from a 2 cm defect in a femur. When bone morphogenetic proteins (BMPs) were introduced into clinical practice, surgeons began in the late 1990s to discuss whether these biologically active proteins could be used to fill segmental defects of bone. The discussions then focused on what size of defect could be healed using a BMP with or without allograft supplementation, primarily at the site of the tibial diaphysis. The term ‘critical-size defect’ was adopted to describe the limit of a defect (in length) which, if exceeded, might no longer heal without the addition of a bone graft or appropriate substitute. Early work by Cook et al.10,11 and Salkeld et al.41 helped pave the way to describing the efficacy of a BMP in critical-size long-bone defects in animal * Corresponding author. Center for Musculoskeletal Surgery, Charite´ Universitatsmedizin ¨ Berlin, Charite´ Platz 1, D-10117 Berlin, Germany. Tel.: +49 30 450 515 223; fax: +49 30 450 515 923. E-mail address: [email protected] (G. Schmidmaier). 0020-1383/ $ – see front matter © 2009 Elsevier Ltd. All rights reserved.
models. Geesink et al.24 then contributed to the early demonstration of its efficacy in human models. Following acceptance of the definition of a critical-size defect in a model, implications for the same term in clinical care expanded to describe the maximum-size defect that could be treated effectively with a BMP substitute. Retrospectively, ambiguity in the use of BMPs in clinical practice apparently began at this point. The qualification of critical-size defects, as measuring 2 cm in length and being effectively managed with placement of a BMP, soon became popular. This number was in fact extrapolated mainly from animal data in which controlled segmental defects were created surgically with minimal trauma to the soft-tissue envelope. There are no reliable data to confirm universal acceptance of this in clinical practice. It has now become clear that clinically numerous factors contribute to what a critical-size defect implies. Most surgeons accept that the use of a BMP for treatment of a segmental defect must be tailored to the individual circumstance. Certainly the bone involved has a bearing on the acceptable value for a critical-size defect. Some long bones heal more readily than others. With comparable stable fixation, the femur clearly is more likely to heal a defect than the tibia. The site on the affected bone can have a bearing on the acceptable segmental defect as well. Some clinicians would argue that the acceptable critical size of a segmental defect at the distal tibial diaphysis (the ‘watershed zone’) would be very limited. What may further confuse the issue is the spontaneous ossification of a bone defect with stable fixation. This is more
S40
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
commonly seen at the distal femoral shaft and seems to be due to preservation of a portion of the periosteal envelope. In these conditions, a 6 or 8 cm defect can spontaneously heal. Hence, a critical-size defect in the distal femur could easily be 8 cm in selected cases. This is in strict contrast to the distal tibial diaphysis, where the acceptable critical-size defect in a severely traumatised limb can be nil. It has therefore become quite clear that the bone segment involved, and often the actual site on the affected bone, have a direct effect on the ability of a defect to heal either on its own or with the isolated addition of a BMP. This fact alone has probably been one of the greatest obstacles in researching and comparing the efficacy of BMPs in the treatment of long-bone non-unions. Equally important in the calculation of an acceptable defect size for a particular limb segment are the amounts of acute and cumulative trauma the affected limb segment has sustained. This would mean that a limb that has sustained a grade 3B open fracture with five subsequent surgeries and a segmental defect would have a much smaller acceptable critical-size defect for treatment with a BMP than would a limb that has sustained a grade 2 open fracture and has undergone a single operative intervention to gain stable fixation and a healed soft-tissue envelope. Options for treatment of bone defects The treatment of bone defects is still a challenge in reconstructive surgery. Different options are available, with differing advantages and disadvantages. The choice of the right procedure depends on many factors and its formulation has changed over recent decades. There is no one strategy to be recommended for all conditions – in every case it is an individual decision and requires a careful analysis of the situation.16 The following aspects have to be considered: (1) The condition of the patient should be noted, including social situation, age, body weight, general state of health including comorbidities (e.g. diabetes), drugs and consumption of alcohol and nicotine. (2) Patient compliance is also important, as the duration of treatment may be prolonged, for example in distraction osteogenesis. (3) It has to be determined whether the defect has a critical size, is loaded or unloaded at the lower or upper extremity in the metaphyseal or diaphyseal part of the bone and whether the situation is stable or unstable. The vascularisation and softtissue coverage impact upon the outcome of every treatment strategy. (4) The history of the defect is of enormous importance. Factors such as the cause of the defect (e.g. trauma or tumour resection), number of previous interventions and particularly infection status have to be considered. In every case a possible infection has to be treated first, including radical debridement of the infected tissue.47,51 Careful analysis leads to diverse treatment options, such as soft-tissue conditioning including vacuum therapy,31 and various flap techniques34 that allow the reconstruction of soft tissue. Bone reconstruction can be achieved by a number of techniques, which for example in the tibia include distraction osteogenesis,38,39 free vascularised fibula grafts23 or fibula-pro-tibia transfer,21 use of autogenic, allogenic or xenogenic materials or de-mineralised bone matrix (DBM),25 and other synthetic bone substitutes and scaffolds.5,33,46,48 For treatment of critical-size defects, platelet-rich plasma43 and growth factors (BMPs)30,52 have been used, as well for osteoinduction. Often a combination of these methods is necessary to achieve bone defect and soft-tissue reconstruction with a good functional outcome. Tissue engineering, mesenchymal stem
cells and gene therapy approaches are newer techniques with or without combination with BMPs and have shown promising early results.37,49,58 Larger bone defects are still treated successfully using distraction osteogenesis. This method allows the in-vivo regeneration of new bone. Even in situations with critical-size bone defects and large soft-tissue defects, distraction osteogenesis in combination with free muscle flap grafts have achieved good results.35 However, the procedure is often very time consuming and side effects such as pin infections have been described in some cases.1,45 Furthermore, the docking site after successful distraction can produce a non-union and require the local application of autologous bone graft with or without application of a BMP.7 With the advances in biotechnology today, larger bone defects can be treated with BMPs in combination with synthetic carriers or graft materials and tissue engineering approaches.40 The ‘diamond concept’26 was successfully introduced to analyse and treat non-union situations. The treatment of atrophic nonunions caused by biological factors is very challenging and often requires re-operation with debridement of the atrophic tissue, re-stabilisation and use of biological techniques, such as local application of BMPs. The principles of the diamond concept can also be used for treatment of bone defect, i.e. mechanical stabilisation, osteoconduction by scaffolds, osteoinduction by growth factors, and osteogenesis by cells and vascularisation.27 After debridement and infection treatment, an adequate mechanical stabilisation is the precondition for successful bone-defect healing.13 Role of grafting materials in bone-defect treatment The treatment of bone defects often requires the use of grafting material. Ideally the graft provides an osteoconductive structure containing osteoinductive growth factors and osteogenic cells. The material must be biocompatible and, if required, should be biodegradable and provide stability.25 At present, it is believed that only autogenic bone meets most of these requirements and this is still considered the gold standard.53 The disadvantages of the use of autogenic material are the additional surgical intervention and the morbidity associated with the harvesting procedure, including donor-site pain, local infection and paraesthesia; additionally, the amount of bone available for autografting is limited.44,54,55 This has led to increased interest in bone-graft substitutes such as allogenic or xenogenic grafts, DBM and various other synthetic materials.13,19,20,42 Osteoinductive factors can be applied exogenously to these materials. Beside autografts, allografts and synthetic materials, DBM is used for bone-defect filling and treatment of non-unions. Different DBM formulations have been introduced into clinical practice in past years. However, not only have differences between the various products been identified with respect to total protein content and the absolute growth factor values, but also considerable variability between successive lots has been observed.61 Another source of bone graft material might be the cuttings produced during intramedullary reaming. The bony reaming debris is a rich source of growth factors comparable with that from iliac crest.50 Platelet-rich plasma (PRP) is in clinical use for bone-defect healing. Most applications described have been in maxillofacial surgery. The components of the autologous growth factors in PRP are promising. However, the total concentration is low compared with that in reaming debris or iliac crest.50 Role of BMPs in bone-defect treatment BMPs, as members of the TGF-b superfamily, are well known to be osteo- and chondroinductive.62 After the landmark study in 1965 by Urist, who discovered that de-mineralised bone induces ectopic
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
bone formation,57 it took 23 years to isolate the DNA and express the proteins which were named BMPs.62 These have been extensively investigated and have shown a strong osteoinductive effect in many experiments.32 Various studies have also been performed to investigate the effect of BMPs on bone-defect healing. Donati et al.15 showed the effect of BMP-7 on allograft integration in a long-bone critical-size defect sheep model, with faster callus formation and bone remodelling being demonstrated in the BMP-7 group. Azad et al.3 evaluated the effect of BMP-2 in a diabetic rat segmental defect model and found an increased area of new bone formation, higher mechanical stability and faster consolidation compared with control. However, studying a chronically infected segmental defect in the rat femur, Chen et al.8 reported significantly more mineralised callus in the BMP-7 group compared with control. BMP-2 and BMP-7 have received approval for restricted clinical use. Besides spinal applications,4,36 BMP-2 is approved for the treatment of open tibial fractures28 and BMP-7 for the treatment of tibial non-unions22,30 and, with limited indications, for spinal fusion. Nevertheless, both growth factors are often used ‘off label’ to stimulate bone and defect healing, not only in the upper and lower extremities6,14,17,60 but also in craniofacial surgery.56 BMPs still represent an expensive treatment option. However, studies clearly demonstrate that the total treatment costs for non-unions using BMP-7 are lower compared with standard treatment.12 BMPs have been investigated in the treatment of critical-size defects but, to date, the studies are not comparable and do not allow clear conclusions as to indications and strategies. Geesink et al.24 performed a prospective, randomised, double-blind study among 24 people undergoing high tibial osteotomy with a criticalsize defect, and found no bony changes in the untreated group but formation of new bone in the BMP-7-group. Other authors found no benefit in the use of BMP-7 compared with autologous bone graft in the healing of metaphyseal defects in the distal radius.18 Jones et al.29 showed, in a randomised controlled trial among people with a diaphyseal tibia fracture with cortical defects, that BMP-2 in combination with allograft was safe and as effective as autologous bone grafting. Clokie et al.9 successfully treated people with a major mandibular defect, following resection of biopsyproven ameloblastoma lesions or osteomyelitis, with a bio-implant containing BMP-7 in a DBM. Warnke et al.59 reported the growth and transplantation of a custom-vascularised bone graft in a man with an extended mandibular defect. In this case a titanium mesh cage was filled with bone mineral blocks and infiltrated with BMP-7. Thus prepared, the transplant was implanted into the latissimus dorsi muscle and, 7 weeks later, was transplanted as a free bone– muscle flap to repair the mandibular defect. Axelrad et al.2 recently reported on the occurrence of heterotopic ossification in limbs treated for a non-union with the commercially available exogenous BMPs. It is interesting to note that all cases in their experience occurred in a location with a well-vascularised muscle envelope circumferentially and all involved the humerus. We have never seen a case of heterotopic ossification to any degree at a level below the tibial plateau, despite the fact that the tibial shaft and distal tibia are the sites at which these exogenous BMPs have been most commonly used. Metaphyseal and diaphyseal critical-size defects One issue of particular importance in evaluating the treatment options for defects is their location in the bone. It is widely accepted that epiphsysio-metaphyseal defects and metaphyseal defects of long bones, with preserved cortical integrity, respond excellently to simple allografting or bone-void substitute filling of the confined defect. There is generally a good vascular supply, and these locations remodel well. We have all had success also with exogenous BMP applied to the proximal tibial metaphysis in selected cases where
S41
simpler methods have failed and there is a well-vascularised softtissue envelope of muscle in direct continuity with the confined bone. The remodelling ability at a diaphyseal level is less clear. Whereas bone graft substitutes do incorporate in partial structural defects of long bones, they do not remodel to the degree seen at the metaphyseal level. It has become quite apparent in clinical practice that the diaphysis of a previously traumatised limb does not represent a suitable source, at least in number, of stem cells to be activated upon by an exogenous BMP implant. For treating criticalsize defects in the diaphyseal region without bone stability, the choice of therapy is distinctly different from what it would be if there were an intact cortical rim and bone stability. Provided that good bone stabilisation can be achieved and there is a healthy muscle envelope in contact with the area of the critical-size defect, the addition of a BMP could potentially provide benefit, possibly in conjunction with a bone-void expander. Authors’ experience with the use of BMPs in bone defects The authors follow the ‘diamond concept’ for treatment of bone defects in special cases. After critical analyses of the patient and defect situations and exclusion of an ongoing infection, all necrotic material undergoes radical debridement; the defect zone needs a good blood supply, or the defect will fail to heal. The next step is adequate stabilisation with internal or external fixation. The use of angular stable implants allows soft-tissue closure and respects the periosteal blood supply important for bone healing and remodelling. The grafting material is then prepared. Depending on the size of the defect, the authors use 3.3–6.6 mg BMP-7 (Osigraft® , StrykerBiotec, West Lebanon, NH) for osteoinduction in combination with resorbable tricalciumphosphate (TCP) as the scaffold necessary for three-dimensional cell orientation (osteoconduction). Depending on the vitality of the defect in some cases, vital cells should be applied in addition (osteogenesis). BMPs stimulate vital cells, and treatment will fail if the osteoinductive growth factor is applied in necrotic situations without sufficient blood supply. Bone aspirate from iliac crest, reaming debris or mesenchymal stem cells (MSCs) can be the source of vital cells. After osteosynthesis, the defect then is filled with the ‘biological cocktail’. The surrounding soft tissue should be protected with, for example, a collagen sponge or polylactide membrane to reduce the risk of ectopic bone formation (Figures 1 and 2). Other workers use a two-step technique. After debridement, the defect is filled with bone cement which forms a membrane surrounding the defect. After a few weeks, the cement is removed and the defect filled with BMP-7 and grafting materials.5 The osteoinductive potential of BMPs may be beneficial for bonedefect treatment, but adequate osteosynthetic stabilisation is fundamental. Users have to realise that BMPs stimulate bone formation and do not compensate for inadequate stabilisation. The initial results are promising but, because of the variability of the treatment strategies, a comparison of the studies is difficult and there is substantial need for prospective investigations to define a clear indication, the right timing of application, the correct dosage and the best application technique. Therefore, most authors still recommend bone transportation and use of autografts as standard therapy for critical-size defect treatment.35 Conclusion BMPs play an increasing role in orthopaedic surgery and have been successfully used for spinal fusion, fracture healing and treatment of delayed or non-unions. Many in-vitro and in-vivo studies and clinical trials clearly show a strong osteoinductive effect of BMPs.
S42
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
Fig. 1. Case report of a critical-size defect treated with bone morphogenetic protein (BMP). (a–d) Infected non-union in a 42-year-old man after a 3º open femur fracture and multiple revision surgeries. (e, f) Segment resection start of distraction osteogenesis. (g, h) Failure of the procedure without any callus formation 5 months later. (i, j) Reaming and bone grafting of the contralateral femur. (k–m) Debridement of the defect – soft-tissue protection with a membrane and defect filling with BMP and reaming aspirate.
Fig. 2. Follow-up over 52 weeks of the BMP-treated critical-size defect. (a, b) At 6 weeks after bone defect filling. (c, d) At 10 weeks after bone defect filling: removal of the fixator and intramedullary nailing with a PDLLA–gentamicin-coated femur nail. (e, f) At 12 weeks after bone defect filling. (g, h) At 16 weeks after bone defect filling: full weight bearing. (i, j) At 24 weeks after bone defect filling. (k, l) Situation 52 weeks from bone filling. PDLLA: poly(D,L-lactide).
However, the standard therapies for critical-size defects are still distraction osteogenesis and autografting. There might be an indication for BMP use in the treatment of critical-size defects in combination or as an alternative to established therapies, such as distraction ostoegenesis. So far, the techniques described have been variable. There is pressing need for further experimental and clinical studies to define clear indications and treatment strategies. Competing interests: The authors declare no conflict of interest. References 1. Antoci V, Ono CM, Antoci V, Jr, Raney EM. Pin-tract infection during limb lengthening using external fixation. Am J Orthop 2008;37:E150–4. 2. Axelrad TW, Steen B, Lowenberg DW, et al. Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients. J Bone Joint Surg Br 2008;90:1617–22. 3. Azad V, Breitbart E, Al Zube L, et al. rhBMP-2 enhances the bone healing response in a diabetic rat segmental defect model. J Orthop Trauma 2009;23:267–76. 4. Benglis D, Wang MY, Levi AD. A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery 2008;62:ONS423–31. 5. Biau DJ, Pannier S, Masquelet AC, Glorion C. Case report: reconstruction of a 16-cm diaphyseal defect after Ewing’s resection in a child. Clin Orthop 2009; 467:572–7. 6. Bishop GB, Einhorn TA. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop 2007;31: 721–7.
7. Burkhart KJ, Rommens PM. Intramedullary application of bone morphogenetic protein in the management of a major bone defect after an Ilizarov procedure. J Bone Joint Surg Br 2008;90:806–9. 8. Chen X, Schmidt AH, Tsukayama DT, et al. Recombinant human osteogenic protein-1 induces bone formation in a chronically infected, internally stabilized segmental defect in the rat femur. J Bone Joint Surg.Am 2006;88:1510–23. 9. Clokie CM, Sandor GK. Reconstruction of 10 major mandibular defects using bioimplants containing BMP-7. J Can Dent Assoc 2008;74:67–72. 10. 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;76:827–38. 11. Cook SD, Wolfe MW, Salkeld SL, Rueger DC. Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates. J Bone Joint Surg Am 1995;77:734–50. 12. Dahabreh Z, Dimitriou R, Giannoudis PV. Health economics: a cost analysis of treatment of persistent fracture non-unions using bone morphogenetic protein-7. Injury 2007;38:371–7. 13. DeLong WG, Jr, Einhorn TA, Koval K, et al. Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis. J Bone Joint Surg Am 2007; 89:649–58. 14. Dimitriou R, Dahabreh Z, Katsoulis E, et al. Application of recombinant BMP-7 on persistent upper and lower limb non-unions. Injury 2005;36(Suppl 4):S51–9. 15. Donati D, Di Bella C, Lucarelli E, et al. OP-1 application in bone allograft integration: preliminary results in sheep experimental surgery. Injury 2008; 39(Suppl 2):S65–72. 16. Drosse I, Volkmer E, Capanna R, et al. Tissue engineering for bone defect healing: an update on a multi-component approach. Injury 2008;39(Suppl 2):S9–20. 17. 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;85:1425–35. 18. Ekrol I, Hajducka C, Court-Brown C, McQueen MM. A comparison of RhBMP-7
G. Schmidmaier et al. / Injury, Int. J. Care Injured 40 (2009) S39–S43
19.
20. 21.
22.
23.
24.
25. 26. 27. 28.
29.
30. 31.
32. 33. 34. 35. 36.
37. 38. 39.
(OP-1) and autogenous graft for metaphyseal defects after osteotomy of the distal radius. Injury 2008;39(Suppl 2):S73–82. Eppley BL, Pietrzak WS, Blanton MW. Allograft and alloplastic bone substitutes: a review of science and technology for the craniomaxillofacial surgeon. J Craniofac Surg 2005;16:981–9. Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am 2002;84:454–64. Fohn M, Bannasch H, Stark GB. Single step fibula-pro-tibia transfer and soft tissue coverage with free myocutaneous latissimus dorsi flap after extensive osteomyelitis and soft tissue necrosis – a 3 year follow up. J Plast Reconstr Aesthet Surg 2008, in press. Friedlaender GE, Perry CR, Cole JD, et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions: a prospective, randomized clinical trial comparing rhOP-1 with fresh bone autograft. J Bone Joint Surg Am 2001;83:S151. Friedrich JB, Moran SL, Bishop AT, Shin AY. Free vascularized fibula grafts for salvage of failed oncologic long bone reconstruction and pathologic fractures. Microsurgery 2009. Geesink RG, 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;81:710–8. Giannoudis PV, Dinopoulos H, Tsiridis E. Bone substitutes: an update. Injury 2005;36S:S20–7. Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury 2007;38(Suppl 4):S3–6. Giannoudis PV, Einhorn TA, Schmidmaier G, Marsh D. The diamond concept – open questions. Injury 2008;39(Suppl 2):S5–8. 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;84:2123–4. Jones AL, Bucholz RW, Bosse MJ, et al. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am 2006;88:1431–41. Kanakaris NK, Calori GM, Verdonk R, et al. Application of BMP-7 to tibial nonunions: a 3-year multicenter experience. Injury 2008;39(Suppl 2):S83–90. Kanakaris NK, Thanasas C, Keramaris N, et al. The efficacy of negative pressure wound therapy in the management of lower extremity trauma: review of clinical evidence. Injury 2007;38(Suppl 5):S9–18. Lane JM. Bone morphogenic protein science and studies. J Orthop.Trauma 2005; 19:S17–22. Laurencin C, Khan Y, El Amin SF. Bone graft substitutes. Expert Rev Med Devices 2006;3:49–57. Levin LS. Principles of definitive soft tissue coverage with flaps. J Orthop Trauma 2008;22:S161–6. Lowenberg DW, Feibel RJ, Louie KW, Eshima I. Combined muscle flap and Ilizarov reconstruction for bone and soft tissue defects. Clin Orthop 1996;332:37–51. Papakostidis C, Kontakis G, Bhandari M, Giannoudis PV. Efficacy of autologous iliac crest bone graft and bone morphogenetic proteins for posterolateral fusion of lumbar spine: a meta-analysis of the results. Spine 2008;33:E680–92. Petite H, Viateau V, Bensaid W, et al. Tissue-engineered bone regeneration. Nat Biotechnol 2000;18:959–63. Raschke M, Ficke J, Freileben C, et al. Posttraumatic segmental and soft tissue defects of the tibia treated with the Ilizarov method. Injury 1993;24:45–53. Raschke M, Oedekoven G, Ficke J, Claudi B. The monorail method for segment bone transport. Injury 1993;24:54–61.
S43
40. Regauer M, Jurgens I, Kotsianos D, et al. [New-bone formation by osteogenic protein-1 and autogenic bone marrow in a critical tibial defect model in sheep.] Zentralbl Chir 2005;130:338–45. 41. 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. 42. Sammarco VJ, Chang L. Modern issues in bone graft substitutes and advances in bone tissue technology. Foot Ankle Clin 2002;7:19–41. 43. Sammartino G, Tia M, Marenzi G, et al. Use of autologous platelet-rich plasma (PRP) in periodontal defect treatment after extraction of impacted mandibular third molars. J Oral Maxillofac Surg 2005;63:766–70. 44. Sasso RC, Lehuec JC, Shaffrey C. Iliac crest bone graft donor site pain after anterior lumbar interbody fusion: a prospective patient satisfaction outcome assessment. J Spinal Disord Tech 2005;18:S77–81. 45. Saulacic N, Zix J, Iizuka T. Complication rates and associated factors in alveolar distraction osteogenesis: a comprehensive review. Int J Oral Maxillofac Surg 2009;38:210–7. 46. Schieker M, Heiss C, Mutschler W. [Bone substitutes.] Unfallchirurg 2008;111: 613–20. 47. Schieker M, Mutschler W. [Bridging posttraumatic bony defects. Established and new methods.] Unfallchirurg 2006;109:715–32. 48. Schieker M, Seitz H, Drosse I, et al. Biomaterials as scaffold for bone tissue engineering. European Journal of Trauma and Emergency Surgery 2006;32:114–24. 49. Schillinger U, Wexel G, Hacker C, et al. A fibrin glue composition as carrier for nucleic acid vectors. Pharm Res 2008;25:2946–62. 50. Schmidmaier G, Herrmann S, Green J, et al. Quantitative assessment of growth factors in reaming aspirate, iliac crest, and platelet preparation. Bone 2006;39: 1156–63. 51. Schmidmaier G, Lucke M, Wildemann B, et al. Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury 2006; 37(Suppl 2):S105–12. 52. Schmidmaier G, Schwabe P, Wildemann B, Haas NP. Use of bone morphogenetic proteins for treatment of non-unions and future perspectives. Injury 2007; 38(Suppl 4):S35–41. 53. Sen MK, Miclau T. Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions? Injury 2007;38(Suppl 1):S75–80. 54. Silber JS, Anderson DG, Daffner SD, et al. Donor site morbidity after anterior iliac crest bone harvest for single-level anterior cervical discectomy and fusion. Spine 2003;28:134–9. 55. Skaggs DL, Samuelson MA, Hale JM, et al. Complications of posterior iliac crest bone grafting in spine surgery in children. Spine 2000;25:2400–2. 56. Smith DM, Cooper GM, Mooney MP, et al. Bone morphogenetic protein 2 therapy for craniofacial surgery. J Craniofac Surg 2008;19:1244–59. 57. Urist MR. Bone: formation by autoinduction. Science 1965;150:893–9. 58. Vacanti CA, Bonassar LJ, Vacanti MP, Shufflebarger J. Replacement of an avulsed phalanx with tissue-engineered bone. N Engl J Med 2001;344:1511–4. 59. Warnke PH, Springer IN, Wiltfang J, et al. Growth and transplantation of a custom vascularised bone graft in a man. Lancet 2004;364:766–70. 60. White AP, Vaccaro AR, Hall JA, et al. Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion. Int Orthop 2007;31:735–41. 61. Wildemann B, Kadow-Romacker A, Haas NP, Schmidmaier G. Quantification of various growth factors in different demineralized bone matrix preparations. J Biomed Mater Res A 2007;81:437–42. 62. Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988;242:1528–34.