transforming-growth-factor-beta and Fractures--Ununited

The development of therapeutics that target anabolic pathways involved in skeletogenesis is of great importance with regard to disease resulting in bone loss, or in cases of impaired bone repair. This review aims to summarize recent developments in this area.. A greater understanding of how drugs that modulate signaling pathways involved in skeletogenesis exert their efficacy, and the molecular mechanisms resulting in bone formation has led to novel pharmacological bone repair strategies. Furthermore, crosstalk between pathways and molecules has suggested signaling synergies that may be exploited for enhanced tissue formation. The sequential pharmacological stimulation of the molecular cascades resulting in tissue repair is a promising strategy for the treatment of bone fractures. It is proposed that a therapeutic strategy which mimics the natural cascade of events observed during fracture repair may be achieved through temporal targeting of tissue repair pathways.

Topics: Adaptor Proteins, Signal Transducing; Anabolic Agents; Antibodies, Neutralizing; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone Remodeling; Bony Callus; Fibroblast Growth Factor 2; Fracture Healing; Fractures, Bone; Fractures, Ununited; Genetic Markers; Humans; Osteogenesis; Platelet-Derived Growth Factor; Signal Transduction; Teriparatide; Transforming Growth Factor beta; Wnt Signaling Pathway

Despite advances in understanding bone healing physiology and surgical techniques, delayed union and nonunion still occur after the treatment of hindfoot arthrodesis. There is increasing appeal of bone morphogenetic proteins (BMPs) owing to the innate osteoinductive abilities of BMPs. Effective treatment with BMPs has been shown in animal studies. Human clinical studies have also shown success. The only study investigating the use of recombinant human BMP (rhBMP)-2 in hindfoot arthrodesis found a significant increase in fusion rate. Treatment cost effective. Complications from their use remain low. rhBMP-2 is a safe and effective bone-healing adjunct in hindfoot arthrodesis surgery.

Topics: Animals; Arthrodesis; Bone Density Conservation Agents; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Transplantation; Foot; Fracture Healing; Fractures, Ununited; Humans; Models, Animal; Recombinant Proteins; Transforming Growth Factor beta

Fracture healing is a complex biological process that requires interaction among a series of different cell types. Maintaining the appropriate temporal progression and spatial pattern is essential to achieve robust healing. We can temporally assess the biological phases via gene expression, protein analysis, histologically, or non-invasively using biomarkers as well as imaging techniques. However, determining what leads to normal versus abnormal healing is more challenging. Since the ultimate outcome of fracture healing is to restore the original functions of bone, assessment of fracture healing should include not only monitoring the restoration of structure and mechanical function, but also an evaluation of the restoration of normal bone biology. Currently few non-invasive measures of biological factors of healing exist; however, recent studies that have correlated non-invasive measures with fracture healing outcome in humans have shown that serum TGFbeta1 levels appear to be an indicator of healing versus non-healing. In the future, developing additional measures to assess biological healing will improve the reliability and permit us to assess stages of fracture healing. Additionally, new functional imaging technologies could prove useful for better understanding both normal fracture healing and predicting dysfunctional healing in human patients.

Topics: Animals; Biomarkers; Extracellular Matrix Proteins; Fracture Healing; Fractures, Bone; Fractures, Ununited; Humans; Mice; Time Factors; Transforming Growth Factor beta

Delay in fracture healing is a complex clinical and economic issue for patients and health services.. To assess the incremental effectiveness and costs of bone morphogenetic protein (BMP) on fracture healing in acute fractures and nonunions compared with standards of care.. We searched The Cochrane Library (2008, Issue 4), MEDLINE, and other major health and health economics databases (to October 2008).. Randomised controlled trials (RCTs) and full or partial economic evaluations of BMP for fracture healing in skeletally mature adults.. All clinical and economic data were extracted by one author and checked by another.. Eleven RCTs, all at high risk of bias, and four economic evaluations were included. Apart from one study, the times to fracture healing were comparable between the BMP and control groups. There was some evidence for increased healing rates, without requiring a secondary procedure, of BMP compared with usual care control in acute, mainly open, tibial fractures (risk ratio (RR) 1.19, 95% CI 0.99 to 1.43). The pooled RR for achieving union for nonunited fractures was 1.02 (95% CI 0.90 to 1.15). One study found no difference in union for patients who had corrective osteotomy for radial malunions. Data from three RCTs indicated that fewer secondary procedures were required for acute fracture patients treated with BMP versus controls (RR 0.65, 95% CI 0.50 to 0.83). Adverse events experienced were infection, hardware failure, pain, donor site morbidity, heterotopic bone formation and immunogenic reactions. The evidence on costs for BMP-2 for acute open tibia fractures is from one large RCT. This indicates that the direct medical costs associated with BMP would generally be higher than treatment with standard care, but this cost difference may decrease as fracture severity increases. Limited evidence suggests that the direct medical costs associated with BMP could be offset by faster healing and reduced time off work for patients with the most severe open tibia fractures.. This review highlights a paucity of data on the use of BMP in fracture healing as well as considerable industry involvement in currently available evidence. There is limited evidence to suggest that BMP may be more effective than controls for acute tibial fracture healing, however, the use of BMP for treating nonunion remains unclear. The limited available economic evidence indicates that BMP treatment for acute open tibial fractures may be more favourable economically when used in patients with the most severe fractures.

Topics: Adult; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cost-Benefit Analysis; Fracture Healing; Fractures, Bone; Fractures, Malunited; Fractures, Ununited; Health Care Costs; Humans; Radius Fractures; Randomized Controlled Trials as Topic; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

The management of open fractures continues to be complicated by high rates of treatment failure and significant patient disability and dissatisfaction. The use of bone morphogenetic proteins (BMPs) in the treatment of open fractures has been assessed by a number of different clinical trials, both in the acute management of open fractures and in the delayed reconstruction of bone defects secondary to open fracture. This review describes the scientific basis for the use of BMPs in open fractures, reviews the current evidence for their use in open fractures, provides grades of recommendation for the different uses of BMPs in open fractures, and identifies important areas for additional research.

Topics: Aged; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Fracture Fixation, Internal; Fracture Healing; Fractures, Open; Fractures, Ununited; Humans; Orthopedic Procedures; Recombinant Proteins; Reoperation; Tibial Fractures; Transforming Growth Factor beta; Treatment Failure

The mandatory stimulus that can optimise the healing pathway can be electrical, mechanical, biological, or a combination of all these parameters. A variety of means has been utilised for biological enhancement, including extracorporeal shock wave, electrical, ultrasound stimulation, the reaming technique of IM nailing, bone graft substitutes, osteogenic cells and bioactive molecules produced by tissue engineering techniques. The aim of this study is to present a review of the existing evidence for the efficacy of reaming, autologous bone grafting and the commercially available growth factors (BMP-2 and BMP-7) for the treatment of aseptic tibial non-unions. The gold standard method of enhancing bone healing in cases of tibial non-union remains the autologous bone graft. Autogenous bone grafts possess osteoconductive, osteoinductive properties and also osteoprogenitor cells. However, their harvesting is associated with high morbidity and many complications reaching percentages of 30%. Intramedullary reamed nailing, either used as an alternative fixation method or as an exchange to a wider implant, offers the unique biomechanical advantages of an intramedullary device, together with the osteoinductive stimulus of the by-products of reaming, and the aptitude for early weight-bearing and active rehabilitation. The safety of administration of the commercial distributed growth factors (BMP-2 and BMP-7), combined with the lack of the morbidity and the quantity restrictions that characterise autologous bone grafts, have given to this family of molecules a principal role between the other bone graft substitutes. On average the union rates reported in the 20 manuscripts that have been evaluated range from 58.3% to 100%, and the average time to union from 12.5 weeks to 48.4 weeks, indicating the significant discrepancies in the reported evidence and the multiplicity of different treatment strategies.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Substitutes; Bone Transplantation; Fracture Healing; Fractures, Ununited; Humans; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome

Since the identification of the osteogenic protein-1 (OP-1) gene, also called bone morphogenetic protein-7 (BMP-7), almost 20 years ago, OP-1 has become one of the most characteristic members of the BMP family. The biological activity of recombinant human OP-1 has been defined using a variety of animal models. These studies have demonstrated that local implantation of OP-1 in combination with a collagen matrix results in the repair of critical size defects in long bones and in craniofacial bones and the formation of bony fusion masses in spinal fusions. Clinical trials investigating long bone applications have provided supportive evidence for the use of OP-1 in the treatment of open tibial fractures, distal tibial fractures, tibial nonunions, scaphoid nonunions and atrophic long bone nonunions. Clinical studies investigating spinal fusion applications have provided supportive evidence for the use of OP-1 in posterolateral lumbar models and compromised patients as an adjunct or as a replacement for autograft. Both long bone repair and spinal fusion studies have demonstrated the efficacy and safety of OP-1 by clinical outcomes and radiographic measures. Future clinical investigations will be needed to better define variables, such as dose, scaffold and route of administration. Clearly the use of BMPs in orthopaedics is still in its formative stage, but the data suggest an exciting and promising future for the development of new therapeutic applications.

Topics: Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Transplantation; Fractures, Bone; Fractures, Ununited; Humans; Orthopedic Procedures; Spinal Fusion; Transforming Growth Factor beta

Recently, several prospective randomized clinical trials have resulted in the publication of critical studies on the efficacy of recombinant human morphogenetic proteins BMP-2 (rhBMP-2) and BMP-7 (OP-1) in spinal fusion and fracture healing. The clinical use of BMPs is now in its infancy and understanding the mechanism and the appropriate application of these proteins is necessary for all practicing orthopedic surgeons. This article will revisit some of the early studies using rhBMPs and review the current literature on their role in fracture healing.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Fracture Healing; Fractures, Bone; Fractures, Ununited; Humans; Recombinant Proteins; Spinal Fusion; Transforming Growth Factor beta

Surgical revision concepts for the treatment of aseptic humeral, femoral, and tibial diaphyseal nonunion were evaluated. It was analyzed if the range of time to bone healing was shorter, and if clinical and radiological long-term outcome was better following application of additional recombinant human Bone Morphogenetic Protein-7 (rhBMP-7) compared to no additional rhBMP-7 use.. In a retrospective comparative study between 06/2006 and 05/2013, 112 patients diagnosed with aseptic diaphyseal humerus (22 patients), femur (41 patients), and tibia (49 patients) nonunion were treated using internal fixation and bone graft augmentation. For additional stimulation of bone healing, growth factor rhBMP-7 was locally administered in 62 out of 112 patients. Follow-up studies including clinical and radiological assessment were performed at regular intervals as well as after at least one year following nonunion surgery.. One hundred and two out of 112 (humerus: 19, femur: 37, tibia: 47) nonunion healed within 12 months after revision surgery without any significant differences between the cohort groups. According to the DASH outcome measure for the humerus (p = 0.679), LEFS for the femur (p = 0.251) and the tibia (p = 0.946) as well as to the SF-12 for all entities, no significant differences between the treatment groups were found.. Aseptic diaphyseal nonunion in humerus, femur, and tibia healed irrespectively of additional rhBMP-7 application. Moreover, the results of this study suggest that successful nonunion healing can be linked to precise surgical concepts using radical removal of nonunion tissue, stable fixation and restoration of axis, length and torsion, rather than to the additional use of signaling proteins.. This clinical trial was conducted according to ICMJE guidelines as well as to the approval of the National Medical Board (Ethics Committee of the Bavarian State Chamber of Physicians; TRN: 2016-104) and has been retrospectively registered with the German Clinical Trails Register (TRN: DRKS00012652 ).

Topics: Adult; Aged; Bone Morphogenetic Protein 7; Bone Screws; Bone Transplantation; Diaphyses; Female; Femoral Fractures; Follow-Up Studies; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Humans; Humeral Fractures; Male; Middle Aged; Radiography; Recombinant Proteins; Reoperation; Retrospective Studies; Tibial Fractures; Time Factors; Transforming Growth Factor beta; Young Adult

External fixation of distal tibial fractures is often associated with delayed union. We have investigated whether union can be enhanced by using recombinant bone morphogenetic protein-7 (rhBMP-7). Osteoinduction with rhBMP-7 and bovine collagen was used in 20 patients with distal tibial fractures which had been treated by external fixation (BMP group). Healing of the fracture was compared with that of 20 matched patients in whom treatment was similar except that rhBMP-7 was not used. Significantly more fractures had healed by 16 (p=0.039) and 20 weeks (p=0.022) in the BMP group compared with the matched group. The mean time to union (p=0.002), the duration of absence from work (p=0.018) and the time for which external fixation was required (p=0.037) were significantly shorter in the BMP group than in the matched group. Secondary intervention due to delayed healing was required in two patients in the BMP group and seven in the matched group. RhBMP-7 can enhance the union of distal tibial fractures treated by external fixation.

Topics: Adult; Aged; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Combined Modality Therapy; External Fixators; Female; Follow-Up Studies; Fracture Fixation; Fracture Healing; Fractures, Ununited; Humans; Male; Middle Aged; Radiography; Recombinant Proteins; Reoperation; Tibial Fractures; Time Factors; Transforming Growth Factor beta; Treatment Outcome

We randomly assigned 17 patients with scaphoid non-union at the proximal pole to three treatment groups: (1) autologous iliac graft (n=6), (2) autologous iliac graft + osteogenic protein-1 (OP-1; n=6), and (3) allogenic iliac graft + OP-1 (n=5). Radiographic, scintigraphic, and clinical assessments were performed throughout the follow-up period of 24 months. OP-1 improved the performance of both autologous and allogenic bone implants and reduced radiographic healing time to 4 weeks compared with 9 weeks in group 1. Helical CT scans and scintigraphy showed that in OP-1-treated patients sclerotic bone was replaced by well-vascularised bone. The addition of OP-1 to allogenic bone implant equalised the clinical outcome with the autologous graft procedure. Consequently the harvesting of autologous graft can be avoided.

Topics: Adolescent; Adult; Analysis of Variance; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Female; Fracture Healing; Fractures, Ununited; Humans; Ilium; Male; Radionuclide Imaging; Scaphoid Bone; Tomography, Spiral Computed; Transforming Growth Factor beta

Nonunions of long bone fractures are considerable therapeutic and economic problems with increasing tendency. Basic surgical options are autogenous cancellous bone grafting, rod dynamization, reamed nailing, plate fixation with compression, and bone transport techniques. If these methods fail to work, alternative treatment options are needed.. Since May 2001 treatment with recombinant human (rh) bone morphogenic protein 7 [BMP-7 or osteogenic protein 1 (OP-1)] in combination with a type one collagen carrier has gained interest. BMP 7 induces the formation of new bone by differentiation of stem cells, thereby initiating the reaction cascade of osteogenesis. Nonunions over 9 months and unsuccessful bone grafting delineate the indication.. We report our experience with 21 patients and nonunion of long bone fractures. Between July 2002 and June 2004, 23 units of BMP 7 were implanted. The implantation sites were 7 femora, 12 tibias, 2 humeri, and 2 forearms. In ten cases BMP 7 was combined with a new osteosynthesis and bone grafting and in five patients with bone grafting alone. In contrast in eight patients BMP 7 was applied as a single procedure without any bone grafting or any change of the osteosynthesis.. There were no peri- or postoperative complications. Follow-up was obtained for a minimum of 6 months. Of 23 implantations, 22 were successful with bony healing revealed by clinical and radiological evaluation. In one patient no bony consolidation of the nonunion has been seen so far. In summary, based on our results we propose BMP 7 as an additional innovative therapy of long bone nonunions.

Topics: Adult; Aged; Arm Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Delayed-Action Preparations; Female; Fractures, Ununited; Humans; Leg Bones; Male; Middle Aged; Radiography; Recombinant Proteins; Transforming Growth Factor beta; Treatment Outcome

The role of bone morphogenetic proteins (BMPs) in osseous repair has been demonstrated in numerous animal models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions. The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone.. One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, partially blinded, multi-center clinical trial between February, 1992, and August, 1996, and were followed at frequent intervals over 24 months. Each patient was treated by insertion of an intramedullary rod, accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft. Assessment criteria included the severity of pain at the fracture site, the ability to walk with full weight-bearing, the need for surgical re-treatment of the nonunion during the course of this study, plain radiographic evaluation of healing, and physician satisfaction with the clinical course. In addition, adverse events were recorded, and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit.. At 9 months following the operative procedures (the primary end-point of this study), 81% of the OP-1-treated nonunions (n = 63) and 85% of those receiving autogenous bone (n = 61) were judged by clinical criteria to have been treated successfully (p = 0.524). By radiographic criteria, at this same time point, 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had healed fractures (p = 0.218). These clinical results continued at similar levels of success throughout 2 years of observation, and there was no statistically significant difference in outcome between the two groups of patients at this point (p = 0.939). All patients experienced adverse events. Forty-four percent of patients in each treatment group had serious events, none of which were related to their bone grafts. More than 20% of patients treated with autografts had chronic donor site pain following the procedure.. rhOP-1 (BMP-7), implanted with a type I collagen carrier, was a safe and effective treatment for tibial nonunions. This molecule provided clinical and radiographic results comparable with those achieved with bone autograft, without donor site morbidity.

Topics: Adult; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Transplantation; Collagen; Drug Carriers; Drug Delivery Systems; Female; Fracture Fixation, Intramedullary; Fracture Healing; Fractures, Ununited; Humans; Male; Prospective Studies; Radiography; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

 The aim of this study was to assess bone density, bone architecture and clinical function of canine nonunion distal appendicular long bone fractures with a defect treated with fixation, compression-resistant matrix and recombinant human bone morphogenetic protein-2 (rhBMP-2)..  Prospective cohort study with dogs at least 1-year post treatment. Computed tomography was performed and quantitative measurements from previous fracture sites were compared with measurements from contralateral limbs. Subjective evaluation included gait assessment and palpation..  Six patients met the inclusion criteria. The rhBMP-2 treated bone exhibited higher density at the periphery and lower density in the centre, similar to the contralateral limb. All patients were weight bearing on the treated limb and all fractures were healed..  The rhBMP-2-treated bone underwent restoration of normal architecture and density. Acceptable limb function was present in all patients. The results of this study can serve as a basis for long-term response in treating nonunion fractures in veterinary patients.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Regeneration; Dog Diseases; Dogs; Fracture Healing; Fractures, Bone; Fractures, Ununited; Humans; Prospective Studies; Recombinant Proteins; Transforming Growth Factor beta

Substantial evidence exists demonstrating the individual effectiveness of both rhBMP-2 and -7 in the treatment of nonunions, data comparing the clinical effectiveness of adjunct rhBMP-2 and -7 remains scarce. Therefore, we examined our large single-center case series to compare the clinical effectiveness of both rhBMP-2 and -7 in non-union therapy aiming to answer: - Does a certain type of BMP have an advantageous effect on radiological outcome of applied lower limb non-union therapy? - Does application of a certain type of BMP have an advantageous effect on radiological outcome of infected lower limb nonunions? - Are there any additional risk factors associated with inferior outcome in context with an adjunct BMP treatment?. Both BMPs have the same effect on the radiological outcome of surgically treated lower limb nonunions.. Single-center retrospective database analysis of a case series of patients with lower limb long bone nonunions receiving either a one- or two-stage (Masquelet-) procedure based on the "diamond concept" with application of rhBMP-2 or -7. The "diamond concept" summarizes core factors that need to be present to achieve bone healing. In particular, these factors relate to the optimization of the mechanical (stability) and biological environment (sufficient osteogenic and angiogenic cells, osteoconductive scaffolds and growth factors). All medical data from patients that received surgical treatment between 01/01/2010 and 31/12/2016 were assessed. In total, 356 patients were treated with BMPs and 156 patients 18 years or older with non-union of their tibia or femur having a follow-up of at least 1 year were included. Consolidation in context with type of rhBMP was compared and the influence of relevant risk factors assessed.. Consolidation rate was significantly higher in patients treated with rhBMP-2 (rhBMP-2: 42/46 (91%) vs. rhBMP-7: 64/110 (58%); p<0.001). In particular, application of rhBMP-2 increased the likelihood of consolidation for tibial nonunions (OR 32.744; 95%CI: 2.909-368.544; p=0.005) and when used in two-stage therapy (OR 12.095; 95% CI: 2.744-53.314; p=0.001). Furthermore, regression modeling revealed a higher correlation between application of rhBMP-2 and osseous consolidation in infected nonunions (OR 61.062; 95% CI: 2.208-1688.475; p=0.015) than in aseptic nonunions (OR 4.787; 95% CI: 1.321-17.351; p=0.017). Risk factors negatively influencing the outcome of non-union treatment in context with rhBMPs were identified as active smoking (OR 0.357; 95% CI: 0.138-0.927; p=0.024), atrophic nonunion (OR 0.23; 95% CI: 0.061-0.869; p=0.030), higher BMI (OR 0.919; 95% CI: 0.846-0.998; p=0.046) and a larger defect size (OR 0.877; 95% CI: 0.784-0.98; p=0.021).. Patients who received rhBMP-2 for the treatment of tibial nonunions and as part of the two-stage treatment had a significantly higher rate of healing compared to patients treated with rhBMP-7 regardless of infection.. III, retrospective case-control study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atrophy; Body Mass Index; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Transplantation; Chemotherapy, Adjuvant; Female; Femoral Fractures; Femur; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Humans; Male; Middle Aged; Radiography; Recombinant Proteins; Retrospective Studies; Risk Factors; Smoking; Tibia; Tibial Fractures; Transforming Growth Factor beta; Treatment Failure; Young Adult

To report the use of compression resistant matrix (CRM) infused with recombinant human bone morphogenetic protein (rhBMP-2) prospectively in the healing of nonunion long-bone fractures in dogs.. A longitudinal cohort of dogs that were presented with nonunion fractures were classified and treated with CRM soaked with rhBMP-2 and fracture fixation. They were followed with serial radiographs and evaluated for healing times and complications according to the time frame and definitions previously established for orthopaedic clinical cases.. Eleven nonunion fractures in nine dogs were included. Median healing time was 10 weeks (range: 7-20 weeks). Major perioperative complications due to bandage morbidity were encountered in two of 11 limbs and resolved. All other complications were minor. They occurred perioperatively in eight of 11 limbs. Minor follow-up complications included short-term in one of two limbs, mid-term in one of three, and long-term in four of five limbs. Nine limbs returned to full function and two limbs returned to acceptable function at the last follow-up.. Nonunion fractures given a poor prognosis via standard-of-care treatment were successfully repaired using CRM with rhBMP-2 accompanying fixation. These dogs, previously at high risk of failure, returned to full or acceptable function.

Topics: Animals; Bone Morphogenetic Protein 2; Cohort Studies; Dog Diseases; Dogs; Drug Implants; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Humans; Longitudinal Studies; Recombinant Proteins; Surgical Sponges; Transforming Growth Factor beta; Treatment Outcome

Pre-clinical models of bony nonunion typically employ critical-length defects. However, these models may not accurately reflect clinical practice since many nonunions are diagnosed without bone loss. We developed a non-displaced rat ulna fracture model in order to examine the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) with an absorbable collagen sponge (ACS) for nonunion treatment.. Transverse diaphyseal ulna fractures were created in 24 Sprague-Dawley rats. Eight animals (Group 1: Nonunion) received no further intervention. The remaining 16 animals were treated with 5 μg rhBMP-2/ACS at 8 weeks after the original intervention (Group 2: Nonunion + BMP) or at the time of initial injury (Group 3: Fresh fracture + BMP).. In Group 1, 7 of 8 fractures demonstrated gross motion and a persistent radiographic gap (12.5% healing rate). In Groups 2 and 3, fractures healed at a rate of 75% (6 of 8 in each group) as determined by manual and radiographic evaluation. Biomechanical testing for torque load-to-failure and torsional stiffness demonstrated no significant difference between healed specimens treated with rhBMP-2.. To our knowledge, this is the first description of a physiologic, non-stabilized, non-defect fracture nonunion model in a rodent. Furthermore, unlike previous nonunion models, the healing rates after treatment with rhBMP-2 are comparable to that of clinical data, suggesting that this model may provide an environment more representative of nonunions in humans.

Topics: Animals; Bone Morphogenetic Protein 2; Disease Models, Animal; Female; Fracture Healing; Fractures, Ununited; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Transforming Growth Factor beta; Ulna Fractures

In an effort to improve fracture healing and decrease the need for autologous bone graft, products such as recombinant human bone morphogenetic protein (rhBMP-2) have been developed and used in both spine and nonspine surgery. There is a paucity of literature regarding the use of rhBMP-2 in scaphoid nonunion surgery with very little reporting on the complications associated with its use. The objective of this study was to retrospectively review the complications documented for a case series of patients treated with revision fixation, bone graft, and rhBMP-2 in revision scaphoid nonunion surgery.. We retrospectively reviewed 6 cases of scaphoid nonunion revision surgery comprising open reduction and internal fixation (ORIF). All cases were performed for persistent nonunion after a previous scaphoid ORIF. All patients were treated with revision screw fixation, bone graft, and rhBMP-2. Union was determined by computed tomography in all cases. Complications of nonunion, heterotopic bone formation, delayed wound healing, functional loss of motion, and need for revision surgery are reported.. Between 2011 and 2014, 6 cases in which rhBMP-2 was used in revision scaphoid nonunion surgery were identified. All patients had failed an initial attempt at ORIF after delayed union or nonunion. The time from injury to index ORIF ranged from 3 months to 4 years (mean, 24 months). Revision surgery with rhBMP-2 was performed at an average of 6 months from the index ORIF. Of the 6 cases, 2 had resultant persistent nonunion. Both underwent scaphoid excision and midcarpal arthrodesis. Four cases developed notable heterotopic ossification (one of which required revision surgery). One patient had a loss of functional motion after the revision surgery. There were no cases of delayed wound healing. Only one of the 6 patients healed without complications.. In this case series, the use of rhBMP-2 in scaphoid nonunions was associated with a higher complication rate than reported in previous studies. Surgeons performing off-label use of rhBMP-2 should be aware of the potential for complications including heterotopic ossification.. Therapeutic IV.

Topics: Adolescent; Adult; Bone Morphogenetic Protein 2; Bone Transplantation; Female; Fracture Fixation, Internal; Fractures, Ununited; Humans; Male; Ossification, Heterotopic; Recombinant Proteins; Reoperation; Retrospective Studies; Scaphoid Bone; Transforming Growth Factor beta; Treatment Outcome; Young Adult

Reconstruction of a segmental fracture with massive bone loss is still a challenge for orthopaedic surgeons. The aim of our study was to develop a suitable biodegradable thermosensitive hydrogel system as a carrier for bone morphogenetic protein (BMP)-2 delivery in the treatment of critical-sized femoral defects.. A block copolymer composed of monomethoxypoly(ethylene glycol) (mPEG), poly(lactic-co-glycolic acid) (PLGA) and 2, 2'-Bis (2-oxazolin) (Box) was synthesized by ring opening polymerization. The synthesized block copolymer was characterized by (1)H-NMR spectroscopy and gel permeation chromatography (GPC). Different biophysical and biochemical properties of the synthesized copolymer, including temperature-induced structure changes, degradation rate, pH changes during hydrolytic degradation, cell toxicity, and the release profile of BMP-2, were also evaluated and/or were compared with those of a well-characterized mPEG-PLGA copolymer. In animal testing, rabbits (n = 36) that received critically sized (10 mm) femoral defects were divided into 6 groups. These experimental groups included an untreated group, autograft, and groups treated with the synthesized copolymer carrying different concentrations of BMP-2 (0, 5, 10, and 20 μg/ml). Bone repair was evaluated using X-ray radiography, histological staining, micro-computed tomography (μCT), biomarker examination and biomechanical testing in a 12-week treatment period.. A new thermosensitive mPEG-PLGA/Box/mPEG-PLGA block copolymer, or named as BOX copolymer, was successfully prepared. Compared to the reported mPEG-PLGA in vitro, the prepared BOX copolymer at the same weight percent concentrations exhibited wider temperature ranges of gelation, slower degradation rates, higher the pH values, as well as less cytotoxicity. Furthermore, the BMP-2 release from BOX hydrogel exhibited a near-linear release profile in vitro. In animal experiments, treatment of critical-sized bony defects with 25 wt% BOX hydrogel carrying BMP-2 effectively promoted fracture healing during the 12-week trial period and higher concentrations of BMP-2 treatment correlated with better bone quality. Most importantly, clinical outcome and bone healing in the BOX-hydrogel group with 20 μg/ml BMP-2 were nearly equivalent to those in the autograft group in a 12-week treatment course.. These data support that the use of BOX hydrogel (25 wt%) as a drug delivery system is a promising method in the treatment of large bone defects.

Topics: Animals; Autografts; Biodegradable Plastics; Biomarkers; Biomechanical Phenomena; Bone Morphogenetic Protein 2; Bone Transplantation; Cell Line; Disease Models, Animal; Drug Carriers; Femoral Fractures; Femur; Fracture Healing; Fractures, Ununited; Humans; Hydrogels; Mice; Polyesters; Polyethylene Glycols; Polyglactin 910; Rabbits; Radiography; Recombinant Proteins; Temperature; Transforming Growth Factor beta; X-Ray Microtomography

The purpose of this study was to evaluate the clinical and radiological outcome following compression plate fixation in combination with autologous bone grafting, with and without additional application of recombinant human bone morphogenetic protein (rhBMP) for treatment of aseptic clavicle non-union.. Between April 2004 and April 2015, 82 patients were treated for clavicle fracture and had developed aseptic clavicle non-union. Seventy-three out of 82 patients were available for follow-up at least one year after revision surgery; among them, 27 women and 46 men, with a median age of 49 (range, 19-86) years. Forty-five patients received compression plate osteosynthesis with autologous bone grafting, and 28 patients obtained compression plate fixation with autologous bone grafting and additional application of rhBMP-2 (3/28 patients) or rhBMP-7 (25/28 patients).. Seventy out of 73 non-unions (96 %) healed within 12 months after revision surgery. Functional outcome according to the DASH Outcome Measure (with rhBMP, 33.16 ± 1.17 points; without rhBMP, 30.58 ± 2.12 points [mean ± SEM]; p = 0.81), non-union healing (p = 0.86), time interval between revision surgery and bone healing (p = 0.37), as well as post-operative complications, did not demonstrate relevant differences between the treatment groups and were not age-dependent.. Functional and radiological results demonstrate that successful healing of aseptic clavicle non-union is dependent on radical resection of non-union tissue, restoration of length of the shoulder girdle and application of stable locking-plate osteosynthesis in combination with autologous bone grafting, but not dependent on application of additional rhBMP.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Plates; Bone Transplantation; Clavicle; Female; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Humans; Male; Middle Aged; Recombinant Proteins; Reoperation; Retrospective Studies; Transforming Growth Factor beta; Transplantation, Autologous; Treatment Outcome; Young Adult

To describe a surgical technique using a regenerative approach and internal fixation for reconstruction of critical size bone defect non-union mandibular fractures.. Case series.. Dogs (n = 6) that had internal fixation of defect non-union mandibular fracture.. In 5 dogs, the repair was staged and extraction of teeth performed during the initial procedure. After 21-98 days (mean, 27 days) pharyngotomy intubation and temporary maxillomandibular fixation were performed. Using an extraoral approach, a locking titanium miniplate was contoured and secured to the mandible. A compression resistant matrix (CRM) infused with rhBMP-2 was implanted in the defect. The implant was then covered with a soft tissue envelope followed by surgical wound closure.. All dogs healed with intact gingival covering over the mandibular fracture site defect and had immediate return to normal function and correct occlusion. Hard-tissue formation was observed clinically within 2 weeks and solid cortical bone formation within 3 months. CT findings in 1 dog at 3 months postoperatively demonstrated that the newly regenerated mandibular bone had 92% of the bone density and porosity compared to the contralateral side. Long-term follow-up revealed excellent outcome.. Mandibular reconstruction using internal fixation and CRM infused with rhBMP-2 is an excellent solution for the treatment of critical size defect non-union fractures in dogs.

Topics: Animals; Bone Morphogenetic Protein 2; Dogs; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Jaw Fixation Techniques; Mandibular Fractures; Mandibular Reconstruction; Plastic Surgery Procedures; Recombinant Proteins; Tomography, X-Ray Computed; Transforming Growth Factor beta; Treatment Outcome

Bone morphogenetic proteins are a necessary component of the fracture healing cascade. Few studies have delineated the efficacy of iliac crest bone graft and recombinant human bone morphogenetic protein 2 (rhBMP-2), especially, in comparison with the gold standard treatment of nonunion, which is autogenous bone graft alone. This study compared the outcome of patients with fracture nonunion treated with autogenous bone graft plus rhBMP-2 adjuvant vs patients treated with autogenous bone graft alone. A total of 118 consecutive patients who were to undergo long bone nonunion surgery with autogenous bone graft (50) or autogenous bone graft plus rhBMP-2 (68) were identified. Surgical intervention included either harvested iliac autogenous bone graft or autogenous bone graft plus 1.5 mg/mL of rhBMP-2 placed in and around the site of nonunion. No differences were found in the distribution of nonunion sites included within each group. Twelve-month follow-up was obtained on 100 of 118 patients (84.7%). Analyses of demographic characteristics (including tobacco), medical comorbidities, previous surgeries, and nonunion type (atrophic vs hypertrophic) did not differ. Postoperative complication rates did not differ. The percentage of patients who progressed to union did not differ. Mean time to union in the autogenous bone graft plus rhBMP-2 group was 6.6 months (±3.9) vs 5.4 (±2.7) months in the autogenous bone graft-only group (P=.06). Rates of revision (16.2% for rhBMP-2 plus autogenous bone graft vs 8% for autogenous bone graft) did not differ statistically (P=.19), nor did 12-month scores of pain and functional assessment. Although rhBMP-2 is a safe adjuvant, there was no benefit seen when rhBMP-2 was added to autogenous bone graft in the treatment of long bone nonunion. Given its high cost, rhBMP-2 should be reconsidered as an aid to autogenous bone graft in the treatment of nonunion.

Topics: Adult; Bone Morphogenetic Protein 2; Bone Transplantation; Combined Modality Therapy; Female; Fracture Healing; Fractures, Ununited; Humans; Ilium; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Registries; Transforming Growth Factor beta; Transplantation, Autologous

The Food and Drug Administration (FDA) indicates that bone morphogenetic protein (BMP) products are contraindicated in pediatric patients. However, it acknowledges the off-label use of BMP in difficult cases. Although the relative safety of BMP in children has been reported for lower extremity and spine procedures, little information exists for the safety of BMP used in the pediatric upper extremity. We present a case of a massive inflammatory reaction after use of recombinant human BMP-2 for repair of a symptomatic ulnar nonunion in a child. The case illustrates the potential difficulties of using the dose-dependent properties of BMP in the treatment of pediatric upper extremity nonunions when the dose calculations of BMP for children have not yet been defined.

Topics: Bone Morphogenetic Protein 2; Bone Resorption; Child; Fractures, Ununited; Humans; Male; Off-Label Use; Osteitis; Recombinant Proteins; Surgical Wound Dehiscence; Transforming Growth Factor beta; Ulna Fractures

Recombinant human bone morphogenetic protein-2 (BMP-2) is Food and Drug Administration-approved for use in acute open tibial shaft fractures. Some surgeons, however, also use BMP-2 in an "off-label" application for other acute fractures and for nonunion care. This retrospective study was performed to assess radiographic outcomes of off-label uses of BMP-2 for acute fractures and nonunions at our institution.. All eligible off-label BMP-2 applications between 2004 and 2008 for acute fractures or nonunions were reviewed. Univariate and multivariate analyses were completed to identify patient and clinical factors that could predict radiographic success or failure of the procedure.. One hundred sixteen of 145 BMP-2 applications in 104 of 128 patients met inclusion and exclusion criteria. The overall radiographic union rate was 66% (76 of 116). In the univariate analysis, five factors correlated with significantly higher union rate: volume of bone defect <4 cm3, >2 cortices in contact at the index procedure, male gender, body mass index <30, and history of closed fracture pattern. Within the multivariate analysis, factors independently predictive of radiographic union included open versus closed fracture, gender, and volume of bone defect.. Off-label use of BMP-2 in acute fractures and nonunions resulted in a 66% success rate. It remains uncertain whether there is any clinical advantage to this approach, but it appears that female gender, open injury, and higher volumes of bone defect may be important negative prognostic factors for obtaining radiographic union. Appropriately powered prospective randomized trials are needed for further clarification, especially in light of the high cost of this treatment.

Topics: Absorbable Implants; Acute Disease; Bone Morphogenetic Protein 2; Female; Follow-Up Studies; Fracture Fixation; Fracture Healing; Fractures, Closed; Fractures, Ununited; Humans; Male; Middle Aged; Off-Label Use; Radiography; Recombinant Proteins; Retrospective Studies; Transforming Growth Factor beta; Treatment Outcome

Recombinant human bone morphogenetic protein (rhBMP) has been found to be a powerful adjunct to healing nonunions and obtaining fusions. Despite the apparent clinical efficacy and good safety profile reported with rhBMP use in adults, there is little data regarding the safety of this product in pediatric patients. We evaluated the use of rhBMP-2 in pediatric patients to determine if any complications were associated with its use.. We performed a retrospective review of 81 patients, all less then 18 years old, in whom rhBMP-2 was used. Theoretical complications associated with rhBMP-2 use were compiled based on a review of the published literature on rhBMP-2. A review of each patient's chart and radiographs was performed to record the occurrences of complications, which may have been associated with the use of rhBMP-2.. A total of 16 complications were found, which may have been attributed to the use of rhBMP-2. There were no incidences of systemic toxicity associated with rhBMP-2 use. Nine patients were noted to have some local operative site problem, 3 deep infections were noted, 1 patient was found to have a postoperative compartment syndrome, 2 patients were found to have neurologic complications (1 with progressive myelopathy and 1 with weakness and dural fibrosis), and 1 patient with neurofibromatosis and previously diagnosed intracranial gliomas was found to have subsequent enlargement of these gliomas. In reviewing these complications, only the case of dural fibrosis and subsequent weakness was thought to possibly be directly related to the use of rhBMP-2.. We found few complications in pediatric patients, which were felt to be directly attributable to the use of rhBMP-2. As such, rhBMP-2 use seems to be relatively safe in this young patient population. Due to the current use of this product in pediatric patients in an "off-label" fashion, we recommend a thorough discussion of the possible risks and benefits of this product with the family before its use.. Therapeutic studies-Level IV.

Topics: Adolescent; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Child; Child, Preschool; Dura Mater; Female; Fibrosis; Follow-Up Studies; Fracture Healing; Fractures, Ununited; Humans; Infant; Male; Recombinant Proteins; Retrospective Studies; Spinal Fusion; Transforming Growth Factor beta

The evolution of a fracture non-union is complex; treatment strategies are therefore challenging. The use of BMP-7 could be an interesting adjunct. We present an overview of the monitored use of this product in tibial non-unions in Belgium. Our retrospective data covers 53% (62 patients) of the cases in which it was used between 2001 and 2006. Questionnaires were sent to surgeons who had been using BMP-7 (OP-1) in tibial non-unions in Belgium. Of 55 surgeons contacted, 27 who had been treating 62 patients with a non-union of a tibial fracture responded. These fractures were most commonly treated with an external fixator and 50% of them had already received some form of graft material. Non-union was diagnosed after a median of 365 days (range, 123-1212). Treatment with OP-1 resulted in a clinical healing rate of 79.6% and a radiographic healing rate of 84.9%. Union was reported after a median of 230 (32-872) days clinically and 232 (32-739) days radiographically. We documented a large number of cases of use of BMP-7 in tibial non-union in Belgium. The healing rates of around 80% are comparable to other reports on success rates with BMP-7. Many cases presented originally with open fractures, infected wounds or fractures with bone loss. This makes the reported results even more promising. Further studies are needed to analyse the socio-economical value of this relatively expensive treatment.

Topics: Adult; Belgium; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Female; Fractures, Ununited; Humans; Male; Middle Aged; Retrospective Studies; Tibial Fractures; Transforming Growth Factor beta

To compare the cost implications of treatment of persistent fracture non-unions before and after application of recombinant human bone morphogenetic protein-7 (BMP-7).. Of 25 fracture non-unions, 9 were treated using BMP-7 alone and 16 using BMP-7 and bone grafting. These patients were prospectively followed up, and the costs incurred were analysed.. The mean number of procedures per fracture performed before application of BMP-7 was 4.16, versus 1.2 thereafter. Mean hospital stay and cost of treatment per fracture before receiving BMP-7 were 26.84 days and pound 13,844.68, versus 7.8 days and pound 7338.4 thereafter. The overall cost of treatment of persistent fracture non-unions with BMP-7 was 47.0% less than that of the numerous previous unsuccessful treatments (p=0.001).. Treating fracture non-unions is costly, but this could be reduced by early BMP-7 administration when a complex or persistent fracture non-union is present or anticipated.

Topics: Adolescent; Adult; Aged; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Costs and Cost Analysis; Drug Costs; Female; Fracture Healing; Fractures, Bone; Fractures, Ununited; Humans; Length of Stay; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Reoperation; Transforming Growth Factor beta; United Kingdom

Distal tibial fractures are rare and difficult to treat because the bones are subcutaneous. External fixation is commonly used, but the method often results in delayed union. The aim of the present study was to find out the factors that affect fracture union in tibial pilon fractures. For this purpose, prospective data collection of tibial pilon fractures was carried out in 1998-2004, resulting in 159 fractures, of which 83 were treated with external fixation. Additionally, 23 open tibial fractures with significant > 3 cm bone defect that were treated with a staged method in 2000-2004 were retrospectively evaluated. The specific questions to be answered were: What are the risk factors for delayed union associated with two-ring hybrid external fixation? Does human recombinant BMP-7 accelerate healing? What is the role of temporary ankle-spanning external fixation? What is the healing potential of distal tibial bone loss treated with a staged method using antibiotic beads and subsequent autogenous cancellous grafting compared to other locations of the tibia? The following risk factors for delayed healing after external fixation were identified: post-reduction fracture gap of >3 mm and fixation of the associated fibula fracture. Fracture displacement could be better controlled with initial temporary external fixation than with early definitive fixation, but it had no significant effect on healing time, functional outcome or complication rate. Osteoinduction with rhBMP-7 was found to accelerate fracture healing and to shorten the sick leave. A staged method using antibiotic beads and subsequent autogenous cancellous grafting proved to be effective in the treatment of tibial bone loss. Healing potential of the bone loss in distal tibia was at least equally good as in other locations of the tibia.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Transplantation; Case-Control Studies; Diaphyses; Equipment Design; External Fixators; Female; Fracture Fixation; Fracture Healing; Fractures, Closed; Fractures, Open; Fractures, Ununited; Humans; Male; Middle Aged; Postoperative Complications; Prospective Studies; Retrospective Studies; Risk Factors; Tibial Fractures; Transforming Growth Factor beta; Transplantation, Autologous; Treatment Outcome

Post-trauma and post-partum pelvic ring instability and non-union are treated operatively with internal fixation and a biological enhancement stimulus. The application of BMP-7 in nine cases of persistent instability located at the anterior or the posterior elements of the pelvic girdle is prospectively evaluated for its safety and efficacy. Fusion was achieved in 89% of the patients. 78% of the patients reported excellent or good subjective functional results at a median follow up period of 12 months (range 12-27). The utilisation of BMP-7 was not associated with any adverse reactions or complications. Encouraging results of biological enhancement of bone healing with BMP-7 at the clinical setting of traumatic pelvic ring non-unions and postpartum instability were achieved. The implantation of BMP-7 in pelvic reconstruction procedures adds another alternative to the treatment methods of contemporary orthopaedics.

Topics: Adult; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Transplantation; Female; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Humans; Male; Middle Aged; Pelvic Bones; Postpartum Period; Prospective Studies; Sacroiliac Joint; Transforming Growth Factor beta; Treatment Outcome

This article identifies the underlying molecular events responsible for fracture nonunions in a subset of fracture patients. Expression profiling of fracture callus tissue from both uneventful fracture repair and nonunion outcomes showed a decrease of COX-2 expression and an inability to mount an immune response in nonunion fractures. Validation in vitro with Saos-2 osteoprogenitor cell lines showed a decrease in osteogenesis potential after the cells were treated with celecoxib, a COX-2 specific inhibitor and anti-inflammatory agent. This article recapitulates that an initial immune response is crucial to fracture healing and suggests limited usage of COX-2 inhibitors in patients with healing fractures.

Topics: Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bony Callus; Celecoxib; Cell Line; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Female; Fracture Healing; Fractures, Ununited; Humans; Male; Membrane Proteins; Middle Aged; Osteogenesis; Pyrazoles; Recombinant Proteins; Sulfonamides; Transforming Growth Factor beta

Identification of patients at risk of developing non-union and institution of procedures preventing non-union could be attractive in routine fracture management. We investigated whether recombinant human bone morphogenetic protein (rhBMP-2) delivered in a hyaluronic acid carrier could prevent non-union development in an experimental non-union model, which simulates the clinical situation of open mid-tibial fractures.. Sixteen rabbits underwent a standard non-union operation comprising mid-tibial osteotomy, excision of periosteum and endosteum, and plate fixation. Before closure of the wound eight rabbits received interfragmentary deposition of 200 microg rhBMP-2 delivered in a hyaluronan gel carrier, and eight rabbits received gel carrier alone.. After 7 weeks, torsional failure moment of the osteotomy and energy absorbed at failure, macroscopic and radiographic appearance, callus area, and interfragmentary bone volume fraction confirmed that rhBMP-2 delivery significantly improved bone healing. Blood flow at the osteotomy site, measured using radiolabelled microspheres, was not higher in the united osteotomies than in non-united osteotomies.. rhBMP-2 delivered in a hyaluronic acid carrier-induced formation of competent bone in an experimental model of compromised healing. We, therefore, propose interfragmentary deposition of rhBMP-2 delivered in a hyaluronic acid carrier to patients encountering fractures at risk of non-union or delayed union.

Topics: Animals; Blood Flow Velocity; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Disease Models, Animal; Drug Carriers; Fracture Healing; Fractures, Ununited; Hyaluronic Acid; Microspheres; Osteotomy; Rabbits; Random Allocation; Recombinant Proteins; Stress, Mechanical; Tibial Fractures; Transforming Growth Factor beta

The purpose of this study was to evaluate the efficacy and safety of recombinant bone morphogenetic protein 7 (rhBMP-7 or OP-1) as a bone-stimulating agent in the treatment of persistent fracture non-unions. Twenty-five consecutive patients [19 males, mean age 39.4 years (range: 18-79)] with 26 fracture non-unions were treated with rhBMP-7. There were 10 tibial non-unions, eight femoral, three humeral, three ulnar, one patellar, and one clavicular non-union. The mean follow-up was 15.3 months. The mean number of operations performed prior to rhBMP-7 application was 3.2, with autologous bone graft and bone marrow injection being used in 10 cases (38.5%). Both clinical and radiological union occurred in 24 (92.3%) cases, within a mean time of 4.2 months and 5.6 months, respectively. Of the remaining two cases, one patient ultimately underwent a below knee amputation, secondary to recurrence of deep sepsis. The other patient with recalcitrant ulnar non-union although the radiological union was incomplete, declined further intervention, as he was asymptomatic. No complications or adverse effects from the use of rhBMP-7 were encountered. This study supports the view that the application of rhBMP-7 as a bone-stimulating agent is safe and a power adjunct to be considered in the surgeon's armamentarium for the treatment of these challenging clinical conditions.

Topics: Adolescent; Adult; Aged; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Transplantation; Female; Femoral Fractures; Femur; Follow-Up Studies; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Humans; Humeral Fractures; Humerus; Knee Injuries; Male; Middle Aged; Patella; Radiography; Recombinant Proteins; Shoulder Fractures; Tibial Fractures; Transforming Growth Factor beta; Ulna Fractures

A prospective study was conducted to determine the efficacy of using recombinant BMP-7 (rhOP-1) as an adjuvant in the treatment of diaphyseal humeral nonunions. Twenty-three consecutive patients with atrophic humeral diaphyseal nonunions were treated at seven separate institutions. All nonunions were fixed with either a compression plate or an intramedullary nail in conjunction with various bone grafting techniques. Recombinant OP-1 was delivered to the fracture site in a Type I collagen carrier at the time of fixation. All fractures went on to eventual union. There were no serious complications and no adverse reactions to the rhOP-I implant. Our study suggests that rhOP-1 may be a safe and effective adjuvant for the treatment of humeral diaphyseal nonunions.

Topics: Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Nails; Bone Plates; Combined Modality Therapy; Female; Fractures, Ununited; Humans; Humeral Fractures; Male; Middle Aged; Neuroprotective Agents; Prospective Studies; Recombinant Proteins; Transforming Growth Factor beta

Fracture-healing slows with age. While six-week-old rats regain normal bone biomechanics at four weeks after a fracture, one-year-old rats require more than twenty-six weeks. The objective of this study was to examine the possible role of altered mRNA gene expression in this delayed union.. Closed midshaft femoral fractures were created in six-week-old and one-year-old Sprague-Dawley female rats. The animals were killed at zero-time (unfractured) or at 0.4, one, two, three, four, or six weeks after the fracture. mRNA levels were measured by reverse transcription-polymerase chain reaction in the fracture callus for twenty-seven matrix, cytokine, and cytokine-receptor genes for the seven animals per time-point per age-group.. The younger rats healed radiographically by four weeks after the fracture, whereas none of the older rats had healed by the sixth week. Despite the difference in healing rates, the levels of mRNA gene expression, in general, followed the same pattern in both age-groups. The mRNA expression levels increased to a peak at one to two weeks after the fracture and then decreased to very low or undetectable levels at four and six weeks after the fracture for both age-groups. Significantly lower levels of mRNA for Indian hedgehog (Ihh) and bone morphogenetic protein-2 (BMP-2) were detected in the fracture calluses of the older rats (p < 0.01 and p < 0.05, respectively).. All genes studied were up-regulated by the fracture in both age-groups. Thus, the failure of the older rats to heal promptly was not due to the lack of expression of any of the studied genes. The increase in mRNA for Ihh and BMP-2 in the older rats was smaller than that in the younger rats, which may contribute to slower fracture repair. The return of mRNA gene expression to baseline in the older rats prior to healing may contribute to the delayed union. The slower healing response of the older rats did not stimulate a negative-feedback increase in the mRNA expression of stimulatory cytokines.

Topics: Age Factors; Aggrecans; Aging; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bony Callus; Collagen Type II; Cytokines; Disease Models, Animal; Extracellular Matrix Proteins; Female; Femoral Fractures; Fracture Healing; Fractures, Ununited; Gene Expression; Hedgehog Proteins; Lectins, C-Type; Osteocalcin; Proteoglycans; Radiography; Rats; Rats, Sprague-Dawley; Receptors, Cytokine; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Analysis, RNA; Trans-Activators; Transforming Growth Factor beta; Up-Regulation

The potential use of bone morphogenetic proteins (BMPs) to promote bone-healing is of great interest to orthopaedic surgeons. Although the complex mechanism leading from the local presence of BMP (whether endogenous or exogenous) to bone formation is increasingly understood, limited information is available as to whether endogenous BMPs, their receptors, or other molecules involved in their signal transduction, such as Smad1, are present or disappear during the development of fracture nonunions. The purpose of the present study was to determine, by immunohistochemical analysis, whether BMPs, BMP receptors, or Smad1 disappear from tissues during the development of a fracture nonunion.. Twenty-one patients (average age, sixty-one years; range, thirty to eighty-five years) with a delayed union (four patients) or a nonunion (seventeen patients) were included. The average duration of the delayed union or nonunion was twenty-two months (range, 3.5 to 120 months). With use of immunohistochemical analysis, we studied the localization of BMP-2, BMP-4, and BMP-7 and their receptors BMPR-IA, BMPR-IB, and BMPR-II as well as pSmad1. With use of a pSmad1 antibody, we also studied whether the BMP receptors that were expressed were activated.. The immunohistochemical localization of all seven BMP-signaling components was demonstrated in seventeen (81%) of the twenty-one patients. The remaining four patients lacked one or more of the components. Areas of newly formed bone had the highest percentage of positively staining cells, with the staining generally decreasing in areas remote from bone formation. However, even in areas of dense fibrous tissue and in specimens that lacked newly formed bone, immunostaining was still present. The staining patterns showed co-localization of the BMP-2, BMP-4, and BMP-7 proteins with the BMP receptors. The presence of pSmad1 signified the activated state of the BMP receptors, which implies that the BMP signal is transduced inside the cell.

Topics: Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein 7; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Protein Receptors, Type II; Bone Morphogenetic Proteins; Clavicle; DNA-Binding Proteins; Female; Fracture Healing; Fractures, Ununited; Humans; Humeral Fractures; Immunohistochemistry; Male; Middle Aged; Protein Serine-Threonine Kinases; Radius Fractures; Receptors, Cell Surface; Receptors, Growth Factor; Signal Transduction; Smad Proteins; Smad1 Protein; Tibial Fractures; Trans-Activators; Transforming Growth Factor beta

The mechanisms involved in pulsed electromagnetic field stimulation of nonunions are not known. Animal and cell culture models suggest endochondral ossification is stimulated by increasing cartilage mass and production of transforming growth factor-beta 1. For the current study, the effect of pulsed electromagnetic field stimulation on cells from human hypertrophic (n = 3) and atrophic (n = 4) nonunion tissues was examined. Cultures were placed between Helmholtz coils, and an electromagnetic field (4.5-ms bursts of 20 pulses repeating at 15 Hz) was applied to 1/2 of them 8 hours per day for 1, 2, or 4 days. There was a time-dependent increase in transforming growth factor-beta 1 in the conditioned media of treated hypertrophic nonunion cells by Day 2 and of atrophic nonunion cells by Day 4. There was no effect on cell number, [3H]-thymidine incorporation, alkaline phosphatase activity, collagen synthesis, or prostaglandin E2 and osteocalcin production. This indicates that human nonunion cells respond to pulsed electromagnetic fields in culture and that transforming growth factor-beta 1 production is an early event. The delayed response of hypertrophic and atrophic nonunion cells (> 24 hours) suggests that a cascade of regulatory events is stimulated, culminating in growth factor synthesis and release.

Topics: Adult; Alkaline Phosphatase; Bone and Bones; Cell Division; Cells, Cultured; Collagen; Dinoprostone; Electromagnetic Fields; Extracellular Matrix; Female; Fractures, Ununited; Humans; Hypertrophy; Male; Middle Aged; Osteocalcin; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Transplantation; Chemokine CX3CL1; Chemokines, CX3C; Chemokines, CXC; Fracture Fixation, Intramedullary; Fractures, Ununited; Humans; Membrane Proteins; Randomized Controlled Trials as Topic; Tibial Fractures; Transforming Growth Factor beta

The aim of the study was to determine, for the first time, the distribution of expression of several important growth factors during the development of atrophic non-unions using an animal model. The sites of expression of TGFbeta, PDGF, FGFb, and BMP 2/4 were determined at the osteotomy sites of both normally healing bones and within atrophic non-unions at 1 and 8 weeks after operation using immunolocalization techniques. At 1 week after operation, the osteotomy gaps of the control group contained fracture haematoma and surrounding granulation tissue, whereas the osteotomy gaps of the non-union group contained only haematoma. The tissues of both the non-union and control groups demonstrated the same presence and distribution of growth factors. By 8 weeks after the operation, the control group osteotomy gaps were filled with bone within which the active osteoblasts stained positively for each of the growth factors. At 8 weeks, the osteotomy gaps of the non-union group contained only fibrous tissue, which failed to stain positively for any of the factors. These findings suggest that the development of atrophic non-union is not directly due to a lack of these four growth factors.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Chondrocytes; Female; Fibroblast Growth Factor 2; Fracture Healing; Fractures, Ununited; Models, Animal; Osteoblasts; Platelet-Derived Growth Factor; Rabbits; Transforming Growth Factor beta; Zebrafish Proteins

Topics: Animals; Bone Morphogenetic Proteins; Bone Substitutes; Cell Biology; Cell Differentiation; Cell Division; Collagen; Extracellular Matrix Proteins; Fractures, Bone; Fractures, Ununited; Humans; Morphogenesis; Osteogenesis; Protein Binding; Transforming Growth Factor beta

This study examined the ability of cells isolated from early healing segmental defects and from tissue from chronic nonunions to support bone and cartilage formation in vivo and their response to transforming growth factor-beta1 in vitro. Ostectomies (3 mm) were created in the radial diaphysis of four dogs. The dogs were splinted 3-5 days postoperatively and then allowed to bear full weight. At 7 days, tissue in the defect was removed and any periosteum was discarded; cells in the defect tissue were released by enzymatic digestion. The dogs were splinted again and allowed to bear full weight for 12 weeks. Radiographs confirmed a persistent nonunion in each dog. Defect tissue was again removed, any periosteum was discarded, and cells were isolated. Cells were also obtained from the defect tissue by nonenzymatic means with use of explant cultures. One-half of the tissue and one-half of any preconfluent, first-passage cultures were shipped to Cleveland by overnight carrier. At second passage, cells were loaded into ceramic cubes and implanted into immunocompromised mice for 3 or 6 weeks. Harvested cubes were examined histologically for cartilage and bone with use of a semiquantitative scoring system. Confluent fourth-passage cultures of 7 and 84-day defect tissue cells were cultured with 0.03-0.88 ng/ml transforming growth factor-beta1 for 24 hours, and [3H]thymidine incorporation and alkaline phosphatase specific activity were determined. Donor-dependent differences were noted in the rate at which defect cells achieved confluence; in general, cells from 7-day tissue divided most rapidly. Seven-day defect cells formed less bone and at a slower rate than was seen in the ceramic cubes containing samples from day 84. Cells derived enzymatically behaved similarly to those from explant cultures. Ceramic cubes contained fibrous connective tissue, cartilage, bone, and fat, indicating that multipotent cells were present. Stimulation of [3H]thymidine incorporation in response to transforming growth factor-beta1 was donor dependent and variable; only two of six separate isolates of cells exposed to it had measurable alkaline phosphatase activity (which was relatively low), and none of the cultures exhibited an increase in response to transforming growth factor-beta1 for 24 hours. This indicates that mesenchymal progenitor cells are present in the healing defect tissue at 7 and 84 days and that the relative proportion of osteochondroprogenitor cells is greater at the l

Topics: Alkaline Phosphatase; Animals; Bone Development; Bony Callus; Cartilage; Cell Division; Cells, Cultured; Chondrocytes; Disease Models, Animal; Dogs; Fracture Healing; Fractures, Ununited; Humans; Immunocompromised Host; Mice; Osteoblasts; Osteogenesis; Osteotomy; Radiography; Radius; Radius Fractures; Recombinant Proteins; Stem Cells; Thymidine; Transforming Growth Factor beta

Topics: Animals; Antithrombins; Biotechnology; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Clinical Trials as Topic; Deoxyribonuclease (Pyrimidine Dimer); DNA Repair; Drug Carriers; Endodeoxyribonucleases; Fibrinolytic Agents; Fractures, Ununited; Hirudin Therapy; Humans; Liposomes; Ointments; Primates; Proteins; Recombinant Proteins; Transforming Growth Factor beta; Xeroderma Pigmentosum

A rabbit ulnar non-union model was used to evaluate the effect of recombinant human osteogenic protein-1 on the healing of a large segmental osteoperiosteal defect. A 1.5-centimeter segmental defect was created in the mid-part of the ulnar shaft of adult rabbits. The defect was filled with an implant containing either recombinant human osteogenic protein-1 or naturally occurring bovine osteogenic protein. The recombinant human osteogenic protein-1 implants consisted of a carrier of 125 milligrams of demineralized, guanidine-extracted, insoluble rabbit bone matrix (the collagen carrier), reconstituted with 3.13, 6.25, 12.5, twenty-five, fifty, 100, 200, 300, or 400 micrograms of recombinant human osteogenic protein-1. Animals that received recombinant human osteogenic protein-1 were compared with animals that received an implant of 250 micrograms of a preparation of naturally occurring bovine osteogenic protein mixed with the collagen carrier. Limbs that served as controls received either the collagen carrier alone or no implant at all. The treated and the untreated defects were examined radiographically and histologically at eight or twelve weeks after implantation. Mechanical testing was performed on six animals. All implants of recombinant human osteogenic protein-1, except for those containing 3.13 micrograms of the substance, induced complete radiographic osseous union within eight weeks. The defects that were treated with an implant of bovine osteogenic protein also healed within this time-period. The bone induced by both types of implants had new cortices with advanced remodeling and marrow elements. Histological evaluation of this new bone at eight weeks postoperatively revealed primarily lamellar bone, with the formation of new cortices and normal-appearing marrow elements. The average torsional strength and energy-absorption capacity of the union induced by recombinant human osteogenic protein-1 was comparable with that of intact bone. The control defects that had been implanted with collagen carrier alone and those with no implant showed no bridging of the defect.

Topics: Animals; Bone Matrix; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Remodeling; Cattle; Drug Carriers; Fracture Healing; Fractures, Ununited; Humans; Male; Osseointegration; Proteins; Rabbits; Recombinant Proteins; Transforming Growth Factor beta; Ulna Fractures