transforming-growth-factor-beta and Tibial-Fractures

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

This article is another review of clinical application of the use of bone morphogenetic proteins, specifically rhBMP2 Infuse Bonegraft, in the treatment of both acute and chronic fracture and fusion situations. Overall experience is reported with particular detail to the use of biologics in the treatment of problems involving the tibia, foot, and ankle.

Topics: Adolescent; Adult; Aged; Ankle Injuries; Arthrodesis; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Female; Fibula; Fracture Healing; Fractures, Bone; Fractures, Comminuted; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Reoperation; Tibial Fractures; Transforming Growth Factor beta; Young Adult

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

Delayed healing and non-union remain common problems in the treatment of open tibial shaft fractures. Additional surgical treatments may be required to facilitate healing. The efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2), as an adjunct to the standard of care, has been investigated in the BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) study. This prospective, randomised, multicentre, controlled study included 450 patients with acute, diaphyseal, open tibial fractures. A significant reduction in the risk of secondary intervention was observed in the 1.50 mg/mL rhBMP-2 group compared with the standard of care alone group (p = 0.0005). In a subgroup analysis of 131 patients with Gustilo-Anderson grade IIIA or IIIB open tibial fractures, using data combined from the BESTT study and a study conducted at 10 level I US trauma centres, a significant reduction in the incidence of secondary autologous bone graft procedures was observed with 1.50 mg/mL rhBMP-2 compared with the standard of care (p = 0.0005). The influence of fracture gap on the re-operation rate has also been examined in the BESTT study. In the 1.50 mg/mL rhBMP-2 group, patients with a 0 mm fracture gap had significantly less re-operations compared with those patients with a greater than 2 mm gap (p = 0.048).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Combined Modality Therapy; Female; Fracture Healing; Humans; Male; Middle Aged; Orthopedic Procedures; Randomized Controlled Trials as Topic; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome; Wounds and Injuries

The addition of recombinant human bone morphogenetic protein (rhBMP-2) to the standard of care, consisting of soft tissue management and intramedullary nailing, in the BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) study led to a significantly better outcome for the patient. Reductions in fracture healing time, secondary interventions for delayed fracture healing and infection rates were observed with 1.50 mg/mL rhBMP-2 compared with the standard of care alone. In Germany the approximate cost of applying one dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) to an open tibial fracture is euro2970. The current German-Diagnosis-Related Group reimbursement system provides one flat rate per hospital stay or treatment case, and does not take into account the costs of rhBMP-2 application. Therefore there is no reimbursement for the price of rhBMP-2 for hospitals by health insurance companies. However, the above mentioned improvements in medical outcome could lead to important savings for health care systems, particularly for health insurance companies. A sound economic model to assess the cost-effectiveness and budget impact of rhBMP-2 is required. Using medical data from the BESTT study the differences in fracture healing time, in reduction of secondary interventions for fracture healing and infection treatment can be transferred into economic savings. It is anticipated that the overall savings that can be achieved by rhBMP-2 treatment in open tibia fractures, offset the upfront price of rhBMP-2 and lead to net savings for health insurance companies.

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cost-Benefit Analysis; Drug Costs; Europe; Germany; Humans; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

Autogenous bone grafts from the iliac crest have long been the gold standard for repair and reconstruction of bone; however harvesting of the grafts from the iliac crest is associated with donor site morbidity, particularly chronic pain. The bone morphogenetic proteins (BMPs) are soluble bone matrix glycoproteins that induce the differentiation of osteoprogenitor cells into osteogenic cells and have the potential to act as autogenous bone graft substitutes. BMP-2, which can be produced with recombinant technology, is highly osteoinductive, inducing bone formation by stimulating the differentiation of mesenchymal cells into chrondroblasts and osteoblasts. At present, more than 1,000 patients have received rhBMP-2 in clinical trials for acute open tibial fracture and interbody fusion procedures for the treatment of degenerative disc disease. Data suggest that rhBMP-2 therapy may offer an effective alternative to autogenous bone graft for recalcitrant bone unions and spinal fusion, obviating donor site morbidity.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Remodeling; Bone Transplantation; Cell Differentiation; Fracture Healing; Humans; Recombinant Proteins; Spinal Fusion; Tibial Fractures; Transforming Growth Factor beta

Recombinant human bone morphogenetic protein-2 is an osteoinductive protein that plays a pivotal role in bone growth and regeneration. Several hundred studies were conducted in the past 7 years in numerous animal models to establish unequivocally the efficacy, safety, mechanism of action, pharmacokinetics, and surgical handling properties of recombinant human bone morphogenetic protein-2, building a solid foundation for clinical development programs. Pilot clinical trials have shown the feasibility and safety of recombinant human bone morphogenetic protein-2 treatment, and defined the effective dose for its use in open long bone fractures and for augmentation or preservation of the alveolar bone in the dental ridge. Prospective observational clinical studies helped define clinical efficacy end points, identify significant variables, and estimate appropriate population sample size for pivotal clinical trials. Pivotal clinical trials of recombinant human bone morphogenetic protein-2 are underway in patients with open tibial shaft fractures and in patients with a deficiency of the alveolar ridge.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Clinical Trials as Topic; Disease Progression; Dose-Response Relationship, Drug; Fracture Healing; Fractures, Open; Humans; Osteogenesis, Distraction; Osteonecrosis; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome

To compare radiographic union of tibia fractures with bone defects treated with recombinant bone morphogenetic protein-2 (rhBMP-2) with allograft to autogenous iliac crest bone graft (ICBG).. FDA-regulated multicenter randomized trial.. Sixteen US trauma centers.. Thirty patients (18-65 years of age) with Type II, IIIA, or IIIB open tibia fracture and bone defect treated with an intramedullary nail.. rhBMP-2 (n = 16) versus ICBG (n = 14).. Radiographic union within 52 weeks. Secondary outcomes included clinical healing, patient-reported function, major complications, and treatment cost. Equivalence was evaluated by testing whether a 90% two-sided confidence interval for the difference in the probability of radiographic union between rhBMP-2 or ICBG is contained with the interval [220% to +20%]. A post hoc Bayesian analysis, using data from a previous trial, was also conducted.. Twenty-three patients had union data at 52 weeks: 7/12 (58.3%) rhBMP-2 were radiographically united compared with 9/11 (81.8%) ICBG, resulting in a treatment difference of -0.23 (90% CI: -0.55 to 0.10). Patients treated with rhBMP-2 had lower rates of clinical healing at 52 weeks (27% vs. 54%), higher mean Short Musculoskeletal Function Assessment scores (dysfunction: 33.3 vs. 23.7; bother score: 32.8 vs. 21.4) and experienced more complications (5 vs. 3). Mean treatment cost for rhBMP-2 was estimated at $14,155 versus $9086 for ICBG.. These data do not provide sufficient evidence to conclude that ICBG and rhBMP-2 are equivalent regarding radiographic union.. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Topics: Adolescent; Adult; Aged; Bone Morphogenetic Protein 2; Bone Transplantation; Collagen; Female; Fracture Fixation; Fracture Healing; Humans; Male; Middle Aged; Recombinant Proteins; Surgical Sponges; Tibial Fractures; Transforming Growth Factor beta; Transplantation, Autologous; Treatment Outcome; Young Adult

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

Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation.. Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone.. Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups.. In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. 24306696

Topics: Adult; Bone Morphogenetic Protein 2; Bone Nails; Calcium Phosphates; Diaphyses; Dose-Response Relationship, Drug; Double-Blind Method; Feasibility Studies; Female; Fracture Fixation, Intramedullary; Fracture Healing; Fractures, Closed; Humans; Injections, Intralesional; Male; Postoperative Complications; Recombinant Proteins; Tibial Fractures; Time Factors; Transforming Growth Factor beta

Recombinant human bone morphogenetic protein-2 (rhBMP-2) improves healing of open tibial fractures treated with unreamed intramedullary nail fixation. We evaluated the use of rhBMP-2 in the treatment of acute open tibial fractures treated with reamed intramedullary nail fixation.. Patients were randomly assigned (1:1) to receive the standard of care consisting of intramedullary nail fixation and routine soft-tissue management (the SOC group) or the standard of care plus an absorbable collagen sponge implant containing 1.5 mg/mL of rhBMP-2 (total, 12.0 mg) (the rhBMP-2/ACS group). Randomization was stratified by fracture severity. The absorbable collagen sponge was placed over the fracture at wound closure. The primary efficacy end point was the proportion of subjects with a healed fracture as demonstrated by radiographic and clinical assessment thirteen and twenty weeks after definitive wound closure.. Two hundred and seventy-seven patients were randomized and were the subjects of the intent-to-treat analysis. Thirteen percent of the fractures were Gustilo-Anderson Type IIIB. The proportions of patients with fracture-healing were 60% and 48% at week 13 (p = 0.0541) and 68% and 67% at week 20 in the rhBMP-2/ACS and SOC groups, respectively. Twelve percent of the subjects underwent secondary procedures in each group; more invasive procedures (e.g., exchange nailing) accounted for 30% of the procedures in the rhBMP-2/ACS group and 57% in the SOC group (p = 0.1271). Infection was seen in twenty-seven (19%) of the patients in the rhBMP-2/ACS group and fifteen (11%) in the SOC group (p = 0.0645; difference in infection risk = 0.09 [95% confidence interval, 0.0 to 0.17]). The adverse event incidence was otherwise similar between the treatment groups.. The healing of open tibial fractures treated with reamed intramedullary nail fixation was not significantly accelerated by the addition of an absorbable collagen sponge containing rhBMP-2.

Topics: Adult; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Nails; Female; Fracture Fixation, Intramedullary; Fracture Healing; Fractures, Open; Humans; Male; Recombinant Proteins; Single-Blind Method; Surgical Wound Infection; Tibial Fractures; Transforming Growth Factor beta

The purpose of this study was to determine the cost savings from a societal perspective for recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) in grade III A and B open tibial fractures treated with a locked intramedullary nail and soft-tissue management in the UK, Germany, and France. Health care system costs (direct health care costs) and costs for productivity losses (indirect health care costs) were calculated using the raw data from the Bone Morphogenetic Protein Evaluation Group in Surgery for Tibial Trauma "BESTT study". Return-to-work time for estimation of productivity losses was assumed to correspond with the time of fracture healing. For calculation of secondary interventions costs and productivity losses the respective 2007/2008 national tariffs for surgical procedures and average national wages for the UK, Germany, and France were used. For a 1 year perspective, overall treatment costs per patient after the initial surgery of the control vs. the rhBMP-2 group were 44,757 euros vs. 36,847 euros for the UK, 50,197 euros vs. 40,927 euros for Germany and 48,766 euros vs. 39,474 euros for France in favour of rhBMP-2 with overall savings overall savings per case of rhBMP-2 treatment of 7911 euros for the UK, 9270 euros for Germany, and 9291 euros for France which was mainly due to reduced productivity losses by significant faster fracture healing in the rhBMP-2 group (p=0.01). These savings largely offset the upfront price of rhBMP-2 of 2266 euros (1790 pounds) in the UK, euros 2970 in Germany, and 2950 euros in France. Total net savings can be estimated to be 9.6 million euros for the UK, 14.5 million euros for Germany, and 11.4 million euros for France. The results depend on the methodology used particularly for calculation of productivity losses and return-to-work time which was assumed to correspond with fracture healing time. In summary, despite the apparent high direct cost of rhBMP-2 in grade III A and B open tibial fractures, at a national level there are net cost savings from a societal perspective for all three countries.

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cost of Illness; Cost Savings; Cost-Benefit Analysis; Employment; Fracture Fixation, Intramedullary; Fracture Healing; Fractures, Open; France; Germany; Health Care Costs; Humans; Incidence; Models, Economic; Prospective Studies; Recombinant Proteins; Reoperation; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome; United Kingdom

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

Topics: Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Child; Child, Preschool; Female; Fracture Fixation, Internal; Fracture Healing; Humans; Infant; Male; Prospective Studies; Pseudarthrosis; Radiography; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome

The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to improve the healing of open tibial shaft fractures has been the focus of two prospective clinical studies. The objective of the current study was to perform a subgroup analysis of the combined data from these studies.. Two prospective, randomized clinical studies were conducted. A total of 510 patients with open tibial fractures were randomized to receive the control treatment (intramedullary nail fixation and routine soft-tissue management) or the control treatment and an absorbable collagen sponge impregnated with one of two concentrations of rhBMP-2. The rhBMP-2 implant was placed over the fracture at the time of definitive wound closure. For the purpose of this analysis, only the control treatment and the Food and Drug Administration-approved concentration of rhBMP-2 (1.50 mg/mL) were compared. Patients who anticipated receiving planned bone-grafting as part of a staged treatment were excluded from enrollment.. Fifty-nine trauma centers in twelve countries participated, and patients were followed for twelve months postoperatively. Two subgroups were analyzed: (1) the 131 patients with a Gustilo-Anderson type-IIIA or IIIB open tibial fracture and (2) the 113 patients treated with reamed intramedullary nailing. The first subgroup demonstrated significant improvements in the rhBMP-2 group, with fewer bone-grafting procedures (p = 0.0005), fewer patients requiring invasive secondary interventions (p = 0.0065), and a lower rate of infection (p = 0.0234), compared with the control group. The second subgroup analysis of fractures treated with reamed intramedullary nailing demonstrated no significant difference between the control and the rhBMP-2 groups.. The addition of rhBMP-2 to the treatment of type-III open tibial fractures can significantly reduce the frequency of bone-grafting procedures and other secondary interventions. This analysis establishes the clinical efficacy of rhBMP-2 combined with an absorbable collagen sponge implant for the treatment of these severe fractures.

Topics: Absorbable Implants; Adult; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Drug Implants; Female; Follow-Up Studies; Fracture Fixation, Intramedullary; Fracture Healing; Fractures, Open; Humans; Male; Prospective Studies; Recombinant Proteins; Tibial Fractures; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Weight-Bearing

Currently, the treatment of diaphyseal tibial fractures associated with substantial bone loss often involves autogenous bone-grafting as part of a staged reconstruction. Although this technique results in high healing rates, the donor-site morbidity and potentially limited supply of suitable autogenous bone in some patients are commonly recognized drawbacks. The purpose of the present study was to investigate the benefit and safety of the osteoinductive protein recombinant human bone morphogenetic protein-2 (rhBMP-2) when implanted on an absorbable collagen sponge in combination with freeze-dried cancellous allograft.. Adult patients with a tibial diaphyseal fracture and a residual cortical defect were randomly assigned to receive either autogenous bone graft or allograft (cancellous bone chips) for staged reconstruction of the tibial defect. Patients in the allograft group also received an onlay application of rhBMP-2 on an absorbable collagen sponge. The clinical evaluation of fracture-healing included an assessment of pain with full weight-bearing and fracture-site tenderness. The Short Musculoskeletal Function Assessment (SMFA) was administered before and after treatment. Radiographs were used to document union, the presence of extracortical bridging callus, and incorporation of the bone-graft material.. Fifteen patients were enrolled in each group. The mean length of the defect was 4 cm (range, 1 to 7 cm). Ten patients in the autograft group and thirteen patients in the rhBMP-2/allograft group had healing without further intervention. The mean estimated blood loss was significantly less in the rhBMP-2/allograft group. Improvement in the SMFA scores was comparable between the groups. No patient in the rhBMP-2/allograft group had development of antibodies to BMP-2; one patient had development of transient antibodies to bovine type-I collagen.. The present study suggests that rhBMP-2/allograft is safe and as effective as traditional autogenous bone-grafting for the treatment of tibial fractures associated with extensive traumatic diaphyseal bone loss.. Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence.

Topics: Adult; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Transplantation; Collagen; Combined Modality Therapy; Diaphyses; Follow-Up Studies; Humans; Prospective Studies; Recombinant Proteins; Surgical Sponges; Tibial Fractures; Transforming Growth Factor beta; Transplantation, Autologous; Treatment Outcome

Osteogenic proteins (OP) are elements of a class of natural growth factors called Bone Morphogenetic Proteins (BMP). A specific member of this class is OP-1, a human recombinant protein that has osteogenic properties. The osteoinductive and osteoconductive properties of OP-1, with its specific collagen matrix, promote the generation of new functionally active, biologically and biomechanically mature bone. We carried out a clinical study to verify the potential of this protein in fresh tibial closed fractures, using OP-1 associated with osteosynthesis by means of a monolateral external fixator.

Topics: Adult; Aged; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Combined Modality Therapy; External Fixators; Female; Fracture Fixation; Fractures, Closed; Humans; Male; Middle Aged; Recombinant Fusion Proteins; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome

The treatment of open fractures of the tibial shaft is often complicated by delayed union and nonunion. The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention.. In a prospective, randomized, controlled, single-blind study, 450 patients with an open tibial fracture were randomized to receive either the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]), the standard of care and an implant containing 0.75 mg/mL of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture at the time of definitive wound closure. Randomization was stratified by the severity of the open wound. The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively.. Four hundred and twenty-one (94%) of the patients were available for the twelve-month follow-up. The 1.50-mg/mL rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary intervention because of delayed union; relative risk = 0.56; 95% confidence interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and significantly faster fracture-healing (p = 0.0022) than did the control patients. Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months (p = 0.0008). Compared with the control patients, those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fewer infections (in association with Gustilo-Anderson type-III injuries; p = 0.0219), and faster wound-healing (83% compared with 65% had wound-healing at six weeks; p =0.0010).. The rhBMP-2 implant was safe and, when 1.50 mg/mL was used, significantly superior to the standard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures, accelerating fracture and wound-healing, and reducing the infection rate in patients with an open fracture of the tibia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Female; Fractures, Open; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Single-Blind Method; Tibial Fractures; Transforming Growth Factor beta

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

Introduction: Chronic hyperglycemia as the main link in DM pathogenesis leads to systemic vessels and nerves lesion with chronic bone complications development consequently. The aim: To evaluate influence of hyperglycemia on reparative osteogenesis after perforated tibial fracture in rats.. Materials and methods: A total of 30 white adult rats were subdivided into two groups: 15 healthy rats in Group 1 (control) and 15 rats with alloxan induced hyperglycemia in Group 2 (investigated) and were carried out of experiment on the 10th, 20th and 30th day after the fracture. Hyperglycemia in rats was verificated as the postprandial glycemic rate ≥ 8,0 mmol/l. Tibia diaphysis fracture was modeled by a cylindrical defect with a diameter of 2 mm with portable frezer. Morphological evaluation. A complex morphological studies included histological, morphometric and immunohistochemical examination.. Results: This is confirmed by an increase in MMP-9 expression in connective tissue, a decrease in TGF-β expression in all phases, an increase in the expression of CD3 and CD20 and a marked decrease in the expression of all vascular markers. During hyperglycemia, incomplete blood supply to the tissues occurs, necrosis of bone and soft tissues develop in the area of the fracture, the reparative reaction slows down considerably and manifests itself in the development of fibrous and, less commonly, cartilage tissue.. Conclusions: In hyperglycemia rats, there was a delay in the callus formation, a decrease in proliferation and ossification, and a slowdown in the processes of angiogenesis.

Topics: Animals; Antigens, CD20; Bone and Bones; Bony Callus; CD3 Complex; Diabetes Mellitus; Disease Models, Animal; Matrix Metalloproteinase 9; Neovascularization, Physiologic; Osteogenesis; Rats; Tibial Fractures; 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

In congenital pseudarthrosis of the tibia, use of intramedullary (IM) fixation and autogenous bone graft has long been the standard of care. This study was undertaken to determine whether the addition of rhBMP-2 to this treatment method further enhances healing potential.. Twenty-one patients with congenital pseudarthrosis of the tibia were evaluated. Fifteen of these patients had neurofibromatosis type 1 (NF1). All had IM fixation and autogenous bone graft, followed by a BMP-soaked collagen sponge wrapped around both the fracture site and bone graft. A minimum 2 years' follow-up was required.. Follow-up averaged 7.2 years (range, 2.1 to 12.8 y). Sixteen of 21 tibias achieved bone union following the index surgery, at an average 6.6 months postoperatively. The 5 persistent nonunions occurred in NF1 patients. Further surgery was undertaken in these 5 NF1 patients, including the use of BMP. One of the 5 healed, 1 had persistent nonunion, and 3 eventually had amputation. Of the 16 patients who healed initially following the index surgery, 5 refractured (3 had NF1). Of these 5 patients, the IM fixation at the index surgery did not cross the ankle joint, and refracture occurred at the rod tip in 4. Three of these 5 patients healed following further surgery, 1 had persistent nonunion, and 1 had amputation. All of those with eventual amputation had NF1. No deleterious effects related to the use of BMP-2 were recognized in any patient.. The addition of rhBMP-2 appears to be helpful in shortening the time required to achieve fracture union in those who healed, but its use does not insure that healing will occur.. Level IV-therapeutic, case series.

Topics: Adolescent; Bone Morphogenetic Protein 2; Bone Transplantation; Child; Child, Preschool; Female; Fracture Fixation, Intramedullary; Humans; Infant; Male; Neurofibromatosis 1; Pseudarthrosis; Radiography; Recombinant Proteins; Retrospective Studies; Tibial Fractures; Transforming Growth Factor beta

There is a lack of studies reporting on rhBMP-2 application in pediatric orthopaedics, although few reports demonstrated promising results of the use of rhBMP-2 in children, especially for spine fusion and for the treatment of congenital pseudarthrosis of the tibia. The objectives of this study were (1) to examine clinical and radiographic healing after rhBMP-2 application for the treatment of congenital pseudarthrosis of the tibia (CPT) or persistent tibial nonunion in children and adolescents, and (2) to investigate the safety of rhBMP-2 use in these cases. Therefore we reviewed the medical records of ten patients with a mean age of 8.6 years (2.3-21) with CPT (n = 7) or persistent tibial nonunion for at least six months (n = 3) who had been treated with rhBMP-2. Nine of ten patients had union at final follow-up, after a mean of 72.9 months (25-127). In the CPT group, primary healing of the pseudarthrosis occurred in six of seven patients at a mean of 5.2 months (3-12). Repeat rhBMP-2 application was performed in three patients; two patients had one additional application each, and one patient had three additional applications. Complications that may be attributed to the use of rhBMP-2 were seen in two of fifteen applications, including a compartmemt syndrome and a hematoma. In this retrospective case series rhBMP-2 has been used successfully to treat CPT or persistent tibial nonunion in pediatric patients. However, prospective randomized controlled trials are warranted to investigate the long-term efficacy and safety of rhBMP-2 use in these cases.

Topics: Adolescent; Bone Morphogenetic Protein 2; Bone Transplantation; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Male; Postoperative Period; Pseudarthrosis; Recombinant Proteins; Retrospective Studies; Tibia; Tibial Fractures; Transforming Growth Factor beta; Young Adult

The authors previously described the generation of vascularized bone in a pig model, using a hemimandibular allograft scaffold, adipose-derived stem cells, recombinant human bone morphogenetic protein-2, and periosteum. This study tests the hypothesis that this "allograft revitalization" technique is as effective as vascularized autograft for repairing critical bony defects.. Three groups of pigs had 3-cm defects created in their bilateral tibial diaphyses for repair using rigid fixation and one of three modalities. Negative control tibias were repaired with allograft tibia alone. To simulate repair using vascularized autograft, the osteotomized bone in positive control animals was left in situ, with the posterior periosteum intact. Experimental animals' defects were repaired with allograft tibia packed with autologous adipose-derived stem cells and recombinant human bone morphogenetic protein-2, with native periosteum intact. After 8 weeks, unilateral midgraft osteotomies were performed to assess graft healing potential. Serial radiographs and terminal micro-computed tomography and histology enabled evaluation of healing.. At week 7 after ostectomy, no negative control tibias had healed (zero of six) whereas most positive control (five of six) and all experimental tibias (six of six) had healed. Unilateral midgraft osteotomies were performed at 8 weeks to assess graft ability to heal. As expected, no negative control tibias (three of three) had radiographic union 7 weeks later. However, all positive control (two of two; p = 0.05) and experimental (three of three; p = 0.01) tibias had healed their repeated osteotomies by this time.. Similar to vascularized autograft, revitalized allograft successfully repaired a critical tibial defect, including after refracture, suggesting that this technique may be an alternative to osseous free flaps.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Transplantation; Female; Fracture Fixation, Internal; Mesenchymal Stem Cell Transplantation; Osteotomy; Periosteum; Recombinant Proteins; Swine; Tibia; Tibial Fractures; Transforming Growth Factor beta; Transplantation, Homologous; Treatment Outcome; Wound Healing

Topics: Bone Morphogenetic Protein 2; Calcium Phosphates; Female; Fractures, Closed; Humans; Male; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Fracture Fixation, Intramedullary; Fracture Healing; Fractures, Open; Humans; Recombinant Proteins; Surgical Sponges; Tibial Fractures; Transforming Growth Factor beta

The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for the treatment of congenital pseudarthrosis of the tibia has been investigated in only one previous study, with promising results. The aim of this study was to determine whether rhBMP-2 might improve the outcome of this disorder. We reviewed the medical records of five patients with a mean age of 7.4 years (2.3 to 21) with congenital pseudarthrosis of the tibia who had been treated with rhBMP-2 and intramedullary rodding. Ilizarov external fixation was also used in four of these patients. Radiological union of the pseudarthrosis was evident in all of them at a mean of 3.5 months (3.2 to 4) post-operatively. The Ilizarov device was removed after a mean of 4.2 months (3.0 to 5.3). These results indicate that treatment of congenital pseudarthrosis of the tibia using rhBMP-2 in combination with intramedullary stabilisation and Ilizarov external fixation may improve the initial rate of union and reduce the time to union. Further studies with more patients and longer follow-up are necessary to determine whether this surgial procedure may significantly enhance the outcome of congenital pseudarthrosis of the tibia, considering the refracture rate (two of five patients) in this small case series.

Topics: Ankle Joint; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Child, Preschool; Combined Modality Therapy; External Fixators; Female; Follow-Up Studies; Fracture Fixation, Intramedullary; Fracture Healing; Humans; Ilizarov Technique; Knee Joint; Male; Pseudarthrosis; Radiography; Range of Motion, Articular; Recombinant Proteins; Retrospective Studies; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome; Young Adult

Topics: Administration, Topical; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Child; Child, Preschool; Female; Fracture Fixation, Intramedullary; Humans; Infant; Intercellular Signaling Peptides and Proteins; Male; Pseudarthrosis; Recombinant Proteins; Retrospective Studies; Tibia; Tibial Fractures; Transforming Growth Factor beta

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Humans; Military Personnel; Recombinant Proteins; Scientific Misconduct; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome

We describe a patient with insufficient bone regeneration of the tibia after bone transport over an intramedullary nail, in whom union was ultimately achieved after exchange nailing and intramedullary application of rh-bone morphogenetic protein-7 at the site of distraction.

Topics: Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Neoplasms; Child; Female; Fractures, Stress; Humans; Ilizarov Technique; Leg Length Inequality; Osteogenesis, Distraction; Recombinant Proteins; Rhabdomyosarcoma; Tibia; Tibial Fractures; Transforming Growth Factor beta

This is a retrospective consecutive case series of 138 Gustillo-Anderson type IIIB and IIIC segmental tibial fractures treated at Walter Reed Army Medical Center in soldiers injured in Iraq between March 2003 and March 2005. Five patients with a head injury and four who were lost to follow-up were excluded. The patients were treated definitively with either a ringed external fixator or a reamed intramedullary nail, evaluated in terms of supplementary bone grafting with either autogenous bone (group 1, 67 patients) or recombinant human bone morphogenetic protein-2 at 1.50 mg/ml applied to an absorbable collagen sponge (group 2, 62 patients). The mechanism of injury, defect size and classification, associated injuries, presence of infection, preliminary treatment/fixation, number of procedures before definitive management, time to and details of definitive management, subsequent infection, re-operation, smoking history and other complications were noted. Radiographs were assessed for union, delayed union or nonunion by an independent investigator. All the patients were male. Their mean age was 26.6 years (20 to 42) and the mean follow-up was for 15.6 months (12 to 32). Group 2 had a slightly higher profile of concomitant injuries and a slightly worse fracture classification, but these were not significant. The rate of union was 76% (51 of 67) for group 1 and 92% for group 2 (57 of 62; p = 0.015). There was also a higher rate of subsequent infection in group 1 (14.9%) compared with group 2 (3.2%; p = 0.001) and a higher rate of re-operation (28%) in group 1 (p = 0.003). There were no observed hypersensitivity reactions to the recombinant human bone morphogenetic protein-2 implant.

Topics: Adult; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Transplantation; Follow-Up Studies; Fracture Fixation; Fractures, Open; Humans; Iraq War, 2003-2011; Male; Military Personnel; Recombinant Proteins; Retrospective Studies; Statistics as Topic; Tibial Fractures; Transforming Growth Factor beta; Transplantation, Autologous; Treatment Outcome; United States

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

Contemporary treatment of critical bone defect remains a significant challenge in the field of orthopedic surgery. Engineered biomaterials combined with growth factors have emerged as a new treatment alternative in bone repair and regeneration. Our approach is to encapsulate bone morphogenetic protein-2 (BMP-2) into a polymeric matrix in different ways and characterize their individual performance in a nude mouse model. The main objective of this study is to examine whether the PLGA/HAp composite fibrous scaffolds loaded with BMP-2 through electrospinning can improve bone regeneration. The hypothesis is that different loading methods of BMP-2 and different HAp contents in scaffolds can alternate the release profiles of BMP-2 in vivo, therefore modify the performance of scaffolds in bone regeneration. Firstly, mechanical strength of scaffolds and HAp nanoparticles distribution in scaffolds were investigated. Secondly, nude mice experiments extended to 6 weeks were carried out to test the in vivo performance of these scaffolds, in which measurements, like serum BMP-2 concentration, ALP activity, X-ray qualification, and H&E/IHC tissue staining were utilized to monitor the growth of new bone and the changes of the corresponding biochemical parameters. The results showed that the PLGA/HAp composite scaffolds developed in this study exhibited good morphology/mechanical strength and HAp nanoparticles were homogeneously dispersed inside PLGA matrix. Results from the animal experiments indicate that the bioactivity of BMP-2 released from the fibrous PLGA/HAp composite scaffolds is well maintained, which further improves the formation of new bone and the healing of segmental defects in vivo. It is concluded that BMP-2 loaded PLGA/HAp composite scaffolds are promising for bone healing.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Regeneration; Bone Substitutes; Delayed-Action Preparations; Drug Carriers; Durapatite; Lactic Acid; Mice; Mice, Nude; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Tibial Fractures; Transforming Growth Factor beta; Treatment Outcome

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Neoplasms; Bone Transplantation; Contraindications; Drug-Related Side Effects and Adverse Reactions; Humans; Product Surveillance, Postmarketing; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

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

We describe a 13-year-old boy with atrophic tibial pseudarthrosis associated with neurofibromatosis who had undergone nine unsuccessful operations. Eventually, union was obtained by the use of bone morphogenetic protein 7 in conjunction with intramedullary stabilisation and autologous bone graft.

Topics: Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Combined Modality Therapy; Fibula; Follow-Up Studies; Fractures, Bone; Humans; Infant; Male; Neurofibromatoses; Pseudarthrosis; Radiography; Tibia; Tibial Fractures; Transforming Growth Factor beta

Topics: Adult; Alopecia; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Humans; Incidental Findings; Male; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

Critical size defects of bone and delayed fracture healing due to metabolic disorders are still problems in orthopaedic surgery. Adenoviral vectors encoding bone morphogenetic protein-2 (Ad.BMP-2) have been used to stimulate bone formation in small animals. The present study evaluated the use of direct adenoviral gene transfer for inducing bone formation in a large animal. Standardized iliac crest defects were created surgically on both sides of the pelvic bone of white mountain sheep. The efficiency of gene transfer was evaluated using recombinant adenoviruses carrying the cDNA for luciferase. High levels of transgene expression, restricted to the site of injection, were found for the 1st week. Transgene expression then fell considerably, but could still be detected for up to 5 weeks. To investigate the effect on bone healing, Ad.BMP-2 (10(11) particles in 200 mul saline) was unilaterally injected into iliac crest defects and into tibial osteotomies. The contralateral defects remained untreated to evaluate possible systemic effects. The controls were treated with saline solution. Bone formation within the defect, assessed by micro-computed tomography (CT) measurement at 8 weeks, and callus formation after osteotomy were significantly reduced following direct application of Ad.BMP-2. The retardation compared to untreated control animals was additionally found at the contralateral iliac crest indicating a systemic inhibitory effect. Histological analysis confirmed the CT measurement and showed an increased number of inflammatory cells within both defects. Antibodies against the adenovirus and the transgene product were detected in all treated animals. These data show a systemic retardation of bone formation following a single local injection of Ad.BMP-2 in sheep. This finding stands in contrast to the data obtained from small animal models. Further studies are needed to determine the contribution of the immune response to these results, and whether a lower dose of Ad.BMP-2 would be advantageous.

Topics: Adenoviridae; Animals; Antibodies, Viral; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bony Callus; Female; Fracture Healing; Fractures, Bone; Gene Expression; Genetic Therapy; Genetic Vectors; Hip Fractures; Luciferases; Models, Animal; Osteogenesis; Osteotomy; Sheep; Tibial Fractures; Time Factors; Transduction, Genetic; Transforming Growth Factor beta; Transgenes

The purpose of the current study was to evaluate savings from the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in open tibia fractures by faster fracture healing and reduction of secondary treatment costs from a health insurance perspective for Germany and to compare them to the upfront price of 2900 EUR of rhBMP-2.. Raw data from a previously published study (BESTT study) were used to conduct an economic calculation for secondary treatment costs for each patient from the standard care group and the 1.5 mg/ml rhBMP-2 group based on G-DRG 2005 prices from a health insurer's perspective for an observation period of 1 year for Germany.. The use of rhBMP-2 leads to savings of 5697 EUR and 3183 EUR per patient for Gustilo-Anderson grade IIIB and all grade IIIA and B injuries, respectively. These savings offset the upfront price of 2900 EUR of rhBMP-2 and, therefore, net savings of 2797 EUR and 283 EUR for grade IIIB and all grade IIIA and B injuries can be achieved, respectively. These savings are mainly due to reduced sickness payments because of faster fracture healing in the rhBMP-2 group.. The current study shows that the use of rhBMP-2 in Gustilo-Anderson grade IIIA and B open fractures leads--besides the better medical outcome for patients as shown previously in the BESTT study--to net savings from a health insurer's perspective.

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cost Savings; Cost-Benefit Analysis; Fracture Healing; Germany; Humans; Insurance, Health; Prospective Studies; Randomized Controlled Trials as Topic; Recombinant Proteins; Tibial Fractures; Time Factors; Transforming Growth Factor beta; Treatment Outcome

This article introduces papers based on presentations from a symposium entitled "Bone Morphogenic Protein Advisory Meeting in Orthopaedic Trauma", where recent clinical findings with human bone morphogenetic protein-2 (rhBMP-2) were reviewed. It also presents two case studies which illustrate the clinical problems with the potential morbidity of tibial fractures and the potential benefits of the use of rhBMP-2 at surgery. The article concludes with a summary of the symposium. Tibial shaft fracture repair is associated with a significant financial burden on the patient, the health care providers and the medical insurance companies. It is anticipated that the clinical advantages of rhBMP-2 could lead to cost savings both inside and outside the hospital setting.

Topics: Adult; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Combined Modality Therapy; Cost-Benefit Analysis; Fracture Healing; Humans; Male; Orthopedic Procedures; Radiography; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta; Wounds and Injuries

Fracture healing can be stimulated by exogenous application of growth factors. Using porcine and rat models the efficacy of locally delivered IGF-I and TGF-beta1 from an implant coating has been demonstrated. A thin and biomechanical stable biodegradable poly(D,L-lactide) was used to coat implants and serve as a drug carrier. Due to reports of possible foreign body reactions caused by polymer materials in orthopedic surgery, this study investigated the biocompatibility of the polylactide implant coating and the locally released growth factors during the time course of rat tibial fracture healing (days 5, 10, 15, and 28 after fracture). Monocytes/macrophages and osteoclast were detected using an monoclonal antibody against ED1 (comparable to CD68 in mice and human). The antibody ED1 stains monocytes, macrophages and osteoclast in the bone marrow and in the newly formed fracture callus. A moderate density of the monocytes/macrophages was seen in the proximal part of the medullary canal, but almost no cells were detectable in the region distal to the fracture. The amount of stained cells increased during the observation time with a maximum at days 10 and 15 followed by a decrease at day 28. No differences were detectable between the investigated groups from day 5 to 15 post fracture indicating, that the used poly(D,L-lactide) or the incorporated growth factors do not evoke an elevated immunological response compared to the uncoated titanium implant at the investigated time points. A significantly higher amount of ED1 positive cells was measured 28 days after fracture in the control group compared to the groups with the coated implants. In conclusion, no indication of a foreign body reaction due to the use of the polylactide or the growth factors was found indicating a good short-term biocompatibility of this bioactive coating.

Topics: Absorbable Implants; Animals; Coated Materials, Biocompatible; Drug Implants; Female; Fracture Healing; Insulin-Like Growth Factor I; Materials Testing; Polyesters; Rats; Rats, Sprague-Dawley; Swine; Tibial Fractures; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Clinical Trials Data Monitoring Committees; Fractures, Open; Humans; International Cooperation; Multicenter Studies as Topic; Musculoskeletal System; Outcome Assessment, Health Care; Patient Selection; Pilot Projects; Randomized Controlled Trials as Topic; Research Design; Tibial Fractures; 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

Osteogenic Protein-1 (OP-1) is known to be a very potent osteoinductive growth factor. However, experimental studies using critical-size defect models in the weight-bearing lower extremity show non-uniform results. Therefore, we studied the osteoinductivity of OP-1 in a tibial worst-case defect model in sheep. Potential improvement of OP-1 induced new bone formation using a composite graft with autogenous bone marrow was to be investigated.. In 19 sheep a 5 cm segmental defect of the tibial diaphysis was treated by intramedullary nailing and filled with the following implants: 5 mg OP-1 + inactivated demineralized bone matrix (group 1; n = 6); 5 mg OP-1 + inactivated demineralized bone matrix + 5 ml autogenous bone marrow (group 2; n = 5); autogenous cancellous bone (group 3; n = 4), or inactivated demineralized bone matrix + 5 ml autogenous bone marrow (group 4; n = 4).. In total, 3 out of 10 defect sites treated with OP-1 were completely bridged radiographically by 12 weeks. Initially, x-rays showed accelerated new bone formation by use of the composite grafts containing OP-1 and autogenous bone marrow. However, 12 weeks post surgery 3D-CT-volumetry could not detect significant differences of new bone formation within the defect sites treated by OP-1 with or without bone marrow, while new bone formation by autogenous cancellous bone was better than by OP-1.. In our worst case defect model, the osteoinductive potential of OP-1 is initially accelerated but 12 weeks post surgery not increased when combined with autogenous bone marrow transplantation. So far, critical segmental bone defects of the weight-bearing lower extremity can not be bridged regularly in our model by use of OP-1. Therefore, for the treatment of such critical defects with rotational instability the examined application device of OP-1 can not yet be recommended.

Topics: Animals; Bone Marrow Transplantation; Bone Matrix; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Substitutes; Bone Transplantation; Follow-Up Studies; Fracture Fixation, Intramedullary; Fracture Healing; Implants, Experimental; Osseointegration; Osteogenesis; Osteotomy; Sheep; Stem Cells; Tibial Fractures; Time Factors; Tomography, Spiral Computed; 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

The long-term stability of bone tissues induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) and poly[L-lactide-co-glycolide] copolymer-coated gelatin sponge (PGS) was examined. In 16 dogs, 2.5 cm unilateral bone defects were created in the left tibial diaphyses. Tibia was fixed with metal plate, and PGS impregnated with (0.4 mg/cm(3)) or without rhBMP-2 was implanted into 15 or one defects, respectively. The metal plates of rhBMP-2-treated limbs were removed 16 weeks after the implantation. The bilateral tibiae of five animals each of the rhBMP-2-treated group were harvested at 32, 52 or 104 weeks, and served for biomechanical testing and histology. Although the defect that received PGS alone resulted in nonunion at 16 weeks, all defects treated with rhBMP-2 achieved radiographic bony union by 8 weeks. Biomechanical properties of the regenerated bones restored to the levels of intact tibiae at 32 weeks, but torsional stiffness was significantly higher. No statistical significances were detected in all parameters between regenerated and intact tibiae at 104 weeks. No radiographic and histological findings suggesting enhanced resorption to the regenerated bones were observed. These results suggest the long-term stability of the bone tissues induced by rhBMP-2, and the usefulness of rhBMP-2-impregnated PGS as a biomaterial for long bone defect filling.

Topics: Animals; Biocompatible Materials; Biodegradation, Environmental; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Dogs; Drug Carriers; Follow-Up Studies; Fracture Healing; Lactic Acid; Male; Materials Testing; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Tensile Strength; Tibial Fractures; Transforming Growth Factor beta

Because of the increasing interest on stimulating fracture healing, knowledge about the role and chronology of growth factors during the healing process is important. The purpose of this study was to quantify the protein concentration of IGF-I and TGF-beta1 during rat tibial fracture healing 5, 10, and 15 days after fracture using ELISA methods and to analyze the distribution of the proteins and the related mRNA expression in the fracture callus by immunohistochemistry and in situ hybridization. The following three groups were analyzed: Fractured tibiae intramedullary stabilized with K-wires coated with IGF-I and TGF-beta1 compared with fractures stabilized with uncoated K-wires and unfractured tibiae. The weight of the callus increased during the healing process in both experimental groups. The protein concentration of IGF-I and TGF-beta1 in the fracture callus showed significant changes between the investigated time points and treatment groups compared with the unfractured tibia. IGF-I increased with healing time whereas TGF-beta1 revealed a constantly elevated level at the investigated time points. Mesenchymal cells, osteoblasts, osteocytes, proliferating and immature chondrocytes, and osteoclasts expressed both growth factors. No differences in the expression and localization pattern of the growth factors were detectable among the groups. Using the different methods for quantification and visualization of the growth factors, no differences (except the increased IGF-I concentration at day 15 in the growth factor group) were seen between the normal and the growth factor-stimulated fracture healing as an indication for physiological healing after exogenous growth factor treatment.

Topics: Absorbable Implants; Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Fracture Healing; Humans; Immunoenzyme Techniques; In Situ Hybridization; Insulin-Like Growth Factor I; Polyesters; Polymers; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tibial Fractures; Transforming Growth Factor beta; Transforming Growth Factor beta1

Evaluate the effects of axial motion and transforming growth factor beta (TGF-beta) on callus formation and fracture healing.DESIGN Prospective experimental design with a 39-day postfracture recovery.. Unrestricted cage activity with weight bearing as tolerated.. Twenty-two skeletally mature, female New Zealand White rabbits.. Displaced, closed tibial fractures were reduced and stabilized in external fixators on the fourth day following fracture. Half of the fixators were locked for the duration of healing. The other fixators were locked for one week, then unlocked for the remaining four weeks. Half of the fractures in each fixator group received two injections of recombinant human TGF-beta1 (rhTGF-beta1). One injection was administered at the time of reduction, and the second was given 48 hours later.. Interfragmentary axial motion was measured during floor activity. Biomechanical properties were measured during a torsion test to failure. Callus area and the distribution of tissues within the callus were determined by computer-aided histomorphometry.. The administration of TGF-beta1 did not alter callus size, mechanical properties, or the distribution of tissues in the callus of fractures that were stabilized in locked external fixators. Recoverable axial motion fixation increased callus size, quantity of mineralized bone bridging the fracture, and maximum torque relative to locked fixation. The injection of TGF-beta1 negated the beneficial effects of axial motion by promoting the formation of a peripheral callus bridged by fibrous tissue rather than mineralized trabecular bone.. Injection of rhTGF-beta1 during the first postfracture week does not provide a biologic boost that improves fracture healing. Injection of TGF-beta1 may be detrimental to healing under conditions when fracture motion is present. The results suggest that there is a tendency for exposure to TGF-beta1 to inhibit the normal development of peripheral callus in response to axial interfragmentary motion.

Topics: Animals; Biomechanical Phenomena; Bony Callus; Female; Fracture Fixation; Fracture Healing; Movement; Rabbits; Tibial Fractures; Transforming Growth Factor beta

The influence of mechanical tissue strain caused by flexible fracture fixation on the systemic occurrence of systemic mitogens during callus healing was investigated. For this purpose the mitogenic capacity and growth factor concentration of sera from patients undergoing fracture treatment were determined. Sera from 9 patients whose fractures had been stabilized by external fixation were collected before and during fracture treatment. The sera were added to cell culture media of the osteoblastic cell line SaOS-2. After 5-6 days cell proliferation was measured. Transforming growth factor-beta1 (TGF-beta1) and insulin-like growth factor-I (IGF-I) concentrations were analyzed in serum samples from different healing stages.. paired Wilcoxon-test. Sera from fracture patients decreased SaOS-2 proliferation in the first week after surgery (p<0.05) compared to sera obtained prior to surgery. In the fourth or fifth week proliferation increased significantly (p<0.03). The increased proliferation of the SaOS-2 cells was associated with elevated levels of TGF-beta and IGF-I (p<0.05). The higher mitogenic activity of sera suggests an increased level of circulating mitogens. In a previous study this increase had also been observed in patients during distraction osteogenesis treatment but not in patients with primary bone healing by a stable fixated plate. It is therefore assumed that their release from the fracture site is a consequence of mechanical stimulation by interfragmentary movement of fracture ends.

Topics: Adult; Bony Callus; Cell Division; Cell Line; Female; Femoral Fractures; Femur; Fracture Fixation; Fracture Healing; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Mitogens; Osteoblasts; Osteogenesis, Distraction; Tibia; Tibial Fractures; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Fractures, Open; Humans; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

Osteogenic protein-1 (OP-1), or bone morphogenetic protein-7, is an osteoinductive morphogen that is involved in embryonic skeletogenesis and in bone repair. In bone defect models without spontaneous healing, local administration of recombinant human OP-1 (rhOP-1) induces complete healing. To investigate the ability of rhOP-1 to accelerate normal physiologic fracture healing, an experimental study was performed. In 40 adult female goats a closed tibial fracture was made, stabilized with an external fixator, and treated as follows: (1) no injection; (2) injection of 1 mg rhOP-1 dissolved in aqueous buffer; (3) injection of collagen matrix; and (4) injection of 1 mg rhOP-1 bound to collagen matrix. The test substances were injected in the fracture gap under fluoroscopic control. At 2 and 4 weeks, fracture healing was evaluated with radiographs, three-dimensional computed tomography (CT), dual-energy X-ray absorptiometry, biomechanical tests, and histology. At 2 weeks, callus diameter, callus volume, and bone mineral content at the fracture site were significantly increased in both rhOP-1 groups compared with the no-injection group. As signs of accelerated callus maturation, bending and torsional stiffness were higher and bony bridging of the fracture gap was observed more often in the group with rhOP-1 dissolved in aqueous buffer than in uninjected fractures. Treatment with rhOP-1 plus collagen matrix did not result in improved biomechanical properties or bony bridging of the fracture gap at 2 weeks. At 4 weeks there were no differences between groups, except for a larger callus volume in the rhOP-1 plus collagen matrix group compared with the control groups. All fractures showed an advanced stage of healing at 4 weeks. In conclusion, the healing of a closed fracture in a goat model can be accelerated by a single local administration of rhOP-1. The use of a carrier material does not seem to be crucial in this application of rhOP-1.

Topics: Absorptiometry, Photon; Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Diaphyses; Female; Goats; Humans; Recombinant Proteins; Tibial Fractures; Tomography, X-Ray Computed; Transforming Growth Factor beta

Fracture healing is influenced by numerous hormones, growth factors, and cytokines. The systemic administration of growth hormone (GH) has shown to accelerate bone regeneration. Local application of growth factors, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta-1 (TGF-beta1), are known to stimulate bone metabolism. Until now, the exact local and systemic mechanisms that lead to improved bone regeneration remain unclear. In addition, the effect of systemic administration of GH as compared with locally delivered growth factors on fracture healing in rats is not known. A midshaft fracture of the right tibia of 5-month-old female Sprague-Dawley rats (n = 80) was intramedullary stabilized with IGF-1 and TGF-beta1 coated vs. uncoated titanium K-wires. The growth factors were incorporated in a poly(D,L-lactide) (PDLLA) coating and released continuously throughout the experiment. Recombinant species-specific (rat) GH was applied systemically (2 mg/kg body weight) by daily subcutaneous injection and compared with a placebo group. The healing process was radiologically monitored. Twenty-eight days after fracture biomechanical torsional testing was performed. The consolidation and callus composition, including quantification of cartilage and mineralized tissue, was traced in histomorphometrical investigations using an image analysis system. Both methods, the systemic administration of GH and the local application of growth factors, showed significant biomechanical and histological effects on fracture healing. The local growth factor application showed a stronger effect on fracture healing than the systemic GH injection. The combined application of both methods did not accelerate the effect on bone healing compared with the single application. It is therefore concluded that combining local and systemic stimulating methods does not provide further additive effects with regard to fracture healing.

Topics: Animals; Drug Therapy, Combination; Female; Growth Hormone; Insulin-Like Growth Factor I; Radiography; Rats; Rats, Sprague-Dawley; Tibial Fractures; Transforming Growth Factor beta; Transforming Growth Factor beta1

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

Stimulation of bone healing and bone formation through local application of growth factors from implants may improve the clinical outcome in fracture treatment. Previous studies demonstrated a high mechanical stability of a thin poly(D,L-lactide) (PDLLA) coating on metallic implants that can withstand the process of intramedullary insertion. Following an initial peak, 80% of incorporated insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1) were released continuously, within 42 days. The goal of the present study is evaluation of the coated implants on fracture healing in a large animal model. A midshaft osteotomy (1 mm gap) of the right tibia of Yucatan minipigs was stabilized with uncoated vs. coated titanium interlocking nails (5 mm). X-ray examinations and blood analyses (including IGF-1 and IGF-binding proteins) were performed, and body weight and body temperature were taken throughout the experiment. After 28 days, both tibiae were dissected for mechanical torsional testing and histomorphometric analyses. No differences were found in the blood analyses, body weight, or temperature due to the coating or the incorporated growth factors between the groups. X-ray examinations revealed a faster consolidation of the osteotomy in the growth factor-treated group. Biomechanical testing showed a significantly higher torsional stiffness and maximum load. Progressive remodeling was observed in the histological and histomorphometric analyses with a larger callus volume in the growth factor group compared with the control groups. We conclude that local application of growth factors from a biodegradable PDLLA coating of intramedullary implants accelerates bone healing in a large animal model without systemic side effects.

Topics: Animals; Biomechanical Phenomena; Bony Callus; Drug Delivery Systems; Drug Implants; Female; Fracture Fixation, Intramedullary; Fracture Healing; Humans; Insulin-Like Growth Factor I; Osteotomy; Polyesters; Recombinant Proteins; Swine; Swine, Miniature; Tibial Fractures; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor (TGF)-beta superfamily, is known to be a very potent osteoinductive growth factor. The purpose of this study was to investigate the effect of BMP-2 (5% [w/w], 50 microg on each nail), locally released from poly(D,L-lactide) (PDLLA)-coated intramedullary implants, on fracture healing. A closed fracture of the right tibia of 5-month-old Sprague-Dawley rats (n = 64) was intramedullary stabilized with uncoated vs. BMP-2-coated titanium Kirschner wires. X-ray examinations (posteroanterior and lateral) were performed throughout the experiment. At 28 and 42 days after fracture, the animals were killed and both tibiae were dissected for biomechanical torsional testing. For histological and histomorphometric evaluation, 5 microm sections were obtained, stained with Safranin-O/light green and von Kossa, and examined using an image analysis system. The radiological results demonstrated progressed callus consolidation in the BMP-2-treated groups compared with the uncoated groups at both timepoints. Histomorphometric evaluation showed progressed callus remodeling with significantly increased mineralization and less cartilage of the periosteal callus. Due to the BMP-2 treatment, increased mineralization of the cortices was detected at 28 and 42 days after fracture. Biomechanical testing revealed significantly elevated maximum load and torsional stiffness in the BMP-2-treated groups compared with controls at both timepoints. The results clearly demonstrate that local application of BMP-2 from PDLLA-coated implants is feasible and significantly accelerates fracture healing. Local administration of growth factors from coated implants could reduce clinical problems in fracture treatment without opening of the fracture, implantation of further devices, or injection with the risk of infection or side effects caused by other carriers.

Topics: Animals; Biomechanical Phenomena; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Remodeling; Drug Implants; Female; Implants, Experimental; Radiography; Rats; Rats, Sprague-Dawley; Tibial Fractures; Titanium; Transforming Growth Factor beta

Fracture healing could be stimulated with osteoinductive bone morphogenetic proteins (bmp's), such as osteogenic protein-1 (OP-1), but little is known about its effectiveness in stimulation of fracture healing. In this study, biomechanical and histological aspects of fracture healing after an injection of OP-1 in the fracture gap were investigated. In 40 goats, a closed fracture was created in the left tibia. The fractures were stabilized with an external fixator and the animals were assigned to four different groups: no injection, injection of 1 mg OP-1, injection of 1 mg OP-1 with collagenous carrier material, and injection of carrier material alone. Twenty-one animals were sacrificed after 2 weeks and 19 after 4 weeks. Biomechanical testing was perfomed on both explanted tibiae. Four longitudinal samples of the fracture were sawn, processed for histology, and examined by two observers. Biomechanical evaluation showed a higher stiffness and strength at 2 weeks after injection of OP-1. Histological evaluation showed normal fracture healing patterns in all animals without adverse effects of the given injections. These data show that fracture healing can be accelerated with a single injection of OP-1, eventually resulting in normally healed bone.

Topics: Animals; Biomechanical Phenomena; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Collagen; Female; Fracture Fixation; Fracture Healing; Goats; Tibial Fractures; Transforming Growth Factor beta

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Transplantation; Clinical Trials as Topic; Humans; Patient Selection; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta

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

In vitro and in vivo studies have demonstrated an osteoinductive effect of growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1). However, for therapeutic use in fracture treatment, questions remain with regard to the local application of these proteins. A controlled, local release of growth factors from a biodegradable polylactide coating of osteosynthetic implants may have a stimulating effect on fracture healing. Such implants could stabilize the fracture and their bioactive surface could function simultaneously as a local drug-delivery system. Previous studies have demonstrated the high mechanical stability of an approximately 10-14-microm-thick poly(D,L-lactide) (PDLLA) coating on metallic implants, which can even withstand the process of intramedullary insertion. Following an initial peak, 80% of incorporated growth factors IGF-1 and TGF-beta1 were continuously released within 42 days. The effect of locally applied IGF-1 and TGF-beta1 from a biodegradable PDLLA coating of intramedullary implants on fracture healing was investigated in a rat model. Midshaft fractures of the right tibia of 5-month-old female Sprague-Dawley rats (n = 127) were stabilized with coated vs. uncoated titanium Kirschner wires. X-ray examinations and blood analyses were performed, and body weight and body temperature measurements were taken throughout the experimental period. After 28 and 42 days, respectively, tibiae were dissected for mechanical torsional testing and histomorphometrical analyses. X-rays demonstrated an almost completely consolidated fracture, biomechanical testing showed a significantly higher maximum load and torsional stiffness, and histological and histomorphometric analyses demonstrated progressed remodeling after 28 and 42 days in the group treated with growth factors as compared with controls. Interestingly, the PDLLA coating itself revealed a positive effect on fracture healing even without incorporated growth factors. No systemic changes of serum parameters, including IGF-1 and IGF binding proteins, and no differences in body weight and body temperature were observed within and between groups. These findings suggest that the local application of growth factors from a biodegradable PDLLA coating of osteosynthetic implants accelerates fracture healing significantly without systemic side effects.

Topics: Animals; Biocompatible Materials; Biomechanical Phenomena; Body Temperature; Body Weight; Female; Fracture Healing; Insulin-Like Growth Factor I; Osteogenesis; Prostheses and Implants; Radiography; Rats; Rats, Sprague-Dawley; Tibial Fractures; Transforming Growth Factor beta

To investigate the reliability of radiographs in the evaluation of healing of closed fractures.. A closed midshaft tibial fracture was created in 40 goats and stabilized with an external fixator. The animals were assigned to four groups: no injection, injection of 1 mg osteogenic protein-1 (OP-1), 1 mg OP-1 with collagenous carrier, or carrier alone. Radiographs were performed weekly until the animals were killed after 2 and 4 weeks. Healing was evaluated using radiographs, biomechanical testing, and histological examination. All radiographs were examined by two independent observers. Interobserver agreement was calculated and radiographic scores were compared with mechanical and histological scores using regression analysis.. Regression analysis showed poor correlation between radiographic scores and biomechanical and histological data. Correlation coefficients varied between 0.39 and 0.63. Good agreement between the observers was seen in only three parameters: visibility of the fracture line, weightbearing ability, and a combined healing parameter.. Plain radiography provides poor parameters for monitoring the fracture healing process.

Topics: Animals; Biomechanical Phenomena; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; External Fixators; Female; Fracture Fixation; Fracture Healing; Goats; Observer Variation; Radiography; Regression Analysis; Reproducibility of Results; Tibia; Tibial Fractures; Transforming Growth Factor beta

In vitro and in vivo studies have demonstrated an osteoinductive effect of growth factors like IGF-I and TGF-beta 1. However, for therapeutic use in fracture treatment, the local application of these bioactive molecules is still an unsolved problem. The controlled release of growth factors from a biodegradable coating of osteosynthetic implants could stimulate fracture healing locally. Coated implants could stabilise the fracture and work as a local drug delivery system. Previous studies demonstrated a high mechanical stability of a thin 10 microns poly(D,L-lactide) (PDLLA) coating on metallic implants that withstands even an intramedullary insertion process. After an initial peak, 80% of incorporated growth factors IGF-I and TGF-beta 1 were continuously released within 42 days. The effect of locally applied IGF-I and TGF-beta 1 from a biodegradable PDLLA coating of intramedullary implants on fracture healing were investigated in a rat model. A fracture of the right tibia of 5-month-old female Sprague-Dawley rats was stabilised with coated versus uncoated titanium K-wires. X-ray examinations and blood analysis were performed, body weight and body temperature monitored throughout the experimental period. After 42 days both tibiae were dissected for mechanical torsional testing and histomorphometric analyses. The results demonstrate a nearly completely consolidated fracture in the X-ray examinations, a significant higher maximum load and torsional stiffness in the biomechanical tests and a progressed remodeling in the histological and histomorphometric analyses after 42 days in the group treated with growth factors compared to the controls. Interestingly, the PDLLA coating itself had a positive effect on fracture healing even without incorporated growth factors. No systemic change of serum parameters including IGF-I and IGF binding proteins and no differences in body weight and body temperature were seen in any group. These findings suggest that the local application of growth factors from a biodegradable poly(D,L-lactide) coating of osteosynthetic implants accelerates fracture healing significantly without systemic side effects.

Topics: Animals; Bone Wires; Coated Materials, Biocompatible; Female; Fracture Fixation, Internal; Fracture Healing; Insulin-Like Growth Factor I; Polyesters; Rats; Rats, Sprague-Dawley; Tibial Fractures; Transforming Growth Factor beta; Transforming Growth Factor beta1

The effects of human recombinant bone morphogenetic protein-2 (rhBMP-2) on rabbit fractures healing under both stable and unstable mechanical conditions were investigated. rhBMP-2 was administered (1) on bioerodible particles, (2) in a collagen gel, and (3) by injection. rhBMP-2 on bioerodible particles has no effect as the particles prevent the migration of cells that produce the callus. The collagen gel is resorbed more rapidly; the development of the callus of mechanically unstable fractures is similar to controls at 14 days. When rhBMP-2 is injected, the callus of mechanically unstable fractures develops more rapidly so that cortical union occurs by 21 days, as compared with 28 days in control fractures. The effects on fractures healing under stable mechanical conditions are minimal. It is argued that mechanical factors influence the size of the callus of normally healing fractures and, although BMP-2 accelerates the rate of development of the callus and cortical union, it does not affect the amounts of bone and cartilage produced.

Topics: Animals; Biocompatible Materials; Biodegradation, Environmental; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bony Callus; Cartilage; Collagen; Drug Administration Routes; Drug Carriers; Fracture Healing; Humans; Male; Rabbits; Recombinant Proteins; Tibial Fractures; Transforming Growth Factor beta; Weight-Bearing

Bone morphogenetic proteins (BMPs) are considered to have important regulatory roles in skeletal embryogenesis and bone healing. Recombinant human BMPs (rhBMPs) have been shown to heal critical size defects and promote spinal fusion. We studied the effects of rhBMP-2 in an absorbable collagen sponge (ACS) on bone healing in a large animal tibial fracture model. Bilateral closed tibial fractures were created in 16 skeletally mature goats and reduced and stabilized using external fixation. In each animal, one tibia received the study device (0.86 mg of rhBMP-2/ACS or buffer/ACS), and the contralateral fracture served as control. The device was implanted as a folded onlay or wrapped circumferentially around the fracture. Six weeks following fracture, the animals were sacrificed and the tibiae harvested for torsional testing and histomorphologic evaluation. Radiographs indicated increased callus at 3 weeks in the rhBMP-2/ACS treated tibiae. At 6 weeks, the rhBMP-2/ACS wrapped fractures had superior radiographic healing scores compared with buffer groups and controls. The rhBMP-2/ACS produced a significant increase in torsional toughness (p = 0.02), and trends of increased torsional strength and stiffness (p = 0.09) compared with fracture controls. The device placed in a wrapped fashion around the fracture produced significantly tougher callus (p = 0.02) compared with the onlay application. Total callus new bone volume was significantly increased (p = 0.02) in the rhBMP-2/ACS fractures compared with buffer groups and controls regardless of the method of device application. The rhBMP-2/ACS did not alter the timing of onset of periosteal/endosteal callus formation compared with controls. Neither the mineral apposition rates nor bone formation rates were affected by rhBMP-2/ACS treatment. The increased callus volume associated with rhBMP-2 treatment produced only moderate increases in strength and stiffness.

Topics: Animals; Biomechanical Phenomena; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bony Callus; Drug Implants; Fracture Healing; Goats; Humans; Male; Radiography; Recombinant Proteins; Surgical Sponges; Tibial Fractures; Transforming Growth Factor beta

Periosteum was obtained within 10 days of injury from the site of 17 adult tibial diaphyseal fractures during internal fixation. Osteogenic cells, non-osteogenic cells and vascular elements were identified in situ using a variety of techniques. In all cases, the periosteum was thickened with randomly distributed plaques of cartilage and bone. Cells covering newly formed bone trabeculae expressed osteocalcin. Lectin-binding revealed high vascularity. Few mast cells were observed. Macrophages and acid phosphatase positive cells, some multinucleate, were observed in abundance. These findings suggest that the repair of the adult human diaphyseal fracture is similar to that of experimental fractures in rapidity of onset, high vascularity and in bone and cartilage formation. They differ in the fact that chondrogenesis and osteogenesis appear to be simultaneous in human fractures but sequential in experimental fractures. The paucity of mast cells suggests that they probably play no significant role in the repair of the human fractures.

Topics: Acid Phosphatase; Adolescent; Adult; Aged; Cartilage; Diaphyses; Fracture Healing; Humans; Middle Aged; Osteocalcin; Osteogenesis; Periosteum; Tibial Fractures; Transforming Growth Factor beta

Clinical trauma suppresses immunity and experimental wound fluids have been shown to be immunosuppressive. To ascertain whether human wounds contain immunosuppressive cytokines, we assayed serum from fracture/soft-tissue hematomas (FSTH) of 22 patients for interleukin (IL)-10, transforming growth factor (TGF)-beta 1, and IL-4. Results were correlated to concurrent plasma cytokine concentrations in the same patients and in volunteer plasma. IL-10 was present in high concentration (1376 +/- 539 pg/mL) in all (7/7) FSTH < 24 h old. In FSTH > 24 h old, IL-10 was found intermittently and at lower levels (239 +/- 106 pg/mL, p = .011 vs. FSTH < 24 h old). IL-10 was rarely detectable in fracture patient plasma and never detectable (< 20 pg/mL) in normal plasma. No significant variations of IL-4 or total TGF-beta 1 were found in FSTH or plasma. FSTH are significant potential sources of IL-10 activity in trauma patients, which may be overlooked when only plasma is assayed. The potential for a relationship between cytokines found locally at sites of injury and clinical immune modulation in trauma requires further study.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Female; Femoral Fractures; Fractures, Bone; Hematoma; Humans; Interleukin-10; Interleukin-4; Internal Fixators; Male; Middle Aged; Pelvic Bones; Reference Values; Retrospective Studies; Tibial Fractures; Transforming Growth Factor beta

Topics: Adult; Animals; Central Nervous System Diseases; Clinical Trials as Topic; Growth Substances; Humans; Tibial Fractures; Transforming Growth Factor beta; Wound Healing

The effect of Transforming Growth Factor beta (TGF-beta) administered locally around the fracture line of healing rat tibial fractures was investigated after 40 days of healing. TGF-beta in a dose of 4 ng or 40 ng was injected every second day during the healing period. The strength, stiffness, energy absorption and deflection of the fractures were measured in a materials-testing machine. Compared with placebo-treated animals, the ultimate load of the fractures increased in the group injected with 40 ng of TGF-beta, but not in those injected with 4 ng. TGF-beta induced a dose-dependent increase in the cross-sectional area of the callus and bone at the fracture line. Consequently, local treatment of fractures with TGF-beta increases the callus formation and strength. The energy absorption and deflection capacities of the healing fractures are preserved.

Topics: Animals; Biomechanical Phenomena; Bony Callus; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Fracture Fixation, Intramedullary; Fracture Healing; Injections, Intralesional; Rats; Rats, Wistar; Tibial Fractures; Transforming Growth Factor beta; Weight-Bearing

The ability of exogenous Transforming Growth Factor-beta (TGF-beta) to stimulate bone formation in fracture healing was investigated. TGF-beta was continuously applied in doses of 1 and 10 micrograms/day for 6 weeks to 2 groups of adult rabbits with unilateral plated mid-tibial osteotomies. A group receiving solvent without TGF-beta served as control. Fracture healing was evaluated by mechanical tests, bone morphometry and bone densitometry. Increased maximal bending strength and callus formation were demonstrated in the groups receiving TGF-beta. TGF-beta had no effect on bending-stiffness, bone mineral content, cortical thickness or haversian canal diameter. We conclude that local application of exogenous TGF-beta may enhance fracture healing in rabbits.

Topics: Animals; Bone Density; Female; Fracture Healing; Male; Rabbits; Tensile Strength; Tibial Fractures; Transforming Growth Factor beta