transforming-growth-factor-beta and Radius-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

To describe a novel surgical approach to treat a critical-sized bone defect due to severe, radial atrophic nonunion in a miniature dog.. Case report ANIMAL: A 1-year-old Yorkshire terrier with a critical-sized left radial defect after failed internal fixation of a transverse radial fracture.. Computed tomographic (CT) images of the radius were imported for three-dimensional (3D) printing of a custom-designed synthetic 3D-printed β-tricalcium phosphate (β-TCP) scaffold. The radius was exposed, and the β-TCP scaffold was press-fitted in the bone gap underneath the plate. Recombinant human bone morphogenic protein-2 (RhBMP-2) collagen sponges were squeezed to soak the scaffold with growth factor and then placed on both sides of the synthetic graft. Two additional cortical screws were also placed prior to routine closure of the surgical site.. Radiographic examination was consistent with complete healing of the radius defect 4 months after surgery. The bone plate was removed 10 months after surgery. According to CT examination 18 months after surgery, there was no evidence of the synthetic graft; instead, complete corticalization of the affected area was noted. Complete functional recovery was observed until the last clinical follow-up 36 months postoperatively.. Screw fixation and use of a 3D-printed ceramic scaffold augmented with rhBMP-2 resulted in excellent bone regeneration of the nonunion and full recovery of a miniature breed dog.. The therapeutic approach used in this dog could be considered as an option for treatment of large-bone defects in veterinary orthopedics, especially for defects affecting the distal radius of miniature dogs.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Transplantation; Calcium Phosphates; Dogs; Fractures, Malunited; Male; Printing, Three-Dimensional; Radius Fractures; Recombinant Proteins; Transforming Growth Factor beta

The treatment of large osseous defects remains a challenging clinical problem in orthopedic surgery. Particularly, strategies to control the appropriate degradation rate adapting to the tissue reconstruction are of essential for tissue regeneration. Here we report on a strategy to achieve adaptive degradation rate using cell-secreted protease as a switch. Disulfide-containing PEG-based scaffolds have been synthesized, and demonstrated to be responsive to the cell-secreted redox microenvironment. Thus, the cell-triggered degradation and liberation of growth factor are achieved. The osteoinductive growth factor, recombinant human bone morphogenetic protein-2 (rhBMP-2), is incorporated into the scaffold for bioactivity promotion. Degradations under the stimuli of reduced glutathione (GSH) at intracellular and extracellular concentrations was studied with the results of duration time ranging from 0.5 h to 22 days regulated by both concentrations of redox medium and polymer precursors. The rhBMP-2 loaded scaffolds evidently induced the ectopic bone formation in the mouse thigh muscles. In addition, we further investigated the in vivo effects of rhBMP-2-loaded scaffolds in a rabbit radius critical defect by radiography, three dimensional micro-computed tomographic (μCT) and synchrotron radiation-based micro-computed tomography (SRμCT) imaging, histological analysis, and biomechanical measurement. Scaffolds underwent gradual resorption and replacement by new bone and induced reunion of bone marrow cavity at 12 weeks, much better than the effect of self-repairing group. The results indicated that both osteoinduction and appropriate degradation played a crucial role in accelerating and promoting bone augmentation, as well as effective proangiogenesis. Such a strategy appears promising as 3D temporal scaffolds for potential orthopedic applications.

Topics: Absorbable Implants; Animals; Bone Morphogenetic Protein 2; Bone Regeneration; Delayed-Action Preparations; Male; Mice; Polyethylene Glycols; Rabbits; Radius Fractures; Recombinant Proteins; Tissue Scaffolds; Transforming Growth Factor beta; Treatment Outcome

This paper is aimed to investigate the repair of rabbit radial bone defect by the recombinant human bone morphogenetic protein 2/poly-lactideco-glycolic acid microsphere with fibrin sealant (rhBMP-2/PLGA/FS). The radial bone defect models were prepared using New Zealand white rabbits, which were randomly divided into 3 groups, experiment group which were injected with eMP-2/PLGA/FS at bone defect location, control group which were injected with FS at bone defect location, and blank control group without treatment. The ability of repairing bone defect was evaluated with X-ray radiograph. Bone mineral density in the defect regions was analysed using the level of ossification. The osteogenetic ability of repairing bone defect, the degradation of the material, the morphologic change and the bone formation were assessed by HE staining and Masson staining. The result showed that rhBMP-2/PLGA/FS had overwhelming superiority in the osteogenetic ability and quality of bone defect over the control group, and it could promote the repair of bone defect and could especially repair the radial bone defect of rabbit well. It may be a promising and efficient synthetic bone graft.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Regeneration; Bone Substitutes; Female; Fibrin Tissue Adhesive; Lactic Acid; Male; Microspheres; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rabbits; Radius Fractures; Recombinant Proteins; Transforming Growth Factor beta

rhBMP-2 solution on a collagen sponge was placed along the diaphysis of an atrophicradius, which had a history of recurring fractures. Two months after rhBMP-2 treatment, new mineralized bone was present, which significantly increased the diameter of the radius and allowed the removal of the external skeletal fixator (ESF). Due to carpo-metacarpal joint compromise, a pancarpal arthrodesis was performed seven months later. At follow-up evaluation two years later the dog was only very mildly lame.

Topics: Absorbable Implants; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Dogs; Drug Implants; Female; Fracture Healing; Radius Fractures; Recombinant Proteins; Transforming Growth Factor beta; Treatment Outcome; Ulna Fractures; Weight-Bearing

Ex vivo gene therapy using stem cells transduced with viral vectors is a useful method for delivering a therapeutic protein to augment bone repair in animal models. However, the duration of cell-mediated protein production and the fate of the transduced cells are unknown. We constructed an adenoviral vector encoding Myc epitope tagged bone morphogenetic protein (BMP)-2 gene (AdBMP-2). Rat bone marrow cells transduced with this vector produced biologically active BMP-2 protein, which was confirmed by Western blot analysis and alkaline phosphatase assay. Implantation of bone marrow cells infected ex vivo with AdBMP-2 caused orthotopic bone formation in mouse hindlimbs and bony union of critical-sized mouse radial defects. Immunohistochemical analysis revealed that rBMCs expressed Myc epitope-tagged BMP-2 protein for 14 days in vivo and became incorporated in the endochondral fracture callus. This novel adenovirus encoding for epitope-tagged BMP-2 can be used for immunohistochemical tracking of transduced cells in ex vivo gene therapy for bone repair.

Topics: Adenoviridae; Animals; Blotting, Western; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Disease Models, Animal; Genes, myc; Genetic Therapy; Genetic Vectors; Immunohistochemistry; Mice; Mice, SCID; Radius Fractures; Rats; Rats, Inbred Lew; Transduction, Genetic; Transforming Growth Factor beta

Regional gene therapy techniques are promising methods to enhance bone formation in large bone defects that would be difficult to treat with allograft or autograft bone stock. In this study, we compared in vivo temporal expression patterns of adenoviral- and lentiviral-mediated gene therapy in two bone formation models. Primary rat bone marrow cells (RBMC) were transduced with lentiviral or adenoviral vectors containing luciferase (Luc) or BMP-2 cDNA, or cotransduced with vectors containing Luc and bone morphogenetic protein 2 (BMP-2). In vitro protein production was determined with luciferase assay or ELISA (for BMP-2 production) weekly for 12 weeks. Two bone formation models were used -- a hind limb muscle pouch or radial defect -- in SCID mice. A cooled charged-coupled device (CCD) camera was used to image in vivo luciferase expression weekly for 12 weeks. In vitro, adenoviral expression of BMP-2 and luciferase was detected by ELISA or luciferase assay, respectively, for 4 weeks. Lentiviral expression of BMP-2 and luciferase was sustained in culture for 3 months. Using the CCD camera, we found that adenoviral vectors expressed luciferase expression for up to 21 days, but lentiviral vectors expressed target gene expression for 3 months in vivo in both bone formation models. There was no detectable difference in the amount of bone formed between the adenoviral and lentiviral groups. Lentiviral-mediated delivery of BMP-2 can induce long term in vitro and in vivo gene expression, which may be beneficial when developing tissue engineering strategies to heal large bone defects or defects with a compromised biologic environment.

Topics: Adenoviridae; Animals; Bone Marrow Cells; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Transplantation; Cells, Cultured; Collagen; Disease Models, Animal; Genetic Therapy; Lentivirus; Luciferases; Male; Mice; Mice, SCID; Osteogenesis; Radiography; Radius Fractures; Rats; Rats, Inbred Lew; Surgical Sponges; Transduction, Genetic; Transforming Growth Factor beta; Transgenes

Bone morphogenetic proteins (BMPs) are biologically active molecules capable of inducing new bone formation, and show potential for clinical use in bone defect repair. However, an ideal system for delivering BMPs that can potentiate their bone-inducing ability and provide initial mechanical strength and scaffold for bone ingrowth has not yet been developed. In this study, to construct a carrier/scaffold system for BMPs, we combined two biomaterials: interconnected-porous calcium hydroxyapatite ceramics (IP-CHA), and the synthetic biodegradable polymer poly D,L,-lactic acid-polyethyleneglycol block co-polymer (PLA-PEG). We used a rabbit radii model to evaluate the bone-regenerating efficacy of rhBMP-2/PLA-PEG/IP-CHA composite. At 8 weeks after implantation, all bone defects in groups treated with 5 or 20 microg of BMP were completely repaired with sufficient strength. Furthermore, using this carrier scaffold system, we reduced the amount of BMP necessary for such results to about a tenth of the amount needed in previous studies, probably due to the superior osteoconduction ability of IP-CHA and the optimal drug delivery system provided by PLA-PEG, inducing new bone formation in the interconnected pores. The present findings indicate that the synthetic biodegradable polymer/IP-CHA composite is an excellent combination carrier/scaffold delivery system for rhBMP-2, and that it strongly promotes the clinical effects of rhBMP-2 in bone tissue regeneration.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Regeneration; Bone Substitutes; Dose-Response Relationship, Drug; Drug Carriers; Drug Delivery Systems; Drug Implants; Fracture Healing; Hydroxyapatites; Lactates; Polyethylene Glycols; Rabbits; Radius Fractures; Tissue Engineering; Transforming Growth Factor beta; Treatment Outcome

To study the effect of platelet-rich plasma in the repair of bone defect.. Segmental bone defects of 1 cm were created in the mid-upper part of bilateral radius of 24 New Zealand white rabbits. One side was randomly chosen as the experimental side, which was filled with artificial bone with platelet-rich plasma (PRP). The other side filled with artificial bone without PRP as the control. After 2, 4, 8 and 12 weeks of implantation, the gross, radiological, histological observations, and computer graphic analysis were performed to investigate the bone healing of the defect in both sides.. Two weeks after operation, new bone and fibrous tissue formation in both the experimental and the control sides were observed only in the areas adjacent to the cut ends of the host bone, but the amount of new tissue in the experimental side was much more than that in the control side. In the 4th and 8th weeks, the surface of the artificial bone was covered with a large amount of new bones, the artificial bone was bridged tightly with the host bone by callus in the experimental side, while new bone was limited mainly in the cut ends and was less mature in the control side. In the 12th weeks, bone defects were entirely healed in the experimental side, which were covered completely with cortical bone, while new bone formation was only observed in the ends of artificial bone and there were not continuous bone callus on the surface in the control side.. Artificial bone with PRP is effective in the repair of segmental bone defects, and PRP could improve the healing of bone defect.

Topics: Animals; Blood Platelets; Bone Regeneration; Bone Substitutes; Ceramics; Female; Fracture Healing; Implants, Experimental; Male; Platelet-Derived Growth Factor; Rabbits; Radius Fractures; Random Allocation; Serum; Transforming Growth Factor beta

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

To investigate effect of effective fraction of Radix Salviae Miltiorrhizae (RS9403) on procollagens and transforming growth factor beta 1(TGF beta 1) gene expression in fracture callus, and to explore the mechanism of RS9403 in enhancing fracture healing.. Standardized radial fractures were performed in 24 Wistar rats, which were randomized into three groups: the RS9403 group, the Sanhua Jiegu powder (SHJGP) group and the blank control model group. They were fed orally with RS9403, SHJGP and normal saline respectively, and were sacrificed on the 3rd day, 1st week, 2nd week and 4th week after fracture in batches. In situ localization of procollagens and TGF beta 1 gene expression were examined on the cryosection of rat fracture callus.. On the 3rd day after fracture, the TGF beta 1 gene expression at the site of fracture in the RS9403 group and the SHJGP group was significantly higher than that in the blank control group, and type-III procollagen gene expression was observed in the two groups. At the end of 1st week after fracture, the pro alpha 1(III) expression in fibroblast and chondrocyte-like cells was dominant. The local type II and I procollagen gene expressions in the RS9403 and the SHJGP group were enhanced simultaneously with TGF beta 1 gene expression compared with those in the blank control group. At the end of 2nd week the RS9403 and the SHJGP group were characterized by a marked increase in the mRNA levels of type I procollagen, the numbers of hypertrophic chondrocytes was larger than that in the control group, and the type II procollagen expression declined markedly. The shared phenotype expression was confirmed at this stage, especially in the RS9403 and the SHJGP group. At the end of 4th week, the cartilagi nous callus was almost all replaced by the bone tissue. In the RS9403 and the SHJGP group, the replacement was nearly complete, few type I procollagen mRNA positive osteoblasts and hypertrophic chondrocytes were found scattering in the woven bone and remnants of cartilaginous callus.. RS9403 could affect the procollagens expression to enhance the healing of bone fracture as SHJGP do, maybe, by modulating the TGF beta 1 expression.

Topics: Animals; Drugs, Chinese Herbal; Fracture Healing; Plant Extracts; Procollagen; Radius Fractures; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Salvia miltiorrhiza; Transforming Growth Factor beta; Vasodilator Agents

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

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

The purpose of the present study was to create an effective bone-graft substitute for the treatment of a diaphyseal nonunion.. A standardized nonunion was established in the midportion of the radial diaphysis in thirty mongrel dogs by creating a three-millimeter segmental bone defect (at least 2 percent of the total length of the bone). The nonunion was treated with implantation of a carrier comprised of poly(DL-lactic acid) and polyglycolic acid copolymer (50:50 polylactic acid-polyglycolic acid [PLG50]) containing canine purified bone morphogenetic protein (BMP) or recombinant human transforming growth factor-beta (TGF-beta1), or both, or the carrier without BMP or TGF-beta1. Five groups, consisting of six dogs each, were treated with implantation of the carrier alone, implantation of the carrier with fifteen milligrams of BMP, implantation of the carrier with 1.5 milligrams of BMP, implantation of the carrier with fifteen milligrams of BMP and ten nanograms of TGF-beta1, or implantation of the carrier with ten nanograms of TGF-beta1. At twelve weeks after implantation, the radii were examined radiographically and the sites of nonunion were examined histomorphometrically.. We found that implantation of the polylactic acid-polyglycolic acid carrier alone or in combination with ten nanograms of TGF-beta1 failed to induce significant radiographic or histomorphometric evidence of healing at the site of the nonunion. The radii treated with the carrier enriched with either 1.5 or fifteen milligrams of BMP showed significantly increased periosteal and endosteal bone formation on histomorphometric (p < 0.05) and radiographic (p < 0.02) analysis.. Bone formation in a persistent osseous defect that is similar to an ununited diaphyseal fracture is increased when species-specific BMP incorporated into a polylactic acid-polyglycolic acid carrier is implanted at the site of the nonunion. TGF-beta1 at a dose of ten nanograms per implant did not induce a similar degree of bone formation or potentiate the effect of BMP in this model.. The biodegradable implant containing BMP that was used in the present study to treat diaphyseal nonunion is an effective bone-graft substitute.

Topics: Absorbable Implants; Animals; Biocompatible Materials; Bone Morphogenetic Proteins; Bone Regeneration; Bone Substitutes; Diaphyses; Dogs; Drug Implants; Drug Therapy, Combination; Fracture Healing; Lactic Acid; Osteogenesis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Radiography; Radius Fractures; Transforming Growth Factor beta