Recombinant Human Bone Morphogenetic Protein-2 Accelerates Healing in a Rabbit Ulnar Osteotomy Model

Bouxsein, Mary L.; Turek, Thomas J.; Blake, C. A.; D'Augusta, Darren; Li, X.; Stevens, Mark L.; Seeherman, Howard; Wozney, John M.

doi:10.2106/00004623-200108000-00012

Cited by 179 publications

(108 citation statements)

References 39 publications

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“…In this study, we tested two modes of rhBMP-2 delivery: surgical implantation with ACS or percutaneous injection with a buffer. Biodistribution studies in a rabbit fracture model indicated that %70Y0 of the administrated dose of rhBMP-2 was initially retained at the fracture site following implantation of rhBMP-2/ACS, and that =I 0% remained two weeks after implantation [3].…”

Section: Discussionmentioning

confidence: 98%

Bone consolidation is enhanced by rhBMP‐2 in a rabbit model of distraction osteogenesis

Bouxsein²,

Luppen³

et al. 2002

Journal Orthopaedic Research

116

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Recombinant human bone morphogenetic protein‐2 (rhBMP‐2) is a differentiation factor which has been shown to induce bone formation and heal bony defects in a variety of animal models. A possible application of rhBMP‐2 is to accelerate bone regeneration during distraction osteogenesis, which clinically is a long procedure, often involving significant complications. In this study we tested the ability of rhBMP‐2 to accelerate the consolidation phase of distraction osteogenesis in a rabbit model of leg lengthening. Tibiae were lengthened 2 cm over a period of ten days. rhBMP‐2 was administered at the end of the lengthening phase. Two modes of rhBMP‐2 application were tested: surgical implantation of rhBMP‐2/ACS (absorbable collagen sponge) into the regenerate (50 μl of 1.5 mg/ml rhBMP‐2, total dose = 75 μg rhBMP‐2), and percutaneous injection of rhBMP‐2/buffer (0.1 ml of 0.75 mg/ml rhBMP‐2, total dose = 75 μg rhBMP‐2) into three sites within the regenerate. Also, there were three groups of control animals: (1) no surgical intervention, (2) surgical implantation of buffer/ACS and (3) percutaneous injection of buffer. Rabbits were sacrificed at 5, 14 and 28 days after the interventions. Radiographic evaluation indicated a significant increase in bony union of the distraction regenerate in the rhBMP‐2 treated groups compared with the untreated groups at 5 and 14 days. At 28 days, formation of a cortex and reestablishment of the medullary canal was evident only in the rhBMP‐2 treated groups. The bone mineral content (BMC) of the regenerate was significantly higher in the rhBMP‐2 treated groups at 5 and 14 days. However, at 28 days, BMC of the regenerate was similar in all groups. The average volumetric density of the regenerate was significantly higher in the rhBMP‐2 injection group at day 14. In summary, both injection of rhBMP‐2/buffer and implantation of rhBMP‐2/ACS enhanced the consolidation stage of distraction osteogenesis in this rabbit model. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

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Section: Discussionmentioning

confidence: 98%

Bone consolidation is enhanced by rhBMP‐2 in a rabbit model of distraction osteogenesis

Bouxsein²,

Luppen³

et al. 2002

Journal Orthopaedic Research

116

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“…[20][21][22][23][24][25][26][27] Gene transfer of BMP-2, BMP-4, BMP-6, and BMP-7 has been shown to induce or enhance bone formation in vivo in several different animal models. Interestingly, gene transfer of LMP-1, a novel intracellular regulator of bone differentiation, has also been demonstrated to induce bone formation in spine fusion models.…”

Section: Discussionmentioning

confidence: 99%

Efficient bone formation by gene transfer of human LIM mineralization protein-3

et al. 2004

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LIM mineralization protein (LMP) is a novel positive regulator of the osteoblast differentiation program. In humans, three different LMP splice variants have been identified: LMP-1, LMP-2, and LMP-3. Gene transfer of human LMP-1 (hLMP-1) induces expression of genes involved in bone formation, including certain bone morphogenetic proteins (BMPs), promotes bone nodule formation in vitro, ectopic bone formation in vivo, and is therapeutic in animal models of posterior thoracic and lumbar spine fusion. To examine the osteoinductive properties of the LMP-3 in vitro and in vivo, we have generated plasmid and adenoviral vectors expressing codon-optimized hLMP-3. Here we demonstrate that gene transfer of hLMP-3 induces expression of the bonespecific genes osteocalcin, osteopontin, and bone sialoprotein and induced bone mineralization in preosteoblastic and fibroblastic cells. We also demonstrate that hLMP-3 is able to induce bone mineralization and the expression of the bonespecific genes, BMP-2, OSX, RunX2, and alkaline phosphatase in human mesenchymal stem cells in a dose-dependent manner. Finally, we demonstrate that direct gene transfer of hLMP-3 into murine skeletal muscle results in ectopic bone formation more efficiently than BMP-2. These results demonstrate that hLMP-3 gene transfer can be used to promote bone formation in cell culture and in vivo as or more efficiently than BMP-2, thus establishing feasibility and efficacy of direct gene delivery of hLMP-3 to produce bone in vivo. These results suggest that gene transfer of hLMP-3 could be developed as a bone-inductive therapeutic agent for clinical applications.

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“…The carbon fibers were anodically polarized in an HNO 3 electrolyte solution at a constant current of 0.5 A using a potentiostat/galvanostat. Preparation of graphite oxide through electrolysis was conducted in an HNO 3 electrolyte with 13 mol/dm 3 . The counter and reference electrodes were composed of platinum and Ag/AgCl, respectively.…”

Section: Fabrication Of Excnfsmentioning

confidence: 99%

Enhancement of the Effects of Exfoliated Carbon Nanofibers by Bone Morphogenetic Protein in a Rat Femoral Fracture Model

Miyazaki

Toyoda

Yoshiiwa

et al. 2014

Journal Orthopaedic Research

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Exfoliated carbon nanofibers (ExCNFs) are expected to serve as excellent scaffolds for promoting and guiding bone-tissue regeneration. We aimed to enhance the effects of ExCNFs with bone morphogenetic proteins (BMPs) and examine their feasibility and safety in clinical applications using a rat femoral fracture model. Group I (n ¼ 16) animals were implanted with control MedGEL. Group II (n ¼ 17) animals were implanted with MedGEL containing ExCNFs. Group III (n ¼ 15) animals were implanted with MedGEL containing 1 mg rhBMP-2. Group IV (n ¼ 15) animals were implanted with MedGEL containing 1 mg rhBMP-2 and ExCNFs. The rats were euthanized after 6 weeks, and their fractured femurs were explanted and assessed by manual palpation, radiographs, and highresolution microcomputerized tomography (micro-CT); the femurs were also subjected to biomechanical and histological analysis. The fusion rates in Group IV (73.3%) were considerably higher than those in Groups I (25. Keywords: exfoliated carbon nanofiber; bone morphogenetic protein; fracture healing; rat femoral fracture model; scaffold Bone morphogenetic proteins (BMPs) are members of the transforming growth factor b superfamily and are powerful osteoinductive molecules. The osteoinductive effects of recombinant human BMPs (rhBMPs) in surgical procedures such as fracture repair, healing of critical-size bone defects, and spinal fusion have been demonstrated in animal models and clinical trials; furthermore, rhBMP-2 and rhBMP-7 have been approved for clinical use. [1][2][3][4][5] Unfortunately, the results of clinical trials show that high doses of BMPs are required to induce adequate bone fusion, as the molecules are soluble and easily diffuse away from the fusion site, becoming inactivated in vivo. 6 In addition, the usefulness of BMPs is limited by their high costs. To address these problems, a number of strategies are being developed to generate safer, less expensive, and more efficacious spinal fusion using rhBMP. However, the efficient immobilization of BMPs onto carriers at low dosage while maintaining desirable in vivo regenerative action remains as a major challenge in bone regeneration research and practice. 7,8 The required rhBMP-2 level in humans, even for the FDA-approved collagen sponge-incorporated treatment, is much higher (over six orders of magnitude greater) than that used for in vitro cell level evaluation and in vivo animal studies. 7,9 Several ongoing investigations aim to develop a scaffold that functions as a delivery vehicle, providing cells with a more controlled and sustained release of bioactive molecules to maintain the local growth factor concentration within the therapeutic range.Carbon nanotubes (CNTs) have received much attention because of their interesting properties, including their exceptional mechanical 10 and high electrical and thermal conductivity, 11 which facilitate their use as reinforcements or additives in materials such as plastics, metals, and ceramics to improve the properties of the materials and introduce nove...

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Recombinant Human Bone Morphogenetic Protein-2 Accelerates Healing in a Rabbit Ulnar Osteotomy Model

Cited by 179 publications

References 39 publications

Bone consolidation is enhanced by rhBMP‐2 in a rabbit model of distraction osteogenesis

Bone consolidation is enhanced by rhBMP‐2 in a rabbit model of distraction osteogenesis

Efficient bone formation by gene transfer of human LIM mineralization protein-3

Enhancement of the Effects of Exfoliated Carbon Nanofibers by Bone Morphogenetic Protein in a Rat Femoral Fracture Model

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