Safety of Recombinant Human Bone Morphogenetic Protein-2 After Spinal Laminectomy in the Dog

Meyer, Ralph A.; Gruber, Helen E.; Howard, Brian A.; Tabor, Owen B.; Murakami, Takanori; Kwiatkowski, Timothy C.; Wozney, John M.; Hanley, Edward N.

doi:10.1097/00007632-199904150-00004

Cited by 77 publications

(20 citation statements)

References 11 publications

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“…As shown by animal studies and clinical trials, this risk is far from theoretical. Although placement of rhBMP-2 5 or bovine whole BMP extract 13 in the posterolateral location in an animal laminectomy model did not result in any significant encroachment of bone into the laminectomy defect, undesired bone formation was seen directly over the laminectomy defect with placement of rhBMP-2 36 or rhBMP-7. 48 Other models have induced spinal stenosis by direct implantation of BMP over the ligamentum flavum.…”

Section: 41mentioning

confidence: 87%

“…37,40 Authors of two animal studies have explored the effect of dural perforation on use of BMP in spinal arthrodesis. Meyer, et al, 36 studied the safety of rhBMP-2 in the setting of dural opening in a canine model. After laminectomy, either autograft or 0.24 mg of rhBMP-2 in a collagen carrier was placed over the laminectomy defect following perforation of the dura by using a 22-gauge needle, with documented egress of cerebrospinal fluid.…”

Section: Animal Models Of Bmp Safetymentioning

confidence: 99%

“…48 Other models have induced spinal stenosis by direct implantation of BMP over the ligamentum flavum. 37,40 In the setting of dural laceration in animal models, significant intradural bone formation and calcification of the spinal cord was seen with rhBMP-7 48 , but not with rhBMP-2, 36 although the studies were not of similar design.…”

Section: 41mentioning

confidence: 99%

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Bone morphogenetic proteins and spinal fusion

Walker¹,

Wright²

2002

FOC

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Bone morphogenetic proteins (BMPs) have increasingly become a focus of research in the laboratory, with animal models, and in human clinical trials for the treatment of spinal disorders. Basic science research has elucidated the putative mechanism of action of BMPs, and the efficacy of BMPs in inducing bone formation has been evaluated in multiple animal models of anterior and posterior spinal fusion. Not only has BMP been shown to improve the quality and amount of bone formation when used as a supplement to autograft, it has also been shown to promote superior fusion in the absence of autograft, even in high-risk fusion models involving the use of nicotine or nonsteroidal antiinflam-matory agents. Both completed and ongoing clinical trials have demonstrated the efficacy of recombinant BMP, leading to the first BMP product being approved for clinical use earlier this year. Animal models and clinical trials have also been used to evaluate the safety of BMPs. Although few complications have been reported, BMPs can induce heterotopic bone formation, especially when placed adjacent to exposed neural elements. Potentially more serious, antibody formation has been seen in up to 38% of patients in some clinical trials. No clinical sequelae have been reported despite the development of antibodies against BMP, a naturally occurring human protein implicated in processes other than osteoinduction. The future directions of biological manipulation of the osteoinduction process include further understanding of the interactions of the BMP subtypes, the interactions of BMP with its receptors, and exploring other molecules capable of osteoinduction.

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Section: 41mentioning

confidence: 87%

Section: Animal Models Of Bmp Safetymentioning

confidence: 99%

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Bone morphogenetic proteins and spinal fusion

Walker¹,

Wright²

2002

FOC

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“…However, only some of these growth factors have demonstrated a significant osteoinductive capacity, and only two of these growth factors have been precisely evaluated in experimental spine fusion. Presently, only BMP-2 [4,5,6,9,12,16,22,34,35,46,47,60,61] and OP-1 (BMP-7) [15,30] have proven to accelerate spinal fusion and to overcome the disadvantages of an autologous bone graft.…”

Section: Introductionmentioning

confidence: 99%

“…BMPs are able to induce de novo bone in ectopic soft tissue sites even in the absence of bone marrow elements [2,61]. Some authors have postulated that there is a necessity for a growth factor to induce ectopic bone to promote interbody fusion sufficiently [4,34,35]. However, this characteristic of BMP-2 or BMP-7 might also be harmful.…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent effects of combined IGF-I and TGF-β1 application in a sheep cervical spine fusion model

et al. 2002

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Combined IGF-I and TGF-β1 application by a poly-(D,Llactide) (PDLLA) coated interbody cage has proven to promote spine fusion. The purpose of this study was to determine whether there is a dosedependent effect of combined IGF-I and TGF-β1 application on intervertebral bone matrix formation in a sheep cervical spine fusion model. Thirty-two sheep underwent C3/4 discectomy and fusion. Stabilisation was performed using a titanium cage coated with a PDLLA carrier including no growth factors in group 1 (n=8), 75 µg IGF-I plus 15 µg TGF-β1 in group 2 (n=8), 150 µg IGF-I plus 30 µg TGF-β1 in group 3 (n=8) and 300 µg IGF-I plus 60 µg TGF-β1 in group 4 (n=8). Blood samples, body weight and temperature were analysed. Radiographic scans were performed pre-and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height and intervertebral angle were measured. After 12 weeks, the animals were killed and fusion sites were evaluated using quantitative computed tomographic (CT) scans to assess bone mineral density, bone mineral content and bony callus volume. Biomechanical testing was performed and range of motion, and

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Optimized procedure for renaturation of recombinant human bone morphogenetic protein‐2 at high protein concentration

Vallejo

Rinas

2004

Biotech & Bioengineering

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The human gene encoding the mature form of bone morphogenetic protein-2 (hBMP-2), a dimeric disulfide-bonded protein of the cystine knot growth factor family, was expressed in recombinant Escherichia coli using a temperature-inducible expression system. The recombinant protein was produced in the form of cytoplasmic inclusion bodies and the effect of different variables on the renaturation of rhBMP-2 was investigated. In particular, variables such as pH, redox conditions, protein concentration, temperature, the presence of different types of aggregation suppressors, and host cell contaminants were studied with respect to their effect on aggregation during refolding and on the final renaturation yield of rhBMP-2. It is shown that the renaturation yield is particularly sensitive to pH, temperature, protein concentration, and the presence of aggregation suppressors. In contrast, little effect of the redox conditions and the ionic strength on the renaturation yield was observed, as equal yields were obtained in a broad range of reduced to oxidized glutathione ratios and concentrations of NaCl, respectively. The aggregation suppressor 2-(cyclohexylamino)ethanesulfonic acid (CHES) proved to be superior with respect to the final renaturation yield, although, in comparison to the more common arginine, it was less efficient in preventing aggregation of rhBMP-2 during refolding. Detergent washing of inclusion bodies was sufficient, as further purification of rhBMP-2 prior to refolding was without effect on the final renaturation yield. An increase in the concentration of renatured rhBMP-2 was achieved by a pulsed refolding procedure by which up to a total amount of 2.1 mg mL(-1) rhBMP-2 could be transferred in seven pulses into the renaturation buffer with an overall refolding yield of 38%, corresponding to 0.8 mg mL(-1) renatured dimeric rhBMP-2. Furthermore, a simplified purification procedure is presented that also includes freeze-drying for long-term storage of biologically active rhBMP-2. Finally, it is shown that the appearance of rhBMP-2 variants could be avoided by using a host strain overexpressing rare codon tRNAs.

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Safety of Recombinant Human Bone Morphogenetic Protein-2 After Spinal Laminectomy in the Dog

Abstract: The rhBMP-2 implant stimulated bone formation in the laminectomy site. Neither autologous bone, rhBMP-2, nor the dural puncture had deleterious consequences for the animals.

Cited by 77 publications

References 11 publications

Bone morphogenetic proteins and spinal fusion

Bone morphogenetic proteins and spinal fusion

Dose-dependent effects of combined IGF-I and TGF-β1 application in a sheep cervical spine fusion model

Optimized procedure for renaturation of recombinant human bone morphogenetic protein‐2 at high protein concentration

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