Experimental Spinal Fusion With Recombinant Human Bone Morphogenetic Protein-2 Delivered by a Synthetic Polymer and β-Tricalcium Phosphate in a Rabbit Model

Namikawa, Takashi; Terai, Hidetomi; Suzuki, Etsuko; Hoshino, Minoru; Toyoda, Hiromitsu; Nakamura, Hiroaki; Miyamoto, Shimpei; Takahashi, Naoyuki; Ninomiya, Tadashi; Takaoka, Kunio

doi:10.1097/01.brs.0000172155.17239.fa

Cited by 52 publications

(41 citation statements)

References 24 publications

(29 reference statements)

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“…3,4,[11][12][13] Namikawa et al used b-tricalcium phosphate and PLA-DX-PEG polymer gel as a carrier and successfully reduced rhBMP-2 doses to 15-30 mg to achieve solid spine fusion in the rabbit model. 14 In this study, the results showed 2.5 mg of rhBMP-2 alone using alginate sheet could not induce intertransverse bone formation. Moreover, the osteogenic potency of MSCs was enhanced …”

Section: Discussionmentioning

confidence: 66%

Enhancement of posterolateral lumbar spine fusion using low‐dose rhBMP‐2 and cultured marrow stromal cells

Chen

et al. 2009

Journal Orthopaedic Research

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We tested the hypothesis that the dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) required to induce spine fusion can be reduced by combination with mesenchymal stem cells (MSCs). Twenty-four adult rabbits underwent posterolateral intertransverse fusion at the L4-L5 level. The animals were divided into four groups based on the implant material: autologous iliac graft, Alginate-MSCs composite, Alginate-BMP-2-MSCs composite, and Alginate-BMP-2 composite. After 16 weeks, the rabbits were euthanized for radiographic examination, manual palpation, biomechanical testing, and histology. Radiographic union of 12 intertransverse fusion areas for the autogenous iliac graft, Alginate-MSCs, Alginate-BMP-2-MSCs, and Alginate-BMP-2 groups was 11, 8, 11, and 0, respectively. Moreover, manual palpation of six fusion segments in each subgroup found solid union to be 6, 1, 5, and 0, respectively. The average torques at failure of the first three groups were 2278 AE 135, 1943 AE 140, and 2334 AE 187 N-mm, respectively. The failure torque did not differ significantly between the autograft and Alginate-BMP-2-MSCs groups; both groups were significantly higher than the Alginate-MSCs group. The results indicate that MSCs delivered with in vitro cellular doses of rhBMP-2 are more osteoinductive than MSCs without rhBMP-2. In combination with MSCs, a low dose (2.5 mg) of rh-BMP-2 could enhance bone formation and posterolateral spine fusion success in the rabbit model. 1-4 However, limitations exist in related clinical applications, including the inconsistent fusion rate and the high cost associated with the high dosage required for osteoinductive factors.During the recent decade, numerous investigators have described techniques for isolating human and animal mesenchymal stem cells (MSCs) from bone marrow.5-7 Culturing MSCs with dexamethasone, ascorbic acid, and b-glycerophosphate directs the cells into the osteogenic lineage.6,7 Additionally, recombinant human bone morphogenetic proteins (rhBMP) were reported to enhance the osteogenic potency of MSCs. 8,9 Theoretically, low-dose rhBMP-2 can improve the osteogenic potency of preconditioned MSCs and can then be used to improve the success of spinal fusion.We tested the hypothesis that rhBMP-2 can enhance the osteogenic potency of preconditioned MSCs and that the dosage of rhBMP-2 to induce intertransverse spine fusion could be lower than previously required.

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Section: Discussionmentioning

confidence: 66%

Enhancement of posterolateral lumbar spine fusion using low‐dose rhBMP‐2 and cultured marrow stromal cells

Chen

et al. 2009

Journal Orthopaedic Research

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“…To manufacture an osteoinductive artificial bone graft substitute, cytokines retaining osteoinductive activity (e.g., BMPs) have been combined with collagen and used to obtain spinal fusion in experimental animals or in human cases [1,4,5,17,25,26,35,36]. This experimental study was designed to achieve solid posterior interspinous lumbar fusion more effectively and less invasively than before with proper use of rhBMP-2 in combination with synthetic carrier materials.…”

Section: Discussionmentioning

confidence: 99%

“…The purpose of adding porous b-TCP powder was to increase the plasticity of the polymer for ease of handling, increase induced bone yields by volume expansion of the rhBMP-2-containing polymer implants and subsequently improve performance of the rhBMP-2. This new bone-inducing biodegradable porous b-TCP might provide effective artificial bone-graft substitutes with osteoinductive capacity and biodegradable properties [20,26]. At the same time, reducing the cost of production for rhBMP-2 is important if clinical use is to become widespread.…”

Section: Discussionmentioning

confidence: 99%

“…We therefore consider that achievement of solid interspinous process fusion using this new biodegradable bone-inducing material could address biomechanical weakness in spinal disorders as a less-invasive option without bone grafting. The carrier material for BMP-2, a composite of PLA-PEG hydrogel and b-TCP powder, was developed by our group and its efficacy as a BMP-2 carrier has been confirmed in several experimental animal models of various bone defects and spinal fusions [15,26]. With the use of equivalent amounts of carrier material, the BMP-2-induced new bone mass at the interspinous process region appeared to depend on the BMP-2 dose, and the optimal dose for consistent, solid posterior fusion was 60-120 lg of BMP-2 in 600 mg of carrier for this rabbit model.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of interspinous process lumbar fusion with recombinant human bone morphogenetic protein-2 delivered with a synthetic polymer and β-tricalcium phosphate in a rabbit model

et al. 2011

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Introduction As a powerful bone-inducing cytokine, rhBMP-2 has been used as a bone graft substitute in combination with animal-derived collagen to achieve interbody or posterolateral spinal fusion. Successful interspinous process fusion using rhBMP-2 in combination with synthetic carrier materials would offer a safe, minimally invasive spinal fusion option for the treatment of spinal disorders. The aims of the present study were to achieve interspinous process fusion by implanting rhBMP-2-retaining degradable material instead of bone grafting and to evaluate efficacy for vertebral stabilization. Materials and methods A polymer gel (200 mg), btricalcium phosphate powder (400 mg), and rhBMP-2 (0, 30, 60 or 120 lg) were mixed to generate a plastic implant, which was then placed during surgery to bridge the L5-6 interspinous processes of 58 rabbits. Control animals received implants either without rhBMP-2 or with autogenous bone chips from the iliac crest. L5-6 vertebrae were recovered 8 weeks postoperatively. Interspinous process fusion was evaluated by radiography, biomechanical bending test, intradiscal pressure (IDP) measurement, and histology. Results In bending tests, strength of fusion was significantly greater in BMP60 and BMP120 groups than in sham, BMP0, BMP30 or autogenous bone groups. IDP at L5-6 was significantly reduced in BMP60 and BMP120 groups compared to sham, BMP0, BMP30, and autograft groups. Histologically, coronal sections of the fusion mass showed a bone mass bridging both spinous processes. ConclusionSolid interspinous process fusion was achieved in rabbit models by 8 weeks after implanting the biodegradable bone-inducing material. These results suggest a potential new less-invasive option without bone grafting for the treatment of lumbar disorders.

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“…Posterolateral fusion in adult rabbits [2-4, 8, 10-12, 20] is one such model that provides insight into the in vivo performance of bone graft materials. Calcium phosphate materials based on hydroxyapatite (HAp) [2-4, 8, 10-12, 20] or beta tricalcium phosphate (b-TCP) alone [13,16] have been reported with varied levels of osteoconductive response in the rabbit posterolateral fusion model. The addition of osteoinductive molecules (e.g.…”

Section: Introductionmentioning

confidence: 99%

Posterolateral spinal fusion in a rabbit model using a collagen–mineral composite bone graft substitute

et al. 2009

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Choosing the appropriate graft material to participate in the healing process in posterolateral spinal fusion continues to be a challenge. Combining synthetic graft materials with bone marrow aspirate (BMA) and autograft is a reasonable treatment option for surgeons to potentially reduce or replace the need for autograft. FormaGraft, a bone graft material comprising 12% bovine-derived collagen and 88% ceramic in the form of hydroxyapatite (HAp) and beta tricalcium phosphate (b-TCP) was evaluated in three possible treatment modalities for posterior spinal fusion in a standard rabbit model. These three treatment groups were FormaGraft alone, FormaGraft soaked in autogenous BMA, and FormaGraft with BMA and iliac crest autograft. No statistically demonstrable benefits or adverse effects of the addition of BMA were found in the current study based on macroscopic, radiology or mechanical data. This may reflect, in part, the good to excellent results of the collagen HA/TCP composite material alone in a well healing bony bed. Histology did, however, reveal a benefit with the use of BMA. Combining FormaGraft with autograft and BMA achieved results equivalent to autograft alone. The mineral and organic nature of the material provided a material that facilitated fusion between the transverse processes in a standard preclinical posterolateral fusion model.

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Experimental Spinal Fusion With Recombinant Human Bone Morphogenetic Protein-2 Delivered by a Synthetic Polymer and β-Tricalcium Phosphate in a Rabbit Model

Abstract: Consistent spinal fusion was obtained by implanting a biodegradable bone-inducing implant composed of beta-TCP, PLA-DX-PEG, and rhBMP-2 within a period of 6 weeks. The rhBMP-2 doses required for the spinal fusion were significantly lower than those reported previously.

Cited by 52 publications

References 24 publications

Enhancement of posterolateral lumbar spine fusion using low‐dose rhBMP‐2 and cultured marrow stromal cells

Enhancement of posterolateral lumbar spine fusion using low‐dose rhBMP‐2 and cultured marrow stromal cells

Efficacy of interspinous process lumbar fusion with recombinant human bone morphogenetic protein-2 delivered with a synthetic polymer and β-tricalcium phosphate in a rabbit model

Posterolateral spinal fusion in a rabbit model using a collagen–mineral composite bone graft substitute

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