The Journal of Bone and Joint Surgery (American). 2006;88:1553-1565.
doi:10.2106/JBJS.E.01006
© 2006 The Journal of Bone and Joint Surgery, Inc.
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rhBMP-2 Delivered in a Calcium Phosphate Cement Accelerates Bridging of Critical-Sized Defects in Rabbit Radii

Howard J. Seeherman, PhD, VMD1, Kodi Azari, MD2, Sean Bidic, MD2, Leif Rogers, MD2, X. Jian Li, MD1, Jeffrey O. Hollinger, DDS, PhD3 and John M. Wozney, PhD1

1 Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140. E-mail address for H.J. Seeherman: hseeherman{at}wyeth.com
2 Division of Plastic and Reconstructive Surgery, University of Pittsburgh, Pittsburgh, PA 15261
3 Bone Tissue Engineering Center, Carnegie Mellon University, 5000 Forbes Avenue, 125 Smith Hall, Pittsburgh, PA 15213

Investigation performed at the Department of Surgery, School of Medicine, Oregon Health Sciences University, Portland, Oregon, and Wyeth Discovery Research, Women's Health and Musculoskeletal Biology, Cambridge, Massachusetts

In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from Wyeth Research (Cambridge, Massachusetts) and ETEX (Cambridge, Massachusetts) (provided funds for rabbits and supplied calcium phosphate paste). In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (Wyeth Research and ETEX). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: Treatment of segmental bone loss remains a challenge in skeletal repairs. This study was performed to evaluate the efficacy of the use of recombinant bone morphogenetic protein-2 (rhBMP-2) delivered in an injectable calcium phosphate cement (alpha bone substitute material [{alpha}-BSM]) to bridge critical-sized defects in the rabbit radius.

Methods: Unilateral 20-mm mid-diaphyseal defects were created in the radii of thirty-six skeletally mature New Zealand White rabbits. The defects in twelve rabbits each were filled with 0.166 mg/mL rhBMP-2/{alpha}-BSM cement, 0.033 mg/mL rhBMP-2/{alpha}-BSM cement, or buffer/{alpha}-BSM cement. Six rabbits from each group were killed at four weeks, and six were killed at eight weeks. Serial radiographs were made to monitor defect-bridging and residual {alpha}-BSM carrier. A semiquantitative histological scoring system was used to evaluate defect-bridging. Histomorphometry was used to quantify residual {alpha}-BSM; trabecular bone area; trabecular bone volume fraction; and cortical length, width, and area.

Results: At four weeks, there had been more rapid resorption of {alpha}-BSM and filling of the defects with trabecular bone in the group treated with 0.166 mg/mL rhBMP-2/{alpha}-BSM than in the other two groups. Histomorphometry confirmed an increased trabecular area and volume fraction in this group compared with the other two groups. In both rhBMP-2/{alpha}-BSM-treated groups, the majority of the trabecular bone was formed by a direct process adjacent to the resorbing {alpha}-BSM. At eight weeks, complete cortical bridging and regeneration of the marrow space were present in all of the defects treated with 0.166 mg/mL rhBMP-2/{alpha}-BSM. That group also had reduced residual {alpha}-BSM and trabecular area and volume, compared with the other two groups, at eight weeks as a result of a rapid remodeling process.

Conclusions: Treatment of a critical-sized defect in a rabbit radius with 0.166 mg/mL rhBMP-2/{alpha}-BSM injectable cement can result in bridging with cortical bone and a regenerated bone-marrow space by eight weeks. Site-specific remodeling appears to be responsible for corticalization and marrow regeneration.

Clinical Relevance: RhBMP-2 delivered in a calcium phosphate cement may be useful to achieve bridging of critical-sized defects in patients. Its injectable properties may allow minimally invasive use. Delayed percutaneous administration would also be possible when augmentation is desired following an initial surgical procedure or when soft-tissue injuries preclude adequate initial treatment.


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