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Recombinant Human Osteogenic Protein-1 Induces Bone Formation in a Chronically Infected, Internally Stabilized Segmental Defect in the Rat Femur
Xinqian Chen, MD1; Andrew H. Schmidt, MD2; Dean T. Tsukayama, MD2; Craig A. Bourgeault, BS1; William D. Lew, MS1
1 Orthopaedic Biomechanics Laboratory, Midwest Orthopaedic Research Foundation, 914 South 8th Street, Mail Code 860C, Minneapolis, MN 55404. E-mail address for W.D. Lew: blew@mmrf.org
2 Orthopaedic Surgery Department (A.H.S.) and Division of Infectious Diseases, Department of Medicine (D.T.T.), Hennepin County Medical Center, 701 Park Avenue, Mail Code G2 (A.H.S.) and Mail Code G5 (D.T.T.), Minneapolis, MN 55415
View Disclosures and Other Information
In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the Midwest Orthopaedic Research Foundation and the Minneapolis Medical Research Foundation. 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 (Stryker Biotech donated the rhOP-1 and carrier, and provided funds for performing the microcomputed tomography). 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.
Investigation performed at the Orthopaedic Biomechanics Laboratory, Midwest Orthopaedic Research Foundation and Minneapolis Medical Research Foundation, Minneapolis, Minnesota

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Jul 01;88(7):1510-1523. doi: 10.2106/JBJS.E.01136
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Abstract

Background: Recombinant human osteogenic protein-1 (rhOP-1), combined with a collagen carrier, has been shown to induce new-bone formation in a variety of animal models. The purpose of the present investigation was to test the hypotheses that rhOP-1 would accelerate bone formation in an internally stabilized, chronically infected, critical-size defect in the rat femur and that this effect would be enhanced by the administration of systemic antibiotic.

Methods: A 6-mm segmental defect was created surgically, stabilized with a polyacetyl plate and six Kirschner wires, and contaminated with 104 colony-forming units of Staphylococcus aureus in one femur in each of 168 Sprague-Dawley rats. After two weeks, these infected defects were débrided surgically and were assigned to one of six treatment groups. The defects in the thirty animals in the first group received lyophilized collagen carrier mixed with 200 µg of rhOP-1 dissolved in buffer, the defects in the thirty animals in the second group received carrier with 20 µg of rhOP-1 in buffer, and the defects in the twenty-four control animals in the third group received carrier mixed with buffer without rhOP-1. The last three groups were treated identically to the first three groups, except that the animals also received the antibiotic ceftriaxone for twenty-eight days after débridement. The animals were killed at two, four, eight, or twelve weeks after débridement. Newly mineralized callus within the defect, and adjacent to and bridging the outside of the defect, was assessed with use of quantitative high-resolution radiography, microcomputed tomography, torsional failure testing, and histological analysis of undecalcified sections.

Results: Bacterial cultures confirmed the presence of a chronic infection during the study period in all animals. At the later time-points, significantly more newly mineralized callus was present within and adjacent to the débrided defects that had been treated with 200 µg of rhOP-1, whereas minimal amounts of callus were present within and adjacent to the defects that had been treated without rhOP-1 and with 20 µg of rhOP-1. At eight and twelve weeks after débridement, there was significantly more newly mineralized callus in the group that had been treated with 200 µg of rhOP-1 with antibiotic than in the group that had been treated with 200 µg of rhOP-1 without antibiotic (p < 0.05). At twelve weeks, the values for torque, energy to failure, and linear stiffness for femora that had been treated with 200 µg of rhOP-1 with antibiotic were not significantly different from the values for intact, contralateral control femora, whereas the values for femora that had been treated with 200 µg of rhOP-1 without antibiotic remained significantly lower than those for the intact, contralateral controls (p < 0.05).

Conclusions: Recombinant human osteogenic protein-1 maintained its osteoinductive capability in the presence of chronic infection, and this property was enhanced by antibiotic therapy. No substantial callus formed in the infected defects without a sufficiently high dose of rhOP-1.

Clinical Relevance: The treatment of an infection at the site of a fracture often necessitates removal of internal fixation. However, internal fixation is needed for fracture stability. This study presents an intervention that may accelerate fracture-healing in the presence of infection and colonized hardware, thereby permitting earlier removal of the hardware and more timely and effective treatment of the infection.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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