Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices

Authors

  • Hugo Schmoekel,

    Corresponding author
    1. Department of Materials and Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) Zurich and the University of Zurich, Zurich 8000, Switzerland
    2. Small Animal Surgery Clinic, University of Bern, Langgastrasse 128, 3012 Bern, Switzerland
    Current affiliation:
    1. Small Animal Surgery Clinic, University of Bern, Langgastrasse 128, 3012 Bern, Switzerland
    • Small Animal Surgery Clinic, University of Bern, Langgastrasse 128, 3012 Bern, Switzerland. Tel.: +41-31-631-22-50; fax: +41-31-631-22-75
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    • These authors made equal contributions to this work.

  • Jason C. Schense,

    1. Department of Materials and Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) Zurich and the University of Zurich, Zurich 8000, Switzerland
    2. Kuros Therapeutics AG, Zurich 8000, Switzerland
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    • These authors made equal contributions to this work.

  • Franz E. Weber,

    1. Dept. Cranio-Maxillofacial Surgery, University Hospital Zurich, Zurich 8000, Switzerland
    2. Zentrum für Zahn-, Mund- und Kieferheilkunde der Universität Zürich, Zürich 8000, Switzerland
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  • Klaus W. Grätz,

    1. Dept. Cranio-Maxillofacial Surgery, University Hospital Zurich, Zurich 8000, Switzerland
    2. Zentrum für Zahn-, Mund- und Kieferheilkunde der Universität Zürich, Zürich 8000, Switzerland
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  • Dania Gnägi,

    1. Dept. Cranio-Maxillofacial Surgery, University Hospital Zurich, Zurich 8000, Switzerland
    2. Zentrum für Zahn-, Mund- und Kieferheilkunde der Universität Zürich, Zürich 8000, Switzerland
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  • Ralph Müller,

    1. Department of Materials and Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) Zurich and the University of Zurich, Zurich 8000, Switzerland
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  • Jeffrey A. Hubbell

    1. Department of Materials and Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) Zurich and the University of Zurich, Zurich 8000, Switzerland
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Abstract

A novel form of recombinant human bone morphogenetic protein-2 (BMP-2) was explored for effective incorporation and long-term retention into fibrin ingrowth matrices. The solubility of native BMP-2 is greatly dependent on its glycosylation. To enhance retention of BMP-2 in fibrin matrices, a nonglycosylated form (nglBMP-2), which is less soluble than the native glycosylated protein, was produced recombinantly and evaluated in critical-size defects in the rat calvarium (group n = 6). When 1 or 20 μg nglBMP-2 was incorporated by precipitation within the matrix, 74 ± 4% and 98 ± 2% healing was observed in the rat calvarium, respectively, as judged radiographically by closure of the defect at 3 weeks. More soluble forms of BMP-2, used as controls, induced less healing, demonstrating a positive correlation between low solubility, retention in vitro, and healing in vivo. Subsequently, the utility of nglBMP-2 was explored in a prospective veterinary clinical trial for inter-carpal fusion in dogs, replacing the standard-of-care, namely autologous cancellous autograft, with nglBMP-2 in fibrin. In a study of 10 sequential canine patients, fibrin with 600 μg/ml nglBMP-2 performed better than autograft in the first weeks of bone healing and comparably thereafter. Furthermore, a greater fraction of animals treated with nglBMP-2 in fibrin demonstrated bone bridging across each of the treated joints at both 12 and 17 weeks than in animals treated with autograft. These results suggest that evaluation in a human clinical setting of nonglycosylated BMP-2 in fibrin matrices might be fruitful. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

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