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The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

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Abstract

Purpose

The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.

Methods

Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.

Results

Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.

Conclusions

Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.

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Acknowledgments

The research leading to these results has received funding from the European Community’s Seventh Framework Programme [FP7/2007-2013] under grant agreement n°HEALTH-F4-2011-279239.

We thank Durdica Car and Mirjana Marija Renic for providing animal care and experimentation in mice and rat studies.

Conflict of interest

HO, M. Jankolija, IP, M. Jurin and MK are employees of Genera Research.

SV is a founder and acts voluntarily as CEO of Genera Research.

DV, JC, JB, M. Pauk, IE, IF, IDC, M. Jelic, DD, TV, RN, VK, TBN, ZBT, JBS, SVT, M. Peric, M. Pecina and LG declare that they have no conflict of interest and certify that they have no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing, arrangements, etc.) that might pose a conflict of interest in connection with the submitted article.

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Authors and Affiliations

  1. Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000, Zagreb, Croatia

    Slobodan Vukicevic, Jasna Curak, Jelena Brkljacic, Martina Pauk, Igor Erjavec, Ivo Dumic-Cule, Ruder Novak, Vera Kufner, Tatjana Bordukalo Niksic, Zrinka Banic Tomisic, Ivancica Bastalic & Lovorka Grgurevic

  2. Genera Research, Rakov Potok, Croatia

    Hermann Oppermann, Morana Jankolija, Irena Popek & Marija Kozlovic

  3. Department for Intercellular Communication, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia

    Donatella Verbanac & Mihaela Peric

  4. Division of Clinical Pharmacology, Clinical Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia

    Igor Francetic

  5. Department of Orthopaedic Surgery, Clinical Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia

    Mislav Jelic

  6. Clinic of Traumatology, Clinical Hospital Centre Sisters of Mercy, Zagreb, Croatia

    Dragan Durdevic & Tomislav Vlahovic

  7. Department of Medical Biology, University of Zagreb School of Medicine, Zagreb, Croatia

    Jadranka Bubic-Spoljar

  8. Research and Technology Transfer Office, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia

    Smiljka Vikic-Topic

  9. Department of Orthopaedic Surgery, University of Zagreb School of Medicine, Zagreb, Croatia

    Marko Pecina

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  1. Slobodan Vukicevic
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  2. Hermann Oppermann
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  25. Lovorka Grgurevic
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Corresponding author

Correspondence to Slobodan Vukicevic.

Additional information

Mladenka Jurin contributed equally to this paper.

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Vukicevic, S., Oppermann, H., Verbanac, D. et al. The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing. International Orthopaedics (SICOT) 38, 635–647 (2014). https://doi.org/10.1007/s00264-013-2201-1

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  • DOI: https://doi.org/10.1007/s00264-013-2201-1

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