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Axonal Loss in Murine Peripheral Nerves Following Exposure to Recombinant Human Bone Morphogenetic Protein-2 in an Absorbable Collagen Sponge
David S. Margolis, MD, PhD1; Eileen W. Wu, MD1; Lisa M. Truchan, MD1
1 Department of Orthopaedic Surgery, University of Arizona, 1609 North Warren Avenue, Room 108, Tucson, AZ 85719. E-mail address for L.M. Truchan: ltruchan@emedicine.arizona.edu
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Investigation performed at the Department of Orthopaedic Surgery, The University of Arizona College of Medicine, Tucson, Arizona

Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

Copyright © 2013 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2013 Apr 03;95(7):611-619. doi: 10.2106/JBJS.K.00225
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With the proven efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) to treat open tibial fractures and promote spine fusion, there has been an increase in its off-label use. Recent studies have shown that BMPs play a role in nerve development and regeneration. Little is known about changes that result when rhBMP-2 is used in the vicinity of peripheral nerves. The purpose of this study is to characterize changes in peripheral nerves following exposure to rhBMP-2-soaked collagen sponges.


rhBMP-2 on an absorbable collagen sponge (ACS) was implanted directly on the sciatic nerves of Wistar rats. One and three weeks following surgery, the nerves were harvested and histological analysis was performed to evaluate inflammatory and structural changes.


rhBMP-2-soaked collagen sponges induced ectopic bone formation in muscle tissue in all animals after three weeks, but did not cause bone formation within the nerve. Axonal swelling and splitting of the myelin sheath were observed in both experimental and control nerves and may be a result of surgical manipulation. The overall incidence of axonal loss was 15.8% in the rhBMP-2/ACS-exposed nerves and was 0% in control nerves (p < 0.05).


rhBMP-2-soaked collagen sponges may adversely affect the axons of peripheral nerves by causing axonal dropout and loss of axons. Ectopic bone formation occurs within muscle tissues and not within the peripheral nerve. The axonal dropout may be a direct effect of rhBMP-2-soaked collagen sponges and not nerve compression as it was observed prior to ectopic bone formation.

Clinical Relevance: 

With the increased off-label use of rhBMP-2, it is important to understand the adverse effects in different anatomic locations. Since rhBMP-2-soaked collagen sponges may cause axonal dropout and loss of axons when used in close proximity to undamaged murine peripheral nerves, surgeons may wish to use caution when placing rhBMP-2-soaked collagen sponges in anatomic locations where they can come into direct contact with peripheral nerves, until the potential clinical consequences in humans are better understood.

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    Accreditation Statement
    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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