The Journal of Bone and Joint Surgery (American). 2006;88:355-365.
doi:10.2106/JBJS.E.00464
© 2006 The Journal of Bone and Joint Surgery, Inc.
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Letters to the Editor: Submit a response
Right arrow Letters to the Editor: View responses
Right arrow Alert me when this article is cited
Right arrow Alert me when Letters to the Editor are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowReprints and Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Betz, O. B.
Right arrow Articles by Evans, C. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Betz, O. B.
Right arrow Articles by Evans, C. H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Technorati  
What's this?

Direct Percutaneous Gene Delivery to Enhance Healing of Segmental Bone Defects

Oliver B. Betz, PhD1, Volker M. Betz, MD1, Ara Nazarian, MSc2, Carmencita G. Pilapil, MS1, Mark S. Vrahas, MD1, Mary L. Bouxsein, PhD2, Louis C. Gerstenfeld, PhD3, Thomas A. Einhorn, MD3 and Christopher H. Evans, PhD1

1 Center for Molecular Orthopaedics, 221 Longwood Avenue, BLI-152, Boston, MA 02115. E-mail address for C.H. Evans: cevans{at}rics.bwh.harvard.edu
2 Orthopaedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215
3 Department of Orthopaedic Surgery, Boston University Medical Center, Boston University School of Medicine, 720 Harrison Avenue, Boston, MA 02118

Investigation performed at the Center for Molecular Orthopaedics and the Orthopaedic Biomechanics Laboratory, Harvard Medical School, and the Department of Orthopaedic Surgery, Boston University School of Medicine, Boston, Massachusetts

In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from National Institutes of Health Grant AR 050243-01, Zimmer, and the Orthopaedic Trauma Association. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. 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: Healing of segmental bone defects can be induced experimentally with genetically modified osteoprogenitor cells, an ex vivo strategy that requires two operative interventions and substantial cost. Direct transfer of osteogenic genes offers an alternative, clinically expeditious, cost-effective approach. We evaluated its potential in a well-established, critical-size, rat femoral defect model.

Methods: A critical-size defect was created in the right femur of forty-eight skeletally mature Sprague-Dawley rats. After twenty-four hours, each defect received a single, intralesional, percutaneous injection of adenovirus carrying bone morphogenetic protein-2 (Ad.BMP-2) or luciferase cDNA (Ad.luc) or it remained untreated. Healing was monitored with weekly radiographs. At eight weeks, the rats were killed and the femora were evaluated with dual-energy x-ray absorptiometry, micro-computed tomography, histological analysis, histomorphometry, and torsional mechanical testing.

Results: Radiographically, 75% of the Ad.BMP-2-treated femora showed osseous union. Bone mineral content was similar between the Ad.BMP-2-treated femora (0.045 ± 0.020 g) and the contralateral, intact femora (0.047 ± 0.003 g). Histologically, 50% of the Ad.BMP-2-treated defects were bridged by lamellar, trabecular bone; the other 50% contained islands of cartilage. The control (Ad.luc-treated) defects were filled with fibrous tissue. Histomorphometry demonstrated a large difference in osteogenesis between the Ad.BMP-2 group (mean bone area, 3.25 ± 0.67 mm2) and the controls (mean bone area, 0.65 ± 0.67 mm2). By eight weeks, the Ad.BMP-2-treated femora had approximately one-fourth of the strength (mean, 0.07 ± 0.04 Nm) and stiffness (mean, 0.5 ± 0.4 Nm/rad) of the contralateral femora (0.3 ± 0.08 Nm and 2.0 ± 0.5 Nm/rad, respectively).

Conclusions: A single, percutaneous, intralesional injection of Ad.BMP-2 induces healing of critical-size femoral bone defects in rats within eight weeks. At this time, the repair tissue is predominantly trabecular bone, has normal bone mineral content, and has gained mechanical strength.

Clinical Relevance: Direct administration of adenovirus carrying BMP-2 could provide a straightforward and cost-effective treatment for large osseous defects with adequate surrounding soft-tissue support. This local in vivo genetherapy approach avoids the cost and complexity of ex vivo methods that require artificial scaffolds and autologous cell culture.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 JBJSHome page
B. C. Carofino and J. R. Lieberman
Gene Therapy Applications for Fracture-Healing
J. Bone Joint Surg. Am., February 1, 2008; 90(Supplement_1): 99 - 110.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
C. G. Zalavras, R. E. Marcus, L. S. Levin, and M. J. Patzakis
Management of open fractures and subsequent complications.
J. Bone Joint Surg. Am., April 1, 2007; 89(4): 884 - 895.
[Full Text] [PDF]

Letters to the Editor:

Read all Letters to the Editor

Alternative Method of Gene Delivery
DHANASEKARAN KOTILINGAM, M.D.
JBJS Online, 16 Feb 2006 [Full text]