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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; 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@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
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 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.
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

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Feb 01;88(2):355-365. doi: 10.2106/JBJS.E.00464
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Abstract

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.

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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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    DHANASEKARAN KOTILINGAM, M.D.
    Posted on February 16, 2006
    Alternative Method of Gene Delivery
    Dept. Surgical Oncology & Cancer Biology, M.D. Anderson Cancer Centre, Hourston, TX 77030

    To The Editor:

    Betz et al (1) have described percutaneous injection of adenovirus tagged with cDNA as a delivery method for gene therapy. We would point out that gene therapy using percutaneous injection has some disadvantages such as rapid efflux of the virus particle from the lesional site leading to low therapeutic concentrations.

    Isolated limb perfusion (ILP)has been presented as a method of gene delivery for extremity sarcomas (2). It is a proven concept, and it might prove useful in treating bone defects as well.

    Since the bone defect model is in the appendicular skeleton (as opposed to axial skeleton),the effectivenss of ILP as a gene delivery vehicle might be evaluated by creation of bone defects and administration of ILP with one incision, and under a single general anesthetic.

    This method of gene delivery is routinely practised in our department for treating sarcomas of the extrmities and extending its use to treating bone defects may be interesting.

    REFERENCES:

    1.Oliver B. Betz, Volker M. Betz, Ara Nazarian, Carmencita G. Pilapil, Mark S. Vrahas, Mary L. Bouxsein, Louis C. Gerstenfeld, Thomas A. Einhorn, and Christopher H. Evans Direct Percutaneous Gene Delivery to Enhance Healing of Segmental Bone Defects J Bone Joint Surg Am 2006; 88: 355-365.

    2. Eggermont AM, de Wilt JH, ten Hagen TL.Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Lancet Oncol. 2003 Jul;4(7):429-37

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