The Journal of Bone and Joint Surgery (American) 84:1123-1131 (2002)
© 2002 The Journal of Bone and Joint Surgery, Inc.
Enhancement of Tendon-Bone Integration of Anterior Cruciate Ligament Grafts with Bone Morphogenetic Protein-2 Gene Transfer
A Histological and Biomechanical Study
Vladimir Martinek, MD,
Christian Latterman, MD,
Arvydas Usas, MD,
Steven Abramowitch, BS,
Savio L-Y. Woo, PhD,
Freddie H. Fu, MD and
Johnny Huard, PhD
Investigation performed at the Growth and Development Laboratory,
Children's Hospital of Pittsburgh, and the Department of Orthopaedic
Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
Vladimir Martinek, MD
Christian Latterman, MD
Arvydas Usas, MD
Steven Abramowitch, BS
Savio L-Y. Woo, PhD
Freddie H. Fu, MD
Department of Orthopaedic Surgery, Musculoskeletal Research Center,
University of Pittsburgh, Pittsburgh, PA 15213
Johnny Huard, PhD
Growth and Development Laboratory, Children's Hospital of Pittsburgh,
Rangos Research Center, Room 4151, 3705 Fifth Avenue, Pittsburgh,
PA 15213. E-mail address: jhuard+@pitt.edu
In support of the research or preparation of this manuscript,
J. Huard received grants from the Pittsburgh Tissue Engineering Initiative
(PTEI) and the National Institutes of Health (Grant 1P60 AR44811-01).
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. Genetics Institute, Cambridge, Massachusetts,
provided the BMP-2 plasmid necessary for construction of the AdBMP-2.
Background:
The integration of tendon grafts used for replacement of the anterior
cruciate ligament is still sometimes unsatisfactory and may be associated
with postoperative anterior-posterior laxity. The goal of this study
was to examine the capacity of bone morphogenetic protein-2 (BMP-2)
gene transfer to improve the integration of semitendinosus tendon
grafts at the tendon-bone interface after reconstruction of the
anterior cruciate ligament in rabbits.
Methods:
The anterior cruciate ligaments of adult New Zealand White rabbits
were replaced with autologous double-bundle semitendinosus tendon
grafts. The semitendinosus tendon grafts had been infected in vitro
with adenovirus-luciferase, adenovirus-LacZ (AdLacZ), or adenovirus-BMP-2
(AdBMP-2); untreated grafts served as controls. The grafts were
examined histologically at two, four, six, and eight weeks after
surgery. In additional experiments, the structural properties of
the femur-anterior cruciate ligament graft-tibia complexes, from animals
killed eight weeks postoperatively, were determined from uniaxial
tests. The stiffness (N/mm) and ultimate load to failure (N) were
determined from the resulting load-elongation curves.
Results:
Genetically engineered semitendinosus tendon grafts expressed reporter
genes as well as BMP-2 in vitro. The AdLacZ-infected grafts showed
two different histological patterns of transduction. Intra-articularly,
infected cells were mostly aligned along the surface, and they decreased
in number between two and eight weeks after surgery. In the intra-tunnel
portions of the grafts, the number of infected cells did not decrease
during the observation period. Moreover, a high number of transduced
cells was found in the deeper layers of the tendons. In the control
group, granulation-type tissue at the tendon-bone interface showed
progressive reorganization into a dense connective tissue, and a
later establishment of fibers resembling Sharpey fibers.
In the specimens with an AdBMP-2-infected anterior cruciate ligament
graft, a broad zone of newly formed matrix resembling chondro-osteoid
had formed at the tendon-bone interface at four weeks after surgery.
This area was increased at six weeks, showing a transition from
bone to mineralized cartilage and nonmineralized fibrocartilage.
In addition, in the AdBMP-2-treated specimens, the tendon-bone interface
in the osseous tunnel was similar to that of a normal anterior cruciate
ligament insertion.
The stiffness (29.0 ± 7.1 N/mm compared with 16.7 ±
8.3 N/mm) and the ultimate load to failure (108.8 ± 50.8
N compared with 45.0 ± 18.0 N) were significantly enhanced
in the specimens with an AdBMP-2-transduced graft when compared
with the control values (p < 0.05).
Conclusion:
This study demonstrates that BMP-2 gene transfer significantly
improves the integration of semitendinosus tendon grafts in bone
tunnels after reconstruction of the anterior cruciate ligament in
rabbits.
Clinical Relevance:
Novel technologies including gene therapy and tissue engineering,
such as those described in this study, may provide useful therapeutic
procedures to enhance biological healing after reconstruction of
the anterior cruciate ligament.
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