Bone Morphogenetic Protein–7 (Osteogenic Protein–1) Promotes Tendon Graft Integration in Anterior Cruciate Ligament Reconstruction in Sheep

Abstract

Background: Bone morphogenetic proteins induce new bone both in patients with bone defects and at extraskeletal sites in animals. After anterior cruciate ligament rupture, tendon graft fixation into a bone tunnel is a widely used method for anterior cruciate ligament reconstruction.

Hypothesis: Bone morphogenetic protein–7 applied to the bone-tendon interface enables better integration of a free tendon graft into the surrounding bone.

Study Design: Controlled laboratory study.

Methods: The anterior cruciate ligament was reconstructed using a free tendon graft in the right rear knees of 30 one-year-old male sheep. Recombinant human bone morphogenetic protein–7 (25 μg) was applied randomly to the bone-tendon interface in 15 animals, and a vehicle was applied in 15 control animals. At 3 weeks, 10 animals from each group were sacrificed, and the remaining sheep were sacrificed at 6 weeks after surgery. Subsequently, histologic analysis and mechanical testing were performed. In another group of 20 sheep, the same procedure was used and mechanical testing was performed after 3 weeks.

Results: More new bone was formed at the bone-tendon interface in the knees treated with bone morphogenetic protein–7 as compared histologically with similar areas in control animals, creating areas of dense trabecular network with significantly greater invasion of the tendon fibrous tissue into the bone marrow space. Mechanical testing showed greater strain resistance to force (368 N) in the knees treated with bone morphogenetic protein–7 than in control specimens (214 N). There was no difference between mechanical testing of samples from 3 and 6 weeks after surgery.

Conclusion: Bone morphogenetic protein–7 promotes complete tendon graft integration into the newly formed surrounding trabecular bone in the reconstruction of the anterior cruciate ligament.

Clinical Relevance: Bone morphogenetic protein–7 in tendon graft integration might be successfully used in reconstructive surgery of ligaments.

Keywords

bone morphogenetic protein–7 (BMP-7)osteogenic protein–1 (OP-1)anterior cruciate ligament (ACL)ligament reconstruction

Get full access to this article

View all access options for this article.

References

Barrett GR

Treacy SH

. The effect of intraoperative isometric measurement on the outcome of anterior cruciate ligament reconstruction: a clinical analysis. Arthroscopy. 1996; 12: 645-651.

Cain EL Jr

Clancy WG Jr

. Anatomic endoscopic anterior cruciate ligament reconstruction with patella tendon autograft. Orthop Clin North Am. 2002; 33: 717-725.

Chang SC

Hoang B

Thomas JT

, et al. Cartilage-derived morpho-genetic proteins: new members of the transforming growth factor–beta superfamily predominately expressed in long bones during human embryonic development. J Biol Chem. 1994; 269: 28227-28234.

Chiroff RT

. Experimental replacement of the anterior cruciate ligament: a histological and microradiographic study. J Bone Joint Surg Am. 1975; 57: 1124-1127.

Clatworthy MG

Annear P

Bulow JU

, et al. Tunnel widening in anterior cruciate ligament reconstruction: a prospective evaluation of ham-string and patella tendon grafts. Knee Surg Sports Traumatol Arthrosc. 1999; 7: 138-145.

Cook SD

Rueger DC

. Preclinical models of recombinant BMP induced healing of orthopedic defects. In:

Vukicevic S

Sampath KT

, eds. Bone Morphogenetic Proteins: From Laboratory to Clinical Pratice. Basel, Switzerland: Birkhauser Verlag; 2002:121-145.

Djapic T

Kusec V

Jelic M

, et al. Compressed homologous cancellous bone and bone morphogenetic protein (BMP)–7 or bone marrow accelerate healing of long-bone critical defects. Int Orthop.2003; 27: 326-330.

Forslund C

Aspenberg P.

Improved healing of transected rabbit Achilles tendon after a single injection of cartilage-derived morpho-genetic protein–2. Am J Sports Med. 2003; 31: 555-559.

Friedlaender GE

Perry CR

Cole JD

, et al. Osteogenic protein–1 (bone morphogenetic protein–7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001; 83: S151-S158.

10.

Grana WA

Egle DM

Mahnken R

, et al. An analysis of autograft fixation after anterior cruciate ligament reconstruction in a rabbit model. Am J Sports Med. 1994; 22: 344-351.

11.

Hayashi K

Ishidou Y

Yonemori K

, et al. Expression and localization of bone morphogenetic proteins (BMPs) and BMP receptors in ossification of the ligamentum flavum. Bone. 1997; 21: 23-30.

12.

Heistein JB

Cook PA

. Factors affecting composite graft survival in digital tip amputations. Ann Plast Surg.2003; 50: 299-303.

13.

Helder MN

Ozkaynak E

Sampath KT

, et al. Expression pattern of osteogenic protein–1 (bone morphogenetic protein–7) in human and mouse development. J Histochem Cytochem. 1995; 43: 1035-1044.

14.

Hoffmann F

Haegele U.

Transplantat-Knochen Verbindung nach Augmentation des vorderen Kreuzbandes durch die autologe Semitendinosussehne: Histologische Befunde an 4 Faellen. Arthroscopie. 1993; 6: 164-168.

15.

Jelic M

Pecina M

Haspl M

, et al. BMPs in articular cartilage repair. In:

Vukicevic S

Sampath KT

, eds. Bone Morphogenetic Proteins: From Laboratory to Clinical Practice. Basel, Switzerland: Birkhauser Verlag; 2002:249-262.

16.

Jelic M

Pecina M

Haspl M

, et al. Regeneration of articular chondral defects by osteogenic protein–1 (bone morphogenetic protein–7) in sheep. Growth Factors. 2001; 19: 101-113.

17.

Jensen TB

Overgaard S

Lind M

, et al. Osteogenic protein 1 device increases bone formation and bone graft resorption around cementless implants. Acta Orthop Scand. 2002; 73: 31-39.

18.

Katic V

Majstorovic L

Maticic D

, et al. Biological repair of thyroid cartilage defects by osteogenic protein–1 (bone morphogenetic protein–7) in dog. Growth Factors. 2000; 17: 221-232.

19.

Martinek V

Imhoff AB

. Revision of failed anterior cruciate ligament reconstruction. Orthopaede. 2002; 31: 778-784.

20.

Martinek V

Latterman C

Usas A

, et al. Enhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morpho-genetic protein–2 gene transfer, histological and biomechanical study. J Bone Joint Surg Am. 2002; 84: 1123-1131.

21.

Martinovic S

Borovecki F

Sampath KT

, et al. Biology of bone morphogenetic proteins. In:

Vukicevic S

Sampath KT

, eds. Bone Morphogenetic Proteins: From Laboratory to Clinical Practice. Basel, Switzerland: Birkhauser Verlag; 2002:87-119.

22.

Parfitt AM

Drezner MK

Glorieux FH

, et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987; 2: 595-610.

23.

Pecina M

Giltaj LR

Vukicevic S.

Orthopaedic applications of osteogenic protein–1 (BMP-7). Int Orthop.2001; 25: 203-208.

24.

Pecina M

Jelic M

Martinovic S

, et al. Articular cartilage repair: the role of bone morphogenetic proteins. Int Orthop.2002; 26: 131-136.

25.

Reddi AH

. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol. 1998; 16: 247-252.

26.

Rodeo S

Suzuki K

Deng X-H

, et al. Use of recombinant human bone morphogenetic protein–2 to enhance tendon healing in a bone tunnel. Am J Sports Med. 1999; 27: 476-488.

27.

Rodeo SA

Arnoczky SP

Torzilli PA

, et al. Tendon-healing in a bone tunnel. J Bone Joint Surg Am. 1993; 75: 1795-1804.

28.

Schulz MS

Russe K

Weiler A

, et al. Epidemiology of posterior cruciate ligament injuries. Arch Orthop Trauma Surg.2003; 123: 186-191.

29.

Scranton PE Jr

Lanzer WL

Ferguson MS

, et al. Mechanisms of anterior cruciate ligament neovascularization and ligamentization. Arthroscopy. 1998; 14: 702-716.

30.

Shelbourne KD

Carr DR

. Combined anterior and posterior cruciate and medial collateral ligament injury: nonsurgical and delayed surgical treatment. Instr Course Lect. 2003; 52: 413-418.

31.

Tanaka H

Nagai E

Murata H

, et al. Involvement of bone morpho-genetic protein–2 (BMP-2) in the pathological ossification process of the spinal ligament. Rheumatology. 2001; 40: 1163-1168.

32.

Tomita F

Yasuda K

Mikami S

, et al. Comparisons of intraosseous graft healing between the doubled flexor tendon graft and bone–patellar tendon–bone graft in anterior cruciate ligament reconstruction. Arthroscopy. 2001; 17: 461-476.

33.

Urist MR

. The first three decades of bone morphogenetic protein research. Osteologie. 1995; 4: 207-223.

34.

Vukicevic S

Krempien B

Stavljenic A.

Effects of 1 alpha, 25- and 24R, 25-dihydroxyvitamin D3 on aluminum-induced rickets in growing uremic rats. J Bone Miner Res. 1987; 2: 533-545.

35.

Vukicevic S

Latin V

Chen P

, et al. Localization of osteogenic protein–1 (bone morphogenetic protein–7) during human embryonic development: high affinity binding to basement membranes. Biochem Biophys Res Commun. 1994; 198: 693-700.

36.

Vukicevic S

Luyten FP

Reddi AH

. Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin. Proc Natl Acad Sci U S A. 1989; 86: 8793-8797.

37.

Vukicevic S

Stavljenic A

Pecina M.

Discovery and clinical application of bone morphogenetic proteins. Eur J Clin Chem Clin Biochem. 1995; 33: 661-671.

38.

Wolfman NM

Hattersley G

Cox K

, et al. Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6 and 7, members of the TGF-beta gene family. J Clin Invest. 1997; 100: 321-330.

39.

Woo BH

Fink BF

Page R

, et al. Enhancement of bone growth by sustained delivery of recombinant human bone morphogenetic protein–2 in a polymeric matrix. Pharm Res. 2001; 18: 1747-1753.

40.

Wozney JM

Rosen V.

Bone morphogenetic protein and bone morphogenetic gene family in bone formation and repair. Clin Orthop.1998; 346: 26-37.