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Letters to the Editor |
Zabreb, Croatia
Dear Editor:
We have been interested in studying the tendon-to-bone healing process. The tendo-osseous attachment is strong and is protected from injury by the tissue structure. Although infrequent, traumatic avulsion of the tendon or ligament insertion at the actual interface with bone may be dangerous, causing an inadequate process of early soft tissue-to-bone healing relative to the tendo-osseous junction. Because of its strength, the tendo-osseous junction represents an interesting region for the early soft tissue-to-bone healing process. Therefore, to override these pitfalls, many studies have reported reliance on tendon healing in a bone tunnel, as used in some reconstructive surgical procedures. However, the bone tunnel model holds some weaknesses; for example, there are torsion forces on healing tendon that promote a tendo-osseous reaction. It is obvious that histological and biomechanical properties are strongly influenced by these forces.
In one of your previous volumes there was an interesting article entitled "Use of Recombinant Human Bone Morphogenetic Protein-2 to Enhance Tendon Healing in a Bone Tunnel" (July/August 1999, pages 476–488) by Rodeo et al. The authors stated that rhBMP-2 enhances tendon healing in a bone tunnel, but that there is no difference in tendon attachment strength between the BMP-treated and control limbs, even though there was increased bone formation in BMP-treated limbs. This study model (and many other similar ones) thus represents bone tunnel tendon healing and not healing at the tendon edge.
Some authors tried to eliminate local forces in the tunnel model by use of various absorbable materials and biodegradable screws, but local reactions may have a significant influence on the experimental outcome.1 It has been determined that there was no significant difference between the simple method of cortical tendon reattachment and the more complex method of bone-tunnel reattachment. Also, the firmness of the tendon insertion zone relies on synthesis and quality of collagen fibers, which is influenced by hormones, exercise, and immobilization.
We performed a simple, sharp Achilles tendon dissection from calcaneal bone in rat as a more reliable model for studying tendon-to-bone healing under repetitive, submaximal loading. We used the novel stable pentadecapeptide, BPC 157, acting alone, which has already shown significant results in bone defects and other different wound healing.2,3 Four days after the sharp Achilles tendon dissection from calcaneal bone, there was a significant decrease in the tendon-to-bone gap in BPC-treated rats compared with the control group. Furthermore, this peptide does not need a carrier system, is stable in gastric juice, and can be given intraperitonealy without side effects. These properties are a significant advantage over those of some known growth factors (such as bone morphogenetic proteins and TGF-ß), where various carrier systems have been tested and for which local application is obligatory.
REFERENCES
ebecic B, Nikolic V, Sikiric P, et al: Osteogenic effect of a gastric pentadecapeptide, BPC-157, on the healing of segmental bone defect in rabbits: A comparison with bone marrow and autologous cortical bone implantation.
Bone 24:195
–202,1999[Medline][Order article via Infotrieve]New York, New York
The junction between bone and tendon/ligament is a complex, specialized structure that serves to transmit mechanical stress from soft tissue to hard tissue. The normal tendon (ligament)-bone junction consists of four distinct tissue types: 1) bone, 2) mineralized fibrocartilage, 3) unmineralized fibrocartilage, and 4) tendon. This structure provides a gradual transition in material properties between soft and hard tissue, thus diminishing stress at the junction.
Most studies demonstrate that a normal tendon (ligament)-to-bone junction is not reformed after surgical attachment of tendon to bone. Healing is likely regulated by numerous factors, including cytokines and other chemical mediators, and mechanical signals.6 Healing at the tendon-bone junction involves formation of tissue in the interface and bone growth into this interface.5 As bone formation at the tendon-bone junction appears to be an important part of healing, we have examined the role of bone formation, bone resorption, and osteoinductive factors. In the 1999 work cited in the letter from Krivic and Sikiric, we found that exogenous rhBMP-2 applied to the tendon-bone interface resulted in greater bone ingrowth into the interface, with increased attachment strength at an early timepoint (2 weeks). It must be noted that failure during biomechanical testing occurred outside the tunnel in the majority of the BMP-treated limbs at 4 and 8 weeks; thus, actual fixation strength of the graft in the tunnel is likely higher. It should also be noted that we used an extraarticular model of a tendon graft in a bone tunnel in this study. This model avoids any variability associated with graft tensioning and positioning, as well as the potential adverse effect of synovial fluid on graft healing. Thus, this model likely represents the "best-case" scenario. Cytokines such as BMP may be even more effective in situations where healing may be impaired, such as in the setting of excessive graft-tunnel motion, synovial fluid influx between the graft and bone, or graft-tunnel mismatch where there is a widened bone tunnel (as may occur during revision surgery).
These findings are supported by other studies that have examined the effect of osteoinductive factors on tendon-bone healing. For example, another study from our laboratory reported that a mixture of bovine bone-derived osteoinductive proteins (including BMPs and TGF-ß) improved attachment strength of a tendon graft in a bone tunnel in a rabbit model of ACL reconstruction.1 In a large animal model of ACL reconstruction (sheep), Nicklin et al.4 reported improved bone formation at the tendon-bone interface with application of OP-1 (osteogenic protein-1, Stryker Corp, Kalamazoo, Michigan). Using a novel approach, Martinek et al.3 recently reported that implantation of cells that were genetically modified to produce BMP-2 also resulted in improved healing of a tendon graft in a bone tunnel. Certainly, further studies are required to determine the most appropriate cytokine(s) that may augment healing between tendon and bone, the ideal dosage, and timing of administration. Carefully controlled studies are required to answer these questions.
Two distinctly different modes of tendon-to-bone attachment are used clinically: 1) tendon healing in a bone tunnel, such as for ACL or PCL reconstruction, and 2) tendon attachment to the bone surface, such as for rotator cuff tendon or quadriceps tendon repair. Although the basic healing process between tendon and bone may well be similar between these two applications, the results of tendon healing in a bone tunnel should not be extrapolated to the process of tendon healing to the bone surface, as there are differences in anatomic site, biomechanical environment, and likely the biological environment between these processes. For these reasons, these processes should be studied separately.
The authors of the letter are studying tendon attachment to the bone surface; this is an important clinical problem and I encourage the authors to continue these investigations. It is likely that an osteoinductive agent could improve healing between tendon and the bone surface. For example, we recently reported that a mixture of osteoinductive proteins applied to the interface between rotator cuff tendon and bone improved tendon attachment strength in a sheep model of rotator cuff tendon repair.7 Hattersley et al.2 used the same rat Achilles tendon model as the authors of this letter to study the effect of BMP-12 and reported improved tissue formation at the attachment site.
The novel pentadecapeptide mentioned in this letter appears promising and I would encourage the authors to evaluate the structural and functional characteristics of specimens treated with this agent. The ability to use systemic administration would be valuable. However, careful safety studies will be required to determine the mechanism of action and potential toxicity.
REFERENCES
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