Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-03-23
2001-02-13
Marschel, Ardin H. (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S350000, C530S399000
Reexamination Certificate
active
06187742
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of tissue repair, specifically, the regeneration of a functional attachment between connective tissue, such as tendon, cartilage or ligament, to bone. This functional attachment may be destroyed by trauma or stress, or by degenerative or congenital disease. Thus, the present invention may be useful in reconstructive surgery or other procedures for the regeneration of a functional attachment between connective tissue and bone.
BACKGROUND OF THE INVENTION
Background of the incidence and etiology of need:
Although several of reconstructive surgical procedures rely on the firm healing or attachment of connective tissue, particularly tendon or ligament, to bone, little is known about the healing process at the tendon-to-bone interface. Since the site of graft fixation to bone represents the weakest area in the early post-transplant period, methods to improve early graft fixation strength have significant clinical application. This is of particular importance in operations on the knee, shoulder, hip, hand, ankle and elbow.
The development of tendon or ligament insertion into bone is poorly understood. The insertion site is mediated by collagen fibers, known as “Sharpey's fibers,” which are continuous from tendon into bone. Sharpey's fibers are thought to form in the developing skeleton by progressive mineralization of ligament or periosteal collagen fibers by advancing bone during growth. Studies have indicated that bone heals to tendon by bone ingrowth into the fibrovascular interface tissue which initially forms between the tendon and bone. There is progressive mineralization of the interface tissue with subsequent bone ingrowth into the outer tendon. Despite the evidence that bone grows into collagenous tissue, the mechanism of such bone ingrowth, and the effectiveness and strength of the attachment, remains uncertain. A previous study of tendon-to-bone healing demonstrated the formation of a fibrous tissue interface between the tendon and bone. Rodeo et al.,
J. Bone and Joint Surgery,
75-A: 1795-1803 (1993).
Accordingly, despite substantial endeavors in this field, there remains a need for an effective method of repair of a functional attachment between connective tissue, such as tendon or ligament, and bone.
SUMMARY OF THE INVENTION
The present invention provides methods and compositions for regenerating a functional attachment between connective tissue and bone. In particular, the present invention comprises methods of treating patients with detached or degenerated attachments of the tendon or ligament to bone. Some examples include reconstructive surgery on the knee, shoulder, hand, ankle and elbow. Particular areas where the present invention may prove useful include reconstruction of the anterior cruciate ligament (ACL), or the rotator cuff. The methods and compositions of the present invention are advantageous in that they utilize osteogenic proteins, which may be produced via recombinant DNA technology, and therefore are of potentially unlimited supply. The methods and compositions of the present invention are further advantageous in that regeneration of the attachment apparatus may be accelerated or may be of greater ultimate strength, and the attachment formed between connective tissue and bone may reach a functional strength sooner after surgery or repair is effected. The methods and compositions of the present invention are further advantageous in that they induce the regeneration of the functional attachment between connective tissue and bone, while minimizing or avoiding formation of fibrous or granulation tissue at the interface between tissue types.
The methods of the present invention are particularly applicable to the fixation of a round tendon in a bone tunnel or a flat tendon onto a bone surface. Several clinical examples are relevant. A common clinical example is reconstruction of the anterior cruciate ligament (ACL). Reconstruction may be performed by using the central third of the patellar tendon with an attached bone block from both the tibia and patella, or by using the semitendinosus and gracilis tendons. Benefits of the use of patellar tendon include immediate bony fixation allowing aggressive post-operative rehabilitation and increased strength. However, the use of central third patellar tendon has been associated with adverse sequelae, including patellar fracture, patellar ligament rupture, and degeneration of the patellofemoral joint. Benefits of the use of semitendinosus and gracilis tendons include easier graft harvest, no disruption of the extensor mechanism of the knee, greater quadriceps strength one year post-operatively, and minimal loss of hamstring strength. The major pitfall is concern about the strength of fixation of the tendon within bone tunnels and risk of graft failure at the fixation site. The major difference between these two methods of ligament reconstruction is fixation of the graft.
The use of BMP to augment tendon-to-bone healing may result in better methods to utilize semitendinosus and gracilis tendons for ACL reconstruction, thus obviating the patellar defect and concomitant extensor mechanism disruption inherent in patellar ligament harvest. Preclinical evaluations indicate that rhBMP-2 improves early healing of bone to a tendon graft, as demonstrated by histologic and biomechanical evaluation. Increased strength of tendon-to-bone fixation will allow earlier and more aggressive rehabilitation, resulting in earlier return to normal activities, work, or sport.
Other common clinical examples for which the invention has direct application include the following: rotator cuff tendon repair to the greater tuberosity of the humerus, reattachment of the glenoid labrum to the scapular neck, reconstruction of the lateral ankle ligaments using a tendon graft placed through bone tunnels, reconstruction of the medial collateral ligament of the elbow or knee using a tendon graft fixed to the surface of the bone or through bone tunnels, reconstruction of the ulnar collateral ligament of the thumb using a tendon graft placed in a bone tunnel, and repair of the flexor or extensor tendons of the digits into bone tunnels or to the surface of the bone of the phalanges. The invention is broadly applicable to any situation in which connective tissue (tendon, ligament, labrum, fascia, or joint capsule) is reattached to bone, either to the surface of the bone or into a tunnel in the bone.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, methods and compositions are provided for treatment of patients who require reconstructive surgery for repair of the functional attachment between connective tissue and bone. The methods and composition are advantageous in that repair or improvement of the entire attachment apparatus may be effected: the tendon or ligament, the adjacent bone, as well as the functional attachment. The methods comprise applying to the site in need of reconstructive surgery, or to the site of a defect, tear or detachment of connective tissue to bone, an amount of a composition comprising one or more purified osteogenic proteins which is effective to regenerate the functional attachment of the connective tissue to the bone. The method may further comprise the administration of a composition comprising a purified or recombinant osteogenic protein to a site in need of regeneration of the connective tissue to bone attachment in a suitable carrier such that the connective tissue, the bone, and the functional attachment apparatus are regenerated, with reduced fibrous or granulation tissue at the site of attachment occurring. The composition is preferably administered in combination with an effective carrier. One of the key advantages of the method of the present invention is that it allows for the controlled regeneration of connective tissue, bone and the functional attachment apparatus in an accelerated manner such that the attachment may attain greater functional strength, at an earlier time point than with a similar procedure performed
Hannafin Jo A.
Rodeo Scott A.
Warren Russell F.
Wozney John M.
Genetics Institute Inc.
Marschel Ardin H.
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