Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1998-10-29
2001-02-06
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S423000, C424S426000, C435S001100, C435S177000, C435S178000, C435S180000, C435S182000, C435S325000, C435S395000, C435S397000, C623S011110
Reexamination Certificate
active
06183737
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is cartilage repair.
BACKGROUND OF THE INVENTION
Cartilage, which is a heterogeneous tissue, can be classified as either articular or epiphyseal/physeal. Disturbances in cartilage structure and function are seen in congenital, infectious, traumatic, degenerative and neoplastic conditions. Biological repair of focal articular cartilage defects has generated great interest, yet some of the variables of this process have not been precisely defined (see, e.g., Brittberg et al.,
New Engl. J. Med.,
331:889-895, 1994; and Mankin,
New Engl. J. Med.,
331:940-941, 1994). Such variables include the biochemical and biomechanical properties of the repair tissue itself and also its bonding with adjacent cartilage and bone.
The morphogenetic scaffold to which chondrocytes may attach and form matrix is one of the variables that have effects on the repair tissue. Materials that have been used as the scaffold include collagen gel (Fujisato et al.,
Biomaterials,
17:155-162, 1995; Hansen et al.,
Clin. Orthop.,
256:286-298, 1990; Mizuno et al.,
Exp. Cell. Res.,
227:89-97, 1996; Nixon et al.,
Am. J. Vet. Res.,
54:349-356, 1993; Sams et al.,
Osteoarthr. Cartil.,
3:47-59, 1995; Sams et al.,
Osteoarthr. Cartil.,
3:61-70, 1995), fibrin glue (Hendrickson et al.,
J. Orthop. Res.,
12:485-497, 1994; Homminga et al.,
Acta Ortopedica Scandinavica,
64:441-445, 1993; Tsai et al.,
J. Formosan Med. Assoc.,
3(Suppl):239-245, 1993), polyglycolic acid (Freed et al.,
Biotechnology,
12:689-693, 1994; Vacanti et al.,
Am. J. Sports Med.,
22:485-488, 1994), polyethylene oxide gel (Sims et al.,
Plast. Reconstr. Surgery,
98:843-850, 1996), alginate gel (Van Susante et al.,
Acta Ortopedica Scandinavica,
66:549-556, 1995), carbon fiber pads (
Brittberg et al., Clin. Orthop.,
326:270-283, 1996) and xenogeneic matrix (Caruso et al.,
J. Orthop. Res.,
14:102-107, 1996).
Isolated and cultured chondrocytes embedded in these various scaffolds have been used for filling and repairing articular cartilage defects in chicks (Itay et al.,
Clin. Orthop.,
220:284-303, 1987), rabbits (Grande et al.,
Anatomical Records,
218:142-148, 1987; Grande et al.,
J. Orthop. Res.
7:208-218, 1989; Wakitani et al.,
J. Bone Joint Surg. [Br.],
71:74-80, 1989), dogs (Shortkroff et al.,
Biomaterials,
17:147-154, 1996), and horses (Hendrickson et al., supra; Sams et al.,
Osteoarthr. Cartil.,
3:47-59, 1995; Sams et al.,
Osteoarthr. Cartil.,
3:61-70, 1995).
Complete repair of partial defects of cartilage implies side-to-side joining of cartilaginous matrices. While such joining has been investigated in several ways (Hunziker et al.,
Trans. Orthop. Res. Soc.,
17:231, 1992; Reindel et al.,
J. Orthop. Res.,
13:751-760, 1995; Wolohan et al.,
J. Orthop. Res.,
9:180-185, 1991), options for accomplishing this still need to be expanded.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that isolated chondrocytes can propagate in the presence of an appropriate biological gel (e.g., fibrin gel) and generate cartilage matrix that firmly bonds two adjacent cartilage pieces.
Accordingly, the invention features a method of bonding two cartilage pieces. In this method, a bonding composition containing isolated chondrocytes mixed with a biological gel is applied to a surface of one (or both) of the cartilage pieces, and the surface is then contacted with the other cartilage piece. New cartilage matrix generated by the bonding composition will provide durable (e.g., 1% or more of normal cartilage strength) bonding between the two contacting cartilage pieces. The order of steps in the above-described method can be altered. For instance, the two cartilage pieces to be bonded can be held in apposition, and then the bonding composition is applied to fill gaps at the interface of the two cartilage pieces.
In another method of the present invention, either or both of the cartilage pieces are first incubated with isolated chondrocytes. A biological gel is then applied to a surface of either or both of the two pieces, and the two pieces are held together at the surface. Alternatively, the two cartilage pieces to be bonded can be held in apposition first to form a cartilage composite; after the composite is incubated with isolated chondrocytes, a biological gel is applied to fill gaps at the interface of the two cartilage pieces.
Isolated chondrocytes are chondrocytes that are separated from cartilage matrix, and they can be obtained from cartilage tissue or bone marrow. Both freshly isolated and cultured chondrocytes can be used.
A biological gel is a flexible, biodegradable (i.e., bioresorbable) and biocompatible (i.e., has no or negligible in vivo toxicity and is compatible with in vivo conditions) composition that typically has pores large enough to allow chondrocytes to populate. An exemplary biological gel is fibrin gel (also called fibrin glue). Fibrin gel has been used as the basis of many biological glues or adhesive matrices, and can be prepared with coagulation factors including thrombin and fibrinogen. Fibrinogen is cleaved by thrombin to form fibrin at the initiation of clotting.
One or both of the cartilage pieces to be bonded can be depleted of endogenous (i.e., innate) chondrocytes before the isolated chondrocytes are applied. The cartilage pieces to be bonded can be articular cartilage, fibrocartilage or growth cartilage, and can be obtained from the patient to be treated, or from a donor of the same or different species.
The new methods can be used to repair (i.e., resurface), in a mammal (e.g., human, mouse, rat, dog, horse, lamb, sheep, etc.), articular cartilage having a defect (e.g., a partial or full thickness defect); in that case, one of the two pieces to be bonded is the defective cartilage, and the other piece constitutes a part of a cartilage implant, and the chondrocytes used can be derived from the mammal itself. The present methods can also be used to treat defects in other types of cartilage, e.g., a meniscal tear in fibrocartilage or a resection defect resulting from excision of a physeal bar from an injured growth plate.
Also featured in the invention is a method of preparing a cartilage implant. In this method, a cartilage piece (e.g., one that contains no or essentially no viable endogenous chondrocytes) of appropriate size and shape is first co-cultured with isolated chondrocytes, and then a biological gel is applied to the cartilage piece to generate an implant. Alternatively, a bonding composition as described above can be applied directly the cartilage piece to generate an implant.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. The materials, methods, and examples described herein are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
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patent: 0 339 607 (1989-02-01), None
Jurgensen et al., “A New Biological Glue for Cartilage-Cartilage Interfaces: Tissue Transglutaminase”, The Journal of Bone and Joint Surgery, Inc. 79-A:185-193, 1997.
Pitman et al., “The Use of Adhesives in Chondrocyte Transplantation Surgery: In-
Caruso Enzo
Peretti Giuseppe
Randolph Mark
Rossetti Francesco
Zaleske David J.
Fish & Richardson P.C.
Naff David M.
The General Hospital Corporation
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