Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Ligament or tendon
Reexamination Certificate
1999-05-14
2001-09-11
McDermott, Corrine (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Ligament or tendon
C623S013130, C623S013140, C623S901000
Reexamination Certificate
active
06287340
ABSTRACT:
BACKGROUND OF THE INVENTION
Every year more than 135,000 Americans tear or rupture their anterior cruciate ligament (ACL) (Chen et al.,
J. Biomed. Mat. Res.
14: 567-586 (1980); Butler, D. L.,
J. Orthop. Res.
7: 910-921 (1989); Langer et al.,
Science
260: 920-926 (1993)). The ACL serves as a primary stabilizer of anterior tibial translation and as a secondary stabilizer of valgus-varus knee angulation, and is often susceptible to rupture or tear resulting from a flexion-rotation-valgus force associated with sports injuries and traffic accidents. Ruptures or tears often result in severe limitations in mobility, pain and discomfort, and the loss of an ability to participate in sports and exercise. Failures of the ACL are classified in three categories: (1) ligamentous (ligament fibers pull apart due to tensile stress), (2) failure at the bone-ligament interface without bone fracture, and (3) failure at the bone-ligament interface with bone fracture at the attachment site of bone and ligament. The most common type of ACL failure is the first category, ligamentous.
Total surgical replacement and reconstruction are required when injury to the ACL involves significant tear or rupture. Four options have been utilized for repair or replacement of a damaged ACL: (1) autografts, (2) allografts, (3) xenografts, and (4) synthetic prostheses (degradable and non-degradable). To date, no surgical repair procedure has been shown to restore knee function completely, and novel treatment options would likely benefit a large number of patients.
The problems associated with the use of synthetic ACL replacements, along with the limited availability of the donor tissue, have motivated research towards the development of functional and biocompatible equivalents of native tissues. This shift from synthetic to biologically-based ACL replacements first applied in early studies in which collagenous ACL prostheses were prepared as composite structures consisting of reconstituted type I collagen fibers in a collagen I matrix with polymethylmethacrylate bone fixation plugs, and used as anterior cruciate ligament replacement tissues in rabbits (Dunn et al.,
Am. J. Sports Medicine
20: 507-515 (1992)). Subsequent studies incorporated active biological components into the process, such as ligament fibroblasts seeded on cross-linked collagen fiber scaffolds that were used as ligament analogs (Dunn et al.,
J. Biomedical Materials Res.
29: 1363-1371 (1995); Dunn, M. G.,
Materials Res. Soc. Bulletin, Nov:
43-46 (1996)), and suggested that structures approximating native ligaments can be generated. A tendon gap model, based on pre-stressed collagen sutures seeded with mesenchymal stem cells provided improved repair of large tendon defects (Young et al., 1998). Goulet et al. modified the collagen-fibroblast system by using ligament fibroblasts in non-cross-linked collagen, with bone anchors to pre-stress the tissue and facilitate surgical implantation (Goulet et al., Tendons and Ligaments. In
Principles of Tissue Engineering
, Ed. R. Lanza, R. Langer, W. Chick. R. G. Landes Co. pp 633-643, R. G. Lanz Co. and Academic Press, Inc., San Diego, Calif. (1997)). Passive tension produced by growing the new ligament in a vertical position induced fibroblast elongation and the alignment of the cells and surrounding extracellular matrix.
However, to date, no human clinical trials have been reported with tissue culture bioengineered anterior cruciate ligaments. This is due to the fact that each approach has failed to address one or more of the following issues: (1) the lack of a readily available cell or tissue source, (2) the unique structure (e.g. crimp pattern, peripheral helical pattern and isometric fiber organization) of an ACL, and (3) the necessary remodeling time in vivo for progenitor cells to differentiate and/or autologous cells to infiltrate the graft, thus extending the time a patient must incur a destabilized knee and rehabilitation. The development of methods for generating more fully functional bioengineered anterior cruciate ligaments would greatly benefit the specific field of knee reconstructive surgery, and would also provide wider benefits to the overall field of in vitro tissue generation and replacement surgery.
SUMMARY OF THE INVENTION
The present invention provides a method for producing an anterior cruciate ligament ex vivo. The method comprises seeding pluripotent stem cells in a three dimensional matrix, anchoring the seeded matrix by attachment to two anchors, and culturing the cells within the matrix under conditions appropriate for cell growth and regeneration, while subjecting the matrix to one or more mechanical forces via movement of one or both of the attached anchors. In a preferred embodiment, the pluripotent cells are bone marrow stromal cells. Suitable matrix materials are materials to which cells can adhere. A preferred matrix material is collagen type I gel. Suitable anchor materials are materials to which the matrix can attach. Preferred anchor material includes Goinopra coral which has been treated to convert the calcium carbonate to calcium phosphate, and also demineralized bone. In a preferred embodiment, the mechanical forces to which the matrix is subjected mimic mechanical stimuli experienced by an anterior cruciate ligament in vivo. This is accomplished by delivering the appropriate combination of tension, compression, torsion, and shear, to the matrix.
Another aspect of the present invention is the bioengineered ligament which is produced by the above method. The ligament is characterized by a cellular orientation and/or matrix crimp pattern in the direction of the applied mechanical forces, and also by the production of collagen type I, collagen type III, and fibronectin proteins along the axis of mechanical load produced by the mechanical forces. In a preferred embodiment, the ligament is characterized by the presence of fiber bundles which are arranged into a helical organization.
Another aspect of the present invention is a method for producing a wide range of ligament types ex vivo using an adaptation of the method for producing an anterior cruciate ligament by adapting the anchor size to reflect the size of the specific type of ligament to be produced, and also adapting the specific combination of forces applied, to mimic the mechanical stimuli experienced in vivo by the specific type of ligament to be produced. Similar adaptations of the method can be made to produce other tissues ex vivo from pluripotent stem cells, by adapting the mechanical forces applied during cell culture to mimic stresses experienced in vivo by the specific tissue type to be produced. The methods of the present invention can be further modified to incorporate other stimuli experienced in vivo by the particular developing tissue, some examples of the stimuli being chemical stimuli, and electromagnetic stimuli.
Another aspect of the present invention relates to the specific tissues which are produced by the methods of the present invention. Some examples of tissue which can be produced include other ligaments in the body (hand, wrist, elbow, knee), cartilage, bone, tendon, muscle, and blood vessels.
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Lopez Valle et al. “Peripheral anchorage of dermal equivalents”, British Journal of Dermatology, 1992.*
Huang et al. “Mechanisms and Dynamics of Mechanical Strengthening in Ligament-Equivalent Fibroblast-Populated Collagen Matrices”, Annals of Biomedical Eng. pp. 289-305, 1993.*
Thomas and El Haj,Ca
Altman Gregory
Kaplan David
Martin Ivan
Vunjak-Novakovic Gordana
Farrell Kevin M.
Koh Choon P.
McDermott Corrine
Trustees of Tufts College
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