Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Bone
Reexamination Certificate
2000-04-07
2004-06-22
Pellegrino, Brian E (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Bone
C623S023750, C514S801000
Reexamination Certificate
active
06752834
ABSTRACT:
The present invention concerns a collagen membrane implant for use in guided tissue regeneration, in particular for use in vivo in the reconstruction of bone or cartilage tissue.
In tissue regeneration, it has long proved difficult to reconstruct cartilage tissue, such as in cartilage lesions. Cartilage injuries can occur in any joint though the larger joints, such as the knee and ankle, are most at risk. Such injuries can result from trauma, from degenerative conditions or osteochondritis dissecans. Cartilage injuries are a principal pathomechanical factor in the development of arthrosis. The liberation of enzymes leads to an inflammatory process of the synovia which in turn leads to abrasion of the cartilage and destruction of the joint surface. Recent attempts to regenerate articular cartilage in chondral defects in vivo include implantation of cultured autogenic articular chondrocytes (CACs). However, this technique has had limited success.
It is now generally accepted that reconstruction of tissue requires the provision of a matrix to serve as a guide for cells, which grow along and between the fibres of the matrix. More recently, the use of CACs seeded in both synthetic and natural resorbable matrices has been proposed. However, attempts to reconstruct cartilage tissue using matrices based on polylactic acid, polyglycolic acid and collagen I or III, have required the matrices to be loaded in vitro with chondrocytes prior to implantation. This gives rise to complications in terms of the sterile culture of the chondrocytes i.e. immunological inflammatory reactions by giant cells and fibroblastic cells at the interface between implants and tissue.
WO-A-96/25961 proposes a matrix implant based on collagen II which can be implanted at the in vivo site and which relies on the growth of native chondrocytes on the surface of the matrix to effect cartilage regeneration. The ability of such a matrix to effect complete regeneration of cartilage tissue is, however, limited.
There is thus a need for a matrix implant which will permit successful ingrowth of native chondrocytes and thus regeneration of cartilage tissue following implantation in vivo. We have now found that cartilage, and ultimately new bone tissue, can be reconstructed by the use of a collagen II matrix which in vivo is shielded not only from the surrounding connective tissue but also from the underlying bone or cartilage defect. It is envisaged that this may be achieved through the use of a multi-layer membrane implant which itself is capable of preventing the undesired ingrowth of any surrounding tissues into the matrix, or which may be surgically implanted at the site of the defect so as to achieve this effect.
Viewed from one aspect the invention thus provides a multi-layer membrane comprising a matrix layer predominantly of collagen II and having an open sponge-like texture, and at least one barrier layer having a close, relatively impermeable texture.
A particular advantage of the membrane according to the invention when used is that native cells are unable to penetrate or grow into the layer having a close, relatively impermeable texture.
Whilst not wishing to be bound by theory, it is now believed that successful cartilage regeneration requires that the rapid ingrowth not only of native tissue cells, such as connective tissues, blood vessels etc., but also of any new bone tissue into the site of the defect be prevented. This may be achieved using a double-layer membrane in accordance with the invention which serves to shield the collagen matrix from the ingrowth of native tissue cells from one side. During surgical implantation this may be used in combination with a tissue graft, e.g. a periosteal graft, effective to prevent the ingrowth of native tissue cells from the opposing side. Thus, for example, a periosteal graft may initially be sutured in place such that this provides a covering over the bone or cartilage defect. A double-layer membrane of the invention may then be implanted at the site of the defect such that this lies in contact with the graft and may be arranged in such a way that the matrix layer faces towards the bone defect. More preferably, a double-layer membrane of the invention is initially implanted at the site of the defect with the barrier layer facing towards the bone or cartilage defect. A periosteal graft is then arranged such that this lies in contact with the matrix layer. The graft may be adhered with a biocompatible adhesive such as fibrin glue, or pinned with resorbable polylactic pins, or if necessary or possible sutured in such a way that this then serves to provide an impermeable barrier to the ingrowth of any surrounding connective tissue.
In an alternative embodiment of the invention, the membrane itself may be effective to prevent the ingrowth of any native tissue cells. Thus, viewed from a further aspect the invention provides a membrane comprising at least three layers in which a matrix layer being predominantly made from collagen II and having an open sponge-like texture is provided between two barrier layers having a close, relatively impermeable texture.
The matrix layer is capable of acting as a medium for the ingrowth of native chondrocytes thereby effecting regeneration of cartilage tissue. However, to further aid in regenerating cartilage tissue the matrix layer may be impregnated with chondrocytes either prior to or following implantation in vivo. Whilst the matrix layer may be impregnated with chondrocytes immediately prior to implantation, e.g. by injection, it is expected that in general the chondrocytes will be introduced into the matrix layer by direct injection of a suspension of chondrocytes following implantation. In this way, chondrocytes present in the matrix layer of the membrane are able to effect regeneration of cartilage, and ultimately new bone, whilst the membrane at the same time prevents the ingrowth of other cell types from the surrounding tissues.
Chondrocytes for use in the invention may be obtained from cell sources which include allogenic or autogenic cells isolated from articular cartilage, periosteum and perichondrium, and mesenchymal (stromal) stem cells from bone marrow. Since allogenic cells carry the potential for immune response and infectious complications, it is preferable to isolate the chondrocytes from autogenic cells, especially from autogenic articular cartilage. Techniques for harvesting cells are known and include enzymatic digestion or outgrowth culture. The harvested cells are then expanded in cell culture prior to reintroduction to the body. In general, at least 10
6
, preferably at least 10
7
cells should be impregnated into the matrix layer to provide for optimal regeneration of cartilage tissue.
In general, it is desirable for the matrix layer of the membrane according to the invention to contain glycosaminoglycans (GAGs) such as hyaluronic acid, chondroitin 6-sulphate, keratin sulphate, dermatan sulphate etc. which serve to provide a natural medium in which chondrocytes can become embedded and grow. Whilst it is possible to incorporate into the collagen matrix glycosaminoglycans from different sources which do not necessarily have the same composition, molecular weight and physiological properties as those from cartilage, preferred glycosaminoglycans are those extracted from cartilage itself. In general, the matrix layer preferably contains from 1 to 10 wt % of glycosaminoglycans, for example 2 to 6 wt %. Although some glycosaminoglycans may be present in the impermeable layer, the greater part will be present in the matrix layer.
In native collagen tissues GAGs occur, at least in part, as a component of proteoglycans (PGs). The use of GAGs in the form of PGs is undesirable in view of potential immunological problems which can be caused by the protein content of the PGs. Preferably, the matrix layer is thus substantially free from any proteoglycans. Conveniently, this may be achieved by preparing the matrix layer from a mixture of a purified telopeptide-free collagen II material and glycosaminoglycans.
Other additives
Eckmayer Zdenek
Geistlich Peter
Schlösser Lothar
Ed Geistlich Soehne AG Fuer Chemische Industrie
Pellegrino Brian E
Rothwell, Figg Ernst & Manbeck, PC
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