Collegan-based matrix

Details Collegan-based matrix Collegan-based matrix

1999-06-18

2002-02-12

Witz, Jean C. (Department: 1651)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C424S426000, C424S435000, C514S774000, C524S022000, C530S356000, C435S273000

Reexamination Certificate

active

06346515

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns a novel collagen-based matrix and devices comprising this matrix. A particular example of such device is a collagen-based sheet -useful in a guided tissue regeneration (GTR), which will be referred to herein as “GTR membrane”.
A particular application of the GTR membrane of the invention is in dentistry, for guided tissue regeneration of periodontal tissue.
The present invention also concerns a process for the preparation of the matrix.
BACKGROUND OF THE INVENTION
Guided tissue regeneration is a surgical procedure intended to restore or regenerate the morphology and function of tissues or organs that were destroyed by disease or trauma. In tissue regeneration, the regenerating tissues have to repopulate the same site and space previously occupied by the healthy tissues that were destroyed. Furthermore, to restore the morphological and functional relationships between the different regeneration tissues at the regeneration site, the repopulation of the affected site and the subsequent differentiation of the repopulating cells should be an orderly and concerted process.
The technique of GTR aims to allow orderly and concerted repopulation of an affected site by regenerating tissues. To this end, a barrier is interposed between the regenerating tissues and the tissue that might intervene with the regenerative process. The barrier is maintained in place until the affected site is repopulated by the proper tissues and the regenerating tissues reach maturity.
Membrane barriers are currently used mainly in dentistry, for GTR of regenerating periodontal tissues that were destroyed by periodontal disease or trauma. Generally, two types of membranes are in use, membranes made of non-degradable material and membranes made of degradable materials.
Collagen are a family of proteins with a well determined triple helical configuration. Among these proteins, collagen Type I is most prevalent, constituting approximately 25% of the body's proteins and 80% of the connective tissues' proteins. Collagen Type I polymerizes to form aggregates of fibers and bundles. Collagen are continuously remodeled in the body by degradation and synthesis. Collagen Type I is degraded only by a specific enzyme—collagenase, and is resistant to any non-specific proteolytic degradation.
Collagen is a weak antigen and most of its antigenicity resides in the non-helical terminals of the molecule. These terminals may be removed by enzymes such as pepsin. Its weak antigenicity and its relative resistance to degradation make collagen a good candidate as a building material of implantable devices.
A molecular solution of type I collagen can be prepared from a connective tissue rich in this protein and the molecular collagen can then be reassembled into fibrils which can then combine to form a collagen matrix. Collagen matrices can be molded in vitro into numerous implantable devices such as, for example collagen sheets, collagen tubes, etc.
When used to form implantable devices, collagen matrices should maintain their integrity for long periods of time. The resistance towards degradation of the collagen fibrils can be increased by increasing the number of intermolecular cross-links. Several agents, such as aldehyde fixatives and imides, and treatments such as radiations have been used to achieve this purpose. The main drawbacks of such treatments are toxicity and inability to accurately control the degree of cross-linking.
SUMMARY OF THE INVENTION
It is the object of the present invention to provide a collagen matrix suitable for use in implantable devices such as membranes or tubes for guided tissue regeneration.
It is furthermore the object of the present invention to provide a process for the preparation of such a matrix.
It is still further the object of the present invention to provide a kit comprising ingredients useful in guided tissue regeneration procedures.
It is still further the object of the present invention to provide a method of guided tissue regeneration (GTR).
It is still further an object to provide space maintainers for use in GTR procedures.
It was found in accordance with the invention, that collagen can be rendered resistant to a collagenolytic degradation by means of cross-linking the collagens by reacting it with a reducing sugar. Thus, in accordance with the present invention a cross-linked collagen matrix is provided which can be maintained substantially intact within the body for long periods of time and is thus useful as a building material of various collagen-based implantable devices.
The present invention provides, in accordance with a first of its aspects, a collagen matrix comprising collagen fibrils, the molecules or microfibrils of which are being cross-linked to one another by a cross-linking agent, the cross-linking agent comprising a reducing sugar, or a reducing sugar derivative.
The present invention further provides a process for preparing a collagen matrix comprising reacting collagen with a reducing agent whereby fibrils of the collagen become cross-linked to one another. Preferably, following preparation, the collagen matrix is dehydrated, e.g. in alcohol solution, and then subjected to critical point drying.
Said cross-linking agent may be an aldehyde mono sugar or a mono sugar derivative wherein the &agr;-carbon exists in an aldehyde or ketone state in an aqueous solution.
Said cross-linking agent may be a compound represented by one of the following formulae I or II:
wherein:
R
1
is H or lower alkyl or alkylene, an amino acid, a peptide, a saccharide, purine or pyrimidine base, a phosphorylated purine or pyrimide base;
n is an integer between 2-9, and
p and q are each independently an integer between 0-8, provided that p and q together are at least 2 and not more than 8.
A reducing sugar can form a Schiff base with an &agr; or &egr; amino groups of amino acids of the collagen molecule. The Schiff base undergoes an Amadori Rearrangement to form a ketoamine product by the following reaction scheme:
Two adjacent ketoamine groups can then condense to form a stable intermolecular or intramolecular crosslink.
When the cross-linking agent is ribose, a stable cross-linked via a pertosidine group may be formed by the following reaction scheme (in the following scheme “A” denotes a first collagen molecule and “B” a second collagen molecule):
Examples of said reducing agent are glycerose, threose, erythrose, lyxose, xylose, arabinose, ribose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, or any other diose, triose, tetrose, pentose, hexose, septose, octose, nanose or decose.
The degradation rate of the collagen matrix when in situ can be controlled by the extent of cross-linking between the collagen molecules in the matrix. This may in turn be controlled by the concentration of the sugar during the preparation of the matrix, the temperature, and the extent of time during which the collagen is exposed to the sugar.
The matrix may comprise also various agents having a certain therapeutic effect which are immobilized within the matrix by said sugars. When the matrix is in situ, these agents are gradually released during the gradual degradation of the matrix. These agents include antimicrobial agents, anti-inflammatory agents, factors having tissue regeneration induction properties, etc.
Examples of antimicrobial agents are antibiotics such as penicillin, cefalosporins, tetracyclines, streptomycin, gentamicin; sulfonamides; and antifungal drugs such as myconazolle.
Examples of anti-inflammatory agents are cortisone, a synthetic derivative thereof, or any synthetic anti-inflammatory drugs.
Examples of factors having tissue inductive properties are growth factors such as fibroblast growth factor, platelet derived growth factors, transforming growth factors, cementum growth factors, insulin-like growth factors, etc; differentiating factors such as bone morphogenetic proteins; attachment factors (these can also be linked to the matrix by means of cross-linkings by the sugars or by taking advantage of their

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