Collagen based biomaterials and methods of preparation and use

Details Collagen based biomaterials and methods of preparation and use Collagen based biomaterials and methods of preparation and use

1999-11-09

2001-04-17

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S021800, C530S356000, C530S409000, C623S005160, C623S006610

Reexamination Certificate

active

06218360

ABSTRACT:

FIELD OF THE INVENTION
This invention comprises purified native state Type VI collagen/&bgr;ig, Type VI-&bgr;ig collagen gel, including the crosslinked gel, and the use of said gel to limit fibrosis during wound healing, and methods of preparation of said collagens and gels.
BACKGROUND OF THE INVENTION
Type VI collagen, a ubiquitous filamentous structural protein, is an integral component of the interfibrillar matrix, and represents a significant fraction of the connective tissue collagens. A sequence listing of one form of Type VI collagen is found in
Structure and Function of Collagen Types
, Eds. Richard Mayne and Robert E. Burgeson, (Academic Press, New York City (1987)), the teachings of which are incorporated herein by reference. Glutaraldehyde crosslinked Type IV collagen, used as a synthetic epikeratoplasty in monkey is degraded by endogenous enzymes and fails to support a healthy epithelium. (Thompson K P, Hanna K D, Gipson I K, Gravagna P, Waring III G O, Johnson-Wint B., “Synthetic epikeratoplasty in Rhesus monkeys with human type IV collagen,”
Cornea.
1993;12:35-45).
Type VI collagen is one of the earliest matrix proteins deposited during cell infiltration within a collagen tissue polymer composite used to repair an abdominal wall defect. Type VI collagen is a heterotrimer composed of polypeptides &agr;1(VI), &agr;2(VI), and &agr;3(VI). Each polypeptide contains globular domains at the amino and carboxyl termini separated by a short triple-helical domain. The dumbbell-shaped monomers assemble into tetramers by lateral association. End-to-end association of these tetramers forms a beaded filamentous structure.
Type VI collagen is arranged as a beaded filament with about 100 nm periods between beads. Type VI collagen is involved in cell-matrix interactions, and believed to interact with extracellular matrix components including collagens, hyaluronan, and proteoglycans. Without being bound by any particular theory, it is believed that as a structural protein, Type VI collagen plays a role in anchoring basal-lamina-containing organs within connective tissues and restricting lateral movement of collagen fibrils.
Native Type VI collagen co-purifies with a protein identified as &bgr;ig-h3, a protein induced in a human adenocarcinoma cell line after treatment with TGF-&bgr;. This protein in rabbit is termed &bgr;ig, and is synthesized in corneal stroma during morphogenesis of normal and healing tissue, indicating that it plays a role in these processes. The 683 amino acids sequence of &bgr;ig has similarity with the protein fasciclin I, a possible surface recognition molecule involved in nerve growth cone guidance, and OSF-2, a protein that has been suggested to function as an adhesion molecule in bone formation.
In corneal stroma, &bgr;ig is associated with the globular domain of native Type VI collagen. This association involves disulfide-dependent linkages. A denatured Type VI collagen preparation containing &bgr;ig was reported as promoting adhesion and spreading of corneal fibroblasts and smooth muscle cells in vitro. Adhesion of cells to Type VI collagen and subsequent cell spreading may be partially mediated by &bgr;ig. As an integral component of the stromal interfibrillar matrix during morphogenesis, &bgr;ig plays a role in development of an ordered fibrillar matrix. Without being bound by any specific theory, it is believed that such order is necessary for corneal transparency.
We have now, surprisingly, established that corneal Type VI collagen/&bgr;ig is efficiently extracted without denaturation by means of phosphate buffered saline. The purified preparation, containing Type VI collagen associated with &bgr;ig forms a viscous substance, which, when concentrated, is in the form of a gel termed “gelsix.” We have further discovered that upon chemical crosslinking with polyethylene glycol the gel becomes a transparent film or shaped object. The crosslinked gel is termed “cxgelsix.” Cxgelsix is mechanically strong enough to present a useful biomaterial in corneal and other applications.
Numerous studies and patents have described the use of collagens alone or in combination with other components as a biomaterial. Note is made of Thompson K P, Hanna K D, Gipson I K, Gravagna P, Waring III G O, Johnson-Wint B., “Synthetic epikeratoplasty in Rhesus monkeys with human type IV collagen,”
Cornea.
1993;12:35-45; Desgrange P, Tardieu M. Loisance D, Barritault D., “Extracellular matrix covered biomaterials for human endothelial cell growth,”
Int J Artif Organs.
1992;15:722-726; Orgill D P, Ehret F W, Regan J F, Glowacki J, Mulliken J B. “Polyethylene glycol/microfibrillar collagen composite as a new resorbable hemostatic bone wax.”
J Biomed Mater Res.
1998;39:358-363; van Luyn M J A, Khouw M S L, van Wachem P B, Blaauw I H, Werkmeister J A., “Modulation of the tissue reaction to biomaterials. II. The function of T cells in the inflammatory reaction to crosslinked collagen implanted in T-cell-deficient rats,”
J Biomed Mater Res.
1998;39:398-406; van Wachem P B, van Luyn M J A, Damink L O, Dijkstra P J, Feijen J, Neiuwenhuis P., “Biocompatibility and tissue regenerating capacity of crosslinked dermal sheep collagens,”
J Biomed Mater Res.
1994;28:353-363; Werkmeister J A, Edwards G A, Casagranda F, White J F, Ranshaw J A M., “Evaluation of a collagen-based biosynthetic material for the repair of abdominal wall defects,”
J Biomed Mater Res.
1998;39:429-436: Chiou A G -Y, Mermoud A, Underdahl J P, Schnyder C C., “An ultrasound biomicroscopic study of eyes after deep scierectomy with collagen implant.”
Ophthalmology.
1998;105:746-750; and Fujioka K, Maeda M, Hojo T, Sano A., “Protein release from collagen matrices,” Advanced Drug Delivery Reviews. 1998;31 :247-266 the teachings of which are incorporated herein by reference. Also noted are U.S. Pat. No. 5,162,430; U.S. Pat. No. 5,219,895; U.S. Pat. No. 5,354,336, the teachings of which are incorporated herein by reference.

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