Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
1999-04-09
2001-01-23
Nutter, Nathan M. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C514S012200, C600S036000, C623S001210, C623S002220, C623S011110, C623S013190
Reexamination Certificate
active
06177514
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of medical devices for implantation into humans. More particularly, it concerns method for processing biological tissues for use as bioprosthetic devices.
2. Description of the Related Art
Bioprostheses are devices derived from processed biological tissues to be used for implantation into humans. The development of such devices originated as an attempt to circumvent some of the clinical complications associated with the early development of the mechanical heart valve, and has since resulted in a rapid proliferation of bioprosthetic devices for a variety of applications. Examples of some of the bioprostheses currently used or under development include heart valves, vascular grafts, biohybrid vascular grafts, ligament substitutes pericardial patches, etc.
The primary component of the biological tissues used to fabricate bioprostheses is collagen, a generic term for a family of related extracellular proteins. Collagen molecules consists of three chains of poly(amino acids) arranged in a trihelical configuration ending in non-helical carboxyl and amino termini. These collagen molecules assemble to form microfibrils, which in turn assemble into fibrils, resulting in collagen fibers. The amino acids which make up the collagen molecules contain side groups, including amine (NH2), acid (COOH) and hydroxyl (OH) groups, in addition to the amide bonds of the polymer backbone, all of which are sites for potential chemical reaction on these molecules.
Because collagenous tissues degrade very rapidly upon implantation, it is necessary to stabilize the tissue if it is to be used clinically. Chemical stabilization by tissue cross-linking, also referred to as tissue fixation, has been achieved using bi-functional and multi-functional molecules having reactive groups capable of forming irreversible and stable intramolecular and intermolecular chemical bonds with the reactive amino acid side groups present on the collagen molecules.
Glutaraldehyde is the most frequently used agent for cross-linking biological tissues. It is a five carbon aliphatic molecule with an aldehyde at each end of the chain, rendering it bifunctional. These aldehyde groups react under physiological conditions with primary amine groups on collagen molecules resulting in the cross-linking of collagen containing tissues.
Despite its widespread use, there are a number of drawbacks associated with glutaraldehyde cross-linking. For instance, under typical storage conditions, glutaraldehyde is self-reactive and will form a variety of polymeric and other species. As a result, a pure solution of monomeric glutaraldehyde becomes highly heterogeneous over time. The ratio of monomeric to polymeric species, the structure of the glutaraldehyde polymer, its formation kinetics, etc, have been described (for example, see Khor, 1997, and references cited therein).
The presence of polymeric glutaraldehyde species and the general heterogeneity of glutaraldehyde solutions can be problematic in a number of regards. For example, polymeric glutaraldehyde is less tissue permeable than low molecular weight forms. Thus, the use of glutaraldehyde solutions containing highly polymeric species can give rise to tissue that is not uniformly cross-linked, i.e. that contains regions of essentially native tissue within a cross-linked matrix. This non-uniformity can compromise the integrity/durability of the cross-linked tissue for many applications.
Another significant drawback associated with glutaraldehyde cross-linking is the propensity of the treated tissues to undergo calcification. Calcification appears to represent the predominant cause of failure of glutaraldehyde-fixed devices (Golomb et al., 1987; Levy et al., 1986; Thubrikar et al., 1983; Girardot et al., 1995). It is believed that the presence of polymeric forms of glutaraldehyde in the cross-linked tissue may contribute to such calcification, possibly by serving as a physical point of calcification (Thoma et al., 1987). In addition, the non-uniform cross-linking that can result from using heterogeneous glutaraldehyde solutions may also contribute to calcification because exposure of incompletely cross-linked regions following mechanical failure can result in calcification at the rapid rate typical of that for native, non-cross-linked tissue.
Yet another drawback to conventional glutaraldehyde cross-linking is that the polymeric product of glutaraldehyde can depolymize in vivo, causing the release of toxic monomeric glutaraldehyde. This leaching of glutaraldehyde can prevent the cellular growth on the bioprosthesis that is necessary for long term biocompatibility.
Thus, it is a significant disadvantage that polymeric forms of glutaraldehyde are present in the solutions generally used for cross-linking biological tissues. The present invention is directed to overcoming or at least reducing the effects of one or more of the problems set forth above. In particular, a method has been developed in which tissue is fixed with glutaraldehyde, that is in a substantially monomeric form, thereby minimizing the complications associated with the use of heterogeneous glutaraldehyde solutions.
SUMMARY OF THE INVENTION
There is a need within the field of bioprosthetics for simple, cost-effective methods for cross-linking biological tissues which overcome some of the limitations associated with glutaraldehyde cross-linking and which provide bioprosthetic devices with desirable mechanical characteristics and a reduced susceptibility to calcification relative to tissues cross-linked with conventional heterogeneous glutaraldehyde solutions. This invention broadly concerns methods for cross-linking biological tissues, and the cross-linked tissue so produced, by employing a chemical blocking/de-blocking approach to minimize or prevent the presence of undesirable polymeric species of a polyflnctional aldehyde during a cross-linking reaction.
Therefore, according to one aspect of the present invention, the aldehyde groups of a substantially monomeric form of a polyfunctional aldehyde are first chemically blocked so as to provide a non-self-reactive, non-tissue-reactive compound. The blocking groups can be essentially any chemical groups or functionalities that can be reversibly reacted under relatively benign conditions with the aldehyde groups of a polyfunctional aldehyde. Examples of suitable blocking groups include dioxolanes, oximes, imines, oxazolidines, inorganic salts, and the like. The blocked polyfunctional aldehyde is contacted with a biological tissue of interest and removal of the blocking group is effected in situ so as to regenerate a substantially monomeric polyfunctional aldehyde. By incubating the tissue in the presence of the de-blocked polyfunctional aldehyde, cross-linked tissue is thereby provided.
In another aspect of the invention, the de-blocking reaction is not carried out in situ. Rather, a solution is first provided which comprises a substantially monomeric polyfunctional aldehyde, the aldehyde groups of which have been blocked with a blocking group as described above. Removal of the blocking groups regenerates substantially monomeric polyfunctional aldehyde which is thereafter contacted with a biological tissue under conditions effective to result in the desired degree of cross-linking. The tissue is preferably contacted with the solution before a time at which the polyfunctional aldehyde has undergone substantial self-reaction into polymeric species.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
Illustrative embodiments of the invention are described below. In the interest of clarity, not all features of an actual implementation are described in this specification. It will of course be appreciated that in the development of any such actual embodiment, numerous implementation-specific decisions must be made to achieve the developers' specific goals, such as compliance with system-related and business-related constraints, which will vary from one implementation to another. Moreover
Moore Mark A.
Pathak Chandrashekhar P.
Philips, Jr. Richard E.
Lyeril Philip S.
Nutter Nathan M.
Scott Timothy L.
Sulzer Carbomedics Inc.
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