Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Tissue
Reexamination Certificate
1999-04-09
2001-11-27
McDermott, Corrine (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Tissue
C623S011110
Reexamination Certificate
active
06322593
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 methods 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, and others.
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 (NH
2
), 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 into a host recipient, 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 bifunctional and polyfunctional 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.
Molecules having two or more reactive aldehyde groups, also referred to herein as polyfunctional aldehydes, represent the most commonly used class of agents for cross-linking biological tissues. The most widely used of these polyfunctional aldehydes is the five carbon molecule, glutaraldehyde, which has an aldehyde at each end of a linear aliphatic chain. The aldehyde groups of glutaraldehyde and other like molecules can react under physiological conditions with the primary amine groups of collagen molecules to produce the desired cross-linked tissue.
Despite its widespread use, there are a number of drawbacks associated with tissue cross-linking with polyfunctional aldehydes. For example, under typical storage conditions, these compounds are generally self-reactive and will rapidly reach an equilibrium in which numerous polymeric and other species are present (see, for example, Khor (1997) and references cited therein). As a result, a pure solution of a monomeric polyfunctional aldehyde will become highly heterogeneous over time. Indeed, it is these heterogeneous solutions that have been conventionally used in the art for cross-linking biological tissues. Unfortunately, the properties of tissues cross-linked with these solutions may suffer as a result of this heterogeneity, as further described below.
An important issue when using polyfunctional aldehydes for treating biological tissues relates to the toxicity of the resulting cross-linked material. This toxicity is not completely understood, but may result from more than one mechanism. For example, the polymeric products of glutaraldehyde that are present in a heterogeneous glutaraldehyde solution can depolymize in vivo, causing the release of toxic monomeric glutaraldehyde into the recipient of the bioprosthesis. Such leaching of glutaraldehyde can prevent the cellular growth on the bioprosthesis following implantation that is necessary for long term biocompatibility. In addition, because of the presence of polymeric species of glutaraldehyde, there is an undesirable abundance of free aldehyde groups present within the cross-linked tissue. These free, unreacted aldehyde groups are also believed to contribute to the toxicity of aldehyde cross-linked tissues, for example, by reacting with cellular proteins present on the endothelial cells that must proliferate on and around the tissue after implantation.
Another significant drawback associated with polyfunctional aldehyde cross-linking is the propensity of the treated tissues to undergo calcification. For instance, 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).
Thus, it is a significant disadvantage that free aldehyde groups are present in tissue that has been cross-linked with heterogeneous polyfunctional aldehyde solutions. 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 greatly reduces the toxicity and increases the biocompatibility of tissues that have been cross-linked with polyfunctional aldehydes.
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 aldehyde cross-linking and which provide bioprosthetic devices with desirable mechanical characteristics and a reduced susceptibility to calcification, while minimizing the potential for toxicity. This invention broadly concerns methods for cross-linking biological tissues, and the cross-linked tissue so produced, by employing a chemical approach for neutralizing the free, unreacted aldehyde groups present in an aldehyde cross-linked tissue.
Therefore, according to one aspect of the present invention, the free aldehyde groups present in a cross-linked tissue may be neutralized by reaction with an appropriate neutralizing agent/compound. The neutralizing agent will contain a chemical group or functionality that can be reacted with free aldehyde groups within a cross-linked tissue to produce a product having reduced cellular toxicity compared to the aldehyde groups with which the neutralizing agent is reacted. Consequently, a cross-linked tissue treated in accordance with the method of the present invention will have a reduced cellular toxicity relative to the a cross-linked tissue that is not treated by this method.
Suitable neutralizing agents for use in the invention may include any of a wide variety of inorganic salts that are aldehyde-reactive, i.e., are capable of reacting with the free aldehyde groups in a cross-linked tissue. By contacting a cross-linked tissue with a neutralizing agent according to this method, free aldehyde groups present in the cross-linked tissue can be effectively neutralized/stabilized, thereby providing a tissue with reduced toxicity and improved biocompatibility.
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, it will be appreciated that such a development effort might be complex and time-consuming, but would nevertheless be a routine undertaking for those of ordinary skill in the art having the benefit of this disclosure.
A method is provided
Moore Mark A.
Pathak Chandrashekhar P.
Philips, Jr. Richard E.
Barrett Thomas
Loo Blossom F.
Lyren Philip S.
McDermott Corrine
Scott Timothy L.
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