Anticalcification treatments for fixed biomaterials

Details Anticalcification treatments for fixed biomaterials Anticalcification treatments for fixed biomaterials

1999-12-13

2002-11-12

Witz, Jean C. (Department: 1651)

Drug, bio-affecting and body treating compositions

Extract, body fluid, or cellular material of undetermined...

C424S569000

Reexamination Certificate

active

06479079

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, the present invention concerns methods for processing biological materials for use as bioprosthetic implantable 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 consist 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), carboxylic acid (COOH) and hydroxyl (OH) groups, in addition to the amide bonds of the polymer backbone, all of which represent sites for potential chemical reaction on these molecules.
Because collagenous tissues degrade rapidly upon implantation into a host recipient, it is necessary to stabilize the tissue if it is to be used for clinical applications. Chemical stabilization by tissue cross-linking, also known as tissue fixation, has been achieved using a variety of compounds. Most typically, chemical fixation has employed polyfunctional molecules having two or more 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. The most widely used of these polyfunctional molecules 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 react under physiological conditions with the primary amine groups of collagen molecules to cross-link the material. Glutaraldehyde cross-linked tissue produced in this way exhibits increased resistance to enzymatic degradation, reduced immunogenicity, and increased stability.
Despite its widespread use, there are certain disadvantages associated with tissue cross-linking with polyfunctional aldehydes and other chemical cross-linking agents. For example, upon implantation, aldehyde fixed tissue is susceptible to the formation of degenerative calcific deposits. Pathologic calcification, e.g., the undesirable deposition of calcium phosphate mineral salts in an implanted tissue, may represent the predominant cause of failure of glutaraldehyde-fixed bioprosthetic devices (Golomb et al., 1987; Levy et al., 1986; Thubrikar et al., 1983; Girardot et al., 1995). The mechanism for pathological calcification of implanted tissue is not fully understood, but may be due to host factors, implant factors, and/or extraneous factors, such as mechanical stress. Additionally, there is some evidence to suggest that deposits of calcium may be related to devitalized cells, and, in particular, to cell membranes in which the calcium pumps (Ca+2-Mg+2 ATPase) responsible for maintaining low intracellular calcium levels are no longer functioning or are malfunctioning.
Detergent pretreatment with non-covalently linked detergents, such as sodium dodecyl sulfate (SDS), or covalently bound detergents, such as amino oleic acid, have been reported to reduce calcification of materials exposed to circulating blood (Gott et al., 1992). However, detergents can adversely affect tissue structure and/or properties, resulting in a diminution of the collagen denaturation temperature, or shrink temperature, which is an important measure of material strength, durability, and integrity. Moreover, use of detergents can result in local toxicity.
In another approach, U.S. Pat. No. 5,746,775 describes the treatment of glutaraldehyde pretreated tissue with lower alcohols (i.e., C1-C3 alcohols), in which the lower alcohol is present at greater than 50% by volume in an alcohol treatment solution. The method is reported to be useful in preparing tissue for implantation into a living being.
Despite previous attempts at providing biomaterials having resistance to calcification, there remains a need for. alternative anticalcification approaches with improved efficacy and ease of use. There is, thus, a need for an effective method of imparting long-term anticalcification properties to bioprosthetic materials, e.g., tissues, that is not accompanied by deleterious effects and that incorporate anticalcification agents and/or treatments into existing protocols for the preparation of clinical-grade biomaterials. The present invention is directed to overcoming or at least reducing the effects of one or more of the problems set forth above.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a method for treating a biomaterial comprising contacting a biomaterial, such as a cross-linked animal tissue, with an anticalcification treatment solution. The anticalcification treatment solutions of this aspect of the invention include solutions comprised higher alcohols or polyols and polar aprotic organic solvents. The anticalcification treatment solutions are contacted with the biomaterial under conditions effective to reduce pathologic calcification of the biomaterial following implantation into a mammalian host. As illustrated herein, this reduction in calcification can be monitored, for example, by evaluating the calcium content of an implanted biomaterial treated with an anticalcification treatment solution of the invention compared with an implanted biomaterial not so treated. Preferably, this reduction in calcification will be greater than 50%, more preferably greater than 75%, and most preferably greater than 90%, compared with an implanted, untreated biomaterial.
The higher alcohol or polyol used in formulating the anticalcification treatment solution may be a linear or branched C4-C36 alcohol or polyol. In certain preferred embodiments of the invention, the higher alcohol or polyol will be selected from a C6-C18 alcohol or polyol, preferably from a C7-C9 alcohol or polyol. Typically, the higher alcohol or polyol comprises less than about 50% by volume of said anticalcification treatment solution. In some instances, however, it will be desired to use an anticalcification treatment solution wherein the higher alcohol or polyol comprises less than about 25% by volume of said anticalcification treatment solution, or even less than about 10% by volume of said anticalcification treatment solution. The anticalcification treatment solution of the present invention may further comprise at least one organic solvent selected from, for example, C1-C3 alcohols. Moreover, the anticalcification treatment solution can also comprise water or an aqueous solvent.
Polar aprotic organic solvents useful in formulating the anticalcification treatment solutions of the present invention will preferably have dielectric constants greater than about 20, more preferably greater than about 30, and they will possess some degree of water solubility. Polar aprotic organic solvents useful in this aspect of the invention include, for example, N-alkyl pyrolidinones and N-alkyl amides, in which the alkyl group or groups comprise branched or linear alkyl chains having from about 1 to 10 carbon atoms. Illustrative solvents of this class include N-methyl pyrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropionamide, and th

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