Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or...
Reexamination Certificate
2000-12-21
2003-07-22
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
C435S040520, C435S029000, C435S040500, C424S423000
Reexamination Certificate
active
06596471
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of preparing tissue for prosthetic use. More particularly, it concerns methods of crosslinking tissues with diunsaturated organic compounds.
2. Description of Related Art
Bioprostheses are devices derived from processed biological tissues to be used for implantation into a mammalian (e.g., human) host. Implantation of bioprostheses is a rapidly growing therapeutic field as a result of improvements in surgical procedures and immunosuppressive treatments, as well as increased knowledge of the graft-host interaction.
Several applications for tissue transplantation are known. For example, heart malfunction due to heart valve disorders can often be treated by surgically implanting a prosthetic valve. Treated tissue derived from porcine aortic valves or bovine pericardium is often used for this application. Other applications include tendons, ligaments, skin patches, pericardial patches, aortic patches, and tympanic membranes, among others. In the majority of known applications, the primary component of a bioprosthesis is collagen.
Several problems associated with tissue transplantation include inflammation, degradation, calcification, and immune rejection. Attempts have been made to overcome these problems by tissue cross-linking (also referred to as “tissue fixation”). Cross-linking involves the use of bi- or multifunctional molecules having reactive groups capable of forming stable intra- and intermolecular bonds with reactive amino acid side groups present in the bioprosthesis, often on collagen.
Glutaraldehyde is a bifunctional molecule capable of reacting under physiological conditions with the primary amine groups of collagen. Although it is the most commonly used chemical fixative for biological tissues, glutaraldehyde has a number of drawbacks associated with its use in cross-linking tissues for bioprosthetic use. For example, the long term durability of glutaraldehyde-fixed bioprostheses is not well established, particularly in view of a number of reports of mechanical failures of the tissue at points of high mechanical stress (Broom, 1977; Magilligan, 1988). Another drawback to glutaraldehyde fixation of bioprostheses is depolymerization of the cross-links in vivo, resulting in release of toxic glutaraldehyde into the host (Moczar et al., 1994; Wiebe et al., 1988; Gendler et al., 1984).
Further shortcomings of glutaraldehyde-cross-linking are related to the chemistry of the molecule. Glutaraldehyde forms a relatively unstable Schiff-base bond with collagen. In water, such as an aqueous solution of glutaraldehyde prior to performing a cross-linking treatment, glutaraldehyde can polymerize to form a water-soluble polyether polymer.
In addition, glutaraldehyde-cross-linked bioprostheses have an undesirable propensity to calcify after implantation. This calcification is widely held to be the predominant cause of failure of glutaraldehyde-cross-linked devices (Golomb et al., 1987; Levy et al., 1986; Thubrikar et al., 1983; Girardot et al., 1995). Increased calcium uptake by a bioprosthesis typically leads to an accumulation of calcium phosphate, which in turn mineralizes into calcium hydroxyapatite. The calcification process is not well understood, but appears to depend on factors such as calcium metabolism diseases, age, diet, degeneration of tissue components such as collagen, and turbulence. Calcification of bioprostheses has been associated with degenerative changes in glutaraldehyde-treated collagen fibers.
A number of approaches have been investigated for reducing calcification of glutaraldehyde-fixed bioprostheses. For example, glutaraldehyde-fixed bioprosthetic heart valves have been treated with surfactants to reduce calcification after implantation (U.S. Pat. No. 5,215,541). In another approach, alpha-aminooleic acid treatment of glutaraldehyde-fixed tissue has been reported as an effective biocompatible, non-thrombogenic approach for minimizing calcification of bioprostheses (Girardot et al., 1991; Gott et al., 1992; Girardot et al., 1993; Hall et al., 1993; Myers et al., 1993; Girardot et al., 1994). The broad applicability of this approach in the production of bioprostheses, however, may be limited by the inability to achieve good tissue penetration by alpha-aminooleic acid into glutaraldehyde-fixed tissue (Girardot, 1994).
With respect to the biocompatibility of prosthetic devices, implantation of bioprostheses in living tissues typically initiates a series of physiological events which can activate host defense mechanisms such as coagulation, platelet adhesion and aggregation, white cell adhesion, and complement activation, among others. In attempts to improve the biocompatibility or hemocompatibility of articles adapted for use in contact with blood or blood products, aliphatic extensions have been added to the surface of bioprostheses in order to provide hydrophobic binding sites for albumin. The binding of albumin to a bioprosthesis has been reported to provide a low activation of coagulation, low complement activation, and reduced platelet and white cell adhesion, thereby providing improved hemocompatibility (U.S. Pat. Nos. 5,098,960 and 5,263,992; Munro et al., 1981; Eberhart, 1989).
Some cross-linking agents have been investigated as alternatives to glutaraldehyde. These include polyepoxides, diisocyanates, di- and polycarboxylic acids, and photooxidation using organic dyes (see Khor, 1997, for review).
Therefore, a need exists within the field of bioprosthetics for simple, cost-effective methods for cross-linking biological tissues which provide bioprostheses with more desirable mechanical characteristics, reduced susceptibility to calcification, or enhanced biocompatibility relative to bioprostheses produced from glutaraldehyde-cross-linked tissue.
It is well known that a thiol may undergo addition to an unsaturated organic compound to form a thioether.
SUMMARY OF THE INVENTION
In one embodiment, the present invention relates to a method of cross-linking a tissue, comprising treating the tissue under effective cross-linking conditions with a diunsaturated organic compound. Preferably, the diunsaturated organic compound is a solute in a fluid comprising a solvent.
In another embodiment, the present invention relates to a cross-linked biological tissue produced by treating the tissue under effective cross-linking conditions with a diunsaturated organic compound. Preferably, the diunsaturated organic compound is a solute in a fluid comprising a solvent.
The method allows cross-linking of tissues to an extent comparable to that seen for glutaraldehyde cross-linking.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
In one embodiment, the present invention relates to a method of cross-linking a tissue, comprising treating the tissue under effective cross-linking conditions with a diunsaturated organic compound.
The tissue to be treated can be any tissue from which it is desired to fashion a bioprosthesis. A variety of tissues can be used, such as tendons, ligaments, heart valves, tissues usable to construct heart valves such as dura mater and pericardium, skin patches, pericardial patches, aortic patches, and tympanic membranes, among others. The tissue to be treated can be derived from any of a variety of animal species, such as humans, cattle, pigs, horses, sheep, rabbits, rats, ostriches, or kangaroos, among others.
By “diunsaturated organic compound” is meant any compound comprising structure I:
wherein R, R′, and R″ are each independently an organic moiety having at least 1 carbon atom. Exemplary organic moieties include alkanes, substituted alkanes, alkenes, substituted alkenes, or oligomers of any of the foregoing, among others. The organic moieties can be linear, branched, cyclic, or polycyclic, among others, and R can independently form a cyclic or polycyclic moiety with R′, R″, or both. If the organic moiety is substituted, exemplary substituents include hydroxy, carboxy, and keto groups; maleimide groups; and halides, among oth
Moore Mark A.
Pathak Chandrashekhar P.
Phillips, Jr. Richard E.
Afremova Vera
Carbomedics Inc.
Saucier Sandra E.
Scott Timothy L.
Williams Morgan & Amerson P.C.
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