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US5935168A
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Glutaraldehyde-fixed bioprostheses
Assignee: Edwards Lifesciences Corp
•
Filing: 1998-03-20
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Granted: 1999-08-10
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Expires: 2018-03-20
Abstract
Abstract Methods for treating glutaraldehyde-fixed collagenous tissues to mitigate there propensity for subsequent calcification and to improve durability. Collagenous tissues which have been harvested and cross-linked by glutaraldehyde are exposed to a carboxyl activating agent to convert the free carboxyl (COOH) groups of the collagen molecules to activated carboxyl moieties (e.g., o-acylisourea). Thereafter, the collagenous tissue is exposed to a compound capable of reacting with the activated carboxyl moieties (e.g., o-acylisourea) to form non-carboxyl side groups. Monofunctional and multifunctional amines are examples of compounds which may be utilized to react with the activated carboxyl moieties to form such non-carboxyl side groups. Thereafter, the collagenous tissue is again exposed to glutaraldehyde. If the non-carboxyl side groups have functional amino groups (NH 2 ), such additional exposure to glutaraldehyde will result in additional glutaraldehyde cross-linking of the collagen molecules and resultant improvement of durability.
Inventors
- 👤 Jun Yang
- 👤 Shih-Hwa Shen
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-06 09:38
CPC Classifications
A; A61; A61L; A61L27/00; A61L27/36; A61L27/3683; A61L27/3687; A61L27/3604; A61L2400/00; A61L2400/02; Y; Y10; Y10S; Y10S623/00; Y10S623/915; Y10S623/916; Y10S623/918; Y10S623/92; Y10S623/921
Claims Analysis
Total Claims: 21
Claim 1
Independent Claim
134 words
A glutaraldehyde-fixed bioprosthesis manufactured by the method comprising the steps of: a) providing a collagen-containing tissue; b) contacting said tissue with glutaraldehyde to form a glutaraldehyde cross-linked tissue; c) rinsing the tissue to remove residual glutaraldehyde such that the tissue is activated carboxyl moieties on the tissue free of exogenous compounds that would deter the subsequent formation of activated carboxyl moieties on the tissue: d) contacting the glutaraldehyde cross-linked tissue with a carboxyl activator compound capable of converting at least some of the carboxyl groups present on collagen molecules of the tissue to activated carboxyl moieties capable of reacting with amino groups; e)contacting the tissue with a compound that will react with the activated carboxyl moieties to form noncarboxyl side groups on the collagen molecules; and, thereafter; f) again contacting said tissue with glutaraldehyde.
Claim 2
Dependent Claim
134 words
A glutaraldehyde-fixed bioprosthesis manufactured by the method comprising the steps of: a) providing a collagen-containing tissue; b) contacting said tissue with glutaraldehyde to form a glutaraldehyde cross-linked tissue; c) rinsing the tissue to remove residual glutaraldehyde such that the tissue is activated carboxyl moieties on the tissue free of exogenous compounds that would deter the subsequent formation of activated carboxyl moieties on the tissue: d) contacting the glutaraldehyde cross-linked tissue with a carboxyl activator compound capable of converting at least some of the carboxyl groups present on collagen molecules of the tissue to activated carboxyl moieties capable of reacting with amino groups; e)contacting the tissue with a compound that will react with the activated carboxyl moieties to form noncarboxyl side groups on the collagen molecules; and, thereafter; f) again contacting said tissue with glutaraldehyde.
Claim 3
Dependent Claim
41 words
The bioprosthesis of claim 14 wherein the collagenous tissue provided in step a is selected from the group consisting of: heart valves; segments of blood vessel; segments of aortic root having an aortic valve positioned therewithin; pericardium; ligaments; tendons; and, skin.
Claim 4
Dependent Claim
12 words
The bioprosthesis of claim 1 wherein the tissue is of porcine origin.
Claim 5
Dependent Claim
12 words
The bioprosthesis of claim 1 wherein the tissue is bovine in origin.
Claim 6
Dependent Claim
19 words
The bioprosthesis of claim 1 wherein the compound contacted with the tissue in step e is a carboxyl-free monoamine.
Claim 7
Dependent Claim
11 words
The bioprosthesis of claim 5 wherein the carboxyl-free monoamine is aliphatic.
Claim 8
Dependent Claim
13 words
The bioprosthesis of claim 6 wherein the carboxyl-free aliphatic monoamine is propyl amine.
Claim 9
Dependent Claim
19 words
The bioprosthesis of claim 1 wherein the compound contacted with the tissue in step e is a carboxyl-free diamine.
Claim 10
Dependent Claim
12 words
The bioprosthesis of claim 8 wherein the carboxyl-free diamine compound is aliphatic.
Claim 11
Dependent Claim
14 words
The bioprosthesis of claim 9 wherein the carboxyl-free, aliphatic diamine compound is ethylene diamine.
Claim 12
Dependent Claim
84 words
The bioprosthesis of claim 10, wherein the compound used in step e contains at least two functional amino groups such that at least one functional amino group will remain on each amide-bound side group formed on the collagen molecules in step e, and wherein: the subsequent contacting of the tissue with glutaraldehyde in step f of the preparation method results in the formation of additional glutaraldehyde cross-linkages between the free amino groups on the amide-bound side groups of the collagen molecules within the tissue.
Claim 13
Dependent Claim
21 words
The bioprosthesis of claim 1 wherein the carboxyl activator compound used in step c of the preparation method is a carbodiimide.
Claim 14
Dependent Claim
23 words
The bioprosthesis of claim 12 wherein said carbodiimide is selected from the group consisting of: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC); dihexylcarbodiimide (DCC); 1-ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide iodide (EAC).
Claim 15
Dependent Claim
99 words
A glutaraldehyde-fixed collagenous bioprosthesis prepared by a method comprising the steps of: a) providing a collagenous bioprosthesis which has been cross-linked with glutaraldehyde and is free of exogenous compounds that would deter the subsequent formation of activated carboxyl moieties on the bioprosthesis; b) reacting at least some of the carboxyl groups present on collagen molecules of the bioprosthesis with a carboxyl activating agent to convert at least some of the carboxyl groups into activated carboxyl moieties; and, c) reacting a carboxyl-free compound with said activated carboxyl moieties, thereby forming carboxyl-free side groups on the collagen molecules of the bioprosthesis.
Claim 16
Dependent Claim
99 words
A glutaraldehyde-fixed collagenous bioprosthesis prepared by a method comprising the steps of: a) providing a collagenous bioprosthesis which has been cross-linked with glutaraldehyde and is free of exogenous compounds that would deter the subsequent formation of activated carboxyl moieties on the bioprosthesis; b) reacting at least some of the carboxyl groups present on collagen molecules of the bioprosthesis with a carboxyl activating agent to convert at least some of the carboxyl groups into activated carboxyl moieties; and, c) reacting a carboxyl-free compound with said activated carboxyl moieties, thereby forming carboxyl-free side groups on the collagen molecules of the bioprosthesis.
Claim 17
Dependent Claim
13 words
The bioprosthesis of claim 14 wherein the carboxyl activating compound is a carbodiimide.
Claim 18
Dependent Claim
24 words
The bioprosthesis of claim 15 wherein the carbodiimide is selected from the group consisting of: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC); dihexylcarbodiimide (DCC); and, 1-ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide iodide (EAC).
Claim 19
Dependent Claim
33 words
The bioprosthesis of claim 14 wherein the carboxyl-free compound is selected from the group consisting of: amines; monofunctional amines; multifunctional amines; aliphatic monofunctional amines; aliphatic multifunctional amines; aliphatic diamines; propyl amine; ethylene diamine.
Claim 20
Dependent Claim
25 words
The bioprosthesis of claim 14 wherein the method by which the bioprosthesis is prepared further comprises the step of: d) contacting the bioprosthesis with glutaraldehyde.
Claim 21
Dependent Claim
93 words
The bioprosthesis of claim 18 wherein the carboxyl-free compound used in step c is an amine which has at least two functional amino groups such that one functional amino group reacts with the activated carboxyl moiety to form an amide linkage therewith and at least one other functional amino group will remain available for subsequent reaction with glutaraldehyde, and wherein the further exposure to glutaraldehyde in step d results in the formation of additional glutaraldehyde cross-linkages between the functional amino groups which remain in the carboxyl free side groups of the collagen molecules.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2002-08-09 | 2003-02-08 | 2003-08-10 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2006-08-09 | 2007-02-08 | 2007-08-10 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2010-08-09 | 2011-02-08 | 2011-08-10 | $7700.00 | Window Closed / Lapsed |