US4378224A
Expired / Lapsed
US
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Coating for bioprosthetic device and method of making same
Assignee: Dow Silicones Corp
•
Filing: 1980-09-19
•
Granted: 1983-03-29
•
Expires: 2000-09-19
Abstract
Abstract A coating and integral treatment for improving the biophysical stability of bioprosthetic devices after implantation, particularly with respect to calcification, and, specifically, a method for treating animal tissues, such as heart valves, to provide improved biophysical stability in allograft and heterograft transplantations. The increased stability results, in-part, from the creation of a three-dimensional matrix of a primary structural component of the prosthetic device and covalently attached calcification inhibitors. Other materials, some having additional stabilizing effects, may be utilized to form additional bridges or fill the interstitial gaps in the matrix. After implantation, the resultant modified device exhibits minimal surface for intramatrix growth of calcium phosphate crystals, and additionally, may inhibit platelet aggregation, enzymatic degradation and host rejection, while minimizing the risk of mechanical failure, in the host organism.
Inventors
- 👤 Marcel E. Nimni
- 👤 David T. Cheung
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-22 22:59
CPC Classifications
A; A61; A61L; A61L27/00; A61L27/36; A61L27/3683; A61L27/3687; A61L2/00; A61L2/16; A61L2/18; A61L27/14; A61L27/22; A61L27/24; A61L33/00; A61L33/0005; A61L33/0011; A61F; A61F2310/00; A61F2310/00005; A61F2310/00365; A61L2400/00; A61L2400/02
Claims Analysis
Total Claims: 79
Claim 1
Independent Claim
110 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a calcification inhibitor; covalently binding the calcification inhibitor to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 2
Dependent Claim
110 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a calcification inhibitor; covalently binding the calcification inhibitor to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 3
Dependent Claim
12 words
The process of claim 1 wherein the calcification inhibitor is a polyanion.
Claim 4
Dependent Claim
13 words
The process of claim 1 wherein the calcification inhibitor is an anionic polysaccharide.
Claim 5
Dependent Claim
13 words
The process of claim 1 wherein the calcification inhibitor is a sulphated polysaccharide.
Claim 6
Dependent Claim
22 words
The process of claim 1 wherein the calcification inhibitor is selected from the group consisting of chondroitin-4-sulfate, chondroitin-6-sulfate, hyaluronate and mixtures thereof.
Claim 7
Dependent Claim
18 words
The process of claim 1 wherein the intiation of cross-links is made by reacting the tissue with glutaraldehyde.
Claim 8
Dependent Claim
24 words
The process of claim 1 wherein the covalent binding of the calcification inhibitor is made by reacting the tissue with a water soluble carbodiimide.
Claim 9
Dependent Claim
11 words
The process of claim 7 wherein the carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl.
Claim 10
Dependent Claim
19 words
The process of claim 1 wherein the matrix is sterilized in a solution containing formaldehyde, alcohol or mixtures thereof.
Claim 11
Dependent Claim
46 words
The process of claim 1 wherein the aqueous solution used during the tissue soaking also contains a bridging agent that will covalently bind to the tissue during the covalent binding step; thereby providing additional sites for peptide bond formation and additional structural stability to the matrix.
Claim 12
Dependent Claim
12 words
The process of claim 10 wherein the bridging agent is a diamine.
Claim 13
Dependent Claim
12 words
The process of claim 11 wherein the diamine is an aliphatic diamine.
Claim 14
Dependent Claim
17 words
The process of claim 1 further including: soaking the tissue in the presence of a bridging agent.
Claim 15
Dependent Claim
24 words
The process of claim 13 wherein the bridging agent is covalently bound to the modified tissue to provide additional sites for covalent bond formation.
Claim 16
Dependent Claim
12 words
The process of claim 13 wherein the bridging agent is a diamine.
Claim 17
Dependent Claim
12 words
The process of claim 15 wherein the diamine is an aliphatic diamine.
Claim 18
Dependent Claim
15 words
The process of claim 1 further including: covalently bonding an antithrombogenic agent to the matrix.
Claim 19
Dependent Claim
11 words
The process of claim 17 wherein the antithrombogenic agent is heparin.
Claim 20
Dependent Claim
23 words
The process of claim 1 further including: soaking the tissue in the presence of materials that fill the interstitial gaps of the matrix.
Claim 21
Dependent Claim
21 words
The process of claim 19 wherein the gap filling material is covalently bound to the matrix during subsequent covalent bonding steps.
Claim 22
Dependent Claim
13 words
The process of claim 19 wherein the gap filling material is a protein.
Claim 23
Dependent Claim
12 words
The process of claim 21 wherein the protein is a globular protein.
Claim 24
Dependent Claim
13 words
The process of claim 19 wherein the gap filling material is a polyelectrolyte.
Claim 25
Dependent Claim
21 words
The process of claim 23 wherein the polyelectrolyte is polylysine, polyglutamic acid, copolymers of polylysine and polyglutamic acid or mixtures thereof.
Claim 26
Dependent Claim
15 words
The process of claim 1 further including: forming additional covalent cross-links in the three-dimensional matrix.
Claim 27
Dependent Claim
21 words
The process of claim 25 wherein the forming of the additional cross-links is made by reacting the three-dimensional matrix with glutaraldehyde.
Claim 28
Dependent Claim
13 words
The process of claim 1 wherein the tissue is an animal connective tissue.
Claim 29
Dependent Claim
26 words
The process of claim 27 wherein the animal connective tissue is a mammalian heart valve, blood vessel, percardium, dura mater, ligament, tendon or other collagen-rich tissue.
Claim 30
Dependent Claim
33 words
The process of claim 1 wherein the step of initiating covalent cross-links in the protein structure is performed before the step of soaking the tissue in an aqueous solution of a calcification inhibitor.
Claim 31
Dependent Claim
16 words
A bioprosthetic device made according to the process of any one of claims 1-5 or 6-28.
Claim 32
Dependent Claim
48 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising: a three dimensional, cross-linked matrix of an exogenous calcification inhibitor covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 33
Dependent Claim
48 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising: a three dimensional, cross-linked matrix of an exogenous calcification inhibitor covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 34
Dependent Claim
12 words
The coating of claim 31 wherein the calcification inhibitor is a polyanion.
Claim 35
Dependent Claim
13 words
The coating of claim 31 wherein the calcification inhibitor is a sulphated polysaccharide.
Claim 36
Dependent Claim
12 words
The coating of claim 38 wherein the calcification inhibitor is a protein-polysaccharide.
Claim 37
Dependent Claim
15 words
The coating of claim 34 wherein the protein-polysaccharide is chondroitin-4-sulfate, chondroitin-6-sulfate, hyaluronate or mixtures thereof.
Claim 38
Dependent Claim
16 words
The coating of claim 31 wherein the matrix also contains an exogenous, covalently bond, antithrombogenic agent.
Claim 39
Dependent Claim
11 words
The coating of claim 36 wherein the antithrombogenic agent is heparin.
Claim 40
Dependent Claim
35 words
The coating of claim 31 wherein the matrix also contains a covalently bound bridging agent to provide additional binding sites for the exogenous reagents and to provide structural integrity to the matrix through additional cross-links.
Claim 41
Dependent Claim
12 words
The coating of claim 38 wherein the bridging agent is a diamine.
Claim 42
Dependent Claim
12 words
The coating of claim 39 wherein the diamine is an aliphatic diamine.
Claim 43
Dependent Claim
22 words
The coating of claim 31 wherein a material is covalently bound to the matrix that fills the interstitial spaces of the matrix.
Claim 44
Dependent Claim
13 words
The coating of claim 41 wherein the gap filling material is a protein.
Claim 45
Dependent Claim
12 words
The coating of claim 42 wherein the protein is a globular protein.
Claim 46
Dependent Claim
13 words
The coating of claim 41 wherein the gap filling material is a polyelectrolyte.
Claim 47
Dependent Claim
21 words
The coating of claim 44 wherein the polyelectrolyte is polylysine, polyglutamic acid, copolymers of polysine and polyglutamic acid or mixtures thereof.
Claim 48
Dependent Claim
95 words
A process for treating heart valves prior to implantation into a human comprising the steps of: harvesting a fresh heart valve from a donor organism; initiating cross-links in the valve by treating with glutaraldehyde; incubating the valve in a solution containing a diamine; reacting the valve with a water soluble carbodiimide; soaking the valve in a solution containing a sulphated polysaccharide; reacting the valve with a water soluble carbodiimide in the presence of a diamine; soaking the valve in a solution containing heparin; reacting the valve with glutaraldehyde; storing the valve in a sterilizing solution.
Claim 49
Dependent Claim
95 words
A process for treating heart valves prior to implantation into a human comprising the steps of: harvesting a fresh heart valve from a donor organism; initiating cross-links in the valve by treating with glutaraldehyde; incubating the valve in a solution containing a diamine; reacting the valve with a water soluble carbodiimide; soaking the valve in a solution containing a sulphated polysaccharide; reacting the valve with a water soluble carbodiimide in the presence of a diamine; soaking the valve in a solution containing heparin; reacting the valve with glutaraldehyde; storing the valve in a sterilizing solution.
Claim 50
Dependent Claim
45 words
A prosthesic heart valve suitable for implantation into a human comprising: a chondroitin sulfate, hexanediamine and heparin covalently attached to a mammalian heart valve through carbodiimide and glutaraldehyde induced bonds, wherein the device is substantially cross-linked and possesses viscoelastic properties similar to natural heart valves.
Claim 51
Dependent Claim
45 words
A prosthesic heart valve suitable for implantation into a human comprising: a chondroitin sulfate, hexanediamine and heparin covalently attached to a mammalian heart valve through carbodiimide and glutaraldehyde induced bonds, wherein the device is substantially cross-linked and possesses viscoelastic properties similar to natural heart valves.
Claim 52
Dependent Claim
108 words
A process for improving the biophysical stability of bioprotheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a diphosphonate. covalently binding the diphosphonate to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 53
Dependent Claim
108 words
A process for improving the biophysical stability of bioprotheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a diphosphonate. covalently binding the diphosphonate to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 54
Dependent Claim
13 words
The process of claim 48 wherein the diphosphonate is 3-amino-1-hydroxypropane 1, diphosphonic acid.
Claim 55
Dependent Claim
108 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a dye; covalently binding the dye to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 56
Dependent Claim
108 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a dye; covalently binding the dye to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 57
Dependent Claim
17 words
The process of claim 50 wherein the dye is alizarin red S, methylene blue or mixtures thereof.
Claim 58
Dependent Claim
108 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a phosphoprotein; covalently binding the phosphoprotein to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 59
Dependent Claim
108 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a phosphoprotein; covalently binding the phosphoprotein to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 60
Dependent Claim
10 words
The process of claim 52 wherein the phosphoprotein is phosvitin.
Claim 61
Dependent Claim
110 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a chelating agent; covalently binding the chelating agent to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 62
Dependent Claim
110 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of a chelating agent; covalently binding the chelating agent to the tissue thereby forming a three-dimensional matrix; and sterilizing the matrix; wherein the modified tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 63
Dependent Claim
13 words
The process of claim 54 wherein the chelating agent is EDTA or EGTA.
Claim 64
Dependent Claim
47 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising; a three dimensional, cross-linked matrix of an exogenuous diphosphonate covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 65
Dependent Claim
47 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising; a three dimensional, cross-linked matrix of an exogenuous diphosphonate covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 66
Dependent Claim
13 words
The coating of claim 56 wherein the diphosphonate is 3-amino-1-hydroxypropane 1, 1-disphosphonic acid.
Claim 67
Dependent Claim
47 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantation, said coating comprising; a three dimensional, cross-linked matrix of an exogenuous dye covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 68
Dependent Claim
47 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantation, said coating comprising; a three dimensional, cross-linked matrix of an exogenuous dye covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 69
Dependent Claim
17 words
The coating of claim 58 wherein the dye is alizarin red S, methylene blue or mixtures thereof.
Claim 70
Dependent Claim
47 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising; a three dimensional, cross-linked matrix of an exogenuous phosphoprotein covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 71
Dependent Claim
47 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising; a three dimensional, cross-linked matrix of an exogenuous phosphoprotein covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 72
Dependent Claim
10 words
The coating of claim 60 wherein the phosphoprotein is phosvitin.
Claim 73
Dependent Claim
48 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising: a three dimensional, cross-linked matrix of an exogenuous chelating agent covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 74
Dependent Claim
48 words
A coating for a prosthetic device that provides increased stability for allograft or heterograft implantations, said coating comprising: a three dimensional, cross-linked matrix of an exogenuous chelating agent covalently bound to accessible regions of the device wherein the coating is substantially non-antigenic and has minimal calcification initiation sites.
Claim 75
Dependent Claim
13 words
The coating of claim 62 wherein the chelating agent is EDTA or EGTA.
Claim 76
Dependent Claim
112 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of chondroitin sulfate; and soaking the tissue in an aqueous solution of a water-soluble carbodiimide; wherein chondroitin sulfate is covalently bonded to the tissue and the tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 77
Dependent Claim
112 words
A process for improving the biophysical stability of bioprostheses for heterograft or allograft implantation, which comprises: harvesting tissue from an organism; initiating covalent cross-links in the protein structure of the tissue to protect the tissue from excessive swelling or other losses of structural integrity; soaking the tissue in an aqueous solution of chondroitin sulfate; and soaking the tissue in an aqueous solution of a water-soluble carbodiimide; wherein chondroitin sulfate is covalently bonded to the tissue and the tissue produced is substantially water insoluble; and, after implantation in a host organism, the matrix is less likely to elicit an antigenic response or to be subject to calcification than natural tissue or tanned tissue.
Claim 78
Dependent Claim
21 words
The process of claim 64 wherein the tissue is soaked in a water-soluble carbodiimide before it is soaked in chondroitin sulfate.
Claim 79
Dependent Claim
12 words
The process of claim 64 wherein the water-soluble carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl.
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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) | 1986-03-28 | 1986-09-27 | 1987-03-29 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-03-28 | 1990-09-27 | 1991-03-29 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-03-28 | 1994-09-27 | 1995-03-29 | $7700.00 | Window Closed / Lapsed |