US3673612A
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Non-thrombogenic materials and methods for their preparation
Assignee: Massachusetts Institute of Technology
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Filing: 1970-08-28
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Granted: 1972-07-04
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Expires: 1990-08-28
Abstract
Abstract Non-thrombogenic materials prepared by reacting a heparin-type anticoagulant, hydroxyl, or combinations of hydroxyl and acetal groups that are part of already synthesized macromolecules having an atomic carbon-to-oxygen ratio in excess of unity, an aldehyde and an acid catalyst. The non-thrombogenic materials can be used for implanted and extracorporeal biomedical devices and prostheses intended to be used in direct contact with blood, including tubes, valves, membrane assemblies for blood dialysis and oxygenation, anesthesia-carrying tubes, etc.
Inventors
- 👤 Edward W Merrill
- 👤 Patrick Seck-Lai Wong
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 21:56
CPC Classifications
A; A61; A61L; A61L33/00; A61L33/0005; A61L33/0011; Y; Y10; Y10T; Y10T428/00; Y10T428/31504; Y10T428/31536
Claims Analysis
Total Claims: 63
Claim 1
Independent Claim
10 words
The composition of claim 1 wherein the anticoagulant is heparin.
Claim 2
Dependent Claim
11 words
The composition of claim 1 wherein the anticoagulant is sodium heparin.
Claim 3
Dependent Claim
10 words
The composition of claim 1 wherein the aldehyde is formaldehyde.
Claim 4
Dependent Claim
10 words
The composition of claim 1 wherein the aldehyde is glutaraldehyde.
Claim 5
Dependent Claim
29 words
The composition of claim 1 wherein the polymer comprises polyvinyl alcohol that has undergone previous reaction with an aldehyde and an acid to render it into a cross-linked state.
Claim 6
Dependent Claim
113 words
A process for making a non-thrombogenic polymer surface or membrane of a shaped blood-contacting biomedical appliance composition which comprises reacting on said shaped appliance polymer surface or membrane in the presence of an acid catalyst an aldehyde, a heparin-type anticoagulant and hydroxyl groups or combinations of hydroxyl and acetal groups, said hydroxyl and acetal groups being constituents of macromolecules and selected from the group consisting of linear water-soluble polymers, three-dimensional network polymers, and solid or rubbery matter owing its coherence to microcrystalline or other secondary valence forces, said hydroxyl and acetal groups being initially in a local milieu containing at equilibrium 50 percent water as measured in equilibrium with pure water or saline.
Claim 7
Dependent Claim
22 words
The process of making a non-thrombogenic composition according to claim 7 wherein the polymer is a hydrogel and the anticoagulant is heparin.
Claim 8
Dependent Claim
23 words
The process of making a non-thrombogenic composition according to claim 7 wherein the polymer is a hydrogel and the anticoagulant is sodium heparin.
Claim 9
Dependent Claim
22 words
The process of making a non-thrombogenic composition accorDing to claim 7 wherein the polymer is a hydrogel and the aldehyde is formaldehyde.
Claim 10
Dependent Claim
22 words
The process of making a non-thrombogenic composition according to claim 7 wherein the polymer is a hydrogel and the aldehyde is glutaraldehyde.
Claim 11
Dependent Claim
19 words
The process of making a non-thrombogenic hydrogel according to claim 7 wherein the hydrogel is prepared from polyvinyl alcohol.
Claim 12
Dependent Claim
24 words
The process of making a non-thrombogenic composition according to claim 7 wherein the polymer is a solid polymer and the anticoagulant is sodium heparin.
Claim 13
Dependent Claim
23 words
The process of making a non-thrombogenic composition according to claim 7 wherein the polymer is a solid polymer and the anticoagulant is heparin.
Claim 14
Dependent Claim
23 words
The process of making a non-thrombogenic composition according to claim 7 wherein the polymer is a solid polymer and the aldehyde is glutaraldehyde.
Claim 15
Dependent Claim
23 words
The process of making a non-thrombogenic composition according to claim 7 wherein the polymer is a solid polymer and the aldehyde is formaldehyde.
Claim 16
Dependent Claim
88 words
The process of making the composition of claim 7 which comprises contacting a polymer membrane or surface of the cross-linked hydrogel forming the base layer with a coating composition comprising an uncross-linked polymer, a heparin type anticoagulant, an aldehyde and an acid catalyst, said acid catalyst being present in sufficient concentrations to establish an acetal-hemiacetal hydroxyl equilibrium on a surface of said base layer and heating said composition to form an outer layer comprising heparin covalently bonded and to covalently bond said outer layer to said base layer.
Claim 17
Dependent Claim
31 words
The process of claim 17 wherein the base layer is dried to a water concentration of less than about 15 wt. % prior to contacting the base layer with said composition.
Claim 18
Dependent Claim
29 words
The process of claim 18 wherein the dried base layer is contacted with an acid to establish an acetal-hemiacetal-hydroxyl equilibrium prior to contacting the base layer with said composition.
Claim 19
Dependent Claim
54 words
The process of claim 17 wherein the base layer contains a reinforcing material and is formed by contacting the reinforcing material with a base composition comprising a polymer an aldehyde and an acid catalyst and heating said base composition to form a crosslinked hydrogel prior to contacting the base layer with said coating composition.
Claim 20
Independent Claim
150 words
The method of making a polymer surface of a shaped blood-contacting biomedical appliance non-thrombogenic comprising the steps of: selecting a water-insoluble polymeric surface thereof that contains in the immediate vicinity of said surface at least 50 wt. % water when in equilibrium with liquid water or dilute saline solutions at temperatures between 0* C. and 50* C., said polymeric substance having hydroxyl groups attached to the principal molecular chains, preparing an aqueous solution of an aldehyde and a heparin type anticoagulant by mixing until homogenous, adding sufficient acid to said aldehyde and anticoagulant solution, either prior to, concomitantly with, or subsequently to bringing said solution of said aldehyde, and anticoagulant into intimate contact with said polymeric surface, heating said polymeric surface in contact with said solution of aldehyde, anticoagulant, and acid for a period of time between 30 minutes and 10 hours and a temperature between 60* and 90* C.
Claim 21
Dependent Claim
21 words
The method of making a non-thrombogenic polymer surface according to claim 21 wherein said anticoagulant is an artificial sulfated anticoagulant polysaccharide.
Claim 22
Dependent Claim
17 words
The method of making a non-thrombogenic polymer surface according to claim 22 wherein said anticoagulant is heparinoid.
Claim 23
Dependent Claim
17 words
The method of making a non-thrombogenic polymer surface according to claim 22 wherein said anticoagulant is heparin.
Claim 24
Dependent Claim
18 words
The method of making a non-thrombogenic polymer surface according to claim 24 wherein said aldehyde is a dialdehyde.
Claim 25
Dependent Claim
17 words
The method of making a non-thrombogenic polymer surface according to claim 25 wherein said dialdehyde is glutarAl-dehyde.
Claim 26
Dependent Claim
18 words
The method of making a non-thrombogenic polymer surface according to claim 26 wherein said acid is sulfuric acid.
Claim 27
Dependent Claim
19 words
The method of making a non-thrombogenic polymer surface according to claim 21 wherein said polymer is cross-linked polyvinyl alcohol-co-formal.
Claim 28
Dependent Claim
100 words
A non-thrombogenic polymeric blood-contacting biomedical device composition shapable in the form of hemodialysis tubing, hemodiafiltration membranes, hollow tube intravenous catheters, vascular prosthesis implants, heart valve and aortic and mitrao heart valve flaps and like devices and prosthesis comprising a heparin-type anticoagulant covalently bonded through an acetal or hemiacetal bridge to a polymer surface or membrane thereof intended to lie in direct contact with blood selected from the group consisting of a hydrogel, cellulose, cellophane and cellulose ester, said bridges being formed from an aldehyde, hydroxyl groups or hydroxyl and acetal groups of said polymer and hydroxyl groups of said anticoagulant.
Claim 29
Dependent Claim
10 words
The composition of claim 29 wherein the anticoagulant is heparin.
Claim 30
Dependent Claim
11 words
The composition of claim 29 wherein the anticoagulant is sodium heparin.
Claim 31
Dependent Claim
10 words
The composition of claim 29 wherein the aldehyde is formaldehyde.
Claim 32
Dependent Claim
10 words
The composition of claim 29 wherein the aldehyde is glutataldehyde.
Claim 33
Dependent Claim
104 words
A process for making a non-thrombogenic polymer surface or membrane of a shaped blood-contacting biomedical appliance composition which comprises reacting on said shaped appliance polymer surface or membrane in the presence of an acid catalyst an aldehyde, a heparin-type anticoagulant and hydroxyl groups or combinations of hydroxyl and acetal groups, said hydroxyl and acetal groups being constituents of macromolecules and selected from the group consisting of linear water-soluble polymers, three-dimensional network polymers, and cellulose, cellophane, and cellulose esters, said hydroxyl and acetal groups being initially in a local milieu containing at equilibrium 50 percent water as measured in equilibrium with pure water or saline.
Claim 34
Independent Claim
159 words
The method of making a polymer surface of a shaped blood-contacting biomedical appliance non-thrombogenic comprising the steps of: selecting a water-insoluble polymeric surface selected from the group consisting of cellulose, cellophane and cellulose esters that contains in the immediate vicinity of said surface at least 50 wt % water when in equilibrium with liquid water or dilute saline solutions at temperatures between 0* and 50* C., said polymeric surface having hydroxyl groups attached to the principal molecular chains, preparing an aqueous solution of an aldehyde and a heparin type anticoagulant by mixing until homogeneous, adding sufficient acid to said aldehyde and anticoagulant solution, either prior to, concomitantly with, or subsequently to bringing said solution of said aldehyde, and anticoagulant into intimate contact with said polymeric surface, heating said polymeric surface in contact with said solution of aldehyde, anticoagulant, and acid for a period of time between 30 min. and 10 hours and a temperature between 60* and 90* C.
Claim 35
Dependent Claim
21 words
The method of making a non-thrombogenic polymer surface according to claim 35 wherein said anticoagulant is an artificial sulfated anticoagulant polysaccharide.
Claim 36
Dependent Claim
18 words
The method of making a non-thrombogenic polymer surface according to claim 36 wherein said anticoagulant is a heparinoid.
Claim 37
Dependent Claim
17 words
The method of making a non-thrombogenic polymer surface according to claim 35 wherein said anticoagulant is heparin.
Claim 38
Dependent Claim
18 words
The method of making a non-thrombogenic polymer surface according to claim 38 wherein said aldehyde is a dialdehyde.
Claim 39
Dependent Claim
17 words
The method of making a non-thrombogenic polymer surface according to claim 39 wherein said dialdehyde is glutaraldehyde.
Claim 40
Dependent Claim
18 words
The method of making a non-thrombogenic polymer surface according to claim 40 wherein said acid is sulfuric acid.
Claim 41
Dependent Claim
22 words
The process of making a non-thrombogeniC composition according to claim 34 wherein the polymer is a hydrogel and the anticoagulant is heparin.
Claim 42
Dependent Claim
23 words
The process of making a non-thrombogenic composition according to claim 34 wherein the polymer is a hydrogel and the anticoagulant is sodium heparin.
Claim 43
Dependent Claim
22 words
The process of making a non-thrombogenic composition according to claim 34 wherein the polymer is a hydrogel and the aldehyde is formaldehyde.
Claim 44
Dependent Claim
22 words
The process of making a non-thrombogenic composition according to claim 34 wherein the polymer is a hydrogel and the aldehyde is glutaraldehyde.
Claim 45
Dependent Claim
19 words
The process of making a non-thrombogenic hydrogel according to claim 34 wherein the hydrogel is prepared from polyvinyl alcohol.
Claim 46
Dependent Claim
21 words
The composition of claim 29 wherein the polymer comprises a copolymer of vinyl alcohol and vinyl acetate originally in aqueous solution.
Claim 47
Dependent Claim
14 words
The composition of claim 29 wherein the polymer is an incompletely substituted cellulose ester.
Claim 48
Dependent Claim
18 words
The process of making a non-thrombogenic composition according to claim 34 wherein the polymer is cellulose or cellophane.
Claim 49
Dependent Claim
20 words
The process of making a non-thrombogenic composition according to claim 34 wherein the polymer is an incompletely substituted cellulose ester.
Claim 50
Dependent Claim
35 words
A multilayer polymeric composition comprising an outer layer comprising the composition of claim 29 covalently bonded to a base shaped blood-contacting biomedical appliance polymer surface or membrane layer comprising a hydrogel cross-linked with an aldehyde.
Claim 51
Dependent Claim
14 words
The composition of claim 51 wherein the aldehyde in the outer layer is formaldehyde.
Claim 52
Dependent Claim
16 words
The composition of claim 51 wherein the aldehyde in the outer layer is formaldehyde and glutaraldehyde.
Claim 53
Dependent Claim
13 words
The composition of claim 51 wherein the base layer is crosslinked with formaldehyde.
Claim 54
Dependent Claim
14 words
The composition of claim 51 wherein the base layer contains a fibrous reinforcing material.
Claim 55
Dependent Claim
28 words
The method of making a non-thrombogenic polymer surface according to claim 35 wherein said polymer is cellulose or cellophane, said anticoagulant is heparin, and said aldehyde is glutaraldehyde.
Claim 56
Dependent Claim
21 words
The method of making a non-thrombogenic polymer surface according to claim 35 wherein said polymer is an incompletely substituted cellulose ester.
Claim 57
Dependent Claim
20 words
The method of making a non-thrombogenic polymer surface according to claim 35 wherein said polymer is partially de-esterified cellulose acetate.
Claim 58
Dependent Claim
21 words
The method of making a non-thrombogenic polymer surface according to claim 35 wherein said polymer is partially de-esterified cellulose acetate butyrate.
Claim 59
Dependent Claim
20 words
The method of making a non-thrombogenic polymer surface according to claim 35 wherein said polymer is partially de-esterified cellulose propionate-butyrate.
Claim 60
Dependent Claim
45 words
The method of making a non-thrombogenic polymer surface according to claim 59 wherein said partially de-esterified polymer is produced by saponifying a surface of cellulose acetate butyrate by maintaining said cellulose acetate butyrate in a 5% NaOH solution at 60* C. for approximately 24 hours.
Claim 61
Dependent Claim
55 words
An implantable or extracorporeal biomedical blood-contacting shaped appliance shaped in the form of hemodialysis tubing, hemodiafiltration membranes, hollow tube intravenous catheters, vascular prosthesis implants, heart valve and aortic and mitrao heart valve flaps and like devices and prosthesis article with non-thrombogenic polymeric surfaces prepared according to claim 41 wherein said polymer is a cellophane membrane.
Claim 62
Dependent Claim
55 words
An implantable or extracorporeal biomedical blood-contacting shaped appliance shaped in the form of hemodialysis tubing, hemodiafiltration membranes, hollow tube intravenous catheters, vascular prosthesis implants, heart valve and aortic and mitrao heart valve flaps and like devices and prosthesis article with non-thrombogenic polymeric surfaces prepared according to claim 41 wherein said polymer is a cellulose ester.
Claim 63
Dependent Claim
57 words
An implantable or extraporeal biomedical blood-contacting shaped appliance shaped in the form of hemodialysis tubing, hemodiafiltration membranes, hOllow tube intravenous catheters, vascular prosthesis implants, heart valve and aortic and mitrao heart valve flaps and the like devices and prosthesis article with non-thrombogenic polymeric surfaces prepared according to claim 41 wherein said polymer is rigid cellulose acetate butyrate.
References Cited (Backward Citations)
US3522346A
Cited
US3549409A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1975-07-04 | 1976-01-03 | 1976-07-04 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1979-07-04 | 1980-01-03 | 1980-07-04 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1983-07-04 | 1984-01-03 | 1984-07-04 | $7700.00 | Window Closed / Lapsed |