Multifunctional thrombo-resistant coatings and methods of manufacture

• US 5,182,317 A
• Filed: 06/17/1991
• Issued: 01/26/1993
• Est. Priority Date: 06/08/1988
• Status: Expired due to Fees

• Current Assignee: InnerDyne, Inc. (Medtronic Plc)
• Original Assignee: CardioPulmonics, Inc. (Johnson Controls International plc)
• Inventors: Solen, Kenneth A., Sanders, Clifton G., Mortensen, J. D., Winters, Suzanne, Berry, Gaylord
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): BROUILLETTE, D GABRIELLE
• Application Number:
  US07/716,843
• Time in Patent Office: 589 Days
• Field of Search: 523/112, 523/113, 530/812, 530/815, 530/816, 604/266
• US Class Current: 523/112
• CPC Class Codes: A61L 33/0029 using an intermediate layer of polymer
• CPC Class Codes: A61L 33/0047 Enzymes, e.g. urokinase, streptokinase
• CPC Class Codes: A61M 1/1678 intracorporal peritoneal dialysis A61M1/28
• CPC Class Codes: A61M 1/1698 Blood oxygenators with or without heat-exchangers intracorporal A61M1/1678; manufacturing of membranes therefor B01D67/00; semi-permeable membranes for separation processes characterised by their properties B01D69/00; semi-permeable membranes characterised by their material B01D71/00
• CPC Class Codes: A61M 1/3673 Anticoagulant coating, e.g. Heparin coating
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y10S 530/812 Peptides or proteins is immobilized on, or in, an organic carrier
• CPC Class Codes: Y10S 530/815 Carrier is a synthetic polymer
• CPC Class Codes: Y10S 530/816 Attached to the carrier via a bridging agent

Abstract

The present invention is directed to multifunctional thrombo-resistant coatings for use with biomedical devices and implants, such as a coating which includes a siloxane surface onto which a plurality of amine functional groups have been bonded. Covalently bonded to the amine functional groups are a plurality of poly(ethylene oxide) chains, such that a single poly(ethylene oxide) chain is bonded to a single amine functional group. A plurality of different bioactive molecules, designed to counteract specific blood-material incompatibility reactions, are covalently bonded to poly(ethylene oxide) chains, such that a single bioactive molecule is coupled to a single polyethylene oxide chain. The method of manufacturing the present invention include preparing a material having a siloxane surface onto which a plurality of amine functional groups have been bonded. This is achieved by plasma etching with ammonia gas or by plasma polymerization of a siloxane monomer in the presence of ammonia gas. The amine-containing siloxane surface is reacted with poly(ethylene oxide) chains terminated with functional groups capable of reacting with the amine groups on the siloxane surface. The material is then reacted with a plurality of different bioactive molecules which counteract the specific blood-material incompatibility reactions, such that a single bioactive molecule is coupled to a single poly(ethylene oxide) chain. The resulting siloxane surface contains a plurality of different bioactive molecules capable of reacting with blood components which come in proximity to the siloxane surface in order to resist blood-material incompatibility reactions.

Claims

1. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood, the method comprising the steps of:

(a) obtained by application of one plasma etching or plasma polymerization a material having a siloxane surface onto which a plurality of amine functional groups have been bonded;

(b) reacting the amine functional groups on the siloxane surface with poly(ethylene oxide) chains terminated with functional groups capable of reacting with the amine functional groups on the siloxane surface, thereby resulting in a product having single poly(ethylene oxide) chains which are bonded to corresponding single amine functional groups;

(c) reacting the product of step (b) with a plurality of at least two different bioactive molecules capable of counteracting specific blood-material incompatibility reactions such that a single bioactive molecule is correspondingly coupled to a single poly(ethylene oxide) chain, thereby resulting in a siloxane surface to which are attached, by a poly(ethylene oxide) chain, a plurality of at least two different bioactive molecules which react with blood components which come in proximity to the siloxane surface of the material in order to resist blood-material incompatibility reactions.

2. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the step of obtaining a material having a siloxane surface onto which a plurality of amine functional groups have been bonded comprises the steps of:

introducing ammonia gas within a plasma chamber capable of performing plasma etching;

exposing the ammonia gas to a radio frequency of sufficient power to create a plasma; and

exposing the siloxane surface to the ammonia plasma for sufficient time to introduce amine functional groups onto the siloxane surface.

3. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 2, further comprising the step of obtaining a hollow fiber having a siloxane surface thereon.

4. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the step of obtaining a material having a siloxane surface onto which a plurality of amine functional groups have been bonded comprises the steps of:

introducing a gaseous mixture of siloxane monomer and ammonia into a plasma chamber capable of performing plasma polymerization;

exposing the gaseous mixture of siloxane monomer and ammonia to a radio frequency of sufficient power to create a plasma; and

exposing the material to the plasma for sufficient time to deposit thereon a siloxane plasma polymer onto which amine functional groups have been bonded.

5. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 4, wherein the mixture of siloxane monomer and ammonia gas is introduced at a ratio of siloxane monomer to ammonia gas in the range from about 10:

1 to about 1;

10.

6. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the step of obtaining a material having a siloxane surface onto which a plurality of amine functional groups have been bonded comprises the steps of:

introducing a gaseous mixture of tetramethyldisiloxane and ammonia into a plasma chamber capable of performing plasma polymerization;

exposing the gaseous mixture of tetramethyldisiloxane and ammonia to a radio frequency of sufficient power to create a plasma; and

exposing the material to the plasma for sufficient time to deposit thereon a siloxane plasma polymer onto which amine functional groups have been bonded.

7. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 4, wherein the mixture of siloxane monomer and ammonia gas is introduced into the plasma chamber in the range from about 3:

1 to about 1;

1 siloxane monomer to ammonia gas.

8. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 4, further comprising the step of obtaining a microporous hollow fiber.

9. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the poly(ethylene oxide) chains terminated with functional groups capable of reacting with the amine functional groups comprises poly(ethylene oxide) bis(glycidyl ether).

10. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the poly(ethylene oxide) chains terminated with functional groups capable of reacting with the amine functional groups comprises poly(ethylene oxide) bis(isocyanate).

11. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the poly(ethylene oxide) chains have a molecular weight in the range from about 1500 to 6000.

12. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the product of step (b) is reacted with a solution having different bioactive molecules capable of resisting at least two of the following blood-material incompatibility reactions:

extrinsic coagulation pathway activation, platelet destruction and injury, platelet adhesion, platelet aggregation, thrombus formation, and complement activation.

13. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the product of step (b) is reacted with a plurality of at least two different bioactive molecules selected from the group including heparin, urokinase, plasmin, and ticlopidine.

14. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the product of step (b) is reacted with a plurality of at least two different bioactive molecules selected from the group including heparin, urokinase, TPA, and prostaglandin E₁.

15. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the product of step (b) is reacted with a plurality of at least two different bioactive molecules selected from the group including heparin, plasmin, and ticlopidine.

16. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 1, wherein the product of step (b) is reacted with a plurality of at least two different bioactive molecules selected from the group including heparin, urokinase, TPA, plasmin, prostaglandin E₁, and ticlopidine.

17. A method for producing a multifunctional thrombo-resistant coating for use on surface which contact blood, the method comprising the steps of:

(a) obtaining by plasma etching or plasma polymerization a material having a siloxane surface;

(b) introducing ammonia gas within a plasma chamber capable of performing plasma etching;

`(c) exposing the ammonia gas to a radio frequency of sufficient power to break the molecular bonds of the ammonia gas and create a plasma;

(d) exposing the siloxane surface to the ammonia plasma for sufficient time to allow the molecular bonds of the siloxane surface to break and to allow the introduction of amine functional groups onto the siloxane surface, thereby resulting in a product having a plurality of amine functional groups bonded onto the siloxane surface;

(e) reacting the product of step (d) with a solution having a plurality of poly(ethylene oxide) spacer chains, having the following general formula

space="preserve" listing-type="equation">R.sub.1 --(CH.sub.2 CH.sub.2 O).sub.n --R.sub.2

wherein R₁ and R₂ are suitable functional groups capable of reacting with the amine functional groups on the siloxane surface; and

(f) reacting the product of step (e) with a plurality of at least two different bioactive molecules capable of counteracting specific blood-material incompatibility reactions such that a single bioactive molecule is corresponding coupled to a single poly(ethylene oxide) spacer chain, thereby resulting in a siloxane surface to which are attached, by a poly(ethylene oxide) chain, a plurality of at least two different bioactive molecules which react with blood components which come in proximity to the surface of the material in order to resist blood-material incompatibility reactions.

18. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 17, wherein R₁ and R₂ comprise glycidyl ether.

19. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 17, wherein R₁ and R₂ comprise isocyanate.

20. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 17, wherein the product of step (e) is reacted with a plurality of at least two different bioactive molecules selected from the group including heparin, urokinase, plasmin, and ticlopidine.

21. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 17, wherein the product of step (e) is reacted with a plurality of at least two different bioactive molecules selected from the group including heparin, urokinase, plasmin, ticlopidine, TPA, and prostaglandin E₁.

22. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood, the method comprising the steps of:

(a) introducing a gaseous mixture of siloxane monomer and ammonia into a plasma chamber capable of performing plasma polymerization;

(b) exposing the gaseous mixture of siloxane monomer and ammonia to a radio frequency of sufficient power to break the molecular bonds of the ammonia and the siloxane monomer and to create a plasma;

(c) exposing a material to the plasma to thereby deposit onto the surface of the material a siloxane plasma polymer onto which amine functional groups have been bound;

(d) reacting the product of step (c) with a solution having a plurality of poly(ethylene oxide) spacer chains, having the following general formula

space="preserve" listing-type="equation">R.sub.1 --(CH.sub.2 CH.sub.2 O).sub.n --R.sub.2

wherein R₁ and R₂ are suitable functional groups capable of reacting with the amine functional groups on the siloxane surface; and

(f) reacting the product of step (e) with a plurality of at least two different bioactive molecules capable of counteracting specific blood-material incompatibility regions such that a single bioactive molecule is corresponding coupled to a single poly(ethylene oxide) spacer chain, thereby resulting in a siloxane surface to which are attached, by a poly(ethylene oxide) chain, a plurality of at least two different bioactive molecules which react with blood components which come in proximity to the surface of the material in order to resist blood-material incompatibility reactions.

23. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, wherein R₁ and R₂ comprise glycidyl ether.

24. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, wherein R₁ and R₂ comprise isocyanate.

25. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, wherein the mixture of siloxane monomer and ammonia gas is introduced into the plasma chamber at a ratio of siloxane monomer to ammonia gas in the range of from about 10:

1 to about 1;

10.

26. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, wherein the introducing step comprises introducing a gaseous mixture of tetramethyldisiloxane and ammonia into a plasma chamber.

27. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, further comprising the step of covalently bonding a plurality of carbonyl functional groups onto the siloxane surface.

28. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, further comprising the step of covalently bonding a plurality of hydroxyl functional groups onto the siloxane surface.

29. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, wherein the product of step (d) is reacted with a plurality of at least two different bioactive molecules selected from the group including heparin, urokinase, plasmin, and ticlopidine.

30. A method for producing a multifunctional thrombo-resistant coating for use on surfaces which contact blood as defined in claim 22, wherein the product of step (d) is reacted with a plurality of at least two different bioactive molecules selected form the group including heparin, urokinase, plasmin, ticlopidine, TPA, and prostaglandin E₁.