Multifunctional medical articles

• US 20070003588A1
• Filed: 12/06/2005
• Published: 01/04/2007
• Est. Priority Date: 12/06/2004
• Status: Active Grant

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Chudzik, Stephen, Stucke, Sean, Chinn, Joseph
• Granted Patent: US 8,377,461 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate

Abstract

The invention provides medical articles that include more than one biocompatibility-promoting function. In one aspect, the invention provides a medical articles that include a polymeric matrix including more than one biocompatible agent, wherein each biocompatible agent is provided at a distinct portion of the medical article surface. Methods of making medical articles, as well as methods of using the same, are also described.

Claims

1. A medical article comprising:

(a) a body member;

(b) a first biocompatible coating at a first surface portion, the first biocompatible coating comprising polymerization initiator and a first biocompatible agent, the first biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups; and

(c) a second biocompatible coating at a second surface portion, the second biocompatible coating comprising polymerization initiator and a second biocompatible agent, the second biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups,

wherein the first biocompatible agent and second biocompatible agent are immobilized at respective surface portions and are selected to provide different biocompatible functions when the surface portions are in contact with bodily fluids of a patient.

2. The article according to claim 1 wherein the medical article is an implantable medical device.

3. The article according to claim 2 wherein the implantable medical device is an implantable sensor catheter, transmyocardial sensor or sensor catheter, osteochondral fixative, embolization coil, artificial valve, stented graft, stented valve, valved graft, transdermal access device or shunt, or tunneled access catheter or shunt.

4. The article according to claim 1 wherein the medical article is an external medical article selected from blood cell separator, concentrator, or counter devices, hemodialysis or other blood filtration device, blood oxygenation or other blood processing device, or blood diagnostic system.

5. The article according to claim 1 wherein the first biocompatible coating, the second biocompatible coating, or both the first biocompatible coating and the second biocompatible coating further comprise a macromer that includes a polymeric backbone and polymerizable groups.

6. The article according to claim 5 wherein the polymeric backbone is selected from polyvinylpyrrolidone, polyethylene glycol, polyacrylamide, polyvinyl alcohol.

7. The article according to claim 5 wherein the polymeric backbone is selected from synthetic polymers formed from monomers comprising methyl methacrylate, butyl methacrylate, dimethyl siloxanes, or combinations of these.

8. The article according to claim 5 wherein the polymerizable groups are independently selected for each surface portion and are selected from vinyl groups, (meth)acrylamide groups, and (meth or eth)acrylate groups.

9. The article according to claim 1 wherein the first surface portion and the second surface portion of the medical article are fabricated from different materials.

10. The article according to claim 1 wherein the first biocompatible agent is a thrombin inhibitor and the second biocompatible agent is an adhesion promoter.

11. The article according to claim 10 wherein the thrombin inhibitor is selected from heparin, heparin derivatives, sodium heparin, low molecular weight heparin, high affinity heparin, low affinity heparin, hirudin, lysine, prostaglandins, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogs, D-phenylalanyl-L-propyl-L-arginine chloromethylketone-thrombin, dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antibody, coprotein IIb/IIIa platelet membrane receptor antibody, recombinant hirudin, thrombin inhibitor, chondroitin sulfate, modified dextran, albumin, streptokinase, tissue plasminogen activator, urokinase, and nitric oxide inhibitors.

12. The article according to claim 10 wherein the adhesion promoter is selected from fibronectin, laminin, collagen, elastin, vitronectin, tenascin, fibrinogen, thrombospondin, osteopontin, von Willibrand Factor, bone sialoprotein, hyaluronic acid, chitosan, methyl cellulose.

13. The article according to claim 1 wherein the polymerization initiator of the first biocompatible coating, the second biocompatible coating, or both the first biocompatible coating and second biocompatible coating, is pendent from a polymeric backbone.

14. The article according to claim 13 wherein the polymerization initiator is independently selected for each surface portion and is selected from initiators pendent from polyvinylpyrrolidone, polyethylene glycol, polysaccharides, and polyacrylamides.

15. The article according to claim 13 wherein the polymerization initiator is independently selected for each surface portion and is selected from 4-benzoylbenzoic acid, [9-oxo-2-thioxanthanyl)-oxy]acetic acid, 2-hydroxy thioxanthone, vinyloxymethylbenzoin methyl ether, ethyl eosin, acetophenone derivatives, thioxanthone, benzophenone, and camphorquinone.

16. The article according to claim 13 wherein the polymerization initiator is independently selected for each surface portion and is selected from 4,4′

azobis(4-cyanopentanoic acid), 2,2-azobis[2-(2-imidazon-2-yl)propane]dihydrochloride, and benzoyl peroxide.

17. The article according to claim 1 wherein the polymerization initiator of the first biocompatible coating, the second biocompatible coating, or both the first biocompatible coating and second biocompatible coating, is independently selected for each surface portion and is selected from a tetrakis(4-benzoylbenzyl ether) of pentaerythritol and a tetrakis(4-benzoylbenzoate ester) of pentaerythritol.

18. The article according to claim 1 wherein in the polymerization initiator of the first biocompatible coating, the second biocompatible coating, or both the first biocompatible coating and the second biocompatible coating, is independently selected for each surface portion and is selected from 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid dipotassium salt, 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid disodium salt, 2,5-bis-(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid dipotassium salt, 2,5-bis-(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid disodium salt, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-disulfonic acid monopotassium salt, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-disulfonic acid monosodium salt, or combinations of any of these.

19. The article according to claim 1 wherein the first biocompatible agent includes one or more photoreactive groups.

20. The article according to claim 1 wherein the biocompatible agent of the first biocompatible coating, the second biocompatible coating, or both the first biocompatible coating and the second biocompatible coating, includes one or more polymerizable groups selected from vinyl groups, (meth)acrylamide groups, and (meth or eth)acrylate groups.

21. The article according to claim 1 wherein the second biocompatible agent includes one or more photoreactive groups.

22. A method for providing two or more functional surface portions on a medical article, the method comprising steps of:

(a) disposing a first composition at a first surface portion of the medical article, the first composition comprising polymerization initiator and a first biocompatible agent, the first biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups;

(b) activating the polymerization initiator, reactive groups, or a combination thereof, to form a biocompatible coating layer at the first surface portion;

(c) disposing a second composition at a second surface portion of the medical article, the second composition comprising polymerization initiator and a second biocompatible agent, the second biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups; and

(d) activating the polymerization initiator, reactive groups, or a combination thereof, to form a biocompatible coating layer at the second surface portion,

wherein the first biocompatible agent and the second biocompatible agent are immobilized at respective surface portions and are selected to provide different biocompatible functions when the surface portions are in contact with bodily fluids of a patient.

23. The method according to claim 22 wherein the medical article is an implantable medical device.

24. The method according to claim 22 wherein the first composition, the second composition, or both the first composition and the second composition further comprise a macromer that includes a polymeric backbone and polymerizable groups.

25. The method according to claim 22 wherein the first biocompatible agent is a thrombin inhibitor and the second biocompatible agent is an adhesion promoter.

26. The method according to claim 22 wherein in the disposing step (a), disposing step (c), or both the steps (a) and (c), the polymerization initiator is pendent from a polymeric backbone.

27. The method according to claim 26 wherein the polymerization initiator is independently selected for each surface portion and is selected from initiators pendent from polyvinylpyrrolidone, polyethylene glycol, polysaccharides, and polyacrylamides.

28. The method according to claim 26 wherein the polymerization initiator is independently selected for each surface portion and is selected from 4-benzoylbenzoic acid, [9-oxo-2-thioxanthanyl)-oxy]acetic acid, 2-hydroxy thioxanthone, vinyloxymethylbenzoin methyl ether, ethyl eosin, acetophenone derivatives, thioxanthone, benzophenone, and camphorquinone.

29. The method according to claim 26 wherein the polymerization initiator is independently selected for each surface portion and is selected from 4,4′

azobis(4-cyanopentanoic acid), 2,2-azobis[2-(2-imidazon-2-yl)propane]dihydrochloride, and benzoyl peroxide.

30. The method according to claim 22 wherein in the disposing step (a), the disposing step (c), or both the steps (a) and (c), the polymerization initiator is independently selected for each surface portion and is selected from a tetrakis(4-benzoylbenzyl ether) of pentaerythritol and a tetrakis(4-benzoylbenzoate ester) of pentaerythritol.

31. The method according to claim 22 wherein in the disposing step (a), the disposing step (c), or both the steps (a) and (c), the polymerization initiator is independently selected for each surface portion and is selected from 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid dipotassium salt, 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid disodium salt, 2,5-bis-(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid dipotassium salt, 2,5-bis-(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid disodium salt, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-disulfonic acid monopotassium salt, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-disulfonic acid monosodium salt, or combinations of any of these.

32. The method according to claim 22 wherein the disposing step (a) comprises disposing a first composition comprising a first biocompatible agent including one or more photoreactive groups.

33. The method according to claim 22 wherein the disposing step (a) comprises disposing a first composition comprising biocompatible agent including one or more polymerizable groups selected from vinyl groups, (meth)acrylamide groups, and (meth or eth)acrylate groups.

34. The method according to claim 22 wherein the disposing step (c) comprises disposing a second composition comprising a second biocompatible agent including one or more photoreactive groups.

35. The method according to claim 22 wherein the disposing step (c) comprises disposing a second composition comprising a second biocompatible agent including one or more polymerizable groups selected from vinyl groups, (meth)acrylamide groups, and (meth or eth)acrylate groups.

36. The method according to claim 22 wherein each disposing step of the method is independently accomplished by immersion coating, and spray coating.

37. A method for providing two or more functional surface portions on a medical article, the method comprising steps of:

(a) providing a primed first surface portion on the medical article, the primed first surface portion comprising a polymeric initiator;

(b) disposing a first composition at the primed first surface portion of the medical article, the first composition comprising a first biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups;

(c) activating the polymerization initiator, reactive groups, or a combination thereof, to form a biocompatible coating layer at the first surface portion;

(d) providing a primed second surface portion on the medical article, the primed second surface portion comprising polymerization initiator;

(e) disposing a second composition at the primed second surface portion of the medical article, the second composition comprising polymerization initiator including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups; and

(f) activating the polymerization initiator, reactive groups, or a combination thereof, to form a biocompatible coating layer at the second surface portion,

wherein the first biocompatible agent is different from the second biocompatible agent.

38. A medical article comprising:

(a) a first portion that is fabricated of a first device material; and

(b) a second portion that is fabricated of a second device material, the second device material being more hydrophobic relative to the first device material,

wherein a first biocompatible agent is immobilized at a surface of the first portion via a first biocompatible coating, the first biocompatible coating comprising a polymerization initiator and the first biocompatible agent, the first biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups,

wherein a second biocompatible agent is immobilized at a surface of the second portion via a second biocompatible coating, the second biocompatible coating comprising a nonionic initiator and the second biocompatible agent, the second biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups, and wherein the first biocompatible agent is different from the second biocompatible agent.

39. A method of making a medical article comprising steps of:

(a) providing a medical article that includes a first portion that is fabricated of a first device material and a second portion that is fabricated of a second device material, the second device material being more hydrophobic relative to the first device material;

(b) disposing a first biocompatible coating on a surface of the first portion, the first biocompatible coating comprising polymerization initiator and a first biocompatible agent, the first biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups;

(c) activating the polymerization initiator, reactive groups, or a combination thereof, to form a biocompatible coating layer at the surface of the first portion;

(d) disposing a second biocompatible coating on a surface of the second portion, the second biocompatible coating comprising nonionic initiator and a second biocompatible agent, the second biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups; and

(e) activating the polymerization initiator, reactive groups, or a combination thereof, to form a biocompatible coating layer at the surface of the second portion,

wherein the first biocompatible agent is different from the second biocompatible agent.

40. A medical article comprising:

(a) a body member;

(b) a first coating layer along a length of the body member, the first coating layer comprising a hydrophilic polymer; and

(c) a biocompatible coating in contact with a portion of the first coating layer, the biocompatible coating comprising a biocompatible agent, the biocompatible agent including one or more reactive groups, one or more polymerizable groups, or a combination of one or more reactive groups and one or more polymerizable groups,

wherein the biocompatible coating is in contact with a distinct portion of the first coating layer, the distinct portion comprising less than 100% of the first coating layer, and wherein the hydrophilic polymer is selected from poly(vinylpyrrolidone), poly(ethylene glycol), poly(ethylene oxide), poly(ethyloxazoline), poly(propylene oxide), polyacrylamide, poly(vinyl alcohol), and copolymers or combinations of any of these.