Biocompatible coating, medical device using the same and methods

• US 5,643,580 A
• Filed: 10/17/1994
• Issued: 07/01/1997
• Est. Priority Date: 10/17/1994
• Status: Expired due to Fees

• Current Assignee: Surface Genesis, Inc.
• Original Assignee: Surface Genesis, Inc.
• Inventors: Subramaniam, Raj
• Primary Examiner(s): Page, Thurman K.
• Application Number:
  US08/324,413
• Time in Patent Office: 988 Days
• Field of Search: 424/400, 623/11, 623/1, 623/66, 427/2, 427/2.12, 427/2.13, 427/2.28, 427/2.3, 427/535, 436/501
• US Class Current: 424/400
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
• CPC Class Codes: A61L 33/0076 Chemical modification of the substrate
• CPC Class Codes: A61L 33/0094 Physical treatment, e.g. plasma treatment
• CPC Class Codes: A61L 33/12 Polypeptides, proteins or derivatives thereof , e.g. degradation products thereof
• CPC Class Codes: Y10S 428/936 Chemical deposition, e.g. electroless plating

Abstract

The invention involves using a plasma to functionalize a surface of medical devices such as catheters, particularly intracardial catheters, with covalently bound thermochemically reactive groups. The surface is further contacted with a bioactive agent, particularly antithrombogenic coatings, which is thermochemically covalently coupled to the reactive group to form a therapeutically effective coating. The selected bioactive agent is then covalently bound to the surface by thermochemical reaction with the surface reactive groups. In another embodiment, the functionalizing step comprises contacting the surface with a Langmuir-Blodgett film comprising an amphipathic compound and a bioactive agent and using a plasma to covalently crosslink the Langmuir-Blodgett film to the medical device surface and to the bioactive agent. Medical devices prepared by the subject methods are also provided.

Claims

1. A method for treating a surface of a medical device to inhibit thrombosis comprising steps:

functionalizing a surface of a medical device by contacting said surface with a low temperature plasma which surface is exposed to blood flow continuous with bodily blood circulation with a first reactive group, contacting said surface with an antithrombogenic agent capable of reacting with said first reactive group, and causing said antithrombogenic agent to react with said first reactive group to covalently bind said antithrombogenic agent to said surface to form a coating on said surface which coating is effective to inhibit the formation of thrombus when said surface is exposed to blood flow continuous with bodily blood circulation.

3. A method according to claim 1 wherein said contacting step comprises contacting said surface with an antithrombogenic agent derivatized with a second reactive group capable of reacting with said first reactive group to covalently bind said antithrombogenic agent to said surface.

4. A method according to claim 1, wherein said contacting step comprises contacting said surface with an antithrombogenic derivatized with a label, wherein said label is capable of providing a detectable signal.

5. A method according to claim 1, wherein said contacting step comprises contacting said surface with an irreversible thrombin inhibitor.

6. A method according to claim 1, wherein said contacting step comprises contacting said surface with an reversible thrombin inhibitor.

7. A method according to claim 1, wherein said contacting step comprises contacting said surface with D-Phe-Pro-Arg-chloromethyl ketone.

8. A method according to claim 1 wherein said contacting step comprises contacting said surface with heparin.

9. A method according to claim 1 wherein said contacting step comprises contacting said surface with a polypeptide comprising the amino acid sequence Ile-Pro-Glu-Glu-Tyr-Leu-Gln.

10. A method according to claim 1 wherein said functionalizing step comprises functionalizing a surface of a catheter, stent, graft, or blood transfer device.

11. A method according to claim 1 for treating a surface of an intracardial catheter probe which is exposed to blood within a body to inhibit formation of thrombus, wherein said catheter probe is for introduction into a chamber of the heart, has proximal and distal extremities and comprises a flexible elongate tubular member having at least one lumen extending therethrough extending the length thereof and having a distal extremity, a plurality of longitudinally and radially spaced apart electrodes, expandable means secured to the distal portion of said flexible elongate tubular member and being movable between a contracted position and an expanded position, means mounting said electrodes on said expandable means whereby when said expandable means is moved to the expanded position in the chamber of the heart the electrodes are moved into engagement with the wall forming the chamber of the heart, means coupled to the expandable means for moving said expandable between said contracted and expanded positions, said expandable means including a plurality of plastic elements having surfaces exposed to the blood and said elements having spaces therebetween when in the expanded position through which the blood can flow, lead means for conducting electrical energy in contact with the electrodes and extending into said flexible elongate tubular member and electrical means connected to said lead means for performing electrical functions with respect to said electrodes, said method comprising steps:

functionalizing a surface of said intracardial medical device with a first reactive group, contacting said surface with an antithrombogenic agent capable of reacting with said first reactive group, and causing said antithrombogenic agent to react with said first reactive group to covalently bind said antithrombogenic agent to said surface to form a coating on said surface which is effective to inhibit the formation of thrombus when said surface is exposed to blood within a body.

16. A method according to claim 1, wherein contacting said surface with an antithrombogenic agent comprises contacting said surface with an antithrombogenic derivatized with a label, wherein said label is capable of providing a detectable signal.

2. A method for treating a surface of a medical device to inhibit thrombosis comprising steps:

contacting a surface of a medical device which surface is exposed to blood flow continuous with bodily blood circulation with a Langmuir-Blodgett film comprising an amphipathic compound;

contacting said surface with an antithromobogenic agent;

covalently crosslinking said antithrombogenic agent with said amphipathic compound;

covalently crosslinking said amphipathic compound to said surface;

to form a coating on said surface which coating is effective to inhibit the formation of thrombus when said surface is exposed to blood flow continuous with bodily blood circulation;

wherein at least one of said crosslinking steps comprises contacting said surface with a low temperature plasma.

12. A method according to claim 2, wherein said coating steps are performed simultaneously.

13. A method according to claim 2, wherein said crosslinking steps are performed simultaneously.

14. A method according to claim 2, further comprising prior to said coating said surface with a Langmuir-Blodgett film:

functionalizing said surface with a first reactive group capable of reacting with at least one of said amphipathic compound and said antithrombogenic agent.

15. A method according to claim 14 wherein said antithrombogenic agent is derivatized with a second reactive group capable of reacting with said first reactive group.

17. A method for treating a surface of a medical device to inhibit thrombosis comprising steps:

contacting an antithrombogenic agent with a surface of a medical device which surface is exposed to blood flow continuous with bodily blood circulation;

thereafter

causing said antithrombogenic agent to become covalently bound to said surface using a low temperature plasma;

thereafter,

washing said surface to remove from said surface any of said antithrombogenic agent which is not covalently bound to said surface;

thereafter,

contacting said surface with a reagent capable of selectively, non-covalently binding said antithrombogenic agent;

causing said reagent to become selectively and noncovalently bound to said antithrombogenic agent;

thereafter,

washing said surface to remove from said surface any of said reagent which is not selectively bound to said antithrombogenic agent;

thereafter,

detecting a radiative signal at an intensity which meets or exceeds a predetermined intensity, wherein a radiative signal at said predetermined intensity correlates with the presence of coating of a predetermined amount of said antithrombogenic agent covalently bound to said surface, said coating being effective to inhibit the formation of thrombus when said surface is exposed to blood flow continuous with bodily blood circulation.

18. A method according to claim 17, wherein said reagent is an antibody and said radiative signal is fluorescence.

19. A method for treating a surface of a medical device to provide said surface with a therapeutic coating comprising steps:

functionalizing a surface of a medical device which surface is exposed to blood flow continuous with bodily blood circulation with a first reactive group using a low temperature plasma, contacting said surface with a bioactive agent capable of reacting with said first reactive group, and causing said bioactive agent to react with said first reactive group to covalently bind said bioactive agent to said surface to form a coating on said surface which coating is therapeutic when said surface is exposed to blood flow continuous with bodily blood circulation.

20. A method for treating a surface of a medical device to provide said surface with a therapeutic coating comprising steps:

contacting a surface of a medical device which surface is exposed to blood flow continuous with bodily blood circulation with a Langmuir-Blodgett film comprising an amphipathic compound;

contacting said surface with an antithromobogenic agent;

covalently crosslinking said bioactive agent with said amphipathic compound;

covalently crosslinking said amphipathic compound to said surface;

to form a coating on said surface which coating is effective to inhibit the formation of thrombus when said surface is exposed to blood flow continuous with bodily blood circulation;

wherein at least one of said crosslinking steps comprises contacting said surface with a low temperature plasma.

21. A method for treating a surface of a medical device to provide said surface with a therapeutic coating comprising steps:

contacting an bioactive agent with a surface of a medical device which surface is exposed to blood flow continuous with bodily blood circulation;

thereafter

causing said bioactive agent to become covalently bound to said surface using a low temperature plasma;

thereafter,

washing said surface to remove from said surface any of said bioactive agent which is not covalently bound to said surface;

thereafter,

contacting said surface with a reagent capable of selectively, non-covalently binding said bioactive agent;

causing said reagent to become selectively and noncovalently bound to said bioactive agent;

thereafter,

washing said surface to remove from said surface any of said reagent which is not selectively bound to said bioactive agent;

thereafter,

detecting a radiative signal at an intensity which meets or exceeds a predetermined intensity, wherein a radiative signal at said predetermined intensity correlates with the presence of coating of a predetermined amount of said bioactive agent covalently bound to said surface, said coating is therapeutic when said surface is exposed to blood flow continuous with bodily blood circulation.

22. A method for treating a surface of a medical device to promote thrombosis comprising steps:

functionalizing a surface of a medical device by contacting said surface with a low temperature plasma which surface is exposed to blood not in continuous flow with bodily blood circulation with a first reactive group, contacting said surface with an thrombogenic agent capable of reacting with said first reactive group, and causing said thrombogenic agent to react with said first reactive group to covalently bind said thrombogenic agent to said surface to form a coating on said surface which is effective to promote the formation of thrombus when said surface is exposed to blood not in continuous flow with bodily blood circulation.