Method for attachment of biomolecules to surfaces of medical devices

• US 6,024,918 A
• Filed: 03/13/1998
• Issued: 02/15/2000
• Est. Priority Date: 03/13/1998
• Status: Expired due to Fees

• Current Assignee: Michael J. Jaro
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Gillissen, Mirian, Cahalan, Linda, Hendriks, Marc, Verhoeven, Michel, Cahalan, Patrick, Koulik, Edouard
• Primary Examiner(s): BIANCO, PATRICIA
• Assistant Examiner(s): BIANCO, PATRICIA
• Application Number:
  US09/041,497
• Time in Patent Office: 704 Days
• Field of Search: 604/4, 604/5, 422/44
• US Class Current: 422/44
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2400/18 Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 33/0029 using an intermediate layer of polymer
• CPC Class Codes: C08L 83/04 Polysiloxanes

Abstract

A method for making a medical device having a biomolecule immobilized on a substrate surface is provided. The method includes coating the substrate surface with an amino-functional polysiloxane; and contacting the amino-functional polysiloxane coated surface with a biomolecule under conditions effective to immobilize the biomolecule.

Claims

1. A method for making a medical device having a biomolecule immobilized on a substrate surface, the method comprising:

coating the substrate surface with an amino-functional polysiloxane; and

contacting the amino-functional polysiloxane coated surface with a biomolecule under conditions effective to immobilize the biomolecule.

4. The method of claim 1 the step of contacting the amino-functional polysiloxane coated surface with a biomolecule under conditions effective to immobilize the biomolecule comprises contacting the amino-functional polysiloxane coated surface with a biomolecule in a liquid carrier at a temperature of at least about 20°

C. for at least about 30 seconds.

5. The method of claim 4 wherein the liquid carrier comprises a periodate in a buffered aqueous solution.

6. The method of claim 5 wherein the periodate comprises an alkali metal periodate.

7. The method of claim 5 wherein the biomolecule comprises heparin and the periodate is present in a sufficient amount to form aldehyde groups on the heparin.

8. The method of claim 7 wherein the buffered aqueous solution has a pH in a range of about 4.5 to about 8.

10. The method of claim 1 wherein the biomolecule is synthetically derived or naturally occurring.

11. The method of claim 1 wherein the substrate is a metal, polymer, ceramic, or glass.

12. The method of claim 1 wherein the surface formed is biocompatible.

13. The method of claim 1 wherein the surface formed is blood compatible.

14. The method of claim 13 wherein the substrate to which there is a biomolecule attached through an amino-functional polysiloxane demonstrates at least a 20% reduction in the amount of elastase formed relative to the same substrate without the biomolecule and the polysiloxane attached thereto when contacted with human blood.

15. The method of claim 13 wherein the substrate to which there is a biomolecule attached through an amino-functional polysiloxane demonstrates at least a 10% reduction in the amount of thrombin-antithrombin complex formed relative to the same substrate without the biomolecule and the polysiloxane attached thereto when contacted with human blood.

16. The method of claim 13 wherein the substrate to which there is a biomolecule attached through an amino-functional polysiloxane demonstrates at least a 15% reduction in the amount of Platelet Factor 4 formed relative to the same substrate without the biomolecule and the polysiloxane attached thereto when contacted with human blood.

17. The method of claim 13 wherein the substrate to which there is a biomolecule attached through an amino-functional polysiloxane demonstrates at least a 40% reduction in the amount of terminal complement complex formed relative to the same substrate without the biomolecule and the polysiloxane attached thereto when contacted with human blood.

18. The method of claim 13 wherein the substrate to which there is a biomolecule attached through an amino-functional polysiloxane has less than about 1% of the surface of the substrate covered by platelets.

19. The method of claim 1 wherein the medical device is a stent.

20. The method of claim 1 wherein the medical device is a blood oxygenator.

23. The method of claim 1 wherein the medical device is a blood oxygenator and the substrate being coated includes hollow fibers.

2. The method of claim I wherein the step of coating the substrate surface comprises:

coating the substrate surface with an amino-functional polysiloxane in a liquid carrier;

removing the liquid carrier; and

contacting the amino-functional polysiloxane coating with water to cure the coating.

3. The method of claim 2 wherein the steps of removing the liquid carrier and contacting the coating with water comprises contacting the substrate surface having the amino-functional polysiloxane in a liquid carrier thereon with moist air.

9. The method of claim I wherein the biomolecule is selected from the group of an antibacterial agent, an antimicrobial agent, an anticoagulant, an antithrombotic agent, a platelet agent, an anti-inflammatory, an enzyme, a catalyst, a hormone, a growth factor, a drugs, a vitamin, an antibody, an antigen, a nucleic acid, a dye, a DNA segment, an RNA segment, a protein, and a peptide.

21. A method for making a medical device having a biomolecule immobilized on a substrate surface, the method comprising:

coating the substrate surface with a solution of an amino-functional polysiloxane;

drying the amino-functional polysiloxane solution to form a coated surface having amine functionality;

contacting the coated surface with the amine functionality with a biomolecule to form a biocompatible surface.

22. The method of claim 21 wherein prior to the step of contacting the coated surface the method includes a step of combining heparin with a periodate to form an aldehyde-functional heparin.