Amphipathic coating for modulating cellular adhesion composition and methods

• US 6,342,591 B1
• Filed: 07/31/2000
• Issued: 01/29/2002
• Est. Priority Date: 09/22/1998
• Status: Expired due to Term

• Current Assignee: Biosurface Engineering Technologies, Inc. (Ferring Holding SA)
• Original Assignee: Biosurface Engineering Technologies, Inc. (Ferring Holding SA)
• Inventors: Zamora, Paul O., Tsang, Ray, Osaki, Shigemasa
• Primary Examiner(s): Fonda, Kathleen Kahler
• Application Number:
  US09/629,059
• Time in Patent Office: 547 Days
• Field of Search: 536/21, 514/56, 523/112, 604/266, 427/2.1, 427/2.24, 427/2.25, 427/2.3
• US Class Current: 536/21
• CPC Class Codes: A61L 27/28 Materials for coating prostheses
• CPC Class Codes: A61L 31/08 Materials for coatings
• 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 33/0029 using an intermediate layer of polymer
• CPC Class Codes: A61L 33/08 Polysaccharides
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08G 77/60 in which all the silicon atoms are connected by linkages other than oxygen atoms
• CPC Class Codes: C08L 83/00 Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
• CPC Class Codes: C09D 105/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C09D 105/10 Heparin; Derivatives thereof

Abstract

The present invention provides an anti-thrombogenic and cellular-adhesion coating composition for blood-contacting surfaces. The coating comprises a covalent complex of from 1 to 30 hydrophobic silyl moieties of Formula I:

wherein R₁ is an C_1-18 alkyl or C_6-32 aryl group, each R₂ is independently selected from the group consisting of C_1-18 alkyl and C_6-32 aryl, R₃ is N or O, n is a number from 1 to 10, directly bound to a heparin molecule via covalent bonding, with an adhesive molecule directly bound to the heparin molecule. In one embodiment, the coating comprises benzyl-(1,2 dimethyl)disilyl heparin, wherein an adhesive molecule, such as fibronectin, is bound to the heparin.

Claims

1. An amphiphatic cell-attachment coating composition for medical device surfaces, said composition comprising a covalent complex of from 1 to 30 hydrophobic silyl moieties of Formula I:

wherein

R₁ is an C_1-18 alkyl or C_6-32 aryl group,

each R₂ is independently selected from the group consisting of C_1-18 alkyl and C_6-32 aryl

R₃ is N or O, and

n is a number from 1 to 10

directly bound to sodium heparin via covalent bonding, with an adhesive molecule directly bound to the sodium heparin.

2. The composition according to claim 1, wherein said hydrophobic silyl moieties bind to said surfaces via hydrophobic bonding interactions.

3. The composition according to claim 1, wherein said complex comprises from 2 to 25 hydrophobic silyl moieties covalently bound to one heparin molecule.

4. The composition according to claim 1, wherein R₁ is benzyl in said hydrophobic silyl moiety of Formula I.

5. The composition according to claim 1, wherein each R₂ is an alkyl in said hydrophobic silyl moiety of Formula I.

6. The composition according to claim 1, wherein n is 2 or 3 in said hydrophobic silyl moiety of Formula I.

7. The composition according to claim 1, wherein said complex is [benzyl-bis(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

8. The composition according to claim 1, wherein said complex is [benzyl-tris(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

9. The composition according to claim 1, wherein said adhesive molecule is fibronectin.

10. The composition according to claim 1, wherein said adhesive molecule is selected from the group consisting of fibronectin, laminin, vitronectin, thrombospondin, gelatin, polylysine, polyornithine, peptide polymers containing adhesive sequences and heparin binding sequences, sulfated complex carbohydrates, dextran sulfate, growth hormones, cytokines, lectins, and peptidic polymers thereof.

11. A non-thrombogenic medical device for cellular attachment, comprising surfaces for contacting blood, said surfaces having coated thereon an non-thrombogenic coating composition comprising a covalent complex of from 1 to 30 hydrophobic silyl moieties of Formula I:

wherein

R₁ is an C_1-18 alkyl or C_6-32 aryl group,

each R₂ is independently selected from the group consisting of C_1-18 alkyl and C_6-32 aryl,

R₃ is N or O, and

n is a number from 1 to 10

directly bound to heparin via covalent bonding, with an adhesive molecule directly bound to the heparin.

12. The device according to claim 11, wherein said hydrophobic silyl moieties bind to said surfaces via hydrophobic bonding interactions.

13. The device according to claim 11, wherein said complex comprises from 2 to 25 hydrophobic silyl moieties covalently bound to one heparin molecule.

14. The device according to claim 11, wherein R₁ is benzyl in said hydrophobic silyl moiety of Formula I.

15. The device according to claim 11, wherein each R₂ is an alkyl in said hydrophobic silyl moiety of Formula I.

16. The device according to claim 11, wherein n is 2 or 3 in said hydrophobic silyl moiety of Formula I.

17. The device according to claim 11, wherein said complex is [benzyl-bis(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

18. The device according to claim 11, wherein said complex is [benzyl-tris(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

19. The device according to claim 11, wherein said device is selected from the group consisting of blood gas exchange devices, blood filters, artificial blood vessels, artificial valves, prosthetics, blood shunts, catheters, bone replacements, cartilage replacements and nerve growth guides.

20. The device according to claim 11, wherein said adhesive molecule is fibronectin.

21. The device according to claim 11, wherein said adhesive molecule is selected from the group consisting of fibronectin, laminin, vitronectin, thrombospondin, gelatin, polylysine, polyornithine, peptide polymers containing adhesive sequences and heparin binding sequences, sulfated complex carbohydrates, dextran sulfate, growth hormones, cytokines, lectins, and peptidic polymers thereof.

22. A method for rendering a tissue- or blood-contacting surfaces of a medical device resistant to fibrin accumulation while promoting cellular adhesion, said method

comprising coating said surfaces with an non-thrombogenic coating composition comprising a covalent complex of from 1 to 30 hydrophobic silyl moieties of Formula I:

wherein

R₁ is an C_1-18 alkyl or C_6-32 aryl group,

each R₂ is independently selected from the group consisting of C_1-18 alkyl and C_6-32 aryl,

R₃ is N or O, and

n is a number from 1 to 10

directly bound to heparin via covalent bonding, and attaching to the heparin an adhesive molecule.

23. The method according to claim 22, wherein said hydrophobic silyl moieties bind to said surfaces via hydrophobic bonding interactions.

24. The method according to claim 22, wherein said complex comprises from 2 to 25 hydrophobic silyl moieties covalently bound to one heparin molecule.

25. The method according to claim 22, wherein R₁ is benzyl in said hydrophobic silyl moiety of Formula I.

26. The method according to claim 22, wherein each R₂ is an alkyl in said hydrophobic silyl moiety of Formula I.

27. The method according to claim 22, wherein n is 2 or 3 in said hydrophobic silyl moiety of Formula I.

28. The method according to claim 22, wherein said complex is [benzyl-bis(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

29. The method according to claim 22, wherein said complex is [benzyl-tris(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

30. The method according to claim 22, wherein further comprising the step of solubilizing said complex in a solvent prior to said step of coating said surface.

31. The method according to claim 22, wherein said step of coating said surface comprises dipping said surface into said coating composition comprising said complex.

32. The method according to claim 22, wherein said step of coating said surface comprises pumping said coating composition comprising said complex onto said surface.

33. The method according to claim 22, wherein said adhesive molecule is fibronectin.

34. The method according to claim 22, w wherein said adhesive molecule is selected from the group consisting of fibronectin, laminin, vitronectin, thrombospondin, gelatin, polylysine, polyornithine, peptide polymers containing adhesive sequences and heparin binding sequences, sulfated complex carbohydrates, dextran sulfate, growth hormones, lectins, and peptidic polymers thereof.

35. The method according to claim 22, wherein further comprising the step of solubilizing said adhesive molecule in a solvent prior to said step of attaching said adhesive molecule.

36. The method according to claim 35, wherein said step of attaching said adhesive molecule comprises dipping said surface coated with said complex into said solubilized adhesive molecule composition.

37. The method according to claim 35, wherein said step of attaching said adhesive molecule comprises pumping said solubilized adhesive molecule composition onto said surface coated with said complex.