Grafting of biocompatible hydrophilic polymers onto inorganic and metal surfaces

• US 6,013,855 A
• Filed: 12/26/1996
• Issued: 01/11/2000
• Est. Priority Date: 08/06/1996
• Status: Expired due to Term

• Current Assignee: Conor Medsystems Incorporated
• Original Assignee: United States Surgical Corporation (Medtronic Plc)
• Inventors: Jo, Seongbong, McPherson, Timothy, Park, Kinam
• Primary Examiner(s): Prebilic, Paul B.
• Application Number:
  US08/774,707
• Time in Patent Office: 1,111 Days
• Field of Search: 623/11, 600/36, 427/2.24, 427/2.25
• US Class Current: 623/23.76
• CPC Class Codes: A61L 27/02 Inorganic materials
• CPC Class Codes: A61L 27/04 Metals or alloys
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: B05D 7/16 using synthetic lacquers or varnishes
• CPC Class Codes: C08L 33/14 of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen
• CPC Class Codes: C08L 51/08 grafted on to macromolecular compounds obtained otherwise than by reactions only involving unsaturated carbon-to-carbon bonds
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

Methods for grafting unmodified PEO or any other water-soluble polymers to the surfaces of metals and glasses to form biocompatible surfaces having low protein affinity is provided. One technique includes the steps of: (a) providing a support member having a plurality of hydroxyl or oxide groups attached to a surface of said support member; (b) exposing said surface to a silane coupling agent to cause the silane coupling agent to form a silane layer that is covalently bound to the surface wherein the silane layer comprises a plurality of vinyl groups; and (c) exposing the silane layer to a hydrophilic polymer and causing the silane layer to react with the hydrophilic polymer to covalently bond to the silane layer. Exposure of the silane layer to γ-radiation to induce grafting with low radiation to induce grafting of the hydrophilic polymer to the silane layer. Another technique comprises grafting a silylated hydrophilic polymer or chain having a hydrophobic domain directly to the metal or inorganic surface.

Claims

1. A method of grafting hydrophilic polymers to a surface of an article comprising the steps of:

(a) providing an article having a plurality of hydroxyl or oxide groups attached to a surface of said article;

(b) exposing said surface to a silanated hydrophilic polymer that has the structure;

##STR14## wherein at least one of said R⁴, R⁵, and R⁶ is a hydrolyzable group each containing 1 to 6 carbon atoms, with the other(s) being nonhydrolyzable alkyl groups each containing 1 to 4 carbons, X is selected from an alkyl group, aryl group that is unsubstitued or substituted by one or more C_1-20 alkyl groups, L is a linking moiety having one or more linking groups that is selected from amide (--C(O)NH--), ester (--C(O)O--), urea (--NHC(O)NH--), urethane (--OC(O)NH--), ether (--O--), thioether(--S--), thiocarbamate (--OC(S)NH--), amine (--NH--), and mixture thereof provided that when L comprises more than one linking group, each is separated from the next by --(CH₂)_m --, wherein m is an integer from 1 to 20, μ

is 0 or 1, and Y is a hydrophilic polymer; and

(c) hydrolyzing the silanated hydrophilic polymer to form a silane layer; and

(d) curing the silane layer to cause the silane layer to be covalently bonded to the surface of the article.

2. The method of claim 1 wherein the article is made of inorganic material or metal.

3. The method of claim 1 wherein the surface is made from a material selected from the group consisting of stainless steel, titanium, titanium nickel alloys, titanium aluminum vanadium alloys, tantalum, aluminum, chrome-cobalt alloys, pyrolytic carbon, glass, ceramics and mixtures thereof.

5. The method of claim 1 wherein R⁴, R⁵, and R⁶ are each a hydrolyzable group selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, phenoxy, pentoxy, bromide, chloride, and iodide.

6. The method of claim 1 wherein X is a nonhydrolyzable group selected from the group containing methyl, ethyl, propyl butyl, hexyl, octyl, benzyl, and cyclohexyl.

7. The method of claim 1 wherein L is a linkage moiety and also extendible, hydrophobic moiety having one or more linking groups that connect linear hydrophobic hydrocarbons selected from the group consisting of hexyl, octyl, decyl, undecyl, and dodecyl, by the linkages selected from the group consisting of urethane, urea and ether.

8. The method of claim 6 wherein L is linear hydrophobic linking moiety consisting of 4-diisocyantobutane, 1,6-diisocyanatohexane, 1,4-diisocyanatobenzene, 1,8-diisocyanatooctane, 1,12-diisocyanatododecane, 10-undecen-1-ol, 9-decen-1-ol, 1,12-diaminododecane, 1,10-diaminodecane, 1,9-diaminononane, 1,8-diaminooctane, or mixtures thereof.

9. The method of claim 1 wherein step (d) forms a biocompatible surface that has a protein adsorption affinity of less than about 0.10 μ

g/cm².

10. The method of claim 1 wherein Y is polyethylene oxide.

11. The method of claim 1 wherein Y is selected from the group consisting of poly(vinyl pyrrolidone), poly(methacrylic acid), poly(acrylic acid), poly(hydroxyethylmethacrylate), and poly(vinyl alcohol).

4. A method of grafting hydrophilic polymers to a surface of an article comprising the steps of:

(a) providing an article having a plurality of hydroxyl or oxide groups on a surface thereof;

(b) exposing said surface to a silanated hydrophilic polymer selected from the group consisting of 8-(m-PEO)octyltrimethoxysilane, 8-(m-PEO)octyltriethoxysilane, 4-(m-PEO)butyltrimethoxysilane, 4-(m-PEO)butyltriethoxysilane, 3-(m-PEO)propyltrimethoxysilane, 3-(m-PEO)propyltriethoxysilane, triethoxysilylpropyl m-PEO carbamate, trimethoxysilylpropyl m-PEO carbamate, trimethoxysilylpropylureidododecylureido m-PEO carbamate, triethoxysilylpropylureidodecylureido m-PEO carbamate, triethoxysilylpropyluredecylureido m-PEO carbamate, trimethoxysilylpropylureidodecylureido m-PEO carbamate, trimethoxysilylpropylthioundecyl m-PEO 1,6-dicarbamatohexane, trimethoxysilylpropylthioundecyl m-PEO 1,4-dicarbamatobutane, trimethoxysilylpropylthioundecyl m-PEO 1,8-dicarbamatooctane, trimethoxysilylpropylthioundecyl m-PEO 1,12-dicarbamatododecane, triethoxysilylpropylthioundecyl m-PEO 1,6-dicarbamatohexane, triethoxysilylpropylthioundecyl m-PEO, 1,4-dicarbamatobutane, triethoxysilylpropylthioundecyl m-PEO 1,8-dicarbamatooctane, triethoxysilylpropylthioundecyl m-PEO 1,12-dicarbamatododecane, and mixtures thereof;

(c) hydrolyzing the silanated hydrophilic polymer to form a silane layer; and

(d) curing the silane layer to cause the silane layer to be covalently bonded to the surface of the article.

12. A device having a biocompatible surface that has hydrophilic polymers grafted onto the surface and having been fabricated by a process comprising the steps of:

(a) providing a device having a plurality of hydroxyl or oxide groups on a surface thereof;

(b) exposing said surface to a silanated hydrophic polymer selected from the group consisting of the group containing 8-(m-PEO)octyltrimethoxysilane, 8-(m-PEO)octyltriethoxysilane, 4-(m-PEO)butyltrimethoxysilane, 4-(m-PEO)butyltriethoxysilane, 3-(m-PEO)propyltrimethoxysilane, 3-(m-PEO)propyltriethoxysilane, triethoxysilylpropyl m-PEO carbamate, trimethoxysilylpropyl m-PEO carbamate, trimethoxysilylpropylureidododecylureido m-PEO carbamate, triethoxysilylpropylureidodecylureido m-PEO carbamate, triethoxysilylpropylureidecylureido m-PEO carbamate, trimethoxysilylpropylureidodecylureido m-PEO carbamate, trimethoxysilylpropylthioundecyl m-PEO 1,6-dicarbamatohexane, trimethoxysilylpropylthioundecyl m-PEO, 1,4-dicarbamatobutane, trimethoxysilylpropylthioundecyl m-PEO 1,8-dicarbamatooctane, trimethoxysilylpropylthioundecyl m-PEO 1,12-dicarbamatododecane, triethoxysilylpropylthioundecyl m-PEO 1,16-dicarbamatohexane, triethoxysilylpropylthioundecyl m-PEO, 1,4-dicarbamatobutane, triethoxysilylpropylthioundecyl m-PEO 1,8-dicarbamatooctane, triethoxysilylpropylthioundecyl m-PEO 1,12-dicarbamatododecane, and mixtures thereof; and

(c) curing the silane layer to cause the silane layer to be covalently bonded to the surface of the device.

13. A method of grafting hydrophilic polymers to a surface of an article comprising the steps of:

(a) providing an article having a plurality of hydroxy or oxide groups attached to a surface of said article;

(b) exposing said surface to trichlorovinylsilane to form a silane layer that is covalently bound to the surface; and

(c) exposing the silane layer to a hydrophilic polymer selected from the group consisting of poly(ethylene oxide) (PEO), polyhydroxyethylmethacrylate (PHEMA), PEO-containing block copolymers, and mixtures thereof and causing the silane layer to react with the hydrophilic polymer to covalently bond to the silane layer.

15. The method of claim 13, wherein the silane layer comprises a plurality of vinyl groups.

16. The method of claim 13 wherein the hydrophilic polymer is poly(ethylene oxide).

14. A device having a biocompatible surface that has hydrophilic polymers grafted onto the surface and having been fabricated by a process comprising the steps of:

(a) providing a device having a plurality of hydroxyl or oxide groups attached to a surface of said device;

(b) exposing said surface to trichlorovinylsilane to form a silane layer that is covalently bound to the surface wherein the silane layer comprises a plurality of vinyl groups; and

(c) exposing the silane layer to a hydrophilic polymer of poly(ethylene oxide) and causing the silane layer to react with poly(ethylene oxide) to covalently bond to the silane layer.