Biofunctional surface modified ocular implants, surgical instruments, medical devices, prostheses, contact lenses and the like

• US 6,387,379 B1
• Filed: 02/28/1994
• Issued: 05/14/2002
• Est. Priority Date: 04/10/1987
• Status: Expired due to Fees

• Current Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Mentak, Khalid, Seeger, James, Erickson, Theresa Rivero, Yahiaoui, Ali, Goldberg, Eugene P.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/202,647
• Time in Patent Office: 2,997 Days
• Field of Search: 424/78.18, 424/400, 427/492, 427/495, 427/496, 427/498, 427/507, 427/535-36, 427/539, 427/491, 427/2.1, 427/2.12, 606/151, 606/159, 604/93, 623/8, 523/6
• US Class Current: 424/400
• CPC Class Codes: A61F 2/0077 Special surfaces of prostheses, e.g. for improving ingrowth A61F2/30767 takes precedence
• CPC Class Codes: A61F 2/16 Intraocular lenses
• CPC Class Codes: A61F 2/1613 having special lens configurations, e.g. multipart lenses; having particular optical properties, e.g. pseudo-accommodative lenses, lenses having aberration corrections, diffractive lenses, lenses for variably absorbing electromagnetic radiation, lenses having variable focus
• CPC Class Codes: A61F 2002/0086 for preferentially controlling or promoting the growth of specific types of cells or tissues of bone tissue onto implantable joints A61F2002/3093
• CPC Class Codes: A61F 2002/009 for hindering or preventing attachment of biological tissue of bone tissue onto implantable joints A61F2002/30932
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/79 Polymers of vinyl pyrrolidone
• 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 2430/16 for reconstruction of eye parts, e.g. intraocular lens, cornea
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• 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 33/0088 by grafting of a monomer onto the substrate
• CPC Class Codes: B05D 3/068 using ionising radiations (gamma, X, electrons)
• CPC Class Codes: B05D 3/142 Pretreatment
• CPC Class Codes: B05D 7/02 to macromolecular substances, e.g. rubber treatment or coating of shaped articles made of macromolecular substances C08J7/00
• CPC Class Codes: C03C 17/32 with synthetic or natural resins C03C17/30 takes precedence
• CPC Class Codes: C03C 2218/31 Pre-treatment
• CPC Class Codes: C03C 23/0035 : by gamma-rays
• CPC Class Codes: C03C 23/004 : by electrons, protons or alpha-particles
• CPC Class Codes: C03C 23/006 : by plasma or corona discharge
• CPC Class Codes: C04B 41/48 : Macromolecular compounds
• CPC Class Codes: C08J 7/18 : using wave energy or particle radiation
• CPC Class Codes: C08L 1/28 : Alkyl ethers
• 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 39/06 : Homopolymers or copolymers of N-vinyl-pyrrolidones
• CPC Class Codes: C08L 5/08 : Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 51/00 : Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds for ABS polymers C08L55/02; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 51/06 : grafted on to homopolymers or copolymers of aliphatic hydrocarbons containing only one carbon-to-carbon double bond
• CPC Class Codes: C23C 26/00 : Coating not provided for in groups C23C2/00 - C23C24/00
• CPC Class Codes: C23C 8/36 : using ionised gases, e.g. ionitriding
• CPC Class Codes: G02B 1/041 : Lenses
• CPC Class Codes: G02B 1/043 : Contact lenses

Abstract

A method for modifying the surface of a material adapted for contact with tissue of a human or non-human animal to impart biofunctional, bioactive or biomimetic properties to the surface comprising:

(a) exposing the surface to a solution comprising (1) an ethylenically unsaturated monomer or mixture thereof capable, via the ethylenic unsaturation, of gamma irradiation or electron beam induced polymerization, and (2) at least one biofunctional agent; and

(b) irradiating the surface with gamma or electron beam irradiation in the presence of the solution to thereby form on the surface a graft polymerized coating, the coating having physically entrapped therein or chemically bonded thereto molecules of the at least one biofunctional agent which imparts biofunctional or biomimetic properties to the surface;

wherein the gamma or electron beam irradiation induced polymerization is conducted under one of the following conditions:

A.

(i) monomer concentration in the solution in the range of from about 0.1% to about 50%, by weight;

(ii) total gamma or electron beam dose in the range of from about 0.001 to less than about 0.50 Mrad; and

(iii) gamma dose rate in the range of from about 10 to about 2,500 rads/min., or electron beam dose rate in the range of from about 10 to about 10⁸ rads/min.;

B.

(i) hydrophilic monomer(s) graft under conditions which may include monomer pre-soak or plasma gamma surface modification (especially for metal or glass substrates in latter case); and

(ii) graft polymerization of monomer(s) with bioactive/biofunctional molecules using (i) as substrate;

C.

(i) Hydrograft™ as in A or B above followed by dehydration and adsorption of bioactive/biofunctional molecules into the hydrophilic polymer graft;

wherein the biological properties of the biofunctional agent are substantially maintained.

Claims

1. A method for modifying the surface of a material adapted for contact with tissue of a human or non-human animal to impart biofunctional, bioactive or biomimetic properties to said surface comprising:

(a) exposing said surface to a solution comprising (1) a neutral or ionic water-soluble, hydrophilic, vinylic monomer, salt or mixture thereof, and (2) at least one biofunctional agent, the concentration of said biofunctional agent in said solution being in the range of from about 0.001% to about 50%, by weight; and

(b) irradiating said surface with gamma or electron beam irradiation in the presence of said solution to thereby form on said surface a graft polymerized coating, said coating having physically entrapped therein or chemically bonded thereto molecules of said at least one biofunctional agent which imparts biofunctional properties to said surface;

wherein said gamma or electron beam irradiation induced polymerization is conducted under the following conditions;

(i) concentration of monomer and biofunctional molecules in the solution in the range of from about 0.1% to about 50%, by weight;

(ii) total gamma or electron beam dose in the range of from about 0.001 to less than about 0.50 Mrad; and

(iii) gamma dose rate in the range of from about 10 to about 2,500 rads/min., or electron beam dose rate in the range of from about 10 to about 10⁸ rads/min.; and

wherein the biological properties of said biofunctional agent are substantially retained under said gamma or electron beam irradiation polymerization conditions.

2. The method according to claim 1 further including one or more of the following conditions:

(d) substantially excluding free oxygen from said graft polymerization solution;

(e) maintaining the thickness of said polymer coating in the range of from about 100 Å

to about 100 microns;

(f) including a free radical scavenger in said aqueous graft polymerization solution; and

(g) including in said aqueous graft polymerization solution a swelling solvent for said plastic surface.

3. The method according to claim 1 wherein said monomer is selected from the group consisting of N-vinyl-pyrrolidone, hydroxyethylmethacrylate, acrylamide, dimethyl-acrylamide, polyethylene glycol monomethacrylate, acryloylpolyethylene glycol, hydroxypropylacrylamide, methacrylic acid, sulfopropylacrylate, sulfopropylmethacrylate, styrenesulfonic acid, 2-acrylamide-2-methyl-1-propane sulfonic acid, vinylsulfonic acid, dimethylaminoethylmethacrylate, mixtures and salts thereof.

4. The method according to claim 1 wherein said monomer-biofunctional molecule solution contains up to about 50 wt. %, based on the total monomer weight, of an ionic monomer, a salt or mixture thereof.

5. The method according to claim 1 further including, prior to said step of polymerization, a step comprising pre-soaking said surface in at least one of said monomers or in an aqueous solution of at least one of said monomers, having a concentration of monomer therein of from about 5 to about 95%, by weight;

said pre-soaking being conducted for a period of time and at a temperature sufficient to facilitate diffusion of said monomer into said surface.

6. The method according to claim 5 wherein said pre-soaking step is conducted at a temperature in the range of from about 25°

C. to about 90°

C. and for a period of time of from about 0.5 hour to about 48 hours.

7. The method according to claim 1 wherein said gamma or electron beam irradiation induced polymerization is conducted in multiple steps;

the first step comprising conducting said steps (a) and (b) of claim 1 under conditions (i), (ii) and (iii) in the absence of any biofunctional agent;

the second step comprising soaking the product of said first step in a solution of said at least one biofunctional said soaking being conducted for a period of time and at a temperature sufficient to facilitate diffusion of said at least one biofunctional agent into said polymerized surface; and

a final step comprising conducting said steps (a) and (b) of claim 1 under conditions (i) and (iii), but wherein said total gamma or electron beam dose (i) is in the range of from about 0.001 to less than about 0.20 Mrad.

8. The method according to claim 7 further including, prior to said step of polymerization, a step comprising pre-soaking said surface in at least one of said monomers or in an aqueous solution of at least one of said monomers, having a concentration of monomer therein of from about 5 to about 95%, by weight;

said pre-soaking being conducted for a period of time and at a temperature sufficient to facilitate diffusion of said monomer into said surface.

9. The method according to claim 7 wherein said pre-soaking step is conducted at a temperature in the range of from about 25°

C. to about 90°

C. and for a period of time of from about 0.5 hour to about 48 hours.

10. The method according to claim 8 wherein a product of said first step is soaked in an aqueous solution of said at least one biofunctional agent, and said aqueous solution may contain a water-soluble organic solvent for the biofunctional component(s).

11. The method according to claim 10 wherein the concentration of said biofunctional agent in said solution is in the range of from about 0.001% to about 10% by weight.

12. The method according to claim 7 wherein said soaking is conducted at a temperature of from about 4°

to about 90° and

for a period of time of from about 5 minutes to about 24 hours.

13. The method according to claim 1 wherein said graft polymerized coating is hydrophilic.

14. The method according to claim 1 wherein said material surface is metallic, polymeric, ceramic, glass or quartz.

15. The method according to claim 14 wherein said material surface is polymeric and is selected from the group consisting of polyacrylates, polymethacrylates, polyolefins, ethylene-propylene copolymers, styrene-butadiene copolymers, styrene-ethylene-butadiene copolymers, polycarbonates, fluorocarbon polymers, polysiloxanes, siloxane block copolymers, polyurethanes, polyvinylchloride, polyesters, mixtures and copolymers thereof.

16. The method according to claim 1 wherein said biofunctional agent is a beta-blocker, a steroidal or non-steroidal anti-inflammatory agent, an anti-bacterial agent, a protein, a cytotoxic or anti-tumor agent, a fibrinolytic agent, a polysaccharide, an anti-oxidant or anti-oxidant enzyme, a growth factor or growth hormone, an anti-bloodclotting agent, a phospholipid, a smooth muscle cell inhibitor, a vascular basement membrane component or an immune modulator.

17. A method according to claim 1 including the step of activating said surface prior to said gamma irradiation or electron beam induced polymerization step by exposing said surface to a glow discharge plasma (GDP) having a power and for a time sufficient to induce grafting sites on said surface which are available for said subsequent gamma irradiation or electron beam polymerization.

18. The method according to claim 17, wherein said GDP is RF-, microwave- or DC discharge-generated.

19. The method according to claim 17, wherein said surface is exposed to RF-GDP having a power in the range of from about 1 W to about 500 W or more.

20. The method according to claim 17, wherein said surface is exposed to RF-GDP for a time in the range of from about 0.1 second to about 120 minutes.

21. The method according to claim 17, wherein said GDP treated surface is exposed to air, water vapor or oxygen before said gamma irradiation induced polymerization.

22. A composition of matter comprising a coating formed on a substrate adapted for contact with tissue of a human or non-human animal by a method comprising:

(a) exposing said substrate to a solution comprising (1) an ethylenically unsaturated neutral or ionic, water-soluble, hydrophilic monomer, salt or mixture thereof capable, via said ethylenic unsaturation, of gamma irradiation or electron beam induced polymerization, and (2) at least one biofunctional agent, the concentration of said biofunctional agent in said solution being in the range of from about 0.001% to about 50%, by weight; and

(b) irradiating said substrate with gamma or electron beam irradiation in the presence of said solution to thereby form on said substrate a graft polymerized coating, said coating having physically entrapped therein or chemically bonded thereto molecules of said at least one biofunctional agent which imparts biomimetic properties to said substrate;

wherein said gamma or electron beam irradiation induced polymerization is conducted under the following conditions;

(i) monomer and biofunctional molecules concentration in the solution in the range of from about 0.1% to about 50%, by weight;

(ii) total gamma or electron beam dose in the range of from about 0.001 to less than about 0.50 Mrad; and

(iii) gamma dose rate in the range of from about 10 to about 2,500 rads/min., or electron beam dose rate in the range of from about 10 to about 10⁸ rads/min.; and

wherein the biological properties of said biofunctional agent are substantially unaffected by said gamma or electron beam irradiation polymerization conditions.

23. The composition according to claim 22 wherein said monomer is selected from the group consisting of N-vinyl-pyrrolidone, hydroxyethylmethacrylate, acrylamide, dimethylacrylamide, polyethylene glycol monomethacrylate, acryloylpolyethylene glycol, hydroxypropylacrylamide, methacrylic acid, sulfopropylacrylate, sulfopropylmethacrylate, styrenesulfonic acid, 2-acrylamide-2-methyl-1-propane sulfonic acid, vinylsulfonic acid, dimethylaminoethylmethacrylate, mixtures and salts thereof.

24. The composition according to claim 22 wherein said monomer-biofunctional molecule solution contains up to about 50 wt. %, based on the total monomer weight, of an ionic monomer, a salt or mixture thereof.

25. The composition according to claim 22 wherein said method further includes, prior to said step of polymerization, a step comprising pre-soaking said substrate in at least one of said monomers or in an aqueous solution of at least one of said monomers, having a concentration of monomer therein of from about 5 to about 95%, by weight;

said pre-soaking being conducted for a period of time and at a temperature sufficient to facilitate diffusion of said monomer into said substrate.

26. The composition according to claim 25 wherein said pre-soaking step is conducted at a temperature in the range of from about 25°

C. to about 90°

C. and for a period of time of from about 0.5 hour to about 48 hours.

27. The composition according to claim 22 wherein said gamma or electron beam irradiation induced polymerization is conducted in multiple steps;

the first step comprising conducting said steps (a) and (b) of claim 22 under conditions (i), (ii) and (iii) in the absence of any biofunctional agent;

the second step comprising soaking the product of said first step in a solution of said at least one biofunctional said soaking being conducted for a period of time and at a temperature sufficient to facilitate diffusion of said at least one biofunctional agent into said polymerized substrate; and

a final step comprising conducting said steps (a) and (b) of claim 22 under conditions (i) and (iii), but wherein said total gamma or electron beam dose (i) is in the range of from about 0.001 to less than about 0.20 Mrad.

28. The composition according to claim 27 further including, prior to said step of polymerization, a step comprising pre-soaking said substrate in at least one of said monomers or in an aqueous solution of at least one of said monomers, having a concentration of monomer therein of from about 5 to about 95%, by weight;

said pre-soaking being conducted for a period of time and at a temperature sufficient to facilitate diffusion of said monomer into said substrate.

29. The composition according to claim 27 wherein said pre-soaking step is conducted at a temperature in the range of from about 25°

C. to about 90°

C. and for a period of time of from about 0.5 hour to about 48 hours.

30. The composition according to claim 22 wherein said graft polymerized coating is hydrophilic.

31. The composition according to claim 22 wherein said substrate is metallic, polymeric, ceramic, glass or quartz.

32. The composition according to claim 31 wherein said substrate is polymeric and is selected from the group consisting of, polyacrylates, polymethacrylates, polyolefins, ethylene-propylene copolymers, styrene-butadiene copolymers, styrene-ethylene-butadiene copolymers, polycarbonates, fluorocarbon polymers, polysiloxanes, siloxane block copolymers, polyurethanes, polyvinylchloride, polyesters, mixtures and copolymers thereof.

33. The composition according to claim 22 wherein said biofunctional agent is a beta-blocker, a steroidal or non-steroidal anti-inflammatory agent, an anti-bacterial agent, a protein, a cytotoxic or anti-tumor agent, a fibrinolytic agent, a polysaccharide, an anti-oxidant or anti-oxidant enzyme, a growth factor or growth hormone, an anti-bloodclotting agent, a phospholipid, a smooth muscle cell inhibitor, a vascular basement membrane component or an immune modulator.

34. A composition according to claim 22 wherein said method includes the step of activating said substrate prior to said gamma irradiation or electron beam induced polymerization step by exposing said substrate to a glow discharge plasma (GDP) having a power and for a time sufficient to induce grafting sites on said substrate which are available for said subsequent gamma irradiation or electron beam polymerization.

35. The composition according to claim 34, wherein said GDP is RF-, microwave- or DC discharge-generated.

36. The composition according to claim 34, wherein said substrate is exposed to RF-GDP having a power in the range of from about 1 W to about 500 W or more.

37. The composition according to claim 34, wherein said substrate is exposed to RF-GDP for a time in the range of from about 0.1 second to about 120 minutes.

38. The composition according to claim 34 wherein said GDP treated substrate is exposed to air, water vapor or oxygen before said gamma irradiation induced polymerization.

39. An article comprised at least in part of a material produced by a method for modifying the surface of a material adapted for contact with tissue of a human or non-human animal to impart biofunctional, bioactive or biomimetic properties to said surface comprising:

(a) exposing said surface to a solution comprising (1) a neutral or ionic water-soluble, hydrophilic, vinylic monomer, salt or mixture thereof, and (2) at least one biofunctional agent, the concentration of said biofunctional agent in said solution being in the range of from about 0.001% to about 50%, by weight; and

(b) irradiating said surface with gamma or electron beam irradiation in the presence of said solution to thereby form on said surface a graft polymerized coating, said coating having physically entrapped therein or chemically bonded thereto molecules of said at least one biofunctional agent which imparts biofunctional properties to said surface;

wherein said gamma or electron beam irradiation induced polymerization is conducted under the following conditions;

(i) concentration of monomer and biofunctional molecules in the solution in the range of from about 0.1% to about 50%, by weight;

(ii) total gamma or electron beam dose in the range of from about 0.001 to less than about 0.50 Mrad; and

(iii) gamma dose rate in the range of from about 10 to about 2,500 rads/min., or electron beam dose rate in the range of from about 10 to about 10⁸ rads/min.; and

wherein the biological properties of said biofunctional agent are substantially retained under said gamma or electron beam irradiation polymerization conditions.

40. An article according to claim 39 wherein said article is an ocular implant material.

41. An article according to claim 39 wherein said article is a surgical instrument.

42. An article according to claim 39 wherein said article is a medical device.

43. An article according to claim 39 wherein said article is a prosthetic implant.

44. An article according to claim 39 wherein said article is a soft or hard contact lens.

45. An article according to claim 39 wherein said article is a vascular graft or stent.

46. An article according to claim 39 wherein said article is a joint replacement composite.

47. An article according to claim 39 wherein said article is a mammary implant.

48. An article according to claim 39 wherein said article is a catheter.

49. An article according to claim 39 wherein said article is a blood bag, blood oxygenator or blood tubing.

50. An article according to claim 39 wherein said article is a dialysis membrane.

51. An article according to claim 39 wherein said article is a nerve regeneration scaffold.