Azlactone-functional substrates, corneal prostheses, and manufacture and use thereof

• US 5,292,514 A
• Filed: 06/24/1992
• Issued: 03/08/1994
• Est. Priority Date: 06/24/1992
• Status: Expired due to Term

• Current Assignee: 3M Company
• Original Assignee: 3M Company
• Inventors: Olson, David B., Heilmann, Steven M., Krepski, Larry R., Kwon, Oh-Seung, Capecchi, John T.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Kulkosky, Peter F.
• Application Number:
  US07/903,367
• Time in Patent Office: 622 Days
• Field of Search: 424/426, 424/422, 424/427, 424/428, 424/429, 424/423, 525/54.2, 525/375
• US Class Current: 424/422
• CPC Class Codes: A61F 2/14 Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
• CPC Class Codes: A61F 2/142 Cornea, e.g. artificial corneae, keratoprostheses or corneal implants for repair of defective corneal tissue
• CPC Class Codes: A61F 2/15 Implant having one or more holes, e.g. for nutrient transport, for facilitating handling
• CPC Class Codes: A61L 27/28 Materials for coating prostheses
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: C07C 45/71 being hydroxy groups
• CPC Class Codes: C07C 49/835 having unsaturation outside an aromatic ring
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C08F 8/30 Introducing nitrogen atoms or nitrogen-containing groups
• CPC Class Codes: C08K 5/15 Heterocyclic compounds having oxygen in the ring
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00

Abstract

Azlactone-functional substrates, (especially hydrogels), mammalian body implants, and methods of making and using them are disclosed. The azlactone-functional substrates are the reaction product of substrates having azlactone-reactive nucleophilic surfaces and a multi-functional azlactone composition having at least two azlactone moieties, where at least one moiety covalently couples to the azlactone-reactive nucleophilic surface and at least one moiety remains available for further nucleophilic reaction, such as with a biologically active material. A preferred use of azlactone-functional hydrogel is as the optical element of a corneal prosthesis which enhances epithethial cell growth.

Claims

1. A mammalian body implant comprising:

a hydrogel having azlactone-reactive nucleophilic surfaces, a multi-functional azlactone composition covalently coupled using at least one azlactone moiety to the azlactone-reactive nucleophilic surfaces, and a biologically active material coupled to the multi-functional azlactone composition using at least one azlactone moiety;

wherein the mammalian body implant has the formula;

##STR5## wherein R¹ and R² independently can be an alkyl group having 1 to 14 carbon atoms, a cycloalkyl group having 3 to 14 carbon atoms, an aryl group having 5 to 12 ring atoms, an arenyl group having 6 to 26 carbon atoms and 0 to 3 S, N, and nonperoxidic O heteroatoms, or R¹ and R² taken together with the carbon to which they are joined can form a carbocyclic ring containing 4 to 12 ring atoms, and n is an integer 0 or 1;

wherein y is at least one and is the number of azlactone moieties less at least one;

wherein R³ is a bridging group capable of covalently connecting a plurality of azlactone moieties; and

wherein B is the hydrogel having azlactone-reactive nucleophilic surfaces and A is a residue of a azlactone-reactive nucleophilic group on the surface on the hydrogel, the azlactone-reactive nucleophilic group comprising O, S, or NR⁴, and wherein R⁴ is hydrogen or an alkyl group containing from 1 to 4 carbon atoms.

2. The mammalian body implant according to claim 1, wherein the implant comprises a corneal prosthesis.

3. The mammalian body implant according to claim 1, wherein the implant comprises a corneal prosthesis and wherein the biologically active material comprises laminin, fibronectin, Type I collagen, Type IV collagen, a cell-free extract prepared from an extracellular matrix of corneal epithelial cells, or combinations thereof.

4. The mammalian body implant according to claim 1, wherein the implant comprises a corneal prosthesis and wherein the hydrogel comprises a poly(vinyl alcohol) copolymer.

5. The mammalian body implant according to claim 1, wherein the implant comprises a corneal prosthesis and further comprising a layer of epithethial cells adhered to the nucleophilic surfaces at the biologically active material.

6. The mammalian body implant according to claim 2, wherein the corneal prosthesis comprises a blend of a poly(vinyl alcohol-co-vinyl acetate) and a copolymer of poly(vinyl alcohol) and a benzophenone ultraviolet light absorber selected from the group consisting of 2-allyloxy-4,4'"'"'-dimethoxy-2-hydroxy benzophenone, 3-allyl-2,2'"'"'-dihydroxy-4,4'"'"'-dimethoxy benzophenone, 2,2'"'"'-dihydroxy-4-methoxy-4'"'"'-(2-methacryloyloxyethoxy) benzophenone and 4-(2'"'"'-acryloyloxyethoxy)-2-hydroxy benzophenone.

7. The mammalian body implant according to claim 2, wherein the corneal prosthesis comprises an optical element which comprises a copolymer of poly(vinyl alcohol), a benzophenone ultraviolet light absorber selected from the group consisting of 2-allyloxy-4,4'"'"'-dimethoxy-2'"'"'-hydroxy benzophenone and 3-allyl-2,2'"'"'-dihydroxy-4,4'"'"'-dimethoxy benzophenone, and a comonomer comprising maleic anhydride.

8. The mammalian body implant according to claim 2, wherein the corneal prosthesis comprises an optical element having an optically transparent central portion and an anterior surface having the reaction product of the multi-azlactone composition and the biologically active material, wherein the anterior surface is capable of supporting a layer of epithethial cells, and a porous outer skirt secured to the periphery of the optical element, the skirt being sufficiently porous to permit cell ingrowth and tissue attachment.

9. The mammalian body implant according to claim 8, wherein the biologically active material comprises laminin, fibronectin, Type I collagen, Type IV collagen, a cell-free extract prepared from an extracellular matrix of corneal epithelial cells, or combinations thereof.

10. The mammalian body implant according to claim 8, wherein the hydrogel comprises a poly(vinyl alcohol) copolymer.

11. The mammalian body implant according to claim 8, further comprising a layer of epithethial cells adhered to the nucleophilic surfaces at the biologically active material.

12. The mammalian body implant according to claim 8, wherein the porous outer skirt comprises a coherent mass of randomly-oriented melt drawn fibers having an interconnected network of pores.

13. The mammalian body implant according to claim 8, wherein the optical element is a poly(vinyl alcohol-co-vinyl acetate) copolymer and the porous outer skirt is a polyolefin material, and

wherein the multi-functional azlactone composition, prior to covalent coupling to the azlactone-reactive nucleophilic surfaces, comprises 2-alkenyl azlactone homopolymers, copolymers, or oligomers, tris [[2-[N-2-(4,4-dimethyl-2-oxazoline-5-one-2-yl)ethyl, N-isopropyl]-2-amino]ethyl]amine, or N,N'"'"', N"-tris-2-(4,4-dimethyl-2-oxazoline-5-one-2-yl)ethyl-bis-(N,N"-isopropyl-2-aminoethyl)amine.

14. The mammalian body implant according to claim 13, wherein the optical element has an anterior surface coated with epithethial cells.

30. The mammalian body implant according to claim 1, wherein the bridging group comprises an alkylene group having up to 14 carbon atoms;

an arylene group having up to 10 carbon atoms;

a cycloalkylene group having up to 6 carbon atoms;

a group resulting from a Michael reaction of a Michael donor nucleophilic compound with a plurality of 2-alkenyl azlactone Michael acceptors, where the Michael donor nucleophilic compound has at least two azlactone-reactive moieties;

or combinations thereof.

31. The mammalian body implant according to claim 8, wherein the bridging group comprises an alkylene group having up to 14 carbon atoms;

an arylene group having up to 10 carbon atoms;

a cycloalkylene group having up to 6 carbon atoms;

a group resulting from a Michael reaction of a Michael donor nucleophilic compound with a plurality of 2-alkenyl azlactone Michael acceptors, where the Michael donor nucleophilic compound has at least two azlactone-reactive moieties;

or combinations thereof.

15. An azlactone-functional substrate, comprising a substrate having azlactone-reactive nucleophilic surfaces, said substrate selected from the group consisting of cellulose;

modified cellulose derivatives;

agarose, dextran;

chitin;

chitosan;

polymers derived from hydroxyethyl methacrylate, hydroxypropyl acrylate, N-methylol acrylamide, allyl alcohol, allyl amine, or N-[3-(N'"'"'-isopropyl) aminopropyl] methacrylamide monomers;

poly(vinyl alcohol) homopolymers; and

poly(vinyl alcohol) copolymers, and a multi-functional azlactone composition covalently coupled thereto using at least one azlactone moiety in a manner such that at least one azlactone moiety remains available for further nucleophilic reaction;

wherein the azlactone-functional substrate has the formula;

##STR6## wherein R¹ and R² independently can be an alkyl group having 1 to 14 carbon atoms, a cycloalkyl group having 3 to 14 carbon atoms, an aryl group having 5 to 12 ring atoms, an arenyl group having 6 to 26 carbon atoms and 0 to 3 S, N, and nonperoxidic O heteroatoms, or R¹ and R² taken together with the carbon to which they are joined can form a carbocyclic ring containing 4 to 12 ring atoms, and n is an integer 0 or 1;

wherein y is at least one and is the number of azlactone moieties less at least one;

wherein R³ is a bridging group capable of covalently connecting a plurality of azlactone moieties; and

wherein B is the substrate having azlactone-reactive nucleophilic surfaces and A is a residue of a azlactone-reactive nucleophilic group on the surface on the substrate, the azlactone-reactive nucleophilic group comprising O, S, or NR⁴, and wherein R⁴ is hydrogen or an alkyl group containing from 1 to 4 carbon atoms.

16. The azlactone-functional substrate, according to claim 15 wherein the multi-functional azlactone composition comprises 2-alkenyl azlactone homopolymers, copolymers, or oligomers, tris[[2-[N-2(4,4-dimethyl-2-oxazoline-5-one-2-yl)ethyl, N-isopropyl]-2-amino]ethyl]amine, or N,N'"'"', N"-tris-2-(4,4-dimethyl-2-oxazoline-5-one-2-yl)ethyl-bis-(N,N"-isopropyl-2-aminoethyl)amine.

17. The azlactone-functional substrate, according to claim 15 wherein the substrate comprises a natural or synthetic composition which has azlactone-reactive, nucleophilic surfaces due to the presence of azlactone-reactive, nucleophilic moieties comprising hydroxyl, amine, or thiol moieties.

18. The azlactone-functional substrate, according to claim 17, wherein the substrate comprises cellulose, modified cellulose derivatives, agarose, dextran, chitin, chitosan, polymers derived from monomers comprising hydroxyethyl methacrylate, hydroxypropyl acrylate, N-methylolacrylamide, allyl alcohol, allyl amine, and N-[3-(N'"'"'-isopropyl)aminopropyl] methacrylamide, and polymers derived by modification of polymers such as silica gel and glass particles reacted with γ

-triethoxysilylpropylamine, γ

-triethoxysilylpropane-1-thiol, or γ

-glycidoxypropyltrimethoxysilane after hydroylsis of epoxide moieties thereon.

19. The azlactone-functional substrate, according to claim 15, wherein the substrate is a hydrogel which comprises a poly(vinyl alcohol) copolymer.

20. The azlactone-functional substrate, according to claim 19, wherein the poly(vinyl alcohol) copolymer comprises vinyl alcohol and vinyl acetate in molar ratio of from about 99.9:

0.1 vinyl alcohol;

vinyl acetate to about 95;

5.

21. The azlactone-functional substrate, according to claim 19, wherein the poly(vinyl alcohol) copolymer comprises vinyl alcohol and vinyl acetate in molar ratio of from about 97:

3 vinyl alcohol;

vinyl acetate to about 99;

1.

22. A biologically active substrate, comprising the reaction product of an azlactone-functional substrate and a biologically active material, wherein the azlactone-functional substrate comprises a substrate having azlactone-reactive nucleophilic surfaces and a multi-functional azlactone composition covalently coupled thereto using at least one azlactone moiety, and wherein the biologically active material is coupled using at least one azlactone moiety to the multifunctional azlactone composition, wherein the azlactone-functional substrate has the same formula as that of claim 19.

32. The mammalian body implant according to claim 15, wherein the bridging group comprises an alkylene group having up to 14 carbon atoms;

an arylene group having up to 10 carbon atoms;

a cycloalkylene group having up to 6 carbon atoms;

a group resulting from a Michael reaction of a Michael donor nucleophilic compound with a plurality of 2-alkenyl azlactone Michael acceptors, where the Michael donor nucleophilic compound has at least two azlactone-reactive moieties;

or combinations thereof.

23. An activated substrate having the formula:

##STR7## wherein R¹ and R² independently can be an alkyl group having 1 to 14 carbon atoms, a cycloalkyl group having 3 to 14 carbon atoms, an aryl group having 5 to 12 ring atoms, an arenyl group having 6 to 26 carbon atoms and 0 to 3 S, N, and nonperoxidic O heteroatoms, or R¹ and R² taken together with the carbon to which they are joined can form a carbocyclic ring containing 4 to 12 ring atoms, and n is an integer 0 or 1;

wherein y is at least one and is the number of azlactone moieties less at least one;

wherein R³ is a bridging group capable of covalently connecting a plurality of azlactone moieties; and

wherein B is a substrate having azlactone-reactive nucleophilic surfaces and A is a residue of a azlactone-reactive nucleophilic group on the surface on the substrate, the azlactone-functional nucleophilic group comprising O, S, or NR⁴, wherein R⁴ is hydrogen or an alkyl group containing from 1 to 4 carbon atoms, and wherein the substrate is selected from the group consisting of cellulose;

modified cellulose derivatives;

agarose;

dextran;

chitin;

chitosan;

polymers derived from hydroxyethyl methacrylate, hydroxypropyl acrylate, N-methylol acrylamide, allyl alcohol, allyl amine, or N-[3-(N'"'"'-isopropyl) aminopropyl] methacrylamide monomers;

poly(vinyl alcohol) homopolymers; and

poly(vinyl alcohol) copolymers.

24. The activated substrate according to claim 23, wherein R³ comprises an alkylene group having up to 14 carbon atoms;

an arylene group having up to 10 carbon atoms;

a cycloalkylene group having up to 6 carbon atoms;

groups resulting from a Michael reaction of a Michael donor nucleophilic compound with a plurality of 2-alkenyl azlactone Michael acceptors, wherein the Michael donor nucleophilic compound has at least two azlactone-reactive moieties;

or combinations thereof.

25. The activated substrate according to claim 24, wherein the Michael donor nucleophilic compounds comprise thiols, secondary amines, carbon acids, enamines, imides, nitrogen heterocycles, or combinations thereof.

26. A method of making an azlactone-functional hydrogel, comprising the steps of:

(a) forming a hydrogel in a dehydrated state comprising a composition having azlactone-reactive nucleophilic surfaces;

(b) reacting a multi-functional azlactone composition with the azlactone-reactive nucleophilic surfaces of the hydrogel in a dehydrated state in a manner that retains at least one azlactone moiety remaining available for further nucleophilic reaction;

wherein the azlactone-functional hydrogel has the formula;

##STR8## wherein R¹ and R² independently can be an alkyl group having 1 to 14 carbon atoms, a cycloalkyl group having 3 to 14 carbon atoms, an aryl group having 5 to 12 ring atoms, an arenyl group having 6 to 26 carbon atoms and 0 to 3 S, N, and nonperoxidic O heteroatoms, or R¹ and R² taken together with the carbon to which they are joined can form a carbocyclic ring containing 4 to 12 ring atoms, and n is an integer 0 or 1;

wherein y is at least one and is the number of azlactone moieties less at least one;

wherein R³ is a bridging group capable of covalently connecting a plurality of azlactone moieties; and

wherein B is the hydrogel having azlactone-reactive nucleophilic surfaces and A is a residue of a azlactone-reactive nucleophilic group on the surface on the hydrogel, the azlactone-reactive nucleophilic group comprising, O, S, or NR⁴, and wherein R⁴ is hydrogen or an alkyl group containing from 1 to 4 carbon atoms.

27. A method of forming a mammalian body implant, comprising the steps of:

(a) forming an azlactone-functional hydrogel according to the method of claim 26 and

(b) reacting a biologically active material with at least one azlactone moiety.

28. The method according to claim 27, further comprising after the reacting step, the step of covering the biologically active material with mammalian cells.

29. The method according to claim 27, wherein the implant comprises a corneal prosthesis and wherein the hydrogel comprises an optical element having a periphery, and wherein the method further comprises the step of securing a porous outer skirt to the periphery.