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

Claim 2

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 R 1 and R 2 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 R 1 and R 2 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 R 3 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 NR 4 , and wherein R 4 is hydrogen or an alkyl group containing from 1 to 4 carbon atoms.

Claim 3

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

Claim 4

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.

Claim 5

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.

Claim 6

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.

Claim 7

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.

Claim 8

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.

Claim 9

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.

Claim 10

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.

Claim 11

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

Claim 12

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.

Claim 13

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.

Claim 14

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.

Claim 15

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

Claim 16

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 R 1 and R 2 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 R 1 and R 2 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 R 3 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 NR 4 , and wherein R 4 is hydrogen or an alkyl group containing from 1 to 4 carbon atoms.

Claim 17

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 R 1 and R 2 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 R 1 and R 2 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 R 3 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 NR 4 , and wherein R 4 is hydrogen or an alkyl group containing from 1 to 4 carbon atoms.

Claim 18

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.

Claim 19

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.

Claim 20

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.

Claim 21

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

Claim 22

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.

Claim 23

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.

Claim 24

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.

Claim 25

An activated substrate having the formula: ##STR7## wherein R 1 and R 2 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 R 1 and R 2 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 R 3 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 NR 4 , wherein R 4 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.

Claim 26

An activated substrate having the formula: ##STR7## wherein R 1 and R 2 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 R 1 and R 2 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 R 3 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 NR 4 , wherein R 4 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.

Claim 27

The activated substrate according to claim 23, wherein R 3 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.

Claim 28

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.

Claim 31

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.

Claim 32

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

Claim 33

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.

Claim 34

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.

Claim 35

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.

Claim 36

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.