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Claims  |
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What is claimed is:
1. A method of providing a solid surface with desired characteristics
comprising choosing a synthetic polymer having the desired
characteristics, contacting the solid surface with a composition
comprising a solution of a plurality of molecules of the synthetic polymer
possessing the desired characteristics, some of the molecules of the
synthetic polymer having covalently bonded thereto at least one latent
reactive group capable of generating an active specie selected from the
group consisting of free radicals, carbenes, nitrenes and excited states
of ketones, in response to activation of the latent reactive groups, by
application of an external stimulus to covalently bond the molecules of
the synthetic polymer through the latent reactive groups to said solid
surface, the average ratio of latent reactive groups, to an extended chain
length, in Angstroms, of the molecules of the synthetic polymer being in
the range of about 1/10 to about 1/700 and the molecules of the synthetic
polymer each having an end, and each molecule of the polymer having no
latent reactive groups capable of active specie generation in response to
activation by application of an external stimulus to covalently bond to
the surface with 10 Angstroms from such end, the composition enabling the
molecules of the synthetic polymer to be so spatially oriented as to
enable the latent reactive groups to come into covalent bonding proximity
with the solid surface, and thereafter activating the latent reactive
groups by application of the external stimulus to covalently bond the
molecules of the synthetic polymer to the solid surface.
2. The method of claim 1 in which the molecules of the synthetic polymer
having number average molecular weights of at least about 400.
3. The method of claim 1, wherein the synthetic polymer is a hydrophilic
polymer.
4. Method of producing a gel of cross-linked molecules of a polymer
selected from the group consisting of polysaccharides, vinyls, nylons,
polyurethanes, collagen, polylactic acid, and polyethylene glycol
comprising providing in solution a plurality of the molecules of the
polymer, some of the molecules having covalently bonded to them a latent
reactive group capable of covalently bonding to a portion of another of
the molecules of the polymer free of latent reactive groups upon
application of an external stimulus, and applying said external stimulus
to cause said bonding between molecules of the polymer.
5. A method of providing a substrate with desired characteristics
comprising choosing a polysaccharide having the desired characteristics,
contacting the substrate with a composition comprising a plurality of
molecules of the polysaccharide possessing the desired physical
characteristics, some of the molecules of the polysaccharide having
covalently bonded to them at least one latent reactive group capable of
active specie generation in response to activation by application of an
external stimulus to covalently bond to the substrate, the composition
enabling the molecules of the polysaccharide to orient spatially so as to
enable said latent reactive groups to come into covalent bonding proximity
with the substrate; and thereafter activating said latent reactive groups
to covalently bond said molecules of the polysaccharide to the substrate.
6. The method of claim 5 wherein the polysaccharide is a linear
polysaccharide.
7. The method of claim 5 wherein the polysaccharide is a branched
polysaccharide.
8. The method of claim 6 wherein the linear polysaccharide is amylose,
dextran, chitosan, or hyaluronic acid.
9. The method of claim 7 wherein the branched polysaccharide is
amylopectin, hyaluronic acid, or a hemi-cellulose.
10. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of polyethylene glycol, some of the molecules of
polyethylene glycol having covalently bonded to them at least one latent
reactive group capable of active specie generation in response to
activation by application of an external stimulus to covalently bond to
the substrate, the composition enabling the molecules of polyethylene
glycol to orient spatially so as to enable said latent reactive groups to
come into covalent bonding proximity with the substrate; and thereafter
activating said latent reactive groups to covalently bond said molecules
of polyethylene glycol to the substrate.
11. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of hyaluronic acid, some of the molecules of
hyaluronic acid having covalently bonded to them at lest one latent
reactive group capable of active specie generation in response to
activation by application of an external stimulus to covalently bond to
the substrate, the composition enabling the molecules of hyaluronic acid
to orient spatially so as to enable said latent reactive groups to come
into covalent bonding proximity with the substrate; and thereafter
activating said latent reactive groups to covalently bond said molecules
of hyaluronic acid to the substrate.
12. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of collagen possessing the desired physical
characteristics, some of the molecules of collagen having covalently
bonded to them at least one latent reactive group capable of active specie
generation in response to activation by application of an external
stimulus to covalently bond to the substrate, the composition enabling the
molecules of collagen to orient spatially so as to enable said latent
reactive groups to come into covalent bonding proximity with the
substrate; and thereafter activating said latent reactive groups to
covalently bond said molecules of collagen to the substrate.
13. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of chitosan, some of the molecules of chitosan
having covalently bonded to them at least one latent reactive group
capable of active specie generation in response to activation by
application of an external stimulus to covalently bond to the substrate,
the composition enabling the molecules of chitosan to orient spatially so
as to enable said latent reactive groups to come into covalent bonding
proximity with the substrate; and thereafter activating said latent
reactive groups to covalently bond said molecules of chitosan to the
substrate.
14. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of heparin, some of the molecules of heparin having
covalently bonded to them at least one latent reactive group capable of
active specie generation in response to activation by application of an
external stimulus to covalently bond to the substrate, the composition
enabling the molecules of heparin to orient spatially so as to enable said
latent reactive groups to come into covalent bonding proximity with the
substrate; and thereafter activating said latent reactive groups to
covalently bond said molecules of heparin to the substrate.
15. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of polyvinyl alcohol, some of the molecules of
polyvinyl alcohol having covalently bonded to them at least one latent
reactive group capable of active specie generation in response to
activation by application of an external stimulus to covalently bond to
the substrate, the composition enabling the molecules of polyvinyl alcohol
to orient spatially so as to enable said latent reactive groups to come
into covalent bonding proximity with the substrate; and thereafter
activating said latent reactive groups to covalently bond said molecules
of polyvinyl alcohol to the substrate.
16. Method of producing a thin film of cross-linked molecules of a polymer
selected from the group consisting of polysaccharides, vinyls, nylons,
polyurethanes, collagen, polylactic acid, and polyethylene glycol
comprising providing in solution a plurality of the molecules of the
polymer, some of the molecules having covalently bonded to them a latent
reactive group capable of covalently bonding to a portion of another of
the molecules of the polymer upon application of an external stimulus, and
applying said external stimulus to cause said bonding between molecules of
a polymer.
17. A method of providing a substrate with desired characteristics
comprising choosing a cellulose-derived polymer having the desired
characteristics, contacting the substrate with a composition comprising a
plurality of molecules of the cellulose-derived polymer, some of the
molecules of the cellulose-derived polymer having covalently bonded to
them at least one latent reactive group capable of active specie
generation in response to activation by application of an external
stimulus to covalently bond to the substrate, the composition enabling the
molecules of the cellulose-derived polymer to orient spatially so as to
enable said latent reactive groups to come into covalent bonding proximity
with the substrate; and thereafter activating said latent reactive groups
to covalently bond said molecules of the cellulose-derived polymer to the
substrate.
18. The method of claim 17 wherein the cellulose-derived polymer is a
polymer of hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose
acetate or cellulose butyrate.
19. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of an acrylate polymer, some of the molecules of
the acrylate polymer having covalently bonded to them at least one latent
reactive group capable of active specie generation in response to
activation by application of an external stimulus to covalently bond to
the substrate, the composition enabling the molecules of the acrylate
polymer to orient spatially so as to enable said latent reactive groups to
come into covalent bonding proximity with the substrate; and thereafter
activating said latent reactive groups to covalently bond said molecules
of the acrylate polymer to the substrate.
20. The method of claim 19 wherein the acrylate polymer is a polymer of
hydroxyethyl acrylate, glyceryl acrylate, acrylic acid, or acrylamide.
21. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of a methacrylate polymer, some of the molecules of
the methacrylate polymer having covalently bonded to them at least one
latent reactive group capable of active specie generation in response to
activation by application of an external stimulus to covalently bond to
the substrate, the composition enabling the molecules of the methacrylate
polymer to orient spatially so as to enable said latent reactive groups to
come into covalent bonding proximity with the substrate; and thereafter
activating said latent reactive groups to covalently bond said molecules
of the methacrylate polymer to the substrate.
22. The method of claim 21 wherein the methacrylate polymer is a polymer of
hydroxyethyl methacrylate, glyceryl methacrtylate, methacrylic acid, or
methacrylamide.
23. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of a vinyl polymer possessing the desired physical
characteristics, some of the molecules of the vinyl polymer having
covalently bonded to them at least one latent reactive group capable of
active specie generation in response to activation by application of an
external stimulus to covalently bond to the substrate, the composition
enabling the molecules of the vinyl polymer to orient spatially so as to
enable said latent reactive groups to come into covalent bonding proximity
with the substrate, and thereafter activating said latent reactive groups
to covalently bond said molecules of the vinyl polymer to the substrate.
24. The method of claim 23 wherein the vinyl polymer is a polymer of vinyl
pyrrolidone or vinyl alcohol.
25. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of a nylon polymer, some of the molecules of the
nylon polymer having covalently bonded to them at least one latent
reactive group capable of active specie generation in response to
activation by application of an external stimulus to covalently bond to
the substrate, the composition enabling the molecules of the nylon polymer
to orient spatially so as to enable said latent reactive groups to come
into covalent bonding proximity with the substrate; and thereafter
activating said latent reactive groups to covalently bond said molecules
of the nylon polymer to the substrate.
26. The method of claim 25 wherein the nylon polymer is a polymer of
caprolactam, lauryl lacam, hexamethylene adipamide or hexamethylene
dodecanediamide.
27. A method of providing a substrate with desired characteristics
comprising contacting the substrate with a composition comprising a
plurality of molecules of a synthetic polymer that is polyurethane or
polylactic acid, some of the molecules of the synthetic polymer having
covalently bonded to them at least one latent reactive group capable of
active specie generation in response to activation by application of an
external stimulus to covalently bond to the substrate, the composition
enabling the molecules of the synthetic polymer to orient spatially so as
to enable said latent reactive groups to come into covalent bonding
proximity with the substrate; and thereafter activating said latent
reactive groups to covalently bond said molecules of the synthetic polymer
to the substrate.
28. The method of claim 4 wherein the polymer is a polysaccaride selected
from the group consisting of chitosan, hyaluronic acid, and heparin.
29. The method of claim 4, wherein the polymer is a vinyl selected from the
group consisting of acrylates, methacrylates, and polyvinyl alcohol.
30. The method of claim 16 wherein the polymer is a polysaccaride selected
from the group consisting of chitosan, hyaluronic acid, and heparin.
31. The method of claim 16, wherein the polymer is a vinyl selected from
the group consisting of acrylates, methacrylates, and polyvinyl alcohol. |
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Claims |
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Description |
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BACKGROUND OF THE INVENTION
It is often desirable to provide the surface of an object with a polymeric
coating to protect the surface or to provide the surface with properties
of the polymer coating. For example, various paint-like coating
compositions are employed to provide the surfaces of metals, wood and the
like with thin, protective polymeric films.
The adhesion of polymeric films such as those described above to the
surfaces to which they are applied are commonly largely mechanical. The
surfaces often are roughened or otherwise prepared before a polymeric
coating is applied so as to increase the degree of mechanical adhesion.
Polymers are generally not chemically bonded to the surfaces upon which
they are applied, and polymer coatings generally have not been used as
coatings for devices which may be implanted in the human body or to
devices which come into contact with body fluids during use, such as
contact lenses. Coatings for objects such as these should adhere
tenaciously to their surfaces even in the presence of body fluids and
other liquids.
To improve the adhesion of certain polymer species to supporting surfaces,
U.S. Pat. Nos. 4,663,232, 4,311,573, 4,595,632 and 4,589,964 teach that
surfaces to be coated must be carefully prepared, as by precoating, using
careful, often time consuming procedures to receive polymer species.
SUMMARY OF THE INVENTION
We have discovered that polymer molecules and reactive chemical molecules
such as monomers and oligomers may be provided with latent reactive groups
covalently bonded to them such that when the molecules are brought into
bonding proximity with a substrate such as a surface, the latent reactive
groups can be energized to form, via free active specie generation,
covalent bonds between these molecules and the substrate. The substrate to
which the polymer molecules are to be so attached need not be specifically
pretreated so as to add to it functional groups to which bonding occurs,
and the invention provides a method by which such molecules may be readily
attached to untreated substrates of various types.
Thus, in one embodiment, the invention relates to a method of providing a
substrate, preferably a surface, with desired physical characteristics
which comprises contacting the substrate with a composition comprising a
plurality of molecules of a polymer possessing the desired physical
characteristics, the polymer molecules each having covalently bonded
thereto at least one latent reactive group. The latent reactive group is
capable of generating an active specie such as a free radical in response
to external stimulation to covalently bond the polymer molecule to the
substrate, through the residue of the latent reactive group. The polymer
molecule is so spatially oriented as to enable one or more of its latent
reactive groups to come into covalent bonding proximity with the substrate
surface, and the method includes the step of thereafter activating the
latent reactive group by applying external stimulation to covalently bond
the polymer molecule to the substrate. The external stimulation that is
employed desirably is electromagnetic radiation, and preferably is
radiation in the ultraviolet, visible or infra-red regions of the
electromagnetic spectrum.
In another embodiment, the invention relates to a latent reactive polymeric
composition which can be applied to a substrate such as a surface and
covalently bonded to it by application of an external stimulus. The
polymeric composition comprises a plurality of polymer molecules each
having covalently bonded thereto at least one latent reactive group
capable of active specie generation in response to applied external
stimulation to covalently bond to the substrate, the polymer molecules
being so spatially oriented as to enable their latent reactive groups to
come into covalent bonding proximity with a surface or other substrate to
which the coating composition is applied. Desirably, the coating
composition includes a vehicle carrying the polymer molecules and within
which the polymer molecules are permitted sufficient freedom of movement
as to enable latent reactive groups of the polymer molecules to be
positioned in bonding proximity with the substrate with which the coating
composition is applied.
In yet another embodiment, the invention relates to a surface or other
substrate bearing a plurality of polymer chains each covalently bonded to
it through a residue of a latent reactive group, which latent group was
initially capable of active specie generation in response to application
of an external stimulus to covalently bond to the substrate; the polymer
chains being present in sufficient quantity as to provide the surface or
other substrate to which they are attached with one or more
characteristics of the polymer.
In yet another embodiment, the invention relates to a method of providing a
surface or other substrate with a plurality of polymer chains covalently
bonded to it, the method comprising contacting the substrate with
chemical, preferably polymerizable, reactive units such as monomers or
oligomers each having covalently bonded to it a latent reactive group, and
externally stimulating the latent reactive group to cause the same to
covalently bond to the substrate via active specie generation. To the thus
bonded reactive units are covalently bonded one or more monomers,
oligomers or polymers via grafting or via polymerization of monomers or
oligomers to provide polymer chains, the resulting chains thus being
covalently bonded to the substrate.
In a further embodiment, the invention relates to a method of forming a
cross-linked polymer comprising providing each of a plurality of polymer
molecules with at least one latent reactive group as above described,
bringing the polymer molecules into reactive association with one another,
and activating the latent reactive groups by application of an external
stimulus to cause said groups to covalently bond to latent reactive group
free portions of others of the molecules. The reaction desirably occurs in
a solvent solution of the polymer molecules, and the resulting
cross-linked polymer molecules may thicken the solution, may form a gel,
or may form a solid such as a film.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The polymers of the invention may be natural or synthetic in origin. Such
polymers include oligomers, homopolymers and copolymers resulting from
addition or condensation polymerization, and natural polymers including
oligosaccharides, polysaccharides, peptides, and proteins. The polymers
may include several distinct polymer types, as prepared by terminal or
side chain grafting The polymers of the invention may include
cellulose-based products such as hydroxyethyl cellulose, hydroxypropyl
cellulose, carboxymethyl cellulose, cellulose acetate and cellulose
butyrate, acrylics such as those polymerized from hydroxyethyl acrylate,
hydroxyethyl methacrylate, glyceryl acrylate, glyceryl methacrylate,
acrylic acid, methacrylic acid, acrylamide and methacrylamide, vinyls such
as polyvinyl pyrrolidone and polyvinyl alcohol, nylons such as
polycaprolactam, polylauryl lactam, polyhexamethylene adipamide and
polyhexamethylene dodecanediamide, polyurethanes, polylactic acids, linear
polysaccharides such as amylose, dextran, chitosan, and hyaluronic acid,
and branched polysaccharides such as amylopectin, hyaluronic acid and
hemi-celluloses. The polymeric species are chosen so as to exhibit one or
more properties desired for the surface or other substrate to which the
polymer molecules are bonded. For example, it may be desired in some
instances to provide surfaces with very hydrophilic properties, in which
case polymer species such as hyaluronic acid may be employed. The polymer
polyethylene glycol may be employed to repel proteins as from a contact
lens surface. Heparin, a polysaccharide, may be used to impart
antithrombogenic characteristics, and chitosan may be employed to provide
hemostatic properties.
The physical characteristics of the polymer molecules employed in the
present invention are generally derived from the nature of the molecular
chains themselves. Thus, polyvinyl alcohol, for example, which bears a
plurality of hydroxyl groups and which is generally water soluble,
provides hydrophilic characteristics to a surface or other substrate to
which it is covalently bonded through the method of the invention. The
polymer molecules of the invention desirably are substantially free of
biologically active groups that are either added to the polymer molecules
after polymerization or that are not normally contained in the precursor
monomers or in identical, repeating units of the polymer. The polymer
molecules that are employed in the invention desirably have extended chain
lengths of at least about 10 Angstroms, preferably at least 25 Angstroms,
and most preferably at least about 50 Angstroms.
Most preferably, the polymer molecules include end portions which are free
from latent reactive groups and which end portions themselves have
extended lengths (measured from the nearest latent reactive group) of at
least 10 Angstroms and preferably at least 25 Angstroms, and most
preferably at least 50 Angstroms. In this manner, the free polymer
molecule end portions may extend as desired away from the surface or other
substrate to which the molecule is attached to provide appropriate
physical or other characteristics. The polymer molecules themselves
preferably have molecular weights of at least about 400. and desirably are
generally hydrophilic in nature, the polymers preferably being soluble in
water to the extent of at least approximately 0.5% by weight at 25.degree.
C. "Extended length", as used herein, refers to the length that a polymer
chain would have if it were stretched out to its maximum length, observing
proper bond angles between adjacent atoms. Polyethylene glycol, hyaluronic
acid, collagen, chitosan, heparin, and polyvinyl alcohol are particularly
preferred polymers.
The polymer molecules employed in the invention carry one or more latent
reactive groups covalently bonded to them. The latent reactive groups,
broadly defined, are groups which respond to specific applied external
stimuli to undergo active specie generation with resultant covalent
bonding to an adjacent support surface. Latent reactive groups are those
groups of atoms in a molecule which retain their covalent bonds unchanged
under conditions of storage but which, upon activation, form covalent
bonds with other molecules. The latent reactive groups generate active
species such as free radicals, nitrenes, carbenes, and excited states of
ketones upon absorption of external electromagnetic or kinetic (thermal)
energy. Latent reactive groups may be chosen to be responsive to various
portions of the electromagnetic spectrum, and latent reactive groups that
are responsive to ultraviolet, visible or infrared portions of the
spectrum are preferred. Latent reactive groups as described are generally
well known.
The azides constitute a preferred class of latent reactive groups and
include arylazides
##STR1##
such as phenyl azide and particularly 4-fluoro-3-nitrophenyl azide, acyl
azides
##STR2##
such as benzoyl azide and p-methylbenzoyl azide, azido formates
##STR3##
such as ethyl azidoformate, phenyl azidoformate, sulfonyl azides
##STR4##
such as benzenesulfonyl azide, and phosphoryl azides
##STR5##
such as diphenyl phosphoryl azide and diethyl phosphoryl azide. Diazo
compounds constitute another class of latent reactive groups and include
diazoalkanes (--CHN.sub.2) such as diazomethane and diphenyldiazomethane,
diazoketones
##STR6##
such as diazoacetophenone and 1-trifluoromethyl-1-diazo-2-pentanone,
##STR7##
such as t-butyl diazoacetate and phenyl diazoacetates, and
beta-ketone-alpha-diazoacetates
##STR8##
such as t butyl alpha diazoacetoacetate. Other latent reactive groups
include the aliphatic azo compounds such as azobisisobutyronitrile, the
diazirines
##STR9##
such as 3-trifluoromethyl-3-phenyldiazirine, the ketenes
(--CH.dbd.C.dbd.O) such as ketene and diphenylketene and photoactivatable
ketones such as benzophenone and acetophenone. Peroxy compounds are
contemplated as another class of latent reactive groups and include
dialkyl peroxides such as di-t-butyl peroxide and dicyclohexyl peroxide
and diacyl peroxides such as dibenzoyl peroxide and diacetyl peroxide and
peroxyesters such as ethyl peroxybenzoate.
Upon activation of the latent reactive groups to cause covalent bond
formation to the surfaces to which polymer molecules are to be attached,
the polymer molecules are covalently attached to the surfaces by means of
residues of the latent reactive groups. Exemplary latent reactive groups,
and their residues upon activation, are as follows:
______________________________________
Latent Reactive Group
Residue Functionality
______________________________________
aryl azides amine RNHR'
acyl azides
##STR10##
azidoformates
##STR11##
sulfonyl azides
##STR12##
phosphoryl azides
##STR13##
diazoalkanes new CC bond
diazoketones new CC bond & ketone
diazoacetates new CC bond & ester
beta-keto-alpha-diazoacetates
new CC bond & B-ketoester
aliphatic azo new CC bond
diazirines new CC bond
ketenes new CC bond
photoactivated ketones
new CC bond & alcohol
dialkyl peroxides
ethers
diacyl peroxides
esters & new CC bonds
peroxyesters ethers, esters, and new CC
bonds
______________________________________
The polymers and oligomers used in the invention may have one or more
latent reactive groups. Desirably, the polymers have at least one latent
reactive group per molecule with the ratio of reactive groups extended
polymer length, in Angstroms, ranging from about 1/10 to about 1/700 and
preferably from about 1/50 to 1/400.
As will be noted from the foregoing description, photoreactive latent
reactive groups are for the most part aromatic and hence generally are
hydrophobic rather than hydrophilic in nature.
The latent reactive groups and the polymer molecules to which they are
bonded may have substantially different solvophilic properties. For
example, the latent reactive groups may be relatively hydrophobic, whereas
the polymer molecules may be relatively hydrophilic; when solution of the
molecules is contacted with a relatively hydrophobic surface, it is
believed that the latent reactive groups, being hydrophobic, tend to
orient nearer the surface so as to improve bonding efficiency when the
latent reactive groups are activated. The preferred latent reactive groups
are benzophenones, acetophenones, and aryl azides.
The loading density of polymers upon a surface may be improved by a process
in which a latent reactive molecule (a molecule having a latent reactive
group) is first brought into close association (as by means of a solvent
solution) to a surface, and thereafter the polymer to be bonded to the
surface is brought into contact with and is covalently bonded to the
latent reactive molecule, as to a reactive group different from the latent
reactive group. Thereafter, the latent reactive groups may be activated to
cause them to covalently bond to the surface to thereby link the polymers
to the surface. This procedure appears to work particularly well when the
latent reactive group is solvophilically compatible with (e.g., similar
to) the surface and wherein the polymer is relatively solvophilically
incompatible with the surface but is more compatible with a portion of the
latent reactive group. Reference is made to Example IX below as being
illustrative of this procedure.
If desired, polymer chains may be provided upon a surface or other
substrate by first covalently bonding to the substrate through a latent
reactive group a monomer, oligomer or other reactive chemical unit. To the
thus bonded reactive units are covalently bonded monomers or oligomers in
a polymerization reaction or polymers via covalent bonding (grafting) of
the reactive units onto the polymer chains.
The reactive chemical units of the invention carry covalently bonded
thereto latent reactive groups as described herein for covalent attachment
to a non pretreated surface or other substrate. These molecules are
characterized as having reactive groups capable of covalent bonding to
polymer molecules of a polymer having the desired characteristics, or of
entering into a polymerization reaction with added monomers or oligomers
to produce polymer chains having the desired characteristics. Reactive
chemical molecules capable of covalently bonding to polymer molecules
include not only monomers and oligomers of various types but also
molecules having such functional groups as carboxyl, hydroxyl, amino, and
N-oxysuccinimide, such groups being reactive with reactive groups carried
by the polymer chain to bond to the chain. The reactive chemical molecules
are preferably monomers or oligomers and most preferably are ethylenically
unsaturated monomers capable of entering into an addition polymerization
reaction with other ethylenically unsaturated monomers. Particularly
preferred are the acrylate and methacrylate monomers which are the
esterification products of acrylic or methacrylic acid and
hydroxy-functional latent reactive groups. Examples of such molecules
include 4-benzoylbenzoyl-lysyl-acrylate.
Utilizing reactive chemical units bearing latent reactive groups, one will
desirably first coat a surface or other substrate with a solvent solution
of such molecules. Upon removal of solvent, the application of an
appropriate external stimulus such as U.V. light will cause the molecules
to covalently bond, through the latent reactive groups, to the substrate.
The substrate may then be appropriately contacted with a solution
containing the desired polymer, monomer or oligomer molecules to cause
bonding to these molecules. For example, if the reactive chemical unit
molecule is carboxyl functional, it may be reactive with, and covalently
bonded to, an appropriate hydroxyl-functional polymer such as dihydroxy
polyethylene glycol. If the reactive chemical molecule is a monomer or
oligomer, e.g., a methacrylate monomer, the substrate to which the
molecule is covalently bonded may be contacted with a solution of
addition-polymerizable monomers such as hydroxyethyl methacrylate and a
free-radical addition polymerization initiator such as dibenzoyl peroxide
under addition polymerization conditions to result in the growth of
polymer chains from the monomer molecules bound covalently to the
substrate. Once the desired polymerization has occurred, the substrate may
be washed to remove residual monomer, solvent and non bound polymer that
was formed.
The term "substrate" refers to any chemical moiety to which polymer
molecules are to be attached through activation of latent reactive groups.
The substrate may take the form of molecules in a solution, but more
desirably, the substrate comprises a definable surface such as the
tangible surface of a contact lens or surgical implant, or the surface
provided by small particles in an emulsion or other suspension or as a
powder, or the surface defined as the interface between two substantially
distinct phases, such as two immiscible liquid phases or the surface of a
soft gel. Although the polymer molecules may be attached to the same or
different polymer molecules in a solution, as described more fully below,
the invention provides the particular advantage of providing means by
which non-pretreated definable (e.g., solid) surfaces may simply and
rapidly be provided with covalently bonded-on polymer coatings in a
simple, rapid and hence economical manner.
"Hydrophilic" and "hydrophobic" are used herein to describe compositions
broadly as water-loving and water hating, respectively, in line with the
following observations: Hydrophilic compounds are usually relatively polar
and often are ionizable. Such compounds usually bind water molecules
strongly. Hydrophobic compounds are usually relatively non-polar and
non-ionizing. Hydrophobic surfaces will generally cause water molecules to
structure in an ice like conformation at or near the surface "Hydrophobic"
and "hydrophilic" are relative terms, of course, and are used herein in
the sense that various compositions, liquids and surfaces may be
hydrophobic or hydrophilic relative to one another. A discourse on the
subject is found in Hoffman, Letter to the Editor: A General
Classification Scheme for "Hydrophilic" and "Hydrophobic" Biomaterial
Surfaces, J.Biol. Mat. Res. 20, pp ix-xi (1986), the teachings of which
are incorporated herein by reference.
The loading density resulting from attachment of polymer molecules to a
surface or other substrate in accordance with the invention may be
regulated in several ways. First, the degree of activation of latent
reactive groups is generally a function of the quantity of the external
stimulus that is applied, and thus the extent of covalent bonding through
the latent reactive groups may be regulated by regulating the intensity
and time of application of the applied stimulus. Regulation of the applied
stimulus is particularly easy when the stimulus is actinic radiation; one
can readily regulate the amount of radiation to which the latent reactive
groups are exposed. Loading density may also be regulated by adjusting the
capacity of polymer molecules of the invention to bring their latent
reactive groups into bonding proximity with a surface. Thus, one may
regulate the viscosity of a solution of polymer molecules in an
appropriate solvent as well as the solubility of polymer in the solvent.
Yet another factor is the concentration of polymer molecules in a coating
composition.
As will be understood from the above discussion and from the examples which
follow, the invention permits a substrate, particularly a solid surface,
to be provided with covalently attached polymer molecules in sufficient
loading density or quantity as to provide an "effective" surface having
the physical properties of the added polymer rather than those differing
physical properties of the uncoated solid surface. In this manner, for
example, the hydrophobic surface of polystyrene may be rendered
comparatively hydrophilic through the covalent bonding of e.g., the
hydrophilic polymer polyethylene glycol to the polystyrene surface.
In a preferred embodiment, the method of the invention is practiced on a
surface or other substrate that has not been pretreated. As used herein,
the terms "pretreatment" and "pretreated" refer to the addition to a
surface or other substrate of functional groups which are chemically
involved in the covalent bonds subsequently formed upon activation of
latent reactive groups. Substrates such as solid surfaces may be
pre-washed, of course, to remove surface contamination and may be modified
as desired to affect solvophilic characteristics without adding functional
groups that are involved in covalent bond formation with latent reactive
groups. For example, polystyrene surfaces may be washed and then exposed
to hydroxyl ions in known water vapor plasma contact procedures so as to
add hydroxyl groups to the surface solely for the purpose of rendering the
surface more readily wetted by aqueous solutions, the hydroxyl groups not
being involved in subsequent covalent bond formation with the surface upon
latent reactive group activation. Avoidance of pretreatment steps, as
above defined, leads not only to important processing economies but also
avoids technical problems associated with the attachment of bond forming
reactive groups to surfaces at uniform loading densities.
The invention may be more easily appreciated by reference to the following
non-limiting examples, in which parts are expressed by weight unless
otherwise indicated.
EXAMPLE I
Modification of the Surfaces of Contact
Lenses and Introcular Lens Implants
The experiments described in this example involved preparations of
hydrophilic polymers that are covalently bonded to contact lens surfaces
through latent reactive groups carried by the polymers.
Preparation of Photolabeled Polyethylene Glycols.
Polyethylene glycols of molecular weights 1000 (PEG-1000) and 4000
(PEG-4000) were labeled with fluoro-2-nitro-4-azidobenzene (FNAB) by
modification of the phase transfer method of Kimura, and S. Regen, Journal
of Organic Chemistry 48; 195 (1983) the teachings of which are
incorporated by reference herein. Briefly, the phase-transfer synthesis of
4-azido-2-nitrophenyl polyethylene glycol (ANP-PEG) involved the mixture
of 60% aqueous potassium hydroxide ("KOH")/toluene with FNAB and PEG,
followed by extraction and thin-layer chromatographic (TLC) purification
as described below.
ANP-PEG-1000. ANP-PEG-1000 was prepared by adding 0.3 mmole PEG-1000 to 5
mls 60% KOH and 0.15 mmole FNAB to 10 ml toluene. This reaction mixture
was rapidly stirred at room temperature for 16 hours. The product was
isolated from the organic layer. TLC in 85/15/1/1
chloroform/methanol/H.sub.2 O acetic acid or ammonium hydroxide separated
mono-and di-substituted derivatives of ANP-PEG-1000 from unlabeled PEG.
The band corresponding to ANP-PEG-1000 (lower R.sub.f value) was extracted
from silica gel with TLC solvent and azeotrophed to remove residual acid
or base. The final product was soluble in water.
ANP-PEG-4000. ANP-PEG-4000 was prepared by the same procedure as that
described above except that the reaction mixture was rapidly stirred at
50.degree. C. to ensure all reagents remained in solution during the
course of the reaction.
Preparation of Photolabeled Jeffamines. Polyoxypropylenepolyamines and
polyoxyethylenepolyamines (referred to as "Jeffamines", a trademark of
Jefferson Chemical Co., Inc.) were photolabeled by coupling the
N-oxysuccinimide ("NOS") esters of ANP-EACA (epsilon-aminocaproic acid),
BBA (4-benzyl benzoic acid) and nBBA (4-(3nitrobenzyl)benzoic acid) to the
polymers. These NOS-derivatives were added to a two molar excess of
Jeffamine in very dry (high purity) solvents (ANP-EAC-NOS in dry
tetrahydrofuran, BBA-NOS in dry dioxane or dimethylformamide and nitro
BBA-NOS in dry dioxane or dimethylformamide). After 16 hours of reaction
at room temperature in the dark, the products were isolated by TLC. in
85/15/1/1/ chloroform/methanol/H.sub.2 O/acetic acid. Monosubstituted
Jeffamine derivatives were extracted with the TLC. solvent and azeotroped
with water to remove the residual acetic acid. The ANP-EAC-Jeffamine,
BBA-Jeffamine, and nBBA-Jeffamine products were water soluble.
Preparation of ANP-Hyaluronic Acid. The terminal sugar of human placental
hyaluronic acid (MW.sub.app 100-130,000) was activated by the periodate
procedure described in E. Junowicz and S. E. Charm, "The Derivatization of
Oxidized Polysaccarides for Protein Immobilization and Affinity
Chromatography," Biochimica et Biophysica Acta, Vol. 428: 157-165 (1976),
incorporated herein by reference. This procedure entailed adding sodium or
potassium periodate to a solution of hyaluranic acid thus activating the
terminal sugar. The hyaluronic acid was added to a 10-fold excess of
Jeffamine and allowed to react 4 hours at room temperature. The linkages
were stabilized by reduction with sodium cyanoborohydride, followed by
exhaustive dialysis to remove non-bound Jeffamine. A 10-fold molar excess
of ANP-EAC-NOS in DMF was added to the Jeffamine-hyaluronate in 0.1 M
carbonate, pH 9.0, by syringe drive. This addition required 16 hours and
was conducted at room temperature in the dark. The excess ANP-EAC-NOS and
ANP-EAC-Jeffamine was removed by gel filtration chromatography. The
integrity of the azide group, which is required for photocoupling of the
moiety to the contact lens polymer backbone, was analyzed by infrared
spectroscopy to detect the azido function of the ANP group, a polyethylene
glycol assay to detect the Jeffamine spacer, and a modified carbazole
assay described in T. Bitter and H. Muir, Analytical Biochemistry Vol. 4:
330-334 (1962) and incorporated herein by reference to determine the
uronic acid content of the derivative.
The polyethylene glycol assay was developed using the Dragendorff reagent
(tetraiodobismuthic acid-barium chloride). A 5-ml portion of stock reagent
(425-mg bismuth nitrate, 10-gm potassium iodide in acetic acid and water)
was added to 10-ml 10% barium chloride in water and a background reading
at 516/nm was noted. Then 0.1-ml of the sample was added and the contents
mixed by inversion of the cuvette. A reading was taken at 516/nm after 1
minute of incubati | | |
