U.S. patent application number 13/129438 was filed with the patent office on 2011-12-01 for surface modification of polymers via surface active and reactive end groups.
This patent application is currently assigned to DSM IP ASSETS B.V.. Invention is credited to Scott Curtin, Xuwei Jiang, Keith Mccrea, Yuan Tian, Shanger Wang, Robert S. Ward.
Application Number | 20110293522 13/129438 |
Document ID | / |
Family ID | 41719260 |
Filed Date | 2011-12-01 |
United States Patent
Application |
20110293522 |
Kind Code |
A1 |
Wang; Shanger ; et
al. |
December 1, 2011 |
SURFACE MODIFICATION OF POLYMERS VIA SURFACE ACTIVE AND REACTIVE
END GROUPS
Abstract
Polymer surface modification method comprising the steps of
first forming a surface of primary reactive end groups tethered to
the polymer chain ends during fabrication of an article, and then
modifying the reactive surface with bio-active molecules,
hydrophilic and hydrophobic monomers, oligomers, or polymers to
attain specific surface properties. Alternatively, a
multifunctional coupling agent can be used to couple the primary
reactive group to a second reactive group capable of reacting with
a functional group associated with bio-active molecules,
hydrophilic and hydrophobic monomers, oligomers, and polymers to
attain specific surface properties. The invention involves bringing
reactive endgroups to the surface with surface active spacer
attached to the polymer chain end. The surface active spacer allows
the migration and enrichment of reactive end groups to the surface
during fabrication. The invention provides medical devices having a
bio-interface with anti-thrombogenic properties, lubricity,
selective adsorption, and antimicrobial properties.
Inventors: |
Wang; Shanger; (Fairfield,
CA) ; Ward; Robert S.; (Orinda, CA) ; Tian;
Yuan; (Alameda, CA) ; Jiang; Xuwei; (El
Sobrante, CA) ; Mccrea; Keith; (Concord, CA) ;
Curtin; Scott; (Berkeley, CA) |
Assignee: |
DSM IP ASSETS B.V.
Heerlen
NL
|
Family ID: |
41719260 |
Appl. No.: |
13/129438 |
Filed: |
November 16, 2009 |
PCT Filed: |
November 16, 2009 |
PCT NO: |
PCT/US09/64560 |
371 Date: |
August 9, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61115337 |
Nov 17, 2008 |
|
|
|
Current U.S.
Class: |
424/9.1 ;
264/328.1; 424/78.17; 525/453; 525/455; 525/54.1; 525/54.2 |
Current CPC
Class: |
C08J 7/12 20130101; A61P
7/02 20180101; C08G 18/837 20130101; C08G 18/08 20130101; A61K
2800/61 20130101; A61P 31/00 20180101; C08J 7/14 20130101 |
Class at
Publication: |
424/9.1 ;
525/453; 525/455; 525/54.1; 525/54.2; 424/78.17; 264/328.1 |
International
Class: |
A61K 49/00 20060101
A61K049/00; B29C 45/00 20060101 B29C045/00; A61P 31/00 20060101
A61P031/00; A61P 7/02 20060101 A61P007/02; C08G 18/83 20060101
C08G018/83; A61K 31/785 20060101 A61K031/785 |
Claims
1. A method of modifying a surface on a polymeric substrate
selected from the group consisting of solid synthetic polymers,
solid natural polymers, and hydrogels, comprising the steps of:
fabricating an article from a polymeric body composed of polymeric
molecules having first reactive endgroups linked to surface active
spacers which surface active spacers comprise endgroups on said
polymeric molecules and forming a surface of said first reactive
endgroups linked to surface active spacers on said polymeric body;
and contacting said surface of said polymeric body with a compound
containing at least one second reactive endgroup and at least one
surface modifying moiety, selected from the group consisting of
bio-active molecules, monomers, oligomers, polymers, organometallic
molecules, and metal compounds, to react said at least one second
reactive endgroup with a first reactive endgroup and link said at
least one surface modifying moiety to one of said polymeric
molecules by a covalent, coordination, or ionic bond.
2. A method of modifying a surface on a polymeric substrate
selected from the group consisting of solid synthetic polymers,
solid natural polymers, and hydrogels, comprising the steps of:
fabricating an article from a polymeric body composed of polymeric
molecules having first reactive endgroups linked to surface active
spacers which surface active spacers comprise endgroups on said
polymeric molecules and forming a surface of said first reactive
endgroups linked to surface active spacers on said polymeric body;
contacting the surface of said polymeric body with a compound
containing at least one third reactive endgroup and at least one
fourth reactive endgroup to react said at least one third reactive
endgroup with a first reactive endgroup and thereby link said at
least one fourth reactive endgroup to the polymeric molecules by a
covalent or ionic bond; and contacting the resulting surface of
said polymeric body with a compound containing at least one second
reactive group and at least one surface modifying moiety, selected
from the group consisting of bio-active molecules, monomers,
oligomers, polymers, organometallic molecules, and metal compounds,
to react said at least one second reactive endgroup with said at
least one fourth reactive endgroup and thereby link said at least
one surface modifying moiety to one of said polymeric molecules by
a covalent, coordination, or ionic bond.
3. The method of claim 1 or 2, wherein the first reactive endgroups
are tethered to surface active spacers as part of polymer chain
ends such that the reactive endgroups are spontaneously brought to
the surface of an article during the fabrication thereof by a
fabrication method which includes thermal forming or solvent-based
processing.
4. (canceled)
5. The method of claim 3, wherein the fabrication method includes
thermal processing selected from extrusion, molding, casting, and
multilayer processing including co-extrusion and over-molding on
top of a base polymer to afford the fabricated article with the
surface properties of the polymer containing surface active or
reactive endgroups.
6. The method of claim 3, wherein said chain ends are selected from
the group consisting of linear polymer chain ends, side chain ends,
hyper-branched chain ends, dentrimer chain ends, and chain ends of
a polymer network.
7. The method of claim 1 or 2, wherein the reactive endgroups are
selected to be stable toward processing conditions used in
fabricating the device or substrate by extrusion, injection
molding, or annealing, or wherein the reactive endgroups are
protected by protecting groups such that the functionality and the
reactivity of the reactive endgroups are retained during the
fabrication of the article, with the reactive endgroups being
recovered by a de-protection reaction subsequent to surface
formation.
8. (canceled)
9. The method of claim 1 or 2, wherein the reactive endgroups are
selected from the group consisting of vinyl groups, alkoxy silanes,
silanes, epoxy groups, anhydrides, primary amino groups, secondary
amino groups, carboxyl groups, aldehyde groups, ketone groups,
azide groups, dienes, amide groups, isothiocyanate groups,
isocyanate groups, halide groups, maleimides, hydroxysuccinimide
esters, hydroxysulfosuccinimide esters, imido esters, hydrazines,
aziridines, cyano groups, and alkynes.
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. The method of claim 1 or 2, wherein the bioactive molecules are
selected from the group consisting of chitosan, heparin, hyaluronic
acid and its derivatives, antimicrobial agents, antibiotic agents,
antithrombogenic agents, peptides, proteins, polypeptides,
poly(amino acids), carbohydrates, contrast agents, drugs,
glycosaminoglycans, and lubricious substances.
15. (canceled)
16. The method of claim 1 or 2, wherein the substrate is selected
from the group consisting of polyolefins, silicones, acrylic
polymers and copolymers, methacrylic polymers and copolymers,
fluoropolymers, vinyl polymers and copolymers, polyurethanes,
polyurethaneureas, polyester urethanes, silicone polyurethanes,
polyvinyl chlorides, polyamides, polyether amides, polyesters,
epoxy polymers, polyimides, polyester amides, polyether amides, and
silicone hydrogels.
17. The method of claim 1 or 2, wherein said article is a medical
device selected from the group consisting of medical tubing,
intravenous bags and catheters, ophthalmic devices, blood
filtration devices, cardiovascular devices, biosensors, orthopedic
implants, and prostheses.
18. A polymeric molecule having a surface modifying moiety linked
to said polymeric molecule by a molecular linkage comprising the
reaction product of a second reactive endgroup on a compound
containing said second reactive endgroup and said surface modifying
moiety with a first reactive endgroup which is linked to a surface
active spacer that comprises an endgroup on said polymeric
molecule.
19. The polymeric molecule of claim 18, having the formula
POLYMER-SPACER-XK-LINK1-Q, wherein POLYMER is a polymer, SPACER is
a surface active spacer linkage, XK is formed by reacting a first
reactive endgroup X with a second reactive endgroup K, LINK1 is a
compound containing a second reactive endgroup K and a surface
modifying moiety, and Q is a surface modifying moiety.
20. The polymeric molecule of claim 19, wherein POLYMER is a
polyolefin, silicone, acrylic polymer or copolymer, methacrylic
polymer or copolymer, fluoropolymer, vinyl polymer or copolymer,
polyurethane, polyurethaneurea, polyester urethane, silicone
polyurethane, polyvinyl chloride, polyamide, polyether amide,
polyester, epoxy polymer, polyimide, polyester amide, polyether
amide, or silicone hydrogel, SPACER is a divalent alkane, polyol,
polyamine, polysiloxane, or fluorocarbon chain from 8 to 24 units
in length, XK comprises a Si--C bond, an Si--O--Si bond, a urethane
linkage, a urea linkage, a carbamate linkage, an amine, an amide
linkage, an imine, an enamine, an oxime, an amidine linkage, an
iminoester linkage, a carbonate linkage, a C--C bond, an ether, an
ester linkage, an acetal, a sulfonate, a sulfide, a sulfinate, a
disulfide, a sulfonamide linkage, a thioester linkage, a
thiocarbonate linkage, a phosphonamide linkage, or a heterocycle,
LINK1 is an aliphatic moiety or aromatic moiety having up to 12
carbon atoms, and Q is a substituted or non-substituted, saturated
or unsaturated alkyl chain, a polyether, a fluorinated polyether, a
silicone chain, an organometallic moiety, chitosan, heparin,
hyaluronic acid, an antimicrobial agent, an antithrombogenic agent,
a peptide, a protein, a poly(amino acid), a carbohydrate, or a
radio-imaging contrast agent.
21. A polymeric molecule having a surface modifying moiety linked
to said polymeric molecule by a molecular linkage comprising both
the reaction product of a second reactive endgroup on a compound
containing said second reactive endgroup and said surface modifying
moiety with a fourth reactive endgroup on a compound containing
third and fourth reactive endgroups and the reaction product of a
third reactive endgroup on said compound containing third and
fourth reactive endgroups with a first reactive endgroup which is
linked to a surface active spacer that comprises an endgroup on
said polymeric molecule.
22. The polymeric molecule of claim 21, having the formula
POLYMER-SPACER-XY-LINK1-ZK-LINK2-Q, wherein POLYMER is a polymer,
SPACER is a surface active spacer linkage, XY is formed by reacting
a first reactive endgroup X with a third reactive endgroup Y, LINK1
is a compound containing a third reactive endgroup Y and a fourth
reactive endgroup Z, ZK is formed by reacting a fourth reactive
endgroup Z with a third reactive endgroup K, LINK2 is a compound
containing a second reactive endgroup K and a surface modifying
moiety, and Q is a surface modifying moiety.
23. The polymeric molecule of claim 22, wherein POLYMER is a
polyolefin, silicone, acrylic polymer or copolymer, methacrylic
polymer or copolymer, fluoropolymer, vinyl polymer or copolymer,
polyurethane, polyurethaneurea, polyester urethane, silicone
polyurethane, polyvinyl chloride, polyamide, polyether amide,
polyester, epoxy polymer, polyimide, polyester amide, polyether
amide, or silicone hydrogel, SPACER is a divalent alkane, polyol,
polyamine, polysiloxane, or fluorocarbon chain from 8 to 24 units
in length, XY comprises a Si--C bond, an Si--O--Si bond, a urethane
linkage, a urea linkage, a carbamate linkage, an amine, an amide
linkage, an imine, an enamine, an oxime, an amidine linkage, an
iminoester linkage, a carbonate linkage, a C--C bond, an ether, an
ester linkage, an acetal, a sulfonate, a sulfide, a sulfinate, a
disulfide, a sulfonamide linkage, a thioester linkage, a
thiocarbonate linkage, a phosphonamide linkage, or a heterocycle,
LINK1 is an aliphatic moiety or aromatic moiety having up to 12
carbon atoms, ZK comprises a Si--C bond, an Si--O--Si bond, a
urethane linkage, a urea linkage, a carbamate linkage, an amine, an
amide linkage, an imine, an enamine, an oxime, an amidine linkage,
an iminoester linkage, a carbonate linkage, a C--C bond, an ether,
an ester linkage, an acetal, a sulfonate, a sulfide, a sulfinate, a
disulfide, a sulfonamide linkage, a thioester linkage, a
thiocarbonate linkage, a phosphonamide linkage, or a heterocycle,
LINK2 is an aliphatic moiety or aromatic moiety having up to 12
carbon atoms, and Q is a substituted or non-substituted, saturated
or unsaturated alkyl chain, a polyether, a fluorinated polyether, a
silicone chain, an organometallic moiety, chitosan, heparin,
hyaluronic acid, an antimicrobial agent, an antithrombogenic agent,
a peptide, a protein, a poly(amino acid), a carbohydrate, or a
radio-imaging contrast agent.
24. A medical device selected from the group consisting of medical
tubing, intravenous bags and catheters, ophthalmic devices, blood
filtration devices, cardiovascular devices, biosensors, orthopedic
implants, and prostheses, wherein all or a portion of said medical
device is made from a polymeric molecule according to claim 18 or
21.
Description
FIELD OF THE INVENTION
[0001] This invention provides methods for modifying the surface
properties of polymeric articles, by first forming a surface of
reactive end groups tethered to the polymer chain ends during
fabrication of an article, and subsequently reacting the reactive
end group surface with bio-active molecules, hydrophilic and
hydrophobic monomers, oligomers or polymers to attain specific
surface properties. In an embodiment of the invention, a
multifunctional coupling agent can be used to couple the primary
reactive group to a second reactive group capable of reacting with
a functional group associated with bio-active molecules,
hydrophilic and hydrophobic monomers, oligomers and polymers to
attain specific surface properties. This method of the invention
involves bringing reactive end groups to the surface of the
polymeric article with surface active spacers attached to the
reactive end groups. The surface active spacers promote the
migration and enrichment of reactive end groups at the surface
during fabrication of an article. External measures including
annealing and melt processing may be used to further promote the
migration and enrichment of reactive end groups at the surface.
BACKGROUND OF THE INVENTION
[0002] The surface modification of a substrate with a biologically
active molecules and synthetic polymers can change the substrate
surface properties such as tissue and blood compatibility,
lubricity, wettability, permeability, antimicrobial properties that
are important to the efficacy and safety of the medical product. Of
these surface modification techniques, covalently bonding of
molecules that are of specific characteristics is know to have the
following advantages. i) This surface modification technique is
advantageous in that a stable bond is formed between a surface and
the modifier; and ii) Characteristic properties can be exhibited
that are attributable to a large difference in affinity for
material existing between a covalently bonded and topically coated.
The process is often described as `grafting` to differentiate from
the surface alternation by ordinary spreading and solidifying.
[0003] Various grafting techniques have been proposed for the
application of surface grafted polymers having aforementioned
advantages by making use of their characteristic properties. Often,
two alternative approaches are distinguished:
"grafting-to"--attaching polymers to the solid surface, and
"grafting-from"--monomers being polymerized from solid surface
using an initiation at the surface. See Prucker et al., J. Am.
Chem. Soc., 1999:121:8766-70. Regardless of which technique is
used, the solid surface must have reactive sites in an area
accessible to the grafting monomers and polymers. This often
requires additional steps of surface preparation prior to the
grafting to provide the initiation sites for "grafting-from"
reaction or have function groups available for "grafting-to"
attachment.
[0004] Physical activation of chemical reactions, especially via
controlled degradation of polymer on the substrate surface has been
attempted in many different ways by using high energy radiation,
e.g. .gamma.- or electron, plasma, UV irradiation. For example,
U.S. Pat. No. 5,094,876 describes the method of modifying the
plastic surfaces using gamma or electron beam irradiation induced
chemical grafting. The method comprises the steps of pre-soaking
the substrate in a monomer or a monomer solution to facilitate
diffusion of said monomer or monomers into said plastic surface.
The method lacks the chemical interaction of pre-formed substrate
with the formed polymer and requires the use of organic solvent to
facilitate diffusion of the monomers to the substrate and therefore
poses the difficulty of removing the organic solvent
afterwards.
[0005] WO 01/17575 A1 describes the radiation method of grafting
hydrogel onto organic substrates. It involves steps of exposing a
substrate to an initiator to generate reactive radical sites on the
surface for graft polymerization of monomers immersed in thereby
forming covalent bonds between monomer molecules and the substrate
at reactive radical sites on the substrate surface. This
"grafting-from" method calls for a separate step of surface
preparation and may not applicable to many radical inert polymer
substrates.
[0006] Plasma initiated hydrophilic coating was disclosed in U.S.
Pat. No. 7,217,769 B2, wherein a double bond(alkene) monomer such
as N-trimethylsilyl-allylamine (TMSAA), ethylene, propylene and
allyl alcohol, was first deposited onto the substrate by plasma
grafting and thereby attaching a reactive site for subsequent
plasma cross-linking of the hydrophilic molecules bearing a
"bifunctional spacer" such as
.alpha.-hydro-.omega.-hydroxypoly(oxy-1,2-ethanediyl)-bis-(1-hydroxbenzot-
riazolyl carbonate) (HPEOC). The method requires the plasma
deposition of primary or secondary amine for the subsequent
coupling reaction with a "bifunctional" spacer and subsequent
bio-conjugation with hydrophilic molecules. The covalent bonding of
"prime" coating of primary or secondary amine to the substrate is
not guaranteed.
[0007] The excitation with high energy irradiation has a low
selectivity, bond scissions in the volume of substrate surface and
sub-surface are inevitable. The excitation with plasma is very
surface specific, however, in addition to the requirement of
vacuum, the ablation tendency of the base polymer may be
significant. Ulbricht et al., J. Appl. Polym. Sci., 1995, 56:325.
Also, the contribution of the high-energy deep-UV radiation during
a direct plasma exposure may lead to an uncontrolled degradation
process. Ulbricht, Polymer, 2006, 47: 2217-2262. In addition, the
delicate topological feature of the surface may be damaged due to
the exposure to the irradiation.
[0008] Other surface functionalization methods such as oxidative
hydrolysis and chemical oxidative etching have also been used to
create reactive surface with functional groups such as amino,
aldehyde, epoxide, carboxyl, or other reactive groups for
subsequent surface modification. These "grafting-to" surface
treatments involve harsh condition which may adversely affect the
bulk properties and surface morphology.
[0009] The above prior arts, regardless of the method being used,
requires the steps of surface preparation to create bonding sites,
either by chemical treatment to generate radicals on the surface or
by physical irradiation activation. Direct coupling on reactive
side groups or end groups of the substrate material (e.g. for
cellulose derivatives polyamide or polysulfones) has been reported.
See Klein, J. Membr. Sci., 2000, 179:1, and Castilho et al., J.
Membr Sci., 2000, 172: 269. However, there has been limited success
due to the limited availability of reactive functional groups on
the surface directly accessible to a surface modifier.
SUMMARY OF THE INVENTION
[0010] The present invention overcomes the aforementioned
shortcomings by providing a method that can be applied to modify
the polymeric surface without the shortcomings of the
aforementioned wet chemical or physical irradiation pre-treatment
of the surface to afford reactive bonding sites.
[0011] A first aspect of the invention is to provide a surface
modification method by first forming a surface of primary reactive
end groups tethered to the polymer chain ends or side chain ends
during fabrication of an article or substrate followed by direct
modification with molecules, moieties, organometallic compounds,
metal compounds, bio-active molecules, hydrophilic and hydrophobic
monomers, oligomers and polymers to attain specific surface
properties.
[0012] A second aspect of the invention is to provide a method of
surface modification using an optional multifunctional coupling
agent to couple the primary reactive groups to second reactive
groups capable of reacting with the functional groups associated
with a surface modifier including bio-active molecule, hydrophilic
and hydrophobic monomers, oligomer and polymer to attain specific
surface properties. A multifunctional coupling agent is a molecule
that can be bound by any mean to two different molecules, such as a
functional group on a substrate and a functional group of a
bio-active molecule, monomer, oligomer and polymer. A
multifunctional coupling agent preferably forms covalent,
coordination or ionic bonds with substrate and modifiers to be
coupled with.
[0013] A third aspect of the invention is to provide a method of
creating a surface that has reactive end groups populated on the
surface via the surface active spacers linked to the reactive end
groups during fabrication of the device.
[0014] Another aspect of the invention is to provide a method of
creating a surface of reactive end groups with a temporary
protecting group. The preferred protecting groups are the ones with
surface activity such that upon formation of the surface the
protecting groups are populated at the surface and can be
selectively removed, leaving the reactive end groups at the surface
thereafter and subsequent surface modification.
[0015] Yet another aspect of the invention is to provide a method
of accelerating the surface enrichment of reactive end groups by
subjecting to a conventional thermal process such as extrusion,
molding, and annealing.
[0016] An additional aspect of the invention is to provide a method
of surface modification using a coating composition containing at
least one surface active and reactive end group thereby providing a
surface with reactive end groups for subsequent bonding of
molecules, moieties, organometallic compounds, metal compounds,
bio-active molecules, hydrophilic and hydrophobic monomers,
oligomers and polymers.
[0017] A method of the invention involves bringing reactive end
groups to the surface with surface active spacers attached to the
polymer chain ends, the surface active spacers promote the
migration and enrichment of reactive end groups to the surface
during fabrication. A thermal process may be used for fabrication
to further encourage the surface enrichment of the reactive end
groups. Thermal process may be extrusion, molding, and annealing.
The method can be useful for providing medical device a surface
with desired properties such as anti-thrombogenic properties,
lubricity, selective adsorption, and antimicrobial properties.
[0018] Two schematic approaches in accordance with the present
invention may be depicted as illustrated in FIGS. 1 and 2. The
approach illustrated in FIG. 1 involves direct surface modification
with surface active and reactive end groups. The approach
illustrated in FIG. 2 illustrates surface modification using a
multifunctional coupling agent. In the formulas shown in FIGS. 1
and 2, X represents reactive end groups, Q represents a surface
modifying molecule, K represents functional groups associated with
molecule Q, Y represents functional groups reactive with X, and Z
represents functional groups reactive with K.
[0019] In the direct surface modification embodiment illustrated in
FIG. 1, the method of this invention comprises the steps of:
providing a polymeric body composed of polymeric molecules having
first reactive endgroups linked to surface active spacers which
surface active spacers comprise endgroups on said polymeric
molecules; fabricating an article from said polymeric body and
forming a surface of said first reactive endgroups linked to
surface active spacers on said polymeric body; and contacting the
surface of said polymeric body with a compound containing second
reactive endgroups and surface modifying moieties to react said
second reactive endgroups with said first reactive endgroups and
thereby form covalent, coordination, or ionic bonds linking the
surface modifying moieties to the polymeric molecules.
[0020] In the multifunctional coupling agent embodiment of the
present invention illustrated in FIG. 2, the method comprises the
steps of: providing a polymeric body composed of polymeric
molecules having first reactive endgroups linked to surface active
spacers which surface active spacers comprise endgroups on said
polymeric molecules; fabricating an article from said polymeric
body and forming a surface of said first reactive endgroups linked
to surface active spacers on said polymeric body; contacting the
surface of said polymeric body with a compound containing third and
fourth reactive endgroups to react said third reactive endgroups
with said first reactive endgroups and thereby form covalent or
ionic bonds linking the fourth reactive endgroups to the polymeric
molecules; and contacting the surface of said polymeric body with a
compound containing second reactive groups and surface modifying
moieties to react said second reactive endgroups with said fourth
reactive endgroups and thereby form covalent, coordination, or
ionic bonds linking the surface modifying moieties to the polymeric
molecules.
[0021] The designations "first reactive endgroups," "second
reactive endgroups," "third reactive endgroups," and "fourth
reactive endgroups" in this application are employed solely for the
purpose of explaining the presently claimed methods in which
reactive endgroups fulfill different roles from one another, as is
clearly illustrated in FIGS. 1 and 2. The ordinal designations have
no significance aside from their use to differentiate different
types of reactive endgroup functions in the presently disclosed and
claimed methods.
[0022] The "first reactive endgroups" mentioned above are normally
tethered to surface active spacers as part of polymer chain ends
such that the reactive endgroups are spontaneously brought to the
surface of an article during the fabrication thereof. The chain
ends may be selected from the group consisting of linear polymer
chain ends, side chain ends, hyper-branched chain ends, dentrimer
chain ends, and chain ends of a polymer network. Fabrication
methods usable in the present invention include, without
limitation, thermal forming and solvent based processing. The
thermal processing may be extrusion, molding, casting, or
multilayer processing including co-extrusion and over-molding on
top of a base polymer to afford the fabricated article with the
surface properties of the polymer containing surface active or
reactive endgroups.
[0023] During processing in accordance with this invention, the
reactive endgroups may be protected by protecting groups such that
the functionality and the reactivity of the reactive endgroups are
retained during the fabrication of the article. The reactive
endgroups may be recovered by a de-protection reaction subsequent
to surface formation.
[0024] In accordance with this inventive method, the reactive
endgroups may be selected from the group consisting of vinyl
groups, alkoxy silanes, silanes, epoxy groups, anhydrides, primary
amino groups, secondary amino groups, carboxyl groups, aldehyde
groups, ketone groups, azide groups, dienes, amide groups,
isothiocyanate groups, isocyanate groups, halide groups,
maleimides, hydroxysuccinimide esters, hydroxysulfosuccinimide
esters, imido esters, hydrazines, aziridines, cyano groups, and
alkynes. The reactive endgroups are usually selected to be stable
toward processing conditions used in fabricating the device or
substrate by extrusion, injection molding, or annealing.
[0025] The surface active and reactive end groups in the context of
the present invention comprise surface active species that exhibit
preferential partition at the interface between the polymeric body
and its environment in response to an environment which is in
direct contact with the surface. The surface active groups may be
selected from the group consisting of silicones, substituted or
non-substituted alkyl chains, saturated or unsaturated alkyl
chains, polyethers, fluorinated alkyl chains, and fluorinated
polyethers. The surface modifying moieties may be selected from the
group consisting of monomers, oligomers, polymers, organometallic
molecules, metal compounds, and bioactive molecules such as
chitosan, heparin, hyaluronic acid and its derivatives,
antimicrobial agents, antibiotic agents, antithrombogenic agents,
peptides, proteins, polypeptides, poly(amino acids), carbohydrates,
contrast agents, drugs, glycosaminoglycans, and lubricious
substances.
[0026] The polymeric substrate in the present method may be
selected from the group consisting of solid synthetic polymers,
solid natural polymers, and hydrogels. Types of polymers that can
be surface-modified in accordance with the novel methods disclosed
herein include polyolefins, silicones, acrylic polymers and
copolymers, methacrylic polymers and copolymers, fluoropolymers,
vinyl polymers and copolymers, polyurethanes, polyurethaneureas,
polyester urethanes, silicone polyurethanes, polyvinyl chlorides,
polyamides, polyether amides, polyesters, epoxy polymers,
polyimides, polyester amides, polyether amides, and silicone
hydrogels.
[0027] Virtually any type of polymeric article can be
surface-modified in accordance with the present invention. In a
preferred embodiment, the article is a medical device selected from
the group consisting of medical tubing, intravenous bags and
catheters, ophthalmic devices, blood filtration devices,
cardiovascular devices, biosensors, orthopedic implants, and
prostheses.
[0028] Finally, the present invention also provides two new types
of polymer molecules. One is a polymeric molecule having a surface
modifying moiety linked thereto by a molecular linkage comprising
the reaction product of a "second" reactive endgroup on a compound
containing said second reactive endgroup and said surface modifying
moiety with a "first" reactive endgroup which is linked to a
surface active spacer that comprises an endgroup on said polymeric
molecule--as illustrated in FIG. 1. The other new polymeric
molecule has a surface modifying moiety linked to it by a molecular
linkage comprising both the reaction product of a second reactive
endgroup on a compound containing said second reactive endgroup and
said surface modifying moiety with a fourth reactive endgroup on a
compound containing third and fourth reactive endgroups and the
reaction product of a third reactive endgroup on said compound
containing third and fourth reactive endgroups with a first
reactive endgroup which is linked to a surface active spacer that
comprises an endgroup on said polymeric molecule--as illustrated in
FIG. 2.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 depicts direct surface modification of a polymer by
surface active and reactive end groups in accordance with the
present invention.
[0030] FIG. 2 depicts polymer surface modification using a
multifunctional coupling agent in accordance with the present
invention.
[0031] FIG. 3 illustrates cleavage of protecting groups from
functional groups following the fabrication of an article in
accordance with the present invention.
[0032] FIG. 4 illustrates epoxy groups reacting with polyamine to
form an amine-rich surface which serves as a platform for
immobilization of aldehyde-functional heparin in accordance with
the present invention.
[0033] FIG. 5 illustrates the synthesis of
11-(9-decenyldimethylsilyl)undecan-1-ol.
[0034] FIG. 6 illustrates the synthesis of
11-(triallylsilyl)undecan-1-ol.
[0035] FIG. 7 depicts a polymer in accordance with the present
invention having a surface of reactive methacrylate end groups.
[0036] FIG. 8 depicts a post-polymerization surface-modified
polymer in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The present invention is applicable to a variety of
polymeric substrates, including but not limited to silicones,
polyurethanes, polyamides, polyether amides, polymethacrylates,
polyacrylates, polyacrylamides, polyolefins, polysulfones,
polyether esters, polyesters, polyimides, polyisobutylenes, and
copolymers thereof, which may be used to make medical devices and
related bio-affecting materials. With the invention, such devices
can be provided with surface modification by reactive end groups at
the surface with or without the use of coupling agents, thereby
providing the device with altered surface characteristics, such as
improved lubriciousness, improved biocompatibility, and specific
surface functionality such as selective adsorption of biomolecules
for affinity therapy, retention of tear fluid and prevention of
protein adsorption for contact lenses, improve permselectivity for
biosensor and blood filtration applications, and antimicrobial
surfaces.
[0038] Thus, according to the invention, biomolecules, monomers,
oligomers, polymers and copolymers can be bonded onto polymer
substrate to provide a surface with various functions, including
but not limited to hydrophilicity, lubricity, biocompatibility, and
ability to serve as a primer for subsequent surface modification.
The present invention further provides a method for surface
modification on inert or difficult-to-adhere-to surfaces, is
capable of being applied to both interior and exterior surfaces of
the devices, and is relatively convenient and inexpensive.
[0039] In accordance with the invention, polymers with surface
active and reactive end groups are first synthesized. The reactive
end groups are tethered to the surface active spacers as part of
the polymer chain ends or side chain ends such that during the
manufacturing of medical device, the reactive end groups are
spontaneously moved to the surface along with surface active
spacers and form a surface constituting of reactive end groups
available for further modification. The reactive functional group
can be part of the surface active spacer or attached at the end or
at the side of the surface active spacer, multiple or singular. The
reactive end groups are preferably attached to the surface active
spacer at the end.
[0040] Various surface active spacers have been used in
constructing a self-assembled surface. Examples of chemicals for
such application are available from Asemblon.TM.. Those skilled in
the art can appreciate that these self-assembling molecules can be
further modified to attach a reactive functional group suitable for
subsequent surface modification.
[0041] Other surface active groups may include, but not limited to
silicones, substituted or non-substituted alkyl chains, saturated
or un-saturated alkyl chains, polyoxyalkylene-polysiloxanes,
polyethers, fluorinated alkyls, fluorinated polyethers, and other
surface active species included in WO 2007/142683 A2. Specific
examples of such surface active groups include quaternary ammonium
molecules as disclosed in U.S. Pat. No. 6,492,445 B2. The
quaternary ammonium moieties may have the following formula:
##STR00001##
wherein R.sub.1, R.sub.2, and R.sub.3 are radicals of straight or
branched or cyclic alkyl groups having one to eighteen carbon atoms
or aryl groups and R.sub.4 is an amino-, hydroxyl-, isocyanato-,
vinyl-, carboxyl-, or other reactive group-terminated alkyl chain
capable of covalently bonding to the base polymer. Due to the
permanent nature of the immobilized organic biocide, the polymer
thus prepared does not release low molecular weight biocide to the
environment and has long lasting antimicrobial activity.
Alternatively, the surface active endgroup may be an amino group,
an isocyanate group, a hydroxyl group, a carboxyl group, a
carboxaldehyde group, or an alkoxycarbonyl group, possibly linked
to the polymer backbone via a self assembling polyalkylene spacer
of different chain lengths, typically between 8 and 24 units. In
some specific embodiments, the surface active endgroup may contain
a moiety selected from the group consisting of hydroxyl, carboxyl,
amino, mercapto, azido, vinyl, bromo, (meth)acrylate,
--O(CH.sub.2CH.sub.2O).sub.3H, --(CH.sub.2CH.sub.2O).sub.4H,
--O(CH.sub.2CH.sub.2O).sub.6H,
--O(CH.sub.2CH.sub.2O).sub.6CH.sub.2COOH,
--O(CH.sub.2CH.sub.2O).sub.3CH.sub.3,
--(CH.sub.2CH.sub.2O).sub.4CH.sub.3,
--O(CH.sub.2CH.sub.2O).sub.6CH.sub.3, trifluoroacetamido,
trifluoroacetoxy, and 2',2',2'-trifluorethoxy.
[0042] Examples of di-functional fluorinated polyether are
available from Solvay Solexis with general structures:
X--CF2-O--(CF2-CF2-O).sub.p--(CF2O).sub.q--CF2-X
[0043] Specific examples are:
FOMBLIN Z DOL 2000, 2500, 4000, X=--CH.sub.2OH
FOMBLIN Z DOL TX, X=--CH.sub.2(O--CH.sub.2--CH.sub.2)pOH
FOMBLIN Z TETRAOL, X=--CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH
[0044] FOMBLIN AM 2001, AM 3001,
X=--CH.sub.2O--CH.sub.2-pyperonyl
[0045] Examples of di-functional silicone
(HOCH.sub.2CH.sub.2CH.sub.2OCH.sub.2CH.sub.2CH.sub.2).sub.2--[Si(OCH.sub.-
3).sub.2].sub.n are available from Gelest, Shin-Etsu. Other amine
functional silicone fluids such as
(H.sub.2NCH.sub.2CH.sub.2CH.sub.2OCH.sub.2CH.sub.2CH.sub.2).sub.2--[Si(OC-
H.sub.3).sub.2].sub.n,
(H.sub.2NCH.sub.2CH.sub.2CH.sub.2).sub.2--[Si(OCH.sub.3).sub.2].sub.n
are also available from Wacker and Gelest.
[0046] Examples of di-functional alkyl may include 1,12-dodecane
diol, 1,14-tetradecane diol, 1,16-hexadecane diol,
1,18-octadecanediol.
[0047] Examples of di-carboxylic acid functional alkyl may include
1,14-tetradecanedicarboxylic acid, 1,16-hexadecanedicarboxylic
acid, 1,18-octadecanedicarboxylic acid.
[0048] Examples of di-amine functional alkyl may include
1,12-dodecane diamine, 1,14-tetradecane diamine, 1,16-hexadecane
diamine, 1,18-octadecane diamine.
[0049] Depending on the functional groups associated with the
surface modifier to be bonded to the surface, polymers with
different surface active and reactive end groups can be prepared
with the matching reactive end group capable of reacting to a
functional group associated with the surface modifier. A surface
modifier is a chemical entity that bears certain characteristic
desirable for intended application. A reactive group is often
associated with the surface modifier to provide the site of
chemical bonding.
[0050] REACTIIONS OF REACTIVE ENDGROUPS. It is well known in the
art that a pair of matching reactive groups can form a covalent
bond or linkage under known coupling reaction conditions, such as,
oxidation-reduction, condensation reaction, addition reaction,
substitution reaction, cationic or anionic ring opening reaction,
Diels-Alder reaction, or Hetero-Diels Alder reaction. For example,
a vinyl group reacts with silane group with the presence of
catalyst such as Karstedt catalyst, Wilkinson's catalyst, to form a
stable Si--C bond; an amino group reacts with aldehyde group to
form a Schiff base which may further be reduced to form a stable
N--C bond; an amino group reacts with an acid chloride or anhydride
to form an amide linkage; an amino group react with isocyanate
group to form a urea linkage; an amino group reacts with epoxide to
form N--C bond; an hydroxyl reacts with isocyanate to form urethane
linkage.
[0051] Examples of reactive groups may include without limitation,
vinyl group, silane, alkoxy silane, epoxy group, anhydride group,
amine group, amide group, hydroxyl group, isocyanate group,
isothiocyanate, halide group, acryl chloride, acrylate,
methacrylate, aldehyde, carboxylic acid, maleimide,
hydroxysuccinimide ester, hydroxysulfosuccinimide ester, imido
ester, hydrazine, azide, alkyne, diene, cyano, ketone, thiol, or
azeridine.
[0052] Preferably, the reactive group is selected from the group
consisting of vinyl groups, alkoxy silane, epoxy groups, anhydride,
primary amino groups, secondary amino groups, carboxyl groups,
aldehyde groups, amide groups, isothiocyanate group, isocyanate
groups, halide groups, alkyne groups, diene, ketone, or azeridine.
More preferably, the reactive groups selected are stable toward the
processing condition used in fabricating the device, even more
preferably, the reactive groups are stable under thermal processing
condition such as extrusion, injection molding.
[0053] LINKAGES. Exemplary covalent bonds or linkage formed between
pairs of reactive end group and functional group associated with
surface modifier may include, without limitation, Si--C bond,
Si--O--Si bond, urethane, urea, carbamate, amine, amide, imine,
enamine, oxime, amidine, iminoester, carbonate, C--C bond, ether,
ester, acetal, sulfonate, sulfide, sulfinate, sulfide, disulfide,
sulfinamide, sulfonamide, thioester, thiocarbonate, thiocarbamate,
phosphonamide, and heterocycles.
[0054] Those skilled in the art will appreciate the use of
protecting groups to temporary mask the reactive end group such
that the reactive end groups are protected while subjecting to the
heat, solvent, or in contacting with other components during the
fabrication of a device or formation of a surface. The protecting
groups can be removed subsequently under mild condition by the
known chemistry without imparting physical and morphological
properties of the formed surface. More preferably, the protecting
groups are the ones with high surface activity, even more
preferably with self-assembling ability to maximize the
concentration of reactive end groups at the surface. Such
protection and de-protection chemistries for many reactive
functional groups such as amino group, hydroxyl group, carbonyl
group, thiol group, carboxylic group, alkyne group are known to the
skilled in the art. For example, a hydroxyl group can be protected
by forming ether linkages such as methyl ethers, ally and benzyl
ethers, triphenylmethyl ethers, oxygen-substituted ethers, and
silyl ethers. It can also be protected by forming an ester linkage
such as acetate ester. The aldehydes and ketones can be protected
by forming acetals, thioacetals, enol ethers, enamines. A phenol
can be protected by using methyl toluene-p-sulfonate to form a
methyl ether. The hydroxyl group can be de-protected by known
chemistry such as hydrolysis. The carbolic acid groups can be
protected by forming esters such as orthoesters. The carboxylic
acid can be recovered by the hydrolysis reaction Amine groups can
be protected by forming imines, enamines, amides, carbamates.
Thiols can be protected by forming thioethers, acetal derivatives,
and thioesters. Other reactive groups such as alkenes, dienes, and
alkynes can also be protected by the formation of chemical bonds
that can be selectively cleaved under established condition.
[0055] Thus, depending on the reactive end groups, various
protecting reagents can be used in forming such a temporary bond.
One can chose an effective protecting group and de-protecting
procedure from well established reference work, such as those
described in the text "ACTIVATING AGENTS AND PROTECTING GROUPS,
HANDBOOK OF REAGENTS FOR ORGANIC SYNTHESIS," Ed. by Pearson et al,
and published by Wiley, June, 1999, ISBN-10: 0471979279, ISBN-13:
978-0471979272. To further facilitate end groups to move to the
surface, the protecting groups are preferably surface active. This
can be achieved by selecting a protecting reagent that bears
surface active moieties or modifying the protecting agents with
surface active groups.
[0056] For example, trifluoroacetamide (TFA) is commonly used in
protecting primary amine in organic synthesis and can be cleaved by
a mild hydrolysis in the presence of methyl ester.
##STR00002##
[0057] TFA also has high surface activity when exposed to the air
and may further assist in concentrating amine end groups at the
surface during the formation of a surface.
[0058] Silyl ethers are among the most frequently used protective
groups for the hydroxyl group, their reactivity and stability can
be tailored by varying the nature of the substituents on the
silicon. One of the well known silyl ether protective groups used
in protecting alcohol is trimethylsilyl ether. For example, one of
the hydroxyl groups in aliphatic diol can be selectively protected
and the purified product can be used as mono-functional end group
in polyurethane synthesis:
##STR00003##
[0059] Because the extra mobility and surface activity in
minimizing the interfacial free energy, the end groups are
kinetically and thermodynamically favored in migrating to and
concentrating at the surface, and even form assembled pattern with
TMS groups forming the out most layer. Upon treatment with
de-protecting agent, the hydroxyl groups can be made available for
the subsequent surface modification with functional and bioactive
molecules. t-Butyldimethylsilyl ether (TBDMS ether) is another
example of popular silyl protective groups used in chemical
synthesis and can be introduced under variety condition and readily
removed under condition that do not attack other functional groups
or chemical bonds.
##STR00004##
[0060] The bulky TBDMS group can be also surface active when
exposed to the air and therefore can facilitate the
self-concentrating of hydroxyl groups at the surface after
cleavage.
[0061] It can be understood to the skilled in the art that a
multifunctional coupling agent can be used to facilitate the
attachment of a surface modifier to a reactive end group at the
surface. A multifunctional coupling agent is described as a
molecules that bears more than 2 functional groups, each reactive
to a reactive end group at the surface and a functional group
associated with a surface modifier. The functional groups in the
coupling agent can be the same or different. A multifunctional
coupling agent that can be bound by any means to two different
molecules, such as a reactive group on a substrate surface and a
functional group of a surface modifier including bio-active
molecules, monomers, oligomers and polymers. A multifunctional
coupling agent preferably forms covalent, coordination or ionic
bonds with substrate and molecules to be coupled with.
[0062] Various multifunctional coupling agents can be found
commercially available or can be synthesized. For example, branched
polyethylene amine is commercially available from Sigma Aldrich and
can be used to couple the aldehyde group at the surface and
aldehyde group associated with heparin. Epoxy silane available from
Gelest can be used to couple the vinyl group at the surface and
amine group associated with amino acids and other biomolecules.
Carbodiimide can be used in the coupling of a carboxyl and an amine
to form an amide linkage between the molecules being coupled.
Examples of carbodiimides includes
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),
N,N'-dicyclohexylcarbodiimide (DCC),
1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, diisopropyl
carbodiimide, or mixture thereof. Difunctional aldehydes such as
glutaraldehyde can be used to immobilize peptide, protein to an
amine surface.
[0063] It can be understood to those skilled in the art that the
method can be applied to a wide variety of medical devices to
attain specific surface properties. The properties of interest to
the medical usage may include, but not limited to, lubricity,
wettability, antimicrobial property, antithrombogenic property,
resistance in protein adhesion. For example, heparin bond surfaces
are know to have improved thrombo resistance, lubricious surface on
urinary Foley catheter is beneficial to reduce the patient
discomfort, while lubricious surface on orthopedic implants may
reduce the wear and improve the life time of the device. Contact
lenses with improved wettability is essential for the maintenance
of vision as well as the health of the cornea. It can also be
useful for surface modification in diagnostic devices and sensors
to improve the separation efficiency.
[0064] This invention thus provides medical devices or prostheses
which are constituted of polymer bodies, wherein the polymer bodies
comprise a plurality of polymer molecules located internally within
said body, at least some of which internal polymer molecules have
end groups covalently bonded with a surface modifier that comprises
a surface of the body. The polymer bodies can include dense,
microporous or macroporous components in implantable medical
devices or prostheses or in non-implantable disposable or
extracorporeal medical devices or diagnostic products. For example,
in one embodiment, the polymer body may comprise a membrane
component or coating containing immuno-reactants in a diagnostic
device. The present invention is particularly adapted to provide
such articles configured as implantable medical devices or
prostheses or as non-implantable disposable or extracorporeal
medical devices or prostheses or as in in vitro or in vivo
diagnostic devices, wherein the device or prostheses has a tissue,
fluid, and/or blood-contacting surface. Where the article of the
present invention is a delivery device, a device for delivering
drugs, growth factors, cells, microbes, islets, osteogenic
materials, neovascular-inducing moieties, the active agent may be
complexed to the surface active and reactive end groups and
released through diffusion, or it may be complexed or bonded to
surface active and reactive end groups which are chosen to slowly
degrade and release the drug over time.
[0065] Those skilled in the art will thus appreciate that the
present invention provides improved blood gas sensors,
compositional sensors, substrates for combinatorial chemistry,
customizable active biochips--that is, semiconductor-based devices
for use in identifying and determining the function of genes,
genetic mutations, and proteins, in applications including DNA
synthesis/diagnostics, drug discovery, and immunochemical
detection, glucose sensors, pH sensors, blood pressure sensors,
vascular catheters, cardiac assist devices, prosthetic heart
valves, artificial hearts, vascular stents and stent coatings,
e.g., for use in the coronary arteries, the aorta, the vena cava,
and the peripheral vascular circulation, prosthetic spinal discs,
prosthetic spinal nuclei, spine fixation devices, prosthetic
joints, cartilage repair devices, prosthetic tendons, prosthetic
ligaments, delivery devices from which the molecules, drugs, cells
or tissue are released over time, delivery devices in which the
molecules, drugs, cells or tissue are fixed permanently to polymer
end groups, catheter balloons, gloves, wound dressings, blood
collection devices, blood processing devices, plasma filters,
plasma filtration catheters and membranes, devices for bone or
tissue fixation or re-growth, urinary stents, urinary catheters,
contact lenses, intraocular lenses, ophthalmic drug delivery
devices, male and female condoms, devices and collection equipment
for treating human infertility, insulation tubing and other
components of pacemaker leads and other electro-stimulation leads
and components such as implantable defibrillator leads, neural
stimulation leads, scaffolds for cell, tissue or organ
growth/re-growth or tissue engineering, prosthetic or cosmetic
breast or pectoral or gluteal or penile implants with or without
leak detection capability, incontinence devices, devices for
treating acid reflux disease, devices for treating obesity,
laparoscopes, vessel or organ occlusion devices, neurovascular
stents and occlusion devices and related placement components, bone
plugs, hybrid artificial organs containing transplanted tissue, in
vitro or in vivo cell culture devices, blood filters, blood tubing,
roller pump tubing, cardiotomy reservoirs, oxygenator membranes,
dialysis membranes, artificial lungs, artificial livers, or column
packing adsorbents or chelation agents for purifying or separating
blood, blood cells, plasma, or other fluids. All such articles can
be made by conventional means and their surface being modified from
surface active and reactive end groups that characterize the
polymers described herein.
EXAMPLES
[0066] The invention will be further illustrated by the following
non-limiting examples:
Example 1
[0067] Using surface active and reactive diamine as an end capping
agent, a polyurethane with amine terminated end groups can be
prepared by a two-step method: I) First, isocyanate terminated
polyurethane was prepared in DMAc solution from diisocyanate such
as MDI, polyol such as PTMO, PEO, and polyol such as polycarbonate
diol, silicone diol, and chain extender such as butane diol,
ethylene diamine, ethanol amine, and other short chain diamine,
diol, and amino alcohol. The stoichiometric ratio of NCO/H was kept
more than 1 so that the polyurethane chain ends were terminated
with isocyanate groups, II) Excess amount of surface active and
reactive diamine was then added to the reaction mixture to allow
the covalent attachment of these end groups at one site, leaving
the other amine group for subsequent surface modification. The
polymer thus prepared can be used as a coating or can be
precipitated and dried for thermal processing such as extrusion,
molding. Because of the surface active alkyl chain, the amine
groups attached were able to move to the surface of coating, an
extruded tubing or injection molded part during processing,
enriched or even self-assembled at the surface, making themselves
available for subsequent bonding or immobilization of heparin as
illustrated in the following formula.
##STR00005##
[0068] Alternatively, diamine with one end protected with
N-t-butoxycarbonyl can be prepared and used in the synthesis of
polyurethane. Following the fabrication of an article, these
protecting groups concentrated at the surface can be cleaved with
selected de-protecting agent under suitable conditions. See FIG.
3.
[0069] Polymers thus prepared can be used in fabricating the
devices that have protected amine end groups enriched at the
surface. Under an environmentally benign condition using mild
reagent such as aqueous phosphoric acid, tert-butyl carbamates can
be effectively and selectively de-protected, leaving amine groups
for subsequent bonding or immobilization of heparin as illustrated
in FIG. 3.
Example 2
[0070] Polyurethane with 10-undecen-1-ol end groups was first
prepared. Tubing was extruded from the resin having the surface
enriched with the vinyl end groups which were then reacted with an
epoxy silane coupling agent to form a surface abundant with
epoxide, the epoxide functional surface can serve as platform for
immobilization of hydrophilic molecules such as PVP, PEO, PVA, PMA,
polyelectrolytes, and other biomolecules bearing functional group
reactive to epoxide to afford wet lubricity. Applying
multifunctional hydrophilic molecules may also lock-in the surface
with desired properties. Reaction may also take place with
underlying reactive end groups due to the penetration/diffusion of
surface modifying agents, these underlying end groups will serve as
the reservoir for replenishing the surface in demand.
Alternatively, the epoxy groups can react with polyamine to form an
amine rich surface which can serve as platform for immobilization
of biomolecules such as commercially available aldehyde functional
heparin, as illustrated in FIG. 4.
[0071] Other surface active unsaturated alkyl amine and alcohol
includes Oleylamine
CH.sub.3(CH.sub.2).sub.7CH.dbd.CH(CH.sub.2).sub.8NH.sub.2, Oleyl
alcohol CH.sub.3(CH.sub.2).sub.7CH.dbd.CH(CH.sub.2).sub.7CH.sub.2OH
(CAS#143-28-2), palmitoleyl alcohol
CH.sub.3(CH.sub.2).sub.5CH.dbd.CH(CH.sub.2).sub.8OH, elaidyl
alcohol CH.sub.3(CH.sub.2).sub.7CH.dbd.CH(CH.sub.2).sub.8OH, erucyl
alcohol CH.sub.3(CH.sub.2).sub.7CH.dbd.CH(CH.sub.2).sub.12OH,
linoleyl alcohol, and hydroxyl terminated unsaturated polybutadiene
resins such as the following
##STR00006##
available, for instance, from Sartomer Company, Inc. of Exton, Pa.,
USA (e.g., as KRASOL resins).
[0072] These reactive end groups can be incorporated into
polyurethane as surface active end group bearing C.dbd.C bonding
sites for bio-conjugation or immobilization of specific molecules.
Using these hydroxyl-functional surface active and reactive end
groups, a thermal plastic polyurethane can be prepared from
diisocyanate such as MDI, polyol such as PTMO, PEO, and
polycarbonate diol, silicone diol, and chain extender including
butane diol, ethylene diamine, ethanol amine, and other short chain
diamine, diol, and amino alcohol. Thus an extruded tubing or
injection molded part will have the surface active unsaturated
alkyl end groups enriched or even self-assembled at the surface and
the C.dbd.C can be available for subsequent bonding or
immobilization, as illustrated below.
##STR00007##
Example 3
[0073] Hydroxyl-functional surface active and reactive end groups
capping agents can also be optimized and incorporated in
polyurethanes as surface active and reactive end group. Examples of
such compounds are 11-(9-decenyldimethylsilyl)undecan-1-ol and
11-(triallylsilyl)undecan-1-ol and 11-(triallylsilyl)undecan-1-ol.
The synthesis of the molecules is described below:
Synthesis of 11-(9-decenyldimethylsilyl)undecan-1-ol
[0074] The title compound was synthesized as illustrated in FIG. 5.
10-undecen-1-ol (85 g, 0.5 mol) and p-toluenesulfonic acid
monohydrate (0.38 g, 2 mmol) were dissolved in dichloromethane (150
mL) and cooled in ice/water bath under nitrogen. To this solution
was then added 3,4-dihydro-2H-pyran (50.4 g, 0.6 mol) dropwise over
an hour. After the addition, the solution was stirred for
additional two hours in ice/water bath and turned into purple. The
solution was then diluted with hexanes (300 mL), washed with
aqueous sodium bicarbonate (150 mL.times.2), and dried over MgSO4.
After removal of solvents by rotary evaporation, the residual light
brown oil was distilled under vacuum and the distillate at
75-79.degree. C. (300 mTorr) was collected to give THP-protected
10-undecen-1-ol (1) as colorless oil (113 g, 89%). To Compound 1
(6.35 g, 25 mmol) was added Karstedt catalyst (2.1% Pt in xylene,
22 mg) and this mixture was then added into a ice/water bath cooled
solution of 1,1,3,3-tetramethydisiloxane (6.7 g, 50 mmol) in
hexanes dropwise over 30 min. After the addition, the mixture was
stirred for additional three hours in ice/water bath. Solvent and
excess 1,1,3,3-tetramethydisiloxane were then removed under vacuum
to give the crude intermediate compound 2 as a light brown oil
which was then added to a solution of 1,9-decadiene (5.2 g, 37.6
mmol) in hexanes (5 mL) dropwise over 30 min at room temperature.
After the addition, the mixture was stirred at room temperature for
additional two hours and volatiles were then removed under vacuum
to give the residual crude intermediate compound 3 as light brown
oil. To this brown oil was then added methanol (50 mL) and
p-toluenesulfonic acid monohydrate (0.2 g) and the mixture was
stirred at room temperature overnight. After removal of volatiles
under reduced pressure, the residual brown oil was purified on
silica gel using hexanes/ethyl acetate (85/15, v/v) as eluent to
give 2.8 g 11-(9-decenyldimethylsilyl)undecan-1-ol as colorless oil
(26.3% over three steps). 1H NMR .delta. 5.75-5.90 (m, 1H),
4.90-5.05 (m, 2H), 3.60-3.68 (t, 2H), 2.00-2.10 (m, 2H), 1.50-1.62
(m, 2H), 1.20-1.45 (br, 28H), 0.45-0.55 (m, 4H), 0.02 (s, 12H).
Synthesis of 11-(triallylsily)undecan-1-ol
[0075] The title compound was synthesized as illustrated in FIG. 6.
Compound 1 (7.62 g, 30 mmol), trichlorosilane (32.4 g, 0.24 mol),
and Karstedt catalyst (2.1% Pt in xylene, 54 mg) were charged into
a 500 mL Schlenk under nitrogen and the mixture was stirred at room
temperature for 60 hours. The excess trichlorosilane was then
removed under vacuum and the flask was backfilled with nitrogen.
Under nitrogen purge, anhydrous THF (200 mL) and granular magnesium
(15 g, 0.625 mol) was added to the flask and the flask was then
cooled in ice/water bath. Allyl bromide (66 g, 0.54 mol) was then
slowly added in over five hours. After the addition, the mixture
was stirred at room temperature overnight. Distilled water (250 mL)
was then added to quench the reaction. The aqueous layer was
extracted with hexanes (100 mL.times.3) and the combined organic
layers was then dried over MgSO4 and concentrated to give a light
brown oil which was purified on silica gel using hexanes/ethyl
acetate (85/15, v/v) to give 11-(triallylsilyl)undecan-1-ol as a
colorless oil (2.2 g, 22.8% over three steps). 1H NMR .delta.
5.7-5.9 (m, 3H), 4.80-4.95 (m, 6H), 3.60-3.68 (t, 2H), 1.50-1.65
(m, 8H), 1.20-1.40 (br, 16H), 0.50-0.65 (t, 2H).
[0076] Another example of a vinyl-substituted functional silicone
is:
##STR00008##
[0077] Polyurethane with surface active and reactive vinyl end
groups as described above can be synthesized as follows, where the
first formula shows monofunctional reactive endgroups and the
second formula shows polyfunctional reactive endgroups:
##STR00009##
[0078] A polyurethane with polyfunctional reactive endgroups as
illustrated above was synthesized as follows: To melted MDI was
added polycarbonate diol and 11-(triallylsilyl)undecan-1-ol and the
reaction was stirred at 70.degree. C. for two hours. The prepolymer
was then chain extended with butanediol. Polymer films were
prepared by dropping 5 wt % solution of the polymer in THF on glass
slides followed by slow evaporation of THF. As comparison, polymer
films of polyurethane without surface modifying end group were
prepared under the same conditions. A set of films of PU with and
without surface modifying end group
(11-(triallylsilyl)undecan-1-ol) were immersed into a solution of
0.6 g 2-aminothioethanol and 0.2 g of AIBN in 10 mL of ethanol in a
25 mL round bottom flask. The system was then deoxygenated by
bubbling nitrogen through for 30 min. The flask was then kept in a
50.degree. C. oil bath overnight. After being taken out of the
flask, the films were flushed with ethanol, dilute HCl, and ethanol
sequentially and dried under a nitrogen stream. Static water
contact angle of the films of PU with surface modifying end group
dropped from 88 degrees for non treated samples to 64 degrees for
treated samples as the result of surface modification while the
contact angle of the films of PU without SME stayed unchanged at 82
degrees.
[0079] The surface of medical device made from polyurethanes with
surface active and reactive vinyl end groups can be modified using
an epoxy silane, such as that of the formula:
##STR00010##
to allow the hydrosilylation reaction between vinyl group tethered
to the polymer chain end and silane group of the coupling agent to
form C--Si bond thereby attaching epoxide group on the surface for
subsequent reaction with polyamine. The excess amine groups can
subsequently react with aldehyde group in heparin, leading to the
covalent immobilization of the Heparin on the surface.
Example 4
[0080] Surface active and reactive end group for coating and
surface grafting application. Using a hydroxyl-functional surface
active and reactive methacrylate end group having the formula
##STR00011##
a polyurethane coating solution in DMAc can be prepared from
diisocyanate such as MDI, polyol such as PTMO, PEO, and
polycarbonate diol, silicone diol, and chain extender including
butane diol, ethylene diamine, ethanol amine, and other short chain
diamine, diol, and amino alcohol. A coating solution thus prepared
can provide a surface of reactive methacrylate end groups for
further grafting from copolymerization with hydrophilic monomer,
macromer and polymers to afford lubricious surface. This
surface-modified polymer is depicted in FIG. 7. Examples of
hydrophilic monomer includes vinyl pyrrolidone, (meth)acrylamide,
PEG (meth)acrylate, PVP (meth)acrylate, (meth)acrylate with charge
center, and other (meth)acrylic functional hydrophilic oligomer and
polymers. The method can be found especially useful for medical
application requiring lubricious surface such as orthopedic device,
CVC catheter, urinary catheter, and the like.
Example 5
[0081] Polymers with surface active and reactive alkyne end groups
or side chains can be synthesized as follows: Using surface active
and reactive 15-Hexadecyn-1-ol as an end capping agent, a
polyurethane with alkyne terminated end groups can be prepared by a
two-step method: I) First, isocyanate terminated polyurethane is
prepared in DMAc solution from diisocyanate such as MDI, polyol
such as PTMO, PEO, and polyol such as polycarbonate diol, silicone
diol, and chain extender such as butane diol, ethylene diamine,
ethanol amine, and other short chain diamine, diol, and amino
alcohol. II) 0.1-5% of surface active and reactive
15-Hexadecyn-1-ol is added to the reaction mixture to allow the
covalent attachment of the hydroxy end groups at one site, leaving
the alkyne group for subsequent surface modification.
##STR00012##
[0082] The surface active alkyne can then be reacted by a Huisgen
1,3-dipolar cycloaddition
##STR00013##
to yield the post-polymerization surface modified polymer depicted
in FIG. 8.
End Use Applications
[0083] Unconfigured specialized endgroup-containing polymers of
this invention may be converted to formed articles by conventional
thermoplastic methods used to process polymers, including methods
such as extrusion, injection molding, compression molding,
calendering, and thermoforming under pressure or vacuum and stereo
lithography. Multilayer processing such as co-extrusion or
over-molding can be used on top of the base polymers to be
economically viable and afford the surface properties from the
polymers. The polymers may also be processed by solution-based
techniques, such as air brush or airless spraying, ink jet
printing, stereo lithography, electrostatic spraying, brushing,
dipping, casting, and coating. Water-based polymer emulsions can be
fabricated by methods similar to those used for solvent-based
methods. In both cases, the evaporation of a volatile liquid (e.g.,
organic solvent or water) leaves behind a film of the polymer. The
present invention also contemplates the use of liquid or solid
polymers with specialized endgroups in computer-controlled
stereolithography--also know as 3D printing. This method is of
particular use in the fabrication of dense or porous structures for
use in applications, or as prototypes, for tissue engineering
scaffolds, prostheses, medical devices, artificial organs, and
other medical, consumer, and industrial end uses. Fabrication
considerations which are applicable to the present invention are
discussed in U.S. Pat. No. 5,589,563, the contents of which are
hereby expressly incorporated by reference.
[0084] Polymers used to make useful articles in accordance with
this invention will generally have tensile strengths of from about
100 to about 10,000 psi and elongations at break of from about 50
to about 1500%. In some particularly preferred embodiments, porous
or non-porous films of the present invention are provided in the
form of flexible sheets or in the form of hollow membranes or
fibers made by melt blowing, spinning, electrostatic spraying, or
dipping, for example. Typically, such flexible sheets are prepared
as long rollable sheets of about 10 to 15 inches in width and up to
hundreds of feet in length. The thicknesses of these sheets may
range from about 5 to about 100 microns. Thicknesses of from about
19 to 25 microns are particularly useful when the article to be
manufactured is to be used without support or reinforcement.
[0085] Polymer membranes of this invention may have any shape
resulting from a process utilizing a liquid which is subsequently
converted to a solid during or after fabrication, e.g., solutions,
dispersion, 100% solids prepolymer liquids, polymer melts, etc.
Converted shapes may also be further modified using methods such as
die cutting, heat sealing, solvent or adhesive bonding, or any of a
variety of other conventional fabrication methods.
[0086] Thermoplastic fabrication methods may also be employed.
Membrane polymers made by bulk or solvent-free polymerization
method may be cast into a mold during the polymerization reaction.
Extrusion, injection molding, calendering, and other conversion
methods that are well-known in the art may also be employed to form
membranes, films, and coatings of the polymers of the present
invention configured into solid fibers, tubing, medical devices,
and prostheses. As those skilled in the art will appreciate, these
conversion methods may also be used for manufacturing components
for non-medical product applications.
[0087] This invention thus provides medical devices or prostheses
which are constituted of polymer bodies, wherein the polymer bodies
comprise a plurality of polymer molecules located internally within
said body, at least some of which internal polymer molecules have
endgroups that comprise a surface of the body. The polymer bodies
can include dense, microporous, or macroporous membrane components
in implantable medical devices or prostheses or in non-implantable
disposable or extracorporeal medical devices or diagnostic
products. For example, in one embodiment, the polymer body may
comprises a membrane component or coating containing
immuno-reactants in a diagnostic device. The present invention is
particularly adapted to provide such articles configured as
implantable medical devices or prostheses or as non-implantable
disposable or extracorporeal medical devices or prostheses or as in
in vitro or in vivo diagnostic devices, wherein the device or
prostheses has a tissue, fluid, and/or blood-contacting
surface.
[0088] Those skilled in the art are also well aware of how to use
such embodiments of the present invention. See for instance: Ebert,
Stokes, McVenes, Ward, and Anderson, Biostable Polyurethane
Silicone Copolymers for Pacemaker Lead Insulation, The 28.sup.th
Annual Meeting of the Society for Biomaterials, Apr. 24-27, 2002,
Tampa, Fla.; Ebert, Stokes, McVenes, Ward, and Anderson,
Polyurethane Lead Insulation Improvements using Surface Modifying
Endgroups, The 28.sup.th Annual Meeting of the Society for
Biomaterials, Apr. 24-27, 2002, Tampa, Fla.; Litwak, Ward,
Robinson, Yilgor, and Spatz, Development of a Small Diameter,
Compliant, Vascular Prosthesis, Proceedings of the UCLA Symposium
on Molecular and Cell Biology, Workshop on Tissue Engineering,
February, 1988, Lake Tahoe, Calif.; Ward, White, Wolcott, Wang,
Kuhn, Taylor, and John, "Development of a Hybrid Artificial
Pancreas with Dense Polyurethane Membrane", ASAIO Journal, J.B.
Lippincott, Vol. 39, No. 3, July-September 1993; Ward, White, Wang,
and Wolcott, A Hybrid Artificial Pancreas with a Dense Polyurethane
Membrane: Materials & Design, Proceedings of the 40.sup.th
Anniversary Meeting of the American Society for Artificial Internal
Organs, Apr. 14-16, 1994, San Francisco, Calif.; Farrar, Litwak,
Lawson, Ward, White, Robinson, Rodvien, and Hill, "In-Vivo
Evaluation of a New Thromboresistant Polyurethane for Artificial
Heart Blood Pumps", J. of Thoracic Surgery, 95:191-200, 1987;
Jones, Soranno, Collier, Anderson, Ebert, Stokes, and Ward, Effects
of Polyurethanes with SMEs on Fibroblast Adhesion and Proliferation
and Monocyte and Macrophage Adhesion, The 28.sup.th Annual Meeting
of the Society for Biomaterials, Apr. 24-27, 2002, Tampa, Fla.; and
Ward, R. S. and White, K. A., Barrier Films that Breathe, CHEMTECH,
November, 1991, 21(11), 670, all of which references are hereby
expressly incorporated by reference.
INDUSTRIAL APPLICATIONS
[0089] The present invention is applicable to a variety of
polymeric substrates, including but not limited to silicones,
polyurethanes, polyamides, polyether amides, polymethacrylates,
polyacrylates, polyacryamides, polyolefins, polysulfones, polyether
esters, polyesters, polyimides, polyisobutylenes, and copolymers
thereof, which may be used to make medical devices and related
bio-affecting materials. With the invention, such devices can be
provided with surface modification by reactive end groups at the
surface with or without the use of coupling agents, thereby
providing the device with altered surface characteristics, such as
improved lubriciousness, improved biocompatibility, and specific
surface functionality such as selective adsorption of biomolecules
for affinity therapy, retention of tear fluid and prevention of
protein adsorption for contact lenses, improve permselectivity for
biosensor and blood filtration applications, and antimicrobial
surfaces.
* * * * *