U.S. patent application number 12/712031 was filed with the patent office on 2010-08-26 for anti-infective functionalized surfaces and methods of making same.
This patent application is currently assigned to ORTHOBOND CORP.. Invention is credited to Randell Clevenger, Jeffrey Schwartz.
Application Number | 20100215643 12/712031 |
Document ID | / |
Family ID | 42631150 |
Filed Date | 2010-08-26 |
United States Patent
Application |
20100215643 |
Kind Code |
A1 |
Clevenger; Randell ; et
al. |
August 26, 2010 |
ANTI-INFECTIVE FUNCTIONALIZED SURFACES AND METHODS OF MAKING
SAME
Abstract
Devices are provided which are functionalized to include surface
regions having anti-infective agents. Methods are provided for
functionalizing various material surfaces to include active surface
regions for binding anti-infective agents. Methods are provided by
which anti-infective moieties or agents are bonded to
functionalized surfaces.
Inventors: |
Clevenger; Randell; (North
Plainfield, NJ) ; Schwartz; Jeffrey; (Princeton,
NJ) |
Correspondence
Address: |
GIBSON & DERNIER LLP
900 ROUTE 9 NORTH, SUITE 504
WOODBRIDGE
NJ
07095
US
|
Assignee: |
ORTHOBOND CORP.
North Brunswick
NJ
|
Family ID: |
42631150 |
Appl. No.: |
12/712031 |
Filed: |
February 24, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61155324 |
Feb 25, 2009 |
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Current U.S.
Class: |
514/1.1 ;
204/192.1; 424/617; 424/618; 424/630; 424/632; 424/637; 424/641;
424/645; 424/660; 424/661; 424/667; 424/693; 424/709; 424/715;
424/718; 427/248.1; 427/430.1; 514/241; 514/396; 514/471; 514/475;
514/635; 514/721; 514/724; 514/735; 514/75 |
Current CPC
Class: |
A61P 31/00 20180101;
A61L 2300/404 20130101; A61L 31/022 20130101; A61L 31/16 20130101;
A61L 2300/208 20130101; C07F 9/3821 20130101; A01N 25/08 20130101;
A01N 25/10 20130101; A01N 25/10 20130101; A01N 59/16 20130101; A01N
59/20 20130101; A01N 25/08 20130101; A01N 31/12 20130101 |
Class at
Publication: |
424/130.1 ;
424/661; 514/241; 424/709; 424/660; 424/715; 424/667; 514/724;
514/735; 514/721; 514/635; 424/618; 424/645; 424/630; 424/637;
424/632; 424/718; 424/693; 514/2; 514/396; 514/471; 514/475;
424/641; 424/617; 514/75; 204/192.1; 427/430.1; 427/248.1 |
International
Class: |
A01N 59/00 20060101
A01N059/00; A01N 59/08 20060101 A01N059/08; A01N 43/66 20060101
A01N043/66; A01N 59/02 20060101 A01N059/02; A01N 59/14 20060101
A01N059/14; A01N 59/12 20060101 A01N059/12; A01N 31/02 20060101
A01N031/02; A01N 31/08 20060101 A01N031/08; A01N 31/14 20060101
A01N031/14; A01N 37/52 20060101 A01N037/52; A01N 59/16 20060101
A01N059/16; A01N 59/18 20060101 A01N059/18; A01N 59/20 20060101
A01N059/20; A01N 59/06 20060101 A01N059/06; A01N 37/18 20060101
A01N037/18; A01N 43/50 20060101 A01N043/50; A01N 43/08 20060101
A01N043/08; A01N 43/20 20060101 A01N043/20; A01N 57/00 20060101
A01N057/00; C23C 14/34 20060101 C23C014/34; B05D 1/18 20060101
B05D001/18; C23C 16/40 20060101 C23C016/40 |
Claims
1. A method of providing a surface with an anti-infective agent
comprising functionalizing the surface with a functional group
effective to bind an anti-infective agent thereto and binding the
functional group with the anti-infective agent.
2. The method of claim 1 wherein the surface is selected from a
metal, alloy, polymer, plastic, ceramic, silicon, glass, fabric,
and a material with at least one acidic proton.
3. The method of claim 1, wherein the anti-infective agent is
selected from the group consisting of disinfectants, antiseptics
and antibiotics.
4. The method of claim 1, wherein the anti-infective agent is a
disinfectant selected from hypochlorites, chloramines,
dichloroisocyanurate and trichloroisocyanurate, wet chlorine,
chlorine dioxide, peracetic acid, potassium persulfate, sodium
perborate, sodium percarbonate and urea perhydrate, iodpovidone,
iodine tincture, iodinated nonionic surfactants, ethanol,
n-propanol and isopropanol and mixtures thereof; 2-phenoxyethanol
and 1- and 2-phenoxypropanol, cresols, hexachlorophene, triclosan,
trichlorophenol, tribromophenol, pentachlorophenol, Dibromol and
salts thereof, benzalkonium chloride, cetyl trimethylammonium
bromide or chloride, didecyldimethylammonium chloride,
cetylpyridinium chloride, benzethonium chloride, chlorhexidine,
glucoprotamine, octenidine dihydrochloride; ozone and permanganate
solutions; colloidal silver, silver nitrate, mercury chloride,
phenylmercury salts, copper, copper sulfate, copper oxide-chloride,
phosphoric acid, nitric acid, sulfuric acid, amidosulfuric acid,
toluenesulfonic acid, sodium hydroxide, potassium hydroxide and
calcium hydroxide.
5. The method of claim 1 wherein the anti-infective agent is
selected from Daquin's solution, 0.5% sodium hypochlorite solution
which is pH-adjusted to pH 7-8, potassium hypochlorite solution
which is pH-adjusted to pH 7-8, 0.5-1% solution of sodium
benzenesulfochloramide, iodopovidone, urea perhydrate solution,
pH-buffered 0.1-0.25% peracetic acid solution, alcohols, weak
organic acids selected from the group consisting of sorbic acid,
benzoic acid, lactic acid and salicylic acid; hexachlorophene,
triclosan, Dibromol, 0.05-0.5% benzalkonium, 0.5-4% chlorhexidine
and 0.1-2% octenidine.
6. The method of claim 1 wherein the anti-infective agent is at
least one of a quaternary ammonium compound, choline, a choline
derivative, a quaternary ammonium dendrimer, silver, copper, a
cationic species, a peptide, an antibody, an antibiotic, an
imidazole derivative, a nitrofuran derivative, a steroid,
chlorhexidine, a phenol compound, an epoxide, a polymer and/or
polypeptide which has anti-infective properties, a zinc oxide, a
titanium oxides, a zeolite, a silicate, calcium hydroxide, iodine,
sodium hypochlorite, a sulfite, and a sulfates.
7. The method of claim 1 wherein the anti-infective agent is
copper.
8. The method of claim 1 wherein the anti-infective agent is
silver.
9. The method of claim 1, wherein the anti-infective agent is an
acid functionalized anti-infective agent.
10. The method of claim 9 wherein the acid is an organophosphonic
acid.
11. The method of claim 9 wherein the acid is selected from the
group consisting of carboxylic, sulfonic, sulfinic, phosphinic,
phosphoric, and hydroxamic acid.
12. The method of claim 1 wherein the anti-infective agent is
introduced to the functionalized surface by covalent bonding,
evaporative, sputter or immersion, deposition.
13. The method of claim 1 wherein the surface includes a metal or a
polymer and the step of functionalizing comprises bonding thereto
an oxide, alkoxide, or mixed oxide/alkoxide layer using an alkoxide
precursor, wherein the functionalized polymer surface is operable
to covalently bond an anti-infective agent thereto.
14. The method according to claim 1 wherein the surface is a metal
or a polymer and the step of functionalizing comprises a)
contacting a metal alkoxide with the surface; and b) subjecting the
metal alkoxide to conditions adequate to form an oxide, alkoxide,
or mixed oxide/alkoxide adhesion layer on the surface, the
conditions selected from one or more of the group consisting of
pyrolysis, microwaving, complete hydrolysis and partial hydrolysis;
and the step of binding the functional group with a reactive group
of the anti-infective agent comprises contacting an anti-infective
agent with the oxide adhesion layer.
15. The process according to claim 14, wherein step a) comprises
vapor deposition or immersion deposition.
16. The method of claim 14, wherein step b) comprises heating the
metal alkoxide to between about 50.degree. C. and the upper working
temperature of the polymer.
17. The method of claim 14, wherein the metal alkoxide is zirconium
tetra(tert-butoxide), silicon tetra(tert-butoxide), titanium
tetra(tert-butoxide), and calcium bis(2-methoxy-ethoxide.
18. The method of claim 14, wherein the metal in the metal alkoxide
is a Group 3-6 or Group 13-14 transition metal.
19. The method of claim 14, wherein the alkoxide is selected from
the group consisting of ethoxide, propoxide, iso-propoxide,
butoxide, iso-butoxide, tert-butoxide and fluorinated alkoxide.
20. The method of claim 14, comprising reacting the oxide adhesion
layer with an anti-infective agent selected from the group
consisting of disinfectants, antiseptics and antibiotics.
21. The method of claim 14, wherein the anti-infective agent is a
disinfectant selected from hypochlorites, chloramines,
dichloroisocyanurate and trichloroisocyanurate, wet chlorine,
chlorine dioxide, peracetic acid, potassium persulfate, sodium
perborate, sodium percarbonate and urea perhydrate, iodpovidone,
iodine tincture, iodinated nonionic surfactants, ethanol,
n-propanol and isopropanol and mixtures thereof; 2-phenoxyethanol
and 1- and 2-phenoxypropanol, cresols, hexachlorophene, triclosan,
trichlorophenol, tribromophenol, pentachlorophenol, Dibromol and
salts thereof, benzalkonium chloride, cetyl trimethylammonium
bromide or chloride, didecyldimethylammonium chloride,
cetylpyridinium chloride, benzethonium chloride, chlorhexidine,
glucoprotamine, octenidine dihydrochloride; ozone and permanganate
solutions; colloidal silver, silver nitrate, mercury chloride,
phenylmercury salts, copper, copper sulfate, copper oxide-chloride,
phosphoric acid, nitric acid, sulfuric acid, amidosulfuric acid,
toluenesulfonic acid, sodium hydroxide, potassium hydroxide and
calcium hydroxide.
22. The method of claim 14 wherein the anti-infective agent is
selected from Daquin's solution, 0.5% sodium hypochlorite solution
which is pH-adjusted to pH 7-8, potassium hypochlorite solution
which is pH-adjusted to pH 7-8, 0.5-1% solution of sodium
benzenesulfochloramide, iodopovidone, urea perhydrate solution,
pH-buffered 0.1-0.25% peracetic acid solution, alcohols, weak
organic acids selected from the group consisting of sorbic acid,
benzoic acid, lactic acid and salicylic acid; hexachlorophene,
triclosan, Dibromol, 0.05-0.5% benzalkonium, 0.5-4% chlorhexidine
and 0.1-2% octenidine.
23. The method of claim 14 wherein the anti-infective agent is at
least one of a quaternary ammonium compound, choline, a choline
derivative, a quaternary ammonium dendrimer, silver, copper, a
cationic species, a peptide, an antibody, an antibiotic, an
imidazole derivative, a nitrofuran derivative, a steroid,
chlorhexidine, a phenol compound, an epoxide, a polymer and/or
polypeptide which has anti-infective properties, a zinc oxide, a
titanium oxides, a zeolite, a silicate, calcium hydroxide, iodine,
sodium hypochlorite, a sulfite, and a sulfates.
24. The method according to claim 23 wherein the anti-infective
agent is copper.
25. The method according to claim 23 wherein the anti-infective
agent is silver.
26. The method according to claim 14 wherein the anti-infective
agent is introduced to the oxide adhesion layer by covalent
bonding, evaporative, sputter, immersion or extractive
deposition.
27. The method according to claim 14, comprising optionally
subjecting the oxide adhesion layer to complete or partial
hydrolysis prior to deposition of the anti-infective agent.
28. The method according to claim 14, wherein the adhesion layer is
continuous.
29. The method of claim 14, wherein the polymer surface contains a
surface coordinating group that is capable of coordinating with the
metal atom of the metal alkoxide.
30. The method of claim 14, wherein the polymer is selected from
the group consisting of polyamides, polyurethanes, polyureas,
polyesters, polyketones, polyimides, polysulfides, polysulfoxides,
polysulfones, polythiophenes, polypyridines, polypyrroles,
polyethers, silicones, polysiloxanes, polysaccharides,
fluoropolymers, amides, imides, polypeptides, polyethylene,
polystyrene, polypropylene, glass reinforced epoxies, liquid
crystal polymers, thermoplastics, bismaleimide-triazine (BT)
resins, benzocyclobutene polymers, Ajinomoto Buildup Films (ABF),
low coefficient of thermal expansion (CTE) films of glass and
epoxies, and composites including these polymers.
31. The method of claim 14, wherein the polymer is selected from
the group consisting of polyethylene terephthalate (PET),
polyetheretherketones (PEEK), polyetherketoneketones (PEKK), and
nylon.
32. The method of claim 14, comprising disposing an adhesion layer
of a metal oxide, alkoxide, or mixed oxide/alkoxide on the surface,
treating the adhesion layer with a phosphonic acid to provide a
phosphonate monolayer thereon, derivatizing the phosphonate
monolayer and contacting the monolayer with an anti-infective
agent.
33. The method of claim 32 wherein the anti-infective agent is a
quaternary alkylammonium moiety.
34. The method of claim 1 wherein the surface contains silicon, and
the step of functionalizing comprises forming a self-assembled film
of an organophosphonic acid bound to a native or synthesized
oxide-coated silicon surface as a film of a corresponding
phosphonate.
35. The method of claim 1 wherein the step of functionalizing
comprises forming a peptide-modified surface-bound phosphonate film
thereon.
36. The method of claim 1, wherein the step of functionalizing
comprises forming a phosphonate monolayer on the surface, immersing
the surface in a solution of 3-(maleimido)propanoic acid
N-hydroxysuccinimide ester and then in an aqueous solution of an
active peptide to derivatize the phosphonate monolayer.
37. The method of claim 1, comprising bonding a self-assembled
phosphonate monolayer to a native oxide surface of a metal, alloy,
metalloid, or ceramic, treating the self-assembled phosphonate
monolayer to provide a distal amino functional group bonded to the
oxide, and quaternizing the distal amino group to provide a
quaternary alkylammonium moiety covalently bonded to the metal
surface through the phosphonate interface.
38. The method of claim 1, comprising bonding a self-assembled
phosphonate monolayer to a native oxide surface of a metal, alloy,
metalloid, or ceramic, treating the self-assembled phosphonate
monolayer to provide an anti-infective agent bonded to the
oxide.
39. The methods of claim 37 wherein the metal is selected from
titanium, stainless steel, cobalt chrome, nickel, molybdenum,
tantalum, zirconium, magnesium, manganese, niobium; and alloys
thereof.
40. A device having an anti-infective surface, the surface
comprising a functionalizing layer disposed thereon and an
anti-infective agent disposed on the functionalizing layer, the
functionalizing layer comprising at least one moiety or functional
group capable of binding the anti-infective agent thereto and at
least one moiety or functional group capable of binding the
functionalizing layer to the surface.
41. The device of claim 40 wherein the surface is selected from a
metal, alloy, polymer, plastic, ceramic, silicon, glass, fabric,
and a material with at least one acidic proton.
42. The device of claim 40, wherein the anti-infective agent is
selected from the group consisting of disinfectants, antiseptics
and antibiotics.
43. The device of claim 40, wherein the anti-infective agent is a
disinfectant selected from hypochlorites, chloramines,
dichloroisocyanurate and trichloroisocyanurate, wet chlorine,
chlorine dioxide, peracetic acid, potassium persulfate, sodium
perborate, sodium percarbonate and urea perhydrate, iodpovidone,
iodine tincture, iodinated nonionic surfactants, ethanol,
n-propanol and isopropanol and mixtures thereof; 2-phenoxyethanol
and 1- and 2-phenoxypropanol, cresols, hexachlorophene, triclosan,
trichlorophenol, tribromophenol, pentachlorophenol, Dibromol and
salts thereof, benzalkonium chloride, cetyl trimethylammonium
bromide or chloride, didecyldimethylammonium chloride,
cetylpyridinium chloride, benzethonium chloride, chlorhexidine,
glucoprotamine, octenidine dihydrochloride; ozone and permanganate
solutions; colloidal silver, silver nitrate, mercury chloride,
phenylmercury salts, copper, copper sulfate, copper oxide-chloride,
phosphoric acid, nitric acid, sulfuric acid, amidosulfuric acid,
toluenesulfonic acid, sodium hydroxide, potassium hydroxide and
calcium hydroxide.
44. The device of claim 40 wherein the anti-infective agent is
selected from Daquin's solution, 0.5% sodium hypochlorite solution
which is pH-adjusted to pH 7-8, potassium hypochlorite solution
which is pH-adjusted to pH 7-8, 0.5-1% solution of sodium
benzenesulfochloramide, iodopovidone, urea perhydrate solution,
pH-buffered 0.1-0.25% peracetic acid solution, alcohols, weak
organic acids selected from the group consisting of sorbic acid,
benzoic acid, lactic acid and salicylic acid; hexachlorophene,
triclosan, Dibromol, 0.05-0.5% benzalkonium, 0.5-4% chlorhexidine
and 0.1-2% octenidine and an acid functionalized anti-infective
agent.
45. The device of claim 40 wherein the anti-infective agent is at
least one of a quaternary ammonium compound, choline, a choline
derivative, a quaternary ammonium dendrimer, silver, copper, a
cationic species, a peptide, an antibody, an antibiotic, an
imidazole derivative, a nitrofuran derivative, a steroid,
chlorhexidine, a phenol compound, an epoxide, a polymer and/or
polypeptide which has anti-infective properties, a zinc oxide, a
titanium oxides, a zeolite, a silicate, calcium hydroxide, iodine,
sodium hypochlorite, a sulfite, and a sulfate.
46. The device of claim 40 wherein the anti-infective agent is
copper.
47. The device of claim 40 wherein the anti-infective agent is
silver.
48. The device of claim 40 wherein the surface includes a polymer
and the functionalizing layer comprises a phosphonate monolayer,
wherein the functionalized polymer surface is covalently bound to
the anti-infective agent.
49. The device of claim 48 wherein the phosphonate monolayer is
attached to an oxide, alkoxide, or mixed oxide/alkoxide layer
deposited onto the polymer and derived from a metal alkoxide.
50. The device of claim 49 where the oxide, alkoxide, or mixed
oxide/alkoxide layer comprises a metal alkoxide selected from
zirconium tetra(tert-butoxide), silicon tetra(tert-butoxide),
titanium tetra(tert-butoxide), and calcium
bis(2-methoxy-ethoxide.
51. The device of claim 50, wherein the metal in the metal alkoxide
is selected from a Group 3-6 and Group 13-14 transition metal.
52. The device of claim 49, wherein the alkoxide is selected from
the group consisting of ethoxide, propoxide, iso-propoxide,
butoxide, iso-butoxide, tert-butoxide and fluorinated alkoxide.
53. The device of claim 48, wherein the anti-infective agent is a
disinfectant selected from hypochlorites, chloramines,
dichloroisocyanurate and trichloroisocyanurate, wet chlorine,
chlorine dioxide, peracetic acid, potassium persulfate, sodium
perborate, sodium percarbonate and urea perhydrate, iodpovidone,
iodine tincture, iodinated nonionic surfactants, ethanol,
n-propanol and isopropanol and mixtures thereof; 2-phenoxyethanol
and 1- and 2-phenoxypropanol, cresols, hexachlorophene, triclosan,
trichlorophenol, tribromophenol, pentachlorophenol, Dibromol and
salts thereof, benzalkonium chloride, cetyl trimethylammonium
bromide or chloride, didecyldimethylammonium chloride,
cetylpyridinium chloride, benzethonium chloride, chlorhexidine,
glucoprotamine, octenidine dihydrochloride; ozone and permanganate
solutions; colloidal silver, silver nitrate, mercury chloride,
phenylmercury salts, copper, copper sulfate, copper oxide-chloride,
phosphoric acid, nitric acid, sulfuric acid, amidosulfuric acid,
toluenesulfonic acid, sodium hydroxide, potassium hydroxide and
calcium hydroxide.
54. The device of claim 48 wherein the anti-infective agent is
selected from Daquin's solution, 0.5% sodium hypochlorite solution
which is pH-adjusted to pH 7-8, potassium hypochlorite solution
which is pH-adjusted to pH 7-8, 0.5-1% solution of sodium
benzenesulfochloramide, iodopovidone, urea perhydrate solution,
pH-buffered 0.1-0.25% peracetic acid solution, alcohols, weak
organic acids selected from the group consisting of sorbic acid,
benzoic acid, lactic acid and salicylic acid; hexachlorophene,
triclosan, Dibromol, 0.05-0.5% benzalkonium, 0.5-4% chlorhexidine
and 0.1-2% octenidine.
55. The device of claim 48 wherein the anti-infective agent is at
least one of a quaternary ammonium compound, choline, a choline
derivative, a quaternary ammonium dendrimer, silver, copper, a
cationic species, a peptide, an antibody, an antibiotic, an
imidazole derivative, a nitrofuran derivative, a steroid,
chlorhexidine, a phenol compound, an epoxide, a polymer and/or
polypeptide which has anti-infective properties, a zinc oxide, a
titanium oxides, a zeolite, a silicate, calcium hydroxide, iodine,
sodium hypochlorite, a sulfite, and a sulfates.
56. The device of claim 48 wherein the anti-infective agent is
copper.
57. The device of claim 48 wherein the anti-infective agent is
silver.
58. The method of claim 40, wherein the anti-infective agent is an
acid functionalized anti-infective agent.
59. The method of claim 40 wherein the acid is an organophosphonic
acid.
60. The method of claim 40 wherein the acid is selected from the
group consisting of carboxylic, sulfonic, sulfinic, phosphinic,
phosphoric, and hydroxamic acid.
61. The device of claim 48, wherein the adhesion layer is
continuous.
62. The device of claim 48, wherein the polymer contains a surface
coordinating group that is capable of coordinating with a metal
atom of a metal oxide.
63. The device of claim 48, wherein the polymer is selected from
the group consisting of polyamides, polyurethanes, polyureas,
polyesters, polyketones, polyimides, polysulfides, polysulfoxides,
polysulfones, polythiophenes, polypyridines, polypyrroles,
polyethers, silicones, polysiloxanes, polysaccharides,
fluoropolymers, amides, imides, polypeptides, polyethylene,
polystyrene, polypropylene, glass reinforced epoxies, liquid
crystal polymers, thermoplastics, bismaleimide-triazine (BT)
resins, benzocyclobutene polymers, Ajinomoto Buildup Films (ABF),
low coefficient of thermal expansion (CTE) films of glass and
epoxies, and composites including these polymers.
64. The device of claim 48, wherein the polymer is selected from
the group consisting of polyethylene terephthalate (PET),
polyetheretherketones (PEEK), polyetherketoneketones (PEKK), and
nylon.
65. The device of claim 48, wherein the surface is
polyetheretherketone (PEEK) and the functionalizing layer is a
derivatized phosphonate monolayer disposed on the PEEK or PEKK
surface.
66. The device of claim 48 wherein the anti-infective agent is a
quaternary alkylammonium moiety.
67. The device of claim 40 comprising a self-assembled phosphonate
monolayer bonded to a native oxide surface of a metal, alloy,
metalloid, or ceramic, wherein the self-assembled phosphonate
monolayer is operable to bond an anti-infective agent.
68. The device of claim 40, the functionalizing layer comprising a
phosphonate monolayer bonded to a native oxide surface of a metal,
the phosphonate monolayer comprising at least one distal amino
functional group bonded to the metal, and a quaternary
alkylammonium moiety covalently bonded to the metal surface through
the phosphonate interface.
69. The device of claim 67 wherein the metal is selected from
titanium, stainless steel, cobalt chrome, nickel, molybdenum,
tantalum, zirconium, magnesium, manganese, niobium, and alloys
thereof.
70. The device of claim 40 comprising a medical device.
71. The device of claim 70 comprising an implantable or
percutaneous medical device
72. The device of claim 70 comprising an endoscopic, arthroscopic,
or laproscopic medical device.
73. The device of claim 70 comprising a cardiac, cardiovascular, or
vascular medical device.
74. The device of claim 40 selected from the group non-woven
meshes, woven meshes, foams, cloth, and fabrics.
75. The device of claim 70 comprising an orthopedic, orthopedic
trauma, or spine medical device.
76. The device of claim 70 selected from the group of general
surgical devices and implants selected from drainage catheters,
shunts, tapes, meshes, ropes, cables, wires, sutures, skin and
tissue staples, burn sheets, external fixation devices; and
temporary/non-permanent implants.
77. The device of claim 40 wherein the functionalizing layer is
disposed on the surface in a pattern or micropattern.
78. The device of claim 40 wherein the anti-infective agent is
disposed on the functionalizing layer in a pattern or
micropattern.
79. The device of claim 40 wherein the functionalizing layer
includes at least two different regions of functionalization.
80. The device of claim 40, wherein the anti-infective agent layer
is continuous.
81. The device of claim 40, wherein the surface is a polymer, and
the polymer is selected from the group consisting of polyamides,
polyurethanes, polyureas, polyesters, polyketones, polyimides,
polysulfides, polysulfoxides, polysulfones, polythiophenes,
polypyridines, polypyrroles, polyethers, polyetheretherketones,
polyetherketoneketones, silicones, polysiloxanes, polysaccharides,
fluoropolymers, amides, imides, polypeptides, polyethylene,
polystyrene, polypropylene, glass reinforced epoxies, liquid
crystal polymers, thermoplastics, bismaleimide-triazine (BT)
resins, benzocyclobutene polymers, Ajinomoto Buildup Films (ABF),
low coefficient of thermal expansion (CTE) films of glass and
epoxies, and composites including these polymers.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/155,324, filed Feb. 25, 2009, the
entirety of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to substrates with
anti-infective surfaces. In particular, methods are provided for
functionalizing various material surfaces to include active surface
regions for binding anti-infective agents.
BACKGROUND OF THE INVENTION
[0003] An activated, or functionalized, layer that is bonded or
otherwise disposed on the surface of a substrate is useful as an
interface between the substrate and other materials such as organic
or metallic materials. This functionalized layer allows the
substrate to react with and to bind to the organic or metallic
material.
[0004] The need for control of infection is a vital concern for
many, from public health officials, hospital and school
administrators and the like, to private citizens. Typically,
control of infection can be achieved by the topical application of
disinfectants, antiseptics, antibacterials and the like to surfaces
likely to be contacted by infectious agents. Common disinfectants
include active chlorine such as hypochlorites, chloramines,
dichloroisocyanurate and trichloroisocyanurate, wet chlorine,
chlorine dioxide and the like, active oxygen, including peroxides,
such as peracetic acid, potassium persulfate, sodium perborate,
sodium percarbonate and urea perhydrate, iodine compounds such as
iodpovidone, iodine tincture, iodinated nonionic surfactants,
concentrated alcohols such as ethanol, n-propanol and isopropanol
and mixtures thereof; 2-phenoxyethanol and 1- and
2-phenoxypropanols, phenolic compounds, cresols, halogenated
phenols, such as hexachlorophene, triclosan, trichlorophenol,
tribromophenol, pentachlorophenol, Dibromol and salts thereof,
cationic surfactants, including quaternary ammonium cations such as
benzalkonium chloride, cetyl trimethylammonium bromide or chloride,
didecyldimethylammonium chloride, cetylpyridinium chloride,
benzethonium chloride and others, and non-quaternary compounds,
such as chlorhexidine, glucoprotamine, octenidine dihydrochloride
etc.); strong oxidizers, such as ozone and permanganate solutions;
heavy metals and their salts, such as colloidal silver, silver
nitrate, mercury chloride, phenylmercury salts, copper, copper
sulfate, copper oxide-chloride and the like, and strong acids
(phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic
acids) and alkalis (sodium, potassium, calcium hydroxides).
However, many of these compounds are harmful to mammalian tissue.
Moreover, these compounds only have a short-term effect, and need
to be reapplied constantly.
[0005] Antibiotics can be administered to stop infection in
individuals. However, such administration is not always effective.
Numerous medical applications, including orthopaedic, trauma, spine
and general surgery applications, where the potential for infection
is a serious concern, are not amenable to simple application of
antiseptic or treatment with antibiotics. For example, infection
can be a devastating complication of a total joint arthroplasty
(TJA). While some infections may be treated by antibiotic
suppression alone, more aggressive therapies, such as two-stage
re-implantation, are often required. The treatment of
post-arthroplasty infections in 1999 cost over $200 million in the
US alone. Spangehl, M. J., et al., J. Bone Joint Surg. Am., 1999,
81(5), 672-682. TJA infections occur when bacteria colonize the
surface of the implant. These species then form a resistant biofilm
on the implant surface, which nullifies the body's normal antibody
response.
[0006] External fixation devices provide temporary but necessary
rigid constraints to facilitate bone healing. However, patients
risk pin-tract infection at the site extending from the skin-pin
interface to within the bone tissue. Such complications can result
in sepsis and osteomyelitis, which could require sequestrectomy for
correction. Even the most stringent pin-handling and post-procedure
protocols have only a limited effect. Studies have shown that such
protocols do not reduce the chance of infection. Davies, R., et al.
J. Bone Joint Surg. Br., 2005, 87-B, 716-719.
[0007] In minimally-invasive spine fusions, pedicle screws are
first implanted in the bone of the vertebrae, and then rods are
fixed into the heads of the screws to immobilize and stabilize the
affected segments. Screws and rods pass through the patient's skin
into the spine space via a cannulated channel. As in external
fixation, screws and rods are also prone to pin-tract infections;
due to the implants' pathway through the skin, the chance of
contacting and/or passing harmful bacteria is greatly
increased.
[0008] Catheters and shunts are placed in any number of body
cavities and vessels to facilitate the injection, drainage, or
exchange of fluids. Infections are common in catheter placements
and are largely dependent on how long the patient is catheterized.
For example, Kass reports an infection rate of virtually 100% for
patients with indwelling urethral catheters draining into an open
system for longer than 4 days. Kass, E. H., Trans. Assoc. Am.
Physicians, 1956, 69, 56-63.
[0009] Therefore, there is a need for anti-infective surfaces that
may be employed in locations particularly susceptible to hosting
infectious agents, such as public places, common areas of
buildings, fixtures and the like. Moreover, there is a need for
substrates and materials with anti-infective surfaces, such as
medical devices including implants, screws, rods, pins, catheters,
stents, surgical tools and the like which could prevent infections
by proactively killing bacteria that attempt to colonize the device
surface both pre- and post-operatively.
SUMMARY OF THE INVENTION
[0010] In accordance with one or more embodiments methods are
provided for functionalizing various material surfaces to include
an active surface region to which are bound anti-infective
agents.
[0011] Depending on the application, a surface of interest is
functionalized in accordance with a suitable functionalization
method and an anti-infective agent is disposed on the
functionalized surface.
[0012] Virtually any surface which may be functionalized is
suitable for the inclusion of an anti-infective agent in accordance
with the disclosed embodiments. Examples of such surfaces include
metals, alloys, polymers, plastics, ceramics and glass. Therefore,
the anti-infective surfaces as described herein may be applied
universally through any environment, for example, in the
environment of a surgical procedure or throughout an operating room
or hospital, thereby eliminating many, if not all, sources of
infection simultaneously and continuously.
[0013] Functionalization of substrates in accordance with the
present invention may be achieved in a variety of ways. For
example, it is possible to functionalize the surface of a polymer
substrate such as but not limited to polyamides, polyurethanes,
polyesters, polyketones, polyethers, polyimides, aramides,
polyfluoroolefins, epoxies, silicones or composites containing
these polymers with an oxide, alkoxide or mixed oxide-alkoxide
layer using an alkoxide precursor. Such functionalized polymer
surfaces can be used to covalently bond subsequent material or
layers thereof on the surface, which in the present invention
includes anti-infective moieties. For example, substrates that
contain acidic protons, such as --OH or --NH groups, are
functionalized by their reaction with Group IV alkoxides. This
procedure yields a molecular adhesion species that is bound to the
surface of the bulk polymer, but is limited to materials that have
acidic groups on their surface.
[0014] It is further possible to form an adherent coating layer
that may be further functionalized with adherent species by heating
a self-assembled layer of a functionalized phosphonic acid on the
native oxide surface of a substrate or a deposited oxide derived
from an alkoxide precursor. A plurality of one or more
anti-infective coating moieties may be bonded to the functional
group of at least one functionalized organophosphonate moiety. Such
native oxides are found on metals including but not limited to
titanium and its alloys; stainless steel; cobalt chrome alloys; and
nickel, molybdenum, tantalum, zirconium, magnesium, and alloys
containing them
[0015] It is yet further possible to bond anti-infective species to
the functional group of a phosphonic acid before attaching said
acid to a native oxide or an oxide derived from an alkoxide
precursor. Such native oxides are found on metals including but not
limited to titanium and its alloys; stainless steel; cobalt chrome
alloys; and nickel, molybdenum, tantalum, zirconium, magnesium, and
alloys containing them
[0016] In another embodiment, functionalization of a silicon
surface may be achieved by a process wherein a self-assembled film
of an organophosphonic acid is bonded to a native or synthesized
oxide-coated Si surface as a film of the corresponding phosphonate.
The phosphonate film is functionalized to enable covalently
coupling biological molecules, ranging in size from small peptides
to large multi-subunit proteins, to the Si surface.
[0017] In still a further embodiment, anti-infective
peptide-modified surface-bound phosphonate films may be bonded to
metal surfaces and polymer surfaces functionalized with
alkoxide-derived oxides.
[0018] It is expected the anti-infective surface modification
methods described herein may eliminate the need for passivation,
frequently a necessary step in the processing of metal implants.
Processes as disclosed herein provide layers bonded to metal
surfaces and transform the surface oxides into chemically- and
physically-robust species, thus eliminating the source of corrosion
in devices such as metal implants.
[0019] Anti-infective agents as discussed herein may include
bactericidal and bacteriostatic agents including disinfectants,
antiseptics and antibiotics. Not all bactericidal and
bacteriostatic agents may be used as antiseptics on mammalian
tissue as they may have adverse effects thereon. Some embodiments
of the present invention may apply to uses that do not involve
contact of an anti-infective surface with mammalian tissue, such as
interior surfaces of plumbing fixtures, building materials,
ductwork, clean rooms, etc. In such applications certain
anti-infective agents may be used, such as disinfectants, which
would not be appropriate for use in applications in which contact
with mammalian tissue was contemplated or possible.
[0020] In some embodiments compounds that may be used as
antiseptics for use in humans include properly diluted chlorine
preparations such as Daquin's solution, 0.5% sodium or potassium
hypochlorite solution, pH-adjusted to pH 7-8, or 0.5-1% solution of
sodium benzenesulfochloramide, some iodine preparations, such as
iodopovidone, peroxides as urea perhydrate solutions and
pH-buffered 0.1-0.25% peracetic acid solutions, alcohols with or
without antiseptic additives, used mainly for skin antisepsis, weak
organic acids such as sorbic acid, benzoic acid, lactic acid and
salicylic acid, some phenolic compounds, such as hexachlorophene,
triclosan and Dibromol, and cation-active compounds, such as
0.05-0.5% benzalkonium, 0.5-4% chlorhexidine, 0.1-2% octenidine
solutions.
[0021] In further embodiments anti-infective agents used in
applications which involve possible contact with mammalian tissue
may include quaternary ammonium compounds such as choline and
choline derivatives, quaternary ammonium dendrimers, silver,
copper, and cationic species; silver and copper.
[0022] As will be apparent to those skilled in the art, the
functionalization method employed to bond or otherwise attach a
particular anti-infective agent in accordance with the present
invention is dependent on the chemical nature of the anti-infective
agent.
[0023] Devices made in accordance with the present disclosure
provide a multitude of clinical benefits. For example, in partially
external devices, anti-infective surfaces thereof may kill
bacterial species at the device-skin interface, thus preventing
pin-site infections. Devices including an anti-infective surface
may prevent the colonization by infectious species of implanted
surfaces, potentially reducing the incidence of deep infection,
especially in high-risk populations. In catheters and shunts with
anti-infective surfaces the potential for infection is minimized by
killing bacteria traveling up the intubated pathway into the
patient. Another example is in total hip arthroplasties;
anti-infective hip stems may kill bacterial species and inhibit
biofilm formation at the device-tissue interface, preventing the
bacterial colonization of the hip replacement, which can lead to
loosening due to infection and could require cost and painful hip
revision surgery. The anti-infective agent is highly stable under
physiological conditions. The anti-infective agent does not leach
from its material host, so there is no undesirable secondary
result. Due to its nanometer scale, the anti-infective agent does
not interfere with desired mechanical surface features that may be
critical to the function of device such as an implant. The
anti-infective agent is not visible to the naked eye and does not
obscure identifying features including colored anodization or
product markings.
[0024] Devices in accordance with the present disclosure are not
limited to medical devices. For example, devices embodying the
present disclosures may include fixtures, structures, fittings,
barriers, and the like having anti-infective surfaces.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 depicts a schematic of an anti-infective agent bound
to a surface in accordance with at least one embodiment of the
present disclosure.
[0026] FIG. 2 depicts an anti-infective agent bound to a surface in
accordance with at least one embodiment of the present
disclosure.
[0027] FIG. 3 depicts a mode of action of an anti-infective agent
in accordance with at least one embodiment of the present
disclosure
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0028] In the following description, for purposes of explanation,
specific numbers, materials and configurations are set forth in
order to provide a thorough understanding of the invention. It will
be apparent, however, to one having ordinary skill in the art that
the invention may be practiced without these specific details. In
some instances, well-known features may be omitted or simplified so
as not to obscure the present invention. Furthermore, reference in
the specification to phrases such as "one embodiment" or "an
embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the invention. The
appearances of phrases such as "in one embodiment" in various
places in the specification are not necessarily all referring to
the same embodiment.
[0029] In general, in accordance with one or more embodiments
methods are provided for functionalizing various material surfaces
to include an active surface region to which are bound
anti-infective agents. Depending on the application, a surface of
interest is functionalized and an anti-infective agent is disposed
on the functionalized surface to provide devices having
anti-infective surfaces.
[0030] Now referring to FIG. 1, in general a surface 10 in
accordance with the present disclosure includes a functionalizing
layer 20 and an anti-infective agent 30.
[0031] Surface 10 may be virtually any material which is amenable
to receiving a functionalizing layer 20. Examples of such materials
include metals, alloys, polymers, plastics, ceramics, silicon,
glass and surfaces with acidic protons, such as --OH or --NH
groups.
[0032] Functionalizing layer 20 may be any layer suitable for a
particular application. The nature and composition of
functionalizing layer 20 is dependent on the surface 10 that is
intended to include an anti-infective agent 30 and the
anti-infective agent 30 that is to be bound to the functionalizing
layer 20. For example, as described in greater detail hereinbelow,
it is possible to functionalize a polymer substrate surface 10 with
an oxide, alkoxide or mixed oxide-alkoxide layer using an alkoxide
precursor. Such functionalized polymer surfaces can be used to
covalently bond subsequent material or layers of anti-infective
agent 30 on the surface.
[0033] Other functionalizing layers 20 may include functionalized
phosphonic acids disposed on a native oxide of a substrate surface;
functionalized phosphonic acids disposed onto an oxide layer,
either directly deposited onto an underlying substrate or derived
from an alkoxide precursor; for surfaces that contain acidic
protons, such as --OH or --NH groups, reacting same with Group IV
alkoxides; for surfaces with a silicon surface, a self-assembled
film of a phosphonic acid bound to the native or synthesized
oxide-coated Si surface as a film of the corresponding phosphonate;
and the like.
[0034] Metal surfaces which may be employed include titanium and
its alloys; stainless steels; cobalt chrome alloys; nickel,
molybdenum, tantalum, zirconium, magnesium, manganese, niobium, and
alloys containing them; and the like.
[0035] Anti-infective agents 30 that may be employed in connection
with embodiments herein may include bactericidal and bacteriostatic
agents including disinfectants, antiseptics and antibiotics.
Disinfectants include active chlorine such as hypochlorites,
chloramines, dichloroisocyanurate and trichloroisocyanurate, wet
chlorine, chlorine dioxide and the like, active oxygen, including
peroxides, such as peracetic acid, potassium persulfate, sodium
perborate, sodium percarbonate and urea perhydrate, iodine
compounds such as iodpovidone, iodine tincture, iodinated nonionic
surfactants, concentrated alcohols such as ethanol, n-propanol and
isopropanol and mixtures thereof; 2-phenoxyethanol and 1- and
2-phenoxypropanols, phenolic compounds, cresols, halogenated
phenols, such as hexachlorophene, triclosan, trichlorophenol,
tribromophenol, pentachlorophenol, Dibromol and salts thereof,
cationic surfactants, including quaternary ammonium cations such as
benzalkonium chloride, cetyl trimethylammonium bromide or chloride,
didecyldimethylammonium chloride, cetylpyridinium chloride,
benzethonium chloride and others, and non-quaternary compounds,
such as chlorhexidine, glucoprotamine, octenidine dihydrochloride
etc.); strong oxidizers, such as ozone and permanganate solutions;
heavy metals and their salts, such as colloidal silver, silver
nitrate, mercury chloride, phenylmercury salts, copper, copper
sulfate, copper oxide-chloride and the like, and strong acids
(phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic
acids) and alkalis (sodium, potassium, calcium hydroxides).
[0036] Not all bactericidal and bacteriostatic agents may be used
as antiseptics on mammalian tissue as they may have adverse effects
thereon. It will be apparent to those skilled in the art that some
embodiments of the present invention may apply to uses that do not
involve contact of an anti-infective surface with mammalian tissue,
such as the fabric used for surgical barriers and the interior
surfaces of plumbing fixtures, building materials, ductwork, clean
rooms, etc. In such applications certain anti-infective agents may
be used, such as disinfectants, which would not be appropriate for
use in applications in which contact with mammalian tissue would be
contemplated or possible.
[0037] The following are some compounds that may be used as
antiseptics for use in humans: properly diluted chlorine
preparations such as Daquin's solution, 0.5% sodium or potassium
hypochlorite solution, pH-adjusted to pH 7-8, or 0.5-1% solution of
sodium benzenesulfochloramide, some iodine preparations, such as
iodopovidone, peroxides as urea perhydrate solutions and
pH-buffered 0.1-0.25% peracetic acid solutions, alcohols with or
without antiseptic additives, used mainly for skin antisepsis, weak
organic acids such as sorbic acid, benzoic acid, lactic acid and
salicylic acid, some phenolic compounds, such as hexachlorophene,
triclosan and Dibromol, and cation-active compounds, such as
0.05-0.5% benzalkonium, 0.5-4% chlorhexidine, 0.1-2% octenidine
solutions.
[0038] In preferred embodiments anti-infective agents used in
applications which involve possible contact with mammalian tissue
include but are not limited to quaternary ammonium compounds such
as choline and choline derivatives, quaternary ammonium dendrimers,
silver, copper, and cationic species. Quaternary ammonium compounds
("quats") with long alkyl chains show proven biocidal properties by
disruption of cell walls. Nakagawa, Y., et al., Appl. Environ.
Microbiol., 1984, 47:3, 513-518, incorporated by reference herein
in its entirety. The quaternary ammonium cation functional group
draws in and disrupts the cell membrane of the bacteria. Quaternary
ammonium dendrimers show similar biocidal activity naturally and
when combined with functional groups or molecules with biocidal
properties, can further enhance antimicrobial activity by increased
loading. Silver and copper have observed oligodynamic effects on
microbes. Research suggests that silver and copper ions denature
proteins in the target organism by binding to reactive groups. This
binding results in precipitation and deactivation. Silver has also
been shown to interfere with enzymes and metabolic processes.
Cationic species are electrostatically attracted to bacterial cell
walls, which are negatively charged. Cationic antimicrobial
peptides have been shown to have inhibitory effects on the
regulatory mechanisms of the target organism.
[0039] In certain applications, it may be useful to functionalize
the anti-infective agent, in which case the the anti-infective
agent may include an acid functionalized group, wherein the acid is
for example an organophosphonic, carboxylic, sulfonic, sulfinic,
phosphinic, phosphonic, phosphoric or hydroxamic acid.
[0040] Now referring to FIG. 2 an embodiment of an anti-infective
surface employs a Self-Assembled Monolayer Phosphonate (AI-SAMP)
surface modification 20 covalently bound to the surface 10 of an
implantable material. Here, the anti-infective agent 30 is a
quaternary ammonium cationic functional group which is bound to the
surface via the SAMP. Covalent bonding creates an exceptionally
strong attachment between the surface treatment and the material to
which it is applied. Schwartz, J., et al., Mat. Sci. Engr. C, 2003,
23, 395-400, the entirety of which is incorporated herein by
reference. Because SAMP is one molecule thick, it completely covers
the material to which it is applied and assures total implant
coverage regardless of the type or texture of the implant material.
Covalent binding of quaternary ammonium salts renders the quats
insoluble, providing lasting anti-infective activity. See, e.g.,
Nakagawa, Y., et al., Appl. Environ. Microbiol., 1984, 47:3,
513-518.
[0041] As shown in FIG. 3, the quaternary ammonium cation
functional group draws in and disrupts the cell membrane of the
bacteria.
[0042] Functionalization Methods
[0043] Several methods are suitable for functionalizing a surface.
As will be apparent to those skilled in the art, the
functionalization method employed to bond or otherwise attach a
particular anti-infective agent in accordance with the present
invention is dependent on the chemical nature of the anti-infective
agent and the surface of interest.
[0044] It is possible to functionalize a polymer substrate surface
such as but not limited to surfaces of polyamides, polyurethanes,
polyesters, polyketones, polyethers, polyimides, aramides,
polyfluoroolefins, polyetheretherketones, polyetherketoneketones,
epoxies, silicones or composites containing these polymers with an
oxide, alkoxide or mixed oxide-alkoxide layer using an alkoxide
precursor. Such functionalized polymer surfaces can be used to
covalently bond subsequent material or layers of anti-infective
agent on the surface. The polymer surface may be coated with a
layer of metal oxide (oxide adhesion layer).
[0045] In one embodiment the polymer surface may be coated with a
continuous oxide adhesion layer, i.e., a layer that is formed by a
matrix of individual molecules that are chemically bonded and
linked to each other, as opposed to individual molecules covering
the surface. In this embodiment metal alkoxide molecules are bonded
together on at least a portion of a polymer surface to form a
continuous layer and then converted to an oxide functionalizing
layer.
[0046] It is further possible to form an adherent coating layer
that may be further functionalized with adherent species by heating
a self-assembled layer of a functionalized phosphonic acid on the
native oxide surface of a substrate. This process, described in
detail in U.S. Patent Application Publication 2004/0023048, the
entirety of which is incorporated herein by reference, provides on
the native oxide surface of a material a multi-segmented,
phosphorous-based coating layer having a difunctional
organophosphonic acid-based segment bonded to the native oxide
surface of the material and a linking segment bonded to the
organophosphonic acid-based segment. In accordance with this
process, a phosphorous-based coating layer may be provided having a
plurality of functionalized organophosphonate moieties bonded to
the native oxide surface of a substrate by a phosphonate bond and a
plurality of one or more anti-infective coating moieties, each
coating moiety being bonded to the functional group of at least one
functionalized organophosphonate moiety. When bonded by means of a
metal complex, the metal complex is further characterized by being
derived from a metal reagent, preferably a metal alkoxide
reagent.
[0047] Other functionalization processes may be employed depending
on the substrate to be functionalized and the anti-infective moiety
desired. For example, it is possible to functionalize substrates
that contain acidic protons, such as --OH or --NH groups, by their
reaction with Group IV alkoxides. This procedure yields a molecular
adhesion species that is bound to the surface of the bulk polymer,
but is limited to materials that have acidic groups on their
surface. This method is described in detail in Dennes, T. J. et
al., High-Yield Activation of Scaffold Polymer Surfaces to Attach
Cell Adhesion Molecules. J. Am. Chem. Soc. 2007, 129, 93-97; and
Dennes, T. J.; Schwartz, J. Controlling Cell Adhesion on
Polyurethanes. Soft Matter 2008, 4, 86-89, both of which are
incorporated herein by reference in their entireties.
[0048] Organic SAM's may be covalently bonded to the surface of
metal oxide or silicon oxide substrates. Forming a self-assembled
organic monolayer on the surface of a metal oxide or silicon oxide
substrate, may entail providing a metal oxide or silicon oxide
substrate overlayer having a surface layer of alkoxides of
transition metals selected from Group IVB, Group VB or Group VIB of
the Periodic Chart covalently bonded thereto, wherein the alkoxides
are bonded at the transition metal atoms to the surface oxygens of
the substrate overlayer; and reacting the transition metal alkoxide
surface layer with an organic compound capable of reacting with the
transition metal alkoxide to form an organic ligand covalently
bonded to the transition metal, thereby forming an organic
self-assembled monolayer on the surface of the substrate,
covalently bonded at the transition metal atoms to the surface
oxygens of the substrate. This method is described in detail in
U.S. Pat. No. 6,146,767 (see e.g., col. 3, lines 1-22 and
Examples), incorporated by reference in its entirety. Suitable acid
functional groups that can react with metal alkoxides include for
example carboxylic, sulfonic, sulfinic, phosphinic, phosphonic,
phosphoric and hydroxamic acid.
[0049] For example, methods described in detail in U.S. Pat. No.
6,645,644 (see e.g., col. 4, lines 15-33 and Examples),
incorporated by reference in its entirety, include forming a
phosphate or phosphonate ligand layer covalently bonded to the
surface of a hydroxide-bearing substrate, which includes coating a
hydroxide-bearing substrate with phosphoric acid or an organic
phosphonic acid and heating the coated substrate until the
phosphoric acid or organic phosphonic acid covalently bonds to the
substrate. When the substrate is a metal or metal alloy, the
phosphoric acid forms an inorganic phosphate coating that is rich
in free hydroxyl groups. Like transition metal monophosphate and
polyphosphate coatings, the hydroxyl groups are available for the
addition of an anti-infective agent.
[0050] In another embodiment, functionalization of a silicon
surface may be achieved by a process wherein a self-assembled film
of an organophosphonic acid is bonded to a native or synthesized
oxide-coated Si surface as a film of the corresponding phosphonate.
The phosphonate film is functionalized to enable covalently
coupling biological molecules, ranging in size from small peptides
to large multi-subunit proteins, to the Si surface. The linking of
antibodies to such surfaces enables the selective recognition of a
wide range of molecules, including antigens on the surfaces of
bacterial pathogens and parasites. This method is described in
detail in Midwood et al., Easy and Efficient Bonding of
Biomolecules to an Oxide Surface of Silicon. Langmuir 2004, 20,
5501-5505, incorporated herein by reference in its entirety.
Experimental details appear at page 5501, col. 2-page 5502, col. 2;
see also discussion at pages 5502-5504 and accompanying
figures.
[0051] In still a further embodiment, surface-bound phosphonate
films may be used to functionalize titanium and alloys thereof
(such as Ti-6Al-4V) to attach anti-infective peptides. As is known
in the art titanium and its alloys have high mechanical strength
and are resistant to chemical attack, and thus are favored
materials for surgical implants which may contact bone. This method
is described in detail in Gawalt et al., Bonding Organics to Ti
Alloys: Facilitating Human Osteoblast Attachment and Spreading on
Surgical Implant Materials" Langmuir 2003, 19, 200-204,
incorporated herein by reference in its entirety. Experimental
details appear at page 200 col. 2-page 201, col. 2; see also
discussion at pages 201-204 and accompanying figures.
[0052] Metal Oxide Adhesion
[0053] Metal oxide adhesion techniques involve an oxide adhesion
layer bonded to a surface thereof via coordination groups, wherein
the oxide adhesion layer is a metal alkoxide, generally M-O--R
wherein M is a metal atom. The oxide adhesion layer is one that has
been subjected to a process such as but not limited to pyrolysis,
microwaving, complete hydrolysis and/or partial hydrolysis. The
technique is well suited for example to polymers or metals.
Functionalized surfaces such as functionalized metals or polymers
can be used to covalently bond subsequent material or layers of
anti-infective agent on the surface.
[0054] Suitable polymeric substrates include any polymer that can
be functionalized, and may include any of various substances
comprising synthetic and/or natural polymer molecules. Examples of
suitable polymer substrates include, but are not limited to,
polyamides, polyurethanes, polyureas, polyesters, polyketones,
polyimides, polysulfides, polysulfoxides, polysulfones,
polythiophenes, polypyridines, polypyrroles, polyethers, silicones,
polysiloxanes, polysaccharides, fluoropolymers, amides, imides,
polypeptides, polyethylene, polystyrene, polypropylene, glass
reinforced epoxies, liquid crystal polymers, thermoplastics,
bismaleimide-triazine (BT) resins, benzocyclobutene polymers,
Ajinomoto Buildup Films (ABF), low coefficient of thermal expansion
(CTE) films of glass and epoxies, and composites including these
polymers. The oxide adhesion layer adheres to the surface of the
polymer by the covalent bonding between the coordinating group on
the surface of the polymer and the metal of the metal alkoxide.
[0055] Alkoxides of transition metals are particularly useful for
the present invention. Periodic Table Group 3-6 and 13-14 metals
are desirable metals for compositions of the present invention. The
preferred metals are Zr, Al, Ti, Hf, Ta, Nb, V and Sn, with the
most preferred metals being Zr, Ti and Ta. Depending upon the
position of the transition metal on the Periodic Table, the
transition metal alkoxide will have from three to six alkoxide
groups or a mixture of oxo and alkoxide groups. Preferred alkoxide
groups have from 2 to 4 carbon atoms, such as ethoxide, propoxide,
iso-propoxide, butoxide, iso-butoxide, tert-butoxide and
fluoronated alkoxide. The most preferred metal alkoxides are
zirconium tetra(tert-butoxide), titanium tetra(tert-butoxide), and
tantalum pentaethoxide.
[0056] Methods of making compositions and devices in accordance
with this embodiment include activating a polymer surface
comprising the steps of a) contacting a metal alkoxide with the
surface; and b) subjecting the metal alkoxide to conditions
adequate to form an adhesion layer on the surface on the surface
comprised of an oxide, alkoxide, or mixed oxide/alkoxide. The
contacting step may be achieved by any suitable technique known to
those skilled in the art such as but not limited to vapor or
immersion deposition. The step of forming an oxide adhesion layer
may be achieved by subjecting the metal alkoxide to conditions of
pyrolysis, microwaving, complete hydrolysis or partial hydrolysis.
When heating conditions are employed, it is preferred that the
metal alkoxide is heated to between about 50.degree. C. and the
upper working temperature of the polymer.
[0057] In one embodiment metal alkoxide molecules may be bonded
together on at least a portion of a polymer surface to form a
continuous layer and then converted to an oxide functionalizing
layer. One major advantage of a continuous layer is that the
entirety of the surface that is covered by the continuous metal
oxide adhesion layer is activated. A more comprehensive discussion
of this process is described in detail in U.S. Patent Application
Publication 2009/0104474, published Apr. 23, 2009, the entirety of
which is incorporated herein by reference. This process provides
functionalized polymer surfaces that can be used to covalently bond
subsequent material or layers thereof on the surface. In general,
the process involves depositing a metal alkoxide on a polymer, and
heating the substrate, with or without hydrolysis (full or
partial), so that the metal alkoxide molecules form a continuous
metal oxide adhesion layer covalently attached to the polymer
surface. For example, the molecules of metal alkoxide are first
brought into reactive proximity to the polymer molecules such as
by, but not limited to, vapor deposition, brush-on or immersion
deposition methods known in the art. If an ultrathin layer is
desired, vapor deposition is the preferred process. The deposited
metal alkoxide molecules are then heated to between about
50.degree. C. and the upper working temperature of the polymer (the
heating should not be at or above the glass transition temperature
of the polymer) to pyrolyze the metal alkoxides. During pyrolysis
or hydrolysis, the individual metal alkoxide molecules are
covalently bonded together forming a continuous metal oxide
adhesion layer. The metal oxide adhesion layer may be thin, about
1nm-1 .mu.m, preferably about 2 nm, such that it is flexible. The
thin layer allows the oxide adhesion layer to bend with the
substrate material without cracking, peeling, or breaking Using
this functionalization method, in one embodiment, a polymer surface
may include acidic functionality regions as well as regions coated
with a metal alkoxide functionalized layer. In such embodiments the
metal alkoxide functionalized layer may be viewed as filling in the
spaces between the regions of acidic functionality. In accordance
with another embodiment metal alkoxide functionalized layers may be
applied to regions of polymer having acidic functionality.
[0058] Compositions in accordance with this embodiment include
anti-infective agents bound via the oxide adhesion layer to the
polymer substrate. Such additional anti-infective material may
include but is not limited to quaternary ammonium compounds,
quaternary ammonium dendrimers, silver, copper, and cationic
species. A more complete, but not exhaustive, list of
anti-infective agents are detailed hereinbelow. The usefulness of
the additional anti-infective material will be apparent to those
skilled in the art. For example, medical and orthopedic implant
devices including anti-infective surface functionality minimizes
infection. Likewise, anti-infective materials can be incorporated
in clean room applications, water supply articles such as well
pumps, water purification pipes and conduit and the like.
[0059] As described in further detail hereinbelow, copper and
silver are exemplified as anti-infective materials.
[0060] The anti-infective material may be introduced to the oxide
adhesion layer by techniques know to those of skill in the art,
including but not limited to covalent bonding, evaporative, sputter
or, immersion deposition. In some embodiments it may be desirable
to subject the oxide adhesion layer to complete or partial
hydrolysis prior to deposition of the additional material. In some
embodiments it may be desirable to subject the deposited additional
material to heat or microwave treatment.
[0061] In accordance with another embodiment the adhesion layer may
be disposed on the substrate in a pattern or micropattern.
[0062] In accordance with another embodiment the anti-infective
material may be disposed on the adhesion layer in a pattern or
micropattern as described in further detail hereinbelow.
[0063] The oxide adhesion layer is reacted with an anti-infective
material as discussed above to bind the anti-infective material to
the polymer surface via the oxide adhesion layer. The additional
material may be added by reaction with the oxide adhesion layer by
various methods available in the art, such as but not limited to
covalent bonding, evaporative, sputter, or immersion deposition. In
one embodiment of the present invention, the material may be added
using lithography, printing or stamping techniques to lay a pattern
of material on to the oxide adhesion layer. The polymer surface may
be completely coated with a photoresist, and exposed to UV light
through a mask. The areas exposed to the UV light can be developed
and removed, leaving openings in the photoresist and access to the
polymer surface in small areas. These areas are functionalized with
the metal oxide adhesion layer. The photoresist is then dissolved
away leaving small patterned areas in the polymer surface that
include the adhesion layer. The patterned areas are preferentially
reactive toward anti-infective agents of choice.
[0064] In accordance with one embodiment, the oxide adhesion layer
may be subjected to complete or partial hydrolysis prior to
deposition of the anti-infective material to achieve the oxide
adhesion layer with one or more alkoxide groups remaining on the
metal atoms. Absorption of solutions of silver or copper salts,
followed by reduction, enables the surface of the metal to be
coated with particulate silver or copper, respectively. Formation
of an adhesion layer of zirconium oxide also enables metallization
of for example, a PEEK surface by absorption of a solution of
either a silver salt (such as silver nitrate) or a copper salt
(such as copper sulfate) followed by reduction with a reducing
agent. For example, diethylaminoborane or sodium borohydride reduce
the aforementioned salts to silver and copper metals, respectively,
which are included in the oxide adhesion layer matrix.
[0065] In a prophetic embodiment, a zirconium oxide adhesion layer
may also be grown on the native oxide surface of a metal such as
titanium.
[0066] Examples of Anti-Infective Agents Using Metal Oxide
Functionalization
[0067] It is believed that one of ordinary skill in the art can,
using the preceding description and the following illustrative
examples, make and utilize the compounds and articles of the
present invention and practice the claimed methods. The following
examples are given to illustrate the present invention. It should
be understood that the invention is not to be limited to the
specific conditions or details described in these examples.
Examples
Example 1
Metallization of Activated Polymers
[0068] Activated polymers of polyimides, aramides and Gore-Tex
composites were produced as follows:
[0069] Formation of a zirconia thin film on polymer substrate:
[0070] All reagents were obtained from Aldrich and were used as
received unless otherwise noted. PET, PEEK, and nylon 6/6 were
obtained from Goodfellow, Inc. Acetonitrile was dried over
CaH.sub.2; and tetrahydrofuran (THF) was dried over KOH overnight.
Both were distilled prior to use. Surface modified samples were
analyzed using a Midac M25 10C interferometer equipped with a
surface optics SOC4000 SH specular reflectance head attachment.
Fluorimetry experiments utilized a Photon Technology International
Fluorescence Spectrometer.
[0071] Polymer substrates (nylon 6/6, PET or PEEK) were placed in a
deposition chamber equipped with two stopcocks for exposure either
to vacuum or to the vapor of zirconium tetra(tert-butoxide). The
chamber was evacuated at 10.sup.-3 ton for 1 hour and polymer
slides were exposed to vapor of zirconium tetra(tert-butoxide)
(with external evacuation) for 1 minute followed by 5 minutes
exposure without external evacuation. This cycle was repeated
twice, after which a heating tape was applied to the chamber, and
the internal temperature of the chamber was raised to 60.degree. C.
and kept at that temperature for 5 minutes (without external
evacuation). The chamber was then allowed to cool and was then
evacuated at 10.sup.-3 ton for 1 hour to ensure removal of excess
zirconium tetra(tert-butoxide) and to give surface activated
polymers. AFM section analysis showed the zirconia film to be thin.
IR analysis shows that some tert-butoxy groups remain in the
deposited and pyrolyzed film.
[0072] Experiments with zirconium tetra(tert-butoxide) employing
the following polymers and resins were performed with good results:
polyimide Kapton.RTM., polylactide-co-glycolate (PLGA),
poly-3-hydroxybutyrate-co-valerate (PHBCV), Gore-Tex, and Aramide.
It is to be expected that similar treatment of other polymers will
yield similar results.
[0073] Activated polymers as prepared were treated with an aqueous
solution of a copper salt, which was absorbed onto the zirconium
oxide adhesion layer. Treatment with either sodium borohydride or
an amine borane gave a copper-coated polymer. Electron dispersive
X-ray based analysis showed the presence of both copper and
zirconium.
[0074] Similarly, silver nitrate was used to deposit silver metal
onto activated PET. It is to be expected that similar treatment of
other polymers will yield similar results, as will the use of other
metal salts using similar reducing agents.
Example 2
Electroless Plating of Copper
[0075] A sample of Kapton treated first with the zirconium-based
adhesion layer, then copper sulfate, and then diethylamineborane as
described in Example 1 was placed in a copper plating bath at
60.degree. C. under nitrogen. The bath consisted of 0.1 M trisodium
citrate dihydrate, 1.2 M ethylenediamine, 0.1 M copper sulfate
hydrate, 0.03 M ferrous sulfate hydrate, 6.4.times.10.sup.-4 M
2,2-dipyridine, 1.2 M NaCl, and sufficient sulfuric acid to give
pH=6. A small amount of PEG 200 (2.5 mg) was added to a 50 ml
bath.
Example 3
Polymer Metallization
[0076] The zirconium oxide/alkoxide adhesion layer nucleates the
growth of copper metal on PET and Kapton.RTM. polyimide film
surfaces; this approach provides a basis for patterned
metallization of polymer-based device substrates.
[0077] The adhesion layer can serve as a matrix to enable polymer
surface metallization. In a typical procedure Kapton.RTM. polyimide
film was coated with a 5 nm thick layer of adhesion layer and was
then soaked in a 200 mM aqueous solution of CuSO.sub.4. Samples
were rinsed in deionized water, and EDX analysis confirmed the
presence of Cu and S. After subsequent (slow) reduction by
dimethylamine borane (1M, aqueous, 6 hrs, 50.degree. C.), metallic
copper was formed. Metallization was also done using an adhesion
layer patterned on Kapton.RTM. polyimide film. The metallized
surface was subjected to sonication in water and physical rubbing
with a Q-tip, which was followed by EDX. In this way it was shown
that patterns of both Zr and Cu on the Kapton.RTM. polyimide film
surface faithfully replicated the mask design.
[0078] A corresponding pattern was also observed by AFM. The
thickness of the generated copper "seed" was measured via AFM to be
ca. 20 times thicker than the starting film of adhesion layer,
indicating the adhesion layer nucleates the growth of CuSO.sub.4 at
the polyimide surface. CuSO.sub.4-treated Kapton.RTM. polyimide
film was reduced rapidly using aqueous sodium borohydride, which
also gave copper metal; here, AFM analysis showed the Cu pattern to
be buried into the polymer surface in pits, the tops of which in
many cases were about 500 nm below the polymer surface. It is
believed that the relatively faster borohydride reduction is
sufficiently exothermic so that the polymer melts in the vicinity
of the reduction reaction.
[0079] Because the adhesion layer is thin (ca. 5 nm), it is
resistant to cracking by physically flexing the polymer, therefore
the adhesion layer is a suitable matrix for polymer metallization
with copper. Copper "seed" layers can serve as nucleation sites for
bulk copper growth by electroless deposition processes (Gu et al.,
Organic Solution Deposition of Copper Seed Layers onto Barrier
Metals. Mat. Res. Soc. Symp. Proc. 2000, 612, D9.19.1-D9.19.6 (p.
D9.19.2, lines 33-40; p. D9.19.5, lines 14-22)). In conjunction
with photolithographic patterning, this further metallization of
the polymer provides a means to prepare copper-based anti-infective
compounds on a variety of flexible substrates under simple
laboratory conditions.
[0080] Metallization of Kapton.RTM. polyimide film and PET.
Patterned or un-patterned copper metallization of the polymer
surfaces was achieved by soaking an activated polymer surface in a
200 mM aqueous solution of CuSO.sub.4 overnight, followed by
reduction in 1M aqueous dimethylamine borane or sodium borohydride
for 6 hrs. Copper metallization was confirmed by Energy Dispersive
X-ray Analysis, which was done using a FEI XL30 FEG-SEM equipped
with a PGT-IMIX PTS EDX system.
[0081] Functionalized Organophosphorous Techniques
[0082] Substrates may be functionalized using functionalized
organophosphorous techniques. See, U.S. Patent Application
Publication 2004/0023048, incorporated herein by reference in its
entirety. The organophosphonic acid-based segment may be derived
from a functionalized organophosphonic acid such as an
omega-functionalized organophosphonic acid containing a hydrocarbon
ligand having from about 2 to about 40 carbon atoms, wherein the
hydrocarbon ligand is a linear or branched, saturated or
unsaturated, substituted or unsubstituted, aliphatic or aromatic
alkylene moiety.
[0083] Substituents on the hydrocarbon portion of phosphonic acids
useful in accordance with the present disclosure may be appended to
any carbon atom of the hydrocarbon ligand. Useful substituents are,
for example, reactive functional groups, for example, a hydroxyl
group, carboxylic group, an amino group, a thiol group, a
phosphonate group, and chemical derivatives thereof. It will be
appreciated that any functional group which can participate in a
further derivatization reaction can be employed. Additionally, an
alkylene hydrocarbon ligand may contain within the structure or
appended to the structure, reactive moieties, for example sites of
unsaturation, which may be further reacted in a polymerization
reaction with reactive substituents on the hydrocarbon ligands
appended to other phosphonate sites bound to the surface of the
native oxide during a phosphonate derivatizing reaction. In this
manner, a phosphonate-organo-polymeric layer may be formed on the
oxide surface. An example of such a polymerization reaction is the
preparation of a surface coating of an acrylic derivative of a
phosphonic acid. When acrylate and methacrylate substituents are
employed, the polymerization proceeds spontaneously upon exposure
to light or air. For less reactive coatings, the polymerization can
be performed by exposing the coating to conventional polymerization
reagents and conditions.
[0084] In some embodiments, coatings are formed from phosphonic
acids having an organic ligand functionalized at a carbon of the
ligand which is further reacted to form covalent bonds with
anti-infective agents. For functionalized phosphonic acids, the
application of the acid to oxide surface generally results in a
self-assembled phosphonic acid film with a carbon directed away
from the substrate surface and available for covalent bonding or
further chemical modification. Preferred functional groups include
hydroxyl, amino, carboxylate, thiol, and phosphonate groups.
[0085] It will also be appreciated that the reactive substituents
pendent on the organic portion of a phosphonate bound to the oxide
surface can be further reacted with reagents which are subject to
hydrolysis reactions. Examples include metal alkoxides, examples of
which are those having the structure M(O--R).sub.n, where M is a
metal, R is a linear or branched, saturated or unsaturated,
aliphatic or aromatic, substituted or unsubstituted hydrocarbon
moiety, and "n" is equal to a stable valance state of the metal.
Examples of metal alkoxide compounds are zirconium
tetra(tert-butoxide), titanium tetra(tert-butoxide), and silicon
tetra(tert-butoxide) where R is a t-butyl group, M is respectively
Zr, Ti, and Si, and "n" is four. It will be appreciated that other
hydrolytically reactive compounds which have two or more alkoxide
ligands in addition to other ligands may also be utilized. For
example, calcium alkoxides such as calcium bis(2-methoxy-ethoxide)
may be employed. In general, alkoxide ligated metals in groups 2
through 14 will find utility in these secondary functionalization
reactions with phosphonate coatings of the present development.
[0086] A process for forming a coated article by the foregoing
technique may include (a) depositing a layer of a functionalized
organophosphorous compound on an oxide substrate; (b) heating the
substrate of step (a) to a temperature sufficient to bond the
functionalized organophosphorous compound to the oxide substrate;
(c) depositing a separate layer onto the layer produced by step
(b); and (d) bonding the layers produced by steps (b) and (c)
through the functional group.
[0087] Preferred functional groups are hydroxyl-, carboxylate-,
amino-, thiol-, and phosphonato-functional groups, or these groups
further derivatized by reaction with a metal or organo-metal
reagent, for example an alkoxide. The groups participate in further
bonding with moieties of the organic, inorganic or bioactive
coating layer, either through strong chemical bonding, for example,
covalent bonding, or through weaker bonding interactions, for
example, hydrogen bonding.
[0088] Preferred metal reagents for derivatizing functional groups
are metal alkoxides, for example zirconium tetra(tert-butoxide),
silicon tetra(tert-butoxide), titanium tetra(tert-butoxide), and
calcium bis(2-methoxy-ethoxide).
[0089] A preferred method of attaching an anti-infective agent to a
native oxide surface comprises providing a phosphorous-based
coating layer as described above wherein the functionalized
organophosphonate moieties are hydroxyl, amine or thiolate that
have been derivatized with a cross-coupling reagent such as
(p-nitrophenyl) chloroformate, and further reacted with an amino or
hydroxylated moiety, wherein the amino or hydroxylated moieties are
a diamine or aminoalcohol bonded by a carbon-nitrogen bond or a
carbon-oxygen bond, respectively, to a carbonyl group, the reaction
providing a urethane, carbonate, urea, thiocarbonate, or thiourea
bond to the derivatized functional group; the terminal amino group
is then quaternized.
[0090] In accordance with another embodiment of the present
invention there is provided a method of bonding a layer of a
phosphorous-based acid moiety to a surface such as but not limited
to an oxide surface (such as titanium, zirconium and tantalum
oxide) comprising coating said oxide surface with a
phosphorous-based acid moiety self-assembled layer and heating said
coated oxide surface until the self-assembled layer is bonded
thereto, the phosphorous-based acid moiety comprising the
self-assembled layer being selected from the group consisting of
phosphoric acid and organophosphonic acids.
[0091] Preferred coatings are those which have been formed from
alkyl, alkylene- and arylene-organophosphonic acids, including
substituted alkyl, alkylene and arylene-phosphonic acids. More
preferred are substituted alkyl and alkylene phosphonic acids with
a reactive substituent to the phosphonic acid functional group.
Preferred oxide surfaces are the native oxide surfaces of titanium,
zirconium and tantalum materials.
[0092] Functionalization of a silicon surface with a self-assembled
film of an organophosphonic acid
[0093] Self-assembled films of an organophosphonic acid may be
bonded to the native or synthesized oxide-coated silicon surface as
a film of the corresponding phosphonate. Midwood et al., Easy and
Efficient Bonding of Biomolecules to an Oxide Surface of Silicon.
Langmuir 2004, 20, 5501-5505, incorporated herein by reference in
its entirety. The phosphonate film is functionalized to enable
covalent coupling of biological molecules that may be
anti-infective; covalent coupling of anti-infective agents or
moieties; and/or covalent coupling of anti-infective agents or
moieties to a biological molecule. As with all functionalizing
techniques disclosed herein, the functionalized surfaces and/or the
anti-infective agents may be patterned on a substrate, depending on
the particular application.
[0094] Functionalization of Titanium with Peptides.
[0095] Peptide-modified surface-bound phosphonate films may be
easily prepared with high surface coverage. Gawalt et al., Bonding
Organics to Ti Alloys: Facilitating Human Osteoblast Attachment and
Spreading on Surgical Implant Materials" Langmuir 2003, 19,
200-204, incorporated herein by reference in its entirety.
Anti-infective peptides may be bound to functionalized surfaces in
accordance with the techniques described in Gawalt.
[0096] Organic anti-infective moieties that may be added to a
functionalizing layer such as those described hereinabove include
quaternary ammonium alkylamines, quaternary ammonium alkanols,
usinic acid; cationic peptides such as cecropins neutrophil
defensins, polyphemusin, gramicidins, thionins, histone-derived
compounds, beta-hairpin, hemoglobin, lactoferrin; anionic peptides
such as neuropeptide precursors, aromatic dipeptides, hemocyanin
derivatives; other antimicrobial peptides such as bacteriacins,
cathelicidin, thrombocidin, and histanins; antibodies, antibiotics,
including tetracyclines, amphenicols, penicillins, cephalosporins,
monobactams, carbapenems, sulfanomides, trimethoprim, macrolides,
lincosamides, streptogramins, streptomycins, quinolones,
glycopeptides, polymyxins, imidazole derivatives, nitrofuran
derivatives; steroids; chlorhexidine; phenol compounds including
triclosan; epoxides; polymers and/or polypeptides which have
anti-infective properties.
[0097] Inorganic anti-infective coating layers that may be bonded
include silver, copper, zinc oxides, titanium oxides, zeolites,
silicates, calcium hydroxide, iodine, sodium hypochlorite,
sulfites, and sulfates.
[0098] Preferred anti-infective moieties are quaternary ammonium
compounds, such as benzethonium chloride, cetrimonium bromide,
cetrimonium chloride, dimethyldioctadecylammonium chloride,
tetramethylammonium hydroxide; quaternary ammonium alkyl
dendrimers, silver, copper, cationic species such as benzalkonium
chloride, Bronidox; and alkylated choline.
[0099] Compositions and devices in accordance with the present
invention include but are not limited to any device(s) specific to
an application by an orthopedic, cardiovascular, plastic,
dermatologic, general, maxillofacial or neuro surgeon or physician
including, but not limited to, cardiovascular or vascular implant
device such as stents, replacement heart valves, replacement heart
valve components, leaflets, sewing cuffs, orifices, annuloplasty
rings, pacemakers, pacemaker polymer mesh bags, pacemaker leads,
pacing wires, intracardiac patches/pledgets, vascular patches,
vascular grafts, intravascular catheters, and defibrillators;
tissue scaffolds; non-woven meshes, woven meshes, and foams;
orthopedic implant devices including orthopedic trauma implants,
joint implants, spinal implants, plates, screws, rods, plugs,
cages, pins, nails, wires, cables, anchors, scaffolds, artificial
joints selected from hand joints, wrist joints, elbow joints,
shoulder joints, spine joints, hip joints, knee joints and ankle
joints; bone replacement, bone fixation cerclage and dental and
maxillofacial implants; spine implant devices including
intervertebral cages, pedicle screws, rods, connectors,
cross-links, cables, spacers, facet replacement devices, facet
augmentation devices, interspinous process decompression devices,
interspinous spacers, vertebral augmentation devices, wires,
plates, spine arthroplasty devices, facet fixation devices, bone
anchors, soft tissue anchors, hooks, spacing cages, and cement
restricting cages; diagnostic implants, biosensors, glucose
monitoring devices, external fixation devices, external fixation
implants, dental implants, maxillofacial implants, external facial
fracture fixation devices and implants, contact lenses, intraocular
implants, keratoprostheses; neurosurgical devices and implants
selected from shunts and coils; general surgical devices and
implants selected from drainage catheters, shunts, tapes, meshes,
ropes, cables, wires, sutures, skin and tissue staples, bone
anchors, soft tissue anchors, burn sheets, and vascular patches;
and temporary/non-permanent implants. Specifically, such devices
include an anti-infective agent to counter infective agents.
Examples
[0100] Derivatization of Adhesion Layer via Organophosphorous
Interfaces
[0101] A zirconium oxide/alkoxide adhesion layer was deposited onto
Nylon 6/6 and then reacted with a solution of
11-hydroxyundecylphosphonic acid to form an organophosphonate
monolayer. See, Dennes, T. J. et al., High-Yield Activation of
Scaffold Polymer Surfaces to Attach Cell Adhesion Molecules. J. Am.
Chem. Soc. 2007, 129, 93-97, incorporated herein by reference in
its entirety. Experimental details appear at page 95, col. 1-page
97, col. 1; see also discussion at pages 94-96 and accompanying
figures.
[0102] The substrate was first immersed in a solution of
3-(maleimido)propanoic acid N-hydroxysuccinimide ester and then in
an aqueous solution of RGDC to derivatize the phosphonate monolayer
with an active peptide. In a prophetic example, an anti-infective
peptide may be bound to the phosphonate monolayer in place of
RGD.
[0103] Antibody Coupling Using Functionalized
Organophosphonates
[0104] 11-Hydroxyundecylphosphonic acid was reacted with the
surface of cleaned and prepared silicon wafers, forming a
self-organized 11-hydroxyundecylphosphonate monolayer on SiO.sub.2.
This was confirmed by QCM and AFM. The omega-functional groups were
derivatized using disuccinimidyl glutarate (DSG) in dry
acetonitrile. Rabbit antimouse IgG (Pierce) was then coupled to the
derivatized monolayer by incubating for 30 min at a concentration
of 100/g/mL in PBS. Antibody coupling was accomplished by
incubation with 10/g/mL anti-R4 integrin antibody P1H4 (Chemicon)
or anti-R5 integrin antibody SAM-1 (Cymbus Technology Ltd.) for 2
h. Antibody activity was confirmed by incubation of CHO.alpha.4 or
CHO.alpha.5 cells; selective cell growth indicated appropriate
activity.
[0105] In a prophetic example, a self-assembled monolayer of
11-hydroxyphosphonate is bonded to the native oxide surface of
titanium and is then treated first with (p-nitrophenyl)
chloroformate and then a solution of 1,12-diaminododecane (Aldrich)
to give an aminododecyl urethane bonded to the titanium through the
phosphonate interface. The distal amino group is then quaternized
using octyl iodide (Aldrich) to give the quaternary alkylammonium
moiety covalently bonded to the substrate through the phosphonate
interface.
[0106] Similarly, in a prophetic example, a quaternary
alkylammonium moiety may be bonded to a polymer such as PEEK by
first preparing an adhesion layer of zirconium oxide on the PEEK
surface followed by treatment with the 11-hydroxyphosphonic acid to
give the 11-hydroxyphosphonate monolayer bonded to the PEEK. The
11-hydroxyphosphonate monolayer is derivatized by reaction,
sequentially, with (p-nitrophenyl) chloroformate,
1,12-diaminododecane, and octyl iodide.
[0107] Although certain presently preferred embodiments of the
invention have been specifically described herein, it will be
apparent to those skilled in the art to which the invention
pertains that variations and modifications of the various
embodiments shown and described herein may be made without
departing from the spirit and scope of the invention. Accordingly,
it is intended that the invention be limited only to the extent
required by the appended claims and the applicable rules of
law.
[0108] All references cited herein are incorporated fully by
reference.
* * * * *