This application claims under 35 USC §119 (e) the benefit of the filing date of U.S. Provisional Application No. 60/435,003 filed Dec. 19, 2002 and all references incorporated therein.
The present invention generally relates to a medical device having an antimicrobial metal-containing layer-by-layer coating thereon and to a method for making the medical device of the invention.
Contact lenses are often exposed to one or more microorganisms during wear, storage and handling. They can provide surfaces onto which the microorganisms can adhere and then proliferate to form a colony. Microbial adherence to and colonization of contact lenses may enable microorganisms to proliferate and to be retained at the ocular surface for prolonged periods and thereby may cause infection or other deleterious effects on the ocular health of the eye in which the lens is used. Therefore, it is desirous to make various efforts to minimize and/or eliminate the potential for microorganism adhesion to and colonization of contact lenses.
Many attempts have been made to develop antimicrobial medical devices. Two approaches have been proposed. One approach is to incorporate antimicrobial compounds into a polymeric composition for molding a contact lens. For example, Chalkley et al. in Am. J. Ophthalmology 1966, 61:866-869, disclosed that germicidal agents were incorporated into contact lenses. U.S. Pat. No. 4,472,327 discloses that antimicrobial agents may be added to the monomer before polymerization and locked into the polymeric structure of the lens. U.S. Pat. Nos. 5,358,688 and 5,536,861 disclose that contact lenses having antimicrobial properties may be made from quaternary ammonium group containing organosilicone polymers. European patent application EP0604369 discloses that deposit-resistant contact lenses can be prepared from hydrophilic copolymers that are based on 2-hydroxyethyl methacrylate and comonomers containing a quaternary ammonium moiety. Another example is an ocular lens material, disclosed in European patent application EP0947856A2, which comprises a quaternary phosphonium group-containing polymer. A further example is U.S. Pat. No. 5,515,117 which discloses contact lenses and contact lens cases made from materials which comprise polymeric materials and effective antimicrobial components. A still further example is U.S. Pat. No. 5,213,801 which discloses contact lenses made from materials comprising a hydrogel and an antimicrobial ceramic containing at least one metal selected from Ag, Cu and Zn. There are some disadvantages associated with this approach for making antimicrobial contact lenses. Polymeric compositions having antimicrobial properties may not possess all properties desired for contact lenses, especially extended-wear contact lenses, which hinders their practice uses.
The other approach for making antimicrobial medical devices is to form antimicrobial coatings, containing leachable or covalently attached antimicrobial agents, on medical devices. Antimicrobial coatings containing leachable antimicrobial agents may not be able to provide antimicrobial activity over the period of time when used in the area of the human body. In contrast, antimicrobial coating containing covalently bound antimicrobial agents can provide antimicrobial activity over a relatively longer period of time. However, antimicrobial compounds in such coatings may exhibit diminished activity when comparing the activity of the unbound corresponding antimicrobial compounds in solution, unless assisted by hydrolytic breakdown of either the bound antimicrobial compounds or the coating itself. Like the above-described approach, the antimicrobial coating may not be able to provide desired surface properties such as hydrophilicity and/or lubricity and also may have adverse effects on the desired bulk properties of a medical device (for example, the oxygen permeability of a contact lens).
Currently, a wide variety of antimicrobial agents have been proposed to be used as coatings for contact lenses (see, for example, U.S. Pat. No. 5,328,954). Prior known antimicrobial coatings include antibiotics, lactoferrin, metal chelating agents, substituted and unsubstituted polyhydric phenols, amino phenols, alcohols, acid and amine derivatives, and quaternary ammonium group-containing compounds. However, such antimicrobial coatings have disadvantages and are unsatisfactory. The overuse of antibiotics can lead to proliferation of antibiotic-resistant microorganisms. Other coatings may not have broad spectrum antimicrobial activity, may produce ocular toxicity or allergic reactions, or may adversely affect lens properties required for ensuring corneal health and for providing the patient with good vision and comfort.
Therefore, there is a need for antimicrobial coatings that can provide high bactericidal efficacy and broad spectrum antimicrobial activity coupled with low cytotoxicity. There is also a need for new contact lenses having antimicrobial coatings, which have high bactericidal efficacy, a broad spectrum of antimicrobial activities, and minimal adverse effects on the wearer's ocular health and comfort. Such contact lenses may have increased safety as extended-wear contact lenses which could provide comfort, convenience, and safety.
Moreover, surgical and device related infection remains to be one of the main clinical and economic challenges in the field of medical devices and in health care industry in general. Each year, as many as 2 million hospital patients in the United States develop nosocomial infections, and approximately 80% of the 80,000 annual deaths due to nosocomial infections are device-related. A potent and cost-effective antimicrobial coating for medical devices would be a key to mitigate the infection-related clinical challenges and economic burden of health care.
One object of the invention is to provide an antimicrobial coating which has a high antimicrobial efficacy coupled with low cytotoxicity.
Another object of the invention is to provide a medical device having an antimicrobial coating that has a high antimicrobial efficacy coupled with low cytotoxicity.
A further object of the invention is to provide a cost-effective and efficient process for forming an antimicrobial coating on a medical device.
SUMMARY OF THE INVENTION
These and other objects of the invention are met by the various aspects of the invention described herein.
The invention, in one aspect, provides a medical device having a core material and an antimicrobial metal-containing layer-by-layer (LbL) coating that is not covalently attached to the medical device and can impart to the medical device an increased hydrophilicity. In a preferred embodiment, the antimicrobial metal-containing LbL coating comprises a member selected from the group consisting of: (a) one layer of charged antimicrobial metal nanoparticles; (b) one layer of charged antimicrobial metal-containing nano-particles; (c) silver-polyelectrolyte complexes formed between silver ions and a polycationic material having amino groups; (d) silver-polyelectrolyte complexes formed between silver ions and a polyionic material having sulfur-containing groups; (e) silver nano-particles; and (f) combinations thereof.
The invention, in another aspect, provides a method for preparing a medical device having an antimicrobial metal-containing LbL coating thereon. The method comprises alternatively applying, in no particular order, one layer of a first charged material and one layer of a second charged material having charges opposite of the charges of the first charged material onto a medical device to form the antimicrobial metal-containing LbL coating, wherein at least one of the first and second charged material is selected from the group consisting of charged antimicrobial metal nanoparticles, charged antimicrobial metal-containing nano-particles, silver-polyelectrolyte complexes formed between silver ions and a polycationic material having amino groups, silver-polyelectrolyte complexes formed between silver ions and a polyionic material having sulfur-containing groups, and combinations thereof.
These and other aspects of the invention will become apparent from the following description of the presently preferred embodiments. The detailed description is merely illustrative of the invention and does not limit the scope of the invention, which is defined by the appended claims and equivalents thereof. As would be obvious to one skilled in the art, many variations and modifications of the invention may be effected without departing from the spirit and scope of the novel concepts of the disclosure.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures are well known and commonly employed in the art. Conventional methods are used for these procedures, such as those provided in the art and various general references. Where a term is provided in the singular, the inventors also contemplate the plural of that term. The nomenclature used herein and the laboratory procedures described below are those well known and commonly employed in the art. As employed throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
An “article” refers to an ophthalmic lens, a mold for making an ophthalmic lens, or a medical device other than ophthalmic lens.
A “medical device”, as used herein, refers to a device or a part thereof having one or more surfaces that contact tissue, blood, or other bodily fluids of patients in the course of their operation or utility. Exemplary medical devices include: (1) extracorporeal devices for use in surgery such as blood oxygenators, blood pumps, blood sensors, tubing used to carry blood and the like which contact blood which is then returned to the patient; (2) prostheses implanted in a human or animal body such as vascular grafts, stents, pacemaker leads, heart valves, and the like that are implanted in blood vessels or in the heart; (3) devices for temporary intravascular use such as catheters, guide wires, and the like which are placed into blood vessels or the heart for purposes of monitoring or repair; (4) artificial tissues such as artificial skin for burn patients; (5) dentifices, dental moldings; (6) ophthalmic devices; and (7) cases or containers for storing ophthalmic devices or ophthalmic solutions.
An “ophthalmic device”, as used herein, refers to a contact lens (hard or soft), an intraocular lens, a corneal onlay, other ophthalmic devices (e.g., stents, glaucoma shunt, or the like) used on or about the eye or ocular vicinity.
“Biocompatible”, as used herein, refers to a material or surface of a material, which may be in intimate contact with tissue, blood, or other bodily fluids of a patient for an extended period of time without significantly damaging the ocular environment and without significant user discomfort.
“Ophthalmically compatible”, as used herein, refers to a material or surface of a material which may be in intimate contact with the ocular environment for an extended period of time without significantly damaging the ocular environment and without significant user discomfort. Thus, an ophthalmically compatible contact lens will not produce significant corneal swelling, will adequately move on the eye with blinking to promote adequate tear exchange, will not have substantial amounts of protein or lipid adsorption, and will not cause substantial wearer discomfort during the prescribed period of wear.
“Ocular environment”, as used herein, refers to ocular fluids (e.g., tear fluid) and ocular tissue (e.g., the cornea) which may come into intimate contact with a contact lens used for vision correction, drug delivery, wound healing, eye color modification, or other ophthalmic applications.
A “monomer” means a low molecular weight compound that can be polymerized. Low molecular weight typically means average molecular weights less than 700 Daltons.
A “macromer” refers to medium and high molecular weight compounds or polymers that contain functional groups capable of further polymerization. Medium and high molecular weight typically means average molecular weights greater than 700 Daltons.
“Polymer” means a material formed by polymerizing one or more monomers.
“Surface modification”, as used herein, means that an article has been treated in a surface treatment process (or a surface modification process), in which, by means of contact with a vapor or liquid, and/or by means of application of an energy source (1) a coating is applied to the surface of an article, (2) chemical species are adsorbed onto the surface of an article, (3) the chemical nature (e.g., electrostatic charge) of chemical groups on the surface of an article are altered, or (4) the surface properties of an article are otherwise modified.
“LbL coating”, as used herein, refers to a coating that is not covalently attached to an article, preferably a medical device, and is obtained through a layer-by-layer (“LbL”) deposition of polyionic or charged materials on an article.
The term “bilayer” is employed herein in a broad sense and is intended to encompass: a coating structure formed on a medical device by alternatively applying, in no particular order, one layer of a first polyionic material (or charged material) and subsequently one layer of a second polyionic material (or charged material) having charges opposite of the charges of the first polyionic material (or the charged material); or a coating structure formed on a medical device by alternatively applying, in no particular order, one layer of a first charged polymeric material and one layer of a non-charged polymeric material or a second charged polymeric material. It should be understood that the layers of the first and second coating materials (described above) may be intertwined with each other in the bilayer.
A medical device having a core material and an LbL coating, which comprises at least one layer of a charged polymeric material and one layer of a non-charged polymeric material that can be non-covalently bonded to the charged polymeric material, can be prepared according to a method disclosed in a co-pending U.S. patent application Ser. No. 10/654,566 filed Sep. 3, 2003, herein incorporated by reference in its entirety.
As used herein, “asymmetrical coatings” on an ophthalmic lens refers to the different coatings on the first surface and the opposite second surface of the ophthalmic lens. As used herein, “different coatings” refers to two coatings that have different surface properties or functionalities.
A “capping layer”, as used herein, refers to the last layer of a coating material which is applied onto the surface of a medical device.
A “capping bilayer”, as used herein, refers to the last bilayer of a first coating material and a second coating material, which is applied onto the surface of a medical device.
A “polyquat”, as used herein, refers to a polymeric quaternary ammonium group-containing compound.
As used herein, a “polyionic material” refers to a polymeric material that has a plurality of charged groups, such as polyelectrolytes, p- and n-type doped conducting polymers. Polyionic materials include both polycationic (having positive charges) and polyanionic (having negative charges) materials.
An “antimicrobial LbL coating”, as used herein, refers to an LbL coating that imparts to a medical device the ability to decrease or eliminate or inhibit the growth of microorganisms on the surface of the medical device or in an adjacent area extending from the medical device. An antimicrobial LbL coating on a medical device of the invention exhibit preferably at least a 1-log reduction (≧90% inhibition), more preferably at least a 2-log reduction (≧99% inhibition), of viable microorganisms.
An “antimicrobial agent”, as used herein, refers to a chemical that is capable of decreasing or eliminating or inhibiting the growth of microorganisms such as that term is known in the art.
“Antimicrobial metals” are metals whose ions have an antimicrobial effect and which are biocompatible. Preferred antimicrobial metals include Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi and Zn, with Ag being most preferred.
“Antimicrobial metal-containing nanoparticles” refers to particles having a size of less than 1 micrometer and containing at least one antimicrobial metal present in one or more of its oxidation states. For example, silver-containing nanoparticles can contain silver in one or more of its oxidation states, such as Ag0, Ag1+, and Ag2+.
“Antimicrobial metal nanoparticles” refers to particles which is made of one or more antimicrobial metals and have a size of less than 1 micrometer. The antimicrobial metals in the antimicrobial metal nanoparticles can be present in one or more of its oxidation state.
An “averaged contact angle” refers to a contact angle (Sessile Drop), which is obtained by averaging measurements of at least 3 individual medical devices.
As used herein, “increased surface hydrophilicity” or “increased hydrophilicity” in reference to a coated medical device means that the coated medical device has a reduced averaged contact angle compared with an uncoated medical device.
The present invention is directed to a medical device having a core material and an antimicrobial metal-containing LbL surface coating (hereinafter LbL coating) formed thereon and to a method for making the same. The antimicrobial metal-containing LbL coating imparts to the medical device an increased surface hydrophilicity (hereinafter hydrophilicity) and exhibits at least 50% inhibition of viable microorganisms. Preferably, the increased hydrophilicity is characterized by having an averaged contact angle of about 80 degrees or less.
It has been discovered here that an antimicrobial metal, silver, in particular silver nano-particles, and silver-polyelectrolyte complexes can be incorporated cost-effectively into an LbL coating according to one of the methods of the invention. It is found that an silver-containing LbL coating of the invention may possess several advantages as follows. It can impart to a medical device not only an antimicrobial activity but also an increased surface hydrophilicity. It has minimal adverse effects on the desired bulk properties of, for example, a contact lens, such as oxygen permeability, ion permeability, and optical properties. An silver-containing LbL coating of the invention formed on a medical device can adhere well to a medical device and be stable, even after several cycles of autoclaving treatments. The process for forming a silver-containing LbL coating of the invention is well suited for automation and can be used to coat a wide range of substrate (polymeric, glass, quartz, ceramic, metal) and in any geometry. Out-diffusion of silver from the silver-containing coating is controllable. In addition, a medical device having an antimicrobial LbL coating of the invention thereon can be further subjected to surface modification, such as plasma treatment to obtain a coating possessing advantages of both plasma coating and an antimicrobial coating of the invention.
In accordance with the present invention, the core material of a medical device (substrate) may be any of a wide variety of polymeric materials. Exemplary core materials include, but are not limited to, hydrogels, silicone-containing hydrogels, polymers and copolymers of styrene, substituted styrenes, ethylene, propylene, acrylates, methacrylates, N-vinyl lactams, acrylamides and methacrylamides, acrylonitrile, acrylic acid, methacrylic acid, or combinations thereof.
A preferred group of core materials to be coated are those being conventionally used for the manufacture of biomedical devices, e.g. contact lenses, in particular contact lenses for extended wear, which are not hydrophilic per se. Such materials are known to the skilled artisan and may comprise for example polysiloxanes, perfluoroalkyl polyethers, fluorinated poly(meth)acrylates or equivalent fluorinated polymers derived e.g. from other polymerizable carboxylic acids, polyalkyl (meth)acrylates or equivalent alkylester polymers derived from other polymerizable carboxylic acids, or fluorinated polyolefins, such as fluorinated ethylene or propylene, for example tetrafluoroethylene, preferably in combination with specific dioxols, such as perfluoro-2,2-dimethyl-1,3-dioxol. Examples of suitable bulk materials are e.g. Lotrafilcon A, Neofocon, Pasifocon, Telefocon, Silafocon, Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Balifilcon A, Fluorofocon, or Teflon AF materials, such as Teflon AF 1600 or Teflon AF 2400 which are copolymers of about 63 to 73 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 37 to 27 mol % of tetrafluoroethylene, or of about 80 to 90 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % of tetrafluoroethylene.
Another group of preferred core materials to be coated is amphiphilic-segmented copolymers comprising at least one hydrophobic segment and at least one hydrophilic segment, which are linked through a bond or a bridge member. Examples are silicone hydrogels, for example those disclosed in PCT applications WO 96/31792 to Nicolson et al. and WO 97/49740 to Hirt et al.
A particular preferred group of core materials to be coated comprises organic polymers selected from polyacrylates, polymethacrylates, polyacrylamides, poly(N,N-dimethylacrylamides), polymethacrylamides, polyvinyl acetates, polysiloxanes, perfluoroalkyl polyethers, fluorinated polyacrylates or -methacrylates and amphiphilic segmented copolymers comprising at least one hydrophobic segment, for example a polysiloxane or perfluoroalkyl polyether segment or a mixed polysiloxane/perfluoroalkyl polyether segment, and at least one hydrophilic segment, for example a polyoxazoline, poly(2-hydroxyethylmethacrylate), polyacrylamide, poly(N,N-dimethylacrylamide), polyvinylpyrrolidone polyacrylic or polymethacrylic acid segment or a copolymeric mixture of two or more of the underlying monomers.
The core material to be coated may also be any blood-contacting material conventionally used for the manufacture of renal dialysis membranes, blood storage bags, pacemaker leads or vascular grafts. For example, the material to be modified on its surface may be a polyurethane, polydimethylsiloxane, polytetrafluoroethylene, polyvinylchloride, Dacron™ or Silastic™ type polymer, or a composite made therefrom.
Moreover, the core material to be coated may also be an inorganic or metallic base material without suitable reactive groups, e.g. ceramic, quartz, or metals, such as silicon or gold, or other polymeric or non-polymeric substrates. e.g., for implantable biomedical applications, ceramics are very useful. In addition, e.g. for biosensor purposes, hydrophilically coated base materials are expected to reduce nonspecific binding effects if the structure of the coating is well controlled. Biosensors may require a specific carbohydrate coating on gold, quartz, or other non-polymeric substrates.
The core material to be coated can be subjected to a surface modification before applying an antimicrobial coating. Exemplary surface treatment processes include, but are not limited to, a surface treatment by energy (e.g., a plasma, a static electrical charge, irradiation, or other energy source), chemical treatments, the grafting of hydrophilic monomers or macromers onto the surface of an article, and layer-by-layer deposition of polyelectrolytes. A preferred class of surface treatment processes are plasma processes, in which an ionized gas is applied to the surface of an article. Plasma gases and processing conditions are described more fully in U.S. Pat. Nos. 4,312,575 and 4,632,844, which are incorporated herein by reference. The plasma gas is preferably a mixture of lower alkanes and nitrogen, oxygen or an inert gas.
The form of the core material to be coated may vary within wide limits. Examples are particles, granules, capsules, fibers, tubes, films or membranes, preferably moldings of all kinds such as ophthalmic moldings, for example intraocular lenses, artificial cornea or in particular contact lenses.
Coating materials for forming an antimicrobial metal-containing LbL coating include, without limitation, polyionic materials, non-charged polymeric materials, polymerized vesicles (liposomes and micelles) with surface charges, charged antimicrobial metal nanoparticles (preferrably charged silver nano-particles), charged antimicrobial metal-containing nanoparticles (preferably charged silver-containing nanoparticles), silver-polyelectrolyte complexes formed between silver ions and a polyionic material having sulfur-containing groups, silver-polyelectrolyte complexes formed between silver ions and a polycationic material having amino groups, a negatively charged polyionic material having —COOAg groups, and combinations thereof.
The polyionic materials that may be employed in the present invention include polyanionic and polycationic polymers. Examples of suitable polyanionic polymers include, for example, a synthetic polymer, a biopolymer or modified biopolymer comprising carboxy, sulfo, sulfato, phosphono or phosphato groups or a mixture thereof, or a salt thereof, for example, a biomedical acceptable salt and especially an ophthalmically acceptable salt thereof when the article to be coated is an ophthalmic device.
Examples of synthetic polyanionic polymers are: a linear polyacrylic acid (PAA), a branched polyacrylic acid, a polymethacrylic acid (PMA), a polyacrylic acid or polymethacrylic acid copolymer, a maleic or fumaric acid copolymer, a poly(styrenesulfonic acid) (PSS), a polyamido acid, a carboxy-terminated polymer of a diamine and a di- or polycarboxylic acid (e.g., carboxy-terminated Starburst™ PAMAM dendrimers from Aldrich), a poly(2-acrylamido-2-methylpropanesulfonic acid) (poly-(AMPS)), an alkylene polyphosphate, an alkylene polyphosphonate, a carbohydrate polyphosphate or carbohydrate polyphosphonate (e.g., a teichoic acid). Examples of a branched polyacrylic acid include a Carbophil® or Carbopol® type from Goodrich Corp. Examples of a copolymer of acrylic or methacrylic acid include a copolymerization product of an acrylic or methacrylic acid with a vinyl monomer including, for example, acrylamide, N,N-dimethyl acrylamide or N-vinylpyrrolidone. Examples of polyanionic biopolymers or modified biopolymers are: hyaluronic acid, glycosaminoglycanes such as heparin or chondroitin sulfate, fucoidan, poly-aspartic acid, poly-glutamic acid, carboxymethyl cellulose, carboxymethyl dextrans, alginates, pectins, gellan, carboxyalkyl chitins, carboxymethyl chitosans, sulfated polysaccharides.
A preferred polyanionic polymer is a linear or branched polyacrylic acid or an acrylic acid copolymer. A more preferred anionic polymer is a linear or branched polyacrylic acid. A branched polyacrylic acid in this context is to be understood as meaning a polyacrylic acid obtainable by polymerizing acrylic acid in the presence of suitable (minor) amounts of a di- or polyvinyl compound.
A suitable polycationic polymer as part of the bilayer is, for example, a synthetic polymer, biopolymer or modified biopolymer comprising primary, secondary or tertiary amino groups or a suitable salt thereof, preferably an ophthalmically acceptable salt thereof, for example a hydrohalogenide such as a hydrochloride thereof, in the backbone or as substituents. Polycationic polymers comprising primary or secondary amino groups or a salt thereof are preferred.
Examples of synthetic polycationic polymers are:
(i) a polyallylamine (PAH) homo- or copolymer, optionally comprising modifier units;
(ii) a polyethyleneimine (PEI);
(iii) a polyvinylamine homo- or copolymer, optionally comprising modifier units;
(iv) a poly(vinylbenzyl-tri-C1-C4-alkylammonium salt), for example a poly(vinylbenzyl-tri-methyl ammoniumchloride);
(v) a polymer of an aliphatic or araliphatic dihalide and an aliphatic N,N,N′,N′-tetra-C1-C4-alkyl-alkylenediamine, for example a polymer of (a) propylene-1,3-dichloride or -dibromide or p-xylylene dichloride or dibromide and (b) N,N,N′,N′-tetramethyl-1,4-tetramethylene diamine;
(vi) a poly(vinylpyridine) or poly(vinylpyridinium salt) homo- or copolymer;
(vii) a poly(N,N-diallyl-N,N-di-C1-C4-alkyl-ammoniumhalide);
(viii) a homo- or copolymer of a quaternized di-C1-C4-alkyl-aminoethyl acrylate or methacrylate, for example a poly(2-hydroxy-3-methacryloylpropyltri-C1-C2-alkylammonium salt) homopolymer such as a poly(2-hydroxy-3-methacryloylpropyltri-methylammonium chloride), or a quaternized poly(2-dimethylaminoethyl methacrylate or a quaternized poly(vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate);
(ix) polyquat; or
(x) a polyaminoamide (PAMAM), for example a linear PAMAM or a PAMAM dendrimer such as an amino-terminated Starbust™ PAMAM dendrimer (Aldrich).
The above mentioned polymers comprise in each case the free amine, a suitable salt thereof, for example a biomedically acceptable salt or in particular an ophthalmically acceptable salt thereof, as well as any quaternized form, if not specified otherwise.
Suitable comonomers optionally incorporated in the polymers according to (i), (iii), (vi) or (viii) above are, for example, hydrophilic monomers such as acrylamide, methacrylamide, N,N-dimethyl acrylamide, N-vinylpyrrolidone and the like.
Examples of polycationic biopolymers or modified biopolymers that may be employed in the bilayer of the present invention include: basic peptides, proteins or glucoproteins, for example, a poly-ε-lysine, albumin or collagen, aminoalkylated polysaccharides such as a chitosan or aminodextranes.
Particular polycationic polymers for forming the bilayer of the present invention include a polyallylamine homopolymer; a polyallylamine comprising modifier units of the above formula (II); a polyvinylamine homo- or -copolymer or a polyethyleneimine homopolymer, in particular a polyallylamine or polyethyleneimine homopolymer, or a poly(vinylamine-co-acrylamid) copolymer.
The foregoing lists are intended to be exemplary, but clearly are not exhaustive. A person skilled in the art, given the disclosure and teaching herein, would be able to select a number of other useful polyionic materials.
It has been discovered previously and disclosed in U.S. application Ser. No. 10/654,566 filed Sep. 3, 2003 (herein incorporated by reference in its entirety) that one layer of a charged polymeric material and one layer of a non-charged polymeric material, which can be non-covalently bonded to the charged polymeric material, can be alternatively deposited onto a substrate to form a biocompatible LbL coating. The non-charged polymeric material according to the invention can be: a homopolymer of a vinyl lactam; a copolymer of at least one vinyl lactam in the presence or in the absence of one or more hydrophilic vinylic comonomers; or mixtures thereof.
The vinyl lactam has a structure of formula (I)
wherein R is an alkylene di-radical having from 2 to 8 carbon atoms; R1 is hydrogen, alkyl, aryl, aralkyl or alkaryl, preferably hydrogen or lower alkyl having up to 7 and, more preferably, up to 4 carbon atoms, such as, for example, methyl, ethyl or propyl; aryl having up to 10 carbon atoms, and also aralkyl or alkaryl having up to 14 carbon atoms; and R2 is hydrogen or lower alkyl having up to 7 and, more preferably, up to 4 carbon atoms, such as, for example, methyl, ethyl or propyl.
The invention, in one aspect, provides a medical device having an antimicrobial metal-containing antimicrobial LbL coating that is not covalently attached to the medical device and having an increased hydrophilicity, preferably characterized by having an averaged contact angle of 80 degrees or less.
In a preferred embodiment, the antimicrobial LbL coating comprises at least one member selected from the group consisting of: (a) one layer of charged antimicrobial metal nanoparticles; (b) one layer of charged antimicrobial metal-containing nano-particles; (c) silver-polyelectrolyte complexes formed between silver ions and a polycationic material having amino groups; (d) silver-polyelectrolyte complexes formed between silver ions and a polyionic material having sulfur-containing groups; (e) silver nano-particles; and (f) combinations thereof.
In accordance with a more preferred embodiment, the charged antimicrobial metal nanoparticles are silver nanoparticles.
Antimicrobial metal nano-particles can be either positively charged or negatively charged, largely depending on a material (or so-called stabilizer) which is present in a solution for preparing the nano-particles and can stabilize the resultant nano-particles. A stabilizer can be any known suitable material. Exemplary stabilizers include, without limitation, positively charged polyelectrolytes, negatively charged polyelectrolytes, surfactants, salicylic acid, alcohols and the like. Where charged antimicrobial metal nanoparticles are silver nanoparticles, a stabilizer preferably is a chemical with at least one sulfur-containing group. It is known that sulfur binds tightly to silver.
Exemplary sulfur-containing groups include, without limitation, thiol, sulfonyl, sulfonic acid, alkyl sulfide, alkyl disulfide, substituted or unsubstituted phenyldisulfide, thiophenyl, thiourea, thioether, thiazolyl, thiazolinyl, and the like.
Any known suitable methods can be used in the preparation of silver or other antimicrobial metal nano-particles. For example, silver ions or silver salts can be reduced by means of a reducing agent (e.g., NaBH4 or ascorbic acid or salts thereof) or of heating or UV irradiation in a solution in the presence of a stabilizer to form silver nano-particles. A person skilled in the art will know how to choose a suitable known method for preparing silver nano-particles. Exemplary silver salts include, without limitation, silver nitrate, silver acetate, silver citrate, silver sulfate, silver lactate, and silver halide.
In accordance with the invention, charged antimicrobial metal-containing nanoparticles can comprises at least one antimicrobial metal selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi and Zn. Preferably, the charged antimicrobial metal-containing nanoparticles are silver-containing nanoparticles.
Any known suitable methods can be used to prepare charged antimicrobial metal-containing nanoparticles. For example, TiO2 nanoparticles are mixed with AgNO3 solution to form a mixture, which is subsequently exposed to UV irradiation to coat completely or partially TiO2 nanoparticles with silver. The TiO2 nanoparticles having a silver coating thereon can be further coated with one or more polyionic materials by layer-by-layer deposition techniques, to form charged silver-containing nanoparticles.
Alternatively, one or more antimicrobial metals can be coated onto nanoparticles made of any biocompatible materials, by using vapor deposition techniques. Physical vapor deposition techniques, which are well known in the art, all deposit the metal from vapor, generally atom by atom, onto a substrate surface. The techniques include vacuum or arc evaporation, sputtering, magnetronsputtering and ion plating. The nanoparticles having an antimicrobial metal coating thereon can be further coated with one or more polyionic materials by layer-by-layer deposition techniques, to form charged antimicrobial metal-containing nanoparticles.