EP4185327A1 - Antimicrobial surfaces via multicomponent chitosan conjugates - Google Patents
Antimicrobial surfaces via multicomponent chitosan conjugatesInfo
- Publication number
- EP4185327A1 EP4185327A1 EP21847217.3A EP21847217A EP4185327A1 EP 4185327 A1 EP4185327 A1 EP 4185327A1 EP 21847217 A EP21847217 A EP 21847217A EP 4185327 A1 EP4185327 A1 EP 4185327A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- chitosan
- catechol
- metal
- modified
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 238000000034 method Methods 0.000 claims description 98
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- 239000007864 aqueous solution Substances 0.000 claims description 26
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 24
- 230000021615 conjugation Effects 0.000 claims description 19
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- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical class [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 0.000 claims description 3
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 2
- 150000003868 ammonium compounds Chemical class 0.000 claims 2
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- 239000000178 monomer Substances 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
- C09D105/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Definitions
- the present disclosure is directed to methods and compositions for use of dopamine, polydopamine, and/or their derivatives, in multipart chitosan conjugates and as attachment motifs for surface modification.
- Polydopamine is one of the most versatile and widely used motifs for surface functionalization.
- catechol 3,4-dihydroxybenzene
- DOPA 3,4-dihydroxy-L- phenylalanine
- primary and secondary amines in the form of lysine and histidine in mussel adhesive proteins.
- catechol/amine systems were used to craft biomimetic adhesion systems including DOPA-Lys polyamino acids, and catechol tethered to polyamines such as chitosan.
- Chitosan is a natural polysaccharide obtained from the partial or full deacetylation of chitin. As described by Dutta et.al. (Chitin and chitosan: chemistry, properties and applications, J. Sci. Ind. Res., vol. 63, pp. 20-31 (2004)), chitin is the most naturally abundant polysaccharide after cellulose. It exists as a mixed polymer of glucosamine and N-acylated glucosamine monomers and is characterized by the degree of deacetylation of the C-2 amine. By convention chitosan is defined as having > 50% deacetylation.
- a glucosamine monomeric unit of chitosan has the following structure, where n is the number of monomeric units present in an oligomer or polymer:
- Each monomeric unit has three readily available sites for chemical modification - the C-2 primary amine, the C-3 secondary -OH and the C-6 primary -OH. These sites allow for easy modification and customization of chitosan for biomedical applications.
- chitosan is biocompatible, biodegradable and its degradation products do not cause inflammatory reactions.
- Chitosan has wide applications in the medical field, for example as vehicles for drug delivery, tissue engineering, as antithrombogenic agents, in bone regeneration and as antimicrobial material. Additionally, chitosan has been used in cosmetics, wastewater treatment and as a feed and food additive. Other applications of chitosan are described at, for example, Vunain et al. Fundamentals of Chitosan for Biomedical Applications (Chitosan Based Biomaterials: Volume 1: Fundamentals, Jennings, J.A., Bumgardner, J.D. ed., pp. 3-30 (2017). [0008] Antimicrobial chitosan is well known in the art and has been recently reviewed. (Freitas et al.
- compositions comprising quaternized chitosan polymers or oligomers, which are further modified by attachment of dopamine or an analog to form three-part conjugates.
- a second inventive aspect is the further modification of these conjugates through attachment to/reaction with metals, their alloys, oxides or nanoparticle forms and methods to effect said attachment.
- compositions comprising doubly conjugated chitosan polymers or oligomers, where the conjugates are quaternary ammonium, phosphonium or pyridinium compounds attached to at least some of the available reaction sites (-NH2, - OH) of the chitosan molecules, followed by attachment of dopamine or an analog thereof to at least some of the remaining available sites of the chitosan molecules.
- Another exemplary embodiment of this application is directed to compositions obtained by the attachment of these doubly modified chitosans to surfaces through their pendant catechol (or analog) groups. Such surfaces may include metals, their alloys, oxides or nanoparticles, ceramics, metaloids, polymers etc.
- Applicants have developed fast and efficient anodic deposition methods in aqueous or organic media under basic or neutral conditions and the attachment of chitosan conjugates with pendant catechols, modified catechols and analogs including dopamine to metal and metal oxide surfaces.
- Anodic deposition provides a relentlessly oxidative environment at the dopamine (DP)/surface interface analogous to the addition of chemical oxidants used to accelerate dopamine attachment and polymerization. This method stands in contrast to other electrodeposition techniques, which use lower voltages and cycle between oxidative and reductive conditions at the DP/surface interface.
- chitosan conjugates are bound to metal and/or metal oxide surfaces through heat whether conventionally applied in an oven or through microwave radiation or by induction.
- Photografting has also been employed to bind quaternized doubly modified chitosan conjugates through their pendant catechol or analog groups.
- None of the known methods of surface functionalization includes a process of bonding a chitosan and/or modified chitosan of this specification to metallic surfaces via a dopamine or dopamine derivative linker to render them bactericidal.
- eluting systems have potentially systemic effects and can engender resistance in bacterial organisms whereas a bound antimicrobial surface would not have these drawbacks.
- a bound surface treatment potentially persists longer and has a longer window of efficacy versus commonly applied washes.
- the subject application describes unique compositions and fast and convenient processes for creating an antimicrobial surface based on a natural product which would have a high likelihood of being biocompatible.
- the method for modifying a polydopamine polymer described herein does not require the use of particular derivatives of dopamine or of particular pre-synthesized compounds and the implementation of different stages.
- modified surfaces may be used in various applications, including, but not limited to, medical devices.
- An inventive aspect of this application aims to address the drawbacks associated with conventional methods for attaching dopamine, polydopamine, and related compounds, to a metallic surface.
- This application also addresses novel coatings and novel devices that include a modified surface.
- An exemplary embodiment is a method of preparing a modified-metal surface by attaching a catechol or derivative thereof to a surface of a metal, the method comprising: preparing an aqueous solution of the catechol or derivative thereof in a buffer, including but not limited to, a phosphate buffer; immersing at least a portion of a metal work piece into the aqueous solution of the catechol or derivative thereof; supplying a voltage or UV radiation for a duration of time to obtain a functionalized metal work piece; and chemically attaching a quaternized chitosan to the functionalized metal work piece.
- a buffer including but not limited to, a phosphate buffer
- immersing at least a portion of a metal work piece into the aqueous solution of the catechol or derivative thereof supplying a voltage or UV radiation for a duration of time to obtain a functionalized metal work piece; and chemically attaching a quaternized chitosan to the functionalized metal work piece.
- Another exemplary embodiment is a method of preparing a metal surface modified by attachment of a catechol or derivative thereof-containing quaternized chitosan double conjugate, the method comprising: preparing an aqueous solution of the chitosan or derivative thereof in a buffer, including but not limited to, a phosphate buffer; immersing at least a portion of a metal work piece into the aqueous solution of the chitosan or derivative thereof; supplying a voltage or UV radiation for a duration of time to obtain a functionalized metal work piece; providing a chemically attached modified chitosan to the metal work piece.
- a buffer including but not limited to, a phosphate buffer
- the method comprises: preparing a solution of a catechol or derivative thereof in a non-aqueous protic solvent in the presence of a base, immersing at least a portion of a metal work piece into the solution of the catechol or derivative thereof; supplying a voltage or UV radiation for a duration of time; to obtain a functionalized metal work piece; and chemically attaching a modified chitosan to the functionalized metal work piece.
- the method comprises: preparing a solution of a doubly conjugated chitosan or derivative thereof in a non-aqueous protic solvent in the presence of a base, immersing at least a portion of a metal work piece into the solution of the chitosan or derivative thereof; supplying a voltage or UV radiation for a duration of time to obtain a functionalized metal work piece with chemically attached modified chitosan to the metal work piece.
- the non-aqueous protic solvent comprises any organic solvent, including but not limited to, an alcohol.
- the alcohol may be selected from, but is not limited to, methanol, ethanol, propanol, butanol, and the like.
- the base may be any organic basis that is miscible with an organic solvent.
- the base may be piperidine.
- the metal work piece covered by a thin layer of a doubly conjugated chitosan in an aqueous or non-aqueous solution may be exposed to ultraviolet light or heat, to form the functionalized metal work piece.
- the process includes exposure to ultraviolet light (photografting), where the metal work piece covered by a thin layer of a doubly conjugated chitosan in a non-aqueous protic solvent is exposed to UV radiation having a wavelength (Amax) of about 100 to about 400 nm.
- the wavelength may be about 100 nm, about 125 nm, about 150 nm, about 175 nm, about 200 nm, about 225 nm, about 250 nm, about 251 nm, about 252 nm, about 253 nm, about 254 nm, about 255 nm, about 256 nm, about 257 nm, about 258 nm, about 259 nm, about 260 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, about 400 nm, or any wavelength between about 100 nm to about 400 nm.
- the photografting may be carried out for a time of about 0.1 second to about 10 minutes.
- the photografting may be carried out for a time of about 0.1 sec, about 0.5 sec, about 1 sec, about 5 sec, about 10 sec, about 15 sec, about 20 sec, about 25 sec, about 30 sec, about 35 sec, about 40 sec, about 45 sec, about 50 sec, about 55 sec, about 60 sec, about 2 min, about 3 min, about 4 min, about 5 min, about 6 min, about 7 min, about 8 min, about 9 min, about 10 min, or any time between about 0.1 seconds and about 10 minutes.
- the catechol or derivative thereof is covalently bonded to a surface of the functionalized metal work piece.
- a surface of the dopamine or derivative thereof-functionalized metal work piece is activated by the addition a diimidazole a derivative thereof or any reagent designed and used to couple, bind or attach molecules, oligomers, or polymers to each other.
- the coupling agent is N-(3- Dimethylaminopropyl)-N’-ethylcarbodiimide chdrochloride (EDCI).
- the metal-linked chitosan-dopamine or analog conjugate is further modified by the attachment of a quaternary ammonium, pyridinium or phosphonium compound.
- the catechol or derivative thereof includes any substituted or unsubstituted catechols, which may be represented by the following formula: , wherein each of Ri, R2, R3, R4and Rs is independently selected from the group consisting of a thiol, a primary amine, a secondary amine, a nitrile, an aldehyde, an imidazole, an azide, a halide, a polyhexamethylene dithiocarbonate, a hydrogen, a hydroxyl, a carboxylic acid, an aldehyde, a carboxylic ester or a carboxamide, provided at least one of Ri, R2, R3,
- R4 and R5 is not a hydrogen atom, wherein a ranges from 0 to 10 and b ranges from 0 to 10, provided that a or b is at least 1.
- the catechol or derivative thereof may include, but is not limited to catecholamines, phenolic aldehydes, tyrosol and derivatives thereof, including hydroxyl-, methoxy- and mixed m ethoxy-hydroxy derivatives of tyrosol, tyramines, and derivatives thereof, including hydroxylated tyramines, dopamines and derivatives thereof, and the like.
- other hydroxyl- containing compounds including but not limited to phenols, both substituted and unsubstituted, may be used as the linker.
- the catechol or derivative thereof is dopamine or polydopamine.
- the dopamine derivative may be the methoxy derivative, the 4-ethanol derivative, and the like.
- the doubly conjugated chitosan may be , wherein each of Ri, R2,
- R3, R4 is independently selected from the group consisting of a thiol, an alkane, an alkene, an alkyne, a secondary amine, a nitrile, an aldehyde, an imidazole, an azide, a halide, a polyhexamethylene dithiocarbonate, a hydrogen, a hydroxyl, a carboxylic acid, an aldehyde, a carboxylic ester, an acetyl, a carboxamide, a urea, and a catechol or an analog thereof, provided at least one of Ri, R2, R3, R4 is not a hydrogen atom.
- n represents the number of monomeric units in the chitosan chain and can range from about 1 to about 500.
- the C-2 nitrogen must be at least 50% deacetylated (as per the definition for chitosan) and each monomeric unit may be attached to one of the two conjugation moieties.
- the most likely attachment point for the conjugates is at the deacetylated amines with secondary attachment at the C-3 and C-5 hydroxyls less likely.
- the doubly conjugated chitosan one conjugate will react with a subset of available deacetylated monomers while the second conjugate will react with a subset of the remaining unconjugated, deacetylated monomers.
- the chitosan may undergo a deacetylation reaction such that about 50% to about 100%, about 55% to about 95%, about 60% to about 90%, about 65% to about 85%, about 70% to about 80%, or any time between about 50% to about 100%, of the acetyl groups may be removed, and further, at least two of the groups Ri — R4 may be modified.
- At least one of the groups Ri — R4 may contain a quaternary ammonium, phosphonium or pyridinium functional group, and the chitosan may have between about 1% to about 99%, about 5% to about 90%, about 10% to about 80%, about 15% to about 75%, about 20% to about 70%, about 25% to about 65%, about 30% to about 60%, about 35% to about 55%, about 40% to about 50% quaternization, or any percentage between about 1% to about 99%.
- At least one of the groups Ri — R4 may be a catechol analog providing a pendant dihydroxy benzyl group for potential immobilization onto a substrate.
- a composition comprising a doubly conjugated chitosan polymer or oligomer having a formula: , wherein each of Ri, R2, R3, R4, Rsand R6 is independently selected from the group consisting of a thiol, an alkane, an alkene, an alkyne, a secondary amine, a nitrile, an aldehyde, an imidazole, an azide, a halide, a polyhexamethylene dithiocarbonate, a hydrogen, a hydroxyl, a carboxylic acid, an aldehyde, a carboxylic ester, a carboxamide, a urea, and a catechol or an analog thereof, provided at least one of Ri, R2, R3, R4, Rs and R6 is not a hydrogen atom, wherein
- At least two of Ri to R6 are independently selected from the group consisting of a thiol, an alkane, an alkene, an alkyne, a secondary amine, a nitrile, an aldehyde, an imidazole, an azide, a halide, a polyhexamethylene dithiocarbonate, a hydrogen, a hydroxyl, a carboxylic acid, an aldehyde, a carboxylic ester, a carboxamide, a urea, and a catechol or analog thereof.
- At least one of Ri to R6 is selected from the group consisting of a quaternary ammonium, a quaternary phosphonium or a quaternary pyridinium functional group, and wherein a degree of quaternization of the doubly conjugated chitosan is about 1% to about 99%.
- the chitosan may undergo a deacetylation reaction such that about 50% to about 100%, about 55% to about 95%, about 60% to about 90%, about 65% to about 85%, about 70% to about 80%, or any time between about 50% to about 100%, of the acetyl groups may be removed, and further, at least two of the groups Ri — R4 may be modified.
- At least one of the groups Ri — R6 may contain a quaternary ammonium, phosphonium or pyridinium functional group, and the chitosan may have between about 1% to about 99%, about 5% to about 90%, about 10% to about 80%, about 15% to about 75%, about 20% to about 70%, about 25% to about 65%, about 30% to about 60%, about 35% to about 55%, about 40% to about 50% quaternization, or any percentage between about 1% to about 99%.
- At least one of the groups Ri — R6 may be a catechol analog providing a pendant dihydroxy benzyl group for potential immobilization onto a substrate.
- At least one of Ri to R6 is a catechol or a derivative or an analog thereof, which provides a pendant dihydroxy benzyl group for immobilizing the doubly conjugated chitosan onto a substrate.
- catechol and quaternary ammonium moieties are randomly distributed among available C-2 amine attachment points of the doubly conjugated chitosan polymer or oligomer, and wherein each of q and n ranges from about 1 to about 500.
- the metal is a non-ferrous metal.
- the metal is selected from, but not limited to, Ti, Zr, Hf, V, Nb, Ta, Al, Co, W, Mg, and alloys, oxides and nanoparticle forms thereof.
- the metal is selected from, but not limited to, titanium, titanium oxides, titanium alloys, aluminum, aluminum oxides and aluminum alloys.
- the metal is stainless steel.
- the concentration of the solution of the catechol or derivative thereof is from about 0.1 % to about 20% by weight.
- the concentration of the solution of the catechol or derivative thereof is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or any percentage between about 0.1% and about 20%.
- the voltage applied may range from about 1 V to about 100 V.
- the voltage applied may the voltage applied may be about 1 V, about 2 V, about 3 V, about 4 V, about 5 V, about 6 V, about 7 V, about 8 V, about 9 V, about 10 V, about 11 V, about 12 V, about 13 V, about 14 V, about 15 V, about 16 V, about 17 V, about 18 V, about 19 V, about 20 V, about 21 V, about 22 V, about 23 V, about 24 V, about 25 V, about 26 V, about 27 V, about 28 V, about 29 V, about 30 V, about 31 V, about 32 V, about 33 V, about 34 V, about 35 V, about 36 V, about 37 V, about 38 V, about 39 V, about 40 V, about 41 V, about 42 V, about 43 V, about 44 V, about 45 V, about 46 V, about 47 V, about 48 V, about 49 V, about 50 V, about 51 V, about 52 V, about 53 V, about 54 V,
- the duration of time is from about 1 second to about 60 minutes. In another exemplary embodiment, the duration of time is about 1 second, about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 60 seconds, about 65 seconds, about 70 seconds, about 75 seconds, about 80 seconds, about 85 seconds, about 90 seconds, about 95 seconds, about 100 seconds, about 105 seconds, about 110 seconds, about 115 seconds, about 120 seconds, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 35 minutes, about 40
- the pH of the aqueous buffer is about 6.0 to about 9.5, about 6.0 to about 6.5, about 6.5 to about 7.0, about 7.0 to about 7.5, about 7.5 to about 8.0, about 8.0, about 8.5, about 9, about 9.5, or any pH between about 6.0 and about 9.5, or any range between about 6.0 and about 9.5.
- the dopamine solution comprises from about 1 wt.% to about 50 wt% dopamine with about 1 wt.% to about 20 wt% piperidine in ethanol or methanol, preferably from about 5 wt% to about 45 wt% dopamine with about 5 wt% to about 15 wt% piperidine, from about 10 wt% to about 40 wt% dopamine with about 10 wt% to about 15 wt% piperidine, or any amount of dopamine from about 1 wt% to about 50 wt% dopamine with about 1 wt% to about 20 wt% piperidine within these ranges, including the end point of these ranges.
- ultraviolet radiation is applied for from about 1 minute to about 60 minutes, from about 5 minutes to about 55 minutes, from about 10 minutes to about 50 minutes, from about 15 minutes to about 45 minutes, from about 20 minutes to about 40 minutes, from about 25 minutes to about 35 minutes, or any time between about 1 minute to about 60 minutes, or any time less than about 3 hours, including the end points of these ranges.
- heat is applied for from about 30 minutes to about 1 hour, from about 1 hour to about 2 hours, from about 2 hours to about 4 hours, from about 4 hours to about 6 hours, from about 6 hours to about 8 hours from about 8 hours to about 10 hours, or any time between 30 minutes to 10 hours, including the end points of these ranges.
- the modified chitosan solution comprises oligo-chitosan.
- the oligo-chitosan may be modified at the C-2 amine by addition of quaternary ammonium, phosphonium or pyridinium compounds, and the modified chitosan may be further modified at the C-6 hydroxyl, C-3 hydroxyl or previously unreacted C-2 amines by attachment of dopamine (polydopamine) through which it is immobilized onto a surface.
- dopamine polydopamine
- the oligo-chitosan may be modified at the C-2 amine by addition of quaternary ammonium, phosphonium or pyridinium compounds, and the modified chitosan may be further modified at the C-6 hydroxyl, C-3 hydroxyl or previously unreacted C-2 amines by attachment of 3,4-dihydroxy hydrocinnamic acid through which it is immobilized onto a surface.
- the modified chitosan solution comprises oligo-chitosan modified at the glucosamine monomers with a quaternary phosphonium compound.
- the modified chitosan solution comprising oligo-chitosan is modified with quaternary phosphonium conjugation at available sites, the degree of conjugation being about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, from about 5% to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from about 25% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, or any value within these ranges, including the end points of these ranges.
- the modified chitosan solution comprising quaternized oligo-chitosan further modified with dopamine or analogs thereof at available remaining sites, the degree of conjugation being about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, from about 5% to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from about 25% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, or any value within these ranges, including the end points of these range
- the modified chitosan solution comprises oligo-chitosan modified at the glucosamine monomers with a quaternary ammonium compound.
- the modified chitosan solution comprising oligo-chitosan modified with quaternary ammonium, phosphonium or pyridinium groups at available sites, wherein the percentage of available sites is about 1%, about 2%, about 3%, about 4%, about 5%, from about 5 to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from 25% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, or any value within these ranges, including the end points of these ranges.
- the modified chitosan solution comprising quaternized chitosan additionally modified with dopamine or its analogs thereof, wherein the dopamine or its analogs are conjugated to the modified chitosan at remaining sites available for conjugation, and the percentage of available sites (not conjugated to quarternary ammonium, phosphonium or pyridinium groups) is about 1%, about 2%, about 3%, about 4%, about 5%, from about 5 to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from 25% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, or any value within these ranges, including the end points of these ranges.
- the oligo-chitosan or modified oligo- chitosan is about 5 monomers in length, from about 5 to about 10 monomers in length, from about 10 to about 20 monomers in length, from about 20 to about 30 monomers in length, from about 30 to about 40 monomers in length, from about 40 to about 50 monomers in length, from about 50 to about 60 monomers in length, from about 60 to about 70 monomers in length, from about 70 to about 80 monomers in length, from about 80 to about 90 monomers in length, from about 90 to about 100 monomers in length, from about 100 to about 200 monomers in length, from about 200 to about 300 monomers in length, from about 300 to about 400 monomers in length, from about 400 to about 500 monomers in length, or any value within these ranges, including the end points of these ranges.
- the method further comprises a method of preparing the modified chitosan-containing solution.
- the weight average molecular weight of the oligo-chitosan is from about 100 to about 5000. In another exemplary embodiment, the weight average molecular weight of the oligo-chitosan is about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about
- the pH of the aqueous solution of chitosan is from about 7.5 to about 10. In another exemplary embodiment, the pH of the aqueous solution of chitosan is about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, or any pH between about 7.5 and about 10.
- a quaternized chitosan may be prepared by addition of glycidyl trimethylammonium chloride, to enable a permanent quaternary ammonium functionality.
- the quaternized molecules may be attached to the chitosan monomer’s C-2 amine; alternate molecules may be attached to the same location for additional functionality; different attachment chemistries may be used between the chitosan and the linker, and the like.
- a quaternized chitosan is further modified by conjugation with dopamine or its analogs thereof.
- a dopamine or its analog-linked quaternized chitosan is attached to a metal, its alloy, oxide or nanoparticle form.
- a metal-, alloy-, oxide-, or nanoparticle- bound dopamine or its analog thereof-linked chitosan or oligo-chitosan may be quaternized by conjugation with a quaternary ammonium, pyridinium or phosphonium compound.
- any of the solutions described herein may include a solvent that is selected from, but not limited to, methanol, ethanol, tetrahydrofuran (THF), demethylformamide (DMF), and mixtures thereof.
- a solvent that is selected from, but not limited to, methanol, ethanol, tetrahydrofuran (THF), demethylformamide (DMF), and mixtures thereof.
- FIG. 1 is an infrared spectrum of a dopamine/polydopamine-modified metallic surface according to an exemplary embodiment.
- FIG. 2 is an infrared spectrum of dopamine/polydopamine-modified metallic surface bound by application of ultraviolet radiation.
- FIG. 3 is an infrared spectrum of a chitosan-modified surface according to an exemplary embodiment.
- FIG. 4 is an infrared spectrum of a doubly conjugated chitosan oligomer.
- FIG. 5 shows potency data against a number of bacterial species based on the results of the experimental examples of the subject application.
- first the terms “first,” “second,” and the like are used for describing various components, these components are not confined by these terms. These terms are merely used for distinguishing one component from the other components, and a first component may be a second component in a technical concept of the present disclosure.
- An exemplary embodiment is a method of preparing a modified-metal surface by attaching a catechol or derivative thereof to a surface of a metal, the method comprising: preparing an aqueous or a non-aqueous protic solution of the catechol or derivative thereof in a buffer or organic solvent; adjustment to basic pH or addition of a base; immersing at least a portion of a metal work piece into the solution of the catechol or derivative thereof; supplying a voltage such that the work piece is the anode in an electrochemical circuit for a duration of time to obtain a functionalized metal work piece; and chemically attaching a modified chitosan to the functionalized metal work piece.
- An exemplary embodiment is a method of preparing a modified-metal surface by attaching a doubly modified chitosan or derivative thereof to a surface of a metal, the method comprising: preparing an aqueous or a non-aqueous protic solution of the chitosan or derivative thereof in a buffer or organic solvent; adjustment to basic pH or addition of a base; immersing at least a portion of a metal work piece into the solution of the doubly modified chitosan or derivative thereof; supplying a voltage such that the work piece is the anode in an electrochemical circuit for a duration of time to obtain a functionalized metal work piece.
- An exemplary embodiment is a method of preparing a modified-metal surface by attaching a catechol or derivative thereof-modified chitosan or derivative thereof to a surface of a metal, the method comprising: preparing an aqueous or a non-aqueous protic solution of the modified chitosan or derivative thereof in a buffer or organic solvent; adjustment to basic pH or addition of a base; immersing at least a portion of a metal work piece into the solution of the modified chitosan or derivative thereof; supplying a voltage such that the work piece is the anode in an electrochemical circuit for a duration of time to obtain a functionalized metal work piece and chemically attaching a quaternary ammonium, pyridinium or phosphonium molecule to obtain a functionalized metal work piece.
- Another exemplary embodiment is a method of preparing a modified-metal surface by attaching a catechol or derivative thereof to a surface of a metal, the method comprising: preparing an aqueous or a non-aqueous protic solution of the catechol or derivative thereof in a buffer or organic solvent; adjustment to basic pH or addition of a base; spraying so as to cover the surface of the metal workpiece and exposing the workpiece to ultraviolet light for a duration of time so as to insure chemical attachment to the workpiece to create a functionalized metal workpiece and chemically attaching a modified chitosan to the functionalized metal workpiece.
- Another exemplary embodiment is a method of preparing a modified-metal surface by attaching a doubly modified chitosan or derivative thereof to a surface of a metal, the method comprising: preparing an aqueous or a non-aqueous protic solution of the chitosan or derivative thereof in a buffer or organic solvent; adjustment to basic pH or addition of a base; spraying so as to cover the surface of the metal workpiece and exposing the workpiece to ultraviolet light for a duration of time so as to insure chemical attachment to the workpiece to create a functionalized metal workpiece.
- Another exemplary embodiment is a method of preparing a modified-metal surface by attaching a catechol or derivative-modified chitosan or derivative thereof to a surface of a metal, the method comprising: preparing an aqueous or a non-aqueous protic solution of the modified chitosan or derivative thereof in a buffer or organic solvent; adjustment to basic pH or addition of a base; spraying so as to cover the surface of the metal workpiece and exposing the workpiece to ultraviolet light for a duration of time so as to insure chemical attachment to the workpiece to create a functionalized metal workpiece and chemically attaching a quaternary ammonium, pyridinium or phosphonium molecule to the functionalized metal workpiece.
- Another exemplary embodiment is a method of preparing a modified metal surface by attaching a modified chitosan or derivative thereof to the surface of a metal, the method comprising: preparing an aqueous or non-aqueous solution of a doubly modified chitosan to which has been attached a quaternary ammonium, pyridinium or phosphonium compound and a catechol or derivative thereof, spraying said solution onto the metal surface so as to cover it and baking in an oven with sufficient time and temperature to affect chemical attachment of the quaternized chitosan conjugate to the surface.
- Another exemplary embodiment is a method of preparing a modified metal surface by attaching a modified chitosan or derivative thereof to the surface of a metal, the method comprising: preparing an aqueous or non-aqueous solution of a doubly modified chitosan to which has been attached a quaternary ammonium, pyridinium or phosphonium compound and a catechol or derivative thereof, spraying said solution onto the metal surface so as to cover it and exposing the surface to ultraviolet light for sufficient time to affect chemical attachment of the quaternized chitosan conjugate to the surface.
- Another exemplary embodiment is a method of preparing a modified metal surface by attaching a modified chitosan or derivative thereof to the surface of a metal, the method comprising: preparing an aqueous or non-aqueous solution of a doubly modified chitosan to which has been attached a quaternary ammonium, pyridinium or phosphonium compound and a catechol or derivative thereof, immersing a metal workpiece into the solution and placing it in contact with the anode of an electrochemical cell. Submersing a cathode and applying a voltage sufficient to effect chemical attachment of the chitosan conjugate to the metal workpiece.
- the catechol or derivative thereof is covalently bonded to a surface of the functionalized metal work piece.
- the catechol or derivative thereof- functionalized work piece is activated by the addition of coupling agents know to those in the art to effect carbon-carbon bond formation, carbon-oxygen bond formation, carbon-sulfur bond formation, carbon-nitrogen bond formation, carbon-phosphorous bond formation, carbon-silicon bond formation and the like and to effect attachment or immobilization of additional functional chemical entities such as modified and unmodified chitosan oligomers.
- the fully formed chitosan conjugates are attached to a metal, alloy, oxide or nanoparticle surface.
- the catechol or derivative thereof includes any substituted or unsubstituted catechols, which may be represented by the following formula: , wherein each of Ri, R2, R3, R4and Rs is independently selected from the group consisting of a thiol, a primary amine, a secondary amine, a nitrile, an aldehyde, an imidazole, an azide, a halide, a polyhexamethylene dithiocarbonate, a hydrogen, a hydroxyl, a carboxylic acid, an aldehyde, a carboxylic ester or a carboxamide, provided at least one of Ri, R2, R3,
- R4 and Rs is not a hydrogen atom, wherein a ranges from 0 to 10 and b ranges from 0 to 10, provided that a or b is at least 1.
- the catechol or derivative thereof may include, but is not limited to catecholamines, phenolic aldehydes, tyrosol and derivatives thereof, including hydroxyl-, methoxy- and mixed m ethoxy-hydroxy derivatives of tyrosol, tyramines, and derivatives thereof, including hydroxylated tyramines, dopamines and derivatives thereof, and the like.
- other hydroxyl- containing compounds including but not limited to phenols, both substituted and unsubstituted, may be used as the linker.
- the catechol or derivative thereof is dopamine or polydopamine.
- the dopamine derivative may be the methoxy derivative, the 4-ethanol derivative, and the like.
- the metal is a non-ferrous metal, and may include their respective oxides, alloys and nanoparticle forms.
- the metal may include, but is not limited to, titanium, and its oxides and alloys, aluminum, and its oxides and alloys, vanadium, and its oxides and alloys, zirconium, and its oxides and alloys, hafnium, and its oxides and alloys, niobium, and its oxides and alloys, tantalum, and its oxides and alloys, tungsten, and its oxides and alloys, magnesium, and its oxides and alloys, stainless steel, cobalt chrome, and the like.
- the material to which the catechol, or derivative thereof, is attached is not limited, and may include polymers, biological polymers, ceramics, and the like.
- the concentration of the solution of the catechol or derivative thereof is from about 0.1 % to about 20% by weight. In another exemplary embodiment, the concentration of the solution of the catechol or derivative thereof is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or any percentage between about 0.1% and about 20%.
- the voltage applied may range from about 1 V to about 100 V.
- the voltage applied may the voltage applied may be about 1 V, about 2 V, about 3 V, about 4 V, about 5 V, about 6 V, about 7 V, about 8 V, about 9 V, about 10 V, about 11 V, about 12 V, about 13 V, about 14 V, about 15 V, about 16 V, about 17 V, about 18 V, about 19 V, about 20 V, about 21 V, about 22 V, about 23 V, about 24 V, about 25 V, about 26 V, about 27 V, about 28 V, about 29 V, about 30 V, about 31 V, about 32 V, about 33 V, about 34 V, about 35 V, about 36 V, about 37 V, about 38 V, about 39 V, about 40 V, about 41 V, about 42 V, about 43 V, about 44 V, about 45 V, about 46 V, about 47 V, about 48 V, about 49 V, about 50 V, about 51 V, about 52 V, about 53 V, about 54 V,
- voltage is applied for a duration of time from about 1 second to about 60 minutes.
- the duration of time is about 1 second, about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 60 seconds, about 65 seconds, about 70 seconds, about 75 seconds, about 80 seconds, about 85 seconds, about 90 seconds, about 95 seconds, about 100 seconds, about 105 seconds, about 110 seconds, about 115 seconds, about 120 seconds, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any duration of time between about 1 second and
- the pH of the buffer is about 7.5, about 8.0, about 8.5, about 9, about 9.5, or any pH between about 7.5 and about 9.5.
- the method further comprises cleaning and drying of the functionalized surface.
- the method further comprises drying of the functionalized surface under vacuum or under an inert or non-reactive atmosphere.
- the inert atmosphere is nitrogen or argon.
- the functionalized metal work piece in the imidazole solution is stirred for about 1 hour to about 10 hours.
- the stirring is carried out for about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, or any duration of time between about 1 hour and 10 hours.
- the modified chitosan solution comprises oligo-chitosan.
- the oligo-chitosan may be modified at the C-2 amines of the monomer units thereof by addition of quaternary ammonium, pyridinium or phosphonium compounds, and modified chitosan may be further modified at the C-6 hydroxyl, the C-3 hydroxyl or C-2 amines by attachment of dopamine (polydopamine) or analogs thereof through which it is immobilized onto a surface.
- the modified chitosan solution comprises oligo- chitosan modified at the glucosamine monomers with a quaternary phosphonium compound.
- the modified chitosan solution comprising oligo- chitosan modified with quaternary phosphonium conjugation at available sites the degree of conjugation being about 1%, about 2%, about 3%, about 4%, about 5%, from about 5 to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from 25% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, or any value within these ranges, including the end points of these ranges.
- the modified chitosan solution comprises oligo- chitosan modified at the glucosamine monomers with a quaternary ammonium, phosphonium or pyridinium compound.
- the modified chitosan solution comprising oligo- chitosan modified with quaternary ammonium, phosphonium or pyridinium conjugation at available sites the degree of which is about 1 %, about 2%, about 3%, about 4%, about 5%, from about 5 to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from 25% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, or any value within these ranges, including the end points of these ranges.
- the oligo-chitosan or modified oligo-chitosan is about 5 monomers in length, from about 5 to about 10 monomers in length, from about 10 to about 20 monomers in length, from about 20 to about 30 monomers in length, from about 30 to about 40 monomers in length, from about 40 to about 50 monomers in length, from about 50 to about 60 monomers in length, from about 60 to about 70 monomers in length, from about 70 to about 80 monomers in length, from about 80 to about 90 monomers in length, from about 90 to about 100 monomers in length, from about 100 to about 200 monomers in length, from about 200 to about 300 monomers in length, from about 300 to about 400 monomers in length, from about 400 to about 500 monomers in length, or any value within these ranges, including the end points of these ranges.
- the method further comprises a method of preparing the modified chitosan-containing solution.
- the weight average molecular weight of the oligo-chitosan is from about 100 to about 5000.
- the weight average molecular weight of the oligo-chitosan is about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about
- the pH of the aqueous solution of chitosan is from about 7.5 to about 10. In another exemplary embodiment, the pH of the aqueous solution of chitosan is about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, or any pH between about 7.5 and about 10.
- a quaternized chitosan may be prepared by addition of glycidyl trimethylammonium chloride, to enable a permanent quaternary ammonium functionality.
- Alternate quaternized molecules may be attached to the chitosan monomer’s C-2 amine, C-3 hydroxyl or C-6 hydroxyl; alternate molecules may be attached to the same location for additional functionality; different attachment chemistries may be used to immobilize the modified oligo-chitosan to the functionalized surface, and the like.
- any of the solutions described herein may include a solvent selected from, but not limited to, methanol, ethanol, tetrahydrofuran (THF), demethylformamide (DMF), and mixtures thereof.
- a solvent selected from, but not limited to, methanol, ethanol, tetrahydrofuran (THF), demethylformamide (DMF), and mixtures thereof.
- Catechol is a phenol derivative that includes an additional hydroxyl group, and has the following chemical structure:
- Dopamine is a substituted catechol having an ethylamine group as a substituent, and has the following chemical structure:
- Catechol, and catechol derivatives such as dopamine attach to metal surfaces by forming covalent bonds with the ring oxygens.
- the dangling amine branch of the dopamine can then stabilize the attached molecule by participating in dopamine polymerization to form polydopamine on the surface.
- Some amines are available to be further reacted with desired molecules to impart surface functionality.
- the utility of such molecules is that they can contain functional groups which can be further modified. This allows for the installation of a variety of chemistries onto the distal end of these molecules. Thus, covalent attachment of these molecules followed by installation of custom chemistries is tantamount to the covalent attachment of said chemistries onto the surface.
- Such functional groups may include, but are not limited to, a substituted or unsubstituted hydroxyl, a substituted or unsubstituted amine, a substituted or unsubstituted ester, a substituted or unsubstituted thiol, a substituted or unsubstituted ether, a substituted or unsubstituted phosphonic acid ester, a substituted or unsubstituted phosphinic acid ester, a substituted or unsubstituted phosphoric acid ester, a substituted or unsubstituted carboxylate, a substituted or unsubstituted acrylate, a substituted or unsubstituted sulfonate, a substituted or unsubstituted sulfinate, a substituted or unsubstituted sulfoxide, a substituted or unsubstituted silane, a substituted or unsubstituted siloxan
- surfaces can be made to be hydrophobic, hydrophilic, oleophobic, lubricious, antimicrobial, and the like. Surfaces may also be made to either enhance or attenuate the effectiveness of adhesives. Further, proteins and protein fragments, amino acids (both natural and synthetic), and peptides may be attached to enhance or attenuate a desired physical, chemical or biological response.
- dopamine or polydopamine is covalently bonded to metallic surfaces, which leaves the amine moieties of the dopamine molecule available on the surface for further functionalization.
- Urethane or urea formation was chosen as the binding chemistry to attach modified chitosan to the polydopamine.
- carbonyl diimidazole (CDI) in methylene chloride was chosen for the activation chemistry to allow the activated amine of dopamine to couple with the C-6 hydroxyl or unreacted C-2 amines of the modified chitosan.
- CDI carbonyl diimidazole
- Other, more environmentally benign coupling chemistries can be used.
- the final step in the process is attachment of modified chitosan to the CDI- activated polydopamine surface.
- the modified chitosan (HTCC) is coupled to the CDI- activated polydopamine surface to impart antimicrobial properties to the surface.
- the most likely point of attachment is shown to be C-2 amines that did not become quaternized in the formation of HTCC. This completes the construction of a compositionally unique antimicrobial surface.
- n represents the number of quaternized monomeric units numbering from about 1 to about 500 and m represents the number of remaining deacetylated unquaternized monomeric units attached to the dopamine surface from about 1 to about 500.
- the first schematic representation above is provided for clarity and should not be construed to be limited to quaternized positions that alternate with dopamine attachment points in a regular pattern, but may also include different chemical environments of the C-2 amines of the chitosan monomers that are randomly distributed between quaternized, dopamine-attached, acetylated and deacetylated sites.
- n represents the number of quaternized monomeric units from about 1 to about 500
- m represents the number of unquaternized, deacetylated monomeric units available for conjugation from about 1 to about 500
- q represents the number of catechol-derivatized monomeric units from about 1 to about 500.
- the second schematic representation above is provided for clarity and should not be construed as being limited to quaternized positions that alternate with cinnamic acid attachment points in a regular pattern, but may also include different chemical environments of the C-2 amines of the chitosan monomers that are randomly distributed between quaternized, cinnamic acid-attached, acetylated and deacetylated sites.
- the fully formed doubly conjugated chitosan is synthesized prior to immobilization onto a metal surface.
- the catechol-pendant HTCC can be isolated and stored until needed adding to the convenience of this method.
- HTCC can be synthesized as described above and in the literature.
- the second conjugation couples HTCC to 3,4-dihydroxy hydrocinnamic acid via the well know EDC/NHS coupling to form an amide linkage.
- Immobilization to a metal surface can be achieved by the methods previously described, i.e., baking, anodization or photografting.
- the prepared workpiece is then analyzed using standard analysis techniques, including, but not limited to, infrared (IR) spectroscopy, contact angle, X-ray Photoelectron Spectroscopy (XPS), Energy-Dispersive X-ray Spectroscopy (EDX), Atomic Force Microscopy (AFM), Time-of-Flight Secondary Ion Mass Spectrometry (Tof-SIMS), Coefficient of Friction (COF) studies, and combinations thereof.
- IR infrared
- XPS X-ray Photoelectron Spectroscopy
- EDX Energy-Dispersive X-ray Spectroscopy
- AFM Atomic Force Microscopy
- Tof-SIMS Time-of-Flight Secondary Ion Mass Spectrometry
- COF Coefficient of Friction
- EXAMPLE 1 MODIFICATION OF METALLIC SURFACES WITH DOPAMINE
- IR infrared
- EXAMPLE 2 PHOTOGRAFTING DOPAMINE ONTO TITANIUM SURFACE
- the metallic coupons with dopamine attached to the surface thereto were immersed in a solutions of 250 ml CH2CI2 and 3 g CDI, and stirred for 4 hours at room temperature at a stirring rate of 400 rpm to 500 rpm.
- the coupons were removed from the CH2CI2/CDI solution and rinsed with acetone, followed by sonication in acetone for 10 min. The rinsing processing was repeated. The coupons were then dried under vacuum.
- EXAMPLE 4 ATTACHMENT OF CHITOSAN OLIGOMERS
- the final step in the process is attachment of modified chitosan to the CDI- activated polydopamine surface.
- the isolated product is an oligo-chitosan having an average MW of about 2000.
- the isolated oligo- chitosan was quaternized via a reaction between the C-2 amine of the glucosamine monomers and glycidyl trimethylammonium chloride to yield the modified chitosan product. This product is then coupled to the CDI-activated polydopamine surface.
- a 1 wt% solution of N-4 in DMSO was prepared. Coupons with the CDI- activated polydopamine surfaces were laid flat in an array and sprayed with the N- 4/DMSO solution, and heated for about 10 minutes at 100°C. The coupons were flipped over, and the process was then repeated. The entire process was repeated for at least two spray/heat cycles for each side. After the final spraying step, the modified coupons were heated for about 4 hours at about 100°C, followed by sonication in ethanol for 10 minutes. The characteristics of the surface after attachment of the modified chitosan was confirmed with infrared (IR) spectroscopy. The resulting IR spectrum is shown in FIG. 3.
- IR infrared
- FIG. 3 shows many of the peaks characteristic of chitosan and oligo-chitosan.
- the broad peaks around 3277 cm 1 are indicative of N-H and O-H stretching, and C-H stretching is indicated by the broad peak around 2869 cm 1 .
- Residual acetyl carbonyl stretching is shown at 1662 crrr 1 and 1376 crrr 1 .
- 1476 crrr 1 is indicative of angular bending of the methyl groups of the quaternary ammonium center.
- Other characteristic peaks are seen at 1151 cm 1 and 1085 cm -1 correspond to C-O-C and C-0 stretching, respectively.
- EXAMPLE 5 FORMATION OF DOUBLY CONJUGATED CHITOSAN
- EDC 1,2-ethyl-3-(dimethylaminopropyl) carbodiimide
- NHS N- hydroxysuccinimide
- EXAMPLE 6 SURFACE ATTACHMENT OF HyCnQ
- HyCnQ dopamine-quaternized chitosan solution
- DMSO dopamine-quaternized chitosan solution
- Coupons were horizontally placed on the plate to improve the thickness uniformity of coating, then reacted in an oven at 100 °C for 20 minutes. Coupons were removed from the oven and sprayed one more and heated an additional 4 hours in vacuo. In the case of coupons, each side was treated as described above. Coupons were sonicated in EtOH for 5 minutes and dried in vacuo.
- TSB tryptic soy broth
- 10 mL of tryptic soy broth (TSB) was inoculated with a single colony of the test organism and incubated overnight at 35 ⁇ 2°C in a shaking incubator at 250 rpm.
- the overnight culture was subcultured into 3 mL TSB and incubated at 35 ⁇ 2°C and 250 rpm until the optical density at 600 nm reached between 0.5 and 0.7.
- Coupon Preparation Test coupons were prepared as described in Examples 1 to 4. Control and test coupons were sterilized in 70% EtOH for 10 minutes and dried for 10 minutes in a laminar flow hood and transferred to the wells of a 24-well plate. [0176] EXPERIMENTAL EXAMPLE 1 - ASTM E2149 WITH LOW-VOLUME MODIFICATION
- Control and test coupons were incubated with 500 pL bacterial inoculum for 1 hour at 35 ⁇ 2°C and 250 rpm. Bacterial concentrations were determined by performing serial dilutions with stasis buffer and using the Miles and Misra method to determine the number of colony forming units (CFU) per milliliter. All experiments were conducted in triplicate and the log reduction in the average CFU/mL was determined by the following equation:
- Table 1 lists potency of treated surfaces versus control against staph aureus (MSSA). As shown in Table 1 , in ASTM 2149 as described above, untreated coupons returned on average 2.3 x 10 6 CFU/ml, treated coupons against MSSA returned zero bacteria for a reduction of 5+ logs or better than 99.999 %. [0180] Table 1
- FIG. 5 shows the potency of bound dopamine — N4 against a bacteria panel.
- MST20-001 was assayed against a variety of bacterial species in the same manner as outlined in Experimental Example 1.
- the various species assayed against MST20-001 are listed on the left of FIG. 5, and the scale on the bottom tracks log reduction versus control (untreated coupons). For example, in the example above the treated samples returned zero bacteria versus 2.34 E+6 cfu/ml on the controls. Taking into account the initial inoculation, this translates to ⁇ 5 logs of killing that can be attributed to the treated coupons.
- These data correspond to the bar (for S. aureus) across the top of the graph.
- the arrow at the right of the data bar indicates that zero bacteria were returned from the treated samples and so the potency of the treatment was at least 5 logs.
- MRSA, S. epidermidis, and L monocytogenes all returned zero bacteria in the 2149 assay.
- potency was less than 2 logs or between 90 and 99 percent effective.
- E. faecium was reduced by more that 3 logs or greater than 99.9%, while P. aeruginosa and S. enterica were reduced by 99.9% or by three logs.
- EXPERIMENTAL EXAMPLE 2 - AUTOCLAVE TESTS Control and test coupons were placed in Chex-AII II instant sealing sterilization pouches and autoclaved at 121°C for 30 minutes (Model HA-300MII, Hirayama Manufacturing Corp., Tokyo, Japan). After each cycle, coupons that were to be autoclaved for more cycles were allowed to cool for about 10 minutes before being transferred to new sterilization pouches. The ASTM E2149 protocol described previously was followed. The results are shown in Table 2, which lists sterilizing testing data based on the results of the experimental examples of the subject application. [0185] Table 2
- Coupon Preparation Test coupons were prepared as described in Examples 5 to 6. Control and test coupons were sterilized in 70% EtOH for 10 minutes and dried for 10 minutes in a laminar flow hood and transferred to the wells of a 24-well plate. [0188] EXPERIMENTAL EXAMPLE 3 - ASTM E2149 WITH LOW-VOLUME MODIFICATION
- Table 3 lists potency of treated surfaces versus control against staph aureus. As shown in Table 1, in ASTM 2149 as described above, untreated coupons returned on average 2.3 x 10 6 CFU/ml, treated coupons against MSSA returned zero bacteria for a reduction of 6+ logs or better than 99.9999 %.
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