WO2004009253A1 - Liberation localisee en surface d'un agent anti-encrassement biologique par l'intermediaire de micro-compositions - Google Patents

Liberation localisee en surface d'un agent anti-encrassement biologique par l'intermediaire de micro-compositions Download PDF

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Publication number
WO2004009253A1
WO2004009253A1 PCT/US2003/022511 US0322511W WO2004009253A1 WO 2004009253 A1 WO2004009253 A1 WO 2004009253A1 US 0322511 W US0322511 W US 0322511W WO 2004009253 A1 WO2004009253 A1 WO 2004009253A1
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sol
substrate
gel
biofouling
group
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PCT/US2003/022511
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English (en)
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Mark H. Schoenfisch
Mary E. Robbins
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University Of North Carolina At Chapel Hill
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Priority to AU2003252033A priority Critical patent/AU2003252033A1/en
Publication of WO2004009253A1 publication Critical patent/WO2004009253A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114—Nitric oxide, i.e. NO
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D5/00—Processes for applying liquids or other fluent materials to surfaces to obtain special surface effects, finishes or structures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D5/00—Processes for applying liquids or other fluent materials to surfaces to obtain special surface effects, finishes or structures
    • B05D5/08—Processes for applying liquids or other fluent materials to surfaces to obtain special surface effects, finishes or structures to obtain an anti-friction or anti-adhesive surface

Definitions

  • MICROPATTERNING which were filed July 19, 2002 and August 5, 2002, respectively, and are incorporated herein by reference in their entireties.
  • the presently claimed subject matter relates to substrates adapted for both in situ and in vivo applications. More specifically, the presently claimed subject matter relates to methods and compositions for imparting surface- localized release of an anti-biofouling agent on a substrate, and to a substrate itself.
  • the method comprises applying an anti-biofouling agent to a substrate in a pre-determined pattern, wherein the anti-biofouling agent comprises: (a) a nitric oxide (NO) donor moiety; and (b) a matrix adapted to release the NO in a controlled release profile.
  • the anti-biofouling agent comprises: (a) a nitric oxide (NO) donor moiety; and (b) a matrix adapted to release the NO in a controlled release profile.
  • the predetermined pattern is a microarrayed pattern.
  • the matrix can comprise a sol-gel.
  • the sol-gel can comprise an aminosilane, an organosilane, or a combination thereof.
  • the aminosilane is present in an amount up to 100% of total silane.
  • the sol-gel can also comprise a composition having the general formula (R 1 ) n -Si-(R 2 ) 4-n , where R 1 and R 2 are the same or different and are selected from the group consisting of hydrogen, amino, alkyl, alkylamino, alkoxy, alkenyl, alkenylamino, alkenoxy, alkynyl, alkynlamino, alkynoxy, aryl, arylarriino, aryl ⁇ xy, arid combinations thereof, and where ri is 1 , 2, 3, or 4.
  • the substrate can be implanted at an implant site in a subject or be used for in situ applications.
  • Figures 1A-1C are schematic diagrams of sol-gel micropatterning methods based on polymeric polydimethylsiloxane (PDMS) templates created from silicon wafers prepared by photolithography ( Figure 1A).
  • the elastomeric template is placed in contact with a substrate, creating a series of microchannels on the surface ( Figure 1 B).
  • Sol droplets are placed at one end of the template and are drawn into microchannels by capillary flow.
  • the sol-gel pattern is allowed to dry for 24 hours before template removal.
  • droplets of sol solution can be placed directly on a surface.
  • the template is then placed on top of solution and pressure is applied to displace sol and allow for contact between template and surface ( Figure 1C).
  • the template is removed after formation and drying of sol-gel for 24 hours.
  • Figures 2A-2D are contact mode atomic force microscopy (AFM) images of 20% (aminoethylaminomethyl)-phenylethyl-trimethoxysilane (AEMP3)/methyltrimethoxysilane (MTMOS; i.e., AEMP3 comprises 20% of total silane) sol-gel micropatterns on glass.
  • AFM atomic force microscopy
  • Substrates in Figures 2A and 2B were fabricated using applied pressure.
  • Substrates in Figures 2C and 2D were fabricated by capillary flow. Horizontal cross sections were used to determine feature dimensions.
  • Figure 3 presents a series of reaction schemes for sol-gel preparation and diazeniumdiolate formation upon exposure to high pressures of NO.
  • Schemes 1 and 2 represent the two-step sol-gel formulation involving condensation and hydrolysis reactions, respectively.
  • Schemes 3 and 4 illustrate formation of diazeniumdiolate structure, which upon submersion in aqueous solution decomposes to release NO and reform the diamine precursor.
  • Figure 4 is a plot of real-time NO (in parts per billion - ppb; time in minutes - min.) released from a 20% AEMP3/MTMOS sol-gel micropattem.
  • Figures 5A-5C are contact mode AFM images used to characterize the stability of 20% AEMP3/MTMOS sol-gel pattern on glass before pressurizing (Figure 5A); after pressurizing to 5 atmospheres (atm) NO for 60 hours ( Figure 5B); and after immersion in buffer for 3 days (Figure 5C).
  • Figures 6A-6D are schematic representations of cell adhesion to homogeneously NO-releasing sol-gel film (Figure 6A); closely- (Figure 6B); medium- (Figure 6C); and widely spaced NO-releasing microstructures (Figure 6D).
  • Figures 7A and 7B are scanning electron microscopy (SEM) images of porcine platelet adhesion (light) to sol-gel micropattem control ( Figure 7A) and NO-releasing sol-gel micropattem ( Figure 7B).
  • Sol-gel 20% AEMP3/MTMOS.
  • NO nitric oxide
  • reducing both platelet and bacterial adhesion, and thus surface induced thrombosis and bacterial infections can improve the biocompatibility of medical implants.
  • the release of nitric oxide (NO) from polymers has been highly effective toward improving the thromboresistivity of blood-contacting devices (Smith et al., 1996; Hanson et al., 1995; Mowery et al., 2000; Schoenfisch et al., 2000; Espadas-Torre et al., 1997) and reducing bacterial adhesion and biofilm formation in vitro (Nablo et al., 2001).
  • Micropatterning techniques offer a novel approach for designing surfaces that release NO while retaining functionality for other applications (e.g., sensors).
  • micropatterned NO-releasing materials based on aminosilane-containing sol- gels.
  • the stability of sol-gel micropatterns under both solution and high-pressure conditions is assessed using atomic force microscopy (AFM).
  • AFM atomic force microscopy
  • Heterogeneously modified substrates are further characterized both with respect to NO release kinetics and in vitro platelet adhesion.
  • In vitro studies indicate that micropatterned sol-gels are capable of releasing NO from distinct regions on a substrate and effectively reducing biofouling L Definitions
  • controlled release profile refers to administration of an active agent such as NO in a pre-selected manner, wherein the temporal features and dose of agent release are predictable.
  • a short continual controlled release profile can be provided.
  • a controlled release profile characterized by an initial surge in release followed by a trailing off of the release can be provided.
  • a controlled release profile characterized by long-term continual controlled release of NO can be provided.
  • subject refers to any proposed recipient of an implant.
  • Contemplated subjects include warm-blooded vertebrates, including mammals such as humans, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economic importance (animals raised on farms for consumption by humans), and/or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), and horses.
  • domesticated fowl for example, poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans.
  • livestock including, but not limited to domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like.
  • biocompatible is used herein to refer to a material or implant that is compatible with a biological system, such as that of a subject as defined herein.
  • biocompatible also refers to a material or substrate that can be implanted internally in a subject, wherein the material or substrate has been adapted to resist biofouling as defined herein, such as by treatment with an anti-biofouling agent.
  • biofouling refers to undesirable contamination of a substrate (e.g., an implantable substrate) by a biological agent.
  • the presently claimed subject matter can encompass biofouling of any substrate by any biological agent (in vivo and in vitro).
  • Representative forms of biofouling include, but are not limited to protein adhesion, platelet adhesion, and microbial adhesion.
  • Representative microbial species include any commonly associated with implant biofouling, such as, but not limited to, Escherichia coli, Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus mutans, Bacillus cereus, Rhodobacter sphaeroides, and Pseudomonas aeruginosa.
  • implant biofouling such as, but not limited to, Escherichia coli, Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus mutans, Bacillus cereus, Rhodobacter sphaeroides, and Pseudomonas aeruginosa.
  • thrombosis is used herein to refer to the aggregation of platelets to form a dense network of cells or a thrombus (blood clot).
  • thromboresistant is used herein to refer to a material or implant that is resistant to biofouling caused by platelet adhesion and subsequent thrombus formation in vitro and/or in vivo.
  • micro micro
  • microscopic micrometer-sized
  • microstructured can be structures ranging in size from about 1 to 1000 ⁇ m, including 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 50, 100, 500 and 750 ⁇ m, as well as intermediate values.
  • a microparticle can have any diameter less than or equal to 1000 ⁇ , including 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 50, 100, 500 and 750 ⁇ m.
  • a microstructure comprising a nitric oxide donor moiety is provided in accordance with the presently claimed subject matter.
  • Nitric oxide a diatomic free radical naturally synthesized in subjects when L-arginine is converted to L-citrulline (Moncada et al., 1993), serves multiple bioregulatory processes in the cardiovascular, respiratory, gastrointestinal, genitourinary, and central and peripheral nervous systems (Marietta et al., 1990).
  • the specific function of NO is regulated by both the location of release and the local amounts generated.
  • the properties of NO that are believed to be beneficial in developing more biocompatible implants include its involvement in the regulation of platelet activation and aggregation and macrophage-induced phagocytosis.
  • NO release from diazemiumdiolate-containing materials can reduce platelet adhesion by mimicking the endothelium NO-release of healthy blood vessels (Diodati et al, 1993; Radomski et al., 1992; Hanson et al., 1995; Smith et al., 1996).
  • an anti-biofouling agent comprises: (a) a nitric oxide (NO) donor moiety; and (b) a matrix adapted to release NO in a controlled release profile.
  • a matrix composition provides for the controlled release of NO in an in vivo or other desired setting.
  • a representative NO donor moiety comprises a diazeniumdiolate moiety ( Figure 3, Scheme 2)
  • Diazeniumdiolates are stable at low temperatures in the absence of hydrogen donors (e.g., water). While stable under ambient conditions, diazeniumdiolates undergo spontaneous (non-enzymatic) generation of NO in aqueous solution as shown in Figure 3, Scheme 3. The rate of this type of NO release is tunable by varying the pH, temperature, environment, and/or amine precursor structure. Depending on the particular structure of the amine precursor, the aqueous solution half-lives of diazeniumdiolates at pH 7.4 and 37°C range from less than one minute to several days. Background research efforts concerning diazeniumdiolates are disclosed in Maragos et al., 1991 ; Hrabie et al., 1993; and Hrabie & Keefer, 2002.
  • a matrix composition comprises a sol-gel.
  • Sol-gels are materials that can be made at low-temperatures from alkoxide precursors and water. Sol-gel preparation processes can generally be divided into the following four categories: mixing (to form a solution), gelation, aging, and drying.
  • an alkoxide precursor is mixed with water, a catalyst (acid or base), and a mutual solvent such as methanol or ethanol, to form a solution (the sol).
  • Hydrolysis results in the formation of silanol groups (Si-OH; Figure 3, Scheme 1), which cross-react further with either silanol groups or ester groups to form siloxane polymers where R is an alkoxy group (e.g., methoxy or ethoxy group), for example, and R' can be an amino moiety, for example ( Figure 3, Scheme 2).
  • R is an alkoxy group (e.g., methoxy or ethoxy group), for example, and R' can be an amino moiety, for example ( Figure 3, Scheme 2).
  • Polycondensation reactions then lead to the formation of polymeric gel. During aging, polycondensation reactions continue, thereby increasing the tensile strength and density of the gel.
  • sol-gel materials capable of generating NO atNariable rates and amounts (without concomitant leaching) is thus provided herein.
  • a range of diazeniumdiolate-containing sol-gels has been synthesized using various processing conditions, silicon alkoxide precursors, and silicon amino-alkoxides (also referred to herein as alkoxysilanes and aminosilanes respectively).
  • sol-gels were prepared in a 2-step synthesis involving the pre-hydrolysis of the alkoxysilane (by combining appropriate amounts of the alkoxysilane, water, co-solvent, and catalyst), followed by the addition of aminosilane.
  • the amine functional groups in the dried sol-gel were converted to diazeniumdiolates by exposure to high pressures of NO (about 5 atmospheres (atm) for 60-72 hours; Keefer et al., 1996) as shown in Figure 3, Scheme 2.
  • Diazeniumdiolate formation was confirmed by the presence of a characteristic peak at 235-250 nm in the UV-Vis spectra of sol-gels spin- coated onto quartz slides.
  • the sol-gel comprises an aminosilane.
  • the aminosilane can be selected from the group consisting of a monoalkoxysilane, a dialkoxysilane, a trialkoxysilane, and combinations thereof.
  • the incorporation of an aminosilane into a silicon-based sol-gel matrix allows for modification of the material to controllably release NO. Exposing diamine groups to high pressures of NO under anaerobic conditions results in the formation of diazeniumdiolates X[N(O)NO] " as shown in Figure 3.
  • aminosilanes can also be combined with a suitable cross-linking agent such as an organosilane (e.g., methyltrimethoxysilane (MTMOS)), ethanol, and water.
  • a suitable cross-linking agent such as an organosilane (e.g., methyltrimethoxysilane (MTMOS)), ethanol, and water.
  • suitable cross-linking agent such as an organosilane (e.g., methyltrimethoxysilane (MTMOS)
  • MTMOS methyltrimethoxysilane
  • AEMP3 aminoethylaminomethyl
  • MTMOS methyltrimethoxysilane
  • AHAP3 N-(6-aminohexyl)aminopropyltrimethoxysilane
  • DET3 (3-trimethoxysilylpropyl)diethylenetriamine
  • BTMOS isobutyltrimethoxysilane
  • aminosilane component of a sol-gel of the presently claimed subject matter is present in an amount up to 100% of the total silane. Particular percentages are chosen for a variety of reasons, including increasing or decreasing viscosity of the sol-gel material and/or providing for more or less NO donor moiety, depending on the desired controlled release profile.
  • a sol-gel comprises a composition having the general formula (I):
  • R 1 and R 2 can be the same or different and can comprise hydrogen, amino, alkyl, alkylamino (including primary, secondary and tertiary amines), alkoxy, alkenyl, alkenylamino (including primary, secondary and tertiary amines), alkenoxy, alkynyl, alkynlamino (including primary, secondary and tertiary amines), alkynoxy, aryl, arylamino (including primary, secondary and tertiary amines), or aryloxy groups as defined herein below, and combinations thereof, and where n is 1 , 2, 3, or 4.
  • composition can be referred to as an "organosilane".
  • an amino group is present, whether as a substituent on the longest carbon chain or as a constituent of the longest carbon chain, the compound is also referred to herein as an “aminosilane", as noted above.
  • Alkyl refers to an aliphatic hydrocarbon group wh ⁇ cTTcari be straight or branched having 1 to about 60 carbon atoms in the chain.
  • the alkyl group can be optionally substituted with one or more alkyl group substituents, which can be the same or different, where "alkyl group substituent” includes halo, amino, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxy, alkoxycarbonyl, oxo, cycloalkyl, and sila (Si).
  • alkyl chain There can be optionally inserted along the alkyl chain one or more oxygen, silicon, sulphur, or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is lower alkyl.
  • nitrogen substituent is lower alkyl.
  • alkyl can also be described as an "alkylamino".
  • Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, serf-butyl, te ⁇ f-butyl, n-pentyl, heptyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and hexadecyl.
  • Exemplary alkyl groups include, but are not limited to branched or straight chain alkyl groups of 6 to 50 carbons, and also include the lower alkyl groups of 1 to about 4 carbons and the higher alkyl groups of about 12 to about 16 carbons.
  • Alkenyl refers to an alkyl group containing at least one carbon- carbon double bond.
  • the alkenyl group can be optionally substituted with one or more "alkyl group substituents".
  • Exemplary alkenyl groups include vinyl, allyl, n-pentenyl, decenyl, dodecenyl, tetradecadienyl, heptadec-8-en- 1-yl, and heptadec-8,11-dien-1-yl.
  • Alkenoxy forms of alkenyls as defined herein are also provided. When an amino group is present the "alkenyl" or “alkenoxy” can also be described as an "alkenylamino" or "alkenoxyamino".
  • Alkynyl refers to an alkyl group containing a carbon-carbon triple bond.
  • the alkynyl group can be optionally substituted with one or more "alkyl group substituents".
  • Exemplary alkynyl groups include ethynyl, propynyl, n- pentynyl, decynyl, and dodecynyl.
  • Exemplary alkynyl groups include the lower alkynyl groups.
  • Alkynoxy forms of alkynyls as defined herein also provided. When an amino group is present the "alkynyl" or “alkynoxy” can also be described as " an "alky ⁇ ylarriiri ⁇ ” or "alkyn ⁇ xyarriiri ⁇ ”;
  • Cycloalkyl refers to a non-aromatic mono- or multicyclic ring system of about 4 to about 10 carbon atoms.
  • the cycloalkyl group can be optionally partially unsaturated.
  • the cycloalkyl group can be also optionally substituted with an aryl group substituent, oxo, and/or alkylene.
  • Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl.
  • Exemplary multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl.
  • Aryl refers to an aromatic carbocyclic radical containing about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more aryl group substituents which can be the same or different, where "aryl group substituent” includes alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, carboxy, aroyl, halo, nitro, trihalomethyl, cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxy, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and --NRR', where R and R' are each independently hydrogen, alkyl, aryl, and aralkyl.
  • acyl refers to an alkyl-CO- group wherein alkyl is as previously described.
  • exemplary acyl groups comprise alkyl of 1 to about 30 carbon atoms.
  • Exemplary acyl groups also include acetyl, propanoyl, 2- methylpropanoyl, butanoyl, and palmitoyl.
  • “Aroyl” refers to an aryl-CO- group wherein aryl is as previously described.
  • Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
  • Alkoxy refers to an alkyl-O-- group wherein alkyl is as previously described.
  • Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, sec-butoxy, terf-butoxy, and heptoxy.
  • the alkoxy group can be optionally substituted with one or more "alkyl group substituents".
  • an amino i group is Tpreserit the '"alkoxy" cafTa ⁇ so be described as " an "alkoxyamino”.
  • Aryloxy refers to an aryl-O- group wherein the aryl group is as previously described.
  • Exemplary aryloxy groups include phenoxy and naphthoxy.
  • the aryloxy group can be optionally substituted with one or more "aryl group substituents”.
  • When an amino group is present the "aryloxy” can also be described as an "aryloxyamino”.
  • Alkylthio refers to an alkyl-S- group wherein alkyl is as previously described.
  • exemplary alkylthio groups include methylthio, ethylthio, i- propylthio, and heptylthio.
  • Arylthio refers to an aryl-S-- group wherein the aryl group is as previously described.
  • Exemplary arylthio groups include phenylthio and naphthylthio.
  • Alkyl refers to an aryl-alkyl- group wherein aryl and alkyl are as previously described.
  • exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
  • Alkyloxy refers to an aralkyl-O-- group wherein the aralkyl group is as previously described.
  • An exemplary aralkyloxy group is benzyloxy.
  • Alkylthio refers to an aralkyl-S-- group wherein the aralkyl group is as previously described.
  • An exemplary aralkylthio group is benzylthio.
  • Dialkylamino refers to an --NRR' group wherein each of R and R' is independently an alkyl group as previously described.
  • Exemplary dialkylamino groups include ethylmethylamino, dimethylamino, and diethylamino.
  • Alkoxycarbonyl refers to an alkyl-O-CO- group.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.
  • Aryloxycarbonyl refers to an aryl-O-CO- group.
  • exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
  • Aralkoxycarbonyl refers to an aralkyl-O--CO-- group.
  • An exemplary aralkoxycarbonyT group is benzyloxycarbonyl.
  • Carbamoyl refers to an H2N-CO- group.
  • Alkylcarbamoyl refers to a R'RN-CO- group wherein one of R and R' is hydrogen and the other of R and R' is alkyl as previously described.
  • Dialkylcarbamoyl refers to R'RN ⁇ CO- group wherein each of R and
  • R' is independently alkyl as previously described.
  • acyloxy refers to an acyl-O- group wherein acyl is as previously described.
  • Acylamino refers to an acyl-NH- group wherein acyl is as previously described.
  • “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.
  • Halo or halide refers to fluoride, chloride, bromide, or iodide.
  • the method comprises applying an anti-biofouling agent to a substrate in a pre-determined pattern.
  • the anti-biofouling agent comprises: (a) a nitric oxide (NO) donor moiety; and (b) a matrix adapted to release NO in a controlled release profile.
  • the substrate is an implantable substrate.
  • the terms "implantable substrate” and “implant” are used interchangeably herein.
  • the substrate can be used for in situ applications, for example, "lab on a chip” applications.
  • a substrate comprising wells, channels, etc. that resist biofouling can be prepared in accordance with the method disclosed herein for experiments dealing with blood or other common biological samples wherein resistance to biofouling is appropriate.
  • the pre-determined pattern can comprise any suitable pattern, and the pattern in typically chosen based an envisioned end use for the substrate.
  • the term "pre-determined pattern" encompasses a pattern that facilitates proper function while enhancing biocompatibility.
  • a coating can influence its ability to function properly.
  • the predetermined pattern can comprise a microarray of wells, channels, etc. for receiving analytes, reagents, etc.
  • modifying a biosensor with a NO- releasing membrane can result in improved biocompatibility at the expense of analytical sensitivity due to reduced analyte diffusion (to the electrode).
  • the substrate is protected from biofouling by the heterogeneous release of NO from strategically positioned microstructures that are patterned in a microarray. While the following discussion focuses on patterning via placement of microarrays, patterning of the surface of the substrate in a macro approach, that is coating only a portion of the surface, is also encompassed.
  • Clark and coworkers employed microfluidic networks to construct arrays (lines) of polymer-encapsulated protein patterns onto glass substrates (Kim et al., 2001).
  • Whitesides et al. have reported on an alternate strategy that involves the application of pressure to a polymeric template in order to produce microarrays of dots and lines on a substrate (Yang et al., 1998; Jackman et al., 1999; James et al., 1998).
  • no methods for patterning a matrix on a substrate to impart resistance to biofouling have been disclosed in the art.
  • Sol-gel micropatterned surfaces can be prepared by both capillary flow and applied pressure methods using elastomeric templates, as shown schematically in Figures 1A-1C.
  • silicon masters are fabricated as follows: 1 ) silicon (Si) wafers are spin- coated with a photoresist, (such as a NFR55cp negative photoresist); 2) a photomask and ultraviolet (UV) light is then used to create a pattern in the resist; and 3) the photo-transferred pattern is developed.
  • the length and width of features on the master are varied by changing the physical size of the chrome-plated features on the photomask used in step (2).
  • Aluminum (Al) metal is then blanket deposited onto the wafers via electron beam (e- beam) evaporation. This metal is patterned using a tape lift-off process to remove any Al covering the resist.
  • the metal serves as a. mask to etch the pattern into the Si with straight sidewalls using magnetically enhanced reactive ion etching. Feature heights are altered by varying the etching time.
  • the Al mask is stripped with a chemically selective wet etch to yield a durable, reusable, dimensionally accurate, and chemically stable mold.
  • the molds are then fluorinated with a suitable fluorination source (e.g., (heptadecafluoro-1 ,1 ,2,2-tetra-hydrodecyl)- trichlorosilane) which is optionally applied as a vapor under a nitrogen environment for a suitable time (e.g., 35 minutes) and which acts to prevent bonding of polydimethylsiloxane (PDMS) with the silicon wafer during the curing process (Espadas-Torre & Meyerhoff, 1995).
  • a suitable fluorination source e.g., (heptadecafluoro-1 ,1 ,2,2-tetra-hydrodecyl)- trichlorosilane
  • PDMS polydimethylsiloxane
  • the fluorinated master is then coated with PDMS, which is allowed to cure, to yield an elastomeric template.
  • Fabrication of surfaces by capillary flow involves placing the template on a substrate to create a series of microchannels. As shown in Figure 1B, sol solution is placed at one end of the array and drawn into the channels by capillary flow. After curing of the sol-gel, the template is removed to yield a micropatterned surface. Micropatterned arrays of sol-gel lines with dimensions including but not limited to 1-15 ⁇ m have been constructed in this embodiment.
  • Patterned surfaces have also been prepared using the method of applied pressure (Figure 1C) where sol solution is placed directly on a substrate and covered with the elastomeric template. Pressure is then applied such that contact is made between the template and the underlying substrate. After formation and drying of the sol-gel features, the template is removed. Microarrays consisting of a variety of geometric constituents including, but not limited to sol-gel lines and spheres (1-5 ⁇ m), have been fabricated using this technique. V. Substrates
  • a substrate is also provided herein.
  • the substrate comprises an anti- biofouling agent disposed on a surface of the substrate, wherein the anti- biofouling agent comprises: (a) a nitric oxide (NO) donor moiety; and (b) a matrix adapted to release the NO in a pre-determined profile.
  • the substrate is an implantable substrate.
  • the terms "implantable substrate” and “implant” are used interchangeably herein.
  • the substrate can be used for in situ applications, for example, "lab on a chip” applications.
  • a substrate comprising wells, channels, etc. that resist biofouling can be prepared in accordance with the method disclosed herein for experiments dealing with blood or other common biological samples wherein resistance to biofouling is appropriate.
  • the anti-biofouling agent is disposed on the substrate in a pre-determined pattern.
  • the predetermined pattern is a microarrayed pattern as disclosed herein above.
  • Representative implants include both intravascular and subcutaneous sensors as well as structural implants and in vitro microfluidic devices.
  • additional representative implants include biosensors, catheters, orthopedic implants, sutures, staples, stents, breast implants, penile implants, other anatomical implants, screws, nails, plates, rods, and prostheses. Indeed, any implant as would be apparent to one of ordinary skill in the art upon review of the present disclosure falls within the scope of the presently claimed subject matter.
  • the presently claimed subject matter also provides a biosensor comprising an anti-biofouling agent disposed on a surface thereof in a predetermined pattern, wherein the anti-biofouling agent comprises: (a) a nitric oxide (NO) donor moiety; and (b) a matrix adapted to release the NO in a pre-determined profile.
  • the predetermined pattern is a microarrayed pattern as disclosed herein above.
  • Implant devices can be modified with various sol-gel patterning architectures to release NO while retaining the analytical response characteristics of an unmodified device (e.g., biosensor), since only specific regions on the substrate are functionalized with sol-gel. In this manner, the release of NO from the sol-gel patterns prevents biofouling without compromising the functionality of the implant.
  • Microarray geometry, dimensions, and spacing between NO-releasing microstructures can be varied to most effectively inhibit cellular (platelets and bacteria) attachment while minimizing the surface area coated with sol-gel as shown schematically in Figure 6.
  • micropatterned sol-gel substrates were characterized using a PICOSPMTM (Molecular Imaging of Phoenix, Arizona, United States of America) atomic force microscope (AFM) with Si 3 N 4 tips (spring constant circa 0.12 N/m).
  • Representative contact mode AFM images of 20% (aminoethylaminomethyl)-phenylethyl-trimethoxysilane (AEMP3) in methyltrimethoxysilane (MTMOS) sol-gel patterns on glass substrates are shown in Figures 2A-2D. These images illustrate the diversity both in terms of feature geometry and spacing between sol-gel regions that can be achieved with micropatterning methods.
  • An array of 1 ⁇ m sol-gel dots separated by distances of 10 ⁇ m and arrays of sol-gel lines ranging from 1-5 ⁇ m separated by spaces ranging from 1-6 ⁇ are included as examples of the variety of surface architectures provided herein.
  • Example 2 Conversion of Sol-Gels to NO-Releasing Materials
  • an aminosilane such as AEMP3 into a silicon- based sol-gel matrix allows for modification of the material to controllably release NO.
  • Exposing diamine groups to high pressures of NO under anaerobic conditions results in the formation of diazeniumdiolates X[N(O)NO] " as shown in Figure 3, Scheme 3.
  • Diazeniumdiolates are stable at low temperatures in the absence of hydrogen donors (e.g., water).
  • a suitable cross-linking agent such as MTMOS, ethanol, and water.
  • Aminosilane-containing sol-gels are then converted to NO-releasing materials by exposure to 5 atm NO for 72 hours.
  • Real-time NO release from micropatterned surfaces is assessed using a chemiluminescence nitric oxide analyzer (Model NOATM 280, available from Sievers Instruments of Boulder, Colorado, United States of America).
  • a representative NO release curve i.e., a predetermined profile or a controlled release profile
  • AEMP3/MTMOS micropattem array of lines
  • Example 3 Evaluating Sol-Gel Micropattem Stability
  • the utility of NO-releasing sol-gel micropatterns for biomedical implant applications is highly dependent on the stability of the patterned features under both high pressure and solution conditions.
  • Micropattem stability was evaluated using contact mode AFM. Representative images of an array comprising 3 ⁇ m sol-gel lines a) before and b) after pressurizing to 5 atm NO for 60 hours are shown in Figures 5A and 5B, respectively. The integrity of the micropatterned array was maintained, indicating that the charging process used to convert aminosilanes to diazeniumdiolates is not destructive to the pattern.
  • micropatterns An equally important consideration is the ability of micropatterns to withstand solution immersion.
  • the charged array was submerged in buffer for 3 days and characterized in situ at distinct intervals using contact mode AFM ( Figures 5A-5C). From these data it was determined that the integrity of microstructures is not compromised by solution, suggesting that sol-gel micropatterns provide a viable approach for heterogeneously releasing NO from a substrate for the purpose of enhancing implant biocompatibility.
  • Example 4 Evaluating the Thromboresistivity of NO-Releasing Sol-Gel Micropatterns
  • the adhesion and activation of platelets in response to implantation results in the formation of a dense network of cells and polymeric fibrin known as a haemostatic plug or thrombus (Cazenave, 1986; Cazenave & Mulvihill, 1993).
  • thromboresistivity of a material is directly related to its ability to prevent the adhesion of platelets, in vitro platelet adhesion studies are used in this Example to characterize the thromboresistivity of heterogeneous NO-releasing sol-gel microarrays.
  • Platelet rich plasma was obtained from acid citrate dextrose (ACD)-anticoagulated porcine blood (1 part ACD to 9 parts whole blood) by centrifugation at 200 x g for 15 min at room temperature. Since calcium is a requirement for normal platelet activity, CaCI 2 was added to a total concentration of 0.25-0.50 mM Ca +2 to maintain platelet activity. PRP was then incubated with sol-gel micropattem controls and identical microarrays capable of NO-release for 30 min at room temperature. The substrates were then rinsed with Tyrode's buffer to remove loosely adhered platelets. Adsorbed platelets were fixed with glutaraldehyde solution (1 %, Tyrode's buffer) to ensure preservation of cell morphology.
  • ACD acid citrate dextrose
  • Endothelial cell seeding improves patency of synthetic vascular grafts: manual versus automatized method. European Journal of Cardio-
  • Ratner BD Molecular design strategies for biomaterials that heal.

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Abstract

L'invention concerne des procédés et des compositions pour permettre la libération localisée en surface d'un agent anti-encrassement biologique sur un substrat, ainsi que le substrat lui-même. Ledit substrat comprend un agent anti-encrassement biologique disposé à la surface du substrat dans une composition prédéterminée, ledit agent anti-encrassement biologique comprenant : (a) une fraction donneur de monoxyde d'azote (NO) et (b) une matrice conçue pour libérer le monoxyde d'azote dans un profil à libération commandée.
PCT/US2003/022511 2002-07-19 2003-07-18 Liberation localisee en surface d'un agent anti-encrassement biologique par l'intermediaire de micro-compositions WO2004009253A1 (fr)

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WO2008027402A2 (fr) * 2006-08-29 2008-03-06 Civatech Oncology Dispositifs de curiethérapie, méthodes et produits programmes informatiques associés
JP2008545714A (ja) * 2005-05-27 2008-12-18 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル 酸化窒素治療及び医生物的応用のための酸化窒素放出粒子
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9187501B2 (en) 2012-08-28 2015-11-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing nanorods and their methods of use
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
WO2019201195A1 (fr) 2018-04-16 2019-10-24 上海岸阔医药科技有限公司 Méthode pour prévenir ou traiter les effets secondaires d'une cancérothérapie

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US20020022046A1 (en) * 1998-09-29 2002-02-21 Arterial Vascular Engineering, Inc. Uses for medical devices having a lubricious, nitric oxide-releasing coating
US20020193336A1 (en) * 2001-04-20 2002-12-19 Elkins Christopher J. Methods for the inhibition of neointima formation
US20030158509A1 (en) * 2002-02-13 2003-08-21 Tweden Katherine S. Cardiac implant and methods

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US8962029B2 (en) * 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US11691995B2 (en) * 2005-05-27 2023-07-04 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
EP3556401A1 (fr) * 2005-05-27 2019-10-23 The University of North Carolina at Chapel Hill Particules libérant de l'oxyde nitrique pour thérapie à base d'oxyde nitrique et applications biomédicales
US20150182543A1 (en) * 2005-05-27 2015-07-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20120034169A1 (en) * 2005-05-27 2012-02-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
AU2006249323B2 (en) * 2005-05-27 2012-08-30 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
JP2013006859A (ja) * 2005-05-27 2013-01-10 Univ Of North Carolina At Chapel Hill 酸化窒素治療及び医生物的応用のための酸化窒素放出粒子
US20140005426A1 (en) * 2005-05-27 2014-01-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20140058124A1 (en) * 2005-05-27 2014-02-27 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
EP2669269A3 (fr) * 2005-05-27 2014-03-05 The University of North Carolina At Chapel Hill Particules libérant de l'oxyde nitrique pour thérapie à base d'oxyde nitrique et applications biomédicales
US8956658B2 (en) * 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
JP2008545714A (ja) * 2005-05-27 2008-12-18 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル 酸化窒素治療及び医生物的応用のための酸化窒素放出粒子
US9403851B2 (en) * 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) * 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
WO2008027402A3 (fr) * 2006-08-29 2008-10-30 Civatech Oncology Dispositifs de curiethérapie, méthodes et produits programmes informatiques associés
US7686756B2 (en) * 2006-08-29 2010-03-30 Ciratech Oncology Brachytherapy devices and related methods and computer program products
WO2008027402A2 (fr) * 2006-08-29 2008-03-06 Civatech Oncology Dispositifs de curiethérapie, méthodes et produits programmes informatiques associés
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US10376538B2 (en) 2009-08-21 2019-08-13 Novan, Inc. Topical gels and methods of using the same
US11583608B2 (en) 2009-08-21 2023-02-21 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9187501B2 (en) 2012-08-28 2015-11-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing nanorods and their methods of use
WO2019201195A1 (fr) 2018-04-16 2019-10-24 上海岸阔医药科技有限公司 Méthode pour prévenir ou traiter les effets secondaires d'une cancérothérapie

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