WO2008060268A2 - Modification de surface hydrophile adaptable - Google Patents

Modification de surface hydrophile adaptable Download PDF

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Publication number
WO2008060268A2
WO2008060268A2 PCT/US2006/041805 US2006041805W WO2008060268A2 WO 2008060268 A2 WO2008060268 A2 WO 2008060268A2 US 2006041805 W US2006041805 W US 2006041805W WO 2008060268 A2 WO2008060268 A2 WO 2008060268A2
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Prior art keywords
hydrophilic polymer
modified
contacting
carboxylic acid
cross
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PCT/US2006/041805
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English (en)
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WO2008060268A3 (fr
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Chad A. Mirkin
Robert Elghanian
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Northwestern University
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Publication of WO2008060268A2 publication Critical patent/WO2008060268A2/fr
Publication of WO2008060268A3 publication Critical patent/WO2008060268A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54393—Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent

Definitions

  • the present disclosure is directed to tailorable hydrophilic surfaces. More specifically, the present disclosure provides methods of producing surfaces, in situ, having activated elements for use in screening or detection assays.
  • the present invention provides a method of modifying a surface comprising contacting (1) an unmodified surface with (2) a compound having an amino functional group and a second functional group capable of covalently bonding to said unmodified surface to form an aminated surface.
  • An aminated surface is a surface modified with a compound having a terminal amino group, wherein that amino group is available for further reaction (e.g., is not a tertiary amine).
  • the aminated surface then is contacted with a hydrophilic polymer, an optional coupling reagent, and.a crosslinking reagent to form the modified surface.
  • Nonlimiting examples of the compound having an amino functional group include silyl alkylamines, thiol alkylamines, disulfide alkylamines, and any amine having a second functionality suitable for bonding to the unmodified surface to provide an aminated surface.
  • the unmodified surface is hydrophobic, e.g., a hydrophobic polymer.
  • the hydrophilic polymer can comprise at least two, and typically a plurality of, carboxylic acid or carboxylic acid ester functional groups.
  • the hydrophilic polymer comprises polyacrylic acid, polycarboxylate, polysulfonate, polyphosphate, polyphosphonate, polyethylene glycol, polyvinyl alcohol, or mixtures thereof.
  • the hydrophilic polymer typically has the carboxylic acid or ester functional groups pendant to the backbone of the polymer.
  • the molecular weight of the hydrophilic polymer can be about 10 kDa to about 500 kDa.
  • the molecular weight of the hydrophilic polymer is less than 250 kDa, or less than 200 kDa.
  • the cross-linking agent typically is a diamine, but alternatively can be any compound having at least two reactive functional groups, e.g., any mixture of -SH, -S-S-, - OH, and -NH 2 , such as dithiols, disulfides, diols, aminoalcohols, and the like.
  • the two reactive functional groups can be separated by up to 20 carbon atoms, but alternatively, can be vicinal or geminal.
  • Typical cross-linking agents are diamines, such as hydrazine or linear or branched C 2-15 diamines.
  • the unmodified surface can be any of a variety of surfaces in need of modification for a desired end use.
  • Surfaces such as glass (e.g., glass slides or glass beads), hydrophobic polymeric beads or surfaces, or gold micro- or nanoparticles all are contemplated as surfaces in the disclosed methods.
  • Hydrophobic polymeric beads or surfaces can be polystyrene, polyethylene, polybutylene, polypropylene, polymerized mixed olefins, polyterpene, polyisoprene, polyvinyltoluene, poly( ⁇ -methylstyrene), poly(o-methylstyrene), poly(m- methylstyrene), poly(p-methylstyrene), poly(dimethylphenylene oxide), polyurethane, polyvinyl chloride, or mixtures thereof.
  • the modified surface is further contacted with an activating agent, which provides a modified surface capable of reacting with a target molecule.
  • an activating agent which provides a modified surface capable of reacting with a target molecule.
  • target molecules include proteins or polypeptides, nucleic acids, and small molecules.
  • the resulting surfaces can be useful in screening or detecting assays.
  • the activating agent is N-hydroxy succinimide, but can be any agent which activates a carboxylic acid.
  • a method of modifying a surface comprising the steps of contacting (1) an unmodified surface with (2) a compound having a carboxylic acid, ester, or anhydride functional group and a second functional group capable of covalently bonding to said unmodified surface to form a carboxylated surface.
  • a carboxylated surface is a surface modified with a compound having a carboxylic acid, ester, or anhydride group, wherein that carboxylic acid, ester, or anhydride group is available for further reaction.
  • the carboxylated surface then is contacted with a hydrophilic polymer, an optional coupling reagent, and a cross-linking reagent to form the modified surface, typically having a -CO 2 H or -CO 2 Ci- 3 alkyl functional group.
  • a hydrophilic polymer typically having a -CO 2 H or -CO 2 Ci- 3 alkyl functional group.
  • Nonlimiting examples of the compound having a carboxylic acid, ester, or anhydride group include silyl alkyl carboxylic acids or esters, thiol alkyl carboxylic acids or esters, and any carboxylic acids or ester having a second functionality suitable for bonding to the unmodified surface to provide a carboxylated surface.
  • Anhydrides can also be used.
  • Cross-linking agents are typically dicarboxylic acids, dicarboxylic esters, and/or anhydrides and include, but are not limited to, HO 2 C-C 0- )5 alkylCO 2 H, C 1-3 alkylO 2 C-Co-i 5 alkylCO 2 C 1-3 alkyl, maleic anhydride, succinic anhydride, phthalic anhydride, or mixtures thereof.
  • Cross-linking agents can optionally be substituted with subsituents such as, but not limited to, halo, hydroxy, alkoxy, cyano, amino, and the like.
  • hydrophilic polymers having at least two, and typically a plurality of, functional groups capable of covalently bonding with a carboxylated surface can be used.
  • Polyamines, polyalcohols (such as polyvinyl alcohols), or polymers having pendant amine, alcohol, and/or thiol functional groups are contemplated.
  • the method can be performed in a manner so as to provide isolated modified sites on the surface, which can be desired for modification of surfaces with numerous target molecules.
  • isolated modified sites on the surface which can be desired for modification of surfaces with numerous target molecules.
  • a glass or plastic slide is to be used in a detection assay
  • multiple sites of modification can be prepared wherein each site is designed to interact with or covalently bind to a different target molecule. Isolation of the modified sites from each other is desirable so as to avoid overlap or "bleeding" of detection signals of adjacent sites on the glass surface in the detection assay.
  • the hydrophilic polymer will have at least two, but typically a plurality of, amine, alcohol, and/or thiol functional groups, and the cross-linking agent will have at least two carboxylic acid functional groups.
  • the choice of initial modification dictates the choice of functional groups on the hydrophilic polymer and the cross-linking agent.
  • the activating agent will be an agent capable of activating the functional group on the hydrophilic polymer.
  • the activating agent will be an agent suitable to increase reactivity of the amine, alcohol, or thiol for reaction with the target molecule.
  • the target molecule will have a functional group which can react with an amine, alcohol, or thiol, such as a phosphate, carboxylic acid, carboxylic ester, and the like.
  • FIG 1 shows a schematic of a method of producing modified surfaces, wherein the reagents are mixed together in one step to produce a random polymer covalently attached to a surface, wherein the polymer has reactive N-hydroxysuccinimide groups capable of reacting with an analyte;
  • FIG 2 shows a schematic of a method of using modified surfaces to attach target molecules such as a biomolecule (e.g., a nucleic acid);
  • a biomolecule e.g., a nucleic acid
  • FIG 3 shows a surface modified with various polymers that have not been cross- linked with cross-linking agent (e.g., C 0 ), and treated with various concentrations of target molecules;
  • cross-linking agent e.g., C 0
  • FIG 4 shows a surface modified with various polymers that have been cross-linked with a C 8 cross- linking agent, then treated with various concentrations of target molecules;
  • FIG 5 shows a surface modified with various polymers that have been cross-linked with a Ci 2 cross-linking agent, then treated with various concentrations of target molecules; and
  • FIG 6 shows images of two different surfaces imprinted with uncross-linked polymers (C 3 ) and polymers cross-linked with a C 8 cross-linking agent; each was then treated with a 1 nM solution of a target molecules.
  • the modified surfaces are used in detection assays.
  • the disclosed methods modify surfaces in a one-step procedure from simple reagents.
  • the surfaces are modified with hydrophilic polymers, hi certain embodiments, the hydrophilic polymers may be cross-linked with cross-linking reagents of varying alkyl lengths, which may affect the contact angle of the deposited hydrophilic polymer on the modified surface.
  • the surfaces may include embedded functionality such as electrodes, hi still other embodiments, the hydrophilic polymers may be modified with activating agents for attachment of target molecules.
  • Nonlimiting examples of suitable surfaces for use in the present methods include, but are not limited to, glass slides or other glass surfaces, polymer films, laminates, polymeric microparticles (including paramagnetic microparticles), metal and metal oxide surfaces, computer chips (such as silicon chips), natural and synthetic membranes, and other silica- based and plastic surfaces, hi some cases, wherein the surface is glass, the glass may be treated with compound having an amino functional group such as an amino alkylsilane or an amino alkylhalosilane, which provides a amino group capable of further reaction to the glass surface.
  • an amino functional group such as an amino alkylsilane or an amino alkylhalosilane
  • Other surfaces may be similarly modified to provide a such amines.
  • the surface may be modified with an amino alkylthiol to provide an amine functionality.
  • Other functional groups may be introduced to the surface via similar approaches to provide, e.g., alcohols, carboxylic acids, thiols, sulfonic acids, and the like, to the surface for modification.
  • Animation, hydroxylation, carboxylation, etc. of a surface can be accomplished using corona discharge or a plasma glow discharge.
  • a plasma glow discharge Such methods are disclosed in, for example, U.S. Patent Nos. 6,355,270; 6,140,127; and 6,053,171, each of which is incorporated in its entirety by reference herein.
  • Hydrophobic polymeric beads or surfaces can be, for example, polystyrene, polyethylene, polybutylene, polypropylene, polymerized mixed olefins, polyterpene, polyisoprene, polyvinyltoluene, poly( ⁇ -methylstyrene), poly(o-methylstyrene), poly(m- methylstyrene), poly(p-methylstyrene), poly(dimethylphenylene oxide), polyurethane, polyvinyl chloride, or mixtures thereof.
  • Hydrophilic polymers suitable for use in the disclosed methods include, but are not limited to, polyacrylic acids and other polymers having accessible carboxylic acid functional groups, amino-functionalized polymers, hydroxyl-functionalized polymers, or polymers with functional groups that may react with a functionalized surface as described above.
  • Nonlimiting examples of hydrophilic polymers suitable for use in the present methods include polyacrylic acid, polycarboxylate, polysulfonate, polyphosphate, polyphosphonate, polyethylene glycol, polyvinyl alcohol, polyvinyl amines, polylactates, and the like.
  • the polymer used is hydrophilic and/or water-soluble.
  • the solubility of the polymer may be controlled by its molecular weight. Typically, the molecular weight is about 10 kDa to about 500 kDa. In some cases, the molecular weight of the polymer is less than 250,000 Da. In other cases, the molecular weight is less than 200,000 Da.
  • the polymeric acids typically are prepared from ethylenically unsaturated monomers having at least one hydrophilic moiety, such as carboxyl, carboxylic acid anhydride, sulfonic acid, and sulfate.
  • the polymeric acid can contain a comonomer, such as styrene, an alkene, and/or a partially or fully fluorinated alkene or styrene to increase the hydrophobicity of the polymeric acid.
  • Examples of monomers used to prepare the polymeric organic acid include, but are not limited to:
  • Carboxyl group-containing monomers e.g., monoethylenically unsaturated mono- or polycarboxylic acids, such as acrylic acid, methacrylic acid, maleic acid, fumaric acid, crotonic acid, sorbic acid, itaconic acid, ethacrylic acid, ⁇ -chloroacrylic acid, ⁇ -cyanoacrylic acid, ⁇ -methlacrylic acid (crotonic acid), ⁇ -phenylacrylic acid, ⁇ -acryloxypropionic acid, sorbic acid, ⁇ -chlorosorbic acid, angelic acid, cinnamic acid, p-chlorocinnamic acid, ⁇ - stearylacrylic acid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, tricarboxyethylene, and cinnamic acid;
  • monoethylenically unsaturated mono- or polycarboxylic acids such as acrylic acid, methacryl
  • Carboxylic acid anhydride group-containing monomers e.g., monoethylenically unsaturated polycarboxylic acid anhydrides, such as maleic anhydride;
  • Sulfonic acid group-containing monomers e.g., aliphatic or aromatic vinyl sulfonic acids, such as vinylsulfonic acid, allylsulfonic acid, vinyltoluenesulfonic acid, styrenesulfonic acid, sulfoethyl (meth)acrylate, 2-acrylamido-2-methylpropane sulfonic acid, sulfopropyl (meth)acrylate, and 2-hydroxy-3-(meth)acryloxy propyl sulfonic acid.
  • vinylsulfonic acid e.g., allylsulfonic acid, vinyltoluenesulfonic acid, styrenesulfonic acid, sulfoethyl (meth)acrylate, 2-acrylamido-2-methylpropane sulfonic acid, sulfopropyl (meth)acrylate, and 2-hydroxy-3-(meth)acryloxy propyl sulf
  • the polymeric acid can contain other copolymerizable units, i.e., other monoethylenically unsaturated comonomers, well known in the art, as long as the polymer is substantially, i.e., at least 10%, and preferably at least 25%, acid group containing monomer units.
  • the polymeric acid contains at least 50%, and more preferably, at least 75%, and up to 100%, acid group containing monomer units.
  • the other copolymerizable units for example, can be styrene, an alkene, an alkyl acrylate, an alkyl methacrylate, and/or a partially or fully fluorinated alkene or styrene.
  • Suitable pairings of functionalized surface, polymeric group, cross-linking agent, and target molecule will be apparent to one of skill in the art in view of the present disclosure.
  • a surface functionalized with carboxylic acids may be reacted with hydrophilic polymers having amines, hydroxyl, and/or thiol groups, with cross-linking agents containing dicarboxylic acids, esters, or anhydrides, and further reacted with target molecules having functionality capable of reacting with amines, hydroxyl, and/or thiol groups, such as carboxylic acids, esters, anhydrides and the like.
  • the disclosed methods may include mixing a cross-linking agent with the polymer and the surface to provide modified surfaces which can be suitable for detection assays.
  • cross-linking agents include diamines of various molecular weights, diols of various molecular weights, thiols of various molecular weights, and dicarboxylic acids of various molecular weights.
  • the molecular weight of the cross-linking agent may play a role in the end properties of the modified surface by changing the contact angle of the available reactive sites on the modified surface for the target molecule with which to react. The difference in contact angle may be reflected in the resulting size of the spot resulting from the polymer attaching to the surface.
  • the molecular weight of the crosslinking agent may also play a role in the amount of possible loading of the target molecule to the modified surface.
  • Specific diamines that may be used in methods disclosed herein include hydrazine, C 2-15 diamines, and specifically, C 8 , and Ci 2 diamines, where the number refers to the length of the alkyl chain separating the amine functional groups.
  • C 8 refers to a diamine with an eight carbon alkyl group separating the two amine functional groups (e.g., 1,8- diaminooctane); and
  • Ci 2 refers to a diamine with a twelve carbon alkyl group separating the two amine functionalities (e.g., 1,12-diaminododecane).
  • a coupling reagent optionally can be added to facilitate the reaction between the functional group on the surface (e.g., an aminated surface having amines or a hydroxylated surface having alcohols) and the carboxylic acid of the polymer.
  • the functional group on the surface e.g., an aminated surface having amines or a hydroxylated surface having alcohols
  • Such coupling agents may include those commonly used in peptide chemistry such as HOAt (l-hydroxy-7- azabenzotriazole), HOBt (1-hydroxybenzotriazole), HATU (O-(7-aza-benzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU (0-(benzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate), EDC (N-(3-Dimethylaminopropyi)-N'- ethylcarbodiimide), DCC (dicyclohexylcarbodiimide), and DIC (diisopropylcarbodiimide).
  • HOAt l-hydroxy-7- azabenzotriazole
  • HOBt 1-hydroxybenzotriazole
  • HATU O-(7-aza-benzotriazol
  • the present methods utilize agents that modify free carboxylic acid sites of the hydrophilic polymer to form more reactive functional groups, e.g., activated sites.
  • activating agents include N-hydroxysuccinimide (NHS) which can transform carboxylic acids to N-hydroxy succinimide esters (NOS).
  • NHS N-hydroxysuccinimide
  • NOS N-hydroxy succinimide esters
  • the coupling agents listed above can be used as activating agents.
  • the activated sites then can be used to attach target molecules.
  • Suitable target molecules include polypeptides and proteins, nucleic acids, and small molecules. Any suitable target molecule will have a suitable functional group to covalently bond to the activated site of the modified surfaces as disclosed herein.
  • a nucleic acid or protein or polypeptide can bind to an activated ester (e.g., a NOS).
  • an activated ester e.g., a NOS
  • Small molecules having an alcohol functional group, an amine functional group, or a thiol functional group can also form a covalent bond to an activated ester at the activated site.
  • nucleic acid refers to an oligonucleotide or polymeric compound comprising bases of DNA, RNA, or combinations thereof.
  • a polynucleotide is referred to herein as a "oligomer", i.e., a DNA oligomer or RNA oligomer.
  • Non-limiting examples of bases that comprise a polynucleotide used in the present invention include adenosine, guanosine, cytosine, thymidine, inosine, cytidine, uridine, pyrimidine, uracil, thymine, purine, methylcytosine, 5-hydroxymethylcytosine, 2-methyladenine, 1- methylguanine, 2,6-diaminopurine, 2-amino-6-chloropurine, 2,6-dichloropurine, 6- thioguanine, 6-iodopurine, 6-chloropurine, 8-azaadenine, allopurine, isoguanine, orotidine, xanthosine, xanthine, hypoxanthine, 1 ,2-diaminopurine, pseudouridine, C-5-propyne, isocytosine, isoguanine, 2-thiopyrimidine, rhodamines,
  • Polypeptides typically comprise 5 to about 600 amino acids, but can be any length or any protein of interest. Amino acids can be either natural or synthesized.
  • the disclosed methods provide modified surfaces which can be used in a variety of assays, including detection assays.
  • detection assays are described in, e.g., U.S. Patent Nos. 7,098,320; 7,063,946; 6,986,989; 6,974,669; 6,969,761; 6,962,786; 6,861,221; 6,858,387; 6,828,432; 6,827,979; 6,812,334; 6,777,186; 6,773,884; 6,767,702; 6,750,016; 6,730,269; 6,720,411; 6,720,147; 6,709,825; 6,682,895; 6,673,548; 6,645,721; 6,582,921; 6,506,564; 6,495,324; and 6,361,944, each of which is incorporated in its entirety by reference herein.
  • the surface can be selectively modified at multiple sites, so as to provide a surface having isolated modified sites suitable for use in a detection assay.
  • Each site can optionally be modified with different target molecules so as to assess each individually in a single detection assay.
  • the sites are isolated from one another so as to ensure that no site influences or falsely indicates an adjacent site has activity, inhibition, or some other type of interaction of interest in the detection assay.
  • FIG. 1 A schematic of a general method is laid out in FIG. 1.
  • a glass slide is modified with an aminoalkylsilane to provide an animated surface.
  • This surface then is treated with a cocktail of reagents, including a random polyacrylic acid co-acrylamide polymer with an average molecular weight of about 200,000 Da, a coupling reagent (EDC), a modifying reagent (NHS), and a cross-linking reagent (diamine).
  • EDC coupling reagent
  • NHS modifying reagent
  • diamine cross-linking reagent
  • the modified surface is suitable for treatment with any analyte having a reactive group compatible with the reactive group on the polymer.
  • the NOS functional groups on the polymer react with a biomolecule having a free amine to covalently attach the biomolecule to the modified surface.
  • a 50 mL polymer "cocktail" solution was prepared in 0.1M morpholinoethylsulfonic acid (MES), 1% poly(acrylamide-co-acrylic acid) partial sodium salt acrylamide 20 wt% (average MW 20OkDa), 750 mg N-hydroxysuccinimide, 500 mg EDC, and 600 ⁇ mol of a diamine. Any diamine, mixture of diamines, or salts of diamines (e.g., amine hydrochlorides) may be used.
  • the slides then were placed in a flat polyethylene dish and the cocktail poured over them and allowed to react for one hour with 80 revolutions per minute (rpm) shaking at room temperature.
  • the slides then were washed three times with distilled water, dried, and passivated using acetic anhydride and 10% methylimidazole in a tetrahydrofuran (THF)/pyridine mixture (50 mL) for 2 min.
  • the slides then were washed with THF two times, acetonitrile two times, and dried under nitrogen.
  • the slides then were placed in a dessicator until use.
  • FIG. 3 shows the results of the detection experiment using surfaces that were modified with C 3 diamine cross-linkers.
  • the amount of synthetic target was varied from 500 fM up to 100 pM, with all concentrations of synthetic successfully detected.
  • FIG. 4 shows similar results with the C 8 diamine cross-linker and FIG. 5 with the C 12 diamine cross-linker.
  • Electrodes Surfaces containing electrodes (electrode chip was made of gold on silicon/silicon oxide (oxide layer 500 nm)) were aminated using aminopropyltrimethoxysilane in a manner similar to that outlined in the preparation of glass slide surfaces. The animation of the surface was followed by immobilization of a polymer cocktail (as described in the glass surface example). Amino oligo-nucleotides were reacted with the immobilized polymers in a phosphate buffer pH 7.8, then allowed to stand at 50% humidity for 4 hours. The slides then were washed and hybridized in a hybridization buffer containing 13 nm gold particles in the presence and absence of a target nucleotide. The electrode that was treated with the target nucleotide has a deposition of silver, while the electrode that was not treated with the target nucleotide has no silver deposition, after silver staining.
  • nucleotide sequences targets, or probes used. It is envisioned that any nucleotide sequence having the appropriate functionality are suitable for use with the surfaces prepared by the methods disclosed herein.

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Abstract

La présente invention concerne des surfaces modifiées et leurs procédés de fabrication. Plus particulièrement, la présente invention concerne des surfaces hydrophobes modifiées avec des polymères hydrophiles et, éventuellement, des molécules cibles. Ces surfaces modifiées peuvent être utilisées dans des analyses de détection ou en tant que moyen pour améliorer la solubilité de la surface non modifiée.
PCT/US2006/041805 2005-10-28 2006-10-27 Modification de surface hydrophile adaptable WO2008060268A2 (fr)

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US73112905P 2005-10-28 2005-10-28
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2287610A1 (fr) * 2009-08-20 2011-02-23 Corning Incorporated Article de modification de l'immobilisation de surface à thiol modifié et procédé
US9324473B2 (en) * 2008-08-25 2016-04-26 Kent State University Nanoparticle composition, a device and a method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1202062A1 (fr) * 2000-10-31 2002-05-02 BioChip Technologies GmbH Surfaces polymères à motifs pour la bioconjugaison et leur procédé de préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1202062A1 (fr) * 2000-10-31 2002-05-02 BioChip Technologies GmbH Surfaces polymères à motifs pour la bioconjugaison et leur procédé de préparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9324473B2 (en) * 2008-08-25 2016-04-26 Kent State University Nanoparticle composition, a device and a method thereof
EP2287610A1 (fr) * 2009-08-20 2011-02-23 Corning Incorporated Article de modification de l'immobilisation de surface à thiol modifié et procédé

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