WO2008135916A1 - Magnetochemical sensor - Google Patents
Magnetochemical sensor Download PDFInfo
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- WO2008135916A1 WO2008135916A1 PCT/IB2008/051677 IB2008051677W WO2008135916A1 WO 2008135916 A1 WO2008135916 A1 WO 2008135916A1 IB 2008051677 W IB2008051677 W IB 2008051677W WO 2008135916 A1 WO2008135916 A1 WO 2008135916A1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/72—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables
- G01N27/74—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids
- G01N27/745—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids for detecting magnetic beads used in biochemical assays
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y25/00—Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/02—Measuring direction or magnitude of magnetic fields or magnetic flux
- G01R33/06—Measuring direction or magnitude of magnetic fields or magnetic flux using galvano-magnetic devices
- G01R33/09—Magnetoresistive devices
- G01R33/093—Magnetoresistive devices using multilayer structures, e.g. giant magnetoresistance sensors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/12—Measuring magnetic properties of articles or specimens of solids or fluids
- G01R33/1269—Measuring magnetic properties of articles or specimens of solids or fluids of molecules labeled with magnetic beads
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- Investigating Or Analyzing Materials By The Use Of Magnetic Means (AREA)
Abstract
The application relates to a magnetochemical sensor, comprising (a) a first material (10), whereby the first material is an elastic material adapted to change its physical dimensions according to interaction with an analyte; (b) a GMR sensor (50); (c) a second material (20) adapted to interact with the sensor whereby the second material is a magentic material not embedded in said first material, whereby the first material, the second material and the GMR sensor are so provided towards each other that upon a change of the physical dimensions of the first material a change in the signal detected by the GMR sensor occurs.
Description
MAGNETOCHEMICAL SENSOR
The present invention is directed to the field of devices for the detection of one or more analytes in a sample, especially to the field of devices for the detection of biomolecules in aqueous solution.
The present invention is directed to the detection of analytes in fluids, especially to the detection of biomolecules in aqueous solution.
A magnetochemical sensor is disclosed in the US 5,821,129 which is hereby incorporated by reference. The device layout is such that the sensor and the sensor read-out are spatially separated, enabling remote sensing. However, the sensor in the US 5,821,129 suffers drawbacks when employing it for continuous monitoring of physiological parameters inside the body of a human. For example the sensor read-out is done by subjecting an alternating magnetic field to the stacked sensor structure and measuring a voltage from a detection unit comprising a coiled structure. This methodology hampers miniaturization of the device. Furthermore the device requires a sensor unit consisting of at least three layers, two being magnetic and one being responsive to a certain stimulus. The invention considers remote sensing which is not desirable in case of long-term implantation where one would desire to have the complete device implanted.
It is therefore an object of the present invention to provide a magnetochemical sensor which allows a quicker detection and can for most applications be miniaturized. This object is solved by a sensor according to claim 1 of the present invention.
Accordingly, a magnetochemical sensor, especially for determining the presence, identity, amount and/or concentration of at least one analyte in a fluid sample is provided, comprising
(a) a first material, whereby the first material is an elastic material adapted to change its physical properties according to interaction with said at least one analyte;
(b) at least one sensor;
(c) at least one second material adapted to interact with the at least one sensor, whereby the second material is a magnetic material not embedded in said first material, and whereby the first, at least one second material and the at least one sensor are so provided towards each other that upon a change of the physical properties of the first material a change in at least one of the signals detected by the at least one sensor occurs. A sensor according to the present invention shows for most applications at least one of the following advantages a suppressed biofouling due to a high water content in said first elastic material a high biocompatibility due to a high water content in said first elastic material a fast response due to small thickness of said first elastic material a high accuracy a small form factor a low-cost system design In the sense of the present invention, the term "elastic" especially means, includes and/or describes a property of a material, that can be at least partially elastic deformed, i.e. the deformation is at least partially (or completely) reversible (gets its old shape, size, dimension back). In the sense of the present invention "elastic" especially means includes and/or describes a fully reversible process of shape recovery.
In the sense of the present invention, the term "interact" especially means and/or includes that the at least one second material comprises a material which presence may be detected by the at least one sensor.
According to a preferred embodiment of the present invention, there is at least one changing direction, essentially in which the change of the first material in response to the at least one analyte occurs.
According to a preferred embodiment of the present invention, the at least one sensor and/or the at least one second material are provided in the changing direction at opposite ends of the first material. According to a preferred embodiment of the present invention, the at least one second material is provided next to the first material.
The term "next" includes that the second material is provided in contact with the first material as well as they are separated by further material(s) which may e.g. be provided in form of a thin layer(s) or other provisions. In case the second material is embedded and/or incorporated into a third matrix material (as will be described later on), the term "next" especially includes that said third matrix material is provided in contact with the first material as well as they are separated by further material(s) which may e.g. be provided in form of a thin layer(s) or other provisions. Preferably the change of the first material includes shrinking and/or swelling.
According to a further embodiment of the present invention, the device comprises a sensor having a sensor direction and the changing direction is essentially perpendicular to the sensor direction. The term "sensor direction" especially means and/or includes that in case the sensor extends itself in one or two dimensions larger than in the other two (or one), so that the sensor is either somewhat flat or forms a needle, the "sensor direction" would then be the direction where the sensor has its longest extension.
In the sense of the present invention, the term "magnetic" especially means, includes and/or describes the property of a material to exhibit a net permanent magnetic dipole moment.
According to a preferred embodiment of the present invention, the at least one second material comprises a superparamagnetic material. In the sense of the present invention, the term "superparamagnetic" especially means, includes and/or describes that this material only exhibits a net magnetic dipole moment in the presence of a magnetic field.
This has been shown to be advantageous for a wide range of application within the present invention, especially in case that the magnetic field is delivered by excitation wires (cf. e.g. Fig. 3). When the magnetic field is switched off, the net magnetic dipole moment of the particles becomes zero again and no field is detected by the sensor. This phenomenon allows modulation of the signal and readout at a specific frequency by which means noise can be largely suppressed.
According to a preferred embodiment of the present invention, the at least one second material comprises a permanently magnetized material.
It has been shown for a wide range of applications within the present invention that by doing so, the signal- to -noise- ratio may be improved due to the high magnetic moment of the at least one second material. Furthermore, in a wide range of applications within the present invention, the power may be lowered and the readout electronics may be simplified.
According to a preferred embodiment of the present invention, the first material changes its size and/or thickness when interacting with the at least one analyte.
According to an embodiment of the present invention, the first material is provided in form of a gel.
According to an embodiment of the present invention, the saturation magnetization of the at least one second material is ≥O.l x 105 A/m and <2 x 106 A/m.
According to an embodiment of the present invention, the saturation magnetization of the at least one second material is > 1,5 x 105 A/m and <8 x 105 A/m. According to an embodiment of the present invention, the saturation magnetization of the at least one second material is >3 x 105 A/m and <6 x 105 A/m.
According to an embodiment of the present invention, the saturation magnetization of the at least one second material is >4x 105 A/m and <5,5 x 105 A/m.
According to an embodiment of the present invention, the Langevin susceptibility (susceptibility at zero applied magnetic field) of the at least one second material is > 10~5 and <105 .
According to an embodiment of the present invention, the Langevin susceptibility (susceptibility at zero applied magnetic field) of the at least one second material is > 10~4 and <104 According to an embodiment of the present invention, the Langevin susceptibility (susceptibility at zero applied magnetic field) of the at least one second material is > 10~3 and <103
According to an embodiment of the present invention said second material is substantially forming a layer. According to an embodiment of the present invention said second material is embedded in a third material substantially forming a layer.
According to a preferred embodiment of the present invention, the thickness of the at least one second material and or said third material is >0.5 μm and <10 μm, preferably >1 μm and <8 μm, most preferably >1.5 μm and <5 μm. According to an embodiment of the present invention, the concentration (expressed as percent of the total volume) of the at least one second material in said third material is >0.1% and <40%.
According to an embodiment of the present invention, the concentration (expressed as percent of the total volume) of the at least one second material in said third material is >1% and <20%
According to an embodiment of the present invention, the concentration (expressed as percent of the total volume) of the at least one second material in said third material is >5% and <10%
According to an embodiment of the present invention, the product of magnetization [in A/m] and concentration [in % of the total volume] of the at least one second material is >103 and < 4* 107.
According to an embodiment of the present invention, the product of magnetization [in A/m] and concentration [in % of the total volume] of the at least one second material is >104 and ≤ 8*106.
According to an embodiment of the present invention, the product of magnetization [in A/m] and concentration [in % of the total volume] of the at least one second material is >5 * 104 and < 7*105.
According to a preferred embodiment of the present invention, the at least one second material is patterned in form of and/or comprises small magnetic particles / moieties, preferably with a diameter of ≥lnm and <5μm, more preferably between >50nm and < 1 μm.
According to an embodiment of the present invention, the average particle size of the at least one second material is >1 nm and <40 nm.
According to an embodiment of the present invention, the average particle size of the at least one second material is >5 nm and <30. According to an embodiment of the present invention, the polydispersity of the at least one second material is >1% and < 40%.
According to an embodiment of the present invention, the polydispersity of the at least one second material is >10% and < 25%.
According to an embodiment of the present invention, the magnetic anisotropy constant of the at least one second material is > 1 * 103 J/m3 and < 1 * 105 J/m3.
According to an embodiment of the present invention, the magnetic anisotropy constant of the at least one second material is >5*103J/m3 and ≤5*104 J/m3. According to an embodiment of the present invention, the magnetic anisotropy constant of the at least one second material is >8*103J/m3 and <1.2*104 J/m3.
According to an embodiment of the present invention, the first material is provided in form of a layer.
The term "layer" means and/or includes especially that the thickness of the first material in one dimension is >0% and <50% than in either one of the other dimensions.
For some applications within the present invention, the layer thickness is bound to a range in order to obtain optimum device properties: On the one hand to thin a layer will yield a low signal and insufficient sensitivity whereas to thick a layer will yield a slow response due to long diffusion times.
According to an embodiment of the present invention, the first material is provided in form of a layer with a thickness of ≥O.l μm and <40 μm. According to an embodiment of the present invention, the first material is provided in form of a layer with a thickness of >0.5 μm and <10 μm.
According to an embodiment of the present invention, the first material is provided in form of a layer with a thickness of >1 μm and <3 μm.
However, according to a different embodiment of the present invention, the first material is provided in form of a layer with a thickness of >3 μm and <10 μm.
According to an embodiment of the present invention, the first material comprises a hydrogelic material.
In the sense of the present invention, the term "hydrogelic material" means and/or includes especially that this material comprises polymers that in water form a water-swollen network.
The term "hydrogel material" in the sense of the present invention furthermore especially means that at least a part of the hydrogel material comprises polymers that in water form a water-swollen network and/or a network of polymer chains that are water-soluble. Preferably the hydrogel material comprises in swollen state >50% water and/or solvent, more preferably >70% and most preferred >90%, whereby preferred solvents include organic solvents, preferably organic polar solvents and most preferred alkanols such as Ethanol, Methanol and/or (Iso-) Propanol. In the sense of the present invention, the term "hydrogelic material" means and/or includes especially that the hydrogel is responsive which means that it
displays a change of shape and total volume upon a change of a specific parameter.
Such parameter can be a physical (temperature, pressure) or chemical property
(ionic concentration, pH, analyte concentration) or biochemical property (enzymatic activity). According to an embodiment of the present invention, the hydrogel material comprises a material selected out of the group comprising poly(meth)acrylic materials, silicagel materials, subsituted vinyl materials or mixture thereof.
According to an embodiment of the present invention, the hydrogel material comprises a substituted vinyl material, preferably vinylcaprolactam and/or substituted vinylcaprolactam.
According to an embodiment of the present invention, the hydrogel material comprises a poly(meth)acrylic material made out of the polymerization of at least one (meth)acrylic monomer and at least one polyfunctional (meth)acrylic monomer.
According to an embodiment of the present invention, the
(meth)acrylic monomer is chosen out of the group comprising (meth)acrylamide, acrylic esters, hydroxyethyl(meth)acrylate, ethoxyethoxyethyl(meth)acrylate or mixtures thereof. According to an embodiment of the present invention, the polyfunctional (meth)acrylic monomer is a bis-(meth)acryl and/or a tri-(meth)acryl and/or a tetra-(meth)acryl and/or a penta-(meth)acryl monomer.
According to an embodiment of the present invention, the polyfunctional (meth)acrylic monomer is chosen out of the group comprising bis(meth)acrylamide, tetraethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, tripropyleneglycol di(meth)acrylates, pentaerythritol tri(meth)acrylate polyethyleneglycoldi(meth)acrylate, ethoxylated bisphenol-A-di(meth)acrylate , hexanedioldi(meth)acrylate or mixtures thereof. According to an embodiment of the present invention, the hydrogel material comprises an anionic poly(meth)acrylic material, , preferably selected out of
the group comprising (meth)acrylic acids, arylsulfonic acids, especially styrenesulfonic acid, itaconic acid, crotonic acid, sulfonamides or mixtures thereof, and/or a cationic poly(meth)acrylic material , preferably selected out of the group comprising vinyl pyridine, vinyl imidazole, aminoethyl (meth)acrylates or mixtures thereof, co -polymerized with at least one monomer selected out of the group neutral monomers, preferably selected out of the group vinyl acetate, hydroxyethyl (meth)acrylate (meth)acrylamide, ethoxyethoxyethyl(meth)acrylate or mixture thereof, or mixtures thereof. These co-polymers change their shape as a function of pH and can respond to an applied electrical field and/or current by as well. Therefore these materials may be of use for a wide range of applications within the present invention.
According to an embodiment of the present invention, the first material comprises a hydrogelic material comprising thermo-sensitive polymers. According to an embodiment of the present invention, the first material comprises a hydrogelic material comprising monomers selected out of the group comprising poly-N-isopropylamide (PNIPAAm) and copolymers thereof with monomers selected out of the group comprising polyoxy ethylene, trimethylol- propane distearate, poly-ε-caprolactone or mixtures thereof.
According to an embodiment of the present invention, the hydrogel material is based on thermo -responsive monomers selected out of the group comprising N-isopropylamide , diethylacrylamide, carboxyisopropylacrylamide, hydroxymethylpropylmethacrylamide, acryloylalkylpiperazine. and copolymers thereof with monomers selected out of the group hydrophilic monomers, comprising hydroxyethyl(meth)acrylate, (meth)acrylic acid, acrylamide, polyethyleneglycol(meth)acrylate or mixtures thereof, and/or co -polymerized with monomers selected out of the group hydrophobic monomers, comprising (iso)butyl(meth)acrylate, methylmethacrylate, isobornyl(meth)acrylate or mixtures thereof. These co-polymers are known to be thermo -responsive and therefore may be of use for a wide range of applications within the present invention.
According to an embodiment of the present invention, the first material comprises a hydrogelic material with a swelling ratio of >1% and <500% at 200C.
In the sense of the present invention, the swelling ratio especially includes, means or refers to a measurement according to the following procedure:
The first material was dried to form a film in an oven under the temperature of 500C. The film was immersed in an excess of deionized water to remove the residual unreacted compounds. The swollen polymer film was then cut into disk forms with 8mm in diameter and dried at 500C until the weight no longer changed. A preweighed dried sample (Wo) was immersed in an excess of deionized water in a thermostatic water bath until the swelling equilibrium was attained. The weight of the wet sample (Wi) was determined after the removal of the surface water via blotting with filter paper. The equilibrium swelling ration was calculated with the following formula swelling ratio = (Wi - W0) / W0
According to an embodiment of the present invention, the first material comprises a hydrogelic material with a swelling ratio of >3% and <200% at 200C.
According to an embodiment of the present invention, the first material comprises a hydrogelic material with a swelling ratio of >5% and <100% at 200C.
According to an embodiment of the present invention, the first material comprises a hydrogelic material with a swelling ratio of >1% and <30% at 200C. According to an embodiment of the present invention, the first material comprises a hydrogelic material with a swelling ratio of >1% and <25% at 200C.
According to an embodiment of the present invention, the first material comprises a hydrogelic material with a swelling ratio of >1% and <20% at 200C.
According to an embodiment of the present invention, the first material comprises a receptor for the analyte to be detected.
In the sense of the present invention, the term "receptor" means and/or includes especially that some chemical moieties are present in the first material which are capable to interact with a selected analyte e.g. by hydrostatic interactions, hydrogen bonding, chemical reception, molecular recognition and the like.
An example of such a receptor system is "calmodulin" which binds to both calcium as well as to a range of anti-spychotic molecules, referred to as the phenothiazines, [J.D. Ehrick (Nature Materials p. 298-302, Vol. 4, April 2005)], which is hereby fully incorporated by reference.
According to an embodiment of the present invention, the first material is a polymeric material.
According to an embodiment of the present invention, the first material is a polymeric material with a conversion of >50% and <100%.
In the sense of the present invention, the conversion especially includes, means or refers to a measurement according to the following procedure:
After the polymerization of the first material and the embedding of the at least one second material, a quantitative amount of inhibitor was introduced into a sample of the first material and the sample was quickly quenched in an ice bath. For the removal of remaining monomers and initiators, the sample as washed with deionized water several times. After that, the sample was dried in vacuum oven at 700C until there was no change in weight anymore. The conversion was calculated as follows: conversion = (P-F)/Mo * 100 % where P is the weight of the dry copolymer composite network obtained from the sample, F is the theoretical weight of the at least one second material incorporated in the first material and M0 is the weight of the monomers in the feed. According to an embodiment of the present invention, the first material is a polymeric material with a conversion of >70% and <95% .
The term "essentially" means and/or includes especially a wt-% content of >90 %, according to an embodiment >95 %, according to an embodiment >99 %.
According to an embodiment of the present invention, the crosslink density in the first material is >0.002 and <1 , preferably >0.05 and <1.
In the sense of the present invention, the term "crosslink density" means or includes especially the following definition: The crosslink density δx is
here defined as δ „ = where X is the mole fraction of polyfunctional x L + X monomers and L the mole fraction of linear chain (= non polyfunctional) forming monomers. In a linear polymer δx = 0 , in a fully crosslinked system δx = 1 .
According to an embodiment of the present invention, the at least one second material comprises a coating.
According to an embodiment of the present invention, the at least one second material comprises a coating which is adapted to increase the ability of the at least one second material to attach to the hydrogel network so that the particles are fixed to the network and cannot diffuse out the network.
According to an embodiment of the present invention, the at least one second material comprises a coating with a thickness of ≥O.l nm and <10 nm, according to an embodiment >1 and <5 nm. According to an embodiment of the present invention, the at least one second material comprises a coating which consists essentially out of a material selected out of the group inorganic oxides, polymeric organic materials, non- polymeric organic materials and mixtures thereof.
According to an embodiment of the present invention the at least one second material and/or the core of the at least one second material is made essentially out of a material selected out of the group comprising iron alloys, iron oxides, nickel alloys, nickel oxides, cobalt oxides, cobalt alloys, rare earth oxides, rare earth alloys rand mixtures thereof that exhibit magnetic properties.
According to an embodiment of the present invention the at least one second material and/or the core of the at least one second material is made essentially out of FesO/t.
According to an embodiment of the present invention, the sensor comprises at least one current delivering means adapted to provide a current in such a way as to cause a change in orientation in the magnetic dipoles in the at least one second material.
Preferably, the sensor is selected from the group comprising electromagnetic detectors, AMR, TMR, GMR, Hall sensors, acoustic and/or optical detectors.
According to an embodiment of the present invention, the distance between the sensor and the first material is > 100 nm and <1 μm, preferably >200 nm and <500 nm.
According to an embodiment of the present invention, the distance between the sensor and at least one second material is > 100 nm and <3 μm, preferably >200 nm and <2000 nm.
However, according to a different embodiment, the distance between the sensor and at least one second material is >3 μm and <20 μm, preferably >5 μm and <10 μm. Surprisingly the inventors have found out that for a wide range of applications within the present invention - especially if a GMR element is used as a sensor - there may be two preferred regions for the distance between the sensor and the first material as well as the thickness of the layer of the first material itself.
Without being bound to any theory, the inventors believe that these two regions may occur due to a turning point in single bead signal (in nV) vs. the distance from the GMR-Element.
However, it should be stressed that although this turning point has been found in a wide range of applications within the present invention, this behaviour does not necessarily need to be found in all applications.
According to an embodiment of the present invention, the sensor comprises at least one sensor and at least one GMR element adapted to measure the change of the resistance of an GMR element caused by the in-plane component of the magnetic stray-field of the oriented dipoles in the at least one second material. A GMR element suitable for use in the present invention is e.g. disclosed in the EP 1459084 and cited documents within this application, which are hereby fully enclosed by reference.
According to a further embodiment of the present invention, the second material is embedded and/or incorporated in a third matrix material. By doing so, it can for a wide range of applications within the present invention be ensured that the arrangement of the second material does not change during the lifetime of the sensor.
Preferably the matrix material is a polymeric organic material, which is preferably and according to a further embodiment of the present invention permeable to the sample to be analyzed by the first material. Suitable and insofar preferred materials for the matrix material include hydrogels, porous polymeric networks obtained e.g. by polymerization induced phases separation. Typical pore size range from a few nanometer to several micrometer.
However, according to another embodiment of the present invention porous inorganic material is used to embed said second material. Suitable materials are porous silica gels, other silicon based structures, or metallic systems such as anodized alumina.
According to a further embodiment of the present invention, the first material is functionalized in order to bind to the at least one second material and/or to the matrix material described above.
According to a further embodiment of the present invention, the first material is partially made out of a material compolymeried with glycidylmethacrylate and/or acrylic acid N-hydroxy succinimide ester. By doing so it has been found that the second material may bind itself to the epoxy groups (in case of the glycidylmethacrylate) or the ester groups (in case of the succinimide ester)s for many applications within the present invention.
According to a further embodiment the first material comprises biotinylated and/or streptavidin functionalized end-groups. By doing so, the biotin /streptavidin link may be used to bind the second material to the first material, which has been shown to be advantageous for a wide range of applications within the present invention.
According to a further embodiment the adhesion between the first and second material(s) is enhanced by applying an adhesion promoter. Alternatively or additionally, according to a further embodiment the first material is provided with primary amine side groups, which may covalently bond to the second material provided with epoxy or NHS functionalities. This has been shown to be advantageous for a wide range of applications within the present invention.
For example the responsive hydrogel monomers can be copolymerized with glycidylmethacrylate (to obtain epoxy side groups) or acrylic acid N-hydroxy succinimide ester (NHS). When functionalized with primary amine groups the magnetite particles can be covalently linked to the hydrogel surface. Alternatively, biotinylated beads can be coupled to a strepavidin- functionalized hydrogel.
According to a further embodiment of the present invention, the first material is at least partly surrounded by a well coated with a non-sticking material, which has a surface tension of <30 mN/m, preferably <25 mN/m.
According to a further embodiment of the present invention the first material is surrounded by the non-sticking material which has a surface tension of <30 mN/m, preferably <25 mN/m in substantially all directions which are perpendicular to the changing direction. According to a further embodiment of the present invention, the non- sticking material is a fluor-containing material, preferably a fluorinated monolayer material, which was preferably made using plasma treatment, e.g. CF4 plasma treatment or by vapour deposition of a fluorsilane e.g. perfluoroalkylchlorosilane.
According to a further embodiment, the device comprises a substrate and/or matrix material in the vicinity of the first material, whereby the device
comprises at least one adhesion promoting layer between the first material and the substrate and/or matrix material.
According to a preferred embodiment of the present invention, the adhesion promoting layer is a monolayer. Preferably the at least one adhesion promoting layer is chosen from the group silane-containing layers, thiol-containing layers, amine-containing layers or mixtures thereof.
The term "silane-containing layer" especially means and/or includes a layer which comprises a material of the form
R3 and R4 are independently selected out of the group halogen, R6-
R7 (whereby R6 is selected out of the group comprising acrylate, methacrylate, acrylamide, methacrylamide, allyl, vinyl, acetyl, amine, epoxy or thiol and R7 is selected out of the group alkyl, aryl, mono- or polyalkoxy, mono- or polyalkylamine, mono- or polyamide, thioether, mono- or polydisulfides), 0-R8
(whereby Rg is selected out of the group hydrogen, alkyl, long-chain alkyl, aryl, heteroaryl, halogen)
R5 represents the group O-R9, where R9 is selected out of the group hydrogen, alkyl, long-chain alkyl, aryl, halogen and/or R5 is a hydrolyzable moiety. Generic group definition: Throughout the description and claims generic groups have been used, for example alkyl, alkoxy, aryl. Unless otherwise
specified the following are preferred groups that may be applied to generic groups found within compounds disclosed herein: alkyl: linear and branched Cl-C8-alkyl, alkylene: selected from the group consisting of: methylene; 1,1 -ethylene; 1,2-ethylene; 1,1-propylidene; 1,2- propylene; 1,3- propylene; 2,2-propylidene; butan-2-ol-l,4-diyl; propan-2-ol-l,3- diyl; 1, 4-butylene; cyclohexane-l,l-diyl; cyclohexan-l,2-diyl; cyclohexan-1,3- diyl; cyclohexan-l,4-diyl; cyclopentane- 1,1 -diyl; cyclopentan-l,2-diyl; and cyclopentan- 1,3-diyl, long-chain alkyl: linear and branched C5-C20 alkyl alkenyl: C2-C6-alkenyl, cycloalkyl: C3-C8-cycloalkyl, alkoxy: Cl-C6-alkoxy, long-chain alkoxy: linear and branched C5-C20 alkoxy aryl: selected from homoaromatic compounds having a molecular weight under 300, arylene: selected from the group consisting of: 1 ,2-phenylene; 1,3- phenylene; 1 ,4-phenylene; 1,2-naphtalenylene; 1,3-naphtalenylene; 1,4- naphtalenylene; 2,3-naphtalenylene; l-hydroxy-2,3-phenylene; l-hydroxy-2,4- phenylene; l-hydroxy-2,5- phenylene; and l-hydroxy-2,6-phenylene, heteroaryl: selected from the group consisting of: pyridinyl; pyrimidinyl; pyrazinyl; triazolyl; pyridazinyl; 1,3,5-triazinyl; quinolinyl; isoquinolinyl; quinoxalinyl; imidazolyl; pyrazolyl; benzimidazolyl; thiazolyl; oxazolidinyl; pyrrolyl; carbazolyl; indolyl; and isoindolyl, wherein the heteroaryl may be connected to the compound via any atom in the ring of the selected heteroaryl, amine: the group -N(R)2 wherein each R is independently selected from: hydrogen; Cl-C6-alkyl; Cl-C6-alkyl-C6H5; and phenyl, wherein when both R are Cl-C6-alkyl both R together may form an - NC3 to an -NC5 heterocyclic ring with any remaining alkyl chain forming an alkyl substituent to the heterocyclic ring, halogen: selected from the group consisting of: F; Cl; Br and I,
polyether: chosen from the group comprising-(O-CH2-CH(R))n-OH and -(O-CH2-CH(R))n-H whereby R is independently selected from: hydrogen, alkyl, aryl, halogen and n is from 1 to 250.
Unless otherwise specified the following are more preferred group restrictions that may be applied to groups found within compounds disclosed herein: alkyl: linear and branched Cl-C6-alkyl, long-chain alkyl: linear and branched C5-C10 alkyl, preferably linear C6-C8 alkyl alkenyl: C3-C6-alkenyl, cycloalkyl: C6-C8-cycloalkyl, alkoxy: Cl-C4-alkoxy,
long-chain alkoxy: linear and branched C5-C10 alkoxy, preferably linear C6-C8 alkoxy aryl: selected from group consisting of: phenyl; biphenyl; naphthalenyl; anthracenyl; and phenanthrenyl, heteroaryl: selected from the group consisting of: pyridinyl; pyrimidinyl; quinolinyl; pyrazolyl; triazolyl; isoquinolinyl; imidazolyl; and oxazolidinyl, wherein the heteroaryl may be connected to the compound via any atom in the ring of the selected heteroaryl, heteroarylene: selected from the group consisting of: pyridin 2,3-diyl; pyridin-2,4-diyl; pyridin-2,6- diyl; pyridin-3,5-diyl; quinolin-2,3-diyl; quinolin-2,4-diyl; isoquinolin-l,3-diyl; isoquinolin-l,4-diyl; pyrazol-3,5-diyl; and imidazole-2,4-diyl, amine: the group -N (R) 2, wherein each R is independently selected from: hydrogen; Cl-C6-alkyl; and benzyl, halogen: selected from the group consisting of: F and Cl, polyether: chosen from the group comprising-(O-CH2-CH(R))n-OH and -(O-CH2-CH(R))n-H whereby R is independently selected from: hydrogen, methyl, halogen and n is from 5 to 50, preferably 10 to 25.
It has been shown for a wide range of applications that this silane- containing layer helps to link the first material to the substrate and/or matrix material essentially without influencing the performance of the sensor device.
The term "thiol-containing layer" especially means and/or includes a layer which comprises a material of the form R-SH with R chosen out of the group alkyl, long-chain alkyl, alkenyl, cycloalkyl.
It has been shown for a wide range of applications that this thiol- containing layer helps to link the first material to the substrate and/or matrix material essentially without influencing the performance of the sensor device. If a thiol- containing layer is used, the surface of the matrix material is chosen out of a thiol- binding material, especially the surface of the matrix material is an Au-surface.
The term "amine-containing layer" especially means and/or includes a layer which comprises a material of the form Ri-NH-R2 with Ri chosen out of the group alkyl, long-chain alkyl, alkenyl, cycloalkyl, polyether and R2 chosen out of the group hydrogen, alkyl, long-chain alkyl, alkenyl, cycloalkyl, polyether.
It has been shown for a wide range of applications that this amine- containing layer helps to link the first material to the substrate and/or matrix material essentially without influencing the performance of the sensor device. If a amine- containing layer is used, the surface of the matrix material is preferably equipped with amine-binding groups, preferably epoxy groups and/ or reactive esters, halogenides and/or amines.
The present invention furthermore relates to a method of measuring the presence, identity, amount and/or concentration of at least one analyte in a sample using a sensor as described above, comprising the steps of (a) Allowing the first material to interact with the at least one analyte to cause a change of physical properties in the first material
(b) Measuring the change of at least one signal detected by the sensor upon interaction with the at least one second material.
According to an embodiment of the present invention, the first material changes its size and/or thickness when interacting with the at least one analyte.
A sensor and/or a method according to the present invention may be of use in a broad variety of systems and/or applications, amongst them one or more of the following: biosensors used for molecular diagnostics - rapid and sensitive detection of proteins and nucleic acids in complex biological mixtures and body fluids such as e.g. blood, urine or saliva high throughput screening devices for chemistry, pharmaceuticals or molecular biology testing devices e.g. for DNA or proteins e.g. in criminology, for on- site testing (in a hospital), for diagnostics in centralized laboratories or in scientific research tools for DNA or protein diagnostics for cardiology, infectious disease and oncology, food, and environmental diagnostics tools for combinatorial chemistry - analysis devices
The aforementioned components, as well as the claimed components and the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept such that the selection criteria known in the pertinent field can be applied without limitations.
Additional details, features, characteristics and advantages of the object of the invention are disclosed in the subclaims, the figures and the following description of the respective figures and examples, which — in an exemplary fashion — show preferred embodiments of a sensor according to the invention.
Fig. 1 shows a very schematic cross-sectional view of a sensor according to a first embodiment of the present invention;
Fig. 2 shows a very schematic cross-sectional view of a sensor according to a second embodiment of the present invention;
Fig. 3 shows a very schematic cross-sectional enlarged view of a first and second material according to a second embodiment of the present invention;
Fig. 4 shows a very schematic cross-sectional enlarged view of a first and second material according to a third embodiment of the present invention;
Fig. 5 shows a diagram of the single bead signal (in nV) vs. the distance from the GMR-Element to the bead (in μm) for an embodiment according to Example I of the present invention; and
Fig. 1 shows a very schematic cross-sectional view of a sensor 1 according to a first embodiment of the present invention. The sensor comprises a first material 10, upon which a second material 20 in form of droplets is provided. The second material in this embodiment comprises a magnetic material and may be placed upon the first material by ink-jet printing. To prevent diffusion of precursors (i.e. monomer, particles) of the second layer into the first layer during processing it is especially preferred that the first layer is then in the collapsed state. In order to ensure a good adhesion between the first and second material, the first material 10 may be on the upper surface be coated with a suitable adhesion promoter. The first material is provided on a matrix material 30, which serves to protect a current wire 40 and a GMR sensor 50. The matrix material 30 itself is placed on a substrate 60.
The matrix or at least the part of the matrix with projects towards the first material is preferably made out of SiC>2 in order to provide for a good attachment of the first material. The substrate material can be any suitable material, preferably silicon.
Fig. 2 shows a very schematic cross-sectional view of a sensor 1 ' according to a first embodiment of the present invention.
In Fig. 2, the components, which are (essentially) identical with the embodiment of Fig. 1 are not discussed to avoid repetitions.
The embodiment of Fig. 2 differs from that of Fig. 1 that a silane- containing layer 35 is provided between the substrate and the first material. It should be noted that in Fig. 2 the dimensions of the silane-containing layer 35 are grossly exaggerated for visibility purposes; in most actual applications of the present invention, the silane-containing layer 35 will be a monolayer.
Furthermore the embodiment of Fig. 2 comprises a non-sticking material 70 which is provided in the directions which are not the changing direction (which in this embodiment is vertical). Here, too the dimensions of the non-sticking material 70 are greatly enlarged for visibility purposes. The non-sticking material essentially ensures a homogenous swelling and/or shrinking of the first material.
As can be seen from Fig. 2 (in conjunction with Fig. 1), the sensor direction is essentially perpendicular (i.e. in this embodiment is the horizontal direction) to the changing direction.
The non-sticking material is itself provided with sidewalls 80, which may be of any suitable material. In some applications, resist materials, such as SU-8 have shown to be advantageous and form therefore a preferred embodiment of the present invention.
Fig. 3 and 4 show very schematic cross-sectional enlarged partial views of a first and second material according to a second and third embodiment of the present invention.
Instead of placing the second material 20 in form of droplets on the first material 10, the second material may be provided in form of a porous material (Fig. 3) or a patterned material (Fig. 4) in order to ensure that analyte-containing fluid may reach the first material. In Fig. 3 and 4, the particles are embedded in a polymer that contains pores for the permeation of the analyte. The pores may either be created by polymerization-induced phase separation (e.g. some accrylates TEGDMA with porogenic solvent, TPG) to create randomly formed pores (Figure 3) or the layer may be pattered by means of photo-lithography through a mask or holography (Figure 4). Although the magnetic particles absorb UV-light and therefore the intensity distribution in the layer will not be homogeneous (in fact a polymerization
gradient in the z-direction will be present) the influence will be marginal since the thickness of the layer is « lμm.
Instead of the embodiments of Fig. 3 and 4, it is also possible and a further embodiment of the present invention (not shown in the figs) to embed the second material in a polymer (= third material), which is permeable for the analyte to be detected. Hydrogels are suitable third materials as the analyte is an aqueous solution. Non-limiting Examples are e.g. Poly(acrylamide/bisacrylamide), Po ly(hydroxyethy lacrylate/ diethyleneglycoldiacrylate) .
EXAMPLES:
The invention is furthermore - in a merely illustrated way - more to be understood by the following examples.
EXAMPLE I
In this example, a sensor according to Fig. 1 was used. In this embodiment PNIPAM hydrogel provided with a receptor for glucose was used as a first material and subsequently a second layer was coated onto the polymerized first layer. The second material was provided in the form of droplets out of Fe3θr on top of the first material, (as shown in Fig. 1)
The concentration of glucose is measured the following way. A current is led through the current wire (whereby the direction of the current is perpendicular to the paper plane). This causes a change in the orientation of the magnetic dipoles of the at least one second material, which can be detected via the GMR-sensor. The resulting voltage drop over the GMR element is dependent on the reaction of the first material with the glucose in that a decrease of the glucose concentration leads to an expansion of the first material which will cause an increase of the electrical resistance of the GMR element. When a constant current is applied to the element, this will lead to an increase of the voltage drop over the element.
In the example, the rise in voltage is in the range of tens of micro Volts per 1% of volume change, as can be seen in Fig. 5.
The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.
Claims
1. A magnetochemical sensor, especially for determining the presence, identity, amount and/or concentration of at least one analyte in a fluid sample comprising
(a) a first material, whereby the first material is an elastic material adapted to change its physical properties according to interaction with said at least one analyte;
(b) at least one sensor;
(c) at least one second material adapted to interact with the at least one sensor whereby the second material is a magnetic material not embedded in said first material. whereby the first, at least one second material and the at least one sensor are so provided towards each other that upon a change of the physical properties of the first material a change in at least one of the signals detected by the at least one sensor occurs.
2. The sensor according to claim 1, comprising a changing direction, essentially in which the change of the first material in response to the at least one analyte occurs.
3. The sensor according to any of the claims 1 to 3, whereby the at least one sensor and/or the at least one second material are provided in the changing direction at opposite ends of the first material.
4. The sensor according to any of the claims 1 to 4, whereby the thickness of the at least one second material is >0.5 μm and <10 μm.
5. The sensor according to any of the claims 1 to 5 whereby the at least one second material is provided next to the first material.
6. The sensor according to any of the claims 1 to 5 whereby the at least one second material is patterned in form of and/or comprises small magnetic particles / moieties, preferably with a diameter of ≥lOnm and <5μm
7. The sensor according to any of the claims 1 to 6 whereby the second material is embedded and/or incorporated in a matrix material.
8. A method of measuring the presence, identity, amount and/or concentration of at least one analyte in a sample using a sensor according to any of the claims 1 to 7, comprising the steps of
(a) Allowing the first material to interact with the at least one analyte to cause a change of physical properties in the first material
(b) Measuring the change of at least one signal detected by the sensor upon interaction with the at least one second material.
9. The method of claim 8, whereby the first material changes its size and/or thickness when interacting with the at least one analyte.
10. A system incorporating a sensor according to any of the Claims 1 to 7, and/or adapted to carry out the method of the claims 8 and 9 and being used in one or more of the following applications: - biosensors used for molecular diagnostics rapid and sensitive detection of proteins and nucleic acids in complex biological mixtures such as e.g. blood or saliva high throughput screening devices for chemistry, pharmaceuticals or molecular biology testing devices e.g. for DNA or proteins e.g. in criminology, for on-site testing (in a hospital), for diagnostics in centralized laboratories or in scientific research tools for DNA or protein diagnostics for cardiology, infectious disease and oncology, food, and environmental diagnostics - tools for combinatorial chemistry analysis devices
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150143432A (en) * | 2013-03-11 | 2015-12-23 | 유니버시티 오브 유타 리서치 파운데이션 | Sensor systems |
| US10491277B2 (en) | 2008-04-29 | 2019-11-26 | Apple Inc. | Feedback based on codebook subset |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6397661B1 (en) * | 1998-12-30 | 2002-06-04 | University Of Kentucky Research Foundation | Remote magneto-elastic analyte, viscosity and temperature sensing apparatus and associated methods of sensing |
| GB2383846A (en) * | 2002-01-02 | 2003-07-09 | Sentec Ltd | Passive biological sensor |
| US20050116831A1 (en) * | 2003-12-01 | 2005-06-02 | Anis Zribi | Contactless humidity/chemical vapor sensor device and associated method of fabrication |
| WO2007072243A1 (en) * | 2005-12-21 | 2007-06-28 | Koninklijke Philips Electronics N.V. | Magnetochemical sensor |
-
2008
- 2008-04-30 WO PCT/IB2008/051677 patent/WO2008135916A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6397661B1 (en) * | 1998-12-30 | 2002-06-04 | University Of Kentucky Research Foundation | Remote magneto-elastic analyte, viscosity and temperature sensing apparatus and associated methods of sensing |
| GB2383846A (en) * | 2002-01-02 | 2003-07-09 | Sentec Ltd | Passive biological sensor |
| US20050116831A1 (en) * | 2003-12-01 | 2005-06-02 | Anis Zribi | Contactless humidity/chemical vapor sensor device and associated method of fabrication |
| WO2007072243A1 (en) * | 2005-12-21 | 2007-06-28 | Koninklijke Philips Electronics N.V. | Magnetochemical sensor |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10491277B2 (en) | 2008-04-29 | 2019-11-26 | Apple Inc. | Feedback based on codebook subset |
| US10848212B2 (en) | 2008-04-29 | 2020-11-24 | Apple Inc. | Feedback based on codebook subset |
| KR20150143432A (en) * | 2013-03-11 | 2015-12-23 | 유니버시티 오브 유타 리서치 파운데이션 | Sensor systems |
| CN105246401A (en) * | 2013-03-11 | 2016-01-13 | 犹他大学研究基金会 | Sensor systems |
| EP2967414A4 (en) * | 2013-03-11 | 2017-02-22 | University Of Utah Research Foundation | Sensor systems |
| RU2670660C2 (en) * | 2013-03-11 | 2018-10-24 | Юнивёрсити Оф Юта Рисёч Фаундейшен | Sensors system |
| RU2670660C9 (en) * | 2013-03-11 | 2018-12-12 | Юнивёрсити Оф Юта Рисёч Фаундейшен | Sensors system |
| US10448895B2 (en) | 2013-03-11 | 2019-10-22 | University Of Utah Research Foundation | Sensor systems |
| KR102242947B1 (en) * | 2013-03-11 | 2021-04-22 | 유니버시티 오브 유타 리서치 파운데이션 | Sensor systems |
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