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WO2003044530A1 - Systeme de detecteur a surface de reference imitant la surface de detection mais a faible capacite de fixation de ligand - Google Patents

Systeme de detecteur a surface de reference imitant la surface de detection mais a faible capacite de fixation de ligand Download PDF

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Publication number
WO2003044530A1
WO2003044530A1 PCT/DK2002/000779 DK0200779W WO03044530A1 WO 2003044530 A1 WO2003044530 A1 WO 2003044530A1 DK 0200779 W DK0200779 W DK 0200779W WO 03044530 A1 WO03044530 A1 WO 03044530A1
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WO
WIPO (PCT)
Prior art keywords
capture
ligand
sensor
surface area
unit
Prior art date
Application number
PCT/DK2002/000779
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English (en)
Inventor
Carsten Faltum
Original Assignee
Cantion A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cantion A/S filed Critical Cantion A/S
Priority to AU2002350427A priority Critical patent/AU2002350427A1/en
Publication of WO2003044530A1 publication Critical patent/WO2003044530A1/fr

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Classifications

    • 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
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings

Definitions

  • the present invention relates to a sensor system for detecting the presence or the amount of a substance e.g. 5 a target biocomponent in a fluid such as a liquid.
  • Measuring the reflection angle from a laser beam that is directed to the cantilever can detect a deflection.
  • Another sensor principle is the use of a piezoresistor integrated into the cantilever. In this detection principle the deflection/stretch is detected as a change in the electrical resistance of the piezoresistor.
  • the signal from the measuring cantilever comprises both the signal from the deflection and stretch of the cantilever but also from noise.
  • a blank 30 cantilever can be coupled e.g. in a Wheatstones bridge with the measuring cantilever in order to eliminate the mechanical noise in the system which may include, but is not limited to, external vibration, temperature changes etc . 35
  • the signal from the reference cantilever can be described as:
  • the noise of the signal has thereby been reduced significantly.
  • the signal measured still includes noise, and it is the object of the present invention to provide a sensor system where the amount of noise is even further reduced than in the prior art solutions described above.
  • the signal from the measuring cantilever will be a combination of several components:
  • S mech no ⁇ se Signal due to mechanical noise, e.g. external vibrations, temperature variation
  • Unspecific binding is a substantial problem in all binding assays as it is impossible today to distinguish between specific and unspecific binding.
  • the formulas above and the use of a traditional reference cantilever do not eliminate this problem.
  • the objective of the invention is therefore to provide a sensor system which system does not have the drawbacks as described above.
  • the invention as it is defined in the claims provides a sensor system with a reduced level of noise compared to prior art sensors.
  • the sensor system comprises at least two flexible units, wherein one of said units is “"a sensor unit ' ' and another one is “a reference unit 1 '.
  • the sensor unit comprises a capture surface area which area has been functionalised by linking one or more functional groups comprising a capture ligand to said capture surface area.
  • the reference unit comprises an imitated capture surface area, which area has been functionalised by linking, preferably covalently linking one or more functional groups.
  • the reference unit differs from the sensor unit in the composition of the functional groups linked to its surface.
  • the main issue of the invention is that the reference unit is functionalised but that it contains less or no functional groups which are identical with the capture ligand of the sensor unit.
  • the imitated surface area contains no or less members of the specific binding pair which is complementary to the same binding partner member as the capture ligand of the sensor unit. Disclosure of the invention
  • the sensor system of the invention concerns a set-up as defined in the claims which system comprises a measuring sensor unit which is coupled to an "intelligent ' ' reference unit.
  • the reference unit can be used to partly or totally eliminate not only mechanical noise, but also to reduce or eliminate the noise originating from unspecific binding.
  • the sensor unit is functionalised by immobilising capture molecules as normally to a capture surface area of the sensor unit. Contrary to the normal procedure, the reference unit is also functionalised at a surface area designated "an imitated capture surface area 1 '.
  • the noise is reduced significantly, e.g. to 50 % or lower compared to prior art technology.
  • the noise resulting from unspecific binding is essentially eliminated i.e. within measuring uncertainty.
  • a ligand' ' means a type of ligand
  • a binding partner'' means a type of binding partner and so on.
  • Both the capture surface area (which means the capture surface area of the sensor unit) , and the imitated capture surface area (which means the imitated capture surface are of the reference unit) are functionalised by linking one or more functional groups to the surfaces, preferably so that the amount of proteins, amino acids and/or lipids that binds via unspecific binding to the imitated capture surface area is closer to the amount of similar components that binds via unspecific binding to the capture surface area than if the reference unit was not functionalised.
  • the functional groups linked to the capture surface area and the reference surface area, respectively, may be linked chemically e.g. covalently or ionic bondings; or physically. In one embodiment, one or more of the functional groups are linked via covalent bonds. In one embodiment, one or more of the functional groups are linked by adsorption.
  • Adsorption means a non-specific physical interaction between the functional groups and the surface area. Adsorption is relatively cheap, easily carried out, and tends to be less disruptive to enzymic proteins than chemical means of attachment, the adsorption binding being mainly by hydrogen bonds, multiple salt linkages, and Van der Waal's forces. Adsorption bears the greatest similarity to the situation found in biological membranes in vivo and may therefore in some embodiments be preferred.
  • the size of the sensor unit capture surface area and the size of the reference unit imitated surface area may differ from each other or it may be equal. If the size of the sensor unit capture surface area and the size of the reference unit are equal to each other, the calculation of the signal with reduced or no noise is easier than if the sizes differ from each other. In the latter case, a correlation factor compensating for the size difference should be implemented.
  • the capture ligand is a member of a specific binding pair.
  • Such ligands which is members of a specific binding pair is well known in the art, and further, information concerning such binding pair can be found in WO 0066266, WO 9938007, US 5,156,810, WO 0036419 and WO 9631557 which publication are hereby incorporated by reference.
  • specific bonding pair any pair of target molecule/capture ligand with an ability to specifically bind to one another e.g. receptor/target ligand, enzyme/substrate (or analogue) , nucleic acid binding protein/nucleic acid etc.
  • specific bonding pair of target molecule/capture ligand is thereby said to be complementary to each other.
  • the binding pair in the form of the capture ligand binding partner and a target binding partner is selected among antigen-antibodies or fragments thereof and nucleic acid strands - nucleic acid strands.
  • a molecule that shows similarity to the capture molecules is immobilised to the reference unit.
  • the molecules on the reference unit though, in this embodiment do not exhibit a specific binding to the analyte that the assay is designed to detect .
  • the one or more functional groups linked to the imitated capture surface area of the reference unit do not include a ligand, which is identical with the capture ligand. In one embodiment, the one or more functional groups linked to the surface area of said reference unit do not include a ligand which is a member of the specific binding pair.
  • the molecules on the reference unit can belong to any class of molecules and do not necessarily have to be of the same class as the molecules on the sensor unit.
  • the functional group linked to the imitated surface area of the reference unit includes a reference ligand.
  • the reference ligand may in one embodiment be present in a number which is 50 % or more such as 75 % or more, such as 90 % or more of the number of capture ligands on the capture surface of the sensor unit.
  • the reference ligand is of the same chemical class as the capture ligand of the sensor unit.
  • the chemical class may e.g. be one of a) nucleic acids and strands thereof such as DNA oligos, PNA oligos, RNA oligos; b) proteins including peptides, antigen, antibodies and hormones; and c) lipids.
  • the sensor system is directed to detecting the presence of a preselected target biocomponent.
  • the sensor unit comprises a capture surface area which area has been functionalised by linking a capture ligand, where said capture ligand is a capture ligand for the preselected target biocomponent.
  • the reference unit comprises an imitated capture surface area which area has been functionalised by linking one or more functional groups, wherein the one or more functional groups of the imitated capture surface have less tendency to bind to the preselected target biocomponent than the capture ligand.
  • the functional groups linked to said imitated capture surface area of said reference unit do not include a ligand, which is a capture ligand for said preselected target biocomponent.
  • the amount of proteins, amino acids and/or lipids that binds via unspecific binding to the imitated capture surface area is 50 % or more, such as 60 % or more, such as 70 % or more, such as 80 % or more, such as 90 % or more, such as essentially the same as the amount of similar components that binds via unspecific binding to the capture surface area. In one embodiment, this is measured by using DAKO Human Serum Protein Calibrator as test medium. In one embodiment, this is measured by using DAKO Lipoprotein (a) Calibrator as test medium.
  • the analyte which is a binding partner to the capture ligand (if present)
  • the capture ligand will bind to the capture ligand on the sensor unit.
  • various other molecules in the sample will unspecifically bind to the functional groups on the sensor unit.
  • the one or more functional groups of the imitated capture surface have a capture tendency of 50 % or less, such as 40 % or less, such as 30 % or less, such as 20 % or less, such as 10 % or less than the capture tendency of the capture ligand toward said preselected target biocomponent.
  • the reference ligand of the reference unit has essentially the same charge as the capture ligand of at least one sensor unit connected to the reference unit.
  • Essentially the same charge means that the charge of the respective capture/reference ligands differs from each other by 10 % or less, preferably by 5 % or less measured in water.
  • the imitated capture surface area of the reference unit has essentially the same pH value as the capture surface area of at least one sensor unit connected to the reference unit.
  • Essentially the same pH value means that the pH value of the respective surface areas differs from each other by 0.5 pH or less, preferably by 0.1 pH % or less measured in water.
  • the reference ligand of the reference unit has essentially the same hydrophility as the capture ligand of the sensor unit.
  • the reference ligand of the reference unit has essentially the same structure as the capture ligand except for the binding site or sites, which may e.g. be blocked, removed or replaced by non-active chemical group (s) .
  • the imitated capture surface area of the reference unit has a surface tension measured as contact angle to a water droplet which is the same + - 2
  • the capture ligand is present in a first concentration linked to the capture surface area, and the capture ligand linked to the imitated capture surface area in a second concentration, wherein said second concentration is substantially less than the first concentration such as 50 % or less, such as 40 % or less, such as 30 % or less, such as 20 % or less, such as 10 % or less than the first concentration.
  • the first concentration such as 50 % or less, such as 40 % or less, such as 30 % or less, such as 20 % or less, such as 10 % or less than the first concentration.
  • this effect may therefore further be used in determining concentrations of a target biocomponent in a sample.
  • the sensor system comprises one or more sensor units and one or more reference units, where at least one, preferably each of the sensor units, is connected to at least one reference unit.
  • the connection may preferably include a coupling of the connected sensor unit and reference unit so that a signal obtained from the reference unit is subtracted from a signal obtained from the sensor unit, more preferably said sensor unit and said reference unit being coupled in a Wheatstones bridge .
  • the sensor and the reference units are coupled in a way so that the signal from the reference unit (e.g. a cantilever) is subtracted from the signal from the sensor unit (e.g. a cantilever) .
  • the sensor system according to the invention may in principle comprise an unlimited number of sensor units and reference units, and the invention includes embodiments wherein two or more sensor units are coupled to one reference unit, and embodiments wherein two or more reference units are coupled to one sensor units.
  • the sensor system may preferably include two or more sensor unit, preferably at least 5 sensor units, more preferably at least 10 sensor units, wherein each of said sensor units preferably comprises a capture surface area which area has been functionalised by linking, preferably by adsorption linking one or more functional groups comprising a capture ligand to said capture surface area, the capture ligand linked to each sensor units being a member of a specific binding pair.
  • the capture ligand on one sensor unit preferably is different from the capture ligand of another sensor unit.
  • At least one sensor unit and at least one reference unit which are preferably coupled, have substantially the same size.
  • substantially the same size 1 ' means within a 10 % variation based on the largest of the sensor/reference units. In one embodiment, “substantially the same size'' means within a 5 % variation based on the largest of the sensor/reference units .
  • the sensor unit(s) and the reference unit (s) which are coupled together, and preferably all of the sensor units and the reference units may preferably have substantially identical shapes.
  • At least one reference unit coupled to a sensor unit has a thickness which is identical +- 10 % of the thickness of the sensor unit.
  • the capture surface area and imitated capture surface area of pair wise sensor/reference flexible units have substantially identical sizes, wherein "substantially identical 1 ' should mean within a difference of 20 %, preferably within a difference of 10 %, even more preferably within a difference of about 5 %.
  • the flexible unit may in principle have any shape.
  • the flexible unit or a part of the unit is sufficiently flexible to perform a measurable change due to a stress reaction on the capture surface area/imitated capture surface area when the analytes or substances to be detected are adsorbed or linked to the capture surface area.
  • the flexible unit should have a free flexing area which is not directly bonded to a solid material.
  • the flexible units comprise one or more units selected from the group consisting of cantilevers, bridges and membranes.
  • the flexible units are of micro size, which means that the flexible units have dimensions which are 500x500x500 ⁇ m or less, preferably 5x100x200 ⁇ m or less.
  • the shape of the flexible units may e.g. be as described in US 6016686 WO 0066266.
  • the flexible units comprise a piezoresistor by use of which it is possible to register change in stress of the capture surface area. Further information concerning this aspect can also be found in WO 0066266, which information is hereby incorporated by reference.
  • the ligand linked to the sensor unit may preferably be linked via a spacer.
  • Information concerning useful spacer molecules can be found in WO 9631557.
  • the capture ligand is selected from the group consisting of RNA oligos-, DNA oligos, PNA oligos, protein, peptides, hormones, blood components, antigen and antibodies.
  • the capture ligand is a specific binding partner for a biocomponent, preferably selected from the group consisting of RNA oligos, DNA oligos, PNA oligos, protein, peptides, hormones, blood components, antigen and antibodies.
  • biocomponent further includes biomolecules and biocomponents selected from the group consisting of tissue, cells, body fluids, blood components, microorganism, derivatives thereof, or parts thereof.
  • biomolecule includes molecules of microbial, plant, animal, viral, fungal or human origin or synthetic molecules resembling them, preferably selected from the group consisting of proteins, glyco proteins, nucleic acids, such as RNA, DNA including cDNA, PNA, LNA, oligonucleotides, peptides, hormones, antigens, antibodies, lipids, sugars, carbohydrates, and complexes including one or more of these molecules, said biomolecule or molecules preferably being selected from the group consisting of nucleic acids, lipids, antibodies, proteins and protein complexes.
  • the functional groups linked to the sensor unit capture surface area may further comprise one or more components selected from the group consisting of carboxylic acids, esters, acid halides, aldehydes, ketons, alcohols, thiols, disulphides, amins, ethers, halides, hydrazines and saccharides .
  • These one or more components linked to the sensor units may preferably also be linked to the imitated capture surface area of a reference unit connected to the sensor unit .
  • the functional groups linked to the reference unit imitated capture surface area comprise one or more components selected from the group consisting of carboxylic acids, esters, acid halides, aldehydes, ketons, alcohols, thiols, disulphides, amins, ethers, halides, hydrazines and saccharides.
  • the functional groups linked to the reference unit imitated capture surface area further comprise one or more reference ligands.
  • the reference ligand is covalently linked to said imitated capture surface area of the reference unit, optionally via a spacer.
  • the reference unit is adhered to said imitated capture surface area.
  • the reference ligand may e.g. be selected from the group consisting of RNA oligos, DNA oligos, PNA oligos, protein, peptides, hormones, blood components, antigen and antibodies, wherein said reference ligand is different from the capture ligand of a sensor unit connected to said reference unit .
  • the flexible units may be driven by an actuator e.g. comprising a piezoelectric element.
  • the flexible units each comprise a piezoresistor by use of which it is possible to register change in stress of the (imitated) capture surface area.
  • the sensor unit comprises one or more interaction chambers, e.g. as described in WO 0066266.
  • the (imitated) capture surface (s) should be exposed partly or totally to a liquid in at least one interaction chamber.
  • the size of the interaction chamber or chambers differs individually from each other by a volume of up to about 1 ml, such as up to about 0.1 ml, such as up to about 0.05 ml such as up to about 1 ⁇ l .
  • a laminar flow of the test sample may be provided in the chamber, which may also reduce or even eliminate noise originating from turbulence.
  • the sensor unit comprises one or more channels for introducing the sample.
  • the (imitated) capture surface (s) should be exposed to a liquid in at least one channel.
  • the cross dimensions of the channel should be sufficiently small to provide for a laminar flow of a liquid sample through the channel.
  • the channel (s) may e.g. have a cross sectional dimension of up to 250000 ⁇ im 2 , such as up to 100000 ⁇ m 2 , such as up to 25000 ⁇ m 2 , such as up to 2500 ⁇ m 2 .
  • the sensor system may e.g. be produced as disclosed in "atomic force microscopy probe with piezoresistive readout and highly symmetrical Wheatstones bridge arrangement'' Sensors and Actuators 83 (2000) 47-53 by Jacob Taysen et al . and WP 00662266, with the difference that the sensor system is modified according to the claims whereby the sensor unit and the reference unit are functionalised as described above.
  • a sensor and reference unit shaped as cantilevers are prepared with a gold surface for immobilising a ligand in the form of capture/reference ligands to the surface.
  • a first thiol-modified-DNA oligo (the capture oligo) is immobilised to the sensor gold cantilever surface using an Au - S bond .
  • a second thiol-modified-DNA oligo (the reference oligo) is immobilised to the reference cantilever.
  • the reference oligo is chosen so the sequence does not resemble any known or expected sequence in the sample to be analysed.
  • Sample is presented to the assay and specific hybridisation will occur between the capture oligo and DNA in the sample, if the counterpart of the capture oligo is present in the sample.
  • Sensor and a reference unit shaped as cantilevers are prepared with a gold surface for immobilising ligands in the form of capture/reference ligands to the surfaces.
  • An aptimer is immobilised to the surface of the sensor cantilever using a thiol-modified spacer.
  • Sample is presented to the assay and specific binding will occur between the aptimer and analyte in the sample, if the counterpart of the aptimer is present in the sample .
  • a sensor and a reference unit shaped as cantilevers are prepared for immobilising a capture ligand and a reference ligand, respectively.
  • a first capture ligand is immobilised on the surface of the sensor cantilever using adsorption.
  • the first capture molecule is for example Rabbit Anti-Human CRP.
  • a reference ligand is immobilised on the reference cantilever.
  • the second capture molecule is for example Human Anti-Rabbit IgG.
  • the reference capture molecule is chosen such that it shows minimal interaction with the capture ligand.
  • Sample is presented to the assay and specific recognition will occur between the capture ligand on the detection cantilever and its complementary target binding partner, if the target binding partner is present in the sample.

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Abstract

L'invention concerne un système de détecteur présentant au moins deux unités souples, une unité détecteur et une unité de référence. L'unité détecteur comprend une surface de capture fonctionnalisée par liaison d'un ou de plusieurs groupes fonctionnels comprenant un ligand de capture, tel qu'un élément d'une paire de fixation spécifique. L'unité de référence comprend une surface de capture imitée, laquelle surface a été fonctionnalisée par liaison d'un ou de plusieurs groupes fonctionnels, le ou lesdits groupes fonctionnels liés à la surface de capture imitée de ladite unité de référence ne contiennent pas de ligand identique audit ligand de capture. Le ligand de capture peut être, par exemple, un partenaire de liaison spécifique d'un bioconstituant, de préférence sélectionné dans le groupe comprenant des oligos ARN, des oligos ADN, des oligos APN, une protéine, des peptides, des hormones, des constituants du sang, un antigène et des anticorps. L'unité de détecteur et le procédé permettent de réduire le bruit étant donné que le signal obtenu par l'unité de référence qui mesure le bruit peut être soustrait d'un signal obtenu de l'unité détecteur.
PCT/DK2002/000779 2001-11-19 2002-11-19 Systeme de detecteur a surface de reference imitant la surface de detection mais a faible capacite de fixation de ligand WO2003044530A1 (fr)

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AU2002350427A AU2002350427A1 (en) 2001-11-19 2002-11-19 Sensor system with a reference surface mimicking the detection surface but with low ligand binding capacity

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DKPA200101724 2001-11-19
DKPA200101724 2001-11-19

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US7284452B2 (en) 2002-12-27 2007-10-23 Nanonord A/S Cantilever sensor using both the longitudinal and the transversal piezoresistive coefficients
US7521257B2 (en) 2003-02-11 2009-04-21 The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Chemical sensor with oscillating cantilevered probe and mechanical stop
US7579052B2 (en) 2004-09-14 2009-08-25 Ut-Battelle, Llc Method of making gold thiolate and photochemically functionalized microcantilevers
US7694346B2 (en) 2004-10-01 2010-04-06 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada Cantilevered probe detector with piezoelectric element
US8524501B2 (en) 2003-10-17 2013-09-03 Board Of Regents Of The Nevada System Of Higher Education Self-sensing array of microcantilevers for chemical detection
WO2015188002A1 (fr) * 2014-06-05 2015-12-10 Avails Medical, Inc. Systèmes et procédés pour détecter une substance dans un fluide corporel
US9377456B1 (en) 2014-12-30 2016-06-28 Avails Medical, Inc. Systems and methods for detecting a substance in bodily fluid
US10060916B2 (en) 2013-11-21 2018-08-28 Avails Medical, Inc. Electrical biosensor for detecting a substance in a bodily fluid, and method and system for same
US10174356B2 (en) 2016-05-31 2019-01-08 Avails Medical, Inc. Devices, systems and methods to detect viable infectious agents in a fluid sample and susceptibility of infectious agents to anti-infectives
US10254245B2 (en) 2016-01-25 2019-04-09 Avails Medical, Inc. Devices, systems and methods for detecting viable infectious agents in a fluid sample using an electrolyte-insulator-semiconductor sensor
US10883135B2 (en) 2015-08-25 2021-01-05 Avails Medical, Inc. Devices, systems and methods for detecting viable infectious agents in a fluid sample
US11385200B2 (en) 2017-06-27 2022-07-12 Avails Medical, Inc. Apparatus, systems, and methods for determining susceptibility of microorganisms to anti-infectives
US11655494B2 (en) 2017-10-03 2023-05-23 Avails Medical, Inc. Apparatus, systems, and methods for determining the concentration of microorganisms and the susceptibility of microorganisms to anti-infectives based on redox reactions

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7284452B2 (en) 2002-12-27 2007-10-23 Nanonord A/S Cantilever sensor using both the longitudinal and the transversal piezoresistive coefficients
US7521257B2 (en) 2003-02-11 2009-04-21 The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Chemical sensor with oscillating cantilevered probe and mechanical stop
US7260980B2 (en) 2003-03-11 2007-08-28 Adams Jesse D Liquid cell and passivated probe for atomic force microscopy and chemical sensing
US10156585B2 (en) 2003-03-11 2018-12-18 Board Of Regents Of The Nevada System Of Higher Education, On Behalf Of The University Of Nevada, Reno Cantilevered probes having piezoelectric layer, treated section, and resistive heater, and method of use for chemical detection
US8524501B2 (en) 2003-10-17 2013-09-03 Board Of Regents Of The Nevada System Of Higher Education Self-sensing array of microcantilevers for chemical detection
US7207206B2 (en) 2004-02-19 2007-04-24 Ut-Battelle, Llc Chemically-functionalized microcantilevers for detection of chemical, biological and explosive material
US7579052B2 (en) 2004-09-14 2009-08-25 Ut-Battelle, Llc Method of making gold thiolate and photochemically functionalized microcantilevers
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