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WO1992010743A1 - Procede de determination d'un ligand specifique dans un echantillon liquide a l'aide d'un dispositif acoustique de mesure, et composant du dispositif de mesure - Google Patents

Procede de determination d'un ligand specifique dans un echantillon liquide a l'aide d'un dispositif acoustique de mesure, et composant du dispositif de mesure Download PDF

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Publication number
WO1992010743A1
WO1992010743A1 PCT/NL1991/000258 NL9100258W WO9210743A1 WO 1992010743 A1 WO1992010743 A1 WO 1992010743A1 NL 9100258 W NL9100258 W NL 9100258W WO 9210743 A1 WO9210743 A1 WO 9210743A1
Authority
WO
WIPO (PCT)
Prior art keywords
ligand
specific binding
binding partners
latex
vibrating object
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/NL1991/000258
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English (en)
Inventor
Richardus Bernardus Maria Schasfoort
Maarten Simon Nieuwenhuizen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Original Assignee
Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
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Filing date
Publication date
Application filed by Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO filed Critical Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Publication of WO1992010743A1 publication Critical patent/WO1992010743A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54346—Nanoparticles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/02—Analysing fluids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/22—Details, e.g. general constructional or apparatus details
    • G01N29/222—Constructional or flow details for analysing fluids
    • 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 invention relates to a method of determining a specific ligand in a liquid sample by bringing the sample into contact with a vibrating object which is accommodated in an acoustic measuring device and whose surface is provided with specific binding partners for the ligand to be determined, and analysing the frequency shift or the change in the acoustic propagation velocity or the change in the amplitude or the phase shift measured at the vibrating object and due to the formation of a complex between the ligand and the specific binding partner.
  • the mass sensitivity S measured in the gas phase is approximately 1 Hz/(ng/cm 2 ), in other words, the adsorption of 1 ng of mass/cm 2 of surface of the quartz crystal, measured in the gas phase, results in a frequency shift of 1 Hz.
  • the Applicant has sought a methodology which can eliminate the disadvantages, such as the undesirably high detection limit, of acoustic methods of measurement, such as the "bulk acoustic wave” method described above and also other acoustic methods of measurement such as the "plate wave” technique, occurring in liquid.
  • the abovementioned object can also be achieved with the aid of a vibrating object whose surface situated at the liquid/solid interface contains a multiplicity of specific binding partners which are provided with a "leaving agent" in the form of a particle reversibly bound to said specific binding partners being a ligand on a latex spherule having a diameter of 50-1000 nm (see Figure 3) •
  • the specific binding partners for the ligand may also be bound to a multiplicity of latex spherules having a diameter of 50-1000 nm as particulate carriers, which spherules are attached to the surface of the vibrating object.
  • the abovementioned object can also be achieved with the aid of a vibrating object whose surface situated at the liquid/solid interface contains a multiplicity of specific binding partners for the ligand which are partly provided with the ligand and the leaving agent in the form of a ligand on a latex spherule having a diameter of 50-1000 nm which is reversibly bound to said specific binding partners in accordance with an established equilibrium with a medium (competition reaction) which is advantageously circulated and which contains a constant concentration of the ligand and the "leaving agent", said established equilibrium being temporarily shifted, resulting in a corresponding frequency shift, after introducing a sample to be investigated (Figure 4a) .
  • a medium mixture reaction
  • a membrane which is permeable to the ligand to be measured but impermeable to the "leaving agent” is preferably installed between the vibrating object and the point at which the sample to be examined is added (Fig.
  • Such a membrane should have pores having a diameter of ⁇ 50 nm and may in principle be any marketed membrane like a cellulose acetate membrane.
  • the abovementioned medium which is advantageously circulated only needs to contain the respective ligand in a constant concentration since the "leaving agent" cannot escape from the space between the membrane and the surface of the vibrating object.
  • a particular variant of the first-mentioned achievement is to use a vibrating object whose surface situated at the liquid/solid interface is provided with a multiplicity of particulate carriers which contain specific binding partners for the ligand, said specific binding partners being provided, in addition, with a "leaving agent" in the form of a particle reversibly bound to said specific binding partners (see Figure 5) •
  • latex particles having a diameter of 50-1000 nm and provided with antibodies for the ligand in question are applied under the formation of a sandwich-complex with the ligand, which is attached to the specific binding partner which in its turn is bound directly or indirectly to the surface of the vibrating object.
  • the vibrating object used in the method according to the invention is advantageously a quartz crystal whose two mutually opposite surfaces are coated with a metal layer, preferably gold or silver.
  • a metal layer preferably gold or silver.
  • the thickness of such a metal layer is normally 10-100 nm and can be applied in a known manner such as vapour deposition and the like.
  • the carriers used are latex spherules having a diameter in the range of, for example, 10-1000 nm, preferably 50-200 nm.
  • suitable materials are, inter alia, (monodisperse) polystyrene latex, polymethyl methacrylate latex, a silica latex or a latex of a conducting polymer such as polypyrrole and polyacetylene.
  • latices are Unisphere latex particles having a diameter of 50 nm (type 10) or 100 nm (type 11) (supplied by Brunschwig Chemie B.V., The Netherlands) and "Polybead" polystyrene microspheres having a diameter of 50, 100 or 200 nm (Polysciences Corp. Niles/Illinois, USA).
  • the "degree of coverage" of the sensor surface of the quartz crystal which is used as vibrating object and which is provided with the loaded particulate carriers can vary considerably.
  • the degree of coverage depends on the size of the carrier particles or on the type of specific binding partner, such as antibodies and DNA strands.
  • the degree of coverage is 50-99- ->% •
  • “degree of coverage” of the sensor surface with the spherules is understood to mean the ratio of the sum of the surface of the cross section of the "spherical" carriers or of the spherical particles reversibly bound to the specific binding partners multiplied by a factor of 100 and divided by the total surface of the sensor surface.
  • “Degree of loading” of the spherules with the specific binding partners is understood to mean the ratio of the loaded surface, i.e. the surface covered with the specific binding partners, of the spherules multiplied by a factor of 100 and divided by the total surface of the spherules in the monolayer or submonolayer. In general, the degree of loading is 10-90JU.
  • ligands can be used as ligands to be determined in a sample or the specific binding partners complimentary thereto.
  • the antigen has already been mentioned above as ligand and the antibody specific for the antigen as specific binding partners.
  • Table A For an incomplete summary of usable ligands or specific binding partners, reference is made to Table A below.
  • the immobilisation of the specific binding partners on the latex spherules is a technique known per se.
  • a general description of the technique is given in "Microparticle Immunoassay Techniques" (Seradyn Inc., ed. Galloway and Hicks, Particle Techno ⁇ logy Division, P.O. Box 1210, Indianapolis, IN 46206, USA).
  • the carriers loaded with specific binding partners can then be bound to the metal layer of the quartz crystal used as vibrating object by means of adsorption or by means of applying a thin layer of glue or a layer of another type of adhesive by a dipping technique, spin coating or other generally known deposition techniques.
  • the above procedure can, if desired, be reversed by first carrying out the adhesion of the spherules to the metal layer of the quartz crystal used as vibrating object and then the immobilisation of the specific binding partners on the spherules acting as carriers.
  • the particulate carriers can also be applied by means of a flat coating, such as a polystyrene coating, to the metal surface, i.e. the particulate carriers are indirectly immobilised on the metal surface.
  • the invention furthermore relates to an object to be set vibrating and suitable for use in an acoustic measuring device such as a "bulk acoustic wave” or a “plate wave” measuring device, comprising an object to be set vibrating, preferably a quartz crystal, two mutually opposite surfaces of which are coated with a metal layer of, advantageously, gold or silver, one of the metal layers or an unmetallised part of the object to be set vibrating being provided with a quantity of latex spherules having a diameter of 50-1000 nm as particulate carriers which have been applied thereto and which contain specific binding partners for the ligand
  • Figure 2 Diagrammatic representation of the method according to the invention in which the specific binding partner is located on particulate carriers attached to the surface of the vibrating object.
  • Figure 3 Diagrammatic representation of the method according to the invention, the "leaving agent” being located on the specific binding partners of the ligand attached to the surface of the vibrating object and being removed by the ligand by means of a displacement reaction.
  • Figure 4a Diagrammatic representation of the method according to the invention, an established equilibrium between the specific binding partners attached to the surface of the vibrating object (1) and the ligand and "leaving agent" contained in the medium being shown.
  • Figure 4a (0-3) These figures show instants in time in relation to a measurement, where Figure 4a(0) : represents the equilibrium phase at the instant t 0 ;
  • Figure 4a(l) represents the sampling at the instant i;
  • Figure 4a(2) represents the equilibrium phase modified by the sampling at the instant t 2 ;
  • Figure 4a(3) represents the restored equilibrium phase (as at t 0 ) at the instant t 3 .
  • Figure 4b Diagrammatic representation of the method according to the invention, in which a membrane
  • FIG. 2 Diagrammatic representation of the method according to the invention, in which the specific binding partner for the ligand is located on the spherules attached to the surface of the vibrating object and in which the specific binding partner of the ligand itself is also provided with a "leaving agent", which "leaving agent” is remov by the ligand by means of a displacement reaction
  • Figure 6 Cross section of the sensor container containing quartz crystal as object to be set vibrating, which:
  • (1) represents the quartz crystal
  • Figure 7-' Frequency diagram obtained with a BAW sens comprising a quartz crystal provided with go electrodes on which there is HSA (adhesive laye and PS spherules.
  • HSA adheresive laye and PS spherules.
  • Figure 8 Frequency diagram obtained with a BAW sensor. Thi is based on a clean quartz crystal provided wit gold electrodes.
  • the numbers 1-2 in Figure 8 hav the following meaning:
  • Figure 9 Frequency diagram obtained with a BAW sensor. Thi was based on a clean crystal provided with gol electrodes. The numbers 1-4 in Figure 9 have t following meaning:
  • FIG. 10 Frequency diagram obtained with a BAW sensor. This was based on the quartz crystal after the treatment described in Figure 9- The numbers 1-9 in Figure 10 have the following meaning:
  • oscillators were used which were contained in a metal housing.
  • the oscillator was fed with a 15 volt direct current supply and consumed approximately 25 milliampere.
  • the supply was connected to the oscillator with the aid of a miniature twin connector.
  • the oscillator signal was fed from a 50 ohm buffer control circuit via a binary connector (BNC) to an external counting device.
  • BNC binary connector
  • the oscillator had only one adjustment device which adjusted both the amplitude and the phase. It was found that, with good, clean crystals and good connections, the oscillator normally functioned without adjustment, even if the quartz crystal sensor was located in liquid on one side.
  • the quartz crystal sensors were installed in the base of a stainless-steel housing, which housing was itself connected to the top of an oscillator with the aid of a two-pin connector. In this way, a very compact measuring device was created which ensured a low noise because of the effective electrical screening and also the absence of long cables to connect the sensor to the oscillator.
  • a cross section of the sensor housing is shown in Figure 6.
  • the frequencies of one or two oscillators, A and B were periodically measured at known instants and stored on a hard disc of a PC.
  • the oscillators were connected to a two-channel counting device (HP 5334B) which was regulated and read out with the PC. These data were used to produce frequency diagrams such as, for example, Figures 7-10.
  • the oscillator(s) and the stirrer(s) were kept in a sealed climatic chamber during the test.
  • the rest of the device for example the oscilloscopes, counting device, supply and PC were outside the climatic chamber.
  • HSA human serum albumin
  • Sigma A 3782 concentration 1 mg/ml
  • a quartz crystal area: 0.5 cm 2
  • a gold electrode area: 0.05 cm 2 , applied by means of a vapour deposition technique.
  • PBS phosphate buffered saline solution
  • Polybead polystyrene (2.5 solids) carboxylated microspheres Polysciences Corp. Niles. 111., USA) (200 nm; PS spherules) were then applied to the coated gold layer. After 10 min, the metal surface was rinsed with PBS.
  • the product obtained was then rinsed with a borate buffer (Polysciences Corp., Niles/Ill., USA).
  • protein HSA, Sigma A 3782
  • storage was carried out for one night at 100% relative atmospheric humidity.
  • the product was again rinsed with PBS.
  • HSA solution (625 nmol/1; Sigma A 1151) (see point (1) of Figure 8) was applied to the gold layer of the crystal surface coated solely with HSA. From Figure 8 it can be deduced that a frequency shift of only 600 Hz occurs. Compared with the two frequency shifts above (1600 Hz for a gold layer coated with PS spherules and 600 Hz for a gold layer not coated with PS spherules) it can be stated that the sensitivity has increased by a factor of approximately 3-
  • This example illustrates the immunological specificity of anti-HSA with respect to HSA applied to the surface of the quartz crystal.
  • This surface was first coated with PS spherules as particulate carriers to increase the surface density of HSA.
  • PS spherules as particulate carriers to increase the surface density of HSA.
  • FIGs 9 and 10 reference is made to the associated frequency diagrams obtained with the underlying BAW sensor ( Figures 9 and 10) .
  • the solution above the BAW sensor was continuously stirred.
  • a solution of HSA (Sigma A 3782; 1.5 ⁇ mol/1) was applied to the surface of a quartz crystal (area: 0.5 cm 2 ) provided with gold electrodes (area: 0.05 cm 2 ) (point (1) of Figure 9)- The solution was removed and the crystal was rinsed with 0.01 mol/1 PBS (point (2) of Figure 9)- A suspension of PS spherules (diameter 100 nm; Polysciences Corp., Niles/Ill., USA; 0.0025% solids) was then applied with the object of coupling the PS spherules, the applied HSA coating acting as adhesive layer (point (3) of Figure 9)-
  • the concentration of the PS spherule suspension was then increased to 0.025% solids (point (1) of Figure 10).
  • the suspension was then removed and the crystal was rinsed with 0.01 mol/1 PBS (point (2) of Figure 10).
  • the crystal surface coated with PS spherules was completely covered with HSA by adding a solution of HSA (Sigma A 3782; 1.5 ⁇ mol/1) (point (3) of Figure 10).

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Abstract

Procédé de détermination d'un ligand dans un échantillon liquide, consistant à mettre l'échantillon en contact avec un objet oscillant reçu dans un dispositif acoustique de mesure et dont la surface est munie de partenaires de liaison spécifique au ligand à déterminer, et à analyser le déplacement de fréquence ou la modification de la vitesse de propagation du son, ou la modification de l'amplitude ou de la variation de phase mesurée au niveau de l'objet oscillant et due à la formation d'un complexe entre le ligand et le partenaire de liaison spécifique. Ce procédé est caractérisé en ce que l'objet oscillant dont la surface se situe au niveau de l'interface solide/liquide est doté soit d'une pluralité de sphérules en latex présentant un diamètre compris entre 50 et 1000 nm et servant de porteurs particulaires contenant des partenaires de liaison spécifique au ligand; soit d'une pluralité de partenaires de liaison spécifique munis d'un 'agent de départ' sous forme de particule liée de manière réversible auxdits partenaires de liaison spécifique et servant de ligand sur une sphérule en latex présentant un diamètre compris entre 50 et 1000 nm; ou bien d'une pluralité de partenaires de liaison spécifique au ligand en partie dotés du ligand et de 'l'agent de départ' sous forme de ligand sur une sphérule en latex présentant un diamètre compris entre 50 et 1000 nm, ledit ligand étant lié de manière réversible auxdits partenaires de liaison spécifique selon un équililbre établi avec un milieu (réaction par compétition) contenant le ligand et 'l'agent de départ', cet équilibre établi étant temporairement décalé après l'introduction d'un échantillon à analyser, ce qui entraîne un déplacement de fréquence correspondant.
PCT/NL1991/000258 1990-12-11 1991-12-10 Procede de determination d'un ligand specifique dans un echantillon liquide a l'aide d'un dispositif acoustique de mesure, et composant du dispositif de mesure Ceased WO1992010743A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL9002724 1990-12-11
NL9002724A NL9002724A (nl) 1990-12-11 1990-12-11 Werkwijze voor het bepalen van een specifiek ligand in een vloeibaar monster met behulp van een acoustische meetinrichting, alsmede een daarvoor geschikt onderdeel van de meetinrichting.

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WO1992010743A1 true WO1992010743A1 (fr) 1992-06-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032419A1 (fr) * 1994-05-25 1995-11-30 Adrian Carl Stevenson Appareil de controle accoustique
FR2878622A1 (fr) * 2004-11-26 2006-06-02 U R Aquitaine De Gestion Urbai Systeme de surveillance autonome, en continu et in situ de la qualite d'une eau
USRE41005E1 (en) 1996-11-06 2009-11-24 Sequenom, Inc. Beads bound to a solid support and to nucleic acids

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982000363A1 (fr) * 1980-07-21 1982-02-04 M Bart Immunosubstrat et revetement superficiel immunoadsorbant pour immunosubstrat en phase solide
EP0215669A2 (fr) * 1985-09-17 1987-03-25 Seiko Instruments Inc. Diagnostique et procédé d'analyse de composés biochimiques, microbes et cellules
EP0296398A1 (fr) * 1987-06-22 1988-12-28 Louisiana State University and Agricultural and Mechanical College Méthode d'essai immunologique pour la détection d'anticorps contre des antigènes
DE3733986A1 (de) * 1987-10-08 1989-04-20 Mueller Schulte Detlef Dr Mittel und verfahren zur herstellung von biosensoren auf der basis eines schwingquarzes und verwendung desselben zur bestimmung von antigenen und affinitaetsliganden
WO1989009937A1 (fr) * 1988-04-06 1989-10-19 E.I. Du Pont De Nemours And Company Test de liaison piezoelectrique specifique amplifie par enzymes
WO1989009938A1 (fr) * 1988-04-06 1989-10-19 E.I. Du Pont De Nemours And Company Test de liaison specifique piezoelectrique avec reactifs a masse amplifiee

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982000363A1 (fr) * 1980-07-21 1982-02-04 M Bart Immunosubstrat et revetement superficiel immunoadsorbant pour immunosubstrat en phase solide
EP0215669A2 (fr) * 1985-09-17 1987-03-25 Seiko Instruments Inc. Diagnostique et procédé d'analyse de composés biochimiques, microbes et cellules
EP0296398A1 (fr) * 1987-06-22 1988-12-28 Louisiana State University and Agricultural and Mechanical College Méthode d'essai immunologique pour la détection d'anticorps contre des antigènes
DE3733986A1 (de) * 1987-10-08 1989-04-20 Mueller Schulte Detlef Dr Mittel und verfahren zur herstellung von biosensoren auf der basis eines schwingquarzes und verwendung desselben zur bestimmung von antigenen und affinitaetsliganden
WO1989009937A1 (fr) * 1988-04-06 1989-10-19 E.I. Du Pont De Nemours And Company Test de liaison piezoelectrique specifique amplifie par enzymes
WO1989009938A1 (fr) * 1988-04-06 1989-10-19 E.I. Du Pont De Nemours And Company Test de liaison specifique piezoelectrique avec reactifs a masse amplifiee

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICSAND FREQUENCY CONTROL vol. 34, no. 2, March 1987, NEW YORK, US pages 127 - 135; M. THOMPSON ET AL.: 'THE POTENTIAL OF THE BULK ACOUSTIC WAVE DEVICE AS A LIQUID-PHASE IMMUNOSENSOR' cited in the application see page 132, left column, paragraph 4 - page SA 54681 030133, left column, paragraph 1; figure 6 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032419A1 (fr) * 1994-05-25 1995-11-30 Adrian Carl Stevenson Appareil de controle accoustique
US5869748A (en) * 1994-05-25 1999-02-09 Biosensing Technologies Limited Acoustic monitor assembly
USRE41005E1 (en) 1996-11-06 2009-11-24 Sequenom, Inc. Beads bound to a solid support and to nucleic acids
USRE44693E1 (en) 1996-11-06 2014-01-07 Sequenom, Inc. Beads bound to a solid support and to nucleic acids
FR2878622A1 (fr) * 2004-11-26 2006-06-02 U R Aquitaine De Gestion Urbai Systeme de surveillance autonome, en continu et in situ de la qualite d'une eau

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