EP0843817A1 - Dispositif de diagnostic - Google Patents

Dispositif de diagnostic

Info

Publication number
EP0843817A1
EP0843817A1 EP96928401A EP96928401A EP0843817A1 EP 0843817 A1 EP0843817 A1 EP 0843817A1 EP 96928401 A EP96928401 A EP 96928401A EP 96928401 A EP96928401 A EP 96928401A EP 0843817 A1 EP0843817 A1 EP 0843817A1
Authority
EP
European Patent Office
Prior art keywords
branch
sample
conduit
liquid
junction
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.)
Withdrawn
Application number
EP96928401A
Other languages
German (de)
English (en)
Inventor
Hendrik Sibolt Van Damme
Eduard Gerard Marie Pelssers
Henricus Joseph Ida Theodorus Kaelen
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.)
Akzo Nobel NV
Original Assignee
Akzo Nobel NV
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 Akzo Nobel NV filed Critical Akzo Nobel NV
Priority to EP96928401A priority Critical patent/EP0843817A1/fr
Publication of EP0843817A1 publication Critical patent/EP0843817A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
    • 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
    • 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
    • G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
    • 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
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G01N33/56988—HIV or HTLV
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0621—Control of the sequence of chambers filled or emptied
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0645—Electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions

Definitions

  • the invention relates to a device for performing an assay for the detection or determination of the amount of an analyte in a test liquid.
  • the closest state of the art comprises a disposable diagnostic device and method of use described in HO 94/19484 (Biocircuits Corporation).
  • This patent application relates to a device comprising a first and second flow path orthogonal to each other.
  • the first flow path connects a sample port via a transport channel and an incubation area to a waste reservoir.
  • the transport channel and/or incubation area comprises a reagent.
  • the incubation area comprises a signal producing system and is underneath an optically clear window.
  • the second flow path connects an inlet port via a side reagent reservoir and the incubation area to a side waste reservoir.
  • the side reagent reservoir comprises for example a substrate if the signal pro ⁇ ducing system is enzyme based.
  • an analyte containing sample is introduced into the sample port and drawn by capillary action through the X transport channel into the incubation area.
  • the analyte participates in the signal producing system' in the incubation area.
  • a buffered wash solution is introduced via the sample port, displacing the sample to the waste reservoir.
  • liquid is introduced into the inlet port at a certain point of time, which liquid dissolves the substrate and enters the incubation area where the visualisation reaction takes place.
  • the device may comprise a capillary valve for enhanced control over liquid flow through the incubation area. In this way it is prevented that wash solution introduced via the sample port enters the side reagent reservoir or the side waste reservoir.
  • a capillary valve may also be used to control the flow into and/or out of the incubation area.
  • the device according to WO 94/19484 has several drawbacks. It is not able to perform an immunoassay procedure autonomously. That is, a plurality of manual operations are required, said operations being inter ⁇ rupted by waiting periods. To obviate this problem the patent application again relies on an apparatus.
  • wash solution is introduced through the same flow path as the sample and thus the wash solution will be contaminated by analyte and reagent due to mixing and desorption of analyte and reagent from the walls of the transport channel, resulting in unsatisfactory washing at the incubation area.
  • readings have to be performed after a specific predetermined period of time.
  • the object of the present invention is to provide a device capable of performing an assay, and in particular an immunoassay, requiring less manual operations with a reduced number of waiting periods.
  • a device for performing an assay for the detection or determination of the amount of an analyte in a liquid sample characterized in that the device comprises a body provided with a conduit having an inlet end and an outlet end, said conduit comprising a first junction branch ⁇ ing off into a first branch and a second branch, and a second junction at which said first branch and second branch join, wherein the first branch comprises a ⁇ ample inlet, and the first branch and second branch are arranged such that, in use, a transporting liquid entering the inlet of the conduit is divided in said first branch and said second branch and promulgates a sample in the fir ⁇ t branch through the second junction before the transporting liquid arrives at the second junction via the second branch, and the outlet end being provided with detection means enabling the detection or determination of the amount of the analyte in the sample.
  • liquid such as washing or transporting liquid
  • the inlet results in transport of the sample via the second junction into the conduit, while in addition to this the liquid arriving at the second junction via the second branch remains uncontaminated by analyte and/or reagent.
  • the timing at which the liquid arrives at the second junction depends on the design chosen, not on the person performing the assay, which eliminates human errors.
  • the first branch is provided with an absorber element between the first junction and the sample inlet.
  • liquid entering the first branch is absorbed quickly by the absorber element, slowing down or stopping the flow of liquid through the second branch. Air is expelled by the absorber pad, promulgating the sample through the first branch, via the second junction towards the outlet end before the liquid via the second branch reaches the second junction. Thu ⁇ , the sample can be promulgated without contact, and thus dilution, with liquid from the first junction. After the absorber pad is saturated liquid is no longer conducted through the first branch.
  • the device according to the invention is characterized in that the sample inlet comprises an outwardly projecting canal allowing the uptake of sample by capillary action into the first branch.
  • the device is arranged to allow the uptake of a predetermined defined volume of sample, which can for example be achieved using capillary valves, and which will be explained in detail later.
  • a predetermined defined volume of sample which can for example be achieved using capillary valves, and which will be explained in detail later.
  • the sample inlet is arranged to receive and hold an application rod comprising means for the uptake and release of sample liquid, a defined volume of sample liquid being released into the first branch when the application rod is received by the sample inlet.
  • an application rod may be used for the delivery of a defined sample volume to devices according to the state of the art.
  • the inlet end of the conduit comprises a container for transporting liquid.
  • a preferred embodiment of the invention is characterized in that said conduit comprises a membrane between said container and the first junction.
  • the membrane offers a means to control the flow rate of washing liquid and thus the time it take ⁇ for the washing liquid to reach the second junction.
  • it instead of having to add the sample after a particular period after having introduced the washing liquid, it can be added immediately after having introduced the washing liquid and no further attention is needed.
  • the advantage of using a membrane is that, in contrast to for example a constriction in the conduit, it is not easily clogged by some dirt, such as a grain of sand or textile fibre.
  • part of the wall of the conduit located between the second junction and the outlet end is formed by a semi-permeable mem ⁇ brane, and an absorber element is arranged immediately adjacent to said semi-permeable membrane outside of the conduit.
  • the sample will contact the semi-permeable membrane and only large complexes, comprising analyte bound by the reagent, will be retained while free unreacted reagent and analyte will pass the membrane and be absorbed by the absorber element, together with the sample liquid.
  • a bound/free separation is accomplished.
  • the washing liquid having followed the second branch reaches the semi-permeable membrane, it can wash the large complexes effectively, especially since it is not contaminated by analyte or reagent from the first branch. After saturation of the absorber element, the large complexes are transported by the washing liquid towards the detection means.
  • Figure l is a schematic cross-sectional view of a first embodiment of the device according to the present invention.
  • Figure 2 shows a cross-section of a part comprising a junction in one embodiment of the invention
  • Figure 3 shows a cross-section of a modification of the outlet end of the device
  • Figures 4a and 4b show a cross-section of the sample inlet of the device
  • Figure 5 shows a cross-section of a device according to the invention with multiple branches
  • Figure 6 shows a cross-section of an alternative embodiment of a device according to the invention.
  • Figure 7 shows a cross-section of a bound/free separation part of the device.
  • Figures 8 -10 show different embodiments of detection means applicable according to the present invention ;
  • a device 1 for performing a ⁇ say ⁇ , in particular immunoas ⁇ ay ⁇ comprising a conduit 2 with an inlet end 3 and an outlet end 4.
  • the conduit 2 comprises a first junction 5 branching of into a first branch 6 and a second branch 7.
  • the first branch 6 and the ⁇ econd branch 7 join at ⁇ econd junction 8 .
  • the fir ⁇ t branch 6 compri ⁇ e ⁇ a ⁇ ample inlet
  • washing liquid is introduced via the inlet end 3 into the conduit 2. Subsequently an analyte containing sample is introduced into the sample inlet 9. Said washing liquid is transported by capillary action, hydrostatic pressure, gravitational force, a simple pump or otherwise from the inlet end 3 to the outlet end 4. As it is generally preferred to perform assays on small samples, the channels will be small for which reason capillary action will usually be the essential force for transport of liquid. When the washing liquid reaches the fir ⁇ t junction 5, it i ⁇ divided over the two branches 6 and
  • the branch 6a is preferably provided with mean ⁇ that promulgate ⁇ the ⁇ ample mediated by gas in the branch 6 in the conduit 2b.
  • this means comprise ⁇ an ab ⁇ orber element 10. Washing liquid reaching the first junction 5 will be absorbed by the absorber element 10. Gas contained in the ab ⁇ orber element 10 i ⁇ expelled in the process and this gas forces the ⁇ ample in branch 6 via the ⁇ econd junction 8 into the conduit 2b. ⁇ soon as the absorber element 10 is saturated, the flow of washing liquid through branch 6 stops.
  • the absorber element 10 is of porous material such as fibre material like cellulose, nylon, glass, cotton, polyester or acrylic fibres, ceramics or any other material expelling ga ⁇ when wetted by the liquid.
  • the device l may be provided with one or more reagents.
  • the reagent may be added together with the sample, but it is preferred that the sample inlet 9 comprises the reagent.
  • the reaction ⁇ tart ⁇ when the ⁇ ample i ⁇ introduced in the device 1. If the reaction require ⁇ more than one reagent these can be included in the ⁇ ample, the ⁇ ample inlet or both, as desired.
  • the reagent is contained in the branch 6b.
  • the reaction is ⁇ tarted only when the ⁇ ample i ⁇ promulgated in branch 6b towards the second junction
  • reagents may comprise various components required to perform an assay for detection of an analyte in a te ⁇ t liquid, ⁇ uch as antigens or fragments thereof, antibodies or fragments thereof, DNA or RNA or fragments thereof, other members of specific binding pairs atc.
  • component ⁇ may be in an unlabeled and/or labeled form.
  • Suitable label ⁇ include enzyme ⁇ , fluore ⁇ cent compound ⁇ , chemilumine ⁇ cent compounds, particulate labels such as gold sols and dyestuff sols.
  • these components may be coupled to a disper ⁇ ed solid phase material to enable an adequate separation between the fraction bound to, for example, an antibody, and the unbound (free) fraction.
  • Suitable solid phase material ⁇ are for example polystyrene latices.
  • the embodiment shown in figure 1 is provided with mean ⁇ for the ⁇ eparation of large complexes formed between reagent and analyte on the one hand and unreacted analyte and reagent on the other hand.
  • the mean ⁇ comprise a semi-permeable membrane 11 forming a part of the wall of the conduit 2b and an absorber element 12 immediately adjacent to said semi-permeable membrane 11 outside the conduit 2b.
  • the mean ⁇ will be referred to as a bound/free separator and is described in detail in our pending European application EP 480 497, the description of which is herein incorporated by reference.
  • the semi-permeable membrane 11 is preferably an absolute membrane.
  • This type of membranes is characterized by the fact that liquid flow through the membrane occurs only perpendicular to the membrane surface.
  • the ⁇ e abso ⁇ lute membranes do no contain so-called dead space ⁇ , a ⁇ for instance in tortuous membranes, which can hold a certain amount of the reaction mixture withstanding the ⁇ uction action of the absorber element. Reagent from from these dead spaces may dif ⁇ fuse back into the conduit 2b, thereby decreasing the efficiency of the separation proces ⁇ .
  • this membrane 11 can be coated for example with a tri-block copolymer of polyethylene oxide and polypropylene oxide, such as F108 Synperonic (ICI Surfactants).
  • a solid phase dispersion such as a disper ⁇ ion of poly ⁇ tyrene latex or gold particles which are very 9 suitable for several types of immunoassay that can be performed using the device according to the invention, can be prevented from attaching to the membrane.
  • absolute membranes examples include track etched mem- branes, such as cyclopore membranes (Whatman, Belgium) and Nucleopore membranes (Nucleopore, USA).
  • Another example of absolute membranes are membranes produced by combined litho ⁇ graphic and etch techniques ⁇ uch a ⁇ micro ⁇ ieve ⁇ (Aquamarijn Microfiltration, the Netherland ⁇ ) .
  • the analyte present in the ⁇ ample will react with the reagents, for example a labeled component and a component coupled to a dispersed solid phase, forming large complexes.
  • the device 1 allows control over the time allowed for the reaction to proceed, a ⁇ will be discussed shortly, and the reagent containing sample will not arrive at the bound/free separator before the reaction is complete. At the bound/free separator all the sample liquid together with unreacted reagent and analyte, if any, passes through the semi-permeable membrane 11 and is absorbed by the absorber element 12. The large complexes however are retained by the semi-permeable membrane 11.
  • the device 1 is arranged in such a way that the wa ⁇ hing liquid, coming from the second branch 7, arrives at the semi-permeable membrane 11 only after the complete absorption of the sample liquid.
  • the capacity of the absorber element 12 to absorb liquid is larger than the volume of the sample liquid.
  • the washing liquid when the washing liquid reaches the semi-permeable membrane 11, it is absorbed by the absorber element 12, resulting in a very effective washing of the retained large complexes and the substantially complete removal of unreacted reagent. It is advantageous if the large complexes are retained in a very small area of the semi-permeable membrane only, the area having reference number Ila. Thus all liquid passes this ⁇ mall area which re ⁇ ult ⁇ in a very effective wa ⁇ hing. To minimi ⁇ e contamination of wa ⁇ hing liquid with reagent, the ⁇ emi-permeable membrane ll is located at or near the second junction 8, a ⁇ a result of which the walls of conduit 2b will be contacted with and contaminated with free reagent as little as pos ⁇ ible. To prevent the ⁇ ample liquid/reagent from entering the ⁇ econd branch 7 a pre ⁇ ure barrier, for example an abrupt increase in diameter, increase in hydrophibicity etc., may be provided.
  • a pre ⁇ ure barrier for example an abrupt increase
  • the conduit 2b can be provided with a moderate pres ⁇ ure barrier.
  • the conduit 2b may compri ⁇ e two ab ⁇ orber element ⁇ 12 opposite to each other, or the conduit may over a part of its length be surrounded by the ab ⁇ orber element 12.
  • the absorber element 12 To increase the capacity of the absorber element 12 it i ⁇ mounted over a long di ⁇ tance along the conduit 2b. It i ⁇ remarked that e ⁇ pecially the fir ⁇ t liquid entering the ab ⁇ orber element 12 will contain reagent. Thi ⁇ reagent will proceed towards the distal end of the device 1. There is no flow of liquid in the lumen of the conduit 2b until the absorber element 12 is ⁇ aturated. When the the ab ⁇ orber element 12 i ⁇ saturated, a high concentration of reagent is present at the distal end of the absorber element 12. If the membrane 11 were permeable at lib, reagent could diffuse back into the carefully wa ⁇ hed large complexe ⁇ containing liquid. Thi ⁇ would to a certain extent negate the effect of washing.
  • the part lib of the semi-permeable membrane may be permeable for gas contained in the absorber element 12 only.
  • the semi-permeable membrane 11 may be made impervious over part of its surface, for example by treating it with chemicals that make the membrane impervious, by covering it, for example with adhesive tape, etc. or a semi-permeable membrane 11 can be used which during manu ⁇ facture was provided with pores in only part Ila of it. other pos ⁇ ibilitie ⁇ to prevent reagent from re-entering the liquid are possible.
  • the conduit 2a, the first branch 6 and the second branch 7 are diverting from the surface of the semi-permeable membrane Ila. Therefore the use of an impervious part of the membrane is not necessary.
  • Thi ⁇ may be achieved u ⁇ ing physical techniques such as pres ⁇ ure, or by la ⁇ ting phy ⁇ i- cal contact, for example by heat-sealing.membrane 11 and absorber element 12 together.
  • a detection chamber 13 may contain further reagents 14 and 15, for example enzyme sub ⁇ trate and chromogen.
  • the detection chamber 13 i ⁇ provided with a tran ⁇ parent window 37, allowing visual inspection or ⁇ pectrophometric reading ⁇ uch a ⁇ ab ⁇ orption measurement, fluorescence measurement, as well as nephelometric measurement etc.
  • Said reagents 14, 15 may also be provided in the conduit 2c. or alternatively in a third branch (not shown), branching of from conduit 2a or branch 7. These reagents are delivered automatically after the bound/free separation reaction is completed. It should be clear that one or more reagent ⁇ may be provided at certain places or delivered at certain places as needed for a particular assay. Thus it is also possible to avoid compounds pre ⁇ ent in the ⁇ ample for interfering with further reagents such as ⁇ ubstrates, because the compounds are removed during the bound/free separation before the bound analyte is transported to the further reagent or the further reagent is delivered.
  • the sample is introduced into the device 1 immediately after the introduction of the wa ⁇ hing liquid.
  • the time available for reaction between analyte and reagent depend ⁇ on the de ⁇ ign of the device l.
  • the device 1 is preferably provided with a container 16 at the inlet end 3, connected to a filler chamber 17, via a membrane 18.
  • the liquid has to pas ⁇ membrane 18 which provide ⁇ flow re ⁇ istance.
  • Other ways of providing flow resi ⁇ tance are po ⁇ sible but the use of a membrane 18 is advantageous in that it is not easily blocked by air, dirt such a ⁇ a grain of ⁇ and etc.
  • Suitable membrane ⁇ are tho ⁇ e with tran ⁇ membrane fluxes in the order of 1 U to 200 ml/min/cm 2 at 10 PSI. Hydrophilic membranes are preferred as these are more easily wetted by the liquid.
  • a tiny absorber element 19 in the filler chamber 17, immediately adjacent to and covering only part of the membrane 18, may be provided, facilitating the initial release of the liquid by the membrane 18.
  • This absorber element is preferably made of glass fibre.
  • the reproducibility of the time delay depends on the uniformity of the tran ⁇ -membrane flux of the type of membrane used.
  • time delay element comprising a container, membrane and filler chamber
  • a time delay element comprising a container, membrane and filler chamber
  • the device according to the invention can be con- ⁇ idered a ⁇ a combination of element ⁇ , each capable of performing one or more assay ⁇ tep ⁇ , alone or in combination, in an auton ⁇ omous way. These elements are combined to carry out a complete assay and can be used in different combinations to carry out a different process.
  • the device takes care of complex fluid move ⁇ ments and makes apparatus with complex mechanics and control software superfluous.
  • the ⁇ hape of the conduit 2 may vary, but for capillary action to occur two opposite walls of the conduit 2 are preferably between 0.01 and 2 mm apart.
  • the outlet end 4 should act as a pres ⁇ ure barrier, u ⁇ ing a ⁇ udden increa ⁇ e in diameter, hydrophobic coating etc.
  • Further control over period of time for reaction can be achieved in several ways.
  • the conduit 2a and the second branch 7 can be or be made more or less hydrophobic, for example by chemical treatment, coating hydrophobic compounds with for example using Teflon spray, fluor-resin or va ⁇ eline, and other methods known per se, and/or the diameter and length of the conduit 2a can be varied.
  • the conduit 2a and second branch 7 may be provided with delay means 20, a ⁇ shown in figure 5, comprising an absorber element 21 and a vent 22. Liquid from the container 16' is absorbed by the absorber element 21 and no liquid is passed on until the absorber element 21 is ⁇ aturated with liquid. Ga ⁇ contained by the ab ⁇ orber element 21 is discharged to the atmosphere via vent 22.
  • the absorber element 10 may be shaped as shown in figure 2.
  • the absorber element extends over a part of the wall of conduit 2a.
  • it ha ⁇ al ⁇ o been given a larger dimension over part of its length in branch 6, to increase the volume of gas the ab ⁇ orber element 10 can expell, nece ⁇ ary for the promulgation of the ⁇ ample.
  • the detection mean ⁇ may overlap with the bound/free separator, as i ⁇ ⁇ hown in figure 3.
  • a transparent device 1 allows visual inspection or quantitative measu ents with a suitable apparatu ⁇ .
  • the ⁇ ample inlet 9 may be provided with a filter 23 allowing removal of lumps, dirt or for example blood cells. Reagent may be provided below the filter (not shown) .
  • the sample inlet 9 can be provided with a reagent 24 containing holding means 25. Thu ⁇ a device 1 can be provided with one of a multi ⁇ tude of holding means 25 each containing different reagents 2 , which offers a choice of as ⁇ ays to be performed with the device 1.
  • the holding means 25 also comprises a filter 23, allowing the removal of cells, such a ⁇ red blood cells, dust etc.
  • sample liquid is introduced in the device 1 by means of an application rod 26 comprising a handle 27 provided with compressible porous material 28 at one end thereof.
  • This porous material 28 is capable of taking up a defined volume of sample liquid which volume is governed by the amount and capacity of said porous material 28.
  • Suitable compres ⁇ ible porous materials are for example Porex porous material (EDP x-2124), and preferably 3M foam type 1563.
  • the compressible porous material 28 can be hydrophilized by plasma treatment or treatment with surfactant ⁇ ⁇ uch a ⁇ a mixture of poly(oxyethylene) ⁇ orbitane mono-laurate (Tween 20) and ⁇ orbitane-monooleate (Span 80).
  • the compre ⁇ ible porou ⁇ material 28 i ⁇ dipped into a sample liquid whereby a defined sample volume is taken up. Subsequently the application rod 26 is in ⁇ erted in the ⁇ ample inlet 9 and the porou ⁇ material 28 i ⁇ compre ⁇ ed, whereby thi ⁇ defined sample volume is released. To this end the handle 27 engages the sample inlet 9 in an airtight fashion, while a sudden decrease in cross-section of the sample inlet 9 provides a surface against which the porous material 28 is compressed. The released volume of sample should be such that it cannot come into contact with the absorber element 10 in the first branch 6a. In an alternative embodiment the compres ⁇ ible porou ⁇ material 28 can be provided with a reagent, offering the same advantage as the holding means 25 described above.
  • the reagents for the device 1, holding means 25 and application rod 26 are u ⁇ ually provided in a lyophilized form, though other forms are possible, for example as a coating obtained by evaporation of a solvent.
  • the substrate and chromogen are added in insoluble, inert, porous pad ⁇ .
  • Suitable material ⁇ for the pad ⁇ are for example Nylon membrane (MSI, USA) with a pore size of 0,2 tot 1,0 mm. Said pads do not block the flow of liquid and allow rapid release of reagent into the liquid.
  • the device 1 comprise ⁇ a conduit 2, container 16, junction ⁇ 5, 8, branche ⁇ 6, 7 and absorber element 10 corresponding to those described with reference to figure 1.
  • the ⁇ araple inlet 9 compri ⁇ e ⁇ an outwardly projecting canal 29 allowing taking up sample liquid by capillary action by dipping the distal end of the canal 29 in the sample liquid.
  • the IH volume of sample liquid introduced in branch 6 is defined by means for stopping the flow of liquid by capillary action. Thu ⁇ the branch 6a and 6b can each be provided with for example hydrophobic walls over part of the length of each branch 6a, 6b. It should be clear that such a sample inlet can also be used separately or in combination with another device for the uptake of a defined sample volume. In the embodiment shown in figure 5, an abrupt increase in diameter of the branches 6a and 6b pro ⁇ vides a pres ⁇ ure barrier which can not be overcome, or be over- come quickly, by the sample liquid.
  • the pres ⁇ ure built up by ga ⁇ expelled by the ab ⁇ orber element 10, a ⁇ discussed in relationship to figure 1, is sufficient to promulgate a defined volume of sample liquid into conduit 2b.
  • a bound/free separator is provided in conduit 2b, comprising a semi-permeable membrane 11 and an ab ⁇ orber element 12. Wa ⁇ hing liquid in a container 16', which may or may not be the same as container 16, is delayed by delay mean ⁇ 20, discus ⁇ ed earlier, and arrives at junction 30 with branches 31 and 32, which branche ⁇ 31, 32 join at junction 33, only after the large complexes retained by the bound/free separator have been transported into the branch 31.
  • Wa ⁇ hing liquid from the inlet end 3 is divided at junction 5. Washing liquid absorbed by the ab ⁇ orber element 10 expel ⁇ gas contained in the absorber element 10, promulgating an as ⁇ ay mixture, compri ⁇ ed of ⁇ ample liquid introduced via ⁇ ample inlet 9 and reagent, into conduit 2b to the semi-permeable membrane 11. Washing liquid passing through the second branch 7 is divided at a junction 41. Washing liquid pas ⁇ ing into branch 42 dissolves sub ⁇ trate/chromogen reagents 14,15 present in this branch 42.
  • gas expelled by an absorber not only can be used to influence the flow of liquid downstream but also upstream.
  • Figure 8 shows a different embodiment of the detec ⁇ tion means, the outlet end 104 being provided with a prism 36 which facilitates vi ⁇ ual inspection and/or measurement of the detection reaction.
  • the pri ⁇ m 36 may have a convex ⁇ urface at the di ⁇ tal end, in effect forming a convex len ⁇ , to further facilitate inspection of the detection chamber 13.
  • the conduit 2b is provided with reagents 1 , 15 which are for example a ⁇ ub ⁇ trate for an enzyme, and a chromogen.
  • the conduit 2b double ⁇ a ⁇ the detection chamber 13.
  • the embodiment shown in figure 9 is similar to the one shown in figure 8, but here an adsorber 38 is provided that can be inspected, for example vi ⁇ ually.
  • An ab ⁇ orber element 39 i ⁇ provided to facilitate the pa ⁇ sage of liquid through the adsorber 38. It may also be advantageou ⁇ to incorporate a reagent, ⁇ uch a ⁇ one for stopping an enzyme reaction, in the adsorber 38.
  • the adsorber 38 may concentrate any coloured prod ⁇ uct formed, increasing the sen ⁇ itivity of the a ⁇ ay. Suitable adsorbers 38 depend on the particular dye used or produced, but Nylon membrane filters (MSI, USA) and preferrably. GF/SE 30 paper (Whatman, UK) appear to be sati ⁇ factory.
  • Mea ⁇ urement ⁇ with the device according to the inven ⁇ tion i ⁇ not limited to optical detection, in contra ⁇ t, a ho ⁇ t of detection methods is possible.
  • a ⁇ an example, figure 10 shows a detection chamber 13 provided with electrodes 40, 40' and reagents 14, 15, allowing electrochemical detection of reaction product ⁇ .
  • An enzyme ⁇ uitable for electrochemical detection i ⁇ glucose-oxidase (GOD) with D-glucose and potassium hexacyano- ferrate as substrates.
  • the device 1 can be made of various materials, pre ⁇ ferably of transparent plastic ⁇ ⁇ uch as polystyrene, poly ⁇ carbonate and polymethylmethacrylate.
  • the device comprises two parts la, lb, of which for optical as ⁇ ay ⁇ usually at least one will be of trans- parent pla ⁇ tic. If a window i ⁇ provided for the detection cham ⁇ ber 13 the part ⁇ la, lb may be opaque.
  • the part ⁇ la, lb are advantageou ⁇ ly formed by injec ⁇ tion molding, and contain the conduit 2 and other element ⁇ a ⁇ recesses.
  • the recesses all lie in one plane, but this i ⁇ not required.
  • the parts are provided with aborber elements, membranes, reagent ⁇ , hydrophobic material to act as pres ⁇ ure barriers etc. as needed for the intended assay.
  • the ab ⁇ orber may advantageously be placed in a cavity of one of the parts, the depth of said cavity being slightly les ⁇ than the thickne ⁇ of the absorber element.
  • a ⁇ ample can be introduced, ⁇ aid ⁇ ample dissolving solid reagent comprising antibodies directed against the analyte and labeled with an /? enzyme, and latex particles coated with antibodies directed against the analyte, said sample and dissolved reagent plus latex particles forming a as ⁇ ay mixture.
  • wa ⁇ hing liquid i ⁇ introduced in the 5 container 16. From there the liquid pa ⁇ es the membrane 18 and enters the conduit 2a. At the first junction 5 the liquid i ⁇ ab ⁇ orbed by the ab ⁇ orber element 10 which expels gas in the proces ⁇ .
  • Thi ⁇ ga ⁇ promulgate ⁇ the a ⁇ say mixture via the second junction 8 to the semi-permeable membrane Ila, where the as ⁇ ay
  • washing liquid passes through the second branch 7 via the second junction 8 to the
  • HRP was di ⁇ olved in 2.81 ml NaH 2 P0 4 buffer (12 g/1), pH 7.5, containing 5.85 g/1 NaCl, and incubated during 30 min. with 0.22 ml of a ⁇ olution of SPDP in ethanol (12.5 g/1).
  • the obtained HRP-SPDP wa ⁇ purified on a PD10 column and eluted with a NaH 2 P0 4 buffer (12 g/1), pH 7.4, containing 5.85 g/1 NaCl and 1.86 g/1 dinatriumedetaat.2H 2 0.
  • Tetramethylbenzidine hydrochloride was dissolved in a solution of 9.1 mg citric acid/ml, 1 mg di-sodium EDTA/ l, 156.5 mg PEG-8000/ml in a concentration of 8 mg TMB/ml. 10 ⁇ l of this solution was sprayed per square cm MSI nylon membrane with a E pore size of 0.22 ⁇ m. After spraying the pads were dried under nitrogen and sub ⁇ equently cut into pieces of 10 by 1mm. These pads were then placed and fixed in the detection chamber (13) of the device (l) by slight mechanical pre ⁇ ure.
  • Sodiumperborate-tetrahydrate was dissolved in a solution of 44 mg citric acid/ml, 80 mg ⁇ odium citrate, 2.6 mg di- ⁇ odium EDTA/ml and 156.5 mg PEG 8000/ml in a concentration of 20 mg/ml. 10 ⁇ l of thi ⁇ ⁇ olution wa ⁇ sprayed per square meter nylon 5 membrane with a pore size of 0.22 ⁇ m. The pads were further handled a ⁇ decribed for the TMB pad ⁇ .
  • the device used is that depictured in Figure 1.
  • the conduit (2a, 2b, 2c) and its branches (6, 7) have a cros ⁇ - ⁇ ection of 2 mm by 0.1mm.
  • the porou ⁇ material (28) of the application rod (26) i ⁇ capable to take up 30 ⁇ l of liquid.
  • the ⁇ emi-permeable membrane (Ila) used is a Cyclopore membrane (Whatman sa, Belgium), with a 5 pore size of 0.6 ⁇ m.
  • Distilled water is added to the container (16) of the device(l) in a volume of 5 ml, which is indicated by a mark on the wall of the container.
  • the application rod (26) is inserted in the ⁇ ample liquid, whereby 30 ⁇ l of sample liquid is taken up.
  • the application rod is then inserted in the sample inlet (9) and the liguid released by pressing.
  • the colour is read through the window (37) and a slight to blue colour is an indication of a positive sample.
  • the colour of a negative sample is not visually detectable. In this way an amount of 20 ng/ml of human monoclonal anti-gp 41 in serum can be detected.

Abstract

L'invention concerne un dispositif de détection ou de détermination de la quantité d'un échantillon à analyser présent dans un liquide d'essai, fonctionnant de manière autonome. Ce dispositif comprend un élément transparent muni d'un conduit ayant une entrée et une sortie. Ce conduit comprend un premier embranchement qui se sépare en deux canaux, et un second embranchement auquel se rejoignent les deux canaux. Le premier canal dispose d'une ouverture permettant l'entrée de l'échantillon et comportant des réactifs. Les deux canaux sont disposés de telle sorte que, lorsqu'ils sont utilisés, un liquide de transport entrant par l'entrée du conduit se répartit entre ledit premier canal et le second canal, et répand l'échantillon dans le premier canal en passant par le second embranchement avant que le liquide de transport ne parvienne au second embranchement en empruntant le second canal. La sortie du conduit est munie d'un moyen de détection de l'échantillon à analyser. Le conduit comprend facultativement une membrane semi-perméable entre le second embranchement et le moyen de détection, afin de permettre une séparation obligatoire/libre.
EP96928401A 1995-08-03 1996-07-30 Dispositif de diagnostic Withdrawn EP0843817A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP96928401A EP0843817A1 (fr) 1995-08-03 1996-07-30 Dispositif de diagnostic

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP95202118 1995-08-03
EP95202118 1995-08-03
EP96928401A EP0843817A1 (fr) 1995-08-03 1996-07-30 Dispositif de diagnostic
PCT/EP1996/003380 WO1997006437A1 (fr) 1995-08-03 1996-07-30 Dispositif de diagnostic

Publications (1)

Publication Number Publication Date
EP0843817A1 true EP0843817A1 (fr) 1998-05-27

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP96928401A Withdrawn EP0843817A1 (fr) 1995-08-03 1996-07-30 Dispositif de diagnostic

Country Status (6)

Country Link
EP (1) EP0843817A1 (fr)
JP (1) JPH11510601A (fr)
KR (1) KR19990036069A (fr)
AU (1) AU6788796A (fr)
CA (1) CA2228485A1 (fr)
WO (1) WO1997006437A1 (fr)

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WO2001026813A2 (fr) * 1999-10-08 2001-04-19 Micronics, Inc. Logique a microfluides sans pompe
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Publication number Publication date
WO1997006437A1 (fr) 1997-02-20
CA2228485A1 (fr) 1997-02-20
JPH11510601A (ja) 1999-09-14
KR19990036069A (ko) 1999-05-25
AU6788796A (en) 1997-03-05

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