WO2014122489A1 - Testing unit for determining the physical characteristics of samples containing liquid components - Google Patents

Testing unit for determining the physical characteristics of samples containing liquid components Download PDF

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Publication number
WO2014122489A1
WO2014122489A1 PCT/HU2014/000011 HU2014000011W WO2014122489A1 WO 2014122489 A1 WO2014122489 A1 WO 2014122489A1 HU 2014000011 W HU2014000011 W HU 2014000011W WO 2014122489 A1 WO2014122489 A1 WO 2014122489A1
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WO
WIPO (PCT)
Prior art keywords
medium
testing unit
transfer opening
medium space
opening
Prior art date
Application number
PCT/HU2014/000011
Other languages
French (fr)
Inventor
Jenö CSIKÓS
Péter Kovács
Bálint Tibor MENDELE
László ORBÁN
László SÜLE
Péter TÓTH-MIKLÓS
Attila Zsolt Tremmel
Gábor VÁRNAGY
Original Assignee
Norma Instruments Zrt.
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 Norma Instruments Zrt. filed Critical Norma Instruments Zrt.
Publication of WO2014122489A1 publication Critical patent/WO2014122489A1/en

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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
    • B01L3/502769—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 multiphase flow arrangements
    • B01L3/502776—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 multiphase flow arrangements specially adapted for focusing or laminating flows
    • G01N15/134—
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Electro-optical investigation, e.g. flow cytometers
    • G01N15/1484—Electro-optical investigation, e.g. flow cytometers microstructural devices
    • 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
    • B01L2300/08—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
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • G01N2015/135—
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Electro-optical investigation, e.g. flow cytometers
    • G01N2015/1486—Counting the particles

Definitions

  • the subject of the invention relates to a testing unit for determining the physical characteristics of samples containing liquid components, especially for the analysis of the components of blood, which has a basic body with a delimiting shell with an upper surface and lower surface surrounding a medium space and side surfaces surrounded by the upper surface and lower surface, where there are at least two current-conducting electrodes located on the inner side of the delimiting shell surrounding the medium space separated at a distance, furthermore, the medium space has an inlet passage serving for inputting the sample to be tested and an outlet passage serving for releasing the tested sample.
  • microfluidic measurement units may also be learned of, among others, publication document number WO 201 1/143075, in patent specification registration number EP 2.523.004 as well as in publication document number US 2012/021 1373.
  • Patent specification registration number EP 2.523.004 presents a testing unit suitable for performing optical measurements while publication document number US 2012/021 1373 presents a measuring unit based on the measurement of impedance change.
  • the undoubted advantage of the applied solutions is that the smaller dimensions create the possibility for moving the equipment more easily and the use of the sample and reagents used for performing the measurements can be greatly reduced.
  • the disadvantage of measurements made on the basis of the volumetric impedance method is that as a consequence of the small-sized current-conducting elements, electrodes and measuring sensors that are forced to be used due to the small dimensions of the sample transporting channels in the dimension range of just a few tens of microns the measurement precision is still relatively low, i.e. the amount of errors occurring during measurement is still relatively high.
  • the recognition that formed the basis of the idea of the invention was that if we solve the medium space of the basic body of the testing unit used for the flow of the tested medium with a network that has a novel arrangement and geometric structure, and, furthermore, if we place the current-conducting electrodes in this network in an unusual way and if we force the particles of the tested sample in the measuring zone in a direction different to that known of, then - as a consequence of the established arrangement - much larger electrically conducting parts may be set up in such a way so as to enable a better signal/noise ratio measurement with the tested medium being forced to flow in the measuring zone in a controlled way, and so the task may be solved.
  • the testing unit for determining the physical characteristics of samples containing liquid components, especially for the analysis of the components of blood - which has a basic body with a delimiting shell with an upper surface and lower surface surrounding a medium space and side surfaces surrounded by the upper surface and lower surface, where there are at least two current-conducting electrodes located on the inner side of the delimiting shell surrounding the medium space separated at a distance, furthermore, the medium space has an inlet passage serving for inputting the sample to be tested and an outlet passage serving for releasing the tested sample - is set up in such a way that the basic body is supplemented with a pressure channel suitable for introducing the diverting medium, with a first seat serving to accommodate the first measuring sensor and with a second seat serving to accommodate the second measuring sensor, furthermore, there is a diverting opening, a first transfer opening and a second transfer opening in the section of the medium space between the inlet passage and the outlet passage, the pressure channel suitable for introducing the diverting medium is connected to the medium space diverting
  • a further feature of the testing unit according to the invention may be that the distance between the upper surface and the lower surface of the delimiting shell of the basic body in contact with the medium space is between 10-100 microns in at least a part of the medium space between the first transfer opening and the second transfer opening.
  • the main axis of the pressure channel and the main progress direction of the sample are at an acute angle to each other when viewed from the inlet passage.
  • an auxiliary passage located in the basic body, in the vicinity of the outlet opening of the medium space, if it is supplemented with a step-over cross-section located between the inlet passage and the outlet passage, and the auxiliary passage is connected to the step-over cross-section of the medium space, also one of the current-conducting electrodes is located in the auxiliary passage.
  • the step-over cross-section is established in the first side surface of the delimiting shell containing the first transfer opening and the second transfer opening.
  • the current-conducting electrodes are formed by vapour-depositing extensive metal conducting layers, e.g. platinum layers, onto the upper surface and/or the lower surface of the delimiting shell, furthermore, the first measuring sensor and the second measuring sensor are formed by vapour-depositing extensive metal conducting layers, e.g. platinum layers, onto the upper surface and/or the lower surface of the delimiting shell.
  • extensive metal conducting layers e.g. platinum layers
  • the testing unit when the testing unit is in its measuring position the first seat and the second seat are at least partly filled with an electricity-conducting medium, and the first measuring sensor of the first seat and the second measuring sensor of the second seat are in an electrically conducting connection via the electricity-conducting medium. Furthermore, when the testing unit is in its measuring state the diverting medium located in a part of the pressure channel and the medium space is favourably an insulating liquid with poor electrical conductance. Also when the testing unit is in its measuring state there is a liquid in a part of the medium space and in the auxiliary passage with good electrical conductance as an electricity- conducting medium.
  • the testing unit according to the invention has numerous advantageous characteristics. The most important of these is that as a consequence of the unique setup of the medium space of the basic body such a small-sized testing unit can be created in which the measuring zone, the electrodes serving to realise four-point measurement, with large measuring electrode surfaces as well as the liquid ducts are located in an integrated way, as a consequence of which a testing unit is established that has a greater measuring speed, which is more effective and has greater performance with a much more precise degree of measuring precision.
  • a further advantage of the set-up according to the invention is that due to the arrangement no recirculation effect is created, when measurements are carried out the approaching and departing cells cannot be “seen” in the measuring zone, and during measurement due to the hydrodynamic focussing the signal/noise ratio is also improved, which further improves measurement precision, and so improves the possibility of more clearly evaluating the results.
  • testing unit according to the invention contains fewer moving parts, the liquid pathways to be travelled by the sample are significantly shortened and so the measurements may be performed with a low amount of energy use, and with a minimal sample and reagent demand.
  • a further advantage deriving from this is the increase in reliability of the testing unit, the reduction of maintenance demand and the reduction of fault probability, which, together, may result in a great increase in the efficiency of the testing unit according to the invention and in a significant decrease in the specific testing expenses as compared with traditional devices.
  • testing unit may be operated without an optical head in a three-part machine, while in a five-part machine it may be operated with an optical head, in other words its area of use may be extended.
  • the testing unit according to the invention may be used to create a bedside, in vitro diagnostic device which is based on a measuring procedure that may be performed using the traditional and medically accepted volumetric impedance method, and which is capable of producing fast and precise results in the hospital ward, which is a fundamental requirement in the case of urgent tests and which the known solutions were unable to comply with in the desired way.
  • Figure 1 shows a top view of the testing unit according to the invention, in partial cross-section
  • Figure 2 shows the view of the testing unit according to figure 1 from the direction II
  • Figure 3 shows a view picture of the testing unit according to the invention, in partial cross-section.
  • the basic body 10 here essentially consists of three pieces, a cover plate 2, a base plate 3 and an internal plate 4. This structure makes it easier to precisely realise the basic body 10, to set up the medium space consisting of small sized passages.
  • the cover plate 2, the base plate 3 and the internal plate 4 are made from a material that has good resistance to the material of the samples and the reagents, e.g. from glass or from plastic with a suitable composition, and they are built together into the basic body 10 using one of the known procedures for producing microfluidic chips.
  • Figure 2 also well illustrates that the delimiting shell 1 1 surrounding the medium space 20 is established between the cover plate 2, the base plate 3 and the internal pate 4 of the basic body 10, which is formed by the upper surface 1 l a from the direction of the cover plate 2, by the lower surface 1 1 b from the direction of the base plate 3 and by the first side surface 1 1 c and the second side surface l i d in the internal plate 4.
  • the distance "f between the upper surface 1 1 a of the cover plate 2 and the lower surface l ib of the base plate 3 falls within the range of 10-100 microns, in this case the distance "t" is 100 microns.
  • the medium space 20 contains a straight tube extending from the inlet passage 21 to the outlet passage 25, which is interrupted by the first transfer opening 22, by the second transfer opening 23 and by the step-over cross-section 26 formed in the first side surface 1 1c, as well as by the diverting opening 24 formed in the second side surface 1 Id.
  • the first transfer opening 22 is in a connection with the first seat 13 formed in the internal plate 4 that permits the flow of the medium, while the second transfer opening 23 is in a connection with the second seat 14 that permits the flow of the medium.
  • the extensive, platinum first measuring sensor 33 is located in the first seat 13, on the lower surface 1 l b of the base plate 3 and is vapour-deposited onto the lower surface l i b
  • the second measuring sensor 34 is located in the second seat 14 and is produced in the same way and is also on the lower surface 1 l b of the base plate 3.
  • the first measuring sensor 33 and the second measuring sensor 34 may also be located on the upper surface 1 l a of the cover plate 2 serving to separate the first seat 13 and the second seat 14, what is more, a set-up is possible where the first measuring sensor 33 and the second measuring sensor 34 are located on the upper surface 1 1 a and on the lower surface 1 l b as well.
  • the step-over cross-section 26 on the first side surface 1 l c of the delimiting shell 1 1 of the medium space 20 is in connection with the auxiliary passage 15.
  • a platinum current-conducting electrode 32 is located in the auxiliary passage 15, favourably also vapour-deposited onto the lower surface l i b of the base plate 3.
  • Such a current- conducting electrode 31 may also be found near to the inlet passage 21 of the medium space 20 on the lower surface 1 1 b of the base plate 3.
  • the first measuring sensor 33 and the second measuring sensor 34 serve to receive the signals required for examining the given physical characteristic of the sample 1 and transmit them to the evaluation unit - not indicated on the figure.
  • the current-conducting electrode 31 and the current-conducting electrode 32, as well as the first measuring sensor 33 and the second measuring sensor 34 do not have to be located on the lower surface l ib of the delimiting shell 1 1 , but they may also be on the upper surface 1 la of the delimiting shell 1 1 , or they may even be located on both.
  • the diverting opening 24 formed on the second side surface 1 I d of the delimiting shell 1 1 of the medium space 20 connects the pressure channel 12 with the medium space 20.
  • the diverting opening 24 is located in the section of the second side surface l i d between the inlet passage 21 and the first transfer opening 22, and the pressure channel 12 is formed in the internal plate 4 so that it main axis 12a is at an actual angle "a" with the main progress direction l a of the sample 1 when viewed from the inlet passage 21 of the medium space 20.
  • This arrangement is important because the task of the pressure channel 12 is to push the sample 1 - electricity-conducting medium 50 mixture flowing in the medium space 20 from the inlet passage 21 in the direction of the outlet passage 25 onto the section of the first side surface 1 1 c lying opposite to the second side surface l id between the first transfer opening 22 and the second transfer opening 23, which, in essence, forms the measuring zone 27 within the medium space 20 of the basic body 10. It is important to highlight that the diverting medium 40 flowing in the pressure channel 12 has poor electricity conduction characteristics, therefore, it does not conduct between the current- conducting electrode 3 1 and the current-conducting electrode 32.
  • FIG 3 On it a view picture of the basic body 10 can be seen that makes it easier to see the passage network formed in the internal plate 4 between the cover plate 2 and the base plate 3 of the basic body 10 in space.
  • the medium space 20 surrounded by the delimiting shell 1 1 consisting of the upper surface 1 1a, the lower surface 1 l b, the first side surface 1 l c and the second side surface 1 I d can also be seen, as can the pressure channel 12 opening to the medium space via the diverting opening 24, the first seat 13 connected to the medium space 20 via the first transfer opening 22 and fitted with the first measuring sensor 33, and the second seat 14 connected to the medium space 20 via the second transfer opening 23 and fitted with the second measuring sensor 34, furthermore the auxiliary passage 15 fitted with the current-conducting electrode 32, which connects to the part of the medium space 20 in the vicinity of the outlet passage 25 with the help of the step-over cross-section 26.
  • the operation of the measuring unit according to the invention takes place in the following way.
  • the sample 1 diluted to the appropriate degree with the electricity- conducting medium 50 - which is a liquid customarily used for the dilution of the sample 1 - arrives in the medium space 20 of the basic body 10 via the inlet passage 21 , and flows all the way through it. While the sample 1 made to be electrically conducting with the help of the electricity-conducting medium 50 enters the medium space 20 through the inlet passage 21 of the medium space 20, the electricity-conducting medium 50 also gets into the auxiliary passage 15, which, through the step-over cross-section 26 reaches the medium space 20 and connects with the sample 1 mixed with the electricity- conducting medium 50 flowing through the medium space 20.
  • the poorly conducting diverting medium 40 arriving at the pressure channel 12 and flowing into the medium space 20 through the diverting opening 24 force the sample 1 and the electricity-conducting medium 50 mixed with it onto the first side surface 1 l c of the delimiting shell.
  • the diverting medium 40 and the sample 1 mixed with the electricity-conducting medium 50 do not get mixed together, instead they progress side-by-side.
  • the diverting medium 40 progresses through the part of the medium space 20 of the part of the medium space 20 surrounded by the delimiting shell 1 1 closer to the second side surface 1 Id, the sample 1 - electricity-conducting medium 50 mixture progresses in the part of the delimiting shell 1 1 close to the first side surface 1 l c.
  • the first seat 13 supplied with the first measuring sensor 33 and the second seat 14 supplied with the second measuring sensor 34 become filled with electricity-conducting medium 50, and these electricity-conducting medium 50 "patches" also become connected with the conducting electricity-conducting medium 50 flowing along the first side surface 1 l c of the delimiting shell 1 1 of the medium space 20 through the first transfer opening 22 and the second transfer opening 23.
  • the first measuring sensor 33 of the first seat 13 is electrically connected with the second measuring sensor 34 of the second seat with the help of the flow of the electricity-conducting medium 50.
  • the measuring zone 27 is that section of the medium space 20 where as a consequence of the interaction of the electricity-conducting mediums 50 an electrical current appears between the current-conducting electrode 31 and the current-conducting electrode 32, and electrical conductivity is also present between the first measuring sensor 33 and the second measuring sensor 34.
  • the components of the sample 1 to be tested enter the measuring zone 27 in the vicinity of the first transfer opening 22, then in accordance with their electrical properties they change the properties of the electrical field running between the first measuring sensor 33 and the second measuring sensor 34, in this case this is electrical resistance, which the first measuring sensor 33 and the second measuring sensor 34 sense together and then send a signal to the processing unit.
  • the desired components of the sample 1 can be tested, e.g. in this case the amount of blood cells can be determined in the given sample.
  • the measured sample 1 passing the second transfer opening 23 leaves the medium space 20 of the basic body 1 0 through the outlet passage 25 of the medium space 20 along with the electricity-conducting medium 50 flowing into the medium space 20 through the first transfer opening 22, the second transfer opening 23 and the step-over cross-section 26 and with the diverting medium 40 that has flowed through the diverting opening 24.
  • the testing unit according to the invention may be used to good effect especially as the measuring head of devices that count blood cells, but it is also suitable for use in other particle-counting devices. List of references

Abstract

A testing unit is disclosed for determining the physical characteristics of samples containing liquid components especially for the analysis of the components of blood which has a basic body (10) with a delimiting shell (11), where there are at least two current-conducting electrodes (31, 32) located on the inner side of the delimiting shell (11) surrounding a medium space (20) separated at a distance (T), furthermore, the medium space (20) has an inlet passage (21) serving for inputting the sample (1) to be tested and an outlet passage (25) serving for releasing the tested sample (1). The characteristic features of the invention are that the basic body (10) is supplemented with a pressure channel (12) suitable for introducing a diverting medium (40), with a first seat (13) serving to accommodate the first measuring sensor (33) and with a second seat (14) serving to accommodate the second measuring sensor (34).

Description

Testing unit for determining the physical characteristics of samples containing liquid components
The subject of the invention relates to a testing unit for determining the physical characteristics of samples containing liquid components, especially for the analysis of the components of blood, which has a basic body with a delimiting shell with an upper surface and lower surface surrounding a medium space and side surfaces surrounded by the upper surface and lower surface, where there are at least two current-conducting electrodes located on the inner side of the delimiting shell surrounding the medium space separated at a distance, furthermore, the medium space has an inlet passage serving for inputting the sample to be tested and an outlet passage serving for releasing the tested sample.
Over the past 15 years the branch of microfluidic science has gone through a great amount of development. The results of this development are also used in equipment used for hematological testing, making it possible to radically reduce the amount of sample and reagent to be used while the tests are being performed. The application of microfluidic solutions makes it possible to perform simultaneous impedance and optical measurements at a quality comparable with high-throughput cytometry. Such so-called "microfluidic measurement units" may also be learned of, among others, publication document number WO 201 1/143075, in patent specification registration number EP 2.523.004 as well as in publication document number US 2012/021 1373. Patent specification registration number EP 2.523.004 presents a testing unit suitable for performing optical measurements while publication document number US 2012/021 1373 presents a measuring unit based on the measurement of impedance change.
The undoubted advantage of the applied solutions is that the smaller dimensions create the possibility for moving the equipment more easily and the use of the sample and reagents used for performing the measurements can be greatly reduced. However, the disadvantage of measurements made on the basis of the volumetric impedance method is that as a consequence of the small-sized current-conducting elements, electrodes and measuring sensors that are forced to be used due to the small dimensions of the sample transporting channels in the dimension range of just a few tens of microns the measurement precision is still relatively low, i.e. the amount of errors occurring during measurement is still relatively high.
Our aim with the solution according to the invention was to overcome the deficiencies of measuring units suitable for making measurements based on the known volumetric impedance method and to create a version that makes greater measurement precision possible whilst retaining the small dimensions and the advantages deriving from this.
The recognition that formed the basis of the idea of the invention was that if we solve the medium space of the basic body of the testing unit used for the flow of the tested medium with a network that has a novel arrangement and geometric structure, and, furthermore, if we place the current-conducting electrodes in this network in an unusual way and if we force the particles of the tested sample in the measuring zone in a direction different to that known of, then - as a consequence of the established arrangement - much larger electrically conducting parts may be set up in such a way so as to enable a better signal/noise ratio measurement with the tested medium being forced to flow in the measuring zone in a controlled way, and so the task may be solved.
In accordance with the set aim the testing unit according to the invention for determining the physical characteristics of samples containing liquid components, especially for the analysis of the components of blood - which has a basic body with a delimiting shell with an upper surface and lower surface surrounding a medium space and side surfaces surrounded by the upper surface and lower surface, where there are at least two current-conducting electrodes located on the inner side of the delimiting shell surrounding the medium space separated at a distance, furthermore, the medium space has an inlet passage serving for inputting the sample to be tested and an outlet passage serving for releasing the tested sample - is set up in such a way that the basic body is supplemented with a pressure channel suitable for introducing the diverting medium, with a first seat serving to accommodate the first measuring sensor and with a second seat serving to accommodate the second measuring sensor, furthermore, there is a diverting opening, a first transfer opening and a second transfer opening in the section of the medium space between the inlet passage and the outlet passage, the pressure channel suitable for introducing the diverting medium is connected to the medium space diverting opening, while the first seat is connected to the first transfer opening and the second seat is connected to the second transfer opening, the first transfer opening and the second transfer opening are arranged near to one another, on the first side surface of the delimiting shell, the diverting opening is located between the inlet passage of the medium space and the first transfer opening on a surface of the delimiting shell different to the first side surface of the delimiting shell including the first transfer opening and the second transfer opening, favourably on its second side surface opposite it, and the main axis of the pressure channel opening into the diverting opening is directed to the section of the delimiting shell before the first transfer opening.
A further feature of the testing unit according to the invention may be that the distance between the upper surface and the lower surface of the delimiting shell of the basic body in contact with the medium space is between 10-100 microns in at least a part of the medium space between the first transfer opening and the second transfer opening.
In the case of another version of the testing unit the main axis of the pressure channel and the main progress direction of the sample are at an acute angle to each other when viewed from the inlet passage. From the point of view of the invention it may be favourable if there is an auxiliary passage located in the basic body, in the vicinity of the outlet opening of the medium space, if it is supplemented with a step-over cross-section located between the inlet passage and the outlet passage, and the auxiliary passage is connected to the step-over cross-section of the medium space, also one of the current-conducting electrodes is located in the auxiliary passage. The step-over cross-section is established in the first side surface of the delimiting shell containing the first transfer opening and the second transfer opening.
In the case of another different embodiment of the testing unit the current-conducting electrodes are formed by vapour-depositing extensive metal conducting layers, e.g. platinum layers, onto the upper surface and/or the lower surface of the delimiting shell, furthermore, the first measuring sensor and the second measuring sensor are formed by vapour-depositing extensive metal conducting layers, e.g. platinum layers, onto the upper surface and/or the lower surface of the delimiting shell.
In the case of a still different embodiment of the invention when the testing unit is in its measuring position the first seat and the second seat are at least partly filled with an electricity-conducting medium, and the first measuring sensor of the first seat and the second measuring sensor of the second seat are in an electrically conducting connection via the electricity-conducting medium. Furthermore, when the testing unit is in its measuring state the diverting medium located in a part of the pressure channel and the medium space is favourably an insulating liquid with poor electrical conductance. Also when the testing unit is in its measuring state there is a liquid in a part of the medium space and in the auxiliary passage with good electrical conductance as an electricity- conducting medium.
The testing unit according to the invention has numerous advantageous characteristics. The most important of these is that as a consequence of the unique setup of the medium space of the basic body such a small-sized testing unit can be created in which the measuring zone, the electrodes serving to realise four-point measurement, with large measuring electrode surfaces as well as the liquid ducts are located in an integrated way, as a consequence of which a testing unit is established that has a greater measuring speed, which is more effective and has greater performance with a much more precise degree of measuring precision.
A further advantage of the set-up according to the invention is that due to the arrangement no recirculation effect is created, when measurements are carried out the approaching and departing cells cannot be "seen" in the measuring zone, and during measurement due to the hydrodynamic focussing the signal/noise ratio is also improved, which further improves measurement precision, and so improves the possibility of more clearly evaluating the results.
Another advantage that may be listed is that the testing unit according to the invention contains fewer moving parts, the liquid pathways to be travelled by the sample are significantly shortened and so the measurements may be performed with a low amount of energy use, and with a minimal sample and reagent demand.
A further advantage deriving from this is the increase in reliability of the testing unit, the reduction of maintenance demand and the reduction of fault probability, which, together, may result in a great increase in the efficiency of the testing unit according to the invention and in a significant decrease in the specific testing expenses as compared with traditional devices.
Another thing that must be viewed as an advantage is that the testing unit may be operated without an optical head in a three-part machine, while in a five-part machine it may be operated with an optical head, in other words its area of use may be extended.
It is also important to highlight the advantage that as a consequence of all of the advantageous characteristics listed above taken together, the testing unit according to the invention may be used to create a bedside, in vitro diagnostic device which is based on a measuring procedure that may be performed using the traditional and medically accepted volumetric impedance method, and which is capable of producing fast and precise results in the hospital ward, which is a fundamental requirement in the case of urgent tests and which the known solutions were unable to comply with in the desired way.
In the following we present the testing unit according to the invention in more detail in connection with construction embodiments, on the basis of drawings. On the drawings
Figure 1 shows a top view of the testing unit according to the invention, in partial cross-section,
Figure 2 shows the view of the testing unit according to figure 1 from the direction II, Figure 3 shows a view picture of the testing unit according to the invention, in partial cross-section.
On figure 2 the general structure of the testing unit according to the invention is visible. It may be observed that the basic body 10 here essentially consists of three pieces, a cover plate 2, a base plate 3 and an internal plate 4. This structure makes it easier to precisely realise the basic body 10, to set up the medium space consisting of small sized passages. The cover plate 2, the base plate 3 and the internal plate 4 are made from a material that has good resistance to the material of the samples and the reagents, e.g. from glass or from plastic with a suitable composition, and they are built together into the basic body 10 using one of the known procedures for producing microfluidic chips.
Figure 2 also well illustrates that the delimiting shell 1 1 surrounding the medium space 20 is established between the cover plate 2, the base plate 3 and the internal pate 4 of the basic body 10, which is formed by the upper surface 1 l a from the direction of the cover plate 2, by the lower surface 1 1 b from the direction of the base plate 3 and by the first side surface 1 1 c and the second side surface l i d in the internal plate 4. The distance "f between the upper surface 1 1 a of the cover plate 2 and the lower surface l ib of the base plate 3 falls within the range of 10-100 microns, in this case the distance "t" is 100 microns.
Moving over to figure 1 , in it the positioning of the medium space 20 formed in the internal plate 4 of the basic body 10 may be observed. In the case of this embodiment the medium space 20 contains a straight tube extending from the inlet passage 21 to the outlet passage 25, which is interrupted by the first transfer opening 22, by the second transfer opening 23 and by the step-over cross-section 26 formed in the first side surface 1 1c, as well as by the diverting opening 24 formed in the second side surface 1 Id. The first transfer opening 22 is in a connection with the first seat 13 formed in the internal plate 4 that permits the flow of the medium, while the second transfer opening 23 is in a connection with the second seat 14 that permits the flow of the medium.
The extensive, platinum first measuring sensor 33 is located in the first seat 13, on the lower surface 1 l b of the base plate 3 and is vapour-deposited onto the lower surface l i b, the second measuring sensor 34 is located in the second seat 14 and is produced in the same way and is also on the lower surface 1 l b of the base plate 3. Naturally, the first measuring sensor 33 and the second measuring sensor 34 may also be located on the upper surface 1 l a of the cover plate 2 serving to separate the first seat 13 and the second seat 14, what is more, a set-up is possible where the first measuring sensor 33 and the second measuring sensor 34 are located on the upper surface 1 1 a and on the lower surface 1 l b as well.
The step-over cross-section 26 on the first side surface 1 l c of the delimiting shell 1 1 of the medium space 20 is in connection with the auxiliary passage 15. Also a platinum current-conducting electrode 32 is located in the auxiliary passage 15, favourably also vapour-deposited onto the lower surface l i b of the base plate 3. Such a current- conducting electrode 31 may also be found near to the inlet passage 21 of the medium space 20 on the lower surface 1 1 b of the base plate 3. While the task of the current-conducting electrode 3 1 and of the current-conducting electrode 32 is to take electricity into the mixture of the sample 1 and the electricity- conducting medium 50 flowing in the medium space, the first measuring sensor 33 and the second measuring sensor 34 serve to receive the signals required for examining the given physical characteristic of the sample 1 and transmit them to the evaluation unit - not indicated on the figure. Natural ly, the current-conducting electrode 31 and the current-conducting electrode 32, as well as the first measuring sensor 33 and the second measuring sensor 34 do not have to be located on the lower surface l ib of the delimiting shell 1 1 , but they may also be on the upper surface 1 la of the delimiting shell 1 1 , or they may even be located on both.
It is also well illustrated on figure 1 that the diverting opening 24 formed on the second side surface 1 I d of the delimiting shell 1 1 of the medium space 20 connects the pressure channel 12 with the medium space 20. The diverting opening 24 is located in the section of the second side surface l i d between the inlet passage 21 and the first transfer opening 22, and the pressure channel 12 is formed in the internal plate 4 so that it main axis 12a is at an actual angle "a" with the main progress direction l a of the sample 1 when viewed from the inlet passage 21 of the medium space 20. This arrangement is important because the task of the pressure channel 12 is to push the sample 1 - electricity-conducting medium 50 mixture flowing in the medium space 20 from the inlet passage 21 in the direction of the outlet passage 25 onto the section of the first side surface 1 1 c lying opposite to the second side surface l id between the first transfer opening 22 and the second transfer opening 23, which, in essence, forms the measuring zone 27 within the medium space 20 of the basic body 10. It is important to highlight that the diverting medium 40 flowing in the pressure channel 12 has poor electricity conduction characteristics, therefore, it does not conduct between the current- conducting electrode 3 1 and the current-conducting electrode 32. As a consequence of this the electricity is finally forced to travel in the sample 1 - electricity-conducting medium 50 mixture inserted near to the first side surface 1 1 c of the delimiting shell 1 1 between the current-conducting electrode 31 and the current-conducting electrode 32. Therefore, in this space a greater current density is formed, which improves the signal/noise ratio; beside this the chance of blockages occurring in the medium space 20 is not increased either. Otherwise, the current-conducting electrode 3 1 and the current- conducting electrode 32 are located on the basic body 10 with a gap "T'\
Now moving over to figure 3, on it a view picture of the basic body 10 can be seen that makes it easier to see the passage network formed in the internal plate 4 between the cover plate 2 and the base plate 3 of the basic body 10 in space. Here the medium space 20 surrounded by the delimiting shell 1 1 consisting of the upper surface 1 1a, the lower surface 1 l b, the first side surface 1 l c and the second side surface 1 I d can also be seen, as can the pressure channel 12 opening to the medium space via the diverting opening 24, the first seat 13 connected to the medium space 20 via the first transfer opening 22 and fitted with the first measuring sensor 33, and the second seat 14 connected to the medium space 20 via the second transfer opening 23 and fitted with the second measuring sensor 34, furthermore the auxiliary passage 15 fitted with the current-conducting electrode 32, which connects to the part of the medium space 20 in the vicinity of the outlet passage 25 with the help of the step-over cross-section 26.
The operation of the measuring unit according to the invention takes place in the following way. The sample 1 diluted to the appropriate degree with the electricity- conducting medium 50 - which is a liquid customarily used for the dilution of the sample 1 - arrives in the medium space 20 of the basic body 10 via the inlet passage 21 , and flows all the way through it. While the sample 1 made to be electrically conducting with the help of the electricity-conducting medium 50 enters the medium space 20 through the inlet passage 21 of the medium space 20, the electricity-conducting medium 50 also gets into the auxiliary passage 15, which, through the step-over cross-section 26 reaches the medium space 20 and connects with the sample 1 mixed with the electricity- conducting medium 50 flowing through the medium space 20. When the electricity- conducting medium 50 in continuous contact with the current-conducting electrode 31 at the inlet passage 21 , and the electricity-conducting medium 50 in continuous contact with the current-conducting electrode 32 of the auxiliary passage 15 meet at the step- over cross-section 26, then the electricity conducted in the current-conducting electrode 31 and the current-conducting electrode 32 starts into the sample 1 mixed with the electricity-conducting medium 50 passing through the medium space 20. The electrically conducting sample 1 itself essentially fills the entire cross-section of the medium space 20 in the vicinity of the inlet passage 21 of the medium space 20 until it reaches the diverting opening 24. When the sample 1 reaches the diverting opening 24, then the poorly conducting diverting medium 40 arriving at the pressure channel 12 and flowing into the medium space 20 through the diverting opening 24 force the sample 1 and the electricity-conducting medium 50 mixed with it onto the first side surface 1 l c of the delimiting shell.
As due to the dimensions of the medium space 20 and other physical characteristics existing there, there is laminar flow in the medium space 20, the diverting medium 40 and the sample 1 mixed with the electricity-conducting medium 50 do not get mixed together, instead they progress side-by-side. The diverting medium 40 progresses through the part of the medium space 20 of the part of the medium space 20 surrounded by the delimiting shell 1 1 closer to the second side surface 1 Id, the sample 1 - electricity-conducting medium 50 mixture progresses in the part of the delimiting shell 1 1 close to the first side surface 1 l c.
While these part-processes are taking place in the medium space 20, the first seat 13 supplied with the first measuring sensor 33 and the second seat 14 supplied with the second measuring sensor 34 become filled with electricity-conducting medium 50, and these electricity-conducting medium 50 "patches" also become connected with the conducting electricity-conducting medium 50 flowing along the first side surface 1 l c of the delimiting shell 1 1 of the medium space 20 through the first transfer opening 22 and the second transfer opening 23. In this way then the first measuring sensor 33 of the first seat 13 is electrically connected with the second measuring sensor 34 of the second seat with the help of the flow of the electricity-conducting medium 50.
With the basic body 1 0 in this filled-up condition prepared for measurement, while moving the components of the sample 1 flowing closer to the first side surface 1 1c of the delimiting shell 1 1 of the medium space 20 reach the measuring zone 27 between the first transfer opening 22 and the second transfer opening 23. In essence the measuring zone 27 is that section of the medium space 20 where as a consequence of the interaction of the electricity-conducting mediums 50 an electrical current appears between the current-conducting electrode 31 and the current-conducting electrode 32, and electrical conductivity is also present between the first measuring sensor 33 and the second measuring sensor 34. When the components of the sample 1 to be tested enter the measuring zone 27 in the vicinity of the first transfer opening 22, then in accordance with their electrical properties they change the properties of the electrical field running between the first measuring sensor 33 and the second measuring sensor 34, in this case this is electrical resistance, which the first measuring sensor 33 and the second measuring sensor 34 sense together and then send a signal to the processing unit.
While the total amount of the sample 1 to be measured passes through the measuring zone 27, the desired components of the sample 1 can be tested, e.g. in this case the amount of blood cells can be determined in the given sample. Following this, the measured sample 1 passing the second transfer opening 23 leaves the medium space 20 of the basic body 1 0 through the outlet passage 25 of the medium space 20 along with the electricity-conducting medium 50 flowing into the medium space 20 through the first transfer opening 22, the second transfer opening 23 and the step-over cross-section 26 and with the diverting medium 40 that has flowed through the diverting opening 24.
The testing unit according to the invention may be used to good effect especially as the measuring head of devices that count blood cells, but it is also suitable for use in other particle-counting devices. List of references
sample la main progress direction cover plate base plate internal plate basic body 1 1 delimiting shell
1 1 a upper surface
1 l b lower surface
1 1 c first side surface l i d second side surface
12 pressure channel 12a main axis
13 first seat
14 second seat
15 auxiliary passage 0 medium space 21 inlet passage
22 first transfer opening
23 second transfer opening
24 diverting opening
25 outlet passage
26 step-over cross-section
27 measuring zone 1 current-conducting electrode 2 current-conducting electrode 3 first measuring sensor 4 second measuring sensor 0 diverting medium 0 electricity-conducting medium "t" distance "T"gap "a" angle

Claims

1 . Testing unit for determining the physical characteristics of samples containing liquid components especially for the analysis of the components of blood which has a basic body ( 10) with a delimiting shell ( 1 1) with an upper surface ( 1 1a) and lower surface (l ib) surrounding a medium space (20) and side surfaces ( 1 1 c, l i d) surrounded by the upper surface ( 1 1a) and lower surface (l i b), where there are at least two current- conducting electrodes (3 1 , 32) located on the inner side of the delimiting shell ( 1 1 ) surrounding the medium space (20) separated at a distance (T), furthermore, the medium space (20) has an inlet passage (21 ) serving for inputting the sample ( 1) to be tested and an outlet passage (25) serving for releasing the tested sample (1 ), characterised by that the basic body (1 0) is supplemented with a pressure channel ( 12) suitable for introducing the diverting medium (40), with a first seat (13) serving to accommodate the first measuring sensor (33) and with a second seat ( 14) serving to accommodate the second measuring sensor (34), furthermore, there is a diverting opening (24), a first transfer opening (22) and a second transfer opening (23) in the section of the medium space (20) between the inlet passage (21) and the outlet passage (25), the pressure channel (12) suitable for introducing the diverting medium (40) is connected to the medium space (20) diverting opening (24), while the first seat (13) is connected to the first transfer opening (22) and the second seat (14) is connected to the second transfer opening (23), the first transfer opening (22) and the second transfer opening (23) are arranged near to one another, on the first side surface (1 1 c) of the delimiting shell (1 1), the diverting opening (24) is located between the inlet passage (21 ) of the medium space (20) and the first transfer opening (22) on a surface of the delimiting shell (1 1 ) different to the first side surface ( 1 1 c) of the delimiting shell (1 1 ) including the first transfer opening (22) and the second transfer opening (23), favourably on its second side surface (l i d) opposite it, and the main axis ( 12a) of the pressure channel (12) opening into the diverting opening (24) is directed to the section of the delimiting shell (1 1 ) before the first transfer opening (22).
2. Testing unit according to claim 1 , characterised by that the distance (t) between the upper surface ( 1 l a) and the lower surface (l i b) of the delimiting shell (1 1 ) of the basic body ( 10) in contact with the medium space (20) is between 10-100 microns in at least a part of the medium space (20) between the first transfer opening (22) and the second transfer opening (23).
3. Testing unit according to claim 1 or claim 2, characterised by that the main axis ( 12a) of the pressure channel ( 12) and the main progress direction ( la) of the sample ( 1 ) are at an acute angle (a) to each other when viewed from the inlet passage (21 ).
4. Testing unit according to any of claims 1-3, characterised by that there is an auxiliary passage (15) located in the basic body (20), in the vicinity of the outlet opening (25) of the medium space (20). it is supplemented with a step-over cross-section (26) located between the inlet passage (21 ) and the outlet passage (25), and the auxiliary passage ( 15) is connected to the step-over cross-section (26) of the medium space (20), and one of the current-conducting electrodes (31 , 32) is located in the auxiliary passage (15).
5. Testing unit according to claim 1 , characterised by that the step-over cross- section (26) is established in the first side surface (1 1 c) of the delimiting shell (1 1 ) containing the first transfer opening (22) and the second transfer opening (23).
6. Testing unit according to any of claims 1-5, characterised by that the current- conducting electrodes (31 , 32) are formed by vapour-depositing extensive metal conducting layers, e.g. platinum layers, onto the upper surface (1 1 a) and/or the lower surface (l i b) of the delimiting shell ( 1 1 ).
7. Testing unit according to any of claims 1-6, characterised by that the first measuring sensor (33) and the second measuring sensor (34) are formed by vapour- depositing extensive metal conducting layers, e.g. platinum layers, onto the upper surface ( 1 1 a) and/or the lower surface (l i b) of the delimiting shell ( 1 1 ).
8. Testing unit according to any of claims 1-7, characterised by that in its operating status the first seat (1 3) and the second seat (14) are at least partly filled with an electricity-conducting medium (50), and the first measuring sensor (33) of the first seat (13) and the second measuring sensor (34) of the second seat (14) are in an electrically conducting connection via the electricity-conducting medium (50).
9. Testing unit according to any of claims 1-8, characterised by that when the testing unit is in its measuring state the diverting medium (40) located in a part of the pressure channel ( 12) and the medium space (20) is favourably an insulating liquid with poor electrical conductance.
10. Testing unit according to any of claims 4-9, characterised by that when the testing unit is in its measuring state there is a liquid in a part of the medium space (20) and in the auxiliary passage ( 1 5) with good electrical conductance as an electricity- conducting medium (50).
PCT/HU2014/000011 2013-02-05 2014-02-04 Testing unit for determining the physical characteristics of samples containing liquid components WO2014122489A1 (en)

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