WO2011070919A1 - Buse de distribution pour analyseur automatique et analyseur automatique la comprenant - Google Patents

Buse de distribution pour analyseur automatique et analyseur automatique la comprenant Download PDF

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Publication number
WO2011070919A1
WO2011070919A1 PCT/JP2010/071079 JP2010071079W WO2011070919A1 WO 2011070919 A1 WO2011070919 A1 WO 2011070919A1 JP 2010071079 W JP2010071079 W JP 2010071079W WO 2011070919 A1 WO2011070919 A1 WO 2011070919A1
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Prior art keywords
dispensing nozzle
sample
automatic analyzer
dispensing
nozzle
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PCT/JP2010/071079
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English (en)
Japanese (ja)
Inventor
谷口伸一
野島彰紘
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株式会社日立ハイテクノロジーズ
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Priority to EP10835841.7A priority Critical patent/EP2511709B1/fr
Priority to US13/515,017 priority patent/US8802008B2/en
Priority to CN201080055689.8A priority patent/CN102652263B/zh
Publication of WO2011070919A1 publication Critical patent/WO2011070919A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/026—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations having blocks or racks of reaction cells or cuvettes
    • 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
    • B01L3/02—Burettes; Pipettes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00584—Control arrangements for automatic analysers
    • G01N35/00594—Quality control, including calibration or testing of components of the analyser
    • G01N35/00613—Quality control
    • G01N35/00623—Quality control of instruments
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1004—Cleaning sample transfer devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
    • 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
    • B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
    • B01L2300/0838—Capillaries
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B01L2300/163—Biocompatibility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00178—Special arrangements of analysers
    • G01N2035/00277—Special precautions to avoid contamination (e.g. enclosures, glove- boxes, sealed sample carriers, disposal of contaminated material)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016—Control of the volume dispensed or introduced
    • G01N2035/102—Preventing or detecting loss of fluid by dripping
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N2035/1025—Fluid level sensing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1002—Reagent dispensers

Definitions

  • the present invention relates to a dispensing nozzle for an automatic analyzer and an automatic analyzer equipped with the same.
  • This type of biochemical analyzer includes a container for storing a specimen and a reagent, a reaction cell for injecting the specimen and the reagent, a dispensing mechanism having a dispensing nozzle for automatically injecting the specimen and the reagent into the reaction cell, and a reaction Automatic stirring mechanism with a stirring bar that mixes the sample and reagent in the cell, mechanism to measure the absorbance of the sample during or after the reaction, and automatic cleaning of the reaction cell by aspirating and discharging the reaction solution after the measurement is completed
  • a cleaning mechanism or the like is provided (for example, Patent Document 1).
  • a sample dispensing nozzle dispenses a predetermined amount of sample from a container for storing a sample such as a blood collection tube and discharges the sample to a reaction cell in which a reagent is reacted.
  • the reagent dispensing nozzle discharges a predetermined amount of reagent dispensed from the reagent storage container to the reaction cell.
  • the measurement result may be affected. This is called carryover.
  • the carry-over problem is deeply related to the recent demand for small amounts of specimens and reagents in the field of automatic analyzers. As the number of analysis items increases, the amount of sample that can be allocated to one analysis item decreases. There are cases where the specimen itself is valuable and cannot be prepared in large quantities, and there is also a demand for higher sensitivity. In addition, as the analysis content becomes more sophisticated, reagents are generally more expensive, and there is a demand for reducing the amount of reagents in terms of cost. Due to the increasing demand for a small amount of specimens and reagents, the diameter of the dispensing nozzle is reduced, and the outer diameter of the tube is about 0.5 mm. Miniaturization of the nozzle diameter increases the ratio of the surface area to the volume of the solution to be dispensed. For this reason, it is important to control substance adsorption on the surface of the dispensing nozzle and reduce carryover.
  • Patent Document 2 In order to reduce carry-over, conventionally, cleaning with a detergent containing pure water or a surfactant has been performed (Patent Document 2). A method is also known in which the residue of the attached specimen is deactivated with active oxygen (Patent Document 3). A method using a disposable disposable nozzle (disposable tip) is also known as one of the solutions for carryover.
  • An object of the present invention is to provide a sample dispensing nozzle of an automatic analyzer that improves surface cleanliness and reduces carryover without using a disposable nozzle, and an automatic analyzer using the same. is there.
  • the chemical solution of the polyethylene glycol (PEG) derivative is applied to the surface of the dispensing nozzle and coated to suppress the adsorption of biological macromolecules such as proteins, thereby solving the above problems.
  • the chemical adsorption means an adsorption mode on a solid surface having a heat of adsorption of about 20 to 100 kcal / mol due to a chemical bond such as a covalent bond or an ionic bond.
  • a distinction is made from physical adsorption with a van der Waals force whose adsorption heat is usually 10 kcal / mol or less as a binding force.
  • the polyethylene glycol derivative is hydrophilic and suppresses adsorption of biopolymers such as proteins by its steric repulsion.
  • the molecular weight of the PEG derivative should be 100 or more because of the requirement that the number of ethylene oxide (—C 2 H 4 O—) groups required is 2 or more and that the intermolecular interaction for arranging the molecules is sufficient. desirable. On the other hand, if the steric repulsive force between molecules is too large, the amount of adsorption of the PEG derivative on the surface is reduced. Therefore, the molecular weight of the PEG derivative is desirably 20000 or less.
  • the chemical structure of the PEG derivative to be coated need not be a single structure, and may be a mixture.
  • the automatic analyzer of the present invention includes a plurality of sample containers each storing a sample, a plurality of reagent containers each storing a reagent, a plurality of reaction cells into which the sample and the reagent are injected, and a sample dispensing nozzle.
  • a sample dispensing mechanism that dispenses the sample in the sample container into the reaction cell
  • a reagent dispensing mechanism that includes a reagent dispensing nozzle and dispenses the reagent in the reagent container into the reaction cell.
  • the injection nozzle has a silicon oxide layer on the surface, and the silicon oxide layer has the following general formula: Si—R 1 — (OCH 2 CH 2 ) n —O—R 2 (n is a positive integer of 2 or more) , R 1 is a hydrocarbon group, R 2 is H or CH 3 ) A silicon derivative having polyethylene glycol represented by the formula is chemically adsorbed.
  • adsorption of biopolymers such as proteins to the dispensing nozzle can be suppressed. Therefore, it is possible to reduce the carry-over during the dispensing operation, and the analysis reliability of the automatic analyzer is improved. In addition, this contributes to the miniaturization of specimens and reagents, and also contributes to reducing the running cost of the automatic analyzer.
  • Figure 1 shows a schematic diagram of the dispensing nozzle.
  • Stainless steel is widely used for the dispensing nozzle body 101 as a material having high corrosion resistance and good workability.
  • the nozzle material is not limited to stainless steel, and may be a resin such as polydimethylsiloxane (PDMS), polyvinyl chloride, polyacrylate, glass, other metal materials (gold, platinum, copper), or ceramic.
  • PDMS polydimethylsiloxane
  • PDMS polydimethylsiloxane
  • polyvinyl chloride polyacrylate
  • glass other metal materials (gold, platinum, copper), or ceramic.
  • an example of a stainless steel dispensing nozzle is shown.
  • the dispensing nozzle is bent at a corner 102 and connected to a suction / discharge mechanism. When the sample or reagent is aspirated, a predetermined amount is aspirated into the hollow portion 103.
  • the outer surface of the dispensing nozzle is also immersed in the specimen or reagent.
  • the area where the polyethylene glycol (PEG) derivative is chemically adsorbed and coated is the inner surface, the outer surface, and the end portion 105 in the case of the dispensing nozzle having the hollow portion 103, and the dispensing nozzle separates the specimen or the reagent. It is sufficiently larger than the region 104 to be immersed in the specimen or reagent when pouring.
  • a molecule represented by the general formula (1) is generally called a silane coupling agent, and can be immobilized by chemical bonding with a surface hydroxyl group. By using an asymmetric molecule in this way, it can be fixed as a monolayer on the surface of the dispensing nozzle.
  • silane coupling agent By using an asymmetric molecule in this way, it can be fixed as a monolayer on the surface of the dispensing nozzle.
  • both ends are silanol group precursors, the polyethylene glycol chain is immobilized on the surface at both ends, and the degree of freedom of movement may be lost, and the inherent non-specific adsorption suppression effect may not be exhibited.
  • R 1 , R 2 , and R 3 are silicon (Si) substituents.
  • ether groups such as methoxy group (MeO), ethoxy group (EtO), propyloxy group (PrO) or halogens such as fluorine (F), chlorine (Cl), bromine (Br), iodine (I) Among them, those selected from these are silicon substituents.
  • R 4 is a hydrocarbon group.
  • R 5 is preferably H or CH 3 from the viewpoint of hydrophilicity.
  • n is a positive integer of 2 or more.
  • Silanol (SiOH) groups have a high affinity with silicon oxide (SiO 2 ). Glass generally has a SiOH group or a SiO 2 layer. Therefore, a silane coupling agent can be fixed as it is by producing a dispensing nozzle with glass. Alternatively, in the case of a dispensing nozzle made of a material other than glass, chemical adsorption and covalent bonding with a silane coupling agent can be realized by providing a silicon oxide layer, a glass layer, or the like in advance on the nozzle surface.
  • stainless steel is widely used for dispensing nozzles of automatic analyzers in view of good workability and corrosion resistance. Therefore, in the embodiment, an example in which a silicon oxide layer is provided in advance on the outermost surface of stainless steel will be described. However, a hydroxyl group is formed on the stainless steel surface, and it is possible to directly fix the silane coupling agent using the hydroxyl group as a reaction point.
  • FIG. 2 is a cross-sectional view of the processing section at the position indicated by the dotted line in FIG. 1 of the dispensing nozzle thus processed.
  • Dispensing nozzle 111 is a main body and is made of stainless steel or the like.
  • the SiO 2 layer 112 is formed on the nozzle 111 by sputtering, CVD film formation, or coating and drying of a chemical solution (SOG: Spin On Glass, coated glass).
  • the PEG derivative layer 113 is chemically bonded to the SiO 2 layer 112 and plays a role of suppressing adsorption of biopolymers such as proteins.
  • the dispensing nozzle includes a hollow portion 114.
  • the formed SiO 2 layer is cleaned with alcohol or acid.
  • the SiO 2 layer is formed only on the outer wall of the nozzle and the PEG derivative layer is formed on the outermost surface.
  • an SiO 2 layer and a PEG derivative layer may be formed on the inner wall of the nozzle.
  • Verification of the adsorption suppression effect was carried out by measuring the amount of protein adsorption by XPS. Specifically, the adsorption amount of BSA (bovine serum albumin) was estimated from the peak area of N1s (nitrogen 1s) XPS. BSA is suitable as a model for serum albumin, which accounts for about 50-65% of serum proteins. In the above surface-treated substrate, it was confirmed that the N1s peak area was below the detection limit even after the BSA adsorption experiment, and a conventional stainless steel or stainless steel formed with a SiO 2 layer. A significant difference was observed.
  • BSA bovine serum albumin
  • the dispensing nozzle of the present invention helps integrate an immunoassay device that is more sensitive to contamination between specimens with an automated biochemical analyzer.
  • the substrate used is a SUS substrate having a silicon oxide (SiO 2 ) layer having a thickness of 10 nm as the outermost surface layer.
  • the size of the substrate was 10 mm ⁇ 10 mm ⁇ 0.5 mm, and the measurement surface for verifying the effect was a 10 mm ⁇ 10 mm surface.
  • Step 1 A SiO 2 layer is formed on the SUS surface.
  • SiO 2 oxygen
  • Ar oxygen
  • the film formation conditions for SiO 2 are as follows.
  • the ultimate vacuum in the chamber was 5 ⁇ 10 ⁇ 5 Torr, and the heater set temperature was 423K.
  • the deposition rate of SiO 2 is 0.2 nm / second.
  • a 10 nm SiO 2 layer was formed on the SUS surface.
  • the SiO 2 layer can be formed not by sputtering but also by applying and drying a chemical solution (SOG: Spin On Glass, coated glass).
  • Step 2 The SiO 2 layer formed in step 1 is washed.
  • the substrate was ultrasonically cleaned in ethanol for 15 minutes.
  • the contact angle with water was measured with a Drop Master 500 manufactured by Kyowa Interface Science.
  • 0.5 ⁇ L of pure water was dropped onto the surface of the substrate using a syringe, and the static contact angle 1 second after the landing was measured by the three-point method.
  • the contact angle of the substrate was 10 ⁇ 1 °. This confirmed that the surface was clean.
  • Step 3 Immerse in a solution containing a polyethylene glycol derivative.
  • the substrate cleaned up to step 2 was subjected to silane coupling treatment with 2-methoxypolyethyleneoxypropyltrimethoxysilane (2- [METHOXY (POLYETHYLENEOXY) PROPYL] TRIMETHOXYSILANE).
  • 2-methoxypolyethyleneoxypropyltrimethoxysilane (2- [METHOXY (POLYETHYLENEOXY) PROPYL] TRIMETHOXYSILANE).
  • a 3 mM toluene solution of 2-methoxypolyethyleneoxypropyltrimethoxysilane was prepared, and concentrated hydrochloric acid (about 35%) was added dropwise to a concentration of 0.8 mL / L and stirred.
  • the substrate prepared in step 2 was immersed in the solution of the silane coupling agent thus prepared for 30 minutes.
  • 2-Methoxypolyethyleneoxypropyltrimethoxysilane (2- [METHOXY (POLYETHYLENEOXY) PROPYL] TRIMETHOXYSILANE) has a molecular weight of 460 to 590 and has 6 to 9 units of ethylene glycol chain.
  • the chemical formula of 2-methoxypolyethyleneoxypropyltrimethoxysilane is shown below.
  • Step 4 Washing and drying The substrate was lifted from the solution, washed once with toluene, washed twice with ethanol, then washed twice with water, and ultrasonically washed in water for 2 minutes. Then, it dried with nitrogen blow.
  • the substrate thus prepared is also referred to as a PEG solution immersion substrate.
  • BSA adsorption test The biopolymer adsorption inhibition effect was verified by an adsorption test of BSA (bovine serum albumin).
  • BSA bovine serum albumin
  • a 2.5 g / L solution of BSA was prepared.
  • Dulbecco's phosphate buffer solution was used as the solvent.
  • the prepared substrate was immersed in the prepared solution for 30 minutes. After lifting the substrate, it was first thoroughly washed with Dulbecco's phosphate buffer solution. Subsequently, it was thoroughly washed with pure water. Finally, it was dried by nitrogen blowing.
  • XPS measurement was performed on the three substrates subjected to the BSA adsorption test, and the surface composition was quantitatively analyzed.
  • XPS measurement was performed with QuanteraSXM manufactured by PHI. Monochromatic Al (1486.6 eV) was used as the X-ray source. The detection region was ⁇ 100 ⁇ m, and the extraction angle was 45 °.
  • the results after the BSA adsorption test are compared.
  • the measurement results of the PEG solution immersion substrate and the reference substrate 1 are shown in FIG.
  • the measurement result of the PEG solution immersion substrate is indicated by a broken line 310.
  • the range of the arrow 311 is a C—C, C—H bond
  • the range of the arrow 312 is a C—O bond
  • the arrow 313 is a range where C ⁇ O, O ⁇ C—O, and CO 3 bonds are detected.
  • the range of the arrow 314 is a peak of potassium 2p derived from glass.
  • FIG. 4 in addition to the CC and C—H bond peaks, a peak attributed to the C—O bond was strongly observed. This reflects the C—O bond derived from the ethylene glycol chain in the molecule.
  • the measurement result of the reference substrate 1 is indicated by a solid line 315.
  • the range of the arrow 316 is the C—C, C—H bond
  • the range of the arrow 317 is the C—O bond
  • the range of the arrow 318 is the range where the C ⁇ O, O ⁇ C—O, and CO 3 bonds are detected.
  • the range of the arrow 319 is a peak of potassium 2p derived from glass.
  • the C—O bond detected in the range of the arrow 312 is sufficiently larger than that of the reference substrate 1 in which the SiO 2 film is formed. Therefore, it was confirmed that the PEG derivative was properly fixed on the PEG solution immersion substrate.
  • the adsorption of BSA on the stainless steel surface can be quantitatively analyzed by XPS and the N1s peak corresponding to the nitrogen atom (N) in BSA.
  • N1s peak is attributed to amines and amides contained in BSA. Therefore, in this example, the relative adsorption amount of each BSA substrate was quantified based on the N1s amount, and the inhibitory effect on protein adsorption on the substrate surface was verified.
  • the thin line 321 is the spectrum of the PEG solution immersion substrate
  • the thick line 322 is the spectrum of the reference substrate 1
  • the broken line 323 is the spectrum of the reference substrate 2.
  • the analysis of the peak area of N1s was performed by subtracting the background from 395 eV to 405 eV with a straight line.
  • Table 1 shows the surface element concentration (atomic%) of N1s obtained from the peak area of each element.
  • the substrate immersed in a 2-methoxypolyethyleneoxypropyltrimethoxysilane solution was a PEG solution immersion substrate
  • the reference substrate 1 having only SiO 2 was an SiO 2 / SUS substrate
  • the reference substrate 2 was a stainless steel substrate.
  • the molecule represented by the chemical formula (2) is used as an example of the silane coupling agent having an ethylene glycol chain.
  • the chemical formula (2) is a mixture having 6 to 9 ethylene glycol chains (ethylene oxide groups).
  • the molecular weight of the PEG derivative is desirably 100 or more from the request that the number of necessary ethylene oxide groups is 2 or more and that the intermolecular interaction for arranging the molecules is sufficient.
  • the molecular weight of the PEG derivative is desirably 20000 or less.
  • the chemical structure of the PEG derivative to be coated need not be single, and may be a mixture.
  • the terminal of the molecule opposite to the silanol group may be a hydroxyl group (OH) or an ether group (O—R, R: alkyl group).
  • the propyl group (C 3 H 6 ) is generally a hydrocarbon group. Therefore, what is effective on the nozzle surface of the present invention is a molecule represented by the following general formula (3).
  • R 1 , R 2 , and R 3 are silicon (Si) substituents.
  • ether groups such as methoxy group (MeO), ethoxy group (EtO), propyloxy group (PrO) or halogens such as fluorine (F), chlorine (Cl), bromine (Br), iodine (I) Among them, those selected from these are silicon substituents.
  • R 4 is a hydrocarbon group.
  • R 5 is preferably H or CH 3 from the viewpoint of hydrophilicity.
  • R 4 may be an ether group, a carboxyl group, a carbonyl group, an ester group, an amide group, etc. in addition to a hydrocarbon group.
  • R 4 may be an ether group, a carboxyl group, a carbonyl group, an ester group, an amide group, etc. in addition to a hydrocarbon group.
  • n is a positive integer of 2 or more.
  • Example 1 In the present embodiment, a case where the same processing as that in the experimental example is performed on the dispensing nozzle will be described.
  • a SiO 2 layer was formed on the surface of a stainless steel dispensing nozzle by sputtering in the same manner as in the experimental example.
  • the region to be processed was the end portion 105 of the dispensing nozzle in FIG. 1 and the region 104 immersed in the specimen.
  • the treated nozzle tip had an outer diameter of 0.5 mm and an inner diameter of 0.3 mm, and a SiO 2 layer having a thickness of 10 nm was formed in the region of the tip of 10 mm.
  • the cost can be reduced by limiting the area to be processed to the part to be immersed.
  • the surface of the dispensing nozzle on which the SiO 2 layer was formed was ultrasonically cleaned with ethanol for 15 minutes.
  • a support base was provided so as not to contact the container.
  • the dispensing nozzle that had been cleaned was immersed in the PEG derivative solution. Specifically, a 3 mM toluene solution of 2-methoxypolyethyleneoxypropyltrimethoxysilane was prepared, and concentrated hydrochloric acid (about 35%) was added dropwise to a concentration of 0.8 mL / L. The washed dispensing nozzle was immersed in the silane coupling agent solution thus adjusted for 30 minutes. The dispensing nozzle was lifted from the solution, washed once with toluene, washed twice with ethanol, then washed twice with water, and ultrasonically washed in water for 2 minutes. Then, it dried with nitrogen blow.
  • the verification of the effect was carried out by measuring the surface residual amount of BSA by XPS as in the experimental example.
  • the protein remaining on the surface of the dispensing nozzle after dispensing is reduced to 1/50 or less (below the detection limit of XPS measurement described in the experimental example) compared to the conventional stainless steel nozzle. confirmed.
  • FIG. 6 is a diagram showing an example of the configuration of the automatic analyzer according to the present invention.
  • One or more sample containers 25 are arranged in the sample storage unit mechanism 1.
  • a sample disk mechanism that is a sample storage unit mechanism mounted on a disk-shaped mechanism unit will be described.
  • a sample generally used in an automatic analyzer It may be in the form of a rack or specimen holder.
  • the specimen here refers to a solution to be inspected used for reacting in a reaction vessel, and may be a collected specimen stock solution or a solution obtained by subjecting it to a processing such as dilution or pretreatment. .
  • the sample in the sample container 25 is extracted by the sample dispensing nozzle 27 of the sample supply dispensing mechanism 2 and injected into a predetermined reaction container.
  • the sample dispensing nozzle was surface-treated with 2-methoxypolyethyleneoxypropyltrimethoxysilane (2- [METHOXY (POLYETHYLENEOXY) PROPYL] TRIMETHOXYSILANE) by the method described in Example 1.
  • the reagent disk mechanism 5 includes a large number of reagent containers 6.
  • the mechanism 5 is provided with a reagent supply dispensing mechanism 7, and the reagent is sucked and injected into a predetermined reaction cell by the reagent dispensing nozzle 28 of the mechanism 7.
  • Reference numeral 10 denotes a spectrophotometer
  • 26 denotes a light source with a condensing filter.
  • a reaction disk 3 that accommodates a measurement target is disposed.
  • 120 reaction cells 4 are installed on the outer periphery of the reaction disk 3. Further, the entire reaction disk 3 is held at a predetermined temperature by a thermostatic chamber 9.
  • a reaction cell cleaning mechanism 11 is supplied with a cleaning agent from a cleaning agent container 13, and suction in the cell is performed by a suction nozzle 12.
  • 19 is a computer, 23 is an interface, 18 is a Log converter and A / D converter, 17 is a reagent pipettor, 16 is a washing water pump, and 15 is a sample pipettor.
  • Reference numeral 20 denotes a printer, 21 denotes a CRT, 22 denotes a flexible disk or hard disk as a storage device, and 24 denotes an operation panel.
  • the sample disk mechanism is controlled and driven by the drive unit 200, the reagent disk mechanism is driven by the drive unit 201, and the reaction disk is driven and driven by the drive unit 202, respectively.
  • Each part of the automatic analyzer is controlled by a computer 19 through an interface.
  • the operator inputs analysis request information using the operation panel 24.
  • the analysis request information input by the operator is stored in a memory in the microcomputer 19.
  • the sample to be measured which is placed in the sample container 25 and set at a predetermined position in the sample storage unit mechanism 1, is stored in the sample pipettor 15 and the sample supply dispensing mechanism 2 according to the analysis request information stored in the memory of the microcomputer 19.
  • a predetermined amount is dispensed into the reaction cell by the sample dispensing nozzle 27 subjected to the surface treatment.
  • the surface-treated specimen dispensing nozzle 27 is washed with water and used for dispensing the next specimen.
  • the sample dispensing nozzle 27 coated with 2-methoxypolyethyleneoxypropyltrimethoxysilane is used to suppress the adsorption of biopolymers typified by proteins, and the carryover between samples is made of conventional stainless steel. Compared to the dispensing nozzle, it could be reduced to 1/2 or less. Carryover is a comparison after cleaning. Therefore, although it is difficult to further reduce the carry-over, it is a remarkable progress that the carry-over rate can be reduced by surface-treating the nozzle.
  • the liquid level is detected using the change in capacitance. I can do it.
  • a predetermined amount of reagent is dispensed into the reaction cell by the reagent dispensing nozzle 28 of the reagent supply dispensing mechanism 7. After the reagent dispensing nozzle 28 is washed with water, the reagent dispensing nozzle 28 dispenses a reagent for the next reaction cell.
  • the liquid mixture of the specimen and the reagent is stirred by the stirring rod 29 of the stirring mechanism 8.
  • the stirring mechanism 8 sequentially stirs the liquid mixture in the next reaction cell.
  • the electrostatic capacity method is adopted for the principle of on-board liquid level detection.
  • the capacitance method the capacitance value between the nozzle and the ground (corresponding to the cell bottom in this embodiment) is measured. It utilizes the fact that the capacitance is larger than that in air when it comes into contact with a substance having a high dielectric constant.
  • FIG. 7 shows a conceptual diagram of liquid level detection by the electrostatic capacity method. This is a case where a metal nozzle that is not surface-modified is used.
  • the metal nozzle 410 does not touch the sample 413 in the sample container 412.
  • the electrostatic capacitance between the nozzle and the ground is determined by the electrostatic capacitance C 0 of air and the electrostatic capacitance C 1 of water.
  • FIG. 8 shows a conceptual diagram when the nozzle touches the liquid surface.
  • the metal nozzle 410 touches the liquid 413 in the sample container 412. If the specimen container has a ground of the apparatus body 411, the electrostatic capacitance between the nozzle and the ground is C 1.
  • FIG. 9 shows an example of liquid level detection with a nozzle coated with silicon oxide.
  • the case where the metal nozzle 410 having the silicon oxide layer 414 is not in contact with the liquid 413 in the specimen container 412 is shown.
  • the apparatus main body 411 in contact with the sample container is set as the ground.
  • FIG. 10 shows a case where the metal nozzle 410 having the silicon oxide layer 414 is in contact with the liquid 413 in the specimen container 412.
  • the apparatus main body 411 in contact with the sample bottle is set as the ground.
  • the liquid level can be detected.
  • the SiO 2 layer of this nozzle breaks due to some impact or contact, the metal nozzle directly contacts air, so the capacitance C 2 of the SiO 2 layer can be ignored. Then, since the electrostatic capacitance changes greatly, it is possible to detect scratches and cracks in the SiO 2 layer on the nozzle. When the SiO 2 layer is scratched or cracked, the carry-over may increase as a result. Therefore, it is important to be able to detect scratches and cracks in the SiO 2 layer.
  • a storage medium 32 that stores a change in the initial value due to nozzle replacement when the deviation of the capacitance from the initial value exceeds a certain threshold.
  • the automatic analyzer of the present embodiment is equipped with a detection mechanism 31 that detects this change in capacitance, and an indicator 30 that informs the nozzle replacement timing and analysis accuracy.
  • This indicator is blue when it is normal, and the change in capacitance is constantly measured.When an abnormality such as a crack or scratch occurs in the silicon oxide layer on the nozzle surface, the abnormality is detected from the change in capacitance.
  • the indicator 30 is displayed and notified in red, for example, via the interface.
  • the sample analyzed at this time is stored on the apparatus, and a program for re-acquisition of analysis data after nozzle replacement is incorporated.
  • FIG. 11 shows a schematic diagram of an automatic analyzer used in this embodiment.
  • a first processing liquid tank 401 and a second processing liquid tank 402 are added to the configuration of the automatic analyzer shown in FIG.
  • the dispensing nozzle 27 in FIG. 11 is a stainless steel dispensing nozzle having a SiO 2 layer of 10 nm formed on the surface.
  • the specimen dispensing nozzle 27 is rotationally moved to the first processing liquid tank 401, descends and is immersed in the first processing liquid.
  • the immersion area at this time is sufficiently larger than the area where the specimen dispensing nozzle 27 is immersed in the specimen during dispensing.
  • 2-methoxypolyethyleneoxypropyltrimethoxysilane as a PEG derivative or a solution of at least one molecule selected from a series of molecular groups represented by the general formula (1) in an experimental example can be used.
  • a 2 mM toluene solution of 2-methoxypolyethyleneoxypropyltrimethoxysilane was used.
  • the soaking time varies depending on the soaking frequency.
  • the dispensing nozzle 27 is rotated and moved to the second processing liquid tank 402, and is lowered and immersed in the second processing liquid. At this time, the immersion area is sufficiently larger than the area immersed in the first treatment liquid.
  • toluene used as a solvent for the treatment liquid in the first treatment liquid tank 401 is used as a solution used in the second treatment liquid tank 402 toluene used as a solvent for the treatment liquid in the first treatment liquid tank 401 is used.
  • the PEG derivative requires two or more ethylene oxide groups and the requirement that the intermolecular interaction for arranging the molecules is sufficient.
  • the molecular weight is desirably 100 or more.
  • the molecular weight of the PEG derivative is desirably 20000 or less.
  • the chemical structure of the PEG derivative to be coated need not be single, and may be a mixture.
  • the carry-over in the sample dispensing nozzle is considered as a problem, but the same effect can be obtained by performing the processing of the present invention on all members that can cause a carry-over, such as a stirring rod.
  • the non-specific adsorption of biopolymers such as proteins on the surface of the dispensing nozzle is dramatically reduced, and the carryover is suppressed, thereby contributing to the improvement of the reliability of the automatic analyzer. I can do it. In addition, this contributes to a small amount of sample and a small amount of reagent, and can reduce running cost and environmental load.

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Abstract

Analyseur automatique permettant l'analyse de prélèvements tels que de l'urine et du sang, comprenant une buse de distribution et conçu de manière à ce que l'effet de rémanence dû à l'utilisation répétée de la buse de distribution n'affecte pas les valeurs analytiques obtenues. La surface de la buse de distribution est revêtue d'un dérivé du poly(éthylèneglycol) chimisorbé pour former une couche moléculaire inhibant l'adsorption de biopolymères, et réduire ainsi l'effet de rémanence dû à la buse de distribution.
PCT/JP2010/071079 2009-12-11 2010-11-26 Buse de distribution pour analyseur automatique et analyseur automatique la comprenant WO2011070919A1 (fr)

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EP10835841.7A EP2511709B1 (fr) 2009-12-11 2010-11-26 Buse de distribution pour analyseur automatique et analyseur automatique la comprenant
US13/515,017 US8802008B2 (en) 2009-12-11 2010-11-26 Dispensing nozzle for automatic analyzer, and automatic analyzer including same
CN201080055689.8A CN102652263B (zh) 2009-12-11 2010-11-26 自动分析装置用分注喷嘴及搭载该分注喷嘴的自动分析装置

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JP2009281539A JP5255553B2 (ja) 2009-12-11 2009-12-11 自動分析装置用分注ノズル及びそれを搭載した自動分析装置

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EP2511709A1 (fr) 2012-10-17
CN102652263B (zh) 2014-11-26
EP2511709B1 (fr) 2019-08-07
JP2011122964A (ja) 2011-06-23
JP5255553B2 (ja) 2013-08-07
US20120251393A1 (en) 2012-10-04
US8802008B2 (en) 2014-08-12
CN102652263A (zh) 2012-08-29

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