WO2006129486A1

WO2006129486A1 - Chemical analyzer

Info

Publication number: WO2006129486A1
Application number: PCT/JP2006/309901
Authority: WO
Inventors: Hironobu Yamakawa; Hideo Enoki; Kunio Harada; Sakuichiro Adachi; Isao Yamazaki
Original assignee: Hitachi High-Technologies Corporation
Priority date: 2005-05-30
Filing date: 2006-05-18
Publication date: 2006-12-07
Also published as: JP4500733B2; JP2006329899A

Abstract

A chemical analyzer to which electro-wetting (EWOD) is applied and which enhances a dispensing accuracy. The chemical analyzer (100) applies a voltage between electrodes formed on the opposing surfaces of a substrate, constituting an analysis device (150) and formed with liquid supplying ports (151), and another substrate disposed facing the first substrate to allow liquid supplied into the substrates to flow. A unit (160) is provided which has a thin tube (180) at the tip end thereof and supplies liquid from the ports using this thin tube. The electrode on the lower-side substrate is provided with electrode rows (152) having many small electrodes. The thin tube can retain liquid larger in volume than droplets moving through the electrode rows. The thin tube is inserted between oppositely disposed substrates through a port to supply a large volume of liquid at a stretch.

Description

Specification

Chemical analyzer

Technical field

[0001] The present invention relates to a chemical analyzer, and more particularly to a chemical analyzer suitable for analyzing a liquid containing a trace amount of substance.

Background art

[0002] An example of a conventional liquid transfer device is described in Patent Document 1. The liquid transfer device described in this patent specification has a microactuator for driving a minute flow rate. This microactuator is based on a phenomenon called electrowetting, has no moving parts, and applies an adhesive energy gradient between the liquid and the solid wall surface to the liquid. Specifically, a common electrode plate has a flat plate with a drive electrode array having a plurality of electrodes insulated from each other on the surface! Speak. By switching the power to each electrode constituting the electrode array, a small amount of liquid droplets supplied to the gap between the common electrode plate and the drive electrode plate are transported along the electrode array.

[0003] Patent Document 1: US Pat. No. 6,565,727

Disclosure of the invention

Problems to be solved by the invention

[0004] According to the liquid transfer apparatus described in Patent Document 1, the voltage is controlled to change the wettability of the surface of the flat plate, and the liquid is transported in the device as the analysis unit. However, since this liquid transfer device focuses only on the transfer of minute droplets, it is sufficient for the dispensing and analysis of droplets necessary for chemical analysis. Is cunning, taking into account.

[0005] In a chemical analyzer, it is necessary to perform a multi-item analysis at high speed by supplying various reagents to a sample using a probe of a device external force capillary. For this reason, samples and reagents must be accurately dispensed and introduced into the device, but at present, no dispensing method has been established and dispensing accuracy is low. In addition, if the sample is not dispensed in excess of the amount required for analysis, the analysis may not be possible, and the amount of reagents and samples to be dispensed will increase. In addition, the efficiency of automation can be improved by handling multiple samples and multiple reagents simultaneously. However, it is difficult to improve throughput because it does not consider handling many reagents at the same time.

[0006] The present invention has been made in view of the above-mentioned problems of the prior art. The purpose of the present invention is to dispense in a chemical analysis apparatus using an electro-wetting-on-electric (EWOD). It is to improve accuracy. Another object of the present invention is to improve the throughput of a chemical analysis apparatus to which EWOD is applied. Means for solving the problem

[0007] A feature of the present invention that achieves the above object is that an electrode is formed between electrodes formed on opposing surfaces of a substrate on which a port for supplying a liquid is formed and a substrate disposed to face the substrate. In a chemical analysis apparatus using EWOD that applies a pressure to flow a liquid supplied into the substrate, a supply means for supplying a liquid from the port using a thin tube at the tip is provided. The electrode on the one substrate includes an electrode array having a large number of small electrodes, can hold a larger volume of liquid than the liquid droplets that move through the electrode array, and the thin tubes are arranged oppositely from the port. It is inserted between the substrates so that a large volume of liquid can be supplied at once.

[0008] Another feature of the present invention that achieves the above object is that an electrode formed on both opposing surfaces of a substrate on which a port for supplying a liquid is formed and a substrate disposed to face the substrate. In the chemical analysis apparatus using EWOD, in which a voltage is applied between the liquid and the liquid supplied in the substrate flows, the port forms a dispensing portion, and a liquid reservoir is provided below the port. An electrode is arranged, and an electrode array composed of a large number of electrodes having a smaller area than that of the liquid storage electrode is arranged with a slight interval from the liquid storage electrode.

[0009] According to these features, the opposing substrate constitutes an analysis device, and the analysis device has an analysis unit arranged at a position different from the dispensing unit having the port. It is preferable that droplets required for one analysis can be separated from the liquid dispensed from the dispensing section by the dispensing section.

[0010] Further, according to the above feature, the dispensing unit has a plurality of ports to which the first liquid and the second liquid can be supplied, respectively, below the plurality of ports and facing the ports. A holding part for mixing and holding the first and second liquids may be formed between the substrates. A stagger that fits in the opening of the port may be provided. Furthermore, it is desirable that the first liquid is a sample liquid and the second liquid is a reagent or a diluent.

[0011] In each of the above features, when an angle formed by the plurality of electrode rows, in which a plurality of electrode rows having a plurality of electrodes are arranged around the liquid storage electrode, is an acute angle, liquid protrudes therebetween. It is preferable to provide a prevention means. Further, the liquid pool electrode, which is open at the tip of the thin tube in the direction of the electrode row, is arranged inside a plurality of crescent-shaped electrodes having different outer diameters and the crescent-shaped electrode. It is preferable to arrange the electrodes in which a part of the circle is cut out with a slight gap between them to form a substantially circular electrode.

[0012] In each of the above features, the fluorine system in which the capillary tube is immersed has a controller for changing the magnitude of the voltage applied to a large number of electrodes of the liquid reservoir electrode and electrode array forming the dispensing part. An oil holding means may be provided, and the controller may control to immerse the thin tube in oil held in the fluorine-based oil holding means before supplying the liquid from the port. Further, the diameter of the narrow tube is smaller than the diameter of the open end of the port. The controller may be formed in a funnel shape inside the port opening. The controller supplies the liquid supplied by the thin tube. The liquid may be supplied so that the order of the analysis and the order of analysis in the analysis unit are different.

The invention's effect

[0013] According to the present invention, in the chemical analyzer, the probe supplied into the device on which the electrode is formed can dispense more than the reagent or sample amount necessary for one analysis, and the dispensing unit This electrode has a structure that forms only the amount of droplets required for one analysis, so the accuracy of the droplet volume can be improved even if a probe with low dispensing accuracy is used. In addition, samples or reagents required for multiple analyzes or multiple analyzes can be dispensed from the probe into the device, so that a large number of droplets can be manipulated simultaneously in the device, improving throughput.

Brief Description of Drawings

FIG. 1 is a perspective view of an embodiment of a chemical analyzer according to the present invention.

FIG. 2 is a longitudinal sectional view of a dispensing probe unit provided in the chemical analyzer shown in FIG. 1.

FIG. 3 is a top view of an analysis device unit provided in the mechanical analysis apparatus shown in FIG. 1.

FIG. 4 is a top view of an analysis device unit provided in the mechanical analysis apparatus shown in FIG. 1. FIG. 5 is a detailed perspective view of a sample dispensing unit of the chemical analyzer shown in FIG. 1.

FIG. 6 is a longitudinal sectional view of another example of the dispensing probe portion.

FIG. 7 is a diagram illustrating a dispensing process.

FIG. 8 is a diagram for explaining a dispensing process.

FIG. 9 is a top view of another example of the analysis device unit.

FIG. 10 is a top view of still another example of the analysis device unit.

FIG. 11 is a longitudinal sectional view of still another embodiment of the dispensing probe portion.

Explanation of symbols

[0015] 110 ··· Sample cup, 120 ··· Sample disc, 150 ··· Analytical device, 180 ··· probe.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, some embodiments of the chemical analysis apparatus according to the present invention will be described with reference to the drawings. FIG. 1 is a perspective view of the chemical analysis apparatus 100 in the first embodiment, which is partially omitted. A large number of sample cups 110, which are cylindrical containers for storing biological samples such as serum, are arranged in the vicinity of the outer periphery of a sample disk 120 that is rotatably provided. Adjacent to the sample disk 120, a reagent disk 140, which is also rotatably provided, is disposed. A large number of reagent bottles 130 are accommodated near the outer periphery of the reagent disk 140.

[0017] An analysis device 150, which will be described in detail later, is disposed at an interval from these two disks 120 and 140. A sample dispensing mechanism 160 is disposed between the analysis device 150 and the sample disk 120. The sample dispensing mechanism 160 has a probe moving mechanism 212 having a main shaft portion that can move up and down and an arm portion in which the main shaft portion force projects in the horizontal direction. At the tip of the arm portion, a narrow tube 182 called a probe that sucks the sample liquid from the sample cup 110 and discharges it to a plurality of ports 151 having openings provided on the surface of the analysis device extends vertically downward. A tube (not shown) is connected to the arm side end of the probe 182. The other end of the tube is connected to a syringe (not shown) disposed in the vicinity of the sample dispensing mechanism 150. The syringe drives 182 reagents in the probe. A reagent dispensing mechanism 170 is disposed between the analysis device 150 and the reagent disk 140. The reagent dispensing mechanism 170 includes a main shaft portion that can move up and down, and a probe moving mechanism 210 that includes an arm portion that protrudes horizontally from the main shaft portion. At the tip of the arm portion, a narrow tube 180 called a probe that sucks a reagent solution from the reagent bottle 130 and discharges it to a plurality of ports 151 having openings provided on the surface of the analysis device extends vertically downward. A tube 190 is connected to the arm side end of the probe 180. The other end of the tube 190 is connected to a syringe 200 disposed in the vicinity of the reagent dispensing mechanism 170. The syringe 200 drives 180 reagents in the probe.

Sample disk 120 and reagent disk 140 are connected to controller 1 85 by electrical wiring 181. The controller 185 is also connected with a sample dispensing mechanism 160 and a reagent dispensing mechanism 170. The sample disk 120 and the sample dispensing mechanism 160, and the reagent disk 140 and the reagent dispensing mechanism 170 are aligned with each other. Control to work

[0020] The analysis device 150 has a rectangular flat plate, and is placed on the stage 220. A plurality of ports 151 are arranged side by side near the sample disk 120 and the reagent disk 140 of the analysis device 150 and near the side edge. An electrode lane 152 in which a large number of electrodes are formed in a row is provided with the port 151 as an end.

[0021] Fig. 2 is a longitudinal sectional view of a dispensing part including the port 151 of the analysis device 150, and Figs. 3 and 4 show one electrode row from the electrode lane 152 formed in the analysis device 150. The top view when taken out is shown. In the analysis device 150, two substrates, a rectangular upper substrate 230 and a lower substrate 240, are arranged facing each other with a gap therebetween. A large number of electrodes 3001, 3002,... With a side length of, for example, several millimeters of power / zm, are arranged at a slight interval on a part of the lower substrate 240 to form an electrode lane 152. To do. The upper surfaces of the electrodes 3001, 3002,... Are covered with an insulating film 250. The upper surface of the insulating film 250 is covered with a water repellent film 260.

The upper substrate 230 as a whole is a ground electrode and is covered with a water-repellent film 260. The ground electrode of the upper substrate 230 is connected to the ground, and the electrodes 3001, 3002,... Of the lower substrate 240 are connected to a power source (not shown) by electric wiring 181. Each electrode of lower substrate 240 3001 , 3002,... Can be switched and applied. The distance between the two substrates 230 and 240 is kept constant by the spacer 280.

The electrodes 3001, 3002,... Of the lower substrate 240 are formed by depositing or sputtering thin film electrodes having conductivity such as Cr, Ti, Al, ITO on the surface of an insulating substrate material such as glass or quartz. And surface treatment such as CVD. On this electrode, an organic insulating film such as Parylene (trade name) manufactured by ThreeBond Co., Ltd. or an inorganic insulating film such as Si02 is processed by vapor deposition, sputtering, CV D, or the like. A fluorine-based water repellent film 260 is coated on the insulating film 250. As a material of the water repellent film 260, Teflon AF1600 (trade name) manufactured by DuPont, Cytop (trade name) manufactured by Asahi Glass, or the like is used.

In the upper substrate 230, a transparent conductive film such as ITO is formed on the entire upper surface of the substrate material. A fluorine-based water-repellent film 260 is coated on the conductive film. Since the water-repellent film 260 is formed on the surface, it is possible to prevent contamination by an impurity solution in which various solutions hardly adhere to the surface of the substrates 230 and 240. Openings are formed at a plurality of locations on the upper surface substrate 230, and cylindrical ports 151 are attached to the openings so that the upper force can be accessed.

[0025] The operation of the analysis device 150 configured as described above will be described below. In the following explanation, the operation of the force reagent for explaining the operation of the sample is the same. The probe 180 is immersed in the sample cup 110, and the syringe 200 is operated to suck the sample liquid 290. The amount of sample liquid to be sucked is for multiple tests. For example, in the case of three tests, the probe 180 is aspirated by adding the dummy amount 2904 with a margin to the first to third sample amounts 2901 to 2903 necessary for the analysis.

The sample dispensing mechanism 160 is driven to position the probe 180 at the predetermined port 152 of the analysis device 150. Thereafter, as shown in FIG. 2 (A), the probe 180 holding the sample solution therein is inserted into the port 152. The tip of the probe 180 is cut obliquely, and the cut surface 185 faces the electrode lane 152. The syringe 200 is driven, and the sample liquid 290 is discharged into the gap between the two substrates 230 and 240 (see FIG. 2 (B)).

[0027] At this time, the notch surface 185 of the probe 180 is held toward the electrode lane 152, and a voltage is applied between the first electrode 3001 to the fourth electrode 3004 and the upper substrate 230. Is applied to the electrodes 3001 to 30 which are energized in the electrode lane 152. Only on 04, wettability becomes large. Then, the sample liquid discharged from the probe 180 does not go in the direction of the spacer but flows so as to crawl on the electrode lane 152. When all of the sample liquid 290 in the probe 180 is discharged, the sample liquid 290 is applied with a voltage to increase the wettability of the first electrode 3001 to the fourth electrode 3004 and the inertial fifth electrode 3005. It extends to the point where the tip is hooked on (see Fig. 2 (C)).

The probe 180 in which the sample liquid 290 is emptied is pulled up, the energization of the first electrode 3001 where the sample rear end 320 is located is stopped, and the fifth electrode 3005 where the sample tip 310 is located is energized. The wettability of the electrode lane 152 decreases at the sample rear end 320 position, and the wettability increases at the sample front end 310 position. As a result, the sample liquid 290 moves to the right in FIG. 2 (see FIG. 2 (D)).

By the way, in the analysis device 150 described in the present embodiment, an electrode lane 1 52 is formed as shown in FIG. That is, the electrode lane 152 includes a transport lane 330 for transporting the sample liquid or reagent solution to a predetermined position, an analysis lane 350 for transporting the liquid separated at the liquid separation point 340 to the analysis position, and a discharge lane. With 360. Liquid separation point 340 is a place where only the amount of liquid used in one analysis is separated from the liquid dispensed from port 151 of the dispensing unit. The discharge lane 360 is continuous with the transfer lane 330, and when the remaining sample liquid 290 separated by an amount necessary for one analysis is temporarily placed, all the droplets necessary for the analysis are separated. Used when the remaining dummy droplets are discharged out of the analysis device 150. Each of these lanes 330, 350, and 360 has a shape in which a large number of rectangular electrodes are arranged on a straight line with a slight gap therebetween.

[0030] Fig. 3 is a diagram showing how the sample amount required for one analysis is separated. Fig. 3 (A) shows the sample liquid dispensed from port 151 of the dispensing unit. This is the case. A voltage is applied to the electrodes 3301 to 3304 marked with X. The wettability of the electrodes 3301 to 3304 is increased, and the sample liquid occupies the electrodes 3301 to 3304. From this state, current is sequentially applied to the electrode located on the right side of the drawing in relation to the electrode 3304. At the same time, energization is sequentially stopped from the electrode 3301 located on the left side. In this way, the sample liquid 290 is conveyed to the right.

[0031] In FIG. 3B, the position of the sample liquid 290 transported to the right includes the liquid separation point 340. It shows a state of being conveyed up to. As a result of sequentially switching the electrode in the transfer lane 330 and the electrode in the discharge lane 360, the sample liquid 290 reaches the liquid separation point 340. In this state, voltage application is continued to the electrode 320 that is located at the corner where the transfer lane 330 branches to the analysis lane 350 and on which the rear end of the sample liquid 290 is placed. Then, the voltage application to the electrode 3601 located at the leftmost part of the discharge lane 360 adjacent to the electrode 320 is stopped. Then, energization of the rightmost electrode 310 on which the sample solution 290 is placed is started. At this time, in the sample liquid 290, the rear end portion is attracted to the electrode 320 and the front end portion is attracted to the electrode 310 side, and the electrode 3601 starts to constrict 370 (see FIG. 3C). When the voltage application state to the electrode lanes 330 and 360 is continued, as shown in FIG. 3 (D), the sample liquid 290 finally has the first sample droplet 3801 corresponding to the sample amount for the first test. The remaining sample liquid 390 is separated. The first sample droplet 3801 is an amount covering almost one electrode.

[0032] The position where the first sample droplet 3801 is held is a branch point to the analysis lane 350, and the amount of the first sample droplet 3801 occupies the area of one electrode. If the voltage application position is changed for each of the zero electrodes, the first sample droplet 3801 is transported on the analysis lane 350. That is, in the drawing of the analysis lane 350, the voltage application is switched sequentially from the electrode 3501 located at the upper end (see FIG. 3E). As with sample 290, the reagent solution is also dispensed at the other port 152 force in analytical device 150 and mixed into this first sample droplet 3801 via other transport and analysis lanes. The mixed solution is subjected to absorbance analysis or the like in an analysis unit (not shown).

[0033] When the first sample droplet 3801 moves to the analysis lane 350 and the first sample droplet 3801 does not occupy the electrode 320, which is a branching point with the analysis lane 350, the discharge lane 360 is The voltage application to the electrode 3601 located at the end is started and the voltage application to the electrode 310 at the tip of the discharge lane 360 is stopped. As a result, the remaining sample liquid 390 from which the first sample droplet 3801 has been separated is returned to the left. Then, when the rear end of the sample liquid 390 comes to occupy the electrode 320 (see FIG. 3 (F)), the procedure shown in FIG. 3 (D) is repeated again for the force of FIG. Separate drops 3802.

[0034] This procedure is repeated a predetermined number of times. In this example, sample solution 290 is used three times. Therefore, when the first to third sample droplets 3801 to 3803 are separated, a dummy amount 2904 that allows a margin for dispensing remains. Since this dummy amount 2 904 is unnecessary for this analysis, the voltage application electrodes of the discharge lane 360 are sequentially switched to the right, the discharge lane 360 is transported to the right, and discharged from a discharge port (not shown). (See Figure 3 (G)).

According to the present embodiment, the amount of liquid separated as the first to third sample droplets 3801 to 3803 is defined by the amount remaining on the electrode 320, so the sample 290 is absorbed by the probe 180. Even if an error occurs during drawing and discharging, since the dummy droplet 3804 acts as a buffer, the liquid amount of the three droplets 3801 to 3803 can be set with high accuracy without excess or deficiency. Therefore, even if the dispensing accuracy of the probe 180 is low, the dispensing accuracy of the amount of liquid used for analysis in the analysis device 150 can be maintained with high accuracy, and high-precision analysis can be performed in the analysis unit. In addition, since a plurality of droplets can be formed with a single dispensing force, a plurality of tests can be dispensed at once, and the throughput of the analyzer that does not need to drive the probe or sample disk each time is improved.

[0036] Note that the number of electrodes for stopping the voltage application in order to form the separated liquid droplets is not limited to one of the electrodes 3601, and the voltage application to a plurality of adjacent electrodes is performed simultaneously. It may be stopped to successfully form a constriction of droplets. In that case, monitor the behavior of the sample solution and reagent at the liquid separation point 340, and monitor the capacitance and images, etc., and determine the number of voltage application stoppages according to the behavior!

FIG. 4 shows a modification of the above embodiment. This modification is different from the above embodiment in that a plurality of analysis lanes 350 branched from a continuous transport lane 330 and a discharge lane 360 are provided to simultaneously separate a plurality of sample droplets. Since there are a plurality of analysis lanes 350 and a plurality of droplets are separated at the same time, the electrodes are formed in a shape that facilitates the separation of the droplets.

[0038] Specifically, up to the first analysis lane 350 located on the transport lane 330 side has the same configuration as the above embodiment, but to the right of the branch with the first analysis lane 350. The second analysis lane 350 is arranged, and the third analysis lane 350 is arranged further to the right. In FIG. 4, electrodes 321 and 322 similar to the electrode 320 at the branch portion are connected to the top of the second and third analysis lanes 350. Arranged above the upper electrode, between electrode 320 and electrode 321, between electrode 321 and electrode 322, and between electrode 322 and leftmost electrode 3601 of discharge lane 360, one side longer than the other electrodes The length is short, and two small electrodes 3311 to 3316 are arranged side by side! The small electrodes 3311 to 3316 constitute a liquid separation point 340.

[0039] A sample liquid 290 force including a sample amount that can be tested a plurality of times is transported on a transport lane 330 to a liquid separation point 340. Liquid separation point 340 includes small electrodes 3311-3316 and large electrodes 320-322. Figure 4 (A) As shown, the sample liquid 290 dispensed from the port 151 of the dispensing unit and transported through the transport lane 330 proceeds to the right in the figure, and the rear end of the electrode is a branched part. Occupies 320. At this time, the front end of the sample liquid 290 reaches the discharge lane 360. The small electrodes 3311 to 3316 arranged at the liquid separation point 340 have a small droplet holding force by electrowetting, so that the sample liquid 290 forms a constriction 370 corresponding to the electrode area at the liquid separation point 340 ( (See Figure 4 (B)).

[0040] In this state, voltage application to the small electrodes 3311 to 3316 at the liquid separation point 340 is stopped simultaneously. The first to third sample droplets 3801 to 3803 are separated from the sample liquid 290, and the remaining remains as a dummy liquid 2904 in the discharge lane (see FIG. 4C). Since only the first to third sample droplets 3801 to 3803 are occupied by the electrodes 3 to 322 of the bifurcation, if the voltage is sequentially applied to the electrodes of the analysis line 350, the sample droplets 3801 to 3803 Are transported in separate analysis lanes 350 (Fig. 4 (D)). At this time, the dummy liquid 2904 is sent from the discharge lane 360 to the discharge port (not shown).

[0041] In this modification, the amount of sample liquid dispensed from the dispensing port at a time is slightly larger than the analysis amount for 3 batches. You may repeat the procedure. As shown in this modification, a plurality of droplets for analysis can be formed at the same time by repeatedly arranging small electrodes for separating droplets in the transport lane and arranging an analysis lane therebetween. Therefore, the throughput of the chemical analyzer is improved.

[0042] Another embodiment of the present invention will be described with reference to FIGS. The difference between the present embodiment and the above-described embodiments and modifications is that dispensing and droplet separation can be performed at the same place. FIG. 5 shows a perspective view of the chemical analyzer 100. In FIG. 5, the sample dispensing unit is shown, and the reagent dispensing unit is omitted. Accommodates a large number of sample cups 1101, 1102, ... The probe 180 of the sample dispensing mechanism 160 that can be moved up and down and is rotatable is disposed on the rotatable sample disk 120. In the middle of the probe 180, a stock 181 is attached. The probe 180 can also access a port 151 formed in the analysis device 150. The sample disk 120 also contains an oil cup 1151 having high chemical resistance such as fluorinated oil and containing inert oil.

[0043] On the lower substrate 240 constituting the analysis device 150, a reservoir electrode 400, which will be described in detail later, and a large number of electrodes are arranged as an extraction electrode lane 410. A transport lane 330 is connected to the extraction electrode lane 410. The transfer lane 330 is connected with first to third holding lanes 4601 to 4603 that hold three different types of samples. Retention lanes 4601 to 4603 are not shown! Are connected to the analysis unit.

The other configurations are the same as those in the above embodiment. As shown in the cross-sectional view of FIG. 6, the inert oil 420 is supplied in advance between the two substrates 230 and 240 of the analysis device 150 from the port 151 using the probe 180. In this state, even if the sample solution or reagent enters between the substrates 230 and 240, the entire substrate 230 and 240 are covered with the oil film, so that the reagents and sample solution are not easily in contact with the substrates 230 and 240. . Therefore, even when the reagent or sample solution is changed for another analysis after one analysis is completed, the carry-over of the solution used in the previous analysis can be avoided. And the same analysis lane can be used to handle different samples.

[0045] The first sample droplet 4701 generated by separating a part of the first sample liquid dispensed from the first sample cup 1101 to the port 151 by using the probe 180 is extracted from the extraction electrode lane. From 410 to transport lane 330, and finally to first sample holding lane 4601 to await mixing and analysis. Similarly, the second and third samples are dispensed into the port 151, and part of the sample is separated by the reservoir electrode 400 to generate sample droplets 4702 and 4703. The separated droplets 4702 and 4703 are drawn out. Electrode Lane 410, next! Move to transport lane 330 with /, and wait on each holding lane 4602, 4603.

[0046] Controller force (not shown) Each sample is moved to the analysis lane as necessary. As a result, the first to third samples can be transported from the holding lanes 4601 to 4603 to the analysis lane in any order in the analysis device 150 without driving the probe 180. Can improve throughput. In addition, it is not necessary to rotate the sample disk 120 each time an analysis is requested to move the sample cup containing the desired sample to the dispensing position of the probe 180.

Details of the droplet separation operation in the present embodiment configured as described above will be described with reference to FIGS. 6 and 7. FIG. In the following description, handling of the sample 290 will be described, but the same applies to the case of the reagent. Place water 191 in syringe 200, tube 190, and probe 180. Immerse probe 180 in oil cup 1104 and suck a small amount of oil.

[0048] The sample disc 120 is rotated to position the sample cup 110 and the probe 180, and then the probe 180 is immersed in the sample cup 110 to suck the sample 290. The amount of sample 290 to be aspirated is the amount that can be executed multiple times or multiple tests plus the dummy amount to allow a margin. At this time, since the probe 180 is previously immersed in the oil cup 1104, the tip of the probe 180 is covered with oil on both the inner and outer surfaces. Therefore, the sucked sample 290 can be prevented from adhering to the surface of the probe 180. The sample 290 can suppress the occurrence of contamination at the probe 180, enabling highly accurate analysis.

[0049] The probe positioning mechanism 210 is driven to move the probe 180 to the dispensing port 151 for positioning (see FIG. 6B). Insert the probe 1 80 holding the sample solution 290 into the port 151. A probe stopper 181 formed in the vicinity of the tip of the probe 180 is fitted into a port connector 1510 formed in the upper part of the port 151 so that the probe 180 and the port 151 are brought into close contact with each other. The stopper 181 provided on the probe 180 compensates for misalignment or insertion misalignment between the probe 180 and the port 151 by the probe positioning mechanism 210, and prevents damage to the bottom surface of the analysis device 180. At the same time, the oil 420 is prevented from overflowing from the port 151 when the probe 180 is inserted into the port 151.

[0050] The syringe 200 is driven to discharge the sample liquid 290 into the analysis device 150. At this time, a voltage is applied only to the reservoir electrode 400. The position of the reservoir electrode 400 to which a voltage is applied is good in wettability, but the wettability is bad in other electrode positions. Therefore, the sample liquid 290 stays on the liquid storage electrode 400 without flowing elsewhere (see FIG. 6C). Extraction electrode Apply voltage to the electrode in lane 410. From this, a part of sample liquid 290 is separated by 2902 force S. The voltage application electrodes 410a, 410b,... Of the extraction electrode lane 410 are sequentially switched to drive the sample droplet 2902 on the electrode lane.

[0051] When the last droplet 2903 necessary for the analysis has been transported from the reservoir electrode 400 to the extraction electrode lane 410, the probe 180 is pulled up from the force of the port 151 while holding the remaining sample 2904. At this time, the remaining sample 2904 is sucked by operating the syringe 200 (see FIG. 6E). Since the sample liquid 290 unnecessary for the analysis is discharged out of the analysis device 150, the analysis process is simplified.

[0052] Here, in the present embodiment, as shown in Fig. 7, the shape of the liquid reservoir electrode 400 is such that droplet separation is easy. The electrode marked with X is an electrode to which a voltage is applied. The liquid reservoir electrode 400 has a circular shape in which a plurality of crescent-shaped electrodes 440a to 440d of different sizes are arranged with a slight gap, and a circle is partially cut inside the smallest crescent-shaped electrode 440a. The electrode 430 is arranged. The electrode of the extraction electrode lane 410 has substantially the same shape as the circular electrode 430 of the liquid storage electrode. That is, when two circles having the same size are arranged so as to partially overlap, the electrodes 410a, 410b,. The individual electrodes 410a, 410b,..., Are arranged in a straight line with a gap f¾ between the forces.

[0053] Since a voltage is applied to the liquid reservoir electrode 440, the sample liquid 290 immediately after being discharged from the probe 180 covers the liquid reservoir electrode 400 as shown by the bold line (Fig. 7 (A See)). In order to dispense the first sample droplet 2902, voltage application to the outermost crescent-shaped electrode 440d of the reservoir electrode 410 is stopped, and the electrode 410a located on the leftmost side in FIG. Apply a voltage to 410b (see Fig. 7 (B)). Since the wettability of the electrodes 410a and 410b of the extraction electrode lane 410 is increased, the sample droplet 290 extends toward the extraction electrode lane 410, and a constricted portion is generated. On the other hand, since the voltage application to the outermost crescent-shaped electrode 400d is stopped, the sample liquid 290 force map defined by the area of the crescent-shaped electrode 400d tries to move to the right.

[0054] The voltage application to the electrode 41 Oa of the extraction electrode lane 410 that hits the constricted portion of the sample liquid 290 is stopped. The wettability of the electrode 410a decreases, and the sample solution 290 Tries to flow out, and a sample droplet 2902 is formed (see FIG. 7C). When the voltage application to the electrodes 410a, 410b,... Of the extraction electrode lane 410 is sequentially switched, the formed sample droplet 2902 is conveyed on the extraction electrode lane 410. At that time, when the voltage application to the crescent-shaped electrode 440c is stopped, the remaining sample liquid 2901 from which the separated droplet 2902 has been separated moves to the right in the figure. This operation is repeated. The timing of stopping the application of voltage to the crescent-shaped electrodes 440c, 440b,... Is determined by monitoring the capacitance values and images between the upper and lower two substrates 230, 240.

[0055] From the sample liquid 290 for a plurality of tests dispensed on the reservoir electrode 400, the droplet force of an amount defined by the shape of the individual electrodes 400a to 400d, 430 of the reservoir electrode 400 It is conveyed as 902. Therefore, if each of the electrodes 400a to 400d and 430 is manufactured with high accuracy, the dispensing accuracy is improved and high accuracy analysis is possible. For the production of these electrodes 400a to 400d and 430, high-accuracy processing can be performed by easily applying a sputtering method or a vapor deposition method used in the manufacture of semiconductors.

[0056] In the embodiment shown in FIG. 6, the remaining residual sample solution was sucked with the probe 180. However, in this embodiment, the residual sample solution 2905 is discharged into the discharge port not shown. (See Fig. 7 (D)). A discharge lane is connected to the extraction electrode lane 410. According to the present embodiment, since the operation of the probe 180 which does not need to drive the syringe 200 is not restrained, the throughput is improved.

Another example of the liquid reservoir electrode 400 is shown in a top view in FIG. In the present embodiment, the drain electrode lane 410 is provided with an electrode 430b having a triangular portion that fits in the fan-shaped part of the liquid reservoir electrode 40Of, which is formed by a circular part of the electrode 400f. ing. The electrode 430b has a rectangular portion and a triangular portion, and is disposed with a slight gap from the liquid storage electrode 400. The other electrodes 431, 432,... Of the extraction electrode lane 410 are rectangular electrodes (see FIG. 8A).

[0058] The sample liquid 290 is discharged so as to have a larger diameter than the liquid storage electrode 400f. A voltage is applied to the electrode located on the leftmost side in the drawing of the liquid storage electrode 410 f and the extraction electrode lane 410. As a result, separated droplets are formed, and thereafter, as in the above embodiments, the voltage application to each electrode of the extraction electrode lane 410 is switched and the separated droplets are conveyed to the analysis unit. [0059] The amount of the sample liquid 290 dispensed from the probe 180 is small! /, And sometimes the separation liquid is generated several times, and the size of the sample liquid 290 located on the liquid reservoir electrode 400f is the size of the liquid reservoir electrode 400f. When the diameter is smaller than the outer diameter, a voltage is applied to the two electrodes 430b and 431 on the leftmost side in the figure of the liquid storage electrode 400 and the extraction electrode lane 410. The wettability is increased and a part of the sample liquid 290 is pulled out and moved to the extraction electrode lane 410 (see FIG. 8B). At this time, the voltage applied to the liquid storage electrode 400f is made smaller than that of the electrode 430b. The wettability of the liquid reservoir electrode 400f decreases, and the suction force of the liquid reservoir electrode 400f sucking the sample liquid 290 decreases. The sample liquid 290 can be easily moved.

[0060] Since the apex portion 4301 of the triangular portion of the electrode 430b that fits in the liquid storage electrode 400f is disposed near the center of the liquid storage electrode 400f, the liquid storage electrode 290b can be obtained even if the diameter of the sample liquid 290 is further reduced. By changing the magnitude of the applied voltage between 400f and the electrode 430b, the sample liquid 290 can be drawn out to the sample electrode 290 drawing electrode lane 410 side. The voltage application to the electrode 430 b is stopped, and the separation droplet 2902 is formed (see FIG. 8C).

[0061] On the transport electrode lane 410, when the voltage applied to one electrode is smaller than the voltage applied to the other electrode of the two electrodes on which the separation droplet 2902 is positioned, the applied voltage is increased. Since the separated droplet 2902 is transported, the magnitude of the applied voltage may be adjusted without necessarily switching the electrode on / off. In this case, the separation droplet 2902 can be smoothly transported and the transport speed can be improved.

[0062] Some modifications of the present embodiment will be described below. In order to reduce the voltage applied to the reservoir electrodes 400 and 400f, the insulating film 250 and the water repellent film 260 of the substrates 230 and 240 are made thicker at the reservoir electrodes 400 and 400f. In this modification, the voltage generated in the sample solution is reduced. Another shape of the reservoir electrode is shown in the top view in FIG. Slits 400h are formed at multiple locations on the reservoir electrode 400g. This reduces the electrode area of the liquid reservoir electrode 400g and reduces the suction force.

FIG. 10 is a top view showing still another modified example of the liquid storage electrode. In this modification, three extraction electrode lanes 4101 to 4103 are connected to the liquid storage electrode 400k. The electrode closest to the reservoir electrode 400k in each of the extraction electrode lanes 4101 to 4103 is a rectangle to which a triangular portion is added in the same manner as in the above embodiment, and the triangular portion is formed on the reservoir electrode 400k. It is a structure that fits into the slit. The angle formed by the first extraction electrode lane 4101 and the second extraction electrode lane 4102 is an acute angle, and a pole 450 is provided between them. A third extraction electrode lane 4103 is arranged 180 degrees opposite to the first extraction electrode lane 4101.

[0064] When transporting extraction electrode lanes arranged in opposite directions like the first extraction electrode lane 4101 and the third extraction electrode lane 4103, a voltage is applied to the electrodes of the extraction electrode lane. The sample solution 290 can be withdrawn at the same time. In the case where the first extraction electrode lane 4101 and the second extraction electrode lane 4102 are adjacent to each other at an acute angle, the sample liquid 290 located between the two extraction electrode lanes 4101 and 4102 is used. May protrude from the reservoir electrode 400k and move outward in the radial direction. Therefore, a pole 450 is arranged so that the sample liquid 290 does not protrude. The pole 450 preferably has a structure like a round bar with a small contact area with the sample liquid 290. Thus, when the space between the extraction electrode lanes is narrow, it is preferable to provide means for preventing the sample liquid from protruding from the liquid storage electrode.

Still another embodiment of the chemical analyzer according to the present invention will be described with reference to FIG. FIG. 11 is a longitudinal sectional view of a dispensing unit of the analysis device 150 provided in the analysis apparatus 100. This embodiment is different from the above embodiments in the dispensing method of the sample liquid 290. Two types of solutions, in this example, a sample solution and a diluting solution are combined and dispensed. As other combinations, it can be applied to combinations of reagents and sample solutions.

[0066] The analysis device 150 for analyzing a sample is provided with a port 151 for the probe 180 to supply the sample. A diluent container 490 is placed at one corner of a table 480 on which an analysis device 150 having a pair of upper and lower substrates 230 and 240 is placed. In the vicinity of the sample port 151, a diluent port 500 for supplying the diluent into the analysis device 150 is disposed. A diluent tube 510 is connected to the diluent port 500 and is connected to the diluent container 490 via the valve 520. Pressure is applied in advance in the diluent container 490.

[0067] The sample 290 is dispensed by inserting the probe 180 into the sample port 151 from the outside. Probe 180 is much smaller than the inner diameter of sample port 151 and has an outer diameter of 0.lm It is made of SUS or resin, and can be deformed. The inside of the sample port 151 is formed in a mouth shape, and even if the probe 180 hits the inner wall surface of the sample port 151, the sample port 151 is deformed and inserted into the analysis device 150 (see FIG. 11A). Since the inner wall of the sample port is formed in a funnel shape, the probe 180 can be positioned in a predetermined position even if the positioning accuracy of the positioning mechanism of the probe 180 is poor.

[0068] The valve 520 interposed in the diluent tube 510 connected to the diluent container 490 is opened for a predetermined time, and a predetermined amount of the diluent 540 is discharged into the analysis device 150 (see FIG. 11 (B)). ). The sample solution 290 and the diluent 540 are mixed, and a mixed solution 550 is generated on the reservoir electrode 400 (see FIG. 11C). Here, the lower substrate 240 is recessed slightly downward at the position of the liquid storage electrode 400, and can store the sample liquid 290 and the dilution liquid 540. If a large amount of the dilution liquid 540 is injected, a high dilution liquid mixture 550 can be prepared. If a large amount of Diluent 540 is injected, oil or sample liquid 290 may overflow from port 151. Therefore, connect a sipper tube 511 to port 151, and excess sample or oil that may overflow from the port opening. Suck out and remove. According to the method described in any of the above-described embodiments, the droplet 551 is separated from the mixed solution 550 by the amount necessary for one analysis in the extraction electrode lane 410.

[0069] According to the present embodiment, the sample port 151 and the diluent port 500 are both arranged on the liquid storage electrode 400, and the two positions are close to each other, so that mixing of the two kinds of liquids becomes easy. The accuracy of the dilution rate can be improved. In general, since the amount of the diluted solution is larger than the amount of the sample solution, the large-volume liquid is dispensed later, and a large flow is generated in the mixed solution by the energy at the time of dispensing to enhance the mixing effect.

[0070] If the weighing error is substantially constant, the weighing accuracy when dispensing a large volume of solution is high, and the volume of the sample liquid 290 depends on the amount of sample liquid 290 previously supplied into the analysis device 150. The dilution liquid 540 may be dispensed. As a result, the dispensing amount can be adjusted with high accuracy. If the dispensing amount of sample 290 and diluent 540 is monitored with the capacitance output between the two substrates 23, 240 of analysis device 150 and the photographed image of the solution, the dispensing accuracy can be further improved.

Claims

The scope of the claims

[1] A voltage is applied between the electrodes formed on the opposing surfaces of the substrate (230) on which the liquid supply port (151) is formed and the substrate (240) arranged opposite to the substrate. Applying and flowing the liquid supplied in the substrate In the chemical analyzer using EWOD, a supply having a thin tube (180) at the tip and supplying the liquid from the port using the thin tube Means (160),

The electrode of the one substrate includes an electrode array (152) having a large number of small electrodes, and can hold a larger volume of liquid than the liquid droplets moving through the electrode array (152).

A chemical analysis apparatus characterized in that a large volume of liquid can be supplied at a time by inserting a thin tube from the port between the opposed substrates.

[2] A voltage is applied between the electrodes formed on the opposing surfaces of the substrate (230) on which the liquid supply port (151) is formed and the substrate (240) arranged opposite to the substrate. In the chemical analyzer using EWOD for applying and flowing the liquid supplied in the substrate, the port (151) forms a dispensing part,

Place the reservoir electrode (400) below this port,

A chemical analysis apparatus characterized in that an electrode array (152) composed of a large number of electrodes having a smaller area than that of the liquid storage electrode is arranged at a powerful interval in place of the liquid storage electrode.

[3] The opposing substrate constitutes an analytical device (150),

This analysis device (150) has an analysis part arranged at a position different from the dispensing part having the port,

2. The chemical analysis apparatus according to claim 1, wherein a droplet required for one analysis can be separated from the liquid dispensed by the dispensing unit force by the dispensing unit.

[4] The dispensing unit has a plurality of ports capable of supplying a first liquid and a second liquid, respectively, below the plurality of ports and between the opposing substrates. 3. The chemical analysis apparatus according to claim 2, wherein a holding portion that holds the liquid by mixing is formed.

[5] The narrow pipe is provided with a stagger (181) that fits into the opening of the port. The chemical analyzer according to claim 2.

[6] The first liquid is a sample liquid,

5. The chemical analyzer according to claim 4, wherein the second liquid is a reagent or a diluent.

7. The chemical analyzer according to claim 2, wherein a plurality of electrode arrays having a plurality of electrodes are arranged around the liquid reservoir electrode.

8. The chemical analysis apparatus according to claim 7, wherein when the angle formed by the plurality of electrode rows is an acute angle, a liquid overflow preventing means is provided between them.

[9] The chemical analyzer according to claim 1, wherein a tip portion of the thin tube opens in the electrode row direction.

[10] The liquid accumulation electrode includes a plurality of crescent-shaped electrodes (440a, 440b, 440c) having different outer diameters, and an electrode (430) arranged inside the crescent-shaped electrode and having a part of a circle cut away. 3. The chemical analysis apparatus according to claim 2, wherein a substantially circular electrode is arranged with a slight gap therebetween.

[11] The chemical analyzer according to claim 1, further comprising a controller (180) for changing a magnitude of a voltage applied to a plurality of electrodes of the electrode array forming the dispensing unit.

[12] Fluorine-based oil retaining means for immersing the capillary tube,

12. The chemical analyzer according to claim 11, wherein the controller controls the thin tube to be immersed in oil held in the fluorine-based oil holding means before supplying the liquid from the port.

13. The chemical analyzer according to claim 1, wherein the diameter of the narrow tube is smaller than the diameter of the opening end of the port, and the inner side of the opening of the port is formed in a funnel shape. .

14. The chemical analysis apparatus according to claim 11, wherein the controller supplies the liquid so that the order of the liquid supplied by the narrow tube is different from the order of analysis in the analysis unit.