JP2005069830A - Dispensation chip and analyzer using it - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a dispensation chip having excellent dispensation accuracy and an analyzer using it. <P>SOLUTION: This long and narrow dispensation chip for sucking and discharging liquid from the tip is equipped with: a cylindrical tip part having the inner diameter enlarged at a fixed rate A1 in proportion to the distance from the tip to the base end direction; the first cylindrical middle part coupled coaxially with the tip part and having the inner diameter enlarged at a fixed rate A2 larger than A1 in proportion to the distance from the tip part to the base end direction; the second cylindrical middle part coupled coaxially with the first middle part and having the approximately constant inner diameter; the third middle part coupled coaxially with the second middle part; and a cylindrical connection part coupled coaxially to the third middle part and connected detachably to a pressure supply part. The dispensation chip is constituted so that A2/A1 becomes not less than 1.5 and not more than 12. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a dispensing tip and an analyzer using the same, and more particularly to a disposable dispensing tip used in fields such as genetic testing, clinical testing, and biochemical analysis.

As a technique related to this invention, at least the lower end portion is attached to the outer peripheral surface of the lower end portion of a cylindrical nozzle made of a wearable material, and the tip end portion is sucked and discharged from the inner hole of the nozzle. A dispensing tip for sucking and discharging liquid from the dispensing tip, the dispensing tip being made of an elastic material, and a sealing surface is formed by contacting the outer peripheral surface of the nozzle on the inner peripheral surface of the dispensing tip A dispensing tip is known in which a circumferential protrusion having an inner diameter smaller than the outer diameter of the outer peripheral surface is provided at a position (see, for example, Patent Document 1).
Japanese Patent Laid-Open No. 11-248715 (FIG. 2)

Such a conventional dispensing tip includes a tip portion having a constant small inner diameter, a tapered portion that is coaxially coupled to the distal end portion, and a base portion that is coaxially coupled to the tapered portion and has a large inner diameter. However, since the inner diameter has a structure that increases rapidly in the axial direction at the joint between the tip portion and the tapered portion, such a dispensing tip does not stabilize the flow of liquid during dispensing, resulting in poor dispensing accuracy. There is a problem.
The present invention has been made in view of such circumstances, and has made a fluid dynamic study on the change in the inner diameter of the dispensing tip, that is, the internal structure to facilitate fluid flow during dispensing. The present invention provides a dispensing tip with improved dispensing accuracy and an analyzer using the same.

The present invention is an elongated dispensing tip that sucks and discharges liquid from the tip, a cylindrical tip having an inner diameter that increases at a constant ratio A1 with respect to the distance from the tip to the proximal direction, A cylindrical first intermediate portion that is coupled coaxially and has an inner diameter that increases at a constant ratio A2 greater than A1 with respect to the distance from the distal end portion to the proximal direction, and a substantially constant inner diameter that is coupled coaxially to the first intermediate portion. A cylindrical second intermediate portion having a cylindrical shape, a cylindrical third intermediate portion that is coaxially coupled to the second intermediate portion, and a cylindrical shape that is coaxially coupled to the third intermediate portion and is detachably connected to the pressure supply portion A dispensing tip having A2 / A1 of 1.5 or more and 12 or less.
Here, the pressure supply unit applies a negative pressure for suction and a positive pressure for discharge to the dispensing tip, and is, for example, a syringe pump.

  According to the present invention, the inner diameters of the distal end portion and the first intermediate portion gradually increase at a constant ratio A1, A2 with respect to the distance from the distal end to the proximal direction, and A2 / A1 is 1.5 or more. Since it is set to 12 or less, the liquid flow is stabilized during dispensing, and high dispensing accuracy is obtained.

FIG. 1 is a longitudinal sectional view showing the form of a dispensing tip according to the present invention.
As shown in FIG. 1, the dispensing tip 1 of the present invention is a cylindrical dispensing tip that sucks liquid from the distal end 2 to the proximal end 3 and discharges the liquid from the proximal end 3 to the distal end 2. The dispensing tip 1 has a cylindrical tip portion 4 whose inner diameter increases at a constant ratio A1 with respect to a distance L1 in the direction from the tip 2 to the base end 3, and is coaxially coupled to the tip portion 4. A cylindrical first intermediate portion 5 whose inner diameter increases at a constant ratio A2 larger than A1 with respect to the distance L2 in the direction of the proximal end 3, and a substantially constant inner diameter D3 coupled coaxially to the first intermediate portion 5 A cylindrical second intermediate portion 6, a cylindrical third intermediate portion 7 that is coaxially coupled to the second intermediate portion 6 and has an inner diameter D 4 that is larger than the second intermediate portion, and is coaxially coupled to the third intermediate portion 7. And a cylindrical connection portion 8 detachably connected to the pressure supply portion (dispensing pump) 9.

That is, the inner diameter of the distal end portion 4 changes from D1 to D2 with respect to the distance L1, and thus A1 = (D2-D1) / L1.
Further, since the inner diameter of the first intermediate portion 5 is from D2 to D3 with respect to the distance L2, A2 = (D3-D2) / L2, and therefore A2 / A1 = (L1 / L2) (D3-D2). ) / (D2-D1).

Here, in order to smooth the flow of fluid during dispensing of the dispensing tip, it is preferable that 1.5 ≦ A2 / A1 ≦ 12, and more preferable that 3 ≦ A2 / A1 ≦ 8. .
Moreover, it is preferable that the inner surface of the front-end | tip part 4 and the 1st intermediate part 5 is mutually smoothly connected, and the inner surfaces of the 1st and 2nd intermediate parts 5 and 6 are also smoothly continuously connected mutually. It is preferable. Thereby, the flow of the liquid is further stabilized, and the quantitative accuracy is improved.

It is preferable that the third intermediate portion 7 includes a hydrophobic filter 10 (for example, an ultrahigh molecular weight polyethylene porous film manufactured by Nitto Denko Corporation) that blocks liquid and allows gas to flow. This filter prevents the sucked liquid from accidentally contaminating the pressure supply unit 8.
Further, (the length L1 of the tip portion 4) + (the length L2 of the first intermediate portion 5) + (the length L2 of the second intermediate portion 6) can be set to 35 mm or less. Accordingly, it is possible to shorten the axial movement distance necessary for attaching / detaching the dispensing tip and dispensing the liquid.

Furthermore, the inner diameter D3 of the second intermediate portion 6 can be set to 2.0 mm or less. As a result, it is possible to dispense into a thin container.
Further, (the length L1 of the tip portion 4) / (the length L2 of the first intermediate portion 5) may be set to 0.4 or more and 0.6 or less.
Examples of the liquid to be dispensed by the dispensing chip of the present invention include specimens and reagents in various analysis processes, and particularly a sample suspected of containing a target nucleic acid in gene amplification detection.

From another standpoint, the present invention is a cylindrical dispensing tip that sucks and discharges liquid from the tip, and is connected to the tip of the tube in a coaxial manner with a distance from the tip to the proximal direction. On the other hand, a cylindrical first intermediate portion whose inner diameter increases at a constant ratio A, a cylindrical second intermediate portion that is coupled coaxially with the first intermediate portion and has a substantially constant inner diameter, and coaxial with the second intermediate portion A cylindrical third intermediate portion that has a larger inner diameter than that of the second intermediate portion, and a cylindrical connection portion that is coaxially connected to the third intermediate portion and is detachably connected to the pressure supply portion. A dispensing tip having A of 0.3 or less is provided.
Since the ratio A is 0.3 or less, it is possible to prevent the inner diameter from changing abruptly, thereby stabilizing the flow of the liquid during dispensing and obtaining high dispensing accuracy. The ratio A is more preferably 0.1 or less. Thereby, the dispensing accuracy can be further increased.

In addition, although the said dispensing tip by this invention is manufactured as a disposable type | mold (disposable) chip | tip, in order to perform an electrostatic capacitance type liquid level detection, it is preferable that it is a conductive plastic containing carbon. In this case, the dispensing tip can be manufactured, for example, by injection molding polypropylene (containing carbon).
Moreover, according to this invention, the analyzer using the said dispensing chip | tip, for example, a gene amplification detection apparatus, is provided.

EXAMPLES Hereinafter, the present invention will be described in detail based on examples shown in the drawings. This does not limit the invention.
Dispensing tips Figure 2 is a longitudinal sectional view showing an embodiment of a dispensing tip according to the present invention.
The dispensing tip 11 has a cylindrical shape penetrating from the distal end 12 to the proximal end 13 and has a total length L of 40 mm. The distal end portion 14, the first intermediate portion 15, the second intermediate portion 16, and the third intermediate portion are sequentially coaxially coupled. It comprises a part 17 and a connection part 18.
The tip 14 has a length of L1 = 6.0 mm, and its inner diameter increases linearly from D1 = 0.40 mm to D2 = 0.50 mm at a constant ratio A1 = 1/60 with respect to the length L1. To do.
The first intermediate portion 15 has a length of L2 = 13.0 mm, and its inner diameter is linear from D2 = 0.50 mm to D3 = 1.60 mm at a constant ratio A2 = 11/130 with respect to the length L2. To increase.
Here, A2 / A1 = 5.1 and L1 / L2 = 0.46.

The second intermediate portion 16 has a length of L3 = 11.0 mm, and its inner diameter slightly increases from D3 = 1.60 mm to D3a = 1.70 mm with respect to the length L3.
The third intermediate portion 17 and the connecting portion 18 have a total length of L4 = 10.0 mm, and the inner diameter of the third intermediate portion 17 and the connecting portion 18 suddenly increases from D3a = 1.70 mm to D4 = 3.0 mm at the joint portion with the second intermediate portion 16. Then increase to D4a = 3.45 mm with a gradient of 2 degrees. The inner diameter D5 at the base end 13 is 3.95 mm.

  The volume of the tip end portion 14 is 0.7 μL, the volume of the first intermediate portion 15 is 12.3 μL, and the volume of the second intermediate portion 16 is 24.0 μL. Further, the base end 13 is provided with a flange portion 19 having an outer diameter D6 = 7.0 mm protruding in the radial direction, and is used when the dispensing tip 11 is attached to or detached from the tip holder as will be described later.

  FIG. 3 is a front view showing the appearance of the dispensing tip shown in FIG. 2. As shown in the figure, at the tip portion 14, the minimum outer diameter E1 = 0.70 mm, the maximum outer diameter E2 = 1.20 mm, In the first intermediate portion 15, the maximum outer diameter E3 = 3.00 mm, in the second intermediate portion 16, the maximum outer diameter E3a = 3.10 mm, and in the third intermediate portion 17 and the connecting portion 18, the maximum outer diameter E4a = 4.70 mm. ing.

The dispensing tip 11 is manufactured by injection molding using polypropylene as a material.
As an embodiment of an analyzer using the analyzer dispensing chip 11, a gene amplification detector will be described below.
FIG. 4 is a perspective view showing a measurement unit of the gene amplification detection apparatus. The measurement unit 101 includes a chip set unit 103, a reagent set unit 104, a sample set unit 105, a reaction detection unit 106, and a chip discard unit 107 in a housing 102. Further, the measurement unit 101 includes an X direction moving mechanism unit 108, a Y direction moving mechanism unit 109, and a Z direction moving mechanism unit 110 on the housing 102. Each of the two dispensing mechanisms 111 includes a syringe pump and is mounted on the Z-direction moving mechanism 110 so as to be independently movable in the arrow Z direction. The Z-direction moving mechanism section 110 is mounted on the X-direction moving mechanism section 108 via the Y-direction moving mechanism section 109, and can move in the arrows X and Y directions.

In the chip set portion 103, 36 dispensing tips 11 shown in FIGS. 2 and 3 are arranged in the vertical direction with the flange portion 19 facing upward. Two sets of enzyme reagent bottles and primer reagent bottles are installed in the reagent setting unit 104, and they are kept at 15 ° C. or lower.
Ten sample containers each containing a sample can be installed in the sample setting unit 105, and they are kept at 15 ° C. or lower.

  The reaction detection unit 106 includes 10 detection cells for containing samples and reagents, a temperature setting unit for setting the liquid temperature of each detection cell to 20 ° C. and 65 ° C., and liquid turbidity in each detection cell And a detection unit for detecting the real time. The tip discarding unit 107 incorporates a tip storage unit for storing the used dispensing tips 11.

  As shown in FIG. 5, the syringe pump 111 a included in the dispensing mechanism unit 111 has a tip holder 112 whose tip is detachably fitted to the connecting portion 18 of the dispensing tip 11 and a base end of the tip holder 112 that is airtight. A cylinder part 113 that is fixed to the cylinder part 113 and a piston drive part 114 that is connected to the cylinder part 113.

  The tip holder 112 has a vent hole 112a that communicates with the dispensing tip 11 at the shaft core, and the cylinder portion 113 has a cylinder hole 116 that communicates with the vent hole 112a and accommodates the piston 115. Then, when the piston driving unit 114 reciprocates the piston 115 in the cylinder hole 116, the liquid is sucked and discharged (dispensed) into the dispensing tip 11, and the liquid dispensing amount is determined by the movement amount of the piston 115. It has come to be. The dispensing tip 11 is preloaded with a hydrophobic filter 10a. An ultra high molecular weight polyethylene porous film manufactured by Nitto Denko Corporation is used for the hydrophobic filter 10a.

FIG. 6 is a block diagram showing the configuration of the gene amplification detection apparatus of this example. As shown in the figure, in response to the detection condition input from the input unit 203, the analysis unit 201 outputs a control signal to the drive control unit 117, and the drive control unit 117 receives the reagent setting unit 104, the sample based on the control signal. The set unit 105, the reaction detection unit 106, the X direction movement mechanism unit 108, the Y direction movement mechanism unit 109, the Z direction movement mechanism unit 110, and the dispensing mechanism unit 111 are driven and controlled. The analysis unit 201 receives the output from the reaction detection unit 106 and performs analysis, and outputs the analysis result from the output unit 202.
Here, the analysis unit 201, the output unit 202, and the input unit 203 can be integrally configured by a personal computer.

The operation in such a configuration will be described next.
First, a sample (excised tissue) is pretreated using a homogenizing reagent, a sample is prepared and stored in a sample container, and the sample container is placed in the sample erection unit 105 shown in FIG. This sample includes, for example, a sample suspected of containing the target nucleic acid. Next, a reagent bottle containing a predetermined reagent, a required number of new detection cells, and a required number of new dispensing chips are connected to the reagent setting unit 104, the reaction detection unit 106, the chip setting unit shown in FIG. Set to 103.
When a “detection start” command is input from the input unit 203, the two dispensing mechanism units 111 shown in FIG. 4 move upward from the chip setting unit 103 and then descend to move each chip holder 112 to FIG. As shown, it is inserted into the connecting portion 18 (FIG. 2) of the dispensing tip 11, and the dispensing tip 11 is fitted into the tip holder 112.

  Next, the two dispensing mechanisms 111 move to the reagent setting unit 104 to suck a predetermined amount of a necessary reagent, move to the reaction detection unit 106, and discharge it to the corresponding detection cell. Next, the two dispensing mechanisms 111 move to the tip discarding section 107, descend, and the flange 19 (FIGS. 2 and 3) of the dispensing tip 11 is attached to the locking portion (illustrated) provided in the tip discarding section 107. The dispensing tip 11 is detached from the tip holder 112 and discarded into the tip accommodating portion. Next, the two dispensing mechanisms 111 attach a new dispensing tip 11 in the chip set 103, suck a sample from the sample container of the sample set 105 and discharge it to a predetermined detection cell of the reaction detector 106. After that, the used dispensing tip 11 is discarded to the tip discarding unit 107. When such an operation is repeated and necessary samples and reagents are dispensed to each detection cell of the reaction detection unit 106, the reaction detection unit 106 performs a reaction detection operation, that is, a time of liquid turbidity in the detection cell. The change detection operation is started. The analysis unit 201 (FIG. 6) analyzes the presence / absence and concentration of the target gene (nucleic acid) from the detected value, and causes the output unit 202 to output the analysis result.

It is a longitudinal cross-sectional view of the dispensing tip which concerns on this invention. It is a longitudinal cross-sectional view which shows the dispensing tip by one Example of this invention. It is a front view which shows the external appearance of the dispensing tip shown in FIG. It is a perspective view which shows the principal part of one Example of this invention. It is sectional drawing which shows the principal part of one Example of this invention. It is a block diagram which shows the structure of one Example of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1,11 Dispensing tip 2,12 Tip 3,13 Base end 4,14 Tip part 5,15 1st intermediate part 6,16 2nd intermediate part 7,17 3rd intermediate part 8,18 Connection part 9 Pressure supply part DESCRIPTION OF SYMBOLS 10 Filter 101 Measuring part 102 Housing 103 Chip setting part 104 Reagent setting part 105 Sample setting part 106 Reaction detection part 107 Chip discarding part 108 X direction moving mechanism part 109 Y direction moving mechanism part 110 Z direction moving mechanism part 111 Dispensing mechanism part 112 Tip holder 112a Vent hole 113 Cylinder part 114 Piston drive part 115 Piston 116 Cylinder hole 117 Drive control part 201 Analysis part 202 Output part 203 Input part

Claims (11)

  An elongated dispensing tip that sucks and discharges liquid from the tip, and has a cylindrical tip having an inner diameter that increases at a constant ratio A1 with respect to the distance from the tip to the base, and is coaxially coupled to the tip. A cylindrical first intermediate portion whose inner diameter increases at a constant ratio A2 larger than A1 with respect to the distance from the distal end portion to the proximal direction, and a cylindrical shape that is coaxially coupled to the first intermediate portion and has a substantially constant inner diameter. A second intermediate portion, a cylindrical third intermediate portion that is coaxially coupled to the second intermediate portion, and a cylindrical connection portion that is coaxially coupled to the third intermediate portion and is detachably connected to the pressure supply portion. A dispensing tip having A2 / A1 of 1.5 or more and 12 or less.   The dispensing tip according to claim 1, wherein A2 / A1 is 3 or more and 8 or less.   The dispensing tip according to claim 1 or 2, wherein inner surfaces of the tip portion and the first intermediate portion are smoothly continuous with each other.   The dispensing tip according to any one of claims 1 to 3, wherein inner surfaces of the first and second intermediate portions are smoothly continuous with each other.   The dispensing tip according to any one of claims 1 to 4, wherein the third intermediate portion has a larger inner diameter than the second intermediate portion, and includes a filter that blocks liquid and allows gas to pass.   The dispensing tip according to any one of claims 1 to 5, wherein the tip portion and the first and second intermediate portions have a sum of lengths of 35 mm or less.   The dispensing tip according to any one of claims 1 to 6, wherein the second intermediate portion has an inner diameter of 2.0 mm or less.   The dispensing tip according to any one of claims 1 to 7, wherein L1 / L2 is 0.4 or more and 0.6 or less, where L1 and L2 are the lengths of the tip portion and the first intermediate portion, respectively.   The dispensing chip according to claim 1, wherein the liquid contains a sample suspected of containing a target nucleic acid.   A cylindrical dispensing tip that sucks and discharges liquid from the tip, and has a cylindrical tip and an inner diameter at a constant ratio A with respect to the distance from the tip to the proximal direction, coaxially coupled to the tip. A cylindrical first intermediate portion that increases in size, a cylindrical second intermediate portion that is coaxially coupled to the first intermediate portion and has a substantially constant inner diameter, and a cylindrical third that is coaxially coupled to the second intermediate portion. A dispensing tip having an intermediate portion and a cylindrical connecting portion that is coaxially coupled to the third intermediate portion and is detachably connected to the pressure supply portion, and the ratio A is 0.3 or less.   The analyzer using the dispensing chip of any one of Claims 1-10.

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