JP2006058112A - Trace sample measuring device, trace sample measuring instrument, and trace sample measuring method - Google Patents
Trace sample measuring device, trace sample measuring instrument, and trace sample measuring method Download PDFInfo
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Abstract
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本発明は、微量の試料を計量して注入することの出来る微量試料計量デバイス、該微量試料計量デバイスの各機構を制御する機構を含む微量試料計量装置、および微量試料の計量方法に関する。 The present invention relates to a micro sample measuring device capable of measuring and injecting a micro sample, a micro sample measuring device including a mechanism for controlling each mechanism of the micro sample measuring device, and a micro sample measuring method.
マイクロ流体デバイスは、内部に有する微細な毛細管状の流路中で反応や分析を行うデバイスであり、マイクロ流体デバイスを使用することにより、反応や分析の迅速化、必要試料量の減少、省資源・省ネルギー、さらには廃棄物の減少が可能となる。このようなマイクロ流体デバイスを例えばマイクロクロマトグラフィー分析に利用して、分析の迅速化、必要試料の微量化、および展開液の減少を計り、化学分析、生化学分析、医療診断などの方面に応用する試みが行われている。 A microfluidic device is a device that performs reaction and analysis in a fine capillary channel inside. By using a microfluidic device, the reaction and analysis are accelerated, the required sample amount is reduced, and resources are saved.・ Energy saving and waste reduction will be possible. Such microfluidic devices are used in, for example, microchromatography analysis to speed up analysis, reduce the amount of necessary samples, and reduce the amount of developing solution, and apply them to fields such as chemical analysis, biochemical analysis, and medical diagnosis. Attempts have been made.
しかしながら、マイクロ流体デバイスのスケールは、従来のポンプ、切り替えバルブ、シリンジ、ピペットなどの試料取り扱い手段や装置に比べて桁違いに小さいため、マイクロ流体デバイスの流路中に極微量の試料を注入することは相当困難であった。例えば、マイクロ・ガスクロマトグラフィー、マイクロ・液体クロマトグラフィー、マイクロ・アフィニティ・クロマトグラフィー、マイクロ・ゲル・パーミエーション・クロマトグラフィーなどのマイクロ・クロマトグラフィー分析においては、短い展開距離で迅速に高分解能の分析を行うためには、試料を短いスポットとして分離カラムに注入する必要があるが、マイクロシリンジやバルブによる流路切り替え法などの従来法による試料注入手段では注入試料の体積が過大になりがちであり、そのため、クロマトグラムのピークの広がりや、テーリングが生じ、良好に分離するためにはカラム長を太く或いは長くする必要があり、分析時間の伸長を招いていた。又、微小な反応槽中へ極微量の溶液を定量して注入し、他の溶液と混合することも同等に困難であった。 However, since the scale of microfluidic devices is orders of magnitude smaller than sample handling means and devices such as conventional pumps, switching valves, syringes, and pipettes, a very small amount of sample is injected into the flow path of the microfluidic device. That was quite difficult. For example, in micro chromatography analysis such as micro gas chromatography, micro liquid chromatography, micro affinity chromatography, micro gel permeation chromatography, etc., high resolution analysis can be performed quickly with a short development distance. In order to perform this procedure, it is necessary to inject the sample into the separation column as a short spot, but the volume of the injected sample tends to be excessive with conventional sample injection means such as a flow switching method using a microsyringe or a valve. Therefore, broadening of the peak of the chromatogram and tailing occur, and it is necessary to make the column length thicker or longer for good separation, leading to an increase in analysis time. In addition, it is equally difficult to quantitatively inject a very small amount of solution into a minute reaction tank and mix it with other solutions.
これを解決する方法として電気泳動分析に於いて、次の方法が試みられている(特許文献1参照。)。即ち、交差部に於いて交差する2本の流路の一方の一端に試料を注入し、該流路の両端に電圧を印加して電気泳動又は電気浸透流にて試料を移送し、試料が前記交差部を通過している時点で該電圧の印加を停止し、次いで、他方の流路の両端に電圧を印加することによって、交差部内の試料のみを他方の流路へ注入する方法である。 As a method for solving this problem, the following method has been attempted in electrophoretic analysis (see Patent Document 1). That is, a sample is injected into one end of two flow paths that intersect at an intersection, a voltage is applied to both ends of the flow path, and the sample is transferred by electrophoresis or electroosmotic flow. This is a method of injecting only the sample in the intersection into the other channel by stopping the application of the voltage at the time of passing through the intersection and then applying a voltage to both ends of the other channel. .
しかし、この方法では、接合部の容積だけの極微量の試料を他方の流路に注入することが可能であるが、電気泳動による試料移送であるため、試料は荷電試料に限られ、また、媒体も電解質媒体に限られるため、多くの液体クロマトグラフィーや、ガスクロマトグラフィーのように気相中へ試料を注入する用途には適用できなかった。 However, in this method, it is possible to inject a very small amount of sample corresponding to the volume of the junction into the other flow path, but because the sample is transferred by electrophoresis, the sample is limited to a charged sample, Since the medium is also limited to the electrolyte medium, it could not be applied to many liquid chromatography and uses such as gas chromatography in which a sample is injected into the gas phase.
また、分析装置として、接合された二本のチャネルを有するデバイスを包含する装置が開示されている(特許文献2参照。)。該装置中のデバイスにおいては、デバイス内のチャネルに圧力勾配を適用させて、試料が注入されたチャネルから電気泳動分析用チャネルに試料を注入するものである。しかし、該方法においては、次のような点で、試料注入方法としては不十分なものであった。(1)試料注入用チャネルと電気泳動分析用チャネルの圧力や、その制御のタイミングを精密に行う必要があるため、ポンプやバルブなどの機構が複雑かつ大がかりとなりがちであること、(2)該公知文献には電気泳動分析用試料の注入について記載されていて、クロマトグラフィーの試料注入については記載されていないが、本発明者等の検討によれば、試料注入用チャネルとクロマトグラフィー用チャネルの二つの流路の圧力を厳密に制御する必要があり、制御装置が大がかりなものに成りがちであること、(3)注入試料がテーリングを生じがちであり、それを抑制するためには、更に複雑な機構や圧力制御操作が必要なこと、および、(4)拡散速度の高い気体試料には適用が困難であること。 Further, an apparatus including a device having two bonded channels is disclosed as an analysis apparatus (see Patent Document 2). In the device in the apparatus, a pressure gradient is applied to the channel in the device, and the sample is injected from the channel into which the sample has been injected into the channel for electrophoretic analysis. However, this method is insufficient as a sample injection method in the following points. (1) Since the pressure of the sample injection channel and the electrophoresis analysis channel and the timing of control thereof must be precisely performed, mechanisms such as pumps and valves tend to be complicated and large-scale, (2) The public literature describes injection of a sample for electrophoretic analysis and does not describe injection of a chromatographic sample. However, according to the study by the present inventors, the channel for sample injection and the channel for chromatography are not described. It is necessary to strictly control the pressures of the two flow paths, and the control device tends to be large. (3) The injected sample tends to cause tailing. Complex mechanisms and pressure control operations are required, and (4) difficult to apply to gas samples with high diffusion rates.
本発明が解決しようとする課題は、微量の試料を取り扱う機構、例えばマイクロ流体デバイスに組み込まれた機構に流体試料を計量して注入するための微量試料計量デバイスおよび微量試料の計量方法において、液体中の荷電試料だけでなく液体中の非イオン性試料や気体試料にも適用可能であり、また、非電解質液体媒体中や気体媒体中への試料を注入する場合の試料計量も可能であり、試料の計量に複雑で大がかりな装置や複雑な制御を要することなく、簡易な操作で、極微量の試料を定量性よく計量できる微量試料計量デバイス、微量試料計量装置、および微量試料計量方法を提供すること。特に、マイクロ・クロマトグラフィーへの試料注入に適した試料計量デバイス、装置、及び計量方法を提供することにある。 A problem to be solved by the present invention is a micro sample measuring device and a micro sample measuring method for measuring and injecting a fluid sample into a mechanism for handling a small amount of sample, for example, a mechanism incorporated in a micro fluid device. It can be applied to non-ionic samples and gas samples in liquid as well as charged samples in it, and sample weighing is possible when injecting samples into non-electrolyte liquid media and gas media, Providing a micro sample weighing device, a micro sample weighing device, and a micro sample weighing method that can measure a very small amount of sample with a simple operation, without requiring complicated and large-scale equipment and complicated control for sample weighing. To do. In particular, it is an object to provide a sample weighing device, apparatus, and weighing method suitable for sample injection into micro chromatography.
本発明者らは、前記の課題を解決すべく鋭意検討した結果、図1に基本構成を示したように、一端に流体試料を流入させる試料流入口(5)を有し、流路途中に流体の移送を制御する移送制御手段(11)を有する第一流路(1)と、一端に流体試料を流出させる試料流出口(6)を有し、流路途中に流体の移送を制御する移送制御手段(12)を有する第二流路(2)と、一端に流体試料を移送する試料移送用流体を流入させる試料移送流体の流入口(7)を有し、流路中の流体試料を検出するセンサ部(20)を有する計量用流路(3)とから構成され、第一流路(1)、第二流路(2)及び計量用流路(3)のそれぞれの他端部が流体試料を流通するように接合部(4)において接合されてなり、
(A)流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際移送制御手段(12)により流体試料の第二流路(2)への流入を停止し、
(B)計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止し、
(C)計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により
第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにすることができる微量試料計量デバイスを用いることにより、前記課題を解決できることを見出し、本発明を完成するに至った。
As a result of intensive studies to solve the above-mentioned problems, the present inventors have a sample inlet (5) for allowing a fluid sample to flow into one end as shown in FIG. A first flow path (1) having a transfer control means (11) for controlling the transfer of fluid, and a sample outlet (6) for allowing a fluid sample to flow out at one end, and a transfer for controlling the transfer of fluid in the middle of the flow path A second flow path (2) having a control means (12) and a sample transfer fluid inlet (7) for introducing a sample transfer fluid for transferring a fluid sample to one end of the second flow path (2). A measuring flow path (3) having a sensor section (20) for detection, and the other end of each of the first flow path (1), the second flow path (2) and the measurement flow path (3) Joined at the joint (4) so as to circulate the fluid sample,
(A) The fluid sample flows in from the sample inlet (5), and the fluid sample flows into the metering channel (3) from the first channel (1). Stop the flow into the second channel (2),
(B) The flow of the fluid sample is stopped by the detection of the sensor unit (20) when the fluid sample flowing into the measuring channel (3) reaches a specified amount,
(C) The fluid sample in the measuring channel (3) is transferred into the second channel (2) by the sample transfer fluid flowing in from the inlet (7), and the measured sample is transferred to the sample outlet (6). At that time, the transfer control means (12) in the second flow path (2) is brought into a liquid-feedable state, and the fluid sample does not flow into the first flow path (1) by the transfer control means (11). The inventors have found that the above problems can be solved by using a micro sample weighing device that can be configured as described above, and have completed the present invention.
本発明のデバイス及び方法は、微量の試料を取り扱う機構、例えばマイクロ流体デバイスに組み込まれた機構に注入するための、微量の流体試料を計量することができる。本発明は、液体中の荷電試料だけでなく液体中の非イオン性試料や気体試料にも適用可能であり、また、非電解質液体媒体中や気体媒体中へ試料を注入する場合の計量も可能であり、試料の計量に複雑で大がかりな装置や複雑な制御を要することなく、簡易な操作で、極微量の試料を定量性よく計量できる。本発明は前記のように適用範囲が広いため、マイクロ・ガスクロマトグラフィー、マイクロ・液体クロマトグラフィー、マイクロ・アフィニティ・クロマトグラフィー、マイクロ・ゲル・パーミエーション・クロマトグラフフィーなどのマイクロ・液体クロマトグラフィーや、マイクロ・ガス・クロマトグラフィーへの試料注入、あるいは、マイクロ流体デバイス内の、即ち、マイクロ流体デバイスに組み込まれた反応槽や反応用流路への定量的試料注入に好適であり、さらに、マイクロ・トータル・アナリシス・システム(μ−TAS)に組み込んむことが容易である。 The devices and methods of the present invention can meter a trace fluid sample for injection into a mechanism that handles a trace sample, eg, a mechanism incorporated in a microfluidic device. The present invention can be applied not only to a charged sample in a liquid but also to a non-ionic sample or a gas sample in a liquid, and can also be measured when a sample is injected into a non-electrolyte liquid medium or a gas medium. Therefore, a very small amount of sample can be weighed with a simple operation without requiring a complicated and large-scale apparatus or complicated control for weighing the sample. Since the present invention has a wide range of applications as described above, micro-liquid chromatography such as micro-gas chromatography, micro-liquid chromatography, micro-affinity chromatography, micro-gel permeation chromatography, Suitable for sample injection into micro gas chromatography, or quantitative sample injection within a microfluidic device, ie into a reaction vessel or reaction channel incorporated in the microfluidic device, -It can be easily incorporated into a total analysis system (μ-TAS).
以下、本発明について、詳細に説明する。
[微量試料計量デバイス]
本発明の微量試料計量デバイスは、部材内部に毛細管状の流路を有するマイクロ流体デバイスとして構成される。微量試料計量デバイスの外形は、板状(柔軟なシート状を含む)、棒状(柔軟なひも状を含む)、チューブ状(毛細管状を含む)、塊状、又は、組み合わせ型マイクロ流体デバイスのコンポーネント(モジュール)となる形状、などの任意の形状であって良い。なかでも形状が板状のものは、製造が容易であり、流路などの構造に高い寸法精度や位置精度を持たせることができ、マイクロ流体デバイスの他の構造と一体化することが容易である上、使用時の温度調節や流路の観測が容易であるため好ましい。
Hereinafter, the present invention will be described in detail.
[Small sample weighing device]
The micro sample weighing device of the present invention is configured as a microfluidic device having a capillary channel inside a member. The external shape of the micro sample weighing device can be a plate shape (including a flexible sheet shape), a rod shape (including a flexible string shape), a tube shape (including a capillary tube), a bulk shape, or a component of a combined microfluidic device ( Any shape such as a module) may be used. In particular, a plate-like shape is easy to manufacture, and can have high dimensional accuracy and position accuracy in the structure such as the flow path, and can be easily integrated with other structures of the microfluidic device. In addition, it is preferable because temperature adjustment during use and observation of the flow path are easy.
微量試料計量デバイスを構成する材料は任意であり、例えば、ガラス、水晶等の結晶、シリコンなどの半導体、金属、セラミック、炭素、有機重合体(ポリジメチルシロキサンのように、主鎖が無機元素のも含む。)、あるいはこれらの発泡体などを使用できる。また、例えば有機重合体などの上に金属やその他の物質を蒸着した複合材料なども使用できる。但し、後述のように、本発明のバルブが流路壁を圧迫変形させることにより流路を開閉するタイプのものである場合には、圧迫部においては、可撓性のある素材を使用する必要がある。前記の素材のなかでも、活性ネルギー線硬化性樹脂が、各種形状への成形が容易であり好ましい。 The material constituting the micro sample weighing device is arbitrary, for example, glass, crystal such as crystal, semiconductor such as silicon, metal, ceramic, carbon, organic polymer (the main chain is inorganic element like polydimethylsiloxane) In addition, these foams can also be used. Further, for example, a composite material in which a metal or other substance is deposited on an organic polymer or the like can be used. However, as described later, when the valve of the present invention is of a type that opens and closes the flow path by compressing and deforming the flow path wall, it is necessary to use a flexible material in the compression portion. There is. Among the above materials, the active energy ray-curable resin is preferable because it can be easily molded into various shapes.
[流路]
微量試料計量デバイスは、試料流入口(5)から接合部(4)に至る第一流路(1)と、該接合部(4)から試料移送流体の流入口(7)に至る計量用流路(3)と、該接合部(4)から試料流出口(6)に至る第二流路(2)から成る。これらの流路を合わせて流路(10)とする。
[Flow path]
The micro sample weighing device includes a first channel (1) extending from the sample inlet (5) to the junction (4), and a metering channel extending from the junction (4) to the inlet (7) of the sample transfer fluid. (3) and a second flow path (2) from the joint (4) to the sample outlet (6). These flow paths are combined into a flow path (10).
前記流路(10)の横断面、即ち、流体の流動方向に直角な断面(以下、特に「縦割り断面」と断らない限り流路の該断面を単に「断面」と略記する。)の形状は特に限定されないが、矩形、台形、または半円形であることが、製造や内部の観察が容易であり好ましい。 The shape of the cross section of the flow path (10), that is, the cross section perpendicular to the fluid flow direction (hereinafter, the cross section of the flow path is simply abbreviated as “cross section” unless otherwise specified as “vertical cross section”). Is not particularly limited, but a rectangular shape, trapezoidal shape, or semicircular shape is preferable because manufacturing and internal observation are easy.
(第一流路)
第一流路(1)は、その一端の試料流入口(5)から接合部(4)までの範囲の流路である。第一流路(1)の横断面、即ち、流体の流動方向に直角な断面(以下、特に「縦割り断面」と断らない限り流路の該断面を単に「断面」と略記する。)の形状は特に限定されないが、矩形、台形、または半円形であることが、製造や内部の観察が容易であり好ましい。断面の寸法は任意であるが、微量試料計量デバイス表面から見た深さは、1〜500μmが好ましく、3〜200μmがさらに好ましく、5〜100μmが最も好ましい。また、微量試料計量デバイス表面から見た幅方向の寸法は1〜3000μmが好ましく、3〜1000μmがさらに好ましく、5〜500μmが最も好ましい。この範囲の下限以上とすることにより、圧力損失が過大になることが無く、また計量と注入操作が不安定になることもない、また、この範囲の上限未満とすることにより、微少な試料の計量が容易に行える。勿論、第一流路(1)の断面形状や断面寸法は、第二流路(2)や試料計量用流路(3)などの他の流路よ異なっていて良いし、第一流路内においても、流路の流れ方向で変化していて良い。
(First flow path)
The first channel (1) is a channel in a range from the sample inlet (5) at one end to the joint (4). The shape of the cross section of the first flow path (1), that is, the cross section perpendicular to the fluid flow direction (hereinafter, the cross section of the flow path is simply abbreviated as “cross section” unless otherwise specified as “vertical section”). Is not particularly limited, but a rectangular shape, trapezoidal shape, or semicircular shape is preferable because manufacturing and internal observation are easy. Although the cross-sectional dimension is arbitrary, the depth viewed from the surface of the micro sample weighing device is preferably 1 to 500 μm, more preferably 3 to 200 μm, and most preferably 5 to 100 μm. Moreover, 1-3000 micrometers is preferable, as for the dimension of the width direction seen from the trace sample weighing device surface, 3-1000 micrometers is more preferable, and 5-500 micrometers is the most preferable. By setting it above the lower limit of this range, the pressure loss will not be excessive, and the weighing and injection operation will not become unstable, and by setting it below the upper limit of this range, Easy to measure. Of course, the cross-sectional shape and cross-sectional dimension of the first flow path (1) may be different from those of other flow paths such as the second flow path (2) and the sample measurement flow path (3). However, it may be changed in the flow direction of the flow path.
第一流路(1)の長さは任意であり、例えば10μm〜100mmであり得るが、1mm〜30mmが好ましい。第二流路(2)へ導入される計量された試料のテーリングを抑制するために、移送制御手段(11)と接合部(4)の間の長さは短い方が良く、実質的にゼロが好ましい。従って、第一流路の長さは、最小の場合には、試料流入口(5)の内部の流路の長さと、移送制御手段(11)内部の流路の長さの和であり得る。 The length of the first channel (1) is arbitrary and may be, for example, 10 μm to 100 mm, but is preferably 1 mm to 30 mm. In order to suppress tailing of the weighed sample introduced into the second flow path (2), the length between the transfer control means (11) and the joint (4) should be short, substantially zero. Is preferred. Accordingly, the length of the first flow path can be the sum of the length of the flow path inside the sample inlet (5) and the length of the flow path inside the transfer control means (11) in the case of the minimum.
試料流入口(5)には、試料計量用流路(3)にて計量する量より多量の試料を第一流路(1)に導入することが出来れば任意であり、例えば、微量試料計量デバイス外に開口した開口部、微量試料計量デバイス外に開口したリザーバタンク、微量試料計量デバイス外と連絡する配管が接続された配管接続部、等であり得るし、また、微量試料計量デバイス中の他の機構、例えばリザーバタンク、濾過機構、透析機構などに接続されていても良い。 The sample inlet (5) is optional as long as a larger amount of sample can be introduced into the first channel (1) than the amount to be measured in the sample metering channel (3). It can be an opening that opens to the outside, a reservoir tank that opens to the outside of the micro sample weighing device, a pipe connection to which a pipe that communicates with the outside of the micro sample weighing device is connected, etc. These mechanisms may be connected to a reservoir tank, a filtration mechanism, a dialysis mechanism, or the like.
又、第一流路(1)の途上には、移送制御手段(11)が設けられている。移送制御手段(11)は、流体移送手段と共に稼働させて、第一流路(1)内の流体の移動と停止を制御する機構であり、バルブ類であり得るが、流体の移送と停止が可能なポンプ機構を用いて、流体移送手段を兼ねても良い。これらは本発明の実施態様により、好適に選択して用いることが出来る。 A transfer control means (11) is provided in the middle of the first flow path (1). The transfer control means (11) is a mechanism that is operated together with the fluid transfer means to control the movement and stop of the fluid in the first flow path (1), and may be valves, but the fluid can be transferred and stopped. A simple pump mechanism may also be used as a fluid transfer means. These can be suitably selected and used according to the embodiment of the present invention.
(第二流路)
第二流路(2)は、計量用流路(3)にて計量された試料が接合部(4)から導入される流路である。第二流路(2)は導入された試料の検出、分析、反応、処理などを行なう場であっても良いし、単に試料流出口(6)へ導くだけの移送用流路であっても良い。
(Second channel)
The second channel (2) is a channel through which the sample weighed in the metering channel (3) is introduced from the joint (4). The second flow path (2) may be a place where detection, analysis, reaction, processing, etc. of the introduced sample is performed, or may be a transfer flow path that simply leads to the sample outlet (6). good.
第二流路(2)の寸法、形状については、基本的に第一流路の場合と同様である。試料流出口(6)に計量された微量試料を利用する機構を接続する場合には、接合部(7)と移送制御手段(12)との間の長さは短い方が好ましく、実質的にゼロであることがさらに好ましい。この距離を短くすることで、試料流出口(12)から流出させる計量された試料のテーリングを少なくすることができる。従って、第二流路の長さは、最小の場合には、移送制御手段(12)内部の流路の長さと試料流出口(6)の内部の流路の長さとの和であり得る。 The dimensions and shape of the second flow path (2) are basically the same as in the case of the first flow path. In the case of connecting a mechanism that uses a minute amount of a measured sample to the sample outlet (6), the length between the joint (7) and the transfer control means (12) is preferably shorter, and substantially More preferably, it is zero. By shortening this distance, tailing of the weighed sample flowing out from the sample outlet (12) can be reduced. Accordingly, the length of the second flow path can be the sum of the length of the flow path inside the transfer control means (12) and the length of the flow path inside the sample outlet (6) in the minimum case.
試料流出口(6)は、微量試料計量デバイスの外部に開口していて、外部機構、即ち、微量試料計量デバイスとは独立した機構を接続したり、廃液を排出する目的に使用することも出来るし、微量試料計量デバイス内の、即ち、該デバイスに組み込まれた他の機構との接続部であっても良い。試料流出口(6)に接続できる好ましい機構としては、マイクロ・ガス・クロマトグラフィー・カラム、マイクロ・液体クロマトグラフィー・カラム、マイクロ・アフィニティ・クロマトグラフィー・カラム、マイクロ・ゲル・パーミエーション・クロマトグラフフィー・カラムなどのマイクロ・液体クロマトグラフィーカラムや、マイクロ・ガス・クロマトグラフィー・カラム、反応槽や反応用流路などの反応場、或いは、酵素増感法などによる検出機構が挙げられる。 The sample outlet (6) is open to the outside of the micro sample weighing device, and can be used for the purpose of connecting an external mechanism, that is, a mechanism independent of the micro sample measuring device or discharging the waste liquid. However, it may be a connection part with another mechanism in the micro sample weighing device, that is, incorporated in the device. Preferred mechanisms that can be connected to the sample outlet (6) include micro gas chromatography column, micro liquid chromatography column, micro affinity chromatography column, micro gel permeation chromatography. A detection mechanism using a micro / liquid chromatography column such as a column, a micro gas chromatography column, a reaction field such as a reaction vessel or a reaction channel, or an enzyme sensitization method.
本発明においては、試料流出口(6)に上記のクロマトグラフィー・カラム類を接続する場合、単に該カラムを接続するだけで良く、計量された試料に続いて、試料流出口(6)から展開液やキャリアガスなどのキャリアをクロマトグラフィー・カラムに導入することが出来る。そのため、キャリア導入用の流路を別に設ける必要がない。しかし、キャリア導入用の流路を別に設けることも可能である。 In the present invention, when the above-mentioned chromatography columns are connected to the sample outlet (6), it is only necessary to connect the column, and the sample is developed from the sample outlet (6) following the weighed sample. Carriers such as liquids and carrier gases can be introduced into the chromatography column. Therefore, it is not necessary to provide a separate channel for introducing the carrier. However, it is also possible to provide a separate channel for introducing the carrier.
試料流出口(6)には、流体を吸引して第二流路(2)に注入できる流体移送手段を接続しても良い。流体移送手段は、計量した微量の試料を利用する機構の後に接続することが好ましく、そのため、これらの試料を利用する機構が微量試料計量デバイス内部に形成されている場合に、試料流出口(6)に流体移送手段を接続する態様が好ましく用いられる。 The sample outlet (6) may be connected to a fluid transfer means that can suck fluid and inject it into the second channel (2). The fluid transfer means is preferably connected after a mechanism that uses a minute amount of a measured sample. Therefore, when the mechanism that uses these samples is formed inside the minute sample weighing device, the sample outlet (6 A mode in which a fluid transfer means is connected to the above is preferably used.
第二流路(2)の途上には、移送制御手段(12)が設けられている。移送制御手段(12)は流体移送手段と共に稼働させて、第二流路(2)内の流体の移動と停止を制御する機構であり、後述のバルブ類であり得るが、流体の移送と停止が可能な後述のポンプやポンプ機構を用いて、流体移送手段を兼ねても良い。これらは本発明の実施態様により、好適に選択して用いることが出来る。 A transfer control means (12) is provided in the middle of the second flow path (2). The transfer control means (12) is a mechanism that is operated together with the fluid transfer means to control the movement and stop of the fluid in the second flow path (2), and may be valves described later. However, it may also serve as a fluid transfer means by using a pump or a pump mechanism, which will be described later. These can be suitably selected and used according to the embodiment of the present invention.
但し、第二流路(2)中に、検出、分析、反応、処理などの、計量された微量試料を利用する機構を設ける場合には、移送制御手段(12)をこれらの機構の下流側、即ちこれらの機構と試料流出部(12)ととの間に設けることもできる。この様にすることにより、計量された微量試料は移送制御手段(12)内で乱されることなく上記の機構に注入されるため、テーリングの少ないパルス状に注入でき、好ましい。この場合、試料流出口(12)はこれらの処理の終わった試料の流出口となる。また、勿論この場合には、第二流路の長さや断面積などの形状寸法は、前記の寸法範囲とする必要はなく、これらの計量された微量試料を利用する機構に必要な寸法形状とすることが出来る。 However, in the case where a mechanism using a measured small amount of sample such as detection, analysis, reaction, treatment, etc. is provided in the second flow path (2), the transfer control means (12) is provided downstream of these mechanisms. That is, it can also be provided between these mechanisms and the sample outflow part (12). By doing so, the weighed trace sample is injected into the mechanism without being disturbed in the transfer control means (12), so that it can be injected in a pulse shape with less tailing, which is preferable. In this case, the sample outlet (12) serves as an outlet for the sample after these treatments. In this case, of course, the shape and dimensions of the second flow path and the cross-sectional area do not need to be in the above-mentioned range of dimensions, and the dimensions and shapes necessary for a mechanism using these measured trace samples. I can do it.
本発明は、計量された微量試料を利用する機構が、微量試料計量デバイス内に設けられたものである場合に、特に効果を発揮する。 The present invention is particularly effective when a mechanism that uses a weighed trace sample is provided in a trace sample weighing device.
(計量用流路)
計量用流路(3)は、試料の計量に用いる流路であり、第一流路(1)から一旦計量用流路(3)に試料を導入して計量した後、第二流路(2)へ注入する目的に使用される。計量用流路(3)の接合部(4)から所定の長さの範囲は試料計量部(3a)とされる。計量用流路(3)の試料計量部(3a)の長さを幅や高さに比べて長くしたり、接合部(4)から計量用流路(3)への接続部の断面積を、試料計量部(3a)の断面積より小さくすることによって、試料とそれ以外の流体とが拡散によって混合することを抑制し、試料注入の定量性を向上させることが出来る。前記の方法は、特に、試料が微少量である場合や、試料が気体である場合に有用である。計量用流路にはセンサ部(20)が設けられている。
(Measuring channel)
The measuring channel (3) is a channel used for measuring the sample. After the sample is once introduced from the first channel (1) into the measuring channel (3) and weighed, the second channel (2) is measured. Used for the purpose of injection. The range of a predetermined length from the junction (4) of the measurement channel (3) is the sample measurement unit (3a). The length of the sample measuring part (3a) of the measuring channel (3) is made longer than the width and height, or the cross-sectional area of the connecting part from the joint (4) to the measuring channel (3) is changed. By making it smaller than the cross-sectional area of the sample measuring part (3a), it is possible to suppress mixing of the sample and other fluids by diffusion and improve the quantitativeness of sample injection. The above-described method is particularly useful when the sample is very small or when the sample is a gas. A sensor section (20) is provided in the measuring channel.
計量用流路(5)の途中に、試料移送手段や移送制御手段を設けることも可能であるが、試料計量の精度を損なわないために、これらを設けないことが好ましい。 Although it is possible to provide a sample transfer means and a transfer control means in the middle of the measurement channel (5), it is preferable not to provide these in order not to impair the accuracy of sample measurement.
計量用流路(5)の寸法、形状は、各流路に特有の構造部分を除いて、第一流路の場合と同様であるが、断面積は1μm2〜0.1mm2が好ましく、3μm2〜0.05mm2がさらに好ましく、10μm2〜0.02mm2が最も好ましい。この下限以上にすることで、大きな困難なく試料の計量が可能となり、この上限未満とすることで、微少な試料の計量が容易に行える。また、各流路の長さも任意であるが、第五流路は10μm〜100mmが好ましく、100μm〜10mmがさらに好ましい。 The dimensions and shape of the measurement flow path (5) are the same as those of the first flow path except for the structure part peculiar to each flow path, but the cross-sectional area is preferably 1 μm 2 to 0.1 mm 2 and 3 μm. 2 to 0.05 mm 2 is more preferable, and 10 μm 2 to 0.02 mm 2 is most preferable. By setting this lower limit or more, it is possible to weigh the sample without great difficulty, and by setting it below this upper limit, it is possible to easily measure a minute sample. Moreover, although the length of each flow path is also arbitrary, 10 micrometers-100 mm are preferable, and, as for a 5th flow path, 100 micrometers-10 mm are more preferable.
[センサ部]
計量用流路(3)の試料計量部(3a)付近にはセンサ部(20)が設けられていて、計量用流路(3)に移送された試料を検知して、試料を計量する。本発明で言うセンサ部(20)とは、試料計量部(3a)に試料が一定量充填されたことを検知するための機構一般をいい、センサの一式、センサの検出部、あるいは微量試料計量デバイス外に設けられたセンサのための読み取り部を言う。センサ部(20)のセンサの種類は任意であり、例えば、蛍光、紫外・可視。赤外光吸収、屈折率、旋光度などを検知する光学式センサ、電気抵抗、電流、電位、電位差、起電力、酸化還元電位、周波数などを検知する電気センサ、共鳴周波数などを検知する電気磁気式センサ、温度、比熱、熱伝導率などを検知する熱的センサ、、特定の化学物質や生化学物質を検知する化学センサやバイオセンサ、放射線センサ、などでありうる。これらセンサは、使用する試料と溶媒などの媒体の種類に応じて、検出感度が高く、かつ溶媒などの媒体の影響を受けにくい方式を適宜選択すればよく、例えば、一般的には、紫外・可視・赤外吸収や屈折率などが、微量試料計量デバイスには検出用の窓を設けるだけで良いため、微量試料計量デバイスを使い捨てとしたり、洗浄を容易にするため好ましく、試料が蛍光性である場合には、蛍光測定が、感度が高く検出も容易であるため好ましく、試料がイオンである場合には、電気伝導度や起電力などのセンサが、感度が高く、センサ本体の機構が単純となるため好ましく使用できる。
[Sensor part]
A sensor unit (20) is provided in the vicinity of the sample measuring unit (3a) of the measuring channel (3), and the sample transferred to the measuring channel (3) is detected and the sample is measured. The sensor unit (20) referred to in the present invention refers to a general mechanism for detecting that the sample weighing unit (3a) is filled with a certain amount of sample, and is a set of sensors, a sensor detection unit, or a micro sample weighing. A reading unit for a sensor provided outside the device. The sensor type of the sensor unit (20) is arbitrary, for example, fluorescence, ultraviolet / visible. Optical sensors that detect infrared light absorption, refractive index, optical rotation, etc., electrical sensors that detect electrical resistance, current, potential, potential difference, electromotive force, redox potential, frequency, etc., electromagnetism that detects resonance frequency, etc. It may be a type sensor, a thermal sensor that detects temperature, specific heat, thermal conductivity, a chemical sensor that detects a specific chemical substance or biochemical substance, a biosensor, a radiation sensor, or the like. For these sensors, a method having high detection sensitivity and being hardly affected by a medium such as a solvent may be appropriately selected according to the type of a sample and a medium such as a solvent. Visible / infrared absorption, refractive index, etc. are preferable because it is only necessary to provide a detection window in the micro sample weighing device, so that the micro sample measuring device is disposable or easy to clean, and the sample is fluorescent. In some cases, fluorescence measurement is preferable because it is highly sensitive and easy to detect. When the sample is ions, sensors such as electrical conductivity and electromotive force have high sensitivity and the mechanism of the sensor body is simple. Therefore, it can be preferably used.
センサの検出部としては、例えば電気式センサの電極が挙げられる。外部センサのための読み取り部としては、例えば、光学式センサのための透明な窓が挙げられる。さらに、計量用流路(3)に複数のセンサ部(20)を設けたり、CCDカメラなどをセンサとして用い、計量用流路(3)の長さ方向に沿った広い範囲をセンサ部(20)として観察し、試料の移送量をモニタすることによって、任意の量だけ計量することも出来る。 As a detection part of a sensor, the electrode of an electric sensor is mentioned, for example. An example of the reading unit for the external sensor is a transparent window for the optical sensor. Further, a plurality of sensor parts (20) are provided in the measurement flow path (3), or a CCD camera or the like is used as a sensor, and a wide range along the length direction of the measurement flow path (3) is defined as the sensor part (20 ) And monitoring the transfer amount of the sample, it is possible to measure an arbitrary amount.
〔流体移送手段〕
本発明の微量試料計量装置及び微量試料の計量方法に於いては、試料を第一流路(1)から計量用流路(3)へ移送したり、試料移送用の流体を移送して試料を計量用流路(3)から第二流路(2)に注入するために、少なくとも一つの流体移送手段を要する。流体移送手段は、微量試料計量デバイス外部の機構であっても、微量試料計量デバイス内部に組み込まれた機構であっても良い。微量試料計量デバイス内部に組み込まれた機構(例えばポンプ機構)である場合、接液部の機構のみを本微量試料計量デバイスに組み込み、駆動部は外部に設けることも好ましい。
[Fluid transfer means]
In the micro sample measuring device and the micro sample measuring method of the present invention, the sample is transferred from the first channel (1) to the metering channel (3), or the sample transfer fluid is transferred to remove the sample. In order to inject from the measuring channel (3) into the second channel (2), at least one fluid transfer means is required. The fluid transfer means may be a mechanism outside the trace sample weighing device or a mechanism incorporated inside the trace sample weighing device. In the case of a mechanism (for example, a pump mechanism) incorporated in the micro sample weighing device, it is also preferable that only the mechanism of the liquid contact part is incorporated in the micro sample measuring device and the driving unit is provided outside.
また、流体移送手段は、実施態様により、少なくとの二台の吸飲可能な流体移送手段、少なくとも一台の吸飲可能な流体移送手段と少なくとも一台の吐出可能な流体移送手段の組み合わせ、或いは、少なくとも一台の双方向に移送可能な流体移送手段であり得る。さらに、これらの流体移送手段は、移送制御機構を兼ねることも出来る。 According to the embodiment, the fluid transfer means includes at least two suckable fluid transfer means, a combination of at least one suckable fluid transfer means and at least one dischargeable fluid transfer means, Alternatively, it may be at least one fluid transfer means that can transfer in both directions. Furthermore, these fluid transfer means can also serve as a transfer control mechanism.
微量試料計量デバイス外部の移送手段であって、吸引による流体の移送が可能なものとしては、例えば、シリンジポンプ、プランジャーポンプ、ダイヤフラムポンプ、ギアポンプ、チューブポンプなどのポンプ、アスピレーターや真空ポンプなどの減圧手段、毛細管、多孔質体、繊維の編織物、紙・不織布、繊維充填物、粉末充填物などの液体吸収機構、音波や超音波発生機構などを例示できる。このような流体移送手段は、試料移送流体の流入口(7)に接続し、吸引により第一流路(1)から試料計量用流路(3)へ試料を移送する場合や、試料流出口(6)に接続し、吸引により計量用流路(3)から第二流路(2)へ試料を注入する場合に使用できる。 Examples of transfer means outside the micro sample weighing device that can transfer fluid by suction include pumps such as syringe pumps, plunger pumps, diaphragm pumps, gear pumps, tube pumps, aspirators, vacuum pumps, etc. Examples include a pressure absorbing means, a capillary, a porous body, a fiber knitted fabric, a paper / nonwoven fabric, a fiber filling, a powder filling, and other liquid absorption mechanisms, a sound wave and an ultrasonic wave generation mechanism, and the like. Such a fluid transfer means is connected to the inlet (7) of the sample transfer fluid, and transfers the sample from the first channel (1) to the sample metering channel (3) by suction, or the sample outlet ( 6) and can be used when a sample is injected from the measuring channel (3) to the second channel (2) by suction.
また、微量試料計量デバイス外部の移送手段であって、吐出によって流体を移送できるものとしては、例えば、前記と同様のポンプ、圧力空気、加圧窒素などの加圧気体、音波や超音波発生機構などを例示できる。このような流体移送手段は、試料移送流体の流入口(7)に接続してこから試料移送流体を導入し、試料を計量楊柳路(3)から第二流路(2)に注入する場合や、試料導入口(5)に接続し、試料を第一流路(1)から計量用流路(3)へ試料を注入する場合に使用できる。 Further, as a transfer means outside the micro sample weighing device and capable of transferring the fluid by discharge, for example, the same pump as described above, pressurized gas such as pressurized air and pressurized nitrogen, sound wave and ultrasonic generation mechanism Etc. can be illustrated. Such a fluid transfer means is connected to the inlet (7) of the sample transfer fluid, introduces the sample transfer fluid from this, and injects the sample from the measuring channel into the second channel (2). The sample can be connected to the sample inlet (5) and used when the sample is injected from the first channel (1) into the metering channel (3).
さらに、微量試料計量デバイス外部の流体移送手段であって、吸引と吐出が可能であるもの、即ち、双方向に流体を移送できるものとして、例えば、シリンジポンプ、ダイヤフラムポンプ、ギアポンプ、チューブポンプなどのポンプが挙げられる。あるいは、前記の吸引が可能な流体移送手段と吐出が可能な流体移送手段の2台を使用して、バルブで切り替える方式も可能であるが、一台で双方向に移送間能な者が好ましい。このような流体移送手段は、試料移送流体の流入口(7)に接続して、第一流路(1)から試料計量用流路(3)への試料の吸引移送と、試料計量用流路(3)から第二流路(2)への試料の注入を行う流体移送手段として使用できるし、上記の吸引又は吐出のいずれかが可能な流体移送手段の代わりに使用できる。 Furthermore, fluid transfer means outside the micro sample weighing device that can suck and discharge, that is, fluid that can be transferred in both directions, such as syringe pump, diaphragm pump, gear pump, tube pump, etc. A pump is mentioned. Alternatively, it is possible to use a valve that uses two fluid transfer means capable of suction and a fluid transfer means capable of discharge, and a method of switching by a valve is possible. . Such a fluid transfer means is connected to the inlet (7) of the sample transfer fluid, and sucks and transfers the sample from the first channel (1) to the sample metering channel (3), and the sample metering channel. It can be used as a fluid transfer means for injecting a sample from (3) to the second channel (2), or can be used in place of the fluid transfer means capable of either suction or discharge.
上記の流体移送機構は、流路を閉じた状態で保持出来るものが好ましく、非運転字には何らエネルギーを消費する事なく、流路を閉じた状態で保持出来るものが好ましい。この観点から、シリンジポンプ、ギヤポンプ、チューブポンプが好ましい。 The above fluid transfer mechanism is preferably one that can be held in a state where the flow path is closed, and one that can hold the flow path in a closed state without consuming any energy for non-operating characters is preferable. From this viewpoint, a syringe pump, a gear pump, and a tube pump are preferable.
微量試料計量デバイス内部に設けられた流体移送手段であって、吸引による流体移送が可能な手段としては、ダイヤフラムポンプ機構、ギヤポンプ機構、シリンジポンプ機構、プランジャンプ機構、しごきポンプ機構などのポンプ機構、減圧気体室、多孔質体、繊維の編織物、紙・不織布、繊維充填物、粉末充填物などの液体吸収機構、流路中の磁性流体を磁場で駆動するによる移送機構、音波や超音波式流体移送機構などを例示でき、こられは、試料計量用流路(3)に設けて、試料を第一流路から計量用流路に移送する流体移送手段や、第二流路(2)に設けて、計量用流路83)から 第二流路(2)へ移送する流体移送手段として使用できる。第二流路(2)に設ける場合には、移送制御手段(12)を兼ねる流体移送手段としても使用出来る。 Fluid transport means provided inside the micro sample weighing device, and means capable of fluid transfer by suction include diaphragm pump mechanisms, gear pump mechanisms, syringe pump mechanisms, plan jump mechanisms, pump mechanisms such as iron pump mechanisms, Depressurized gas chamber, porous material, fiber knitted fabric, paper / nonwoven fabric, fiber filling, powder filling, etc., liquid absorption mechanism, transfer mechanism by driving magnetic fluid in flow path with magnetic field, sound wave and ultrasonic type Examples include a fluid transfer mechanism, which is provided in the sample measurement channel (3), and is provided in a fluid transfer means for transferring the sample from the first channel to the measurement channel, or in the second channel (2). It can be used as a fluid transfer means for transferring from the metering channel 83) to the second channel (2). When provided in the second flow path (2), it can also be used as a fluid transfer means that also serves as a transfer control means (12).
微量試料計量デバイス内部に設けられた流体移送手段であって、吐出による流体移送が可能な流体移送手段としては、手段としては、ダイヤフラムポンプ機構、ギヤポンプ機構、シリンジポンプ機構、プランジャンプ機構、しごきポンプ機構などのポンプ機構、加圧気体、上記磁性流体式流体移送機構、音波や超音波式流体移送機構などを例示できる。このような吐出が可能な移送手段は、試料計量用流路(3)に設け、試料を試料計量用流路から第二流路(2)へ注入する流体移送手段や、第一流路(2)に設け、試料を第一流路から計量用流路(3)へ移送する流体移送手段として使用できる。第一流路(2)に設ける場合には、移送制御手段(11)を兼ねる流体移送手段として使用出来る。 A fluid transfer means provided inside a micro sample weighing device, which is capable of transferring a fluid by discharge, such as a diaphragm pump mechanism, a gear pump mechanism, a syringe pump mechanism, a plan jump mechanism, and a peristaltic pump Examples thereof include a pump mechanism such as a mechanism, pressurized gas, the above-described magnetic fluid type fluid transfer mechanism, and a sound wave or ultrasonic fluid transfer mechanism. The transfer means capable of such discharge is provided in the sample measurement flow path (3), the fluid transfer means for injecting the sample from the sample measurement flow path to the second flow path (2), and the first flow path (2 ) And can be used as fluid transfer means for transferring the sample from the first flow path to the measurement flow path (3). When provided in the first flow path (2), it can be used as a fluid transfer means that also serves as a transfer control means (11).
微量試料計量デバイス内部に設けられた流体移送手段であって、双方向に流体移送が可能な流体移送手段としては、ダイヤフラムポンプ機構、ギヤポンプ機構、シリンジポンプ機構、しごきポンプ機構などのポンプ機構、、上記の磁性流体式流体移送機構、、音波や超音波式流体移送機構などを例示できる。このような吐出が可能な移送手段は、試料計量用流路(3)に設け、第一流路(1)から試料計量用流路(3)への試料の吸引移送と、試料計量用流路(3)から第二流路(2)への試料の注入を行うことができる。勿論、双方向に移送可能な流体移送手段を吸引又は吐出が可能な流体移送手段として使用することも可能である。第一流路(1)や第二流路(2)の途中に設ける、微量試料計量デバイス内部の流体移送手段は、移送制御手段(11)や移送制御手段(12)が兼ねることが出来る。即ち、これらの移送制御手段として、少なくとも一方向に移送可能であるような流体移送機能を持つものであって、流体の移送を停止したときに流路を閉じた状態で保持できるもの、好ましくは、常態で、即ち非駆動時には何らのネルギーも消費せずに、流路を閉じた状態に保持できるものを用いることによって、別途流体移送手段を用いる必要が無くなる。 Fluid transfer means provided inside the micro sample weighing device and capable of transferring fluid in both directions include a pump mechanism such as a diaphragm pump mechanism, a gear pump mechanism, a syringe pump mechanism, and a squeeze pump mechanism, Examples thereof include the above-described magnetic fluid type fluid transfer mechanism, and a sound wave or ultrasonic fluid transfer mechanism. The transfer means capable of such discharge is provided in the sample measurement flow path (3), and the suction and transfer of the sample from the first flow path (1) to the sample measurement flow path (3), and the sample measurement flow path. The sample can be injected from (3) into the second channel (2). Of course, it is also possible to use a fluid transfer means capable of transferring in both directions as a fluid transfer means capable of suction or discharge. The fluid transfer means inside the micro sample weighing device provided in the middle of the first flow path (1) and the second flow path (2) can also serve as the transfer control means (11) and the transfer control means (12). That is, these transfer control means have a fluid transfer function that can be transferred in at least one direction, and can hold the channel in a closed state when the fluid transfer is stopped, preferably In the normal state, that is, when it is not driven, no energy is consumed, and it is possible to keep the flow path closed, thereby eliminating the need for a separate fluid transfer means.
前記の微量試料計量デバイス内部の流体移送手段として、例えば本発明者等の出願になる、特開2002−371954号公報に記載されているような、流路中に配された磁性流体を磁気で移動させることにより移送すべき流体を移送する機構、特開2003−139065号公報、特開2003−139065号公報、および特開2003−083256号公報に記載されているような、逆止弁とダイヤフラムで構成されたダイヤフラム式ポンプ機構、特開2003−139660号公報に記載されている様な、常態では流路を閉じており、バルブの少なくとも一方の側の圧力が一定以上になると任意の低圧側へ流体を流通させる、或いは、両側の圧力差が一定以上になると任意の低圧側へ流体を流通させる弁(以下、このような弁を「圧力弁」と称する)を用い、柔軟な流路壁を圧迫することによって流体を送液するダイヤフラム式ポンプ機構、チューブポンプのようにローラーで柔軟な流路壁をしごく、しごきポンプ機構を好適に使用できるし、ギアポンプ機構、プランジャーポンプ機構、プランジャーの代わりに磁性流体を使用したプランジャー式ポンプ機構、なども使用可能である。なお。ここで言う「微量試料計量デバイス内部の流体移送手段」とは少なくとも流体移送機構の接液部が微量試料計量デバイス内に組み込まれていることをいい、駆動部は微量試料計量デバイスの外部にあって良い。 As a fluid transfer means inside the micro sample weighing device, for example, a magnetic fluid arranged in a flow path as described in Japanese Patent Application Laid-Open No. 2002-371554 filed by the present inventors is magnetically used. A mechanism for transferring a fluid to be transferred by moving, a check valve and a diaphragm as described in Japanese Patent Application Laid-Open Nos. 2003-139065, 2003-139065, and 2003-083256 A diaphragm type pump mechanism composed of the above-mentioned, as described in Japanese Patent Application Laid-Open No. 2003-139660, the flow path is normally closed, and when the pressure on at least one side of the valve becomes a certain level or higher, any low pressure side A valve that allows fluid to flow to any low pressure side when the pressure difference between both sides exceeds a certain level (hereinafter referred to as “pressure”). A diaphragm type pump mechanism that sends fluid by pressing the flexible flow path wall, and a flexible flow path wall with a roller like a tube pump, and a peristaltic pump mechanism is used favorably It is also possible to use a gear pump mechanism, a plunger pump mechanism, a plunger type pump mechanism using a magnetic fluid instead of the plunger, and the like. Note that. The term “fluid transfer means inside the micro sample weighing device” as used herein means that at least the liquid contact part of the fluid transfer mechanism is incorporated in the micro sample measuring device, and the drive unit is located outside the micro sample measuring device. Good.
前記のポンプ機構の中で、圧力弁とダイヤフラムによるポンプ機構や、しごきポンプ機構が、圧迫位置を変えること、或いは、しごきの方向を変えることによって、双方向に移送可能であるため、双方向に移送可能な流体移送用手段として好ましい。 Among the pump mechanisms described above, the pump mechanism using the pressure valve and the diaphragm and the iron pump mechanism can be transferred in both directions by changing the compression position or changing the direction of ironing. This is preferable as a transportable fluid transporting means.
微量試料計量デバイス内部に組み込まれたポンプ機構を使用することによって、外部ポンプを接続する必要が無くなるため、配管接続機構を設ける必要が無くなる。また、試料流入口(5)に導入する試料や、試料移送流体の流入口(7)から導入する移送用の流体を交換することも容易になる。 By using a pump mechanism incorporated in the micro sample weighing device, it is not necessary to connect an external pump, so that it is not necessary to provide a pipe connection mechanism. It is also easy to exchange the sample introduced into the sample inlet (5) and the transfer fluid introduced from the sample inlet fluid inlet (7).
[移送制御手段]
試料を計量用流路(3)から第二流路(2)に移送する際に、試料が第一流路(1)へ逆流することを防ぐ機構を有することが必要である。そのために、第一流路(1)の途中に移送制御手段(11)を設ける。移送制御手段(11)は、試料を試料流入口(5)から第一流路(1)を経て計量用流路(3)へと導入する際に流体を通過させ、次いで、計量用流路(3)内の試料を接合部(4)を経て第二流路(2)へ注入する際には、流体を通過させないことができる機構であり、バルブを好ましく用いることが出来る。或いは、例えばそのようなバルブを機構の一部に使用したような、流体の移送と停止を制御できるポンプ機構とすることも可能である。このバルブは、流体移送手段の駆動に同期させた制御によって、例えば前記試料移送流体の流入口(7)の吸引/流体導入に同期した制御によって開閉する開閉バルブであっても良いし、試料流入口(5)から接合部(4)方向に流体を通過させる向きに設置された逆止弁であっても良いし、少なくとも一方の側の圧力が一定以上になると開いたり、両側の圧力差が一定以上になると開く圧力弁であっても良い。
[Transfer control means]
It is necessary to have a mechanism for preventing the sample from flowing back to the first channel (1) when the sample is transferred from the metering channel (3) to the second channel (2). Therefore, a transfer control means (11) is provided in the middle of the first flow path (1). The transfer control means (11) allows the fluid to pass when the sample is introduced from the sample inlet (5) through the first channel (1) to the metering channel (3), and then the metering channel ( 3) When injecting the sample in the second flow path (2) through the joint (4), it is a mechanism that prevents the fluid from passing through, and a valve can be preferably used. Alternatively, it is possible to provide a pump mechanism that can control the transfer and stop of fluid, such as using such a valve as part of the mechanism. This valve may be an open / close valve that opens and closes by control synchronized with the driving of the fluid transfer means, for example, by control synchronized with suction / fluid introduction of the inlet (7) of the sample transfer fluid. It may be a check valve installed in a direction that allows fluid to pass from the inlet (5) to the joint (4), and may open when the pressure on at least one side exceeds a certain level, or the pressure difference between the two sides It may be a pressure valve that opens when it exceeds a certain level.
逆止弁は、特別な開閉操作を行わなくても、試料移送流体の流入口(7)を吸引する際には流路内の流体の圧力差によって自動的に開き、試料移送流体の流入口(7)から流体を導入する際には流路内の流体の圧力差によって自動的に閉じる。移送制御手段(11)は、注入試料の定量性を増し、テーリングを防ぐために、成るべく接合部(4)に近い位置に設けることが好ましく、接合部〔4〕に接して設けることがさらに好ましい。移送制御手段(11)は閉状態で僅かな漏れがあっても良く、注入試料のテーリングを防ぐために、極僅かな漏れがあることが、かえって好ましい。 The check valve automatically opens due to the pressure difference of the fluid in the flow path when sucking the inlet (7) of the sample transfer fluid without performing a special opening / closing operation. When the fluid is introduced from (7), it is automatically closed due to the pressure difference of the fluid in the flow path. The transfer control means (11) is preferably provided as close to the joint (4) as possible, and more preferably in contact with the joint [4] in order to increase the quantitativeness of the injected sample and prevent tailing. . The transfer control means (11) may be slightly leaked in the closed state, and in order to prevent tailing of the injected sample, it is preferable that there is very little leak.
前記移送制御手段(11)として好ましく使用できる開閉バルブの構造は任意であり、例えば、本発明者等の出願になる下記の機構を使用できる。特開2004−073995号公報に記載されているような、流路内に配した磁性流体を磁気で駆動して流路を開閉するバルブ機構 、特開2002−239374号公報に記載されているようなダイヤフラム式バルブ、特開2002−219697号公報、特開2002−08639号公報、特開2003−084001号公報、に記載されているような、流路壁を外部から圧迫することによって流路断面積を変化させる開閉バルブ、などである。また、試料流出口(6)から他の機器への試料注入圧力が、例えば200KPa以下であるように、あまり高くない場合には、移送制御手段(11)として、特開2003−139660号公報に開示されたいるような、常態では閉じており、流路の一方の側の圧力が一定以上となると流体を通過させるバルブ機構を使用することも出来る。 The structure of the on-off valve that can be preferably used as the transfer control means (11) is arbitrary, and for example, the following mechanism as filed by the present inventors can be used. A valve mechanism that opens and closes a flow path by magnetically driving a magnetic fluid disposed in the flow path as described in Japanese Patent Application Laid-Open No. 2004-073995, as described in Japanese Patent Application Laid-Open No. 2002-239374 As described in Japanese Patent Application Laid-Open No. 2002-219697, Japanese Patent Application Laid-Open No. 2002-08639, Japanese Patent Application Laid-Open No. 2003-084001, a diaphragm is pressed by externally pressing a flow path wall. An open / close valve that changes the area. In addition, when the sample injection pressure from the sample outlet (6) to another device is not so high, for example, 200 KPa or less, Japanese Patent Application Laid-Open No. 2003-139660 discloses a transfer control means (11). A valve mechanism that is normally closed and that allows fluid to pass through when the pressure on one side of the flow path exceeds a certain level, as disclosed, can also be used.
移送制御手段(11)として逆止弁を使用する場合には、例えば、本発明者等の出願になる、特開2002−086399号公報、特開2003−139661号公報、特開2002−239374号公報に開示されているような、フラップ型の弁体をフォトリソグラフィーで形成した逆止弁や、ゲルを弁体とした逆止弁を使用することが出来る。 In the case of using a check valve as the transfer control means (11), for example, Japanese Patent Application Laid-Open No. 2002-086399, Japanese Patent Application Laid-Open No. 2003-139661, Japanese Patent Application Laid-Open No. 2002-239374, which are filed by the present inventors. It is possible to use a check valve in which a flap-type valve element is formed by photolithography or a check valve using a gel element as disclosed in the publication.
前記移送制御手段(11)は、接合部(4)に対する第一流路(1)側の加圧や計量用流路(3)側の減圧、または計量用流路(3)側の加圧や第三流路(3)側の減圧によって開閉を制御できるものであることが、操作が単純となり好ましく、そのため逆止弁または圧力弁が好ましい。また、ゲルを弁体とする逆止弁が、構造が簡単であり、かつ、閉状態で、過剰でない程度の漏れを生じさせることが容易であるため好ましい。勿論、移送制御手段(11)に圧力弁を用いる場合には、例えば移送制御手段(11)が開く圧力は、計量用流路(3)への注入圧力以上の圧力に調節するなど、その特性は実施態様に合わせて調節する必要がある。 The transfer control means (11) is configured to pressurize the joint (4) on the first channel (1) side, depressurize on the metering channel (3) side, or pressurize on the metering channel (3) side. It is preferable that the opening and closing can be controlled by reducing the pressure on the third flow path (3) side, because the operation is simple, and therefore a check valve or a pressure valve is preferable. In addition, a check valve using gel as a valve body is preferable because it has a simple structure and it is easy to cause a leakage that is not excessive in the closed state. Of course, when a pressure valve is used for the transfer control means (11), for example, the pressure at which the transfer control means (11) opens is adjusted to a pressure higher than the injection pressure to the metering channel (3). Need to be adjusted according to the embodiment.
移送制御手段(11)として用いることの出来るポンプ機構としては、流体移送手段として挙げた、微量試料計量デバイス内に組み込み可能なポンプ機構が挙げられる。 Examples of the pump mechanism that can be used as the transfer control means (11) include the pump mechanism that can be incorporated into the micro sample weighing device mentioned as the fluid transfer means.
また、試料を第一流路(1)から計量用流路(3)へ移送する際に、試料が第二流路(2)へ侵入することを防ぐ機構を設けることが必要である。そのために、第二流路(2)の途中に移送制御手段(12)、を設ける。移送制御手段(12)は、試料移送流体の流入口(7)を吸引して試料を試料流入口(5)から第一流路(1)を経て計量用流路(3)へと導入する際には第二流路(2)を閉じ、次いで、試料移送流体の流入口(7)から流体を導入して、計量用流路(3)内の試料を接合部(4)を経て第二流路(2)へ注入する際には、流体を通過させることができるバルブを好ましく用いることが出来る。このバルブに関しては、前記移送制御手段(11)の場合と同様である。即ち、このバルブは前記試料移送流体の流入口(7)の吸引/流体導入に同期した制御によって開閉する開閉バルブであっても良いし、接合部(4)から試料流出口(6)方向には流体を通過させ、逆方向には通過させない向きに設置された逆止弁であっても良いし、圧力弁であっても良い。勿論、該バルブに圧力弁を用いる場合には、例えば第一流路(1)から計量用流路(3)への試料移動時には、バルブは閉じた状態を保つように、開く圧力を調節する必要がある。逆止弁や圧力弁は、特別な開閉操作を行わなくても、試料移送流体の流入口(7)を吸引する際には流路内の流体の圧力差によって自動的に閉じ、試料移送流体の流入口(7)から流体を導入する際には流路内の流体の圧力差によって自動的に開くため、駆動機構が単純になり好ましい。移送制御手段(12)のバルブも、注入試料の定量性を増すために、成るべく接合部(4)に近い位置に設けることが好ましく、接合部(4)に接して設けることがさらに好ましい。 Further, it is necessary to provide a mechanism for preventing the sample from entering the second channel (2) when the sample is transferred from the first channel (1) to the metering channel (3). Therefore, a transfer control means (12) is provided in the middle of the second flow path (2). When the transfer control means (12) sucks the inlet (7) of the sample transfer fluid and introduces the sample from the sample inlet (5) through the first channel (1) to the metering channel (3). Then, the second channel (2) is closed, and then the fluid is introduced from the inlet (7) of the sample transfer fluid, and the sample in the metering channel (3) passes through the joint (4) to the second. When injecting into the flow path (2), a valve capable of passing a fluid can be preferably used. This valve is the same as in the case of the transfer control means (11). That is, this valve may be an open / close valve that opens and closes in synchronization with the suction / fluid introduction of the inlet (7) of the sample transfer fluid, or from the joint (4) to the sample outlet (6). May be a check valve installed in a direction that allows fluid to pass but not in the reverse direction, or may be a pressure valve. Of course, when a pressure valve is used for the valve, for example, when the sample is moved from the first channel (1) to the metering channel (3), it is necessary to adjust the opening pressure so as to keep the valve closed. There is. The check valve and the pressure valve are automatically closed by the pressure difference of the fluid in the flow path when sucking the inlet (7) of the sample transfer fluid without performing a special opening / closing operation. When the fluid is introduced from the inflow port (7), it automatically opens due to the pressure difference of the fluid in the flow path. The valve of the transfer control means (12) is also preferably provided as close as possible to the joint (4), and more preferably in contact with the joint (4) in order to increase the quantitativeness of the injected sample.
移送制御手段(12)のバルブの構造などについては、移送制御手段(11)の場合と同様であるが、閉状態での僅かな漏れは許容されるものの、試料計量の定量性を増すためには、漏れは少ない方が好ましい。移送制御手段(12)として用いることの出来るポンプ機構としては、流体移送手段として挙げた、微量試料計量デバイス内に組み込み可能なポンプ機構が挙げられる。 The structure of the valve of the transfer control means (12) is the same as that of the transfer control means (11), but slight leakage in the closed state is allowed, but in order to increase the quantitativeness of sample weighing. It is preferable that there is less leakage. Examples of the pump mechanism that can be used as the transfer control means (12) include a pump mechanism that can be incorporated into a micro sample weighing device, which is mentioned as the fluid transfer means.
移送制御手段(11)の機構と移送制御手段(12)の機構の組み合わせ方法は、それぞれ前記のバルブ類やポンプ類から選択できる。但し、移送制御手段(11)と移送制御手段(12)共に圧力弁を用いる場合、一方が圧力弁を用いたポンプ機構で、他方が圧力弁である場合、又は、共に圧力弁を用いたポンプ機構を用いる場合、には、これらのバルブが開く圧力を、例えば第一流路(1)から計量用流路(3)への試料移動時には、移送制御手段(11)は移送制御手段(12)より低い圧力で開き、計量用流路(3)から第二流路(2)への試料注入字には、移送制御手段(11)は移送制御手段(12)より高い圧力で開くように、少なくとも一方を、順方向と逆方向で開く圧力が異なる圧力弁を使用する必要がある。 The combination method of the mechanism of the transfer control means (11) and the mechanism of the transfer control means (12) can be selected from the above-mentioned valves and pumps, respectively. However, when both the transfer control means (11) and the transfer control means (12) use pressure valves, one is a pump mechanism using a pressure valve and the other is a pressure valve, or both are pumps using a pressure valve. In the case of using a mechanism, when the sample is moved from the first flow path (1) to the measurement flow path (3), for example, the transfer control means (11) is operated by the transfer control means (12). Open at a lower pressure, so that the transfer control means (11) opens at a higher pressure than the transfer control means (12) for sample injection from the metering channel (3) to the second channel (2), It is necessary to use a pressure valve having different pressures for opening at least one of the forward direction and the reverse direction.
本発明の微量試料計量デバイスは、前記の構造の他、任意の他の機構を有することが出来る。こそのような構造としては、例えば、センサ部(20)や移送制御手段(11)、(12)のための電源、電源への接続部、センサ部(20)と外部に設けられたセンサ本体との接続機構、移送制御手段(11)、(12)のための圧力気体接続機構、接続機構、移送制御手段(11)、(12)や外部ポンプの制御のためのシーケンサやコンピュータなどを例示できる。 The micro sample weighing device of the present invention can have any other mechanism in addition to the above structure. Such a structure includes, for example, a power source for the sensor unit (20) and the transfer control means (11) and (12), a connection unit to the power source, and a sensor main body provided outside the sensor unit (20). Connection mechanism, pressure gas connection mechanism for transfer control means (11), (12), connection mechanism, transfer control means (11), (12), sequencer and computer for controlling external pump, etc. it can.
[微量試料計量装置]
本発明の微量試料計量装置は、本発明の微量試料系呂腕バイス徳見合わせて使用することにより、(A)流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際移送制御手段(12)により流体試料が第二流路(2)に流入しないようにする機構、(B)計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止する機構、及び/又は(C)計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにする機構を有する。
[Small sample weighing device]
By using the micro sample metering device of the present invention in combination with the micro sample system of the present invention, the fluid sample flows in from the sample inlet (5), and the fluid sample flows into the first channel (1 ) Flow into the metering channel (3), and at that time, the mechanism for preventing the fluid sample from flowing into the second channel (2) by the transfer control means (12), (B) the metering channel (3 ) A mechanism that stops the inflow of the fluid sample upon detection of the sensor unit (20) when the fluid sample that has flowed in reaches a specified amount, and / or (C) the fluid sample in the measurement channel (3). Is transferred into the second channel (2) by the sample transfer fluid flowing in from the inlet (7), and the weighed sample is caused to flow out from the sample outlet (6). At this time, the second channel (2) The transfer control means (12) in the inside is in a liquid-feedable state, and the fluid sample is moved to the first position by the transfer control means (11). It has a mechanism to prevent flow into the flow channel (1).
前記(A)および(C)の機構は、まず、流体移送手段に関しては、その駆動のタイミングを決める論理機構を有する。この論理機構は任意であり、例えばシーケンサやコンピュータが使用できる。また、移送制御手段(11)、(12)は、これらに逆止弁や圧力弁を使用した場合にはこれら自体がその機能を有するため、それ以外の特別な機構を要しないが、これらが開閉バルブやポンプ機構である場合には、前記の論理とタイミングで開閉あるいは流体移送する論理機構と駆動機構を用いる。この論理機構は任意であり、例えばシーケンサやコンピュータが使用できる。開閉バルブやポンプ機構の駆動機構としては、それらの種類に応じて、先に示した開閉バルブやポンプ機構の駆動機構、例えば、アクチュエータ、圧力気体、電磁力、などを使用できる。 The mechanisms (A) and (C) have a logic mechanism for determining the driving timing of the fluid transfer means. This logic mechanism is arbitrary, for example, a sequencer or a computer can be used. Moreover, since the transfer control means (11) and (12) have their functions when a check valve or a pressure valve is used for them, no other special mechanism is required. In the case of an opening / closing valve or a pump mechanism, a logic mechanism and a driving mechanism that open / close or fluid-transfer at the above logic and timing are used. This logic mechanism is arbitrary, for example, a sequencer or a computer can be used. As the driving mechanism for the on-off valve and the pump mechanism, the above-described driving mechanism for the on-off valve and the pump mechanism such as an actuator, pressure gas, electromagnetic force, and the like can be used depending on the type.
また、(B)の、計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止するための判断機構は、微量試料計量デバイスに組み込まれた、或いは、微量試料計量デバイス外の電気回路やコンピューターであって良い。センサ部(20)が、検出部のみが微量試料計量デバイスに組み込まれ、本体が微量試料計量デバイス外の機構である場合や、微量試料計量デバイスに、光学的に透明な窓などの読み取り部が設けられ、センサ本体が微量試料計量デバイス外の機構である場合には、これらのセンサ機構も、微量試料計量デバイス外の微量試料計量装置の一部とされる。 In addition, the determination mechanism for stopping the inflow of the fluid sample by detection of the sensor unit (20) when the fluid sample that has flowed into the measurement channel (3) reaches a specified amount in (B), It may be an electric circuit or a computer incorporated in the micro sample weighing device or outside the micro sample weighing device. When the sensor unit (20) has only the detection unit incorporated in the micro sample weighing device and the main body is a mechanism outside the micro sample measuring device, or the micro sample measuring device has a reading unit such as an optically transparent window. When the sensor main body is a mechanism outside the trace sample weighing device, these sensor mechanisms are also part of the trace sample weighing device outside the trace sample weighing device.
本発明の微量試料計量装置が微量試料計量デバイス外部の機構を有する場合には、微量試料計量デバイスと外部機構とを一体化して稼働させるが、微量試料計量デバイス部分を取り替え可能とすることが好ましい。中でも、微量試料計量デバイスにはセンサ部(20)としてセンサ機構の一部、センサの取り付け用構造、あるいはセンシング用の窓を設けた構造とし、さらに、ポンプ機構(及び、開閉バルブを使用する場合には開閉バルブも)の駆動部を微量試料計量デバイスの外部機構とすることにより、接液部である微量試料計量デバイスを単純な機構として、該デバイスを交換可能とすることが好ましい。 When the micro sample weighing device of the present invention has a mechanism external to the micro sample measuring device, the micro sample measuring device and the external mechanism are integrated and operated, but it is preferable that the micro sample measuring device can be replaced. . In particular, a small sample weighing device has a part of the sensor mechanism, a sensor mounting structure, or a sensing window as the sensor unit (20), and a pump mechanism (and an open / close valve). It is preferable that the drive unit of the open / close valve be an external mechanism of the micro sample weighing device, so that the micro sample measuring device which is a wetted part can be replaced with a simple mechanism.
[試料注入方法]
本発明の微量試料の計量方法、前記の微量試料計量デバイスや微量試料計量装置を使用して、流体試料を試料流入口(5)から第一流路(1)に流入させ、第一流路(1)の移送制御手段(11)を送液可能状態、第二流路(2)の移送制御手段(12)を送液停止状態とし、試料を第一流路(1)から接合部(4)を経由して計量用流路(3)に移送し、計量用流路(3)に流入する試料が計量用流路(3)中のセンサ部(20)において検出された際に試料の移送を停止して、計量用流路内に微量の一定量の試料を計量し、次いで、第一流路(1)の移送制御手段(11)を送液停止状態、第二流路(2)の移送制御手段(12)を送液可能状態とし、計量した試料を、予め計量用流路(3)に充填した試料移送用流体により、第一流路(1)から接合部(4)を経由して計量用流路(3)に移送し、試料流出口(6)より微量の一定量の試料を得る。
[Sample injection method]
Using the method for measuring a micro sample of the present invention, the micro sample measuring device and the micro sample measuring device described above, a fluid sample is caused to flow from the sample inlet (5) into the first channel (1), and the first channel (1 ) The transfer control means (11) in the liquid feedable state, the transfer control means (12) in the second flow path (2) is in the liquid feed stop state, and the sample is moved from the first flow path (1) to the joint (4). The sample is transferred to the metering channel (3) and the sample flowing into the metering channel (3) is detected by the sensor section (20) in the metering channel (3). Stop and weigh a small amount of sample into the metering channel, then move the transfer control means (11) of the first channel (1) to the stop state, transfer to the second channel (2) The control means (12) is set in a liquid-feedable state, and the weighed sample is preliminarily filled with the sample transfer fluid previously filled in the measurement flow path (3). 1) via joints (4) transferred to metering channel (3) from, obtaining a sample of a constant amount of trace from a sample outlet (6).
本発明の試料注入方法に適用できる試料や移送用の流体の種類は任意であり、液体、超臨界流体、気体であり得るが、液体であることが、定量性が向上し好ましい。液体試料の種類は任意であり、単一液体、混合液体、溶液、分散液であり得る。溶質は任意であり、化学物質、生化学物質、有機物質、無機物質、揮発性物質、不揮発性物質、ノニオン性物質、カチオン性物質、アニオン性物質、両性イオン性物質、親水性物質、疎水性物質、両親媒性物質、などであり得るし、溶媒は電解質、非電解質であり得る。 The type of sample and transfer fluid that can be applied to the sample injection method of the present invention is arbitrary, and may be a liquid, a supercritical fluid, or a gas. However, a liquid is preferable because of improved quantitativeness. The type of liquid sample is arbitrary, and may be a single liquid, a mixed liquid, a solution, or a dispersion. Solute is optional, chemical substance, biochemical substance, organic substance, inorganic substance, volatile substance, non-volatile substance, nonionic substance, cationic substance, anionic substance, zwitterionic substance, hydrophilic substance, hydrophobic The substance may be a substance, an amphiphile, etc., and the solvent may be an electrolyte or a non-electrolyte.
本発明の試料注入方法によれば、計量用流路(3)の試料計量部(3a)の断面積や長さの設計により、微少量、特に0.1nl(但し、1nl=1×10−12m3)〜500nl、さらに好ましくは1nl〜100nl、最も好ましくは3nl〜50nl程度の微少量の試料を計量して注入することができる。 According to the sample injection method of the present invention, the cross-sectional area and length of the design of the sample measuring section of the metering channel (3) (3a), a small amount, in particular 0.1 nl (where, 1nl = 1 × 10 - A very small amount of a sample of 12 m 3 ) to 500 nl, more preferably 1 nl to 100 nl, and most preferably 3 nl to 50 nl can be metered and injected.
本発明の試料注入方法を適用する際の好適な態様の例としては、クロマトグラフィー・カラムへの微量試料の注入方法が挙げられる。この場合には、前記試料流出口(6)に該カラムを接続して使用する。該カラムは、微量試料計量デバイスが形成されたマイクロ流体デバイスの内部に組み込まれたカラムであっても良いし、該マイクロ流体デバイスの外部に設けられたものであっても良い。この場合のクロマトグラフィー・カラムの種類は勿論任意であり、例えば内面に多孔質層が形成されたマイクロ流路、キャピラリー・カラム、モノリス型カラム、充填カラムなどであり得る。 An example of a preferred embodiment when applying the sample injection method of the present invention is a method of injecting a small amount of sample into a chromatography column. In this case, the column is connected to the sample outlet (6). The column may be a column incorporated in a microfluidic device in which a micro sample weighing device is formed, or may be provided outside the microfluidic device. The kind of the chromatography column in this case is of course arbitrary, and may be, for example, a microchannel having a porous layer formed on the inner surface, a capillary column, a monolithic column, a packed column, or the like.
本発明の方法においては、前記微量試料計量デバイスの各部の構造、例えば、流体移送手段として用いる機構の種類、流体移送手段として用いる機構の接続部、流体移送制御機構(11)として用いる機構の種類、流体移送制御機構(11)、として用いる機構の種類、の組み合わせによって非常に多くの場合があり、前記の方法が可能な組み合わせを任意に選択することが出来るが、以下に、特に好ましく用いることの出来る代表的な実施態様を示す。 In the method of the present invention, the structure of each part of the micro sample weighing device, for example, the type of mechanism used as the fluid transfer means, the connection part of the mechanism used as the fluid transfer means, the type of mechanism used as the fluid transfer control mechanism (11) There are many cases depending on the combination of the mechanism used as the fluid transfer control mechanism (11), and a combination capable of the above method can be arbitrarily selected. A representative embodiment is shown.
(I)第一態様
本発明の第一態様は、図2に示したように、第一流路(1)の途中に移送制御手段(11)として開閉バルブを設け、第二流路(2)の途中に移送制御手段(12)として開閉バルブを設けた微量試料計量デバイスを使用し、試料移送流体の流入口(7)に吐出と吸引が可能な流体移送手段(15)として例えばシリンジポンプなどのポンプを接続する。
(i)流路(10)内は空気であっても良いが、試料流出口(6)に接続したクロマトグラフィー・カラムへ計量した試料を注入する場合など、用途によってはあらかじめ流路(10)全体、或いは第一流路(1)と計量用流路(3)に液体を充満させておくことが好ましい。該液体としては、例えば試料溶液の溶媒やクロマトグラフィーの展開液を用いることができる。その状態で、まず、例えば試料流入口(5)に試料を配する。これは、例えば試料流入口(5)に接続されたリザーバタンク(51)にピペットなどで試料を注入することで実施できる。試料流入口(5)に配する試料の量は、計量すべき量以上であれば任意である。次いで、
(ii)移送制御手段(11)である開閉バルブを開き、移送制御手段(12)である開閉バルブは閉じた状態で、移送用流体が満たされたリザーバタンク(52)が接続された流体移送手段(15)であるポンプを吸引側に駆動し、試料移送流体の流入口(7)を吸引して、試料計量部(3a)へ移送する。試料計量部(3a)に試料が一定量充填されたことを、センサ部(20)の蛍光測定用の窓を観測している光電子増倍管付きの蛍光顕微鏡にて検知すると、コンピューター制御により、
(iii)移送制御手段(11)である開閉バルブを閉じ、移送制御手段(12)である開閉バルブを開き、流体移送手段(15)のポンプを吐出方向に駆動して流入口(7)から移送用流体を導入して、該流体により計量用流路(3)内の試料を第二流路(2)へ移送する。このとき、第一流路(1)内の試料は移送制御手段(11)の開閉バルブが閉じているため移動せず、計量用流路(3)内の試料のみが第二流路(2)に移送される。試料流出口(6)に接続したクロマトグラフィー・カラムへ計量した試料を注入する場合には、移送用流体として、クロマトグラフィーの展開液液を用いることが出来る。
(I) 1st aspect As shown in FIG. 2, the 1st aspect of this invention provides the opening-and-closing valve as a transfer control means (11) in the middle of the 1st flow path (1), and the 2nd flow path (2). As a fluid transfer means (15) that can be discharged and aspirated to the inlet (7) of the sample transfer fluid, for example, a syringe pump is used. Connect the pump.
(I) The flow path (10) may be air, but depending on the application, the flow path (10) may be used in advance, such as when a weighed sample is injected into a chromatography column connected to the sample outlet (6). It is preferable to fill the whole or the first channel (1) and the metering channel (3) with liquid. As the liquid, for example, a solvent of a sample solution or a developing solution for chromatography can be used. In this state, first, for example, a sample is arranged at the sample inlet (5). This can be performed, for example, by injecting the sample with a pipette or the like into the reservoir tank (51) connected to the sample inlet (5). The amount of the sample disposed at the sample inlet (5) is arbitrary as long as it is greater than the amount to be weighed. Then
(Ii) Fluid transfer in which the open / close valve as the transfer control means (11) is opened, the open / close valve as the transfer control means (12) is closed, and the reservoir tank (52) filled with the transfer fluid is connected The pump which is means (15) is driven to the suction side, the inlet (7) of the sample transfer fluid is sucked and transferred to the sample metering section (3a). When it is detected by a fluorescence microscope with a photomultiplier tube that observes the fluorescence measurement window of the sensor unit (20) that a certain amount of sample is filled in the sample weighing unit (3a), by computer control,
(Iii) Close the open / close valve as the transfer control means (11), open the open / close valve as the transfer control means (12), and drive the pump of the fluid transfer means (15) in the discharge direction from the inlet (7). A transfer fluid is introduced, and the sample in the measurement channel (3) is transferred to the second channel (2) by the fluid. At this time, the sample in the first channel (1) does not move because the open / close valve of the transfer control means (11) is closed, and only the sample in the metering channel (3) is in the second channel (2). It is transferred to. When injecting a weighed sample into a chromatography column connected to the sample outlet (6), a chromatographic developing solution can be used as the transfer fluid.
本態様は、逆止弁でなく開閉バルブを用いるため動作が確実であり、流路が微細な場合にも開閉バルブを作製することが容易であるため、特に微量の試料を注入する場合に好ましい方法である。 Since this mode uses an on-off valve instead of a check valve, the operation is reliable, and it is easy to produce an on-off valve even when the flow path is fine, so it is preferable particularly when a small amount of sample is injected. Is the method.
本第一態様の変形として、図3に示されたように、試料移送流体の流入口(7)に接続する流体移送手段(15)としての外部ポンプの代わりに、微量試料計量デバイス内に組み込まれた、双方向に吐出可能なポンプ機構を使用することも好ましい。また、センサ部(20)も電気式などの他のセンサ機構を使用しても良い。 As a modification of the first aspect, as shown in FIG. 3, it is incorporated in a micro sample weighing device instead of an external pump as a fluid transfer means (15) connected to an inlet (7) of a sample transfer fluid. It is also preferable to use a pump mechanism that can discharge in both directions. Further, the sensor unit (20) may use another sensor mechanism such as an electric type.
(II)第二態様
本発明の第二態様は、移送制御手段(11)及び移送制御手段(12)として逆止弁を使用したこと以外は前記第一態様と同じ微量試料計量デバイスを使用する。移送制御手段(11)の逆止弁は試料流入口(5)から接合部(4)方向には流体を通過させ、逆方向には通過させない向きに設置されており、移送制御手段(12)の逆止弁は接合部(4)から試料流出口(6)方向には流体を通過させ、逆方向には通過させない向きに設置されている。
(II) Second Aspect The second aspect of the present invention uses the same micro sample weighing device as the first aspect except that a check valve is used as the transfer control means (11) and the transfer control means (12). . The check valve of the transfer control means (11) is installed in such a direction that allows fluid to pass from the sample inlet (5) in the direction of the joint (4) but not in the reverse direction. The check valve is installed in such a direction as to allow fluid to pass from the joint (4) to the sample outlet (6) but not in the reverse direction.
第一態様と同様に、好ましくはあらかじめ流路(10)全体に液体を充満させておき、試料流入口(5)に試料を配して試料移送流体の流入口(7)をポンプ(40)などで吸引すると、自動的に移送制御手段(11)の逆止弁は開き、移送制御手段(12)の逆止弁は閉じて、試料は計量用流路(3)の試料計量部(3a)に移送される。試料が試料計量部(3a)に一定量充填されたことをセンサ部(20)で検知して、流体移口(7)から移送用流体を導入すると、自動的に移送制御手段(11)の逆止弁は閉じ、移送制御手段(12)の逆止弁は開いて、該流体により計量用流路(3)内の試料は接合部(4)から第二流路(2)へ移送される。このように、開閉バルブの開閉操作を行わないこと以外は上述の第一態様と同様である。 As in the first embodiment, preferably, the entire flow path (10) is preliminarily filled with the liquid, the sample is arranged at the sample inlet (5), and the inlet (7) of the sample transfer fluid is pumped (40). The check valve of the transfer control means (11) is automatically opened, the check valve of the transfer control means (12) is closed, and the sample is placed in the sample measuring section (3a) of the measuring channel (3). ). When the sensor unit (20) detects that the sample has been filled in the sample metering unit (3a) and introduces a transfer fluid from the fluid transfer port (7), the transfer control means (11) automatically The check valve is closed, the check valve of the transfer control means (12) is opened, and the fluid transfers the sample in the metering channel (3) from the joint (4) to the second channel (2). The Thus, it is the same as that of the above-mentioned 1st aspect except not opening / closing operation | movement of an on-off valve.
本第二態様は、バルブの操作が全く不要で、1つのポンプの操作のみによって試料の計量と注入が可能であるため、駆動装置を簡略化できる。 In the second aspect, no valve operation is required, and the sample can be measured and injected only by operating one pump, so that the driving device can be simplified.
本第一態様の変形例として、流体移送手段として、外部ポンプの代わりに、微量試料計量デバイス内に組み込まれた、双方向に吐出可能なポンプ機構を使用することも好ましい。 As a modification of the first aspect, it is also preferable to use a pump mechanism that can be discharged in both directions, incorporated in a micro sample weighing device, instead of an external pump, as the fluid transfer means.
また、本第二態様の他の変形例として、移送制御手段(12)を、逆止弁でなく圧力弁を使用する例を挙げることが出来る。該圧力弁が開く圧力を、第二流路端(7)の吸引による試料の移送時には開かず、計量用流路(3)から第二流路(2)への試料移送圧力では開くような圧力に設定することによって、好ましく使用することが出来る。本変形例は、移送制御手段(12)部の死容積を逆止弁より小さくすることが出来るため、計量して注入する試料のテーリングを減少させることができる。 Further, as another modified example of the second aspect, an example in which the transfer control means (12) uses a pressure valve instead of a check valve can be given. The pressure opened by the pressure valve is not opened when the sample is transferred by suction of the second flow path end (7), but is opened by the sample transfer pressure from the measurement flow path (3) to the second flow path (2). It can be preferably used by setting the pressure. In this modification, since the dead volume of the transfer control means (12) can be made smaller than that of the check valve, tailing of the sample to be metered and injected can be reduced.
(III)第三態様
本発明の第三態様は、図4に示されたように、移送制御手段(11)および移送制御手段(12)としてそれぞれ、流体移送手段を兼ねたポンプ機構か設けられた微量試料計量デバイスを使用する。そして、計量用流路(3)や流入口にポンプ機構(23)やポンプ(40)を接続せず、試料移送流体の流入口(7)は微量試料計量デバイス外のリザーバタンクに接続する。リザーバタンクは微量試料計量デバイス内に設けられたものであっても良い。
(III) Third Aspect In the third aspect of the present invention, as shown in FIG. 4, each of the transfer control means (11) and the transfer control means (12) is provided with a pump mechanism that also serves as a fluid transfer means. Use a small sample weighing device. Then, the pump mechanism (23) and the pump (40) are not connected to the measuring flow path (3) and the inlet, but the inlet (7) of the sample transfer fluid is connected to a reservoir tank outside the trace sample measuring device. The reservoir tank may be provided in the micro sample weighing device.
移送制御手段(11)や移送制御手段(12)のポンプ機構としては、前記の、特開2003−139660号公報に記載されているような、常態では流路を閉じている圧力弁を用いたポンプ機構、逆止弁を用いたポンプ機構、或いはしごきポンプ機構を好ましく用いることが出来る。
(i)好ましくはあらかじめ流路(10)全体に液体を充満させておき、試料流入口(5)に試料を配して、
(ii)移送制御手段(11)のポンプ機構を駆動すると、試料は第一流路(1)から計量用流路(3)に導入される。試料が試料計量部(3a)に一定量充填されたことをセンサ部(20)で検知すると移送制御手段(11)のポンプ機構を停止する。
(iii)次いで、移送制御手段(12)のポンプ機構を駆動すると、試料計量部(3a)中の試料は吸引されて接合部(4)から第二流路(2)へ注入される。試料に続いて、流入口(7)から導入された移送用流体が第二流路(2)に注入される。
As the pump mechanism of the transfer control means (11) and the transfer control means (12), a pressure valve that normally closes the flow path as described in JP-A-2003-139660 was used. A pump mechanism, a pump mechanism using a check valve, or an iron pump mechanism can be preferably used.
(I) Preferably, the entire channel (10) is preliminarily filled with liquid, and the sample is arranged at the sample inlet (5),
(Ii) When the pump mechanism of the transfer control means (11) is driven, the sample is introduced from the first channel (1) into the metering channel (3). When the sensor unit (20) detects that the sample is filled in the sample metering unit (3a), the pump mechanism of the transfer control means (11) is stopped.
(Iii) Next, when the pump mechanism of the transfer control means (12) is driven, the sample in the sample metering section (3a) is sucked and injected from the joint section (4) into the second channel (2). Following the sample, the transfer fluid introduced from the inlet (7) is injected into the second flow path (2).
本第三態様は、バルブの操作が全く不要で、2つのポンプの操作のみによって試料の計量と注入が可能であるため、駆動装置を簡略化できる。また、第二流路(2)の移送制御手段(12)により試料が第二流路(2)に導入されるため、他の流路に圧力負担が掛からず、試料を高圧で注入する場合に好適である。 In the third aspect, the operation of the valve is unnecessary, and the sample can be measured and injected only by the operation of the two pumps. Therefore, the driving device can be simplified. In addition, since the sample is introduced into the second channel (2) by the transfer control means (12) of the second channel (2), pressure is not applied to other channels, and the sample is injected at a high pressure. It is suitable for.
以下、実施例を用いて本発明を更に詳しく説明するが、本発明は、以下の実施例の範囲に限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated in more detail using an Example, this invention is not limited to the range of a following example.
本実施例で使用する紫外線硬化樹脂組成物の調製方法、および、紫外線照射方法を以下に示す。 The preparation method of the ultraviolet curable resin composition used in this example and the ultraviolet irradiation method are shown below.
[流路形成用の紫外線硬化性組成物(X1)の調製]
活性ネルギー線重合性化合物として、大日本インキ化学工業株式会社製の平均分子量約2000の3官能ウレタンアクリレートオリゴマー「ユニディックV−4263」60部、第一工業製薬株式会社製1,6−ヘキサンジオールジアクリレート「ニューフロンティアHDDA」20部、及び、第一工業製薬株式会社製ノニルフェノキシポリエチレングリコール(n=17)アクリレート「N−177E」20部、光重合開始剤としてチバガイギー社製1−ヒドロキシシクロヘキシルフェニルケトン「イルガキュア184」5部、及び、重合遅延剤として関東化学株式会社製2,4−ジフェニル−4−メチル−1−ペンテン0.1部を均一に混合して組成物(X1)を調製した。
[Preparation of UV curable composition (X1) for forming a channel]
As an active energy ray polymerizable compound, 60 parts of a trifunctional urethane acrylate oligomer “Unidic V-4263” having an average molecular weight of about 2000 manufactured by Dainippon Ink and Chemicals, Inc., 1,6-hexanediol manufactured by Daiichi Kogyo Seiyaku Co., Ltd. 20 parts of diacrylate “New Frontier HDDA”, 20 parts of Nonylphenoxypolyethylene glycol (n = 17) acrylate “N-177E” manufactured by Daiichi Kogyo Seiyaku Co., Ltd., 1-hydroxycyclohexylphenyl manufactured by Ciba Geigy as a photopolymerization initiator A composition (X1) was prepared by uniformly mixing 5 parts of ketone “Irgacure 184” and 0.1 part of 2,4-diphenyl-4-methyl-1-pentene manufactured by Kanto Chemical Co., Ltd. as a polymerization retarder. .
[蓋形成用の紫外線硬化性組成物(X2)の調製]
ネルギー線重合性化合物として前記「ユニディックV−4263」60部、前記「ニューフロンティアHDDA」20部、前記「N−177E」20部、光重合開始剤として前記「イルガキュアー184」2部を混合して、蓋用組成物を調製した。
[Preparation of UV curable composition (X2) for lid formation]
Mixing 60 parts of “Unidic V-4263”, 20 parts of “New Frontier HDDA”, 20 parts of “N-177E” as energy-polymerizing compound, and 2 parts of “Irgacure 184” as photopolymerization initiator Then, a composition for a lid was prepared.
[蓋形成用の紫外線硬化性組成物(X3)の調製]
ネルギー線重合性化合物として前記「ユニディックV−4263」60部、前記「ニューフロンティアHDDA」40部、光重合開始剤として前記「イルガキュアー184」2部を混合して、蓋用組成物を調製した。
[Preparation of UV curable composition (X3) for lid formation]
A composition for a lid is prepared by mixing 60 parts of the “Unidic V-4263” as the energy-line polymerizable compound, 40 parts of the “New Frontier HDDA” and 2 parts of the “Irgacure 184” as the photopolymerization initiator. did.
[多孔質層形成用の紫外線硬化性組成物(Y)の調製]
ネルギー線重合性化合物として、前記「ユニディックV−4263」72質量部、ジシクロペンタニルジアクリレート「R−684」(日本化薬株式会社製)18質量部、メタクリル酸グリシジル(和光純薬工業株式会社製)10質量部、貧溶剤(R)としてデカン酸メチル(和光純薬工業株式会社製)を180質量部、揮発性の良溶剤としてアセトンを10質量部、紫外線重合開始剤として前記「イルガキュアー184」3質量部を、均一に混合して多孔質層形成用の組成物(Y)を調製した。
[Preparation of UV curable composition (Y) for forming porous layer]
As the energy-ray polymerizable compound, 72 parts by mass of “Unidic V-4263”, 18 parts by mass of dicyclopentanyl diacrylate “R-684” (manufactured by Nippon Kayaku Co., Ltd.), glycidyl methacrylate (Wako Pure Chemical Industries, Ltd.) 10 parts by mass), 180 parts by mass of decanoic acid methyl (Wako Pure Chemical Industries, Ltd.) as the poor solvent (R), 10 parts by mass of acetone as the volatile good solvent, and “ 3 parts by mass of “Irgacure 184” was uniformly mixed to prepare a composition (Y) for forming a porous layer.
[ゲル形成用の紫外線硬化性組成物(Z)の調製]
活性ネルギー線重合性化合物として和光純薬社製アクリルアミド10部及びN,N−ジメチルビスアクリルアミド0.15部、光重合開始剤として「イルガキュア184」2部、及び、蒸留水90部を均一に混合して、ゲルを形成用の組成物(Z)を調製した。
[Preparation of UV curable composition (Z) for gel formation]
Uniform mixing of 10 parts of acrylamide and 0.15 part of N, N-dimethylbisacrylamide manufactured by Wako Pure Chemical Industries as active energy linear polymerizable compounds, 2 parts of “Irgacure 184” as a photopolymerization initiator, and 90 parts of distilled water Thus, a composition (Z) for forming a gel was prepared.
[紫外線ランプ1による照射]
3000Wメタルハライドランプを光源とするアイグラフィックス株式会社製のUE031−353CHC型UV照射装置を用い、365nmにおける紫外線強度が40mW/cm2の紫外線を特に指定が無い限り室温、窒素雰囲気中で照射した。
[Irradiation by ultraviolet lamp 1]
Using a UE031-353CHC type UV irradiation device manufactured by Eye Graphics Co., Ltd. using a 3000 W metal halide lamp as a light source, ultraviolet rays having an ultraviolet intensity at 365 nm of 40 mW / cm 2 were irradiated in a nitrogen atmosphere at room temperature unless otherwise specified.
[紫外線ランプ2による照射]
250W高圧水銀ランプを光源とするウシオ電機株式会社製のマルチライト250Wシリーズ露光装置用光源ユニットを用い、365nmにおける紫外線強度が50mW/cm2の紫外線を、特に指定が無い限り室温、窒素雰囲気中で照射した。
[Irradiation by ultraviolet lamp 2]
Using a light source unit for multi-light 250W series exposure apparatus manufactured by USHIO INC., Which uses a 250W high-pressure mercury lamp as a light source, ultraviolet light with an ultraviolet intensity at 365 nm of 50 mW / cm 2 is used in a nitrogen atmosphere at room temperature unless otherwise specified. Irradiated.
(実施例1)
本実施例では本発明の第一態様である、移送制御手段(11)及び移送制御手段(12)として開閉バルブを使用した例であり、図2に示したように、流体移送手段(15)として外部ポンプを用いる例を示す。本実施例ではまた、第二流路(2)に接続して微量試料計量デバイス内に形成されたクロマトグラフィー・カラムに計量した試料を注入する例を示す。
Example 1
In this embodiment, an opening / closing valve is used as the transfer control means (11) and the transfer control means (12), which is the first aspect of the present invention. As shown in FIG. 2, the fluid transfer means (15) As an example, an external pump is used. This example also shows an example in which a sample weighed is injected into a chromatography column connected to the second flow path (2) and formed in the micro sample weighing device.
[クロマトグラフィー・カラム用の多孔質層(23)の形成]
厚さ1mmのアクリル樹脂製の基板(21)にスピンコーターを用いて、組成物(X2)を塗布し、紫外線ランプ1にて 1秒間紫外線を照射して塗膜を半硬化させて第一樹脂層(22)とした。その上にスピンコーターにて組成物(Y)を塗工し、フォトマスクを通して紫外線ランプ2により、多孔質層(23)が形成される多孔質層形成領域(23)とする部分に紫外線を40秒照射して照射部分の組成物(Y)の塗膜を硬化させると同時に相分離させ、n−ヘキサンで貧溶剤(R)を洗浄除去して多孔質層(23)を形成した。
[Formation of Porous Layer (23) for Chromatography Column]
The composition (X2) was applied to a 1 mm-thick acrylic resin substrate (21) using a spin coater, and the coating was semi-cured by irradiating ultraviolet rays with an
[流路となる溝の形成]
前記多孔質層(23)の上に、バーコーターを用いて組成物(X1)を塗工し、第一流路(1)、第二流路(2)、計量用流路(3)、およびクロマトグラフィー・カラム(25)と成すべき部分以外の部分にフォトマスクを通して紫外線ランプ2による紫外線照射を40秒行って組成物(X1)の塗膜を半硬化させて第二樹脂層(24)を形成し、非照射部分の未硬化の前記組成物(X1)をエタノールで洗浄除去して、第一流路(1)、第二流路(2)、計量用流路(3)、接合部(4)、およびクロマトグラフィー・カラム(25)となる溝を形成した。
[Formation of grooves to be flow paths]
On the porous layer (23), the composition (X1) is applied using a bar coater, and the first channel (1), the second channel (2), the metering channel (3), and The second resin layer (24) is formed by semi-curing the coating film of the composition (X1) by irradiating the portion other than the portion to be formed with the chromatography column (25) with an
[蓋(26)の固着]
一方、組成物(X2)を、片面がコロナ放電処理された厚さ30μmの2軸延伸ポリプロピレンシート(二村化学株式会社製)を一時的な支持体(図示略)として、その上にバーコーターを用いて塗工し、紫外線ランプ1により紫外線を1秒照射して半硬化させ、これを前記で形成された溝を有する部材の溝形成面に張り合わせ、紫外線ランプ1により紫外線を40秒照射して完全に硬化させて蓋(26)を固着した。次いで、前記一時的な支持体を剥離除去して、毛細管状の第一流路(1)、第二流路(2)、計量用流路(3)、及び接合部(4)から成る流路(10、及び、試料流出口(6)に接続されたクロマトグラフィー・カラム(25)を有する微量試料計量デバイス前駆体を形成した。
[Fixing of lid (26)]
On the other hand, the composition (X2) was prepared by using a biaxially oriented polypropylene sheet (manufactured by Nimura Chemical Co., Ltd.) having a thickness of 30 μm, one side of which was subjected to corona discharge treatment, as a temporary support (not shown), and a bar coater thereon. The
[その他の構造の形成]
この後、ドリルを使用して、前記蓋(26)を貫通し、試料流入口(5)において第一流路(1)に通じる直径0.5mmの孔(28)を開け、該開口部にルアーフィッティング(35)を接着して接続口(35)とした。同様にして、流出口(6)に接続されたクロマトグラフィー・カラム(25)の他端(27)に直径0.5mmの孔(29)を開け、ルアーフィッティング(36)を接着して接続口(36)を形成し、さらに、試料流出口(7)に直径0.5mmの孔(30)を開け、該開口部にルアーフィッティング(37)を接着して接続口(37)として、微量試料計量デバイス(100)を得た。この微量試料計量デバイス(100)の第一流路の途中の一部は図6に示された圧迫部(41)とされ、該圧迫部(41)と、それに相対する流路部分(42)とで開閉バルブ(43)が構成され、移送制御機構(11)とされている。同様の機構が第二流路の途中に設けられ、移送制御機構(12)とされている。
[Formation of other structures]
Thereafter, using a drill, a hole (28) having a diameter of 0.5 mm communicating with the first channel (1) is opened in the sample inlet (5) through the lid (26), and a lure is formed in the opening. A fitting (35) was adhered to form a connection port (35). Similarly, a hole (29) having a diameter of 0.5 mm is formed in the other end (27) of the chromatography column (25) connected to the outlet (6), and a luer fitting (36) is adhered to the connection port. (36) is formed, and further, a hole (30) having a diameter of 0.5 mm is formed in the sample outlet (7), and a luer fitting (37) is adhered to the opening to form a connection port (37). A weighing device (100) was obtained. A part of the first flow path of the micro sample weighing device (100) is a compression part (41) shown in FIG. 6, and the compression part (41) and a flow path part (42) opposed to the compression part (41). The open / close valve (43) is configured as a transfer control mechanism (11). A similar mechanism is provided in the middle of the second flow path to serve as a transfer control mechanism (12).
[流路の構造観察]
得られた微量試料計量デバイス(100)の各部の寸法を光学顕微鏡にて観察した。流路(10)全体の深さ、及びクロマトグラフィー・カラム(25)の深さ(但し、多孔質層の厚みを除く)は約50μmであり、幅は、第一流路(1)、第二流路(2)、及び、クロマトグラフィー・カラム(25)が約150μm、計量用流路(3)が約50μmであった。また、基板(21)の厚みは1mm、第一樹脂層(22)の厚みは10μm、多孔質層(23)の厚みは約5μm、第二樹脂層(24)の厚みは50μm、蓋(26)の厚みは約100μmであった。
[Observation of channel structure]
The dimension of each part of the obtained micro sample weighing device (100) was observed with an optical microscope. The total depth of the flow path (10) and the depth of the chromatography column (25) (excluding the thickness of the porous layer) is about 50 μm, and the width is the first flow path (1), the second The flow path (2) and the chromatography column (25) were about 150 μm, and the measurement flow path (3) was about 50 μm. The thickness of the substrate (21) is 1 mm, the thickness of the first resin layer (22) is 10 μm, the thickness of the porous layer (23) is about 5 μm, the thickness of the second resin layer (24) is 50 μm, and the lid (26 ) Was about 100 μm.
[微量試料計量装置]
(A)「流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際移送制御手段(12)により流体試料が第二流路(2)に流入しないようにする機構」として、ゴム製の押圧部(65)を有し、コンピュータ(61)制御による、電磁式のアクチュエータ(64)を作製した。
[Small sample weighing device]
(A) “The fluid sample flows in from the sample inlet (5), and the fluid sample flows from the first channel (1) into the metering channel (3). As a mechanism for preventing the gas from flowing into the second flow path (2), an electromagnetic actuator (64) having a rubber pressing portion (65) and controlled by the computer (61) was produced.
(B)「計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止する機構」として、センサ部(20)を観察する蛍光顕微鏡(62)、試料を検知し、電気信号に変換する、蛍光顕微鏡に付属した光電子増倍管(63)、及び該電気信号を受けて流体移送手段(15)の送液を制御するコンピュータ(61)でもって上記機構とした。 (B) As a “mechanism for stopping the inflow of the fluid sample by detection of the sensor unit (20) when the fluid sample that has flowed into the measuring channel (3) reaches a specified amount”, the sensor unit (20) A fluorescence microscope (62) for observing the sample, a photomultiplier tube (63) attached to the fluorescence microscope for detecting a sample and converting it into an electrical signal, and receiving the electrical signal to send a liquid transport means (15) The above-mentioned mechanism is formed by a computer (61) to be controlled.
(C)「計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また送液移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにする機構」として、ゴム製の押圧部(67)を有し、コンピュータ(61)制御による電磁式のアクチュエータ(66)を作製した。 (C) “The fluid sample in the measuring channel (3) is transferred into the second channel (2) by the sample transfer fluid flowing in from the inlet (7), and the measured sample is transferred to the sample outlet (6 The transfer control means (12) in the second flow path (2) is brought into a liquid feedable state at that time, and the fluid sample is transferred to the first flow path (1) by the liquid feed transfer control means (11). As a mechanism for preventing the air from flowing into, an electromagnetic actuator (66) having a rubber pressing portion (67) and controlled by a computer (61) was produced.
(D)流体を送液及び停止する機構」として、流体移送手段(15)であるシリンジポンプ(15)を使用した。 The syringe pump (15) that is the fluid transfer means (15) was used as “(D) Mechanism for feeding and stopping fluid”.
以上の機構と、前記微量試料計量デバイス(100)でもって、図8に示したような微量試料計量装置(101)を構成した。 The above-described mechanism and the trace sample weighing device (100) constitute a trace sample weighing apparatus (101) as shown in FIG.
[試料計量試験]
図2および図8に示しように、接続口(27)に、リザーバタンク(52)と流体移送手段(15)とを兼ねた機構として、蒸留水の入ったシリンジポンプ(15)を接続し、移送制御手段(11)の開閉バルブ及び移送制御手段(12)の開閉バルブを共に開いた状態で該シリンジポンプ(15)を吐出方向に駆動することによって、流路(10)全体に蒸留水を充満させた。
[Sample weighing test]
As shown in FIG. 2 and FIG. 8, a syringe pump (15) containing distilled water is connected to the connection port (27) as a mechanism that serves as both the reservoir tank (52) and the fluid transfer means (15). By driving the syringe pump (15) in the discharge direction with both the open / close valve of the transfer control means (11) and the open / close valve of the transfer control means (12) open, distilled water is supplied to the entire flow path (10). Charged.
次いで、図5および図7に示した移送制御手段(11)の圧迫部(41)及び移送制御手段(12)の圧迫部(41)を図8に示した押圧機構(64)、(66)であるアクチュエータ(64)、(66)にて圧迫して、両開閉バルブを閉じ、試料流入口(5)のルアーフィッティング(35)内にピペットにてに蛍光色素フルオレシン(和光純薬製)の1×10−6M水溶液を10μl配した。 Next, the pressing mechanism (64), (66) shown in FIG. 8 is applied to the compression part (41) of the transfer control means (11) shown in FIGS. 5 and 7 and the compression part (41) of the transfer control means (12). The actuators (64) and (66) are pressed to close both open and close valves, and the fluorescent dye fluorescin (manufactured by Wako Pure Chemical Industries, Ltd.) is pipetted into the luer fitting (35) of the sample inlet (5). 10 μl of 1 × 10 −6 M aqueous solution was disposed.
その後、圧迫を解除して移送制御手段(11)を開き、計量用流路(3)の途上に設けられたセンサ部(20)である測定用窓を蛍光顕微鏡(62)で蛍光測定しながらシリンジポンプ(15)を吸引方向に駆動したところ、試料は第一流路(1)を通り接合部(4)を経て第二流路に入った。試料が試料計量部(3a)を満たし、センサ部(20)に達したことを蛍光顕微鏡(62)の光電子増倍管(63)が検出した。コンピュータ(61)により、光電子増倍管(63)の検出該信号を受けたところでシリンジポンプ(15)を停止した。 Thereafter, the pressure is released, the transfer control means (11) is opened, and the measurement window, which is the sensor section (20) provided in the middle of the measuring flow path (3), is measured with the fluorescence microscope (62). When the syringe pump (15) was driven in the suction direction, the sample passed through the first channel (1) and entered the second channel through the joint (4). The photomultiplier tube (63) of the fluorescence microscope (62) detected that the sample filled the sample weighing section (3a) and reached the sensor section (20). When the computer (61) received the signal detected by the photomultiplier tube (63), the syringe pump (15) was stopped.
圧迫部(41)を圧迫して移送制御手段(11)の開閉バルブを閉じる一方、圧迫を解除して移送制御手段(12)を開いた後、同シリンジポンプ(15)を吐出方向に駆動したところ、計量用流路(3)の試料計量部(3a)内の試料は、試料移送流体の流入口(7)から計量用流路(3)に導入される蒸留水によって押され、接合部(4)を経て第二流路(2)に移送され、試料流出口(6)からクロマトグラフィー・カラム(25)に注入されて、接続口(36)から微量試料計量デバイス(100)外へ排出された。上記の移送制御手段(11)、(12)の開閉、流体移送手段(15)の駆動は全てコンピュータ(61)制御により行った。 The compression part (41) is compressed to close the opening / closing valve of the transfer control means (11), and after releasing the pressure and opening the transfer control means (12), the syringe pump (15) is driven in the discharge direction. However, the sample in the sample metering section (3a) of the metering channel (3) is pushed by distilled water introduced into the metering channel (3) from the inlet (7) of the sample transfer fluid, and the joint portion. It is transferred to the second flow path (2) via (4), injected into the chromatography column (25) from the sample outlet (6), and out of the micro sample weighing device (100) from the connection port (36). It was discharged. The opening / closing of the transfer control means (11) and (12) and the driving of the fluid transfer means (15) were all controlled by the computer (61).
このとき、蛍光顕微鏡(62)と光電子増倍管(63)を用いて、試料流出口(6)に於ける蛍光強度の時間変化を測定し、試料のフルオレセインに起因する蛍光強度の積分値を検量線と比較して注入量を求めたところ、注入量は約7.3nlと見積もられた。 At this time, the fluorescence microscope (62) and the photomultiplier tube (63) are used to measure the temporal change of the fluorescence intensity at the sample outlet (6), and the integrated value of the fluorescence intensity due to the fluorescein of the sample is obtained. When the injection amount was determined by comparison with the calibration curve, the injection amount was estimated to be about 7.3 nl.
(実施例2)
本実施例では本発明の第二態様である、移送制御手段(11)及び移送制御手段(12)として逆止弁を使用した例であり、図2に示したように、流体移送手段(15)として外部ポンプを用いる例を示す。本実施例ではまた、第二流路(2)に接続して微量試料計量デバイス(100)内に形成されたクロマトグラフィー・カラムに計量した試料を注入する例を示す。
(Example 2)
In this embodiment, a check valve is used as the transfer control means (11) and the transfer control means (12), which is the second aspect of the present invention. As shown in FIG. 2, the fluid transfer means (15 ) Shows an example using an external pump. This example also shows an example in which a weighed sample is injected into a chromatography column connected to the second flow path (2) and formed in the micro sample weighing device (100).
(イ)樹脂第二層(24)の形成時に、第一流路の途中の接合部(4)の近くに移送制御手段(11)である逆止弁の弁室(44)となる凹部(44)を、また、第二流路の途中の接合部(4)の近くに移送制御手段(12)である逆止弁の弁室(44)となる凹部(44)を形成したこと、
(ロ)第二樹脂層(24)の溝と凹部(44)いっぱいに組成物(Z)を充填し、移送制御手段(11)である逆止弁の弁体(45)及び移送制御手段(12)である逆止弁の弁体(45)となす部分に紫外線ランプ2を用いて紫外線を40秒間照射し、未照射部の未硬化の組成物(Z)を蒸留水で洗浄除去して、移送制御手段(11)となる逆止弁の弁室(44)と移送制御手段(12)となる逆止弁の弁室(44)内に、それぞれゲル製の弁体(45)を形成したこと、
(ハ)蓋(26)の固着の工程に先だって、前記2箇所のゲル製の弁体(45)の上面に筆でシリコンオイルを塗布し、該塗布部分を非接着性としたこと、
以外は実施例1と同様にして、微量試料計量デバイス(100)を作成し、移送制御手段(11)と移送制御手段(12)の両者を開閉バルブ(43)の代わりに逆止弁(46)としたこと以外は実施例1と同様の微量試料計量デバイス(100)を得た。
(A) When forming the resin second layer (24), a recess (44) that becomes a valve chamber (44) of a check valve that is a transfer control means (11) near the joint (4) in the middle of the first flow path. ), And the formation of a recess (44) that becomes the valve chamber (44) of the check valve, which is the transfer control means (12), near the joint (4) in the middle of the second flow path,
(B) Fill the groove and the recess (44) of the second resin layer (24) with the composition (Z), and transfer the valve body (45) of the check valve as the transfer control means (11) and the transfer control means ( 12) Irradiate ultraviolet light for 40 seconds to the portion of the check valve valve body (45) using the
(C) Prior to the step of fixing the lid (26), silicone oil was applied to the upper surface of the two gel valve bodies (45) with a brush to make the applied part non-adhesive;
Except for the above, the micro sample weighing device (100) was prepared in the same manner as in Example 1, and both the transfer control means (11) and the transfer control means (12) were replaced with a check valve (46) instead of the on-off valve (43). Except for the above, a micro sample weighing device (100) similar to Example 1 was obtained.
[流路の構造観察]
得られた微量試料計量デバイス(100)の各部の寸法を光学顕微鏡にて観察したところ、図7に示したように、弁室(44)は共に幅が約300μmの、平面形状が砲弾型の柱状、弁体は共に、一辺が約300μmの三角柱状であった。これらの高さは流路(10)と同じ50μmであった。それ以外は実施例1と同様であった。この弁体(45)は両者とも、底と両側壁部において弁室(44)内面に固着していたが、蓋(26)には接触しているが固着していなかった。
[Observation of channel structure]
When the dimensions of each part of the obtained micro sample weighing device (100) were observed with an optical microscope, as shown in FIG. 7, both the valve chambers (44) had a width of about 300 μm, and the planar shape was a cannonball type. Both the columnar shape and the valve body were triangular prism shapes with sides of about 300 μm. Their height was 50 μm, which is the same as that of the flow path (10). Otherwise, it was the same as Example 1. Both valve bodies (45) were fixed to the inner surface of the valve chamber (44) at the bottom and both side walls, but were in contact with the lid (26) but not.
[微量試料計量装置]
アクチュエータ(64)、(66)を有さないこと以外は実施例1と同様の微量試料計量装置(101)を作製した。
[Small sample weighing device]
A micro sample weighing device (101) similar to Example 1 was prepared except that the actuators (64) and (66) were not provided.
なお、本実施例に於いては、(A)「流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際移送制御手段(12)により流体試料が第二流路(2)に流入しないようにする機構」及び(C)「計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また送液移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにする機構」は微量計量デバイス(100)内に形成された2つの逆止弁(7)が上記機構となる。 In this embodiment, (A) “fluid sample flows from the sample inlet (5), fluid sample flows from the first channel (1) into the metering channel (3), The mechanism for preventing the fluid sample from flowing into the second flow path (2) by the transfer control means (12) "and (C)" The fluid sample in the measuring flow path (3) flows in from the inlet (7) " The sample transfer fluid is transferred into the second channel (2) by the sample transfer fluid, and the weighed sample is caused to flow out from the sample outlet (6). At that time, the transfer control means (12) in the second channel (2) The mechanism that makes the liquid sample ready to be fed and prevents the fluid sample from flowing into the first flow path (1) by the liquid feeding and transfer control means (11) is the two inverses formed in the micrometering device (100). The stop valve (7) is the above mechanism.
[試料計量試験]
実施例1と同様に接続し、あらかじめ流路(10)に蒸留水を充満させるに当たって、接続口(35)と接続口(36)の内側をそれぞれリザーバタンク(51)(52)として用い、これらに蒸留水を満たしておき、流体移送手段(15)であるシリンジポンプ(15)を吸引した後吐出して、流路(10)全体に蒸留水を充満させたこと、微少試料計量装置(101)が押圧機構(64)、(66)を持たず、移送制御手段(11)と移送制御手段(12)の特別な開閉操作を一切行わなかったこと以外は、実施例1と同様にして試料注入試験を行った。
[Sample weighing test]
In the same manner as in Example 1, when the flow path (10) was previously filled with distilled water, the insides of the connection port (35) and the connection port (36) were used as reservoir tanks (51) and (52), respectively. The sample was filled with distilled water, and the syringe pump (15) as the fluid transfer means (15) was sucked and discharged to fill the entire channel (10) with distilled water. ) Does not have the pressing mechanism (64), (66), and the sample is not subjected to any special opening / closing operation of the transfer control means (11) and the transfer control means (12). An injection test was performed.
その結果、移送制御手段(11)と移送制御手段(12)は、流体移送手段(15)であるシリンジポンプ(15)の吸引と吐出に応じて自動的に開閉したこと、計量してクロマトカラムに注入した試料は、実施例1よりテーリングが多かったこと、及び、注入量が約7.1nlと見積もられた以外は、実施例1と同様であった。 As a result, the transfer control means (11) and the transfer control means (12) are automatically opened and closed according to the suction and discharge of the syringe pump (15) as the fluid transfer means (15), and the chromatographic column is measured. The sample injected into was similar to Example 1 except that it had more tailing than Example 1 and that the injection volume was estimated to be about 7.1 nl.
(実施例3)
本実施例では本発明の第二態様である、移送制御手段(11)及び移送制御手段(12)として逆止弁を使用した例であり、図3に示したように、流体移送手段(15)として内部ポンプを用いた例を示す。本実施例ではまた、第二流路(2)に接続して微量試料計量デバイス(100)内に形成されたクロマトグラフィー・カラムに計量した試料を注入する例を示す。
(Example 3)
In this embodiment, a check valve is used as the transfer control means (11) and the transfer control means (12), which is the second aspect of the present invention. As shown in FIG. 3, the fluid transfer means (15 ) Shows an example using an internal pump. This example also shows an example in which a weighed sample is injected into a chromatography column connected to the second flow path (2) and formed in the micro sample weighing device (100).
(イ)樹脂第二層(24)の形成時に、計量用流路の途中のセンサ部(20)と試料移送流体の流入口(7)との間の部分に、流体移送手段(15)としてのポンプ機構(15)用の圧力弁(49)となる堰状構造(47)を形成したこと、
(ロ)蓋(26)の固着の工程に先だって、該堰状構造(47)の上面に筆でシリコンオイルを塗布し、該塗布部分を非接着性としたこと、
以外は実施例2と同様の方法で作製し、
(ハ)圧力弁(49)の堰状構造(47)上面と蓋(26)との接触面が接触しているが固着していない構造を持つこと、
(二)上記圧力弁(49)とセンサ部(20)との間の計量用流路(3)の一部を圧迫部(48a)、前記堰状構造(47)と試料移送流体の流入口(7)との間の計量用流路(3)の一部を圧迫部(48b)とし、圧力弁(49)、圧迫部(48a)、及び圧迫部(48b)とで、双方向に流体を移送可能なポンプ機構(15)を構成したこと、
以外は実施例2と同様の微量試料計量デバイス(100)を得た。
(A) When the resin second layer (24) is formed, a fluid transfer means (15) is provided at a portion between the sensor part (20) and the sample transfer fluid inlet (7) in the middle of the measurement flow path. Forming a weir-like structure (47) to be a pressure valve (49) for the pump mechanism (15) of
(B) Prior to the step of fixing the lid (26), silicon oil was applied to the upper surface of the weir-like structure (47) with a brush to make the applied part non-adhesive;
Except for the above, the same method as in Example 2 was used.
(C) The weir-like structure (47) of the pressure valve (49) has a structure in which the contact surface between the upper surface and the lid (26) is in contact but not fixed;
(2) A part of the metering flow path (3) between the pressure valve (49) and the sensor part (20) is a compression part (48a), the weir-like structure (47) and the inlet of the sample transfer fluid A part of the metering channel (3) between (7) is used as a compression part (48b), and the pressure valve (49), the compression part (48a), and the compression part (48b) provide fluid in both directions. A pump mechanism (15) capable of transferring
A micro sample weighing device (100) was obtained in the same manner as in Example 2 except for the above.
[流路の構造観察]
得られた微量試料計量デバイス(100)の各部の寸法を光学顕微鏡にて観察したところ、堰状構造(45)は流路方向の長さが約150μm、高さ50μm四角柱状であり、その上面は蓋に接触しているが固着していなかった。
[Observation of channel structure]
When the dimensions of each part of the obtained micro sample weighing device (100) were observed with an optical microscope, the weir-like structure (45) had a square columnar shape with a length in the flow path direction of about 150 μm and a height of 50 μm. Was in contact with the lid but not stuck.
[微量試料計量装置]
上記微量試料計量デバイス(100)、図8に示されたような、センサ部(20)を観測する、光電子増倍管(63)付き蛍光顕微鏡(62)、ポンプ機構(15)の圧迫部(48a)を駆動するためのアクチュエータ(64)、ポンプ機構(15)の圧迫部(48b)を駆動するためのアクチュエータ(64)、および制御用のコンピュータ(61)から成る微量試料計量装置(101)を作製した。
[Small sample weighing device]
The microscopic sample weighing device (100), the fluorescence microscope (62) with a photomultiplier tube (63), and the compression part (15) of the pump mechanism (15) for observing the sensor unit (20) as shown in FIG. A micro sample weighing device (101) comprising an actuator (64) for driving 48a), an actuator (64) for driving the compression part (48b) of the pump mechanism (15), and a control computer (61). Was made.
なお、本実施例に於いては、微量計量デバイス(100)内部のポンプ機構(15)、アクチュエータ(64)、(66)及び制御用のコンピュータ(61)が(B)「計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止する機構」となる。また、実施例2と同様に、(A)「流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際移送制御手段(12)により流体試料が第二流路(2)に流入しないようにする機構」及び(C)「計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また送液移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにする機構」は微量計量デバイス(100)内に形成された2つの逆止弁(7)が上記機構となる。 In this embodiment, the pump mechanism (15), actuators (64), (66) and the control computer (61) inside the micrometer device (100) are connected to (B) “metering channel ( 3) “Mechanism for stopping the inflow of the fluid sample by detection of the sensor unit (20) when the amount of the fluid sample introduced therein reaches a specified amount”. Similarly to Example 2, (A) “fluid sample flows in from the sample inlet (5), fluid sample flows into the measuring channel (3) from the first channel (1), "Mechanism to prevent fluid sample from flowing into second flow path (2) by transfer control means (12)" and (C) "Fluid sample in measurement flow path (3) flows from inlet (7)" The sample transfer fluid is transferred into the second channel (2) and the weighed sample is allowed to flow out of the sample outlet (6). At this time, the transfer control means (12) in the second channel (2) is The “mechanism for making the liquid feedable state and preventing the fluid sample from flowing into the first flow path (1) by the liquid feed transfer control means (11)” is two check elements formed in the micrometering device (100). The valve (7) serves as the mechanism.
[試料注入試験]
図3の構成において、
(あ)シリンジポンプ(15)を吸引方向に駆動する代わりに、ゴム製の押圧部(65)を持つアクチュエータ(64)を駆動し圧迫部(48a)を繰り返し圧迫して、図11(a)および図11(b)に示したように、圧迫により流路(10)内の一部の液体が圧迫されて堰状構造(45)を乗り越えて送液されたこと、及び、
(い)シリンジポンプ(15)を吐出方向に駆動する代わりに、前記ポンプ機構(15)の圧迫部(48b)をゴム製の押圧部(67)を持つアクチュエータ(66)を用いて繰り返し圧迫して、上記(あ)とは逆の方向に送液したこと、
以外は、実施例2と同様にして試料注入試験を行い、実施例2と同様の結果を得た。
[Sample injection test]
In the configuration of FIG.
(A) Instead of driving the syringe pump (15) in the suction direction, the actuator (64) having the rubber pressing portion (65) is driven to repeatedly press the compression portion (48a), and FIG. And as shown in FIG. 11 (b), a part of the liquid in the flow path (10) was pressed by the pressure and passed over the weir-like structure (45), and the liquid was sent.
(Ii) Instead of driving the syringe pump (15) in the discharge direction, the compression part (48b) of the pump mechanism (15) is repeatedly compressed using an actuator (66) having a rubber pressing part (67). The liquid was sent in the opposite direction to (a) above,
Except for the above, a sample injection test was performed in the same manner as in Example 2, and the same result as in Example 2 was obtained.
(実施例4)
本実施例では本発明の第三態様であり、図4に示したような構成の、移送制御手段(11)及び移送制御手段(12)として流体移送手段(15)を兼ねる内部ポンプを使用した例を示す。本実施例ではまた、第二流路(2)に接続して微量試料計量デバイス(100)内に形成されたクロマトグラフィー・カラムに計量した試料を注入する例を示す。
Example 4
In this embodiment, an internal pump which is the third aspect of the present invention and has the structure shown in FIG. 4 is used as the transfer control means (11) and the transfer control means (12) which also serves as the fluid transfer means (15). An example is shown. This example also shows an example in which a weighed sample is injected into a chromatography column connected to the second flow path (2) and formed in the micro sample weighing device (100).
(イ)2つの逆止弁(46)の代わりに、樹脂第二層(24)の形成時に、第一流路の途中の接合部(4)に接する部分に移送制御手段(11)と流体移送手段(15)を兼ねるポンプ機構(15)の圧力弁(49)用の堰状構造(47)を、また、第二流路(2)の途中に移送制御手段(12)と流体移送手段(15)を兼ねるポンプ機構(15)の圧力弁(49)用の堰状構造(47)をを形成したこと、
(ロ)蓋(26)の固着の工程に先だって、2箇所の堰状構造(47)の上面にシリコンオイルを塗布し、該部分を非接着性としたこと、
以外は実施例1と同様にして作製し、
(ハ)第一流路(1)上部の蓋部分の、試料流入口(5)と前記堰状構造(47)との間の部分を圧迫部(48a)とし、該圧迫部(48a)と前記堰状構造(47)とでポンプ機構(15)を構成し、これを流体移送手段(15)を兼ねた移送制御手段(11)としたこと
(ニ)第二流路(1)上部の蓋部分の、前記接合部(4)と前記堰状構造(47)との間の部分を圧迫部(48a)とし、圧迫部(48a)と前記堰状構造(47)とでポンプ機構(15)を構成し、これを流体移送手段(15)を兼ねた移送制御手段(12)としたこと
(ホ)開閉バルブ(43)は設けなかったこと、
以外は実施例1と同様の微量試料計量デバイス(100)を得た。
(A) Instead of the two check valves (46), when forming the resin second layer (24), the transfer control means (11) and the fluid transfer to the part in contact with the joint (4) in the middle of the first flow path The weir-like structure (47) for the pressure valve (49) of the pump mechanism (15) that also serves as the means (15), and the transfer control means (12) and the fluid transfer means ( 15) forming a weir-like structure (47) for the pressure valve (49) of the pump mechanism (15) that also serves as the
(B) Prior to the step of fixing the lid (26), silicon oil was applied to the upper surfaces of the two weir-like structures (47) to make the portions non-adhesive;
Except for the same as in Example 1,
(C) A portion between the sample inlet (5) and the weir-like structure (47) in the lid portion on the upper part of the first flow path (1) serves as a compression portion (48a), and the compression portion (48a) and the above-mentioned The weir-like structure (47) constitutes the pump mechanism (15), which is used as the transfer control means (11) that also serves as the fluid transfer means (15). (D) The upper cover of the second flow path (1) The portion of the portion between the joint (4) and the weir-like structure (47) is a compression portion (48a), and the pump mechanism (15) is composed of the compression portion (48a) and the weir-like structure (47). And that this is the transfer control means (12) that also serves as the fluid transfer means (15). (E) The opening / closing valve (43) was not provided.
A micro sample weighing device (100) similar to Example 1 was obtained except for the above.
[流路の構造観察]
得られた微量試料計量デバイス(100)の各部の寸法を光学顕微鏡にて観察したところ、2つの堰状構造(47)は流路方向の長さが約150μm、高さ50μm四角柱状であり、その上面は蓋に接触しているが固着していなかった。
[Observation of channel structure]
When the dimensions of each part of the obtained micro sample weighing device (100) were observed with an optical microscope, the two weir-like structures (47) were about 150 μm in length in the flow channel direction and 50 μm high in a rectangular column shape, The upper surface was in contact with the lid but not fixed.
[微量試料計量装置]
上記微量試料計量デバイス(100)、図8に示されたような、センサ部(20)を観測する、光電子増倍管(63)付き蛍光顕微鏡(62)、移送制御手段(11)を兼ねるポンプ機構(15)を駆動するためのアクチュエータ(64)、移送制御手段(12)を兼ねるポンプ機構(15)を駆動するためのアクチュエータ(66)、および制御用のコンピュータ(61)から成る、シリンジポンプ(15)を持たないこと以外は実施例1と同様の微量試料計量装置(101)を作製した。
[Small sample weighing device]
The above-mentioned micro sample weighing device (100), a fluorescence microscope (62) with a photomultiplier tube (63), and a transfer control means (11) as shown in FIG. Syringe pump comprising an actuator (64) for driving the mechanism (15), an actuator (66) for driving the pump mechanism (15) also serving as the transfer control means (12), and a computer (61) for control A micro sample weighing device (101) similar to that in Example 1 was prepared except that (15) was not provided.
なお、本実施例に於いては、実施例1と異なり、
(A)「流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際移送制御手段(12)により流体試料が第二流路(2)に流入しないようにする機構」として、微量計量デバイス(100)内部の移送制御手段(11)を兼ねるポンプ機構(15)、アクチュエータ(64)及び制御用のコンピュータ(61)が使用され、
(B)「計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止する機構」として、光電子増倍管(63)付き蛍光顕微鏡(62)、制御用のコンピュータ(61)、アクチュエータ(64)、及び微量試料計量デバイス(100)内の移送制御手段(11)を兼ねるポンプ機構(15)が使用され、
(C)「計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにする機構」として、微量計量デバイス(100)内部の移送制御手段(12)を兼ねるポンプ機構(15)、アクチュエータ(66)及び制御用のコンピュータ(61)が使用される。
In this example, unlike Example 1,
(A) “The fluid sample flows in from the sample inlet (5), and the fluid sample flows from the first channel (1) into the metering channel (3). As a mechanism for preventing the liquid from flowing into the second flow path (2) ", a pump mechanism (15) also serving as a transfer control means (11) inside the micrometering device (100), an actuator (64), and a control computer ( 61) is used,
(B) As a “mechanism for stopping the inflow of the fluid sample upon detection of the sensor unit (20) when the fluid sample flowing into the measuring channel (3) reaches a specified amount”, a photomultiplier tube ( 63) a fluorescence microscope (62) equipped with, a control computer (61), an actuator (64), and a pump mechanism (15) that also serves as a transfer control means (11) in the micro sample weighing device (100),
(C) “The fluid sample in the measuring channel (3) is transferred into the second channel (2) by the sample transfer fluid flowing in from the inlet (7), and the measured sample is transferred to the sample outlet (6 ) At that time, the transfer control means (12) in the second flow path (2) is brought into a liquid-feedable state, and the fluid sample flows into the first flow path (1) by the transfer control means (11). As the mechanism for preventing the operation, a pump mechanism (15) that also serves as a transfer control means (12) inside the micrometering device (100), an actuator (66), and a control computer (61) are used.
[試料注入試験]
(あ)あらかじめ流路(10)に蒸留水を充満させるに当たって、蒸留水を第一接続口(35)と第二接続口(36)に満たしておき、移送制御手段(11)の圧迫部(48a)をゴム製の押圧部(65)を持つアクチュエータ(64)により繰り返し圧迫することで移送制御手段(11)を駆動して、計量用流路に蒸留水を充填し、次いで、移送制御手段(12)の圧迫部(48a)をゴム製の押圧部(67)を持つアクチュエータ(66)で繰り返し圧迫することで移送制御手段(12)を駆動して、第二流路に蒸留水を充填したこと、
(い)シリンジポンプ(15)を吸引駆動する代わりに移送制御手段(11)を駆動することで試料を試料流入口(5)から第二流路へ移送したこと、
(う)シリンジポンプ(15)を吸引駆動する代わりに、移送制御手段(12)を駆動することで試料を計量用流路(3)から第二流路(2)へ注入したこと、
以外は、実施例2と同様にして試料注入試験を行った。
[Sample injection test]
(A) When filling the flow path (10) with distilled water in advance, the first connection port (35) and the second connection port (36) are filled with distilled water, and the compression part (11) of the transfer control means (11) 48a) is repeatedly pressed by an actuator (64) having a rubber pressing portion (65) to drive the transfer control means (11) to fill the metering channel with distilled water, and then transfer control means By repeatedly pressing the pressure part (48a) of (12) with an actuator (66) having a rubber pressing part (67), the transfer control means (12) is driven and the second flow path is filled with distilled water. What
(Ii) The sample was transferred from the sample inlet (5) to the second channel by driving the transfer control means (11) instead of driving the syringe pump (15) by suction,
(C) Instead of driving the syringe pump (15) by suction, the transfer control means (12) is driven to inject the sample from the measuring channel (3) into the second channel (2);
Except for the above, a sample injection test was conducted in the same manner as in Example 2.
その結果、注入した試料は、実施例1より僅かにテーリングが大きかったこと以外は実施例1と同様であった。 As a result, the injected sample was the same as Example 1 except that the tailing was slightly larger than Example 1.
1 第一流路
2 第二流路
3 計量用流路
3a 試料計量部
4 接合部
5 試料流入口
6 試料流出口
7 流入口
10 流路
11、12、13 移送制御手段
15 流体移送手段、シリンジポンプ、ポンプ機構
20 センサ部
10 流路
21 基板
22 第一樹脂層
23 多孔質層、多孔質層形成領域
24 第二樹脂層
25 クロマトグラフィー・カラム
26 蓋
27 カラムの他端
28、29、30 孔
35、36、37 ルアーフィッティング、接続口
41 圧迫部
42 圧迫部に相対する流路部分
43 開閉バルブ
44 弁室、凹部
45 ゲル、弁体
46 逆止弁
47 堰状構造
48a、48b 圧迫部
49 圧力弁
51,52 リザーバタンク
61 コンピュータ
62 蛍光顕微鏡
63 光電子増倍管
64、66 押圧機構、アクチュエータ
65,67 押圧部
DESCRIPTION OF
Claims (9)
(A)流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際移送制御手段(12)により流体試料の第二流路(2)への流入を停止し、
(B)計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止し、
(C)計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにすることが可能な微量試料計量デバイス。 A first flow path (1) having a sample inlet (5) for allowing a fluid sample to flow into one end, and having a transfer control means (11) for controlling the transfer of the fluid in the middle of the flow path, and allowing the fluid sample to flow out to one end A second flow path (2) having a sample outlet (6) and having a transfer control means (12) for controlling the transfer of fluid in the middle of the flow path, and a sample transfer fluid for transferring a fluid sample to one end A metering channel (3) having a sample transfer fluid inlet (7) and a sensor unit (20) for detecting a fluid sample in the channel, the first channel (1), The other end of each of the two channels (2) and the metering channel (3) is joined at the junction (4) so that the fluid sample flows.
(A) The fluid sample flows in from the sample inlet (5), and the fluid sample flows into the metering channel (3) from the first channel (1). Stop the flow into the second channel (2),
(B) The flow of the fluid sample is stopped by the detection of the sensor unit (20) when the fluid sample flowing into the measuring channel (3) reaches a specified amount,
(C) The fluid sample in the measuring channel (3) is transferred into the second channel (2) by the sample transfer fluid flowing in from the inlet (7), and the measured sample is transferred to the sample outlet (6). At that time, the transfer control means (12) in the second flow path (2) is brought into a liquid-feedable state, and the fluid sample does not flow into the first flow path (1) by the transfer control means (11). Trace sample weighing device that can be
(A)流体試料を試料流入口(5)より流入し、流体試料を第一流路(1)から計量用流路(3)内に流入し、その際送液移送制御手段(12)により流体試料が第二流路(2)に流入しないようにする機構、
(B)計量用流路(3)中に流入された流体試料が指定量になった時点でセンサ部(20)の検知により流体試料の流入を停止する機構、
(C)計量用流路(3)中の流体試料を流入口(7)から流入する試料移送流体により
第二流路(2)中に移送し、計量された試料を試料流出口(6)より流出させ、その際に第二流路(2)中の移送制御手段(12)を液送可能状態とし、また送液移送制御手段(11)により該流体試料が第一流路(1)に流入しないようにする機構、および、
(D)流体を移送及び停止する機構
を有することを特徴とする微量試料計量装置。 The micro sample weighing device according to claim 1, wherein the micro sample weighing device is incorporated in the micro sample weighing device, or independent from the micro sample weighing device.
(A) The fluid sample flows in from the sample inlet (5), and the fluid sample flows into the metering channel (3) from the first channel (1). A mechanism for preventing the sample from flowing into the second flow path (2);
(B) a mechanism for stopping the inflow of the fluid sample upon detection of the sensor unit (20) when the fluid sample flowing into the metering channel (3) reaches a specified amount;
(C) The fluid sample in the measuring channel (3) is transferred into the second channel (2) by the sample transfer fluid flowing in from the inlet (7), and the measured sample is transferred to the sample outlet (6). At that time, the transfer control means (12) in the second flow path (2) is brought into a liquid feedable state, and the fluid sample is transferred to the first flow path (1) by the liquid feed transfer control means (11). A mechanism to prevent inflow, and
(D) A micro sample weighing device having a mechanism for transferring and stopping fluid.
第一流路(1)の移送制御手段(11)を送液可能状態、第二流路(2)の移送制御手段(12)を送液停止状態とし、試料を第一流路(1)から接合部(4)を経由して計量用流路(3)に移送し、
計量用流路(3)に流入する試料が計量用流路(3)中のセンサ部(20)において検出された際に試料の移送を停止して、計量用流路内に微量の一定量の試料を計量し、
次いで、第一流路(1)の移送制御手段(11)を送液停止状態、第二流路(2)の移送制御手段(12)を送液可能状態とし、計量した試料を、予め計量用流路(3)に充填した試料移送用流体により、第一流路(1)から接合部(4)を経由して計量用流路(3)に移送し、試料流出口(6)より微量の一定量の試料を得ることを特徴とする微量試料の計量方法。 Using the micro sample weighing device according to any one of claims 1 to 4, a fluid sample is caused to flow from the sample inlet (5) into the first flow path (1),
The transfer control means (11) of the first flow path (1) is in a liquid feedable state, the transfer control means (12) of the second flow path (2) is in a liquid feed stop state, and the sample is joined from the first flow path (1). Transferred to the metering channel (3) via the section (4),
When the sample flowing into the metering channel (3) is detected by the sensor section (20) in the metering channel (3), the transfer of the sample is stopped, and a small amount of the sample is placed in the metering channel (3). Weigh a sample of
Next, the transfer control means (11) of the first flow path (1) is in a liquid feed stop state, the transfer control means (12) of the second flow path (2) is in a liquid feed ready state, and a weighed sample is used for weighing in advance. The sample transfer fluid filled in the flow path (3) is transferred from the first flow path (1) to the measurement flow path (3) via the joint (4), and a trace amount is transferred from the sample outlet (6). A method for weighing a small amount of sample, characterized by obtaining a certain amount of sample.
The method for measuring a trace amount sample according to claim 7 or 8, wherein the method is for measuring a sample to be injected into a chromatographic separation column.
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