This invention relates to a liquid transfer apparatus for transferring a micro-volume of liquid in a micro-reactor that can suitably be used in a micro-total analysis system (μ-TAS).
As a result of the development of three-dimensional micro-processing technologies in recent years, systems for chemical analysis to be conducted on a glass or silicon substrate, on which liquid handling elements such as micro-flow paths, pumps and valves are integrally formed with sensors, have been attracting attention. Such a system is called as miniaturized analysis system, μ-TAS (micro-total analysis system) or lab on a chip. With a downsized chemical analysis system, it is possible to remarkably reduce the ineffective volume and the volume of the specimen. It is also possible to reduce the analysis time and the power consumption of the entire system. Additionally, small systems may be marketed with low price tags. Thus, the μ-TAS is expected to find applications in the medical field including home medical care and bedside monitor and also in the biotechnological field including DNA analysis and proteome analysis because it is very small and can remarkably reduce the price and the analysis time.
Japanese Patent Application Laid-Open No. 10-337173 discloses a micro-reactor that allows to carry out a series of operations of mixing solutions, causing them to react each other, subsequently quantifying and analyzing the components and separating them in a biochemical experiment by means of a combination of several cells.
Japanese Patent Application Laid-Open No. 2001-158000 discloses a multifunctional device realized by using a micro-reactor.
However, a number of problems arise when operating such a micro-reactor, which will be discussed below. Since the flow paths formed on the substrates have a very small diameter of tens of several μm to hundreds of several μm, they can easily become clogged as liquid of various different types is made to flow through them. Then as a result, there arises a problem of stains and the operation of restoring the original conditions to the device is a cumbersome one. Thus, when the micro-reactor is partly clogged or become inoperative, it has to be replaced by a new one because it is an integrated body of various components. Another problem is that, in a series of operations involving reactions using a micro-reactor, it is difficult to modify the composition of a reactive solution and/or other conditions of reaction on the way.
In the case of a chemical integrated circuit disclosed in the above cited Japanese Patent Application Laid-Open No. 2001-158000, while the microchips having different respective single functions can be separated from each other, any of them has to be replaced entirely when only a single part becomes inoperative out of a plurality of parts mounted on it and having a single function.
Finally, an electric technique such as one using electroendosmosis or one utilizing electrophoresis, and a mechanical technique such as a pump are conventionally employed as means for moving each liquid. However, the former technique has a drawback that the quantity and the flow rate of each liquid that is made to flow are remarkably influenced by the properties of the liquid and the operation of controlling them individually is very cumbersome, whereas the latter technique is accompanied by a problem that the pump is currently fitted to the outside to make the entire device bulky and liquid can leak from the connector connecting the pump and the related flow path.
In view of the above identified circumstances, it is therefore the object of the present invention to provide a liquid transfer apparatus that can efficiently transfer and process a micro-volume of liquid and a method of manufacturing a liquid flow path device.
In an aspect of the invention, the above object is achieved by providing a liquid transfer apparatus comprising: a liquid containing section for containing liquid; a liquid introducing section for introducing liquid into said liquid containing section; and a liquid leading out section for leading out the liquid introduced into said liquid containing section, characterized in that said liquid introducing section and said liquid leading out section are arranged so as to make the liquid leading out section of a liquid transfer apparatus connect with the liquid introducing section of another liquid conveyor.
In another aspect of the invention, there is provided a method of manufacturing a liquid flow path device having a continuous liquid flow path by arranging a plurality of liquid transfer apparatuses side by side, each of said liquid transfer apparatuses comprising: a liquid containing section for containing liquid; a liquid introducing section for introducing liquid into said liquid containing section; and a liquid leading out section for leading out the liquid introduced into said liquid containing section, such that the liquid leading out section of a liquid conveyor communicates with the liquid introducing section of another liquid transfer apparatus.
In other words, the present invention provides a composite liquid transfer apparatus that can efficiently convey and process a micro-volume of liquid.
The problem of a stained device can hardly arise when a composite liquid transfer apparatus according to the invention is used because the flow path is formed basically only by liquid leading out sections and liquid introducing sections. Additionally, when a problem occurs to a liquid transfer apparatus in the composite device, only the liquid transfer apparatus in problem can be replaced easily and quickly restore the proper operation of the device. Furthermore, the composition of a reactive solution and/or other conditions of reaction can be modified by replacing one or more than one liquid transfer apparatuses on the way of a series of reactions.
Now, the present invention will be described in greater detail.
According to the invention, there is provided a liquid transfer apparatus comprising: a liquid containing section for containing liquid; a liquid introducing section for introducing liquid into said liquid containing section; and a liquid leading out section for leading out the liquid introduced into said liquid containing section; characterized in that said liquid introducing section and said liquid leading out section are arranged so as to make the liquid leading out section of a liquid transfer apparatus communicate with the liquid introducing section of another liquid conveyor.
A liquid transfer apparatus according to the invention may comprise a plurality of liquid introducing sections and a plurality of liquid leading out sections.
Each liquid transfer apparatus constituting a composite liquid conveyor according to the invention may comprise at least a processing means for heating, condensing, agitating, mixing or causing a chemical or biochemical reaction of the liquid ejected from said liquid introducing section into said liquid containing section in the latter.
Preferably, each liquid conveyor of a composite liquid conveyor according to the invention is provided with a check valve arranged at the ejection port to prevent the ejected liquid from flowing back.
The liquid leading out section of each liquid conveyor of a liquid processing device according to the invention is provided with an energy applying means as means for ejecting liquid. Preferably, a thermal jet system that is characterized by utilizing energy of expanding bubbles generated by rapidly heating the liquid with a heat generating element or a piezo jet system characterized by utilizing energy generated by a vibrator plate stacked with a plate-shaped piezoelectric element to apply pressure on the liquid leading out section may be used for applying energy in order to eject liquid.
A liquid transfer method according to the invention is characterized by comprising a step of removably connecting to unite a plurality of liquid conveyors, each comprising a liquid containing section for containing liquid, a liquid introducing section for introducing liquid into said liquid containing section and a liquid leading out section for leading out the liquid introduced into said liquid containing section, and a step of transfering liquid from the liquid introducing section of a liquid conveyor to the liquid leading out section of another liquid transfer apparatus by ejecting the liquid contained in the liquid containing section of the former liquid transfer apparatus.
A liquid flow path device according to the invention is characterized by comprising a plurality of liquid transfer apparatuses arranged side by side, each having a liquid containing section for containing liquid, a liquid introducing section for introducing liquid into said liquid containing section and a liquid leading out section for leading out the liquid introduced into said liquid containing section, such that the liquid leading out section of a transfer apparatus connects with the liquid introducing section of another transfer apparatus to form a liquid flow path continuing from the liquid introducing section of the former liquid transfer apparatus to the liquid leading out section of the latter liquid transfer apparatus.
The liquid transfer apparatus of
The liquid introduced from the liquid introducing section 103 into the liquid containing section 102 may be subjected to a processing operation of heating, condensing, agitating, mixing or causing a chemical or biochemical reaction there. For this purpose, the liquid containing section 102 may be provided with an element that promotes the processing operation. For example, the liquid containing section 102 may have a heat generating element in order to heat and agitate the introduced liquid.
The liquid containing section 102 may contain liquid before additional liquid is introduced from the liquid introducing section 103. Then, both the liquid that is already in the liquid containing section 102 and the newly introduced liquid may be subjected to a processing operation of heating, condensing, agitating, mixing or causing a chemical or biochemical reaction in it.
A liquid transfer apparatus according to the invention may comprise a plurality of each section formed on a same base member. Particularly, when liquids of different types are introduced from respective liquid introducing sections 103 into a single liquid containing section 102, the liquids can be collectively subjected to a processing operation of heating, condensing, agitating, mixing or causing a chemical or biochemical reaction in the liquid containing section 102.
The base member is provided with a connection/disconnection recess 108 and a connection/disconnection projection 109 for reversibly connecting liquid processing devices.
The position of each section on the base member of a liquid transfer apparatus according to the invention is not particularly limited so long as it does not significantly adversely affect the mechanical strength of the device. Therefore, it may be selected so as to optimize the operation of the liquid processing device comprising it as will be described hereinafter.
The liquid transfer apparatus of
The liquid introduced from the liquid introducing section 203 into the liquid containing section 202 may be subjected to a processing operation of heating, condensing, agitating, mixing or causing a chemical or biochemical reaction there. For this purpose, the liquid containing section 202 may have an element that promotes the processing operation. For example, the liquid containing section 202 may be provided with a heat generating element in order to heat and agitate the introduced liquid.
The liquid containing section 202 may contain liquid before additional liquid is introduced from the liquid introducing section 203. Then, both the liquid that is already in the liquid containing section 202 and the newly introduced liquid may be subjected to a processing operation of heating, condensing, agitating, mixing or causing a chemical or biochemical reaction in it.
A liquid transfer apparatus according to the invention may comprise a plurality of each section formed on a same base member. Particularly, when liquids of different types are introduced from respective liquid introducing sections 203 into a single liquid containing section 202, the liquids can be collectively subjected to a processing operation of heating, condensing, agitating, mixing or causing a chemical or biochemical reaction in the liquid containing section 202.
The substrate is provided with a connection/disconnection recess 208 and a connection/disconnection projection 209 for removably connecting liquid processing devices.
The position of each section on the substrate of a liquid transfer apparatus according to the invention is not particularly limited so long as it does not significantly adversely affect the mechanical strength of the device. Therefore, it may be selected so as to optimize the operation of the liquid processing device comprising it as will be described hereinafter.
Referring to
Liquid C is introduced into the liquid introducing section 353-1 of the liquid transfer apparatus 350 from the liquid leading out section 324 at a desired rate and at a desired frequency. On the other hand, liquid D introduced from the liquid introducing section 343 of the liquid transfer apparatus 340 is contained in the liquid containing section 342 and then introduced into the liquid introducing section 353-2 of the liquid transfer apparatus 350 from the liquid leading out section 344 at a desired rate and at a desired frequency. In the liquid transfer apparatus 350, the liquid C and the liquid D introduced respectively from the liquid introducing section 353-1 and the liquid introducing section 353-2 are contained in the liquid containing section 352 and heated/agitated to react with each other and become liquid E at the original position by a heat generating element denoted by 256-2.
Liquid E is introduced into and contained in the liquid containing section 362 by way of the liquid introducing section 363 of the liquid transfer apparatus 360 from the liquid leading out section 354 at a desired rate and at a desired frequency, where it is heated/agitated by a heat generating element denoted by 266-2 to give rise to a chemical change and become liquid F at the original position. Liquid F is then conveyed from the liquid leading out section 364 to a subsequent step, which may be a separation/refinement step or a detection step, at a desired rate and at a desired frequency. Methods that can be used for the detection step include an electrochemical detection method and a detection method that utilizes fluorescence.
While a method of ejecting liquid by means of a heat generating element is described above, liquid can be ejected alternatively by means of a piezoelectric element or an electrostatic actuator that is popularly used in a known ink-jet head.
As described above, since the flow path of a liquid flow path device according to the invention is formed basically by liquid leading out sections and liquid introducing sections, the stain problem can hardly take place and, if a problem arises, the ongoing operation of the device can be restored easily and quickly by replacing the transfer apparatus(es) where the problem takes place. Additionally, since any of the liquid transfer apparatuses of a liquid flow path device can be replaced during a series of reactions, it is possible to change the composition and/or the conditions of reaction of a reaction liquid. Furthermore, since the liquid leading out section of each liquid transfer apparatus is provided with a means for moving liquid as functional feature of producing an ink jet, it is easy to control the operation of the liquid transfer apparatus and downsize the device.
Now, the present invention will be described further by way of an example. Note that the dimensions, the profiles, the materials and the conditions of reaction are cited only for the sake of easy understanding in the description of the example and may be altered appropriately so long as the requirements of the invention are met.
Observation of Activity of Carnitine Palmitoyl Transferase in the Liver of a Rat
A part (about 3 g) of the liver of a rat that is cleaned with physiological saline is homogenized by means of a homogenizing buffer solution (3 mM tris-HCl (pH 7.2) containing 0.25M sucrose and 1 mM EDTA) and centrifuged by 500×g for 10 minutes (4° C.). The obtained supernatant is transferred to another centrifuge tube and centrifuged by 9,000×g for 10 minutes (4° C.) to obtain a specimen as supernatant. Note that “M” represents the concentration expressed by “mol/l”.
As solvent, a buffer solution (16 mM tris-HCl buffer, 2.5 mM EDTA, 0.2% Triton X-100 (tradename: available from Kishida Chemical Co., pH 8.0, 0.5 ml) was added to the specimen with 0.005 ml of a source of enzyme, to which water is added to make the final volume equal to 0.97 ml. The mixture is mixed well and 100 μl of the mixture is introduced into a liquid transfer apparatus 81 whose temperature is held to 30° C. Note that a liquid flow path device as shown in
As shown in
An operation is conducted in a controlled manner firstly by introducing 1 μl of liquid from the liquid transfer apparatus 82 and 5 μl of liquid from the liquid transfer apparatus 83 into the liquid transfer apparatus 81. Subsequently, the introduced liquids are held in the containing section of the liquid transfer apparatus 81 at 30° C. for 30 seconds and then 50 μl of liquid is introduced from each of the liquid transfer apparatuses 81 and 84 into the liquid transfer apparatus 85. The liquid in the liquid transfer apparatus 84 is held to 30° C. and the liquid in the liquid transfer apparatus 85 is ejected by 5 μl at a time at every 20 seconds and diluted by a buffer solution to observe the absorption of light of 500 nm.
With this device, it is possible to observe the change with time of the activity of carnitine palmitoyl transferase in the liver of a rat by using only a minute amount of liquid.
Number | Date | Country | Kind |
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NO. 2002-229244 | Aug 2002 | JP | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/JP03/09923 | 8/5/2003 | WO | 1/26/2005 |