JP2009288009A - Fluid discrimination device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a fluid discriminating device suitably detecting a change of type of fluid. <P>SOLUTION: In a micro channel, a plurality of types of fluid is made to pass at a controlled flow velocity, and the type of flowing fluid in the micro channel is discriminated based on the temperature change detected by a resistance 40 which heats each fluid interposed in the micro channel. For example, when the flowing fluid changes from the fluid with comparatively small heat conductivity to the fluid with comparatively large heat conductivity, the temperature of the resistance 50 with a large resistance value and small heat generation quantity is not changed while the temperature of the resistance 40 with a small resistance value and large heat generation quantity is lowered because of larger heat removal. Therefore, since the resistance value of the resistance 40 decreases, the balance of a bridge circuit collapses. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a technique for discriminating the type of fluid.

  In recent years, by making full use of micromachine technology and ultra-fine processing technology, conventional equipment or means for performing sample preparation, chemical analysis, chemical synthesis, etc. (for example, pumps, valves, flow paths, sensors, etc.) have been miniaturized. Systems that are integrated on a single chip have been developed.

  This is also called μ-TAS (MICRO Total Analysis System), bioreactor, lab-on-chip, or biochip, and is in the medical examination / diagnosis field, environmental measurement field The application is expected in the field of agricultural production. In reality, as seen in genetic testing, when complex processes, skilled procedures, or instrument operations are required, automated, accelerated and simplified micro-analytical systems are cost-effective, It can be said that not only the required sample amount and the required time but also the benefits of enabling the analysis regardless of time and place are great. Below, the case where a genetic test system is constructed on a chip will be described as an example.

  In order to perform a genetic test, a process called pretreatment is required, in which DNA is extracted from cells in the blood. First, blood is mixed with a cell disruption solution to destroy cells in the blood. Next, this mixed solution is caused to flow through a microchannel packed with glass beads to adsorb DNA onto the glass beads. Next, the glass beads are washed by flowing a washing solution through the microchannel, and the mixed solution is selectively removed. Next, DNA is dissolved in water from the glass beads by flowing water through the microchannel. By extracting DNA from this water, it is possible to selectively extract DNA from a mixture of blood and cell disruption liquid.

  That is, in order to perform the pretreatment on the chip, a channel filled with glass beads is provided on the chip, and the mixed solution, the washing solution, and water are passed through the channel in this order (DNA was eluted). It is necessary to selectively remove water.

  In order to selectively extract water, there is a method of detecting the boundary between fluids by photographing the fluid with a CCD, or flowing each liquid at a sufficient interval. However, such a method has a problem that the apparatus becomes large and takes a long time.

  In order to solve such a problem, in Patent Document 1, a thermopile (temperature sensor) is disposed in a direction (two locations) substantially orthogonal to the direction of fluid flow with respect to the heater, and the temperature change of the temperature sensor is measured. A fluid discrimination device that detects that the type of fluid has changed by detection is disclosed.

JP 2001-12988 A

  In the fluid discrimination device disclosed in Patent Document 1, since the heater and the temperature sensor are arranged apart from each other, there is a time lag in detecting a change in the type of fluid, or depending on the state of the boundary between fluids and the accuracy of parts. The detection accuracy of changes in the type of fluid may decrease. That is, there has been a problem that a change in the type of fluid cannot be detected properly.

  The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a fluid discrimination device that can appropriately detect a change in the type of fluid.

  In order to solve the above-described problem, a fluid discrimination device according to the invention described in claim 1 controls a plurality of types of fluids in one channel that sequentially flows a plurality of types of fluid, and the one channel. Fluid driving means for passing at a flow rate, and one heating detecting means for detecting a temperature change while heating each fluid, and detected by the heating detecting means. Discriminating means for discriminating the type of fluid flowing in the one flow path based on a temperature change.

  A fluid discrimination device according to a second aspect of the present invention is the fluid discrimination device according to the first aspect, wherein the heating detection means is composed of a first resistor, and the discrimination means is the first discrimination device. A second resistor having a resistance value greater than that of the first resistor and connected in parallel to the first resistor, the amount of heat generated in the first resistor, and the second resistor Based on the difference from the calorific value, the type of the fluid flowing in the one flow path is determined.

  The fluid discrimination device according to claim 3 is the fluid discrimination device according to claim 1 or 2, wherein the plurality of types of fluid crush blood and cells in the blood. A cell disruption solution, a washing solution for washing a mixed solution of the blood and the cell disruption solution, and water, wherein the one channel has a DNA obtained by disrupting cells in the blood with the cell disruption solution. It includes a microchannel packed with adsorbing glass beads.

  A fluid discrimination device according to a fourth aspect of the invention is the fluid discrimination device according to any one of the first to third aspects, wherein the plurality of types of fluid discrimination devices according to a discrimination result by the discrimination means. Separation means for separating a predetermined type of the fluid and a fluid having a different type from the predetermined type of fluid into different paths and flowing out.

  Since the fluid discrimination device according to the present invention detects a temperature change while heating each fluid by using one heating detection unit, the fluid discrimination device can be compared with the case where the heating unit and the detection unit are arranged apart from each other. It is possible to prevent a time lag from occurring in the detection of the type change, and the detection accuracy of the change in the type of fluid from being lowered due to the state of the boundary between the fluids and the accuracy of the parts. Can be detected.

<Embodiment 1>
FIG. 1 is a schematic diagram showing a pretreatment process for extracting DNA from cells in blood in a genetic test system including a fluid discrimination device according to Embodiment 1.

  As shown in FIG. 1, water, cell lysate, blood, and washing solution are respectively flowed by a fluid drive means (for example, a pump) 21 while the flow rate is controlled, and enter a cell lysis area 10 that is composed of a microchannel. Poured and mixed. The cell lysis area 10 is filled with glass beads having a diameter of 20 to 50 μm at the end portion thereof.

  In FIG. 1, first, blood is mixed with a cell disruption solution to destroy cells in the blood. Next, the mixed solution is allowed to flow through the cell lysis area 10 to adsorb (trap) DNA on the glass beads. Next, the glass beads are washed by flowing a washing solution to the cell lysis area 10 to selectively remove the mixed solution. Next, DNA is dissolved in water from the glass beads by flowing water through the cell lysis area 10. By extracting DNA from this water, it is possible to selectively extract DNA from a mixture of blood and cell disruption liquid.

  Specifically, a sensor 20 capable of detecting boundaries (interfaces) between a plurality of types of fluids is inserted into the microchannel, and the mixed liquid, the cleaning liquid, and the water that sequentially flow from the cell lysis area 10 Determine the boundary. Then, the switch 22 switches the flow path in synchronization with the determination result of the sensor 20, thereby causing the mixed liquid and the cleaning liquid to flow out to the flow path through which unnecessary liquid flows and water to the flow path through which necessary liquid flows. By selectively flowing out, the mixed liquid and the cleaning liquid are separated from the water.

  FIG. 2 is a schematic diagram showing the operation principle of the sensor 20 of FIG. Unlike the fluid discriminating apparatus according to Patent Document 1, the sensor 20 includes a heating unit (heater) that heats a fluid and a detection unit that detects a temperature rise due to heating by the same resistor 40. It is characterized by that. Since FIG. 2 is a schematic diagram, components other than those necessary for understanding the invention are omitted.

  In the sensor 20 of FIG. 2, one terminal of the resistor 40 serving as both a heating unit and a detection unit and one terminal of the temperature compensating resistor 50 are electrically connected at a contact point N1.

  The other terminal of the resistor 40 is electrically connected to one terminal of the semi-fixed resistor 41 at the contact N2. The other terminal of the semi-fixed resistor 41 is electrically connected to one terminal of the fixed resistor 42 at the contact N4. The other terminal of the fixed resistor 42 is grounded at the contact N6.

  The other terminal of the resistor 50 is electrically connected to one terminal of the semi-fixed resistor 51 at the contact N3. The other terminal of the semi-fixed resistor 51 is electrically connected to one terminal of the fixed resistor 52 at the contact N5. The other terminal of the fixed resistor 52 is grounded at the contact N6.

  The other terminal of the resistor 40 is connected to the negative input terminal of the operational amplifier op at the contact N2. The other terminal of the resistor 50 is connected to the positive input terminal of the operational amplifier op at the contact N3. The output terminal of the operational amplifier op is electrically connected to one terminal of the resistor 40 and one terminal of the resistor 50 at the contact N1 via the amplifier means amp. Thereby, a bridge circuit is configured. The voltage VO output from the operational amplifier op is not only fed back to the resistors 40 and 50 but also used for discrimination of the type of fluid by the fluid discrimination circuit 60 in the sensor 20. The fluid discrimination circuit 60 discriminates the boundary of the fluid based on the input voltage VO, and switches the switch 22 according to the control signal.

  The resistor 40, the semi-fixed resistor 41, and the fixed resistor 42 all have a resistance value on the order of several hundred ohms, and constitute a low resistance system. The resistor 50, the semi-fixed resistor 51, and the fixed resistor 52 all have a resistance value on the order of several kΩ and constitute a high resistance system.

  In the circuit of FIG. 2, only the resistors 40 and 50 are in thermal contact with the fluid (exchanges heat with the fluid). When the resistor is in thermal contact with a fluid having a temperature lower than its own temperature, the heat is deprived in accordance with the physical property value (thermal conductivity, etc.) inherent to the fluid and the flow velocity of the fluid, and the temperature decreases. It will be. However, since the resistor 50 has an extremely high resistance value compared to the resistor 40, current does not flow so much, and therefore the amount of heat generated is small. In the following, when the resistors 40 and 50 are in thermal contact with the fluid A having a relatively low thermal conductivity and are in an equilibrium state, the flowing fluid changes to a fluid B having a relatively high thermal conductivity. An example will be described. Note that fluids A and B have the same temperature.

  When the fluid A is in thermal contact with the fluid A and is in an equilibrium state, the resistor 50 having a small calorific value maintains the same temperature as that of the fluid A, and the resistor 40 having a large calorific value maintains a temperature higher than that of the fluid A. While the fluid A is being heated. That is, the resistors 40 and 50 maintain an equilibrium state with a constant temperature difference, and the potential difference between the potential input to the negative input terminal of the operational amplifier op and the potential input to the positive input terminal of the operational amplifier op is zero. .

  Next, when the flowing fluid changes to the fluid B having a relatively high thermal conductivity, the temperature of the resistor 50 does not change, but the resistor 40 having a large calorific value is deprived of heat, so the temperature decreases. To do. Therefore, since the resistance value of the resistor 40 is lowered, the balance of the bridge circuit is lost. Specifically, since the voltage dividing ratio of the resistor 40 is low in the low resistance system voltage division composed of the resistor 40, the semi-fixed resistor 41, and the fixed resistor 42, it is input to the negative input terminal of the operational amplifier op. The potential increases. On the other hand, since the resistance value of the resistor 50 does not change, the potential input to the positive input terminal of the operational amplifier op does not change.

  As a result, the voltage VO output from the operational amplifier op increases, and the voltage fed back from the amplifying unit amp also increases. Accordingly, the potential input to the positive input terminal of the operational amplifier op also increases, and the potential difference between the potential input to the negative input terminal of the operational amplifier op and the potential input to the positive input terminal of the operational amplifier op decreases. That is, by repeating such a feedback operation, the balance of the bridge circuit is restored (in other words, the potential difference between the potential input to the negative input terminal of the operational amplifier op and the potential input to the positive input terminal of the operational amplifier op). (Returns to equilibrium by decreasing to 0).

  However, as described above, in the equilibrium state related to the fluid B, compared to the equilibrium state related to the fluid A, in the partial resistance of the low resistance system including the resistor 40, the semi-fixed resistor 41, and the fixed resistor 42, Since the voltage dividing ratio of the resistor 40 is low, the voltage VO is stabilized in a higher state. That is, the change from the fluid A to the fluid B can be detected by detecting the change in the voltage VO.

  FIG. 3 is a perspective view schematically showing the configuration of the sensor 20 of FIG. As shown in FIG. 3, the sensor 20 includes a substrate 31 provided with a groove-shaped microchannel 33, resistors 40 and 50, and a sheet-like member 32. The substrate 31 is made of resin, and the microchannel 33 has a width of several hundred μm to several mm and a depth of several hundred μm.

  The sheet-like member 32 is made of, for example, resin, and the resistors 40 and 50 are formed on the sheet-like member 32. The resistors 40 and 50 are made of platinum or thermistor.

  4 is a peripheral view of FIG. 3, and FIG. 5 is a cross-sectional view of FIG. As shown in FIGS. 4 to 5, fluids A and B are caused to flow through the micro flow path 33 while being controlled at a predetermined flow rate by the fluid driving means 21, and flow into the micro flow path 33 to be mixed. ing.

  In FIG. 5, when the fluid A flowing directly under the resistor 40 is changed to the fluid B, the flow velocity (and temperature) is constant between the fluid A and the fluid B, and therefore the physical property values of the fluid A and the fluid B ( Since the temperature of the resistor 40 changes only according to the difference in thermal conductivity), the voltage VO output from the operational amplifier op changes. Therefore, as shown in FIG. 6, by detecting the change in the voltage VO output from the operational amplifier op with the fluid discrimination circuit 60, it is possible to detect the change of the physical property value of the fluid, that is, the boundary between the fluids. Become.

  As described above, the fluid discrimination device according to the present embodiment uses the resistor 40 as one heating detection unit to detect a temperature change while heating each fluid. Therefore, a time lag occurs in the detection of a change in the type of fluid, the state of the boundary between fluids, and parts compared to Patent Document 1 where the heater as the heating means and the temperature sensor as the detection means are arranged apart from each other. Since it is possible to prevent the detection accuracy of the change of the fluid type from being lowered due to the accuracy of the above, it is possible to appropriately detect the change of the fluid type.

  In the above description, the case where the voltage VO is constant, that is, the flow velocity is constant in each fluid has been described with reference to FIG. However, the present invention is not limited to this, and in each fluid, the flow velocity may change as long as it is within a very small range compared to the change in the physical property value. That is, as shown in FIGS. 7 to 8, even if the flow rate changes, if it is within a very small range compared to the change in the physical property value, the threshold value for detecting the change in the voltage VO is appropriately set. It becomes possible to appropriately determine the boundary between fluids.

It is a schematic diagram which shows the pre-processing process which extracts DNA from the cell in the blood in a genetic test | inspection system provided with the fluid discrimination | determination apparatus which concerns on Embodiment 1. FIG. FIG. 4 is a schematic diagram illustrating the operation principle of the sensor of the fluid discrimination device according to Embodiment 1. 2 is a perspective view schematically showing a configuration of a sensor of the fluid discrimination device according to Embodiment 1. FIG. 2 is a perspective view schematically showing a configuration of a sensor of the fluid discrimination device according to Embodiment 1. FIG. FIG. 3 is a cross-sectional view schematically showing a configuration of a sensor of the fluid discrimination device according to Embodiment 1. 6 is a graph showing a change in voltage in the fluid discrimination device according to Embodiment 1. 6 is a graph showing a change in voltage in the fluid discrimination device according to Embodiment 1. 6 is a graph showing a change in voltage in the fluid discrimination device according to Embodiment 1.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Cell lysis area 20 Sensor 21 Fluid drive means 22 Switch 31 Board | substrate 32 Sheet-like member 33 Micro flow path 40 Resistor 41 Semi-fixed resistor 42 Fixed resistor 50 Resistor 51 Semi-fixed resistor 52 Fixed resistor 60 Fluid discrimination circuit A, B, C fluid N1-N6 contact VO voltage amp amplification means op operational amplifier

Claims (4)

One flow path for flowing multiple types of fluids sequentially,
Fluid driving means for passing a plurality of types of fluids at a controlled flow rate in the one flow path;
Including one heating detection means that is inserted in the one flow path and detects a temperature change while heating each fluid, and based on the temperature change detected by the heating detection means, in the one flow path A discriminating means for discriminating the type of flowing fluid;
A fluid discrimination device. The fluid discrimination device according to claim 1,
The heating detection means comprises a first resistor,
The discrimination means further includes a second resistor having a resistance value larger than that of the first resistor and connected in parallel to the first resistor, and a heating value in the first resistor A fluid discrimination device that discriminates the type of the fluid flowing in the one flow path based on a difference from a calorific value in the second resistor. The fluid discrimination device according to claim 1 or 2,
The plurality of types of fluids include blood, a cell crushing solution for crushing cells in the blood, a washing solution for washing a mixed solution of the blood and the cell crushing solution, and water,
The fluid discrimination apparatus, wherein the one channel includes a micro channel packed with glass beads that adsorb DNA obtained by crushing cells in the blood with the cell disruption solution. The fluid discrimination device according to any one of claims 1 to 3,
According to a determination result by the determination unit, a separation unit that separates a predetermined type of the plurality of types of fluid and a fluid different in type from the predetermined type of fluid into different paths,
A fluid discrimination device further comprising:

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