JP2007093496A - Chemical micro laboratory system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a micro laboratory inspection system hardly affected by variation every device, change over time of the devices, and individual difference of a test body. <P>SOLUTION: The micro laboratory inspection system comprises a device having an electrode to which voltage is applied from the outside, an insulating film formed in an upper part of the electrode, and a structure that can store these in a transparent container and take a reagent and a test body sample from the outside, a means for optically observing a liquid drop in the device, a means for recognizing the shape and position of concerned liquid based on the image data, and a means for simulating the shape and position of at least the liquid drop. The micro laboratory system calculates an applied signal to the electrode based on the deviation between an optical observation result and a simulation result, and controls the liquid drop behavior. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a biochemical / immunological test apparatus, and more particularly, to a microlab system that can perform high-speed and high-accuracy tests with very few specimen samples using MEMS.

As a technique for taking out a very small amount of microliters or picoliters from a specimen sample and reacting with a test drug for biochemical / immunological tests, a device called a chemical microlab chip using MEMS has attracted attention. Among them, EWOD
The technology called (Electro-Wetting on Dielectric) is a chip that takes out minute droplets, transports them on the chip, reacts them with the test drug, and conducts a predetermined test. Because it is possible to perform an immunological test, it is attracting attention as a next-generation test technique.

As a chip (device) for driving droplets using an electrostatic force, for example, a configuration shown in FIG. 2 (Patent Document 1) of Japanese Patent Application Laid-Open No. 2004-935 is known. A similar description can be found in Japanese Patent Application Laid-Open No. 2004-22165 (Patent Document 2). In either case, electrodes spaced apart from each other are provided adjacent to each other, and the droplets are driven by electrostatic force through a dielectric layer surrounding the electrodes. In principle, by this operation, the reaction can be observed by removing the required amount of droplet sample from the specimen sample, reacting with the reagent extracted by the same principle, and observing the result by some method. Is possible.

JP 2004-935 A JP 2004-22165 A

  Phenomena that occur in devices utilizing EWOD are generally very sensitive to surface tension due to their extremely low liquidity. For this reason, the behavior of the liquid droplets is affected by the dielectric, the electrode, and the surface state of the inner surface of the container that cannot be completely controlled during the manufacturing process. As a result, variations among devices cannot be ignored, which is an important issue.

  Even in the same device, when the device changes with time, the behavior of the droplet changes, so that control cannot be performed with good reproducibility. Furthermore, in medical examinations, there are individual differences between specimens, and this is also one factor that prevents uniform control.

  If these points are to be improved, an extremely accurate device manufacturing process and surface treatment technology that does not cause changes over time are necessary, which ultimately leads to higher costs, and is inherently extremely inexpensive with a small sample. The result is a loss of the original characteristics of the microlab chip.

  Therefore, the problem of the present invention is to eliminate the point that the characteristic variation from device to device, the device characteristic variation with time, and the measurement variation due to the specimen difference, which are frequently encountered in conventional devices, are so large that they cannot be ignored. It is to provide a microlab system with no variation in results.

The first means for solving the above-mentioned problem is that an electrode to which voltage can be applied from the outside, an insulating film formed on the electrode, and further, these can be stored in a transparent container so that a reagent and a specimen sample can be taken from the outside. A structured device; a means for optically observing a droplet in the device; a means for recognizing the shape and position of a liquid of interest from the image data; and a means for simulating at least the shape and position of the droplet And an application signal to the electrode is calculated based on the deviation between the optical observation result and the simulation result, and the observation device (microlab system) for a small amount of liquid that controls the droplet behavior.

  The second means for solving the above-mentioned problem is that, in the first means, an algorithm for simulating the liquid surface pressure, wetting tension, and contact angle hysteresis at the contact surface is added to the means for simulating the shape and position of the liquid droplet. Incorporating it gives the function of calculating the deviation between shape and position in real time.

  A third means for solving the above problem uses an algorithm for calculating the surface tension by calculating the pressure from the six lattice points on the surface of the droplet when calculating the surface tension of the droplet in the second means. That is.

  The microlab system of the present invention is capable of high-accuracy inspection with a small number of sample samples with little variation in characteristics among devices, changes in device characteristics over time, and measurement variations due to sample differences.

  The feature of the present invention is that the deviation is calculated based on the information of the optical observation result and the simulation result, and the droplet behavior is controlled based on the deviation.

  FIG. 1 shows an example of the configuration of the device of the present invention. A device (microlab chip) is composed of the electrode 2 and the insulator 3 formed on the surface thereof in the transparent container 1. The electrode 2 is masked and formed by sputtering or a sol-gel method, and is made of a noble metal such as platinum or gold. The insulator 3 is formed of an insulator such as SiO or SiN by sputtering, sol-gel method or the like, and voltage is applied from a power source 7 having a voltage control unit via a lead wire 4.

  In the transparent container 1, the specimen 5 introduced into the container from the specimen introduction port 6 is conveyed by electrostatic force. An optical observation means 8 is disposed above the transparent container, whereby the observation unit 8 captures the behavior of the droplet as an image and converts it into a digital signal to send data to the control device 9.

  The control device 9 includes a recognition unit 10, a simulation unit 11, and a control unit 12. First, the shape and size of a droplet are determined by a recognition unit using a general digital image processing technique. Next, the current shape and position of the droplet are predicted based on the shape and position information of the droplet observed at the previous time (before Δt) and information on the applied voltage by the simulation unit 11. The control unit obtains a deviation between the information on the shape and position of the droplet sent from the recognition unit (image processing unit) and the information on the shape and position of the droplet predicted by the simulation unit.

  If the deviation is equal to or greater than a certain value, the control unit performs control such as increasing or decreasing the voltage application signal from the set value, repeats this process, and sets the basic voltage of the operation in a direction that falls within the certain deviation. Change. In actual usage, it is desirable to always perform this calculation and constantly calculate the deviation and adjust the applied voltage in real time.

  By performing such an operation, instead of the conventional uniform voltage control, the state of the droplet is always observed, and the correlation between the phenomenon of the droplet and the applied voltage value is corrected by a real-time simulation. It becomes possible to control. As a result, it is possible to achieve predetermined droplet behavior (shape and position control) even if there is an influence of device-to-device variation, device aging, and individual differences between specimens, enabling high-precision inspection. Become.

  Another embodiment of the present invention will be described below. The basic configuration is the same as in FIG. The simulation unit 11 uses the physical property value of the material constituting the device and the physical property value of the droplet as input parameters, and obtains the position and size of the droplet by simulation for each Δt.

  The feature of this embodiment is that, in the simulation, an algorithm for simulating droplet surface pressure, wetting tension, and contact angle hysteresis at the contact surface is incorporated to calculate the shape and position and calculate the deviation.

  As described above, in the microlab chip, since the droplets are extremely small droplets such as microliters and picoliters, surface tension and wetting tension dominate a considerable part of the droplet behavior. Then, variations among devices, changes with time of devices, and the like are caused by these differences and changes. Therefore, it is possible to feedback from the deviation between the actual measurement and the prediction for the first time by the simulation incorporating these.

  For example, if the current position is calculated based on the position x measured at a certain time t and a deviation from the actual measurement occurs, parameters such as surface tension and contact angle, which are simulation parameters, are changed. Select the data set that can reproduce the most. Using this, a voltage capable of realizing a predetermined displacement by inverse analysis is analyzed as an inverse problem, and the value is applied to the electrode as a control signal. Similar calculations are repeated to perform voltage control most suitable for the device being tested.

  In addition, as a practical method, a region for preliminarily operating the droplets is provided in the vicinity of the sample introduction part of the device, and the above operation is performed there, and then the reaction with the test drug is performed. This is effective in increasing accuracy.

  Also, if you know the relationship between the deviation and the incremental decrease of the voltage to be fed back to some extent, it is possible to prepare these as a data set and perform feedback control, enabling high-speed and highly accurate control It can converge at high speed.

  Even in this example, it is possible to realize a medical inspection apparatus that is not easily affected by variations from device to device, aging of devices, and individual differences between test specimens, and high-precision and high-speed inspection with a small number of test specimens with high reproducibility. realizable.

  Another embodiment of the present invention will be described. The basic configuration is the same as in FIG. 1, and a subroutine for calculating pressure from six lattice points as shown in FIG.

Here, a conventional method for calculating the surface pressure (arbitrary shape) will be described first. Conventionally, as shown in the left diagram of FIG. 3, the intermediate points are obtained by interpolating the pressures of the four lattice points. That is, when the area of the portion represented by the potential E (X, Y, Z) and the lattice point I of the point (x, y, z) is Si,
E (X, Y, Z) = νS
S = ΣSi
P = │-∇E│ / S / 2
Si: Pressure at i
ν: surface tension
P: Pressure In this case, it was impossible to reproduce in real time the droplet behavior inside the microlab chip where the pressure calculation error was large and the surface tension was dominant.

In the present embodiment, as shown on the right side of FIG. 3, a method of calculating the internal pressure from six points was adopted. in this case,
P = │-∇E│ / (S / 3)
The calculation error at the center of the six points is 0.01% or less. As a result, in order to obtain the same accuracy, the calculation can be performed at a speed 1000 times that of the conventional method, and the liquid droplets inside the microlab chip can be simulated in real time.

  According to the present invention, it is possible to realize a medical inspection apparatus that is not easily affected by variations among devices, aging of devices, and individual differences of test specimens, and can realize high-precision and high-speed inspection with a small number of specimens with high reproducibility. .

  The microlab test system of the present invention can be applied to a biochemical / immunological test system that enables a highly accurate test even with a small number of specimens.

1 is a basic configuration diagram of the present invention. Example 1 It is explanatory drawing of a prior art. The figure which shows the characteristic of the calculating part of this invention. (Example 3)

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Transparent container, 2 ... Electrode, 3 ... Insulator, 4 ... Lead wire, 5 ... Sample (test body and reagent), 6 ... Sample inlet, 7 ... Power supply, 8 ... Optical observation means (observation part), DESCRIPTION OF SYMBOLS 9 ... Control apparatus, 10 ... Recognition part, 11 ... Simulation part, 12 ... Control part.

Claims (3)

A device part having an electrode for applying a voltage from the outside, an insulating film provided in contact with the electrode, the electrode and the insulating film, and a container capable of storing a reagent and a test body therein, and the liquid test body An observation unit for observing the liquid specimen by an optical means, a recognition unit for recognizing the shape and position of the liquid specimen based on information obtained from the observation section, and a simulation section for simulating the shape and position of the liquid specimen Have
A microlab system comprising a control unit that controls voltage application to the electrode based on information obtained from the recognition unit and the simulation unit.   2. The microlab system according to claim 1, wherein the simulation unit has an algorithm that uses surface tension, wetting tension, and contact angle hysteresis on a contact surface of a specimen. 3. The microlab system according to claim 2, wherein the simulation unit has an algorithm for calculating the surface tension of the specimen from six lattice points on the specimen surface.

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