JP4573239B2 - Multi-probe having stimulus supply function and detection function of physical phenomenon or chemical phenomenon based thereon - Google Patents

Description

  The present invention relates to a multi-probe capable of obtaining information on a physical phenomenon or a chemical phenomenon, and more specifically, to a multi-probe having a stimulus supply function and a physical phenomenon or chemical phenomenon detection function based thereon.

  In recent years, in various fields including the medical field, there is a demand for understanding various physical or chemical phenomena such as component concentration, temperature, pressure, flow rate, potential, reaction rate in biological samples such as cells and blood. On the other hand, a method of detecting an abnormality of a living body based on a reaction to a specific artificial stimulus has been performed on a trial basis.

In recent years, there has been an increasing demand for measurement in a fine region, and therefore, a multi-probe type sensor in which a probe and a signal processing circuit are integrated has been proposed. Specifically, as shown in FIG. 5, a probe 2 made up of a large number of needle-like protrusions and a signal processing circuit 3 for processing an electric signal input from each probe 2 are formed on the semiconductor substrate 1. There are multiple probes. This sensor includes an NMOSFET for each probe 2 as a switch array of the signal processing circuit 3. Each probe 2 is a protrusion which is crystal-grown using the drain (high concentration diffusion layer) of the NMOSFET as a base. Here, by using the VLS (Vapor-Liquid-Solid) method for forming the protrusions, the probe forming method is simpler than the conventional method, and the probe diameter and the interval between adjacent probes are smaller. (For example, refer to Patent Document 1).
JP 2000-333921 A

  However, the conventional methods for detecting abnormalities in the living body have some problems because the means for applying the stimulus and the means for detecting the physical or chemical phenomenon caused thereby are different. Specifically, the following points are mainly mentioned.

  (1) It is very difficult to always keep the positional relationship between the means for applying stimuli and the detecting means constant. If the positional relationship is not constant, the positional relationship between the two must be corrected for the detected result. Therefore, an incidental apparatus and means are required, and the apparatus is complicated and complicated.

  (2) When the means for giving a stimulus and the detection means are operated separately, contact or interference between the two may occur, and maintenance of each means is necessary, which may lead to deterioration in detection accuracy.

  (3) Information on minute parts is also indispensable for grasping physical or chemical phenomena, and even when it is desired to obtain information on materials or the inside of cells, it is necessary to measure directly with conventional methods. It was difficult.

  Therefore, an object of the present invention is to provide a multi-probe capable of giving a specific stimulus to an object and grasping a physical phenomenon or a chemical phenomenon based on the stimulus. Another object of the present invention is to provide a multi-probe as a means for enabling the imaging of a physical phenomenon or chemical phenomenon by quantifying such a physical phenomenon or chemical phenomenon and having high measurement accuracy and excellent responsiveness.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the above object can be achieved by the multiprobe shown below, and have completed the present invention.

In order to achieve the above object, the present invention provides a multi-probe having a plurality of protrusions (probes) grown on a semiconductor substrate as a base, having a stimulus supply function, and a physical or chemical phenomenon detection function based thereon. As a part of the constituent elements, the probe having the stimulus supply function is provided with a power supply circuit, and the probe having the detection function is provided with an amplifier circuit and / or a signal processing circuit. It is characterized by being.

  That is, some of the probes that make up the multi-probe have a stimulus supply function, and the other part has a detection function, so that the mutual positional relationship can be fixed, and a highly reproducible physical phenomenon Alternatively, the chemical phenomenon can be grasped. In addition, a simple configuration that does not require position correction or other incidental means enables accurate quantification of physical or chemical phenomena. In addition to two-dimensional as well as three-dimensional multiprobes, 3D imaging of physical or chemical phenomena based on the stimulus of

  The present invention is the multi-probe described above, characterized in that at least one probe having the detection function is arranged in the vicinity of the probe having the stimulus supply function.

  The relationship between the stimulus supply function and the detection function in the present invention is to recognize the characteristics and properties of the target object by grasping the physical phenomenon or chemical phenomenon based on the stimulus supply as a starting point. Therefore, a probe having one or more detection functions (hereinafter referred to as “detection probe”) is necessarily arranged at a position close to a probe having one stimulus supply function (hereinafter referred to as “stimulation probe”). It is preferable that a physical phenomenon or chemical phenomenon with high selectivity can be grasped.

  The present invention is a multi-probe described above, wherein a plurality of probes having the detection function are arranged at a predetermined distance from the probe having the stimulus supply function.

  As described above, the present invention has an advantage that the mutual positional relationship between the stimulus supply function and the detection function can be fixed. Furthermore, when the stimulus probe is centered, a plurality of detection probes are arranged around the predetermined distance, so that a difference in physical phenomenon or chemical phenomenon in the object from the detection site or the stimulation site to the detection site can be reduced. It is possible to grasp clearly. This is a useful tool for finding the concentration distribution in the solution and detecting abnormalities in the cells.

  The present invention is the multi-probe described above, wherein the probe having the stimulus supply function and the probe having the detection function have the same configuration.

  Usually, a probe having different functions, i.e., a stimulus supply function and a detection function, needs to have a different structure in at least a part such as a different crystal growth process or a tip. However, when the probe is formed of, for example, an Au-Si alloy, it is possible to provide a stimulus supply function by applying a relatively high voltage to the tip in the same structure, while the tip is relatively low. By detecting a change in current while applying a voltage, the function as a potential measurement end can be exhibited.

  As described above, when the multi-probe according to the present invention is used in the case of recognizing the characteristics and properties of an object through grasping a physical phenomenon or a chemical phenomenon based on the stimulus supply, it is difficult in the past. It is possible to easily obtain information on physical phenomena or chemical phenomena with high reproducibility and continuity. In particular, it is possible to grasp a physical phenomenon or a chemical phenomenon having high measurement accuracy and excellent responsiveness by optimally arranging probes having different functions of a stimulus supply function and a detection function. Therefore, it is particularly useful in the field of solutions or living bodies.

Hereinafter, embodiments of the present invention will be described with reference to the drawings.
FIG. 1 illustrates a basic configuration of a multi-probe according to the present invention. An electronic circuit 3 connected to each probe 2 is formed on a semiconductor substrate (silicon substrate) 1 with a probe 2 composed of a large number of needle-like protrusions, a stimulation probe 2a being partly disposed and a detection probe 2b being disposed around the probe 2a. Is configured. A change in a physical phenomenon or a chemical phenomenon in an object caused by a stimulus applied from the stimulation probe 2a can be grasped by the detection probe 2b.

  At this time, the detection probe 2b has a specific detection function due to the characteristics of its constituent materials as in the case of a potential detection probe described later, or by applying a predetermined treatment to the surface or inside thereof, the tip portion 4 or the side surface portion. 5. It can have a specific function for physical or chemical phenomena. In addition, the stimulation probe 2a can also be subjected to predetermined processing on the surface or inside thereof when the probe itself is simply heated or a voltage is applied. Examples of the physical phenomenon or chemical phenomenon to be targeted include potential, concentration, density, flow rate, temperature, magnetism, light, pressure, chemical reaction, polymer polymerization degree, and the like.

  The height of the probes is preferably the same or several kinds of heights and is preferably arranged at a predetermined interval. By fixing the position of the probe, it is possible to grasp the stimulus from the stimulation probe 2a by the detection probe 2b with good reproducibility and to detect by the plurality of detection probes 2b corresponding to one stimulation probe 2a, It is possible to accurately grasp a subtle difference in the state of the peripheral part of the stimulated part. Of course, it is also possible to arrange them at equal intervals.

  Further, the probe 2 is not limited to the case where only the distal end portion 4 has a specific function, and the side surface portion 5 of the probe can have a similar function or a different function. By supplying the stimulus uniformly as a line rather than as a point, it is possible to track changes in two-dimensional or three-dimensional physical or chemical phenomena. Specifically, as illustrated in FIG. 2, the object is supplied with stimulation from the distal end portion 4a and the side surface portion 5a of the stimulation probe 2a, and the detection probe 2b can detect changes corresponding thereto, It is possible to grasp the physical or chemical characteristics of an object.

  As the shape of the probe 2, it is possible to select any shape suitable for the purpose, such as a cylindrical shape or a tapered shape in which the outer diameter of the distal end portion 4 is reduced. As for the method for producing the probe 2, not only the VLS method but also another liquid phase epitaxy method or a method of growing a crystal having a fine structure by using a gas phase epitaxy method or the like if the probe 2 has a low height. It is possible to apply.

  Further, by covering the portion other than the distal end portion 4 or the side surface portion 5 of the probe 2 having a specific function with an insulator or a protective film, the probe 2 can be prevented from being contaminated or deteriorated or affected by disturbances. Prevention can be performed.

  Among these, it is also preferable to improve the detection sensitivity by applying a predetermined process to the detection probe 2b. In particular, as in a specific example described later, by forming the sensing portion with the probe tip portion 4 as a very minimized portion, a multisensor having high measurement accuracy and excellent responsiveness can be provided.

  Various electronic circuits 3 can be formed on the semiconductor substrate 1. For example, the stimulation probe 2 a has a power supply circuit, and the detection probe 2 b has at least one amplification circuit and / or signal processing. A circuit is preferably formed. By converting the minute output from each probe into a pre-stabilized signal, and transmitting and outputting the signal, it is possible to obtain an output with high accuracy and stability with little disturbance influence. In particular, the formation of an impedance conversion circuit using an amplifier circuit (op-amp) is a condition in which various disturbances are likely to occur because the object varies physically or chemically, such as solution measurement and intracellular measurement. In that case, it is very effective. In addition, the formation of the signal processing circuit can increase not only the stable output but also the independence of the multi-sensor, and the versatility of the configuration of the measuring apparatus such as wireless transmission.

  In the formation of the probe 2, the base on which the protrusion is crystal-grown may be a high-concentration diffusion layer of an element constituting the signal processing circuit of the sensor. In addition to the NMOSFET portion, the source or drain of PMOSFET or CMOSFET, Bi -Emitter or collector of CMOS or bipolar transistor, n + layer or p + layer of diode, etc. It can also be formed in the gate circuit portion of the MOS transistor.

  Further, as described above, the tip of each projection of the multi-probe has an alloy part made of an Au—Si alloy, so that it contacts or is supported by Si, which is coated with or supported by Au, Pt, Ir, or the like. Resistance can be lowered. Therefore, the conductivity of the probe itself can be increased and used as a conductive probe. Further, subsequent impurity diffusion can also be used depending on the purpose.

  In general, a probe having a different function needs to have a different structure in at least a part such as a different crystal growth process or a tip, but the probes 2a and 2b are formed of, for example, an Au-Si alloy as in the present invention. In this case, it is possible to obtain a probe having both functions by using a probe having the same structure formed by the same manufacturing process. That is, even if the probe 2 itself is a probe having different functions of a stimulus supply function and a detection function, the basic configuration of the multi-probe as a means for imaging a physical phenomenon or a chemical phenomenon can be made common. . Specifically, it is possible to provide a stimulus supply function by applying a relatively high voltage to the tip, while detecting a change in current while applying a relatively low voltage to the tip. The function as a measurement end can be exhibited.

  FIG. 3 illustrates the overall configuration of a multi-probe formed from such stimulation probes and detection probes. The stimulation probe 2a applies a predetermined voltage from the power supply unit 11a to the tip (stimulation supply unit) 4a to give a stimulus, and the detection probe 2b applies a predetermined voltage from the power supply unit 11b to the tip (sensing unit) 4b. The change in potential of each sensing unit 4b at that time is taken out by the detection means 12 as a change in current value, and the physical or chemical change of the object relative to the stimulus can be grasped.

  Specifically, various application examples can be given. In one embodiment, voltage application to nerve cells may be used as a stimulating material. When the stimulation probe 2a and the detection probe 2b are inserted into the cell tissue and a voltage is applied to the stimulation probe 2a in contact with the cell, not only the cell but also surrounding cells may change depending on the stimulation. is there. Since the change appears as a change in cell potential, the change in potential can be detected by the detection probe 2b that is separated from the stimulation probe 2a by a predetermined distance and is in contact with the cell and the surrounding cells.

  Moreover, as another embodiment of the multi-probe according to the present invention, a case where the multi-probe is used for evaluation of retinal cells is illustrated in FIG. As shown in FIG. 4A, retinal cells have several types of cells having a multilayer structure. Each cell has a different function, and when measuring its function, it is necessary to install a detection probe accurately at the location of each cell. In addition, when a stimulus is supplied from the outside, it is very important which layer the stimulus is applied to, and an accurate probe setting is required. The multi-probe of the present invention satisfies these requirements and can freely change the position and length of the probe 2 as necessary.

  FIG. 4B illustrates a state in which a multi-probe is inserted into a cell. By applying a light stimulus to the cell from the tip portion 4a of the stimulation probe 2a that forms the light guide path, and detecting a change in potential at the contact surface with the cell by the detection probe 2b, the function of the retinal cell is detected. Normality can be determined. In addition, a plurality of stimulation probes 2a can be installed as shown in FIG. 4B, and it is possible to easily measure the behavior of cells when stimulating different places in the same layer. . Of course, it is also possible to use a three-dimensional multi-probe in which stimulation probes 2a and detection probes 2b having different heights are combined.

  The distance between the cell layers at this time is about several μm, and the distance between the stimulation probe 2a and the detection probe 2b is preferably within that range. As a method for producing a multi-probe applicable to such a purpose, a method suitable for producing a probe in a fine region, such as the above-described VLS method, is preferable.

  In the above description, the embodiment of the multi-probe in which the stimulation probe 2a and the detection probe 2b are integrated is illustrated. However, the present invention is not limited to this, and the stimulation probe 2a and the detection probe 2b are separated from each other. A method is also possible in which a sample cell is stimulated from above or below while being clamped from both ends of the cell, and the change in potential is taken out by the detection probe 2b.

  As described above, by using the multi-probe according to the present invention and applying a stimulus suitable for the property of the object, it can be easily detected as a physical phenomenon or a chemical phenomenon. In addition, a physical or chemical phenomenon can be quantified by providing a plurality of stimulation probes, and a two-dimensional or three-dimensional measurement image can be obtained.

As described above, the present invention can be suitably used for measurement of cell function and the like as described above, and can also be applied to the following fields.
(1) Application field as chemical microscope: ion concentration measurement / electrochemical field, gas distribution measurement field / two-dimensional dynamic observation and analysis of titration (2) environmental measurement / environment; application to bioremediation (3) Food inspection / food, microorganisms (4) ME field / medicine / ecological tissue; tissue cell surface and internal ion concentration measurement, cell surface and internal optical / potential measurement, DNA measurement (5) bio field (6) animal and plant field / Plant; callus surface and internal potential distribution measurement, organism, front view animal (7) Corrosion measurement field, metal; metal corrosion and coating, coating (8) surface analysis such as zeta potential, zeta potential of powder and ceramics.

  The object (sample) may be any of gas, liquid, solid, and powder. By detecting various physical or chemical phenomena caused by stimulation, the functional characteristics of the object can be grasped. Useful for.

Explanatory drawing which shows the basic structure of the multi probe which concerns on this invention. Explanatory drawing which shows the detail of the multiprobe based on this invention roughly. Explanatory drawing which shows the whole structure of the multi sensor which concerns on this invention. Explanatory drawing which illustrates the embodiment of the multiprobe which concerns on this invention. Explanatory drawing of the conventional multi-probe sensor.

Explanation of symbols

1 Semiconductor substrate (silicon substrate)
2 Probe 2a Stimulation probe 2b Detection probe 3 Signal processing circuit 4 Tip 4a Stimulation supply unit 4b Sensing unit

Claims (4)

A multi-probe having a plurality of protrusions (probes) grown on a semiconductor substrate as a base,
A probe having a stimulus supply function and a probe having a function of detecting a physical phenomenon or a chemical phenomenon based on the probe as part of the constituent elements ,
A power supply circuit is formed in the probe having the stimulus supply function,
An amplifying circuit and / or a signal processing circuit is formed in the probe having the detection function .   2. The multi-probe according to claim 1, wherein at least one probe having the detection function is arranged in a proximity position of the probe having the stimulus supply function.   The multi-probe according to claim 1 or 2, wherein a plurality of probes having the detection function are arranged at a predetermined distance from the probe having the stimulus supply function.   The multi-probe according to claim 1, wherein the probe having the stimulus supply function and the probe having the detection function have the same configuration.

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