JP2012115179A - Microinjection actuator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a microinjection apparatus in which introducing of an introducing substance to transductants, such as a cell can be carried out certainly and efficiently by two or more injection needles, and improvement in treatment efficiency is possible, and which can eliminate displacement in a tip of an injection needle affected by assembly accuracy.SOLUTION: A conveyer 4 for moving an injection needle 11 has two degrees of freedom which make a first moving body 41 and a second moving body 42 to freely advance and retreat in directions which intersect perpendicularly and mutually at least. A first and a second advance and retreat driving units 45 and 46 which make the first and the second moving bodies 41 and 42 move respectively are installed at a base 40. A first sensor S1 which detects relative displacement of the base 40 and the first moving body 41, and a second sensor S2 which detects relative displacement of the first moving body 41 and the second moving body 42 are formed. Signals of these sensors S1 and S2 are used, and a conveyance controller 80 controls the first and the second advance and retreat driving units 45 and 46. A correction means 88a which corrects controlling of the conveyance controller 80 is prepared.

Description

  The present invention relates to a microinjection apparatus that introduces a substance to be introduced, such as a gene cell factor, into a body to be introduced such as a cell with a minute injection needle under a microscope.

  Typical methods for introducing substances into cells include electroporation (electrical), lipofection (chemical), vector method (biological), microinjection method (mechanical), and laser injection (optical). . In the electrical method, the cell membrane is broken by a large current, so that the cell is greatly damaged. The chemical method is limited in the genes that can be introduced, and the introduction efficiency is low. Biological methods have limitations such as the limitation of the types of genes that can be introduced and safety issues. The microinjection method has an advantage that a substance can be reliably injected into a cell by controlling the injection position with high accuracy. Patent Document 1 describes a method of performing microinjection using a capillary (microneedle).

  Although the above-mentioned method is mentioned as a method for introducing a gene into a cell, there is still no technology having both certainty and efficiency. The microinjection method in which a gene is introduced into each cell is the most reliable method, but the operation requires skill and time, so that the throughput is low. As a method for increasing the throughput of the microinjection method, for example, as in the method described in Patent Document 2, a microcapillary array in which a large number of injection needles are regularly arranged has been developed, and a chamber is provided at a position corresponding to this. There is an example of trying batch injection using a microchamber array.

  FIG. 20 shows a conventional example of an apparatus to which the microinjection method is applied. In this microinjection apparatus, a petri dish 90 containing cells to be introduced is gripped by a container mounting table 91, a local planar image inside the petri dish 90 is captured by an imaging unit 92, and the planar image is image processing unit 93. The position information of the cells is obtained by processing in step (1). The container mounting table 91 is moved by a horizontal biaxial direction container position adjusting means composed of an XY stage device by 94, thereby positioning the cells so that the cells are positioned in the insertion direction of the injection needle 95. Next, the manipulator holding the injection needle 95 is moved in the insertion direction of the injection needle 95 by the conveying means 97 having the Z stage device 96. In this way, the injection needle 95 is pierced into the positioned cell, and the introduction substance filled in the injection needle 95 is introduced into the cell. These series of operations are automatically performed under the control of the control device 98. An ultrasonic motor or a ball screw is used for the conveying means 97.

Japanese Patent No. 2624719 Japanese Patent No. 3035608

  Since the shape, size, and elastic force of the cells are different, the microcapillary array system such as Patent Document 2 that collectively controls the position of the injection needle with respect to the cells does not pierce many cells, or many The result is that the cells are destroyed. In addition, since the method using the microcapillary array requires cells to be arranged at the same position as the microcapillary array, it can only handle floating cells that can move in the culture solution, and can be used for cells attached to the bottom of the medium or petri dish. Can not be used.

  In order to increase the throughput of the microinjection method, the injection speed of the injected substance and the positioning speed of the manipulator are improved. Currently, there is one that achieves a single cell injection process in less than 1 second. However, the requirements for medical use are not limited to the type of substance to be introduced, high introduction efficiency, and the ability to supply a large amount of substance-introduced cells. It cannot be satisfied.

  Even if it is desired to use a plurality of injection needles, there is a problem in that a plurality of manipulators cannot be arranged because the size of a manipulator equipped with injection needles is large at present. In the current microinjection device, the cell stage is moved by moving the petri dish stage, and the manipulator equipped with the injection needle moves only in the direction to puncture the injection needle. Could not be done at the same time.

  For example, in the current microinjection apparatus shown in FIG. 20, a manipulator equipped with an injection needle 95 by moving a container mounting table 91 that supports a petri dish 90 containing cells by a container position adjusting means 94 in order to position cells. Is moved only in the direction in which the injection needle 96 is inserted into the cell, it was impossible to position a plurality of cells and insert the injection needle 95 into each cell simultaneously.

  When the injection needle 95 moves in two degrees of freedom in the X-axis direction and the Y-axis direction in which the injection needle 95 is orthogonal, for example, the Y-axis movement mechanism is stacked on the X-axis movement mechanism. It was. Therefore, since the X-axis moving mechanism drives both the injection needle 95 and the Y-axis moving mechanism, high-speed movement is difficult.

  Therefore, the present applicant tried to drive a plurality of manipulators in parallel at high speed by taking the following measures in the above-described method for increasing the throughput of the microinjection method. In other words, the plurality of transfer means for moving the plurality of injection needles individually so as to be movable are assumed to have at least two degrees of freedom, and the first moving body is installed to be movable in the linear direction with respect to the base. The second moving body is installed on the first moving body so as to be able to advance and retreat in a direction orthogonal to the linear direction, and the manipulator holding the injection needle is supported by the second moving body. The first advancing / retreating drive means for advancing / retreating the first moving body and the second advancing / retreating driving means for advancing / retreating the second moving body are both installed on the base, and a guide portion for guiding the moving body, advancing / retreating driving means, etc. To separate the power part. As a result, the tip of the injection needle can be positioned by the manipulator alone. Further, the transport means can be reduced in size and the mass of each moving body can be reduced, and each manipulator can be driven at high speed.

  However, in the above configuration, since the second moving body is installed on the first moving body, the operation of one moving body interferes with the other moving body due to the influence of assembly accuracy, and the injection needle This causes a large position difference at the position. For example, when the first moving body is moved by driving the first advance / retreat driving means, the second moving body installed in the first moving body is not driven even if the second advance / retreat driving means is not driven. May be displaced. Even if this displacement is slight, it is a large displacement at the tip of the injection needle.

  There is also a method of controlling the tip position of the injection needle by measuring with a CCD camera, but this method requires time to calculate the tip position of the injection needle from the image and cannot be performed every time due to the problem of the injection processing speed. . Even when a laser displacement meter is used, it is difficult to accurately detect the tip position of the moving injection needle. Another problem is that the laser displacement meter is expensive.

  An object of the present invention is that introduction of a substance to be introduced, such as a cell, can be efficiently and reliably performed with a plurality of injection needles, processing efficiency can be improved, and the assembly accuracy is affected. An object of the present invention is to provide a microinjection device that can eliminate displacement at the tip of an injection needle.

  The microinjection apparatus of the present invention is an apparatus for introducing an introduced substance into an introduced body by inserting an injection needle filled with the introduced substance into the introduced body, and a container containing the introduced body A container position adjusting means for adjusting the position of the container, a plurality of conveying means for individually moving a plurality of injection needles with respect to the introduction body inside the container whose position is adjusted by the container position adjusting means, and the container position An imaging unit that images the inside of the container whose position has been adjusted by the adjusting unit through a magnifying lens, a position determination unit that determines the position of the introducer from the image obtained by the imaging unit, and the position determination unit Transport control means for causing each of the transport means to move the injection needle according to the obtained position information, and the transport means includes at least a first moving body and a second moving body. It has two degrees of freedom to be able to advance and retreat in directions orthogonal to each other. The injection needle is supported by a second moving body, and the first moving body is linearly connected to the base via the first guide. The second movable body is installed on the first movable body via a second guide so as to be movable back and forth in a direction perpendicular to the linear direction. The first movable body and the first movable body The first advancing / retreating driving means and the second advancing / retreating driving means for advancing and retreating each of the two moving bodies are installed on the base, and an output member of the second advancing / retreating driving means moves forward and backward with respect to the second moving body. A first sensor that is connected to or in contact with a direction orthogonal to a possible direction to detect relative displacement between the base and the first moving body, and the first moving body And a second sensor for detecting relative displacement between the second moving body and the transport control. The means controls the first and second advancing / retreating means from the position information of the introduced body obtained by the position determining means and at least the signals of the first and second sensors, When the first moving body moves, the control of the transport control means is corrected so that the displacement generated in the direction perpendicular to the moving direction of the first moving body becomes small at the tip of the injection needle. A correction means is provided.

  According to this configuration, the conveying means separates the moving body and the advancing / retreating driving means, and the advancing / retreating driving means for each degree of freedom are installed on the base, so that the conveying means can be reduced in size and the mass of the moving object is reduced. As a result, the conveying means can be driven at high speed. Although the advancing / retreating driving means for each degree of freedom are all installed on the base, the second advancing / retreating driving means of the second moving body installed on the base via the first moving body is provided. The output member is movably connected to or in contact with the direction orthogonal to the advancing / retreating direction, so that the advancing / retreating drive of the second advancing / retreating drive unit is performed regardless of the position of the first moving body Can be transmitted to the second moving body.

  In addition, since the conveying means can be reduced in size, a plurality of conveying means can be arranged around a container such as a petri dish containing an introduced body such as a cell. Therefore, the positioning of the tip of the injection needle can be performed simultaneously with respect to a plurality of introduced bodies, and injection processing to a large number of introduced bodies can be executed at a time, thereby enabling high throughput.

  When introducing the introduced body, the position of the container containing the introduced body is adjusted by the container position adjusting means, a planar view image inside the position-adjusted container is taken by the imaging means, and the cell position is determined from the image. By determining the position by the position determining means, an introduced body such as a cell in charge of each injection needle is determined. At this time, the position of the introduced body can be recognized with high accuracy by locally enlarging the container with the magnifying lens and performing image processing on the position of the introduced body such as cells. In addition, for example, from the positional relationship in the image of the introducer such as the recognized cells, the introducer in charge of each transport unit can be determined.

  After determining the introduction body to be in charge of each injection needle in this way, each injection needle is individually moved by a plurality of conveying means, and the injection needle is inserted into each introduction body, whereby each introduction body is inserted into each introduction body. Introduce introduced material. For this reason, the introduction substance can be simultaneously introduced into a plurality of introduction bodies such as cells, and the efficiency of the injection process can be improved. In addition, it is possible to introduce multiple types of introduction substances into the introduction body at the same time by filling each injection needle with at least two different types of injection substances and sequentially introducing them into the same introduction body. It becomes. Therefore, a plurality of kinds of introduction substances can be introduced without replacing the injection substance in the injection needle, and the efficiency of the injection process can be improved.

  In the microinjection apparatus having this configuration, the first and second advance / retreat driving is performed by the transport control means from the position information of the introduced body obtained by the position determination means and the signals of the first and second sensors. When the first moving body moves by controlling the means and further by the correcting means, the transfer is performed so that the displacement generated in the direction perpendicular to the moving direction of the first moving body is reduced at the tip of the injection needle. The control of the control means is corrected. Thereby, the displacement at the tip of the injection needle which is affected by the assembly accuracy can be eliminated. In particular, when the second moving body undergoes a movement that rotates about an axis that is orthogonal to both the advancing / retreating direction of the first moving body and the advancing / retreating direction of the second moving body, a large displacement occurs at the tip of the injection needle. Although it appears, the above correction is effective to eliminate this displacement.

In this invention, the position where the third sensor for detecting the relative displacement between the first moving body and the second moving body is separated from the second sensor in the advancing / retreating direction of the first moving body. It is good to provide in.
When the third sensor is provided, a rotational motion described later of the second moving body can be estimated by comparing the signal of the second sensor and the signal of the third sensor.

  In the case where the third sensor is provided, the correction means causes the second moving body to change the first movement based on a signal from the third sensor and a change in the control amount of the second advance / retreat driving means. A translational movement that is a movement that moves in the advancing / retreating direction of the second moving body relative to the body, or an axis that is orthogonal to both the advancing / retreating direction of the first moving body and the advancing / retreating direction of the second moving body A correction for determining whether or not the rotary motion, which is a motion that rotates around, or both the translational motion and the rotational motion is performed, and correcting the control target value of the second forward / backward drive means according to the determination result It is good to determine the amount. Thereby, the correction | amendment suitable for the movement condition of the 2nd moving body can be performed.

For example, when it is determined by the correcting means that the second moving body has made a translational movement, the transfer control means may change the injection needle after the translational movement from a change in the control amount of the second advancing / retreating driving means. The target movement amount of the first and second moving bodies is calculated from the position of the tip of the injection needle obtained by this calculation and the position information of the introduced body obtained by the position determining means. To correct the position of the tip of the injection needle. The position correction of the tip of the injection needle by the transport control means is performed by operating the control amount of the second advance / retreat driving means and moving the second moving body along the second guide. By correcting to, even if the second moving body is translated, the tip of the injection needle can be accurately positioned at the target position.

Further, when it is determined by the correcting means that the second moving body has made a rotational movement, the correcting means calculates the rotation angle of the second moving body from the change in the signal of the third sensor. The transfer control means calculates the position of the tip of the injection needle after the rotational movement from the distance from the second sensor to the tip of the injection needle and the rotation angle of the second moving body. The target movement amount of the first and second moving bodies is calculated from the position of the tip of the injection needle obtained by the above and the position information of the introduced body obtained by the position determination means, and the position of the tip of the injection needle is calculated. It is better to make corrections. The distance from the second sensor to the tip of the injection needle is a known value stored in advance. The position correction of the tip of the injection needle by the conveyance control means is performed by operating the control amount of the second advance / retreat driving means and moving the second moving body along the second guide.
By correcting in this way, the tip of the injection needle can be accurately positioned at the target position even if the second moving body rotates.

For the position correction of the tip of the injection needle by the transport control means, the first position correction for moving the second moving body along the second guide is performed, and after the first correction is completed, the same is performed. It is desirable to repeat the second and subsequent position corrections.
By repeatedly correcting the position in this way, the position of the tip of the injection needle can be positioned with higher accuracy when the second moving body rotates.

Further, when it is determined by the correction means that the second moving body has performed both translational movement and rotational movement, the correction means detects the second moving body from the change in the signal of the third sensor. A rotation angle is calculated, and the transfer control means calculates the position of the tip of the injection needle after translational movement from the change in the control amount of the second advance / retreat driving means, and the tip of the injection needle obtained by this calculation And a target movement amount of the first and second moving bodies from the position information of the introduced body obtained by the position determining means, and correcting the position of the tip of the injection needle, The position of the tip of the injection needle after rotational movement is calculated from the distance from the sensor 2 to the tip of the injection needle and the rotation angle of the second moving body, and the tip of the injection needle obtained by this calculation is calculated. Position and position of the introduced body obtained by the position determining means The target movement amount of the first and second moving bodies is calculated from the information, and the position of the tip of the injection needle is corrected. That is, the position when it is determined that the second moving body has previously translated. Correction is performed, and then position correction is performed when it is determined that the second moving body has made a rotational motion. When position correction is performed in this order, correction control can be simplified.

Each of the first to third sensors may be a magnetic sensor or an optical sensor.
Any sensor can detect each relative position between the base and each moving body.

In this invention, the first guide and the second guide are a rail installed on the base or the first moving body which is a fixed side member, and the first moving body or the moving side member which is a moving side member. In the case of a guided body provided on the second moving body and capable of moving back and forth along the rail, between either the rail or the guided body, either or both of the first guide and the second guide It is preferable to provide preload generating means for generating preload.
When the preload generating means is provided, the rigidity of the guide portion of the moving side member with respect to the fixed side member in the conveying means can be increased, the accuracy of guiding the first moving body by the first guide, and the second guide The accuracy of guidance of the second moving body is improved. Thereby, the tip of the injection needle can be accurately positioned.

For example, the preload generating means includes a permanent magnet disposed on one of the fixed side member and the movable side member, and a magnetic body disposed on the other side, and the rail is generated by a magnetic attraction force between the permanent magnet and the magnetic body. And a preload can be generated between the guided bodies.
Alternatively, the preload generating means arranges permanent magnets on opposite surfaces of the fixed side member and the moving side member so that different magnetic poles face each other, and the rail and the covered member are applied by the magnetic attraction force of these two permanent magnets. A preload may be generated between the guide bodies.
Further, the preload generating means arranges permanent magnets on opposite surfaces of the fixed side member and the moving side member so that the same magnetic poles face each other, and the rail and the covered member are applied by the magnetic repulsive force of these two permanent magnets. A preload may be generated between the guide bodies.
Each of the preload generating means does not apply preload to the first and second guides individually, but applies preload between the stationary member and the moving member, so that the rail of each guide and the guided body. Generate preload in between. Therefore, it is not necessary to provide a mechanism for generating preload in each of the first and second guides, and the structure can be simplified. As a result, the conveyance means can be reduced in size and the mass of each moving body can be reduced, which is advantageous for driving each manipulator at high speed.

In this invention, when the position determination means has a function of measuring the relative position between the position of the introducer and the tip of the injection needle from the image obtained by the imaging means, the conveyance control means It is preferable to provide a fine adjustment operation control unit that causes each of the transporting means to move the injection needle so that the relative position measured by the position determining means is close.
When the position of the introducer and the tip position of the injection needle approach each other, it becomes possible to image both simultaneously by the imaging means. Therefore, the relative position between the position of the introducer and the tip position of the injection needle can be measured from the image obtained by the imaging means. If the relative position is directly measured from the image, a part of the calculation processing can be omitted, and fine adjustment of the positioning of the injection needle tip is facilitated.

In the present invention, each forward / backward drive means in the transport means may use a piezoelectric element laminate in which a plurality of piezoelectric elements are stacked and expand and contract in the stacking direction.
When a laminated piezoelectric element is used as a driving source, the conveying means can be further reduced in size, a large number of conveying means can be arranged in a limited space around the container, and a large number of injection needles are used. It is possible to improve the efficiency of the injection process.

In the present invention, a plurality of conveying means for moving the injection needle may be arranged around a body to be introduced in the container whose position is adjusted by the container position adjusting means.
When a large number of conveying means for moving the injection needle are arranged around the body to be introduced, a plurality of types of introduced substances can be introduced with a compact configuration.

In the present invention, the introduced substance may be a cell, and the introduced substance may be a gene regulatory factor such as DNA and protein.
In the case of injecting a gene regulatory factor into such a cell, the advantage of being able to efficiently and surely perform with a plurality of injection needles in this invention and improving the processing efficiency is effectively exhibited. .

  The microinjection apparatus of the present invention is an apparatus for introducing an introduced substance into an introduced body by inserting an injection needle filled with the introduced substance into the introduced body, and a container containing the introduced body A container position adjusting means for adjusting the position of the container, a plurality of conveying means for individually moving a plurality of injection needles with respect to the introduction body inside the container whose position is adjusted by the container position adjusting means, and the container position An imaging unit that images the inside of the container whose position has been adjusted by the adjusting unit through a magnifying lens, a position determination unit that determines the position of the introducer from the image obtained by the imaging unit, and the position determination unit Transport control means for causing each of the transport means to move the injection needle according to the obtained position information, and the transport means includes at least a first moving body and a second moving body. It has two degrees of freedom to be able to advance and retreat in directions orthogonal to each other. The injection needle is supported by a second moving body, and the first moving body is linearly connected to the base via the first guide. The second movable body is installed on the first movable body via a second guide so as to be movable back and forth in a direction perpendicular to the linear direction. The first movable body and the first movable body The first advancing / retreating driving means and the second advancing / retreating driving means for advancing and retreating each of the two moving bodies are installed on the base, and an output member of the second advancing / retreating driving means moves forward and backward with respect to the second moving body. A first sensor that is connected to or in contact with a direction orthogonal to a possible direction to detect relative displacement between the base and the first moving body, and the first moving body And a second sensor for detecting relative displacement between the second moving body and the transport control. The means controls the first and second advancing / retreating means from the position information of the introduced body obtained by the position determining means and at least the signals of the first and second sensors, When the first moving body moves, the control of the transport control means is corrected so that the displacement generated in the direction perpendicular to the moving direction of the first moving body becomes small at the tip of the injection needle. Since the correction means is provided, the introduction of the introduced substance such as cells into the introduction target can be performed efficiently and reliably with a plurality of injection needles, the processing efficiency can be improved, and the assembly accuracy is affected. Displacement at the tip of the injection needle can be eliminated.

It is the figure which added and added the block diagram of the control system to the conceptual diagram of the microinjection apparatus concerning one Embodiment of this invention. It is a top view of the container position adjustment means of the microinjection apparatus. It is a top view which shows arrangement | positioning of the conveyance means in the same microinjection apparatus. (A) is a plan view of the conveying means, (B) is a side view thereof. It is the figure which added and added the block diagram of the control system to the fracture | rupture side view of the X-axis moving mechanism of the conveyance means. It is the figure which added and added the block diagram of the control system to the fracture | rupture side view of the Y-axis moving mechanism of the conveyance means. It is the figure which added and added the block diagram of the control system to the fracture | rupture side view of the Z-axis moving mechanism of the conveyance means. It is a top view which shows the contact part of the output member and moving body in the advance / retreat drive means of the conveyance means. (A) The top view which shows schematic structure of the preload generation means provided in the conveyance means, (B) is the side view. It is a block diagram which shows a part control system of the control apparatus of the microinjection apparatus. It is a top view which shows the state which the 2nd moving body of the conveyance means made the rotational motion. It is a top view of a different conveyance means. It is a top view which shows the state which the 2nd moving body of the conveyance means made the rotational motion. It is a top view which shows the other example of the contact part of the output member and moving body in the advance / retreat drive means of the conveyance means. (A) The top view which shows schematic structure of the example from which the preload generation means provided in a conveyance means differs, (B) is the side view. (A) The top view which shows schematic structure of the further different example of the preload generation means provided in a conveyance means, (B) is the side view. (A) The top view which shows schematic structure of the further different example of the preload generation means provided in a conveyance means, (B) is the side view. (A) The top view which shows schematic structure of the further different example of the preload generation means provided in a conveyance means, (B) is the side view. (A) is the figure which added and displayed the block diagram of the control system to the fracture | rupture side view of the Y-axis movement mechanism concerning different embodiment, (B) is the fracture | rupture side view of the X-axis movement mechanism concerning different embodiment, It is the figure displayed adding the block diagram of a control system. It is a conceptual diagram of the conventional microinjection apparatus.

  A first embodiment of the present invention will be described with reference to FIGS. FIG. 1 shows a conceptual diagram of this microinjection apparatus. This microinjection apparatus is an apparatus for introducing an introduction substance into the introduction target body 66 by inserting a minute injection needle 11 filled with the introduction substance into the introduction target body 66. The introducer 66 is, for example, a cell. This cell may be a human body cell or a cell of an organism such as any other animal or plant.

  The microinjection apparatus includes a container position adjusting unit 1, an imaging unit 2, a position determining unit 3, a plurality of transfer units 4 that are manipulators provided individually for a plurality of injection needles 11, and a transfer control unit 80. With. In this embodiment, the position determination unit 3 and the conveyance control unit 80 are included in the control device 5 that controls the operation of the entire apparatus, but they may be provided independently of the control device 5.

The container position adjusting means 1 is a means for adjusting the position of the container 12 by moving the container mounting table 13 in which the container 12 such as a petri dish for storing the introduction object 66 is held in a horizontal state in two horizontal orthogonal directions. And is constituted by an XY stage device 6. For example, as shown in a plan view in FIG. 2, the XY stage device 6 includes a lower movable table 183 that is installed on a base 181 so as to be movable in the Y-axis direction via a guide 182, and the lower movable table 183. The upper movable table 185 that is movable in the X-axis direction via the guide 184, and the movable table drive mechanisms 186 and 187 for the respective axes that move the lower movable table 183 and the lower movable table 185 in the movable direction. It consists of. The movable table driving mechanisms 186 and 187 may be ultrasonic motors or linear motors, or may be composed of a motor and a rotation / linear motion conversion mechanism such as a ball screw. The container mounting table 13 shown in FIG. 1 is installed on the upper movable table 185, or the upper movable table 185 itself becomes the container mounting table 13.
Note that the X axis, Y axis, and Z axis in this specification do not represent each axis of rectangular coordinates defined as a common coordinate system in the entire microinjection apparatus, but each freedom in the description of the individual apparatus. Expressed as an axis for degrees.

  In FIG. 1, only one imaging means 2 is installed at a predetermined position above the container mounting table 13 so as to look down on the container 12. The imaging means 2 includes a camera or the like that locally enlarges the inside of the container 12 through an enlargement lens 2a. The captured image is processed by the image processing means 7.

  The position determination means 3 is a means for determining the position of the introduced body 66 from the image obtained by the imaging means 2, and is included as a part of the control device 5, for example, as in this embodiment. The position determination unit 3 determines the position of the introduction target 66 by checking the image processing result by the image processing unit 7 with a setting reference that is appropriately set and stored in the storage unit 3a. For example, the position determination means 3 determines the position of each introducer 66 from the positional relationship of each introducer 66 in the entire image. Further, the position determination unit 3 has a function of measuring the relative position between the position of the introducer 66 and the position of the tip of the injection needle 11 from the image obtained by the imaging unit 2.

  The transport means 4 is a means composed of an XYZ stage device or the like that moves each injection needle 11, and a plurality of such means are provided. As shown in a plan view in FIG. 3, the plurality of transport means 4 are positioned above the container mounting table 13 and are arranged substantially radially with respect to the center of the container 12 so as to surround the container 12. In the example of the figure, a plurality of (for example, three) conveying means 4 are arranged at equal angular intervals on the left and right sides of the container 12, and the left and right conveying means 4 are collinear with respect to the radiation center. Located opposite to each other.

  FIG. 4 shows one conveying means 4. The transport means 4 has three degrees of freedom, and the moving mechanism that bears one degree of freedom is one of two directions (X-axis direction and Y-axis direction) perpendicular to the horizontal direction with respect to the container mounting table 13 ( The X-axis moving mechanism 14 moves the injection needle 11 together with the first moving body 41 in the X-axis direction). The moving mechanism responsible for another degree of freedom is the Y-axis moving mechanism 15 that moves the injection needle 11 together with the second moving body 42 in one direction (Y-axis direction) of two directions orthogonal to each other in the horizontal direction. is there. Still another moving mechanism that bears one degree of freedom is a Z-axis moving mechanism 16 that moves the injection needle 11 in the direction of the injection needle central axis (Z-axis direction), which is a direction inclined toward the inside of the container 12.

  The first moving body 41 constituting the X-axis moving mechanism 14 is installed on the base 40 of the transport means 4 via the first guide 43 so as to be able to advance and retreat in the linear direction (X-axis direction). The second moving body 42 constituting the Y-axis moving mechanism 15 has a linear direction (Y-axis direction) orthogonal to the linear direction (X-axis direction) via the second guide 44 on the first moving body 41. ) Can be moved forward and backward. Each of the first moving body 41 and the second moving body 42 has a rectangular plate shape. As shown in FIG. 4B, the fixed base 17 of the Z-axis moving mechanism 16 is mounted on the second moving body 42. A needle support member 18 that supports the injection needle 11 is provided on the fixed base 17 so as to be movable back and forth in the Z-axis direction. The injection needle 11 is installed to be inclined downward. In FIG. 4A, the Z-axis moving mechanism 16 is not shown.

  The first guide 43 includes a rail 43a installed on the base 40, and a guided body 43b such as a linear motion rolling bearing provided on the lower surface of the first moving body 41 and capable of moving forward and backward along the rail 43a. And two are provided in parallel to each other. The second guide 44 includes a rail 44a installed on the first moving body 41, a linear motion rolling bearing provided on the lower surface of the second moving body 42 and capable of moving forward and backward along the rail 44a. It consists of guided bodies 44b, and two are provided in parallel to each other. The guided bodies 43b and 44b of the first and second guides 43 and 44 are provided with grooves along the length direction on the bottom surfaces, and the upper portions of the rails 43a and 44a are fitted into the grooves.

  The first advancing / retreating drive means 45 and the second advancing / retreating driving means 46 for moving the first moving body 41 and the second moving body 42 forward and backward are installed on the base 40. The first advancing / retreating drive means 45 is a means for advancing / retreating the output member 45a in the linear direction by the drive means body 45b. The output member 45a of the first advancing / retreating drive means 45 is relative to the direction (Y-axis direction) orthogonal to the direction (X-axis direction) in which the first moving body 41 can advance / retreat with respect to the first moving body 41. And move freely. The second advancing / retreating drive means 46 is a means for advancing / retreating the output member 46a in the linear direction by the drive means body 46b. The output member 46a of the second advancing / retreating drive unit 46 is relative to the second moving body 42 in the direction (X axis direction) orthogonal to the direction in which the second moving body 42 can move back and forth (Y axis direction). And move freely. By pressing the moving bodies 41 and 42 against the output members 45a and 46a by pressing means (not shown) such as an elastic body, the moving bodies 41 and 42 can be freely driven in both forward and reverse directions.

  In a contact portion between the moving bodies 41 and 42 and the output members 45a and 46a of the advance / retreat driving means 45 and 46, the movable bodies 41 and 42 can move in any direction on a plane perpendicular to the moving direction of the moving bodies 41 and 42. It is desirable to take measures to reduce the coefficient of friction. In this embodiment, the tip of the output member 45a of the first advance / retreat driving means 45 that contacts the first moving body 41 is spherical as shown in FIG. Although illustration is omitted, the output member 46a of the second advance / retreat driving means 46 also has a spherical tip at the output member 46a, like the first advance / retreat drive means 45. Instead of making the front end portions of the output members 45a and 46a spherical, the side surfaces of the moving bodies 41 and 42 with which the front end portions of the output members 45a and 46a are in contact with each other are formed in a semi-columnar shape extending in the sliding direction. 46a may be flat.

  Further, as shown in FIG. 8, a coating 101 for reducing friction may be applied to one or both of the contact portions between the output members 45 a, 46 a of the advance / retreat driving means 45, 46 and the moving bodies 41, 42. good. In the illustrated example, the output members 45a and 46a are coated. The coating is preferably diamond-like carbon, molybdenum disulfide, fluororesin, or graphite.

  Instead of making the tips of the output members 45a, 46a hemispherical or semi-cylindrical as in the example of FIG. 8, as shown in FIG. 14, the output members 45a, 46a and the moving bodies 41, 42 are made of balls or rollers. You may make it contact via rolling elements 49, such as. In the example of FIG. 14, the rolling element 49 is a ball and is rotatably accommodated in the holding members 45 aa and 46 aa provided at the tips of the output members 45 a and 46 a so as to partially protrude. Further, the output member 46a of the second advance / retreat driving means 46 has a direction (Y-axis direction) in which the second moving body 42 can move forward and backward with respect to the second moving body 42 via a guide (not shown). ) May be coupled so as to be movable in a direction (X-axis direction) orthogonal to. When connected via the guide, the drive transmission of the output member 46a in both the forward and backward directions can be reliably performed even when the output member 46a operates at high speed.

  In order to increase the rigidity of the X-axis moving mechanism 14 and the Y-axis moving mechanism 15, the conveying means 4 is provided between the rails 43a and 44a of the first guide 43 and the second guide 44 and the guided bodies 43b and 44b. Preload generating means for generating preload is provided. In the case of this embodiment, for example, as shown in FIG. 9, the preload generating means 110 includes a permanent magnet 111 and a magnetic body 112, and a base 40 that is a fixed member and a first moving body 41 that is a moving member. The permanent magnet 111 is arranged on one side, the magnetic body 112 is arranged on the other side, and the first magnet 43 is preloaded by the force by which the permanent magnet 111 magnetically attracts the magnetic body 112 so as to increase the rigidity. . In the example of the figure, the permanent magnet 111 is arranged on the base 40 and the magnetic body 112 is arranged on the first moving body 41, but the reverse may be possible. Although FIG. 9 shows the preload generating means 110 of the X axis moving mechanism 14, the same applies to the preload generating means (not shown) of the Y axis moving mechanism 15. In the case of the Y-axis moving mechanism 15, the first moving body 41 is a fixed member, and the second moving body 42 is a moving side member.

  As in the preload generating means 110 shown in FIG. 15, the permanent magnet 111 </ b> A, the different magnetic poles face each other on the surfaces facing the fixed side member (base 40) and the moving side member (first moving body 40). 111B may be arranged, and a preload may be generated between the stationary member and the moving member by the magnetic attractive force of these two permanent magnets 111A and 111B. Further, like the preload generating means 110 shown in FIG. 16, the permanent magnet is arranged such that the same magnetic poles face each other on the surfaces of the fixed side member (base 40) and the moving side member (first moving body 40) facing each other. 111A and 111B may be arranged, respectively, and a preload may be generated between the stationary member and the moving member by the magnetic repulsive force of these two permanent magnets 111A and 111B.

  15 and 16, the preload generator 110 generates a preload in the vertical direction between the fixed member (base 40) and the movable member (first moving body 40). As shown in the figure, the preload generating means 110 is horizontally placed between the stationary member (base 40) and the movable member (first movable body 40) by the magnetic attractive force or magnetic repulsive force of the pair of permanent magnets 111C and 111D. A preload in the direction may be generated. A horizontal preload may be generated by a combination of a permanent magnet (not shown) and a magnetic body (not shown).

  The transport means 4 is provided with the following sensors for detecting the operating positions of the first and second moving bodies 41 and 42. The first sensor S 1 detects the relative displacement between the base 40 and the first moving body 41. The second sensor S <b> 2 detects the relative displacement between the first moving body 41 and the second moving body 42. In this embodiment, the second sensor S <b> 2 is disposed at the center between the pair of second guides 44. The third sensor S3 is also a sensor that detects the relative displacement between the first moving body 41 and the second moving body 42, but the installation location is the first moving body with respect to the second sensor S2. 41 is shifted in the advancing and retracting direction (X-axis direction). These sensors S1 to S3 may be magnetic sensors or optical sensors. Any sensor can detect the relative positions of the base 40 and the first and second moving bodies.

  FIG. 5 shows an internal configuration of the first advance / retreat driving means 45, and FIG. 6 shows an internal configuration of the second advance / retreat driving means 46. The first forward / backward drive means 45 and the second forward / backward drive means 46 have basically the same configuration except that the X-axis direction and the Y-axis direction are opposite to each other. The means 45 will be described. The second advancing / retreating drive means 46 is represented by attaching the same reference numerals to the parts having the same configuration as the first advancing / retreating drive means 45 in the drawing, and the description thereof is omitted.

  In FIG. 5, the first advancing / retreating drive means 45 includes a fixed base 25, a movable piece 26, and two sets of piezoelectric element laminates 19C and 19D serving as a drive source. The fixing base 25 includes a main frame portion 25a extending in the Y-axis direction, a pair of side frame portions 25b and 25d extending in the width direction (X-axis direction) from both ends of the main frame portion 25a, and a front end of the side frame portion 25b. A horizontal cross section extending in the Y-axis direction in parallel with the main frame portion 25a has a hollow box shape having an L-shaped sub frame portion 25c.

  The movable piece 26 extends from the tip of the side frame portion 25b at one end of the fixed base 25 toward the side frame portion 25d at the other end, and has a horizontal cross section in an L shape. The movable piece 26 serves as an enlargement mechanism that enlarges the displacement of the piezoelectric element laminates 19C and 19D, and is formed of an elastic material such as metal or synthetic resin together with the fixed base 25. The movable piece 26 includes a main frame parallel piece portion 26a extending substantially parallel to the main frame portion 25a from the side frame portion 25b at one end of the fixed stand 25, and the other end of the fixed stand 25 from the other end of the main frame parallel piece portion 26a. The side frame parallel piece portion 26b extends in parallel to the side frame portion 25d on the inner side of the side frame portion 25d.

  The connecting portion between the side frame portion 25b of the fixed base 25 and the main frame parallel portion 26a of the movable piece 26 and the connecting portion between the main frame parallel piece portion 26a and the side frame parallel piece portion 26b of the movable piece 26 are both thin portions. 26c. Further, the middle portion in the longitudinal direction of the main frame parallel piece portion 26a of the movable piece 26 is also a thin portion 26d. As a result, the side frame parallel piece portion 26b of the movable piece 26 can be swung so as to be bent with the thin-walled portion 26c at the base end as a swing center. Further, the main frame parallel piece 26a of the movable piece 26 is bent at the thin-walled portion 26d at the middle portion in the longitudinal direction, and the middle portion in the direction perpendicular to the longitudinal direction (X-axis direction) due to increase / decrease in the bending angle. Can be moved forward and backward.

  The two sets of piezoelectric element laminates 19C and 19D are both laminated piezoelectric elements, and are arranged in parallel in the front-rear direction so as to be parallel to the main frame portion 25a of the fixed base 25 along the lamination direction. These two sets of piezoelectric element laminates 19 </ b> C and 19 </ b> D are connected in series via a fastening member 58. The fastening member 58 includes a longitudinal portion 58a disposed in parallel with both the piezoelectric element laminates 19C and 19D between the front and rear piezoelectric element laminates 19C and 19D, and a longitudinal direction at both ends of the longitudinal direction portion 58a. Are generally Z-shaped having protrusions 58b and 58c protruding in opposite directions.

  One set of piezoelectric element laminates 19 </ b> C is supported at one end by the side frame 25 b of the fixed base 25, and the other end is connected to the protrusion 58 b of the fastening member 58 facing the side frame 25 d of the fixed base 25. ing. The other set of piezoelectric element laminates 19 </ b> D has one end connected to the protrusion 58 c of the fastening member 58 facing the side frame 25 b of the fixed base 25 and the other end parallel to the side frame of the movable piece 26. It is connected to the piece 26b.

  A spring member 27A such as a leaf spring for applying a preload to the piezoelectric element laminate 19C is provided between the side portion 25ca extending in the width direction at the front end of the sub-frame portion 25c of the fixing base 25 and the protruding portion 58b of the fastening member 58. Intervene. Between the side frame portion 25d of the fixed base 25 and the side frame parallel piece portion 26b of the movable piece 26, a spring member 27B such as a leaf spring for applying a preload to the piezoelectric element laminate 19D is interposed. Further, a preload is applied to the side frame parallel piece portion 26b of the movable piece 26 between the side portion 25ca extending in the width direction of the tip of the sub frame portion 25c of the fixed base 25 and the side frame parallel piece portion 26b of the movable piece 26. A spring member 27C is provided.

  With the above configuration, the side frame parallel piece 26b of the movable piece 26 swings due to the displacement caused by the expansion and contraction in the stacking direction of the two sets of piezoelectric element stacks 19C and 19D, and the swing displacement is enlarged and parallel to the main frame. The displacement is in the X-axis direction of the piece 26a. In the case of the second advance / retreat driving means 46 shown in FIG. 6, the displacement is in the Y-axis direction.

  The two sets of piezoelectric element laminates 19C and 19D are displaced by a positioning signal that is a voltage applied from the X-axis position control unit 59X (Y-axis position control unit 59Y). The X-axis position control unit 59X (Y-axis position control unit 59Y) receives a position command from the position command unit 60 to the voltage generator 61, and based on the position command, the voltage generator 61 outputs the piezoelectric element laminate 19C. , 19D is applied. The X-axis position control unit 59X (Y-axis position control unit 59Y) is provided in the conveyance means individual control unit 88a in the injection operation control unit 88 of FIG. Further, the position command section 60 uses the target position determined by the assigned body determining section 87 as the position command based on the position information obtained by the position determination means 3 of FIG. The position command unit 60 may be provided as a part of the assigned introducer determining unit 87.

  The X-axis moving mechanism 14 and the Y-axis moving mechanism 15 may be configured as shown in FIGS. These are provided with a link mechanism 75 as an expansion mechanism for expanding the expansion and contraction of the piezoelectric element laminates 19G and 19H to a displacement in a direction orthogonal to the expansion and contraction direction. The link mechanism 75 includes a crank / slider mechanism including one fixed joint 76, two movable joints 77A and 77B, and two links 81A and 81B. The crank / slider mechanism is in the extension direction of the piezoelectric element. The displacement may be converted into an arbitrary direction on the circumference of the fixed joint 76 via the two movable joints 77A and 77B and the two links 81A and 81B, so that the displacement can be further expanded.

  FIG. 19A shows the Y-axis moving mechanism 15 provided with the link mechanism 75. Similarly to the embodiment of FIG. 6, the Y-axis moving mechanism 15 also includes a fixed base 73 and two sets of piezoelectric element laminates 19G and 19H serving as a drive source. The fixed base 73 includes a pair of main frame portions 73a and 73b extending in the X-axis direction, a pair of side frame portions 73c and 73d extending in the width direction (Y-axis direction) from both ends of the main frame portions 73a and 73b, and 4 Side plates 73e for fastening the two frame portions. On the side frame portion 73c at one end of the fixed base 73, an expansion / contraction direction moving body 74 facing the side frame portion 73d at the other end is supported via a spring member 27D so as to be movable in the X-axis direction.

  The two sets of piezoelectric element laminates 19G and 19H are both laminated piezoelectric elements, and are arranged in parallel in the front-rear direction so as to be parallel to the main frame portions 73a and 73b of the fixed base 73 along the lamination direction. . These two sets of piezoelectric element laminates 19G and 19H are connected in series via a fastening member 78. The fastening member 78 includes a longitudinal direction portion 78a arranged in parallel with both the piezoelectric element laminates 19G and 19H between the front and rear piezoelectric element laminates 19G and 19H, and a longitudinal direction at both ends of the longitudinal direction portion 78a. And the projections 78b and 78c projecting so as to be opposite to each other. One set of the piezoelectric element laminates 19G is supported at one end by the side frame portion 73c of the fixed base 73, and the other end is connected to the protrusion 78b of the fastening member 78 facing the movable body 74 in the telescopic direction. The other set of piezoelectric element laminates 19H has one end connected to the protrusion 78c of the fastening member 78 facing the fixed base side frame 73d side and the other end connected to the telescopic moving body 74. Yes. The spring member 27D applies a preload to the piezoelectric element laminate 19H. Thereby, the expansion-contraction direction moving body 74 can be displaced in the X-axis direction in accordance with the expansion / contraction displacement of the piezoelectric element laminates 19G, 19H.

In this example, a link mechanism 75 is provided as an expansion mechanism that expands and contracts the piezoelectric element laminates 19G and 19H to displacement in a direction (Y-axis direction) orthogonal to the expansion / contraction direction (X-axis direction). The link mechanism 75 is connected to the fixed base side frame 73d by one fixed joint 76, and is connected to the telescopic direction moving body 74 by one movable joint 77A.
According to this configuration, the movable joint 77A is displaced in the X-axis direction due to the expansion and contraction of the piezoelectric element laminates 19G and 19H, and the movable joint 77B rotates about the fixed joint 76. Therefore, the movable part 82 fixed to the first link 81A is displaced in the Y-axis direction. Therefore, by setting the output portion at an arbitrary position on the circumference of the fixed joint 76, the displacement can be expanded in an arbitrary direction. Therefore, the number of parts of the advance / retreat drive means 45 and 46 can be reduced and the size can be reduced.

  FIG. 19B shows the X-axis moving mechanism 14 provided with the link mechanism 75. This X-axis moving mechanism 14 has the same configuration as the Y-axis moving mechanism 15 in FIG. 19A, and the X-axis direction can be changed by changing the positions of the movable joint 77B and the movable portion 82 fixed to the link 81A. It is displaced to. Therefore, by setting the output portion at an arbitrary position on the circumference of the fixed joint 76, the displacement can be expanded in an arbitrary direction. Therefore, the number of parts of the Y-axis moving mechanism 15 can be reduced and the size can be reduced.

  FIG. 7 is a diagram showing an internal configuration of the Z-axis moving mechanism 16. The Z-axis moving mechanism 16 includes a hollow box-shaped fixing base 17, a needle support member 18 provided at one end of the fixing base 17 so as to protrude upward from the fixing base 17, and the fixing base 17. The advance / retreat / vibration driving means 50 is provided. The advance / retreat / vibration driving means 50 serves as a drive source for positioning the needle support member 18 in the Z-axis direction and vibrating the needle support member 18 in the Z-axis direction.

  The needle support member 18 is configured to detachably support the injection needle 11 so that the injection needle 11 can be easily replaced in order to damage the injection needle 11 or replace the introduced substance. . The needle support member 18 is substantially T-shaped having a vertical piece 18a and a horizontal piece 18b, and the horizontal piece 18b moves on the fixed base 17 via the guide mechanism 21 in the protruding direction of the injection needle 11. The standing piece portion 18a is supported on an inward surface of one end portion of the fixed base 17 via a spring member 20A made of a leaf spring or the like.

  The advancing / retreating / vibrating drive means 50 includes piezoelectric element laminates 19A, 19B1, and 19B2. Each piezoelectric element laminate 19A, 19B1, 19B2 is a laminated piezoelectric element in which a plurality of piezoelectric elements 19a are laminated in the displacement direction to form a rod-like body. Of these piezoelectric element laminates 19A, 19B1 and 19B2, the two piezoelectric element laminates 19B1 and 19B2 are arranged in a straight line and connected to each other in series by a fastening member 47. The laminated body 19B is obtained. The piezoelectric element laminate 19B and the remaining one piezoelectric element laminate 19A are arranged in parallel in the vertical direction so as to be parallel to each other along the lamination direction, and these two sets of piezoelectric element laminate 19A, 19B is connected in series via the fastening member 48. The fastening member 48 is disposed between the upper and lower piezoelectric element laminates 19A and 19B in the longitudinal direction portion 48a disposed in parallel with the piezoelectric element laminates 19A and 19B, and at both ends of the longitudinal direction portion 48a. It is a general Z-shape having protrusions 48b and 48c that protrude in opposite directions.

One set of piezoelectric element laminates 19 </ b> A has one end connected to a protrusion 48 b on one end side of the fixing base 17 of the fastening member 48, and the other end supported by the other end of the fixing base 17. Between the protrusion 48b of the fastening member 48 and one end of the fixed base 17, a spring member 20B such as a leaf spring that preloads the piezoelectric element laminate 19A is interposed. One end of the piezoelectric element laminate 19B, that is, the end of the one piezoelectric element laminate 19B1 constituting the piezoelectric element laminate 19B opposite to the connecting portion by the fastening member 47 is an upright piece of the needle support member 48. 48a. Further, the other end of the piezoelectric element laminate 19B, that is, the end opposite to the connecting portion by the fastening member 47 in the other piezoelectric element laminate 19B2 constituting the piezoelectric element laminate 19B is fixed to the fixed base 17. The other end side is connected to the protrusion 48c of the fastening member 48. The piezoelectric element laminate 19 </ b> B is preloaded by a spring member 20 </ b> A such as a leaf spring interposed between the standing piece 18 a of the needle support member 18 and the other end of the fixed base 17.
With the above configuration, the needle support member 18 can advance and retract in the protruding direction (Z-axis direction) of the injection needle 11 by displacement in the stacking direction of the two sets of piezoelectric element stacks 19A and 19B. The Z-axis direction is the direction in which the injection needle 11 is inserted into the body to be introduced.

  Of the piezoelectric element laminates 19A and 19B, the piezoelectric element laminate 19A and one piezoelectric element laminate 19B2 in the piezoelectric element laminate 19B are used for positioning the needle support member 18, that is, for positioning the injection needle 11. Used as a driving source. That is, these piezoelectric element laminates 19 and 19B are displaced by a positioning signal that is a voltage applied from the Z-axis position control unit 51.

  Of the piezoelectric element laminates 19A and 19B, the piezoelectric element laminate 19B1 directly connected to the needle support member 18 in the piezoelectric element laminate 19B is a drive source for causing the needle support member 18 to vibrate in the insertion direction of the injection needle 11. Used as. The displacement of the piezoelectric element laminate 19 </ b> B <b> 1 for applying vibration is repeatedly changed by a vibration driving signal that is a voltage applied from the vibration driving means 54. Alternatively, the piezoelectric element laminate for applying vibration may not be provided separately, and the same piezoelectric element may be used by superimposing the forward / backward movement of the Z-axis moving mechanism 16 and the vibration drive signal.

  The Z-axis position control unit 51 receives a position command from the position command unit 52 to the voltage generation unit 53, and applies a voltage corresponding to the piezoelectric element stacks 19A and 19B2 from the voltage generator 53 based on the position command. . The Z-axis position control unit 51 is provided in the Z-axis transport means individual control unit 88a in the injection operation control unit 88 of FIG. Further, the position command unit 52 uses the target position determined by the assigned body determination unit 87 as the position command based on the position information given by the position determination unit 3 of FIG. The position command unit 52 may be provided as a part of the assigned introduction determining unit 87.

  The vibration drive means 54 applies an alternating voltage having a predetermined frequency to the piezoelectric element laminate 19B1 as the vibration drive signal from the voltage generator 56. The frequency of the alternating voltage, that is, the frequency of vibration applied to the needle support member 18 can be switched by a command from the frequency variable means 55 to the voltage generator 56.

  As shown in FIG. 1, the control device 5 includes the position determination unit 3 and a conveyance control unit 80. The conveyance control unit 80 is configured to determine the target position of the tip of the injection needle 11 from the position information of the introduction target 66 obtained by the position determination unit 3, and to each of the conveyances according to the target position. An injection operation control unit 88 for controlling the operation of the means 4. The injection operation control unit 88 includes a plurality of conveyance unit individual control units 88 a that control the individual conveyance units 4. The individual conveyance unit 88a includes an X-axis position control unit 59X of the first advance / retreat drive unit 45, a Y-axis position control unit 59Y of the second advance / retreat drive unit 46, and an advance / retreat / vibration drive unit 50. A Z-axis position control unit 51, vibration drive means 54 (FIG. 7), and correction means 88b are included. In addition to the injection operation control unit 88, the transfer control unit 80 is provided with a fine adjustment operation control unit 89 that controls the transfer unit 4 when the tip of the injection needle 11 approaches the introduced body 66. Yes.

The transport means individual control unit 88a is shown in the block diagram of FIG.
Charge a target position signal x ₀ of the first advancing drive means 45b which is determined by the transductant determination unit 87, an output signal of the first sensor S1 is input to the X-axis position adjusting unit 59x, X-axis position adjustment from part 59X to the first advancing drive means 45b, the instruction signal x ₁ is output to specify the control quantity. Similarly, charge the target position signal y ₀ of the second advancing drive means 46b which is determined by the transductant determination unit 87, an output signal of the second sensor S2 are input to the Y-axis position adjusting unit 59Y, Y from the axis position adjustment unit 59Y to the second advancing drive means 46b, the instruction signal y ₁ is output to specify the control quantity. By performing feedback control in this way, the tip of the injection needle 11 is brought close to the body 66 (FIG. 1).

Further, the above-described instruction signal _{y 1,} the output signal of the second and third sensors S1, S2 is input into the correction unit 88b, a correction unit 88b to the Y-axis position adjusting unit 59Y, the second reciprocating drive means 46b A correction signal Δy that specifies a correction amount for correcting the control amount is output. This correction of the control amount is to cope with the situation described below. That is, when the first moving body 41 is operating due to the assembly accuracy of the transport means 4, such as the influence of the perpendicularity between the first guide 43 and the second guide 44, etc., the second moving body 42 performs a translational motion that moves in the Y-axis direction, performs a rotational motion that rotates around an axis O that is orthogonal to both the X-axis direction and the Y-axis direction, and performs both the translational motion and the rotational motion. Sometimes. In these cases, the second moving body 42 is displaced in the Y-axis direction. Even if this displacement is slight, it is a large displacement at the tip of the injection needle 11.

Correcting means 88b from the output signal of the command signal y ₁ and the second and third sensors S1, S2, determine the operating status of the second moving member 42 when the first moving body 41 moves To do.
Specifically, by comparing the change in the control amount of the second advance / retreat driving means 46 with the output signal of the second sensor S2, the presence / absence of the translational motion and its degree can be determined. When the second moving body 42 performs translational movement, the position of the Y-axis moving mechanism 15 is controlled based on the output signal of the second sensor S2, but the detection value of the second sensor S2 does not change. The control amount of the second advance / retreat driving means 46 of the Y-axis moving mechanism 15 changes. That is, when the control amount of the second advance / retreat driving means 46 is changed with respect to the operation of only the X-axis moving mechanism 14, the tip position of the injection needle 11 is also displaced in the Y-axis direction. Therefore, it is determined that it is in translation. When there is a translational motion, the amount of displacement of the second moving body 42 in the Y-axis direction is calculated from the amount of control, and the amount of control of the second forward / backward drive means 46 is corrected.

  Further, by comparing the detection values of the second sensor S2 and the third sensor S3, it is possible to determine the presence / absence and the degree of the rotational movement of the second moving body 42. For example, when the first moving body 41 moves in the X-axis direction, if the operation is normally performed, the detection value of the second sensor S2 and the detection value of the third sensor S3 should be the same. is there. However, when the second moving body 42 rotates around the axis O with respect to the first moving body 41, as shown in FIG. 11, a deviation D1 occurs in the position in the Y-axis direction of both sensors S2, S3, Accordingly, a difference appears in the detection values of both sensors S2 and S3. Therefore, when there is a difference between the detection values of both sensors S2 and S3, it is determined that a rotational motion has occurred.

  When there is a rotational movement, the rotation angle θ of the second moving body 41 is calculated from the distance L2 between the second sensor S2 and the third sensor S3. Then, from the relationship between the rotation angle θ and the distance L1 from the second sensor S2 to the tip of the injection needle 11, the tip position of the injection needle 11 prepared in advance and the rotation angle of the second moving body 41 are prepared. The amount of displacement at the tip of the injection needle 11 is obtained using a table or the like indicating the relationship between and the control amount of the second advance / retreat driving means 46 is corrected accordingly. Further, in the correction of the rotational movement, there is a case where a difference occurs in the relative displacement between the second sensor S2 and the third sensor S3 due to the operation of the second advance / retreat driving means 46. The rotation angle θ is obtained again and the correction is repeated.

  That is, the correction of the tip position of the injection needle 11 does not correct the angle itself of the second moving body 42 but controls the control amount of the second advancing / retreating drive means 46 to control the second moving body 42. This is done by moving along the second guide 44. By correcting in this way, the tip of the injection needle 11 can be accurately positioned when the second moving body 42 rotates. Further, a mechanism for rotating the second moving body 42 is unnecessary, and a simple configuration can be achieved.

When the second moving body 42 performs both translational motion and rotational motion, the correction is performed first when the translational motion is performed, and then the correction is performed when the rotational motion is performed thereafter. If correction is performed in this order, the correction is simplified.
As described above, the correcting means 88b corrects the control amount of the second advancing / retreating driving means 46 in accordance with the movement state of the second moving body 42 when the first moving body 41 moves, thereby assembling. Displacement of the tip of the injection needle 11 caused by the influence of accuracy and the like can be eliminated, and the tip of the injection needle 11 can be accurately positioned.

  When the position of the introducer 66 and the tip position of the injection needle 11 approach each other and both the tip of the introducer 66 and the injection needle 11 are reflected in the image obtained by the imaging means 2, The position determination unit 3 measures the relative position between the position of the introduction target 66 and the position of the tip of the injection needle 11 from the image, and the relative position measured by the position determination unit 3 by the fine adjustment control unit 89 is determined. Each conveying means 4 is operated so as to be close to each other, and the position of the tip of the injection needle 11 is finely adjusted. Thus, if the relative position is directly measured from the image, a part of the arithmetic processing can be omitted, and the fine adjustment of the positioning of the tip of the injection needle 11 is facilitated.

  In this embodiment, the detection value of the second sensor S2 is compared with the detection value of the third sensor S3 in order to determine the presence or absence of the rotational movement of the second moving body 42. As shown in FIG. Two third sensors S3 may be provided with their positions shifted in the X-axis direction, and the detection values of the two third sensors S3 may be compared. In this case, as shown in FIG. 13, when the second moving body 42 rotates around the axis O with respect to the first moving body 41, the two third sensors S3 are positioned at the positions in the Y-axis direction. Deviation (D1 + D2) occurs, and a difference appears in the detection values of the two third sensors S3. When two third sensors S3 are provided, the distance between the sensors to be compared can be made larger than when there is only one third sensor S1 as shown in FIG. 4 (L3> L2), so the deviation is large. Appearing can improve detection accuracy.

  According to the microinjection apparatus of this configuration, the position of the container 12 that accommodates the introduction body 66 is adjusted by the container position adjusting means 1, and the planar view image inside the position-adjusted container 12 is imaged by the imaging means 2, By determining the position of the introduced body 66 from the image by the position determining means 3, the introduced body 66 in charge of each injection needle 11 is determined. At this time, by enlarging the container 12 locally by the magnifying lens 2a and performing image processing on the position of the introduced body 66, the position of the introduced body 66 can be accurately recognized. Further, for example, the introduced body 66 that each injection needle 11 takes charge of can be determined from the positional relationship in the image of the recognized introduced body 66. Thus, after determining the introduction body 66 in charge of each injection needle 11, each injection needle 11 is moved by a plurality of individual conveying means 4, and the injection needle 11 is inserted into each introduction body 66. Thus, the introduction substance is introduced into each of the introduction bodies 66.

  Since the transport unit 4 has a drive mechanism having at least two degrees of freedom with respect to the introduced body 66, the tip of the injection needle 11 can be positioned as a single unit. Each conveying means 4 operates in parallel and repeats the injection operation. After the processing of the introduced object 66 in the image is completed, the container 12 is moved by the container position adjusting means 1, the arrangement of the introduced object 66 at another adjacent position is recognized by image processing, and the injection operation is performed in the same manner as described above. repeat.

  In this way, the introduction substance can be introduced into a plurality of introduced bodies 66 such as cells at the same time, and the efficiency of the injection process can be improved. In addition, it is possible to introduce a plurality of types of introduction substances into the introduction target body 66 almost simultaneously by filling at least two kinds of different injection substances for each injection needle 11 and sequentially introducing them into the same introduction target body 66. It becomes possible. Therefore, a plurality of types of introduced substances can be introduced into one introduced body 66 without replacing the injected substance in the injection needle 11, and the efficiency of the injection process can be improved.

  In particular, the transport means 4 has the moving bodies 41, 42 and the advance / retreat drive means 45, 46 separated, and the advance / retreat drive means 45, 46 are both installed on the base 4, so the transport means 4 can be reduced in size. In addition, the mass of the moving bodies 41 and 42 can be reduced. For this reason, the conveying means 4 can be driven at high speed. Both the advancing / retreating drive means 45 and 46 are installed on the base 4, but the output member 46a of the second advancing / retreating drive means 46 is movable in a direction perpendicular to the advancing / retreating direction with respect to the second moving body 42. Therefore, the forward / backward drive of the second forward / backward drive means 46 can be transmitted to the second mobile body 42 regardless of the position where the first mobile body 41 has moved.

  Moreover, since the conveyance means 4 can be reduced in size, a plurality of conveyance means 4 can be arranged around a container 12 such as a petri dish containing an introduced body 66 such as cells as shown in FIG. Therefore, the tip of each injection needle 11 can be simultaneously positioned with respect to the plurality of introduced bodies 66. That is, the injection process to a large number of introduction bodies 66 can be performed at a time, and high throughput can be achieved.

  Since the correction means 88b is provided in each conveyance means individual control section 88a of the injection operation control section 88 that controls the operation of each conveyance means 4, the displacement of the tip position of the injection needle 11 caused by the influence of assembly accuracy and the like is eliminated, The tip position of the injection needle 11 can be accurately positioned. Thereby, the injection | pouring precision of the introductory substance to the to-be-introduced body 66 by the injection needle 11 can be raised.

  Further, when the advancing / retreating drive means 45, 46 of each moving body 41, 42 of the transport means 4 is a laminated body of piezoelectric elements, the following effects can be obtained. That is, conventionally, a mechanism using a ball screw or an ultrasonic motor has been used to drive the injection needle. In this embodiment, the injection needle 11 is driven by combining a small actuator using a piezoelectric element. The conveying means 4 to be reduced is downsized. Actuators using piezoelectric elements have a high conversion effect for converting electrical energy to mechanical energy. By changing the applied voltage, the generated displacement can be changed relatively easily and has excellent controllability. .

  In addition, the conveying means 4 generates a preload between the rails 43a and 44a of the first guide 43 and the second guide 44 and the guided bodies 43b and 44b, so that the X-axis moving mechanism 14 and the Y-axis moving mechanism. 15 is provided with the preload generating means 110 for increasing the rigidity of the first moving body 41, and the second guide 44 is guided by the second guide 44. Can be improved. Thereby, the tip of injection needle 11 can be positioned with high accuracy.

  In particular, in this embodiment, the preload generating means 110 does not apply preload to the first and second guides 43 and 44 individually, but instead of the fixed side member (the base 40 and the first moving body 41). A configuration in which a preload is generated between the rails 43a and 44a of the guides 43 and 44 and the guided bodies 43b and 44b by applying a preload between the moving side members (the first moving body 41 and the second moving body 42). It is said that. Therefore, it is not necessary to provide a mechanism for generating a preload in each of the first and second guides 43 and 44, and the structure can be simplified. As a result, it is possible to reduce the size of the transport means 4 and reduce the mass of each moving body 41, 42, which is advantageous for driving each manipulator at high speed.

DESCRIPTION OF SYMBOLS 1 ... Container position adjustment means 2 ... Imaging means 3 ... Position determination means 4 ... Conveyance means 5 ... Control apparatus 11 ... Injection needle 12 ... Container 14 ... X-axis movement mechanism 15 ... Y-axis movement mechanism 16 ... Z-axis movement mechanism 19A, 19B1, 19B2, 19c, 19D ... Piezoelectric element laminate 40 ... Base (fixed side member)
41 ... 1st moving body (moving side member, fixed side member)
42 ... 2nd moving body (moving side member)
43 ... first guide 43a ... rail 43b ... guided portion 44 ... second guide 44a ... rail 44b ... guided portion 45 ... first advance / retreat drive means 45a ... output member 46 ... second advance / retreat drive means 46a ... Output member 80 ... Conveyance control means 88b ... Correction means 110 ... Preload generation means 111, 111A, 111B ... Permanent magnet 112 ... Magnetic body S1 ... First sensor S2 ... Second sensor S3 ... Third sensor

Claims (19)

A microinjection device that introduces an introduction substance into an introduction body by inserting an injection needle filled with the introduction substance into the introduction body,
A container position adjusting means for adjusting the position of the container containing the introduced body, and a plurality of injection needles for individually moving the plurality of injection needles with respect to the introduced body inside the container whose position is adjusted by the container position adjusting means. A transfer means, an image pickup means for picking up an image of the inside of the container whose position is adjusted by the container position adjusting means through a magnifying lens, and a position determination for determining the position of the introducer from the image obtained by the image pickup means Means and a transport control means for causing the transport means to move the injection needle in accordance with the position information obtained by the position determination means,
The transport means has at least two degrees of freedom in which the first moving body and the second moving body can freely advance and retract in directions orthogonal to each other, and the injection needle is supported by the second moving body, The first moving body is installed on the base so as to be able to advance and retreat in a linear direction via the first guide, and the second moving body is disposed on the first moving body via the second guide in the linear direction. The first advancing / retracting driving means and the second advancing / retreating driving means for moving the first moving body and the second moving body forward and backward, respectively, are installed on the base. The output member of the two advancing / retreating drive means is connected to or in contact with the second moving body so as to freely move in a direction perpendicular to the direction in which the second moving body can advance and retreat;
A first sensor that detects relative displacement between the base and the first moving body; and a second sensor that detects relative displacement between the first moving body and the second moving body. The conveyance control means controls the first and second advance / retreat driving means from the position information of the introduced body obtained by the position determination means and at least the signals of the first and second sensors. When the first moving body moves, the transport control means reduces the displacement generated in the direction perpendicular to the moving direction of the first moving body at the tip of the injection needle. A microinjection apparatus comprising correction means for correcting the control of the above.   The third sensor for detecting relative displacement between the first moving body and the second moving body is separated from the second sensor in the advancing / retreating direction of the first moving body. Microinjection device provided at the position.   3. The correction unit according to claim 2, wherein the second moving body is compared with the first moving body based on a signal from the third sensor and a change in a control amount of the second forward / backward driving means. Rotated around an axis orthogonal to both the forward / backward direction of the first moving body and the forward / backward direction of the second moving body, or a translational movement that is a movement that moves in the forward / backward direction of the second moving body It is determined whether the rotary motion that is the motion to be performed or both the translational motion and the rotational motion are performed, and a correction amount for correcting the control target value of the second forward / backward drive means is determined according to the determination result Microinjection device.   4. The method according to claim 3, wherein when the correction unit determines that the second moving body has undergone translational motion, the transfer control unit is configured to perform post-translational motion based on a change in a control amount of the second forward / backward driving unit. The position of the tip of the injection needle is calculated, and from the position of the tip of the injection needle obtained by this calculation and the position information of the introduced body obtained by the position determination means, the first and second moving bodies A microinjection device that calculates the target movement amount and corrects the position of the tip of the injection needle.   5. The position correction of the tip of the injection needle by the conveyance control means according to claim 4, wherein the second moving body is moved along the second guide by operating a control amount of the second advance / retreat driving means. Microinjection device to be performed.   4. The rotation angle of the second moving body according to claim 3, wherein when the correcting means determines that the second moving body has rotationally moved, the correcting means determines the rotation angle of the second moving body from a change in the signal of the third sensor. The transport control means calculates the position of the tip of the injection needle after the rotational movement from the distance from the second sensor to the tip of the injection needle and the rotation angle of the second moving body. The target movement amount of the first and second moving bodies is calculated from the position of the tip of the injection needle obtained by this calculation and the position information of the introduced body obtained by the position determination means, A microinjection device that corrects the tip position.   7. The position correction of the tip of the injection needle by the conveyance control means according to claim 6, wherein the second moving body is moved along the second guide by operating a control amount of the second advance / retreat driving means. Microinjection device to be performed.   7. The position correction of the tip of the injection needle by the transport control means according to claim 6, wherein the first position correction is performed to move the second moving body along the second guide, and the first time A micro-injection apparatus that repeatedly performs the second and subsequent position corrections after the correction is completed.   4. The method according to claim 3, wherein when it is determined by the correction means that the second moving body has performed both translational movement and rotational movement, the correction means determines whether the second sensor has changed from the change in the signal of the third sensor. The rotation angle of the moving body is calculated, and the transfer control means calculates the position of the tip of the injection needle after translation from the change in the control amount of the second advance / retreat driving means, and the injection obtained by this calculation The target movement amount of the first and second moving bodies is calculated from the position of the tip of the needle and the position information of the introduced body obtained by the position determination means, the position of the tip of the injection needle is corrected, and then The position of the tip of the injection needle after the rotary motion is calculated from the distance from the second sensor to the tip of the injection needle and the rotation angle of the second moving body, and the injection needle obtained by this calculation The position of the tip of the lead and the guide obtained by the position determination means It calculates a target amount of movement of the first and second moving body from the position information of the body, the microinjection apparatus that performs position correction of the tip of the injection needle.   10. The microinjection device according to claim 2, wherein each of the first to third sensors is a magnetic sensor.   10. The microinjection device according to claim 2, wherein each of the first to third sensors is an optical sensor.   12. The first guide and the second guide according to claim 1, wherein the first guide and the second guide are a fixed side member, the rail installed on the base or the first moving body, and the moving side. It is a guided body provided on the first moving body or the second moving body, which is a member, and is capable of moving back and forth along the rail, and either or both of the first guide and the second guide A microinjection apparatus provided with preload generating means for generating a preload between the rail and the guided body.   13. The preload generating means according to claim 12, wherein a permanent magnet is disposed on one of the fixed side member and the moving side member, and a magnetic body is disposed on the other, and a magnetic attractive force between the permanent magnet and the magnetic body. A microinjection device that generates a preload between the rail and the guided body.   13. The preload generating means according to claim 12, wherein permanent magnets are arranged on opposite surfaces of the fixed side member and the moving side member so that different magnetic poles face each other, and the rail is generated by a magnetic attractive force of these two permanent magnets. And a microinjection device for generating a preload between the guided bodies.   13. The preload generating means according to claim 12, wherein permanent magnets are respectively disposed on opposing surfaces of the fixed side member and the moving side member so that the same magnetic poles face each other, and the rails are generated by the magnetic repulsive force of these two permanent magnets. And a microinjection device for generating a preload between the guided bodies.   16. The position determination unit according to claim 1, wherein the position determination unit measures a relative position between the position of the introducer and the position of the tip of the injection needle from the image obtained by the imaging unit. And a micro-adjustment operation control unit that causes each of the transfer means to move the injection needle so that the relative position measured by the position determination means is close to the transfer control means. Injection device.   17. The microinjection device according to claim 1, wherein each of the advancing / retreating driving units in the transport unit uses a piezoelectric element stack in which a plurality of piezoelectric elements are stacked and expand and contract in a stacking direction.   18. The microinjection according to any one of claims 1 to 17, wherein a plurality of conveying means for moving the injection needle are arranged around a body to be introduced in a container whose position is adjusted by the container position adjusting means. apparatus.   The microinjection apparatus according to any one of claims 1 to 18, wherein the introducer is a cell, and the introduced substance is a gene regulatory factor such as DNA and protein.

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