JP2008292282A - Imaging device, and specimen photographing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an imaging device which detects fluorescence accurately, even when a deposited matter on a photoreception face disturbs the detection of the fluorescence. <P>SOLUTION: This imaging device has: an imaging element 39 for imaging a plurality of spot areas; and a detection control part 43 for comparing a spot position of each spot area with a position of the deposited matter on the photoreception face in the imaging element 39, on a picked-up image outputted from the imaging element 39. The detection control part 43 uses the image of the effective spot area as an inspection image, when the effective spot area with the deposited matter not overlapped by any of the spots exists in the respective spot areas. The detection control part 43 obtains the effective spot area by complementing the spot overlapped by the deposited matter with the other corresponding spot, between at least two spot areas, when no effective spot area exists. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a biochemical reaction analyzer that detects a sample of cells, microorganisms, chromosomes, nucleic acids, and the like in a specimen using a biochemical reaction such as an antigen-antibody reaction or a nucleic acid hybridization reaction, and in particular, photographs the specimen. The present invention relates to an imaging device.

  Methods for analyzing a sample such as blood include an immunological method using an antigen-antibody reaction and a method using nucleic acid hybridization.

  In the immunological analysis method, a protein such as an antibody or an antigen that specifically binds to a substance to be detected is used as a probe. The probe is immobilized on a solid phase surface such as fine particles, beads, or a glass plate, and an antigen-antibody reaction with a substance to be detected in a specimen is performed. In an analysis method using nucleic acid hybridization, a single-stranded nucleic acid is used as a probe and immobilized on a solid phase surface such as a fine particle, a bead, or a glass plate, and nucleic acid hybridization is performed with a substance to be detected in a sample. In these analytical methods, a labeled antibody, labeled antigen, or labeling that has a specific interaction and carries a labeling substance with high detection sensitivity, such as an enzyme, a fluorescent substance, or a luminescent substance. Use nucleic acid or the like. Then, an antigen-antibody compound or a hybridized double-stranded nucleic acid is detected, and the presence or absence of a substance to be detected (target) is detected or quantified.

  As a development of these techniques, a so-called DNA array is known in which a large number of DNA (deoxyribonucleic acid) probes having different base sequences are arranged in an array on a substrate. There is also a method in which many types of proteins are arranged on a membrane filter to produce a protein array having the same structure as a DNA array. As described above, by using a DNA array, a protein array, or the like, it is possible to inspect an extremely large number of items at once.

  In addition, disposable biochemical reaction cartridges that allow biochemical reactions to be performed internally are proposed for the purpose of reducing sample contamination, improving reaction efficiency, miniaturizing equipment, and simplifying operations in various sample analyses. Has been. Some have a plurality of chambers disposed in a biochemical reaction cartridge including a DNA array. According to this biochemical reaction cartridge, it is possible to cause a reaction such as extraction, amplification, or hybridization of DNA in the specimen to be performed internally by moving the solution to each chamber using a pressure difference.

  As a method for injecting a solution from the outside into the biochemical reaction cartridge, there is a method using an external electric syringe pump or a vacuum pump. Further, as a method for moving a solution inside a biochemical reaction cartridge, a method using gravity, capillary action, or electrophoresis is known in addition to a pressure difference. Furthermore, diaphragm pumps, pumps using heating elements, and pumps using piezoelectric elements are known as small micro pumps that can be arranged inside the biochemical reaction cartridge.

  There is also a configuration in which an IC for information storage is provided on a DNA chip used in a biochemical reaction cartridge or a part thereof, and DNA is identified using identification information stored in the IC. In the information storage IC, DNA chip base sequence information and specimen information are written.

  There is also a method of reading a fluorescent substance (fluorescent label) attached to a sample in order to detect the hybridization state of the sample on the DNA chip. In order to detect the target by reading the fluorescent substance, the excitation light applied to the DNA chip is appropriately calibrated so as to generate fluorescence.

  A biochemical reaction cartridge that contains various solutions for supplying a biochemical reaction and is supplied with a specimen is preferably a disposable type from the viewpoint of prevention of secondary infection and contamination and ease of use. However, there is a problem that a biochemical reaction cartridge incorporating a micropump is expensive. Therefore, a disposable biochemical reaction cartridge with a structure that allows a solution to be moved by the action of an external pump without a built-in pump, and allows a series of biochemical reactions to proceed without injecting the solution to the outside after sample injection. Is generally used.

  Each DNA chip is for performing only a single biochemical reaction called hybridization. On the other hand, a biochemical reaction cartridge containing a DNA chip performs various biochemical reactions continuously, and a detection step may be performed last. In this detection step, fluorescence from a fluorescent substance (fluorescent label) attached to the sample is detected by using an image sensor composed of a CMOS sensor, a CCD sensor, or the like.

  In fluorescence detection using an image sensor, dust or dust may adhere to the sensor unit (light receiving surface) of the image sensor. Depending on the position of adhering dust or dust (hereinafter referred to as adhering matter), the fluorescence detection accuracy may decrease.

  Patent Document 1 describes a digital camera that can detect the deposit on the sensor unit. This digital camera performs shooting in a state where the focus of the photographic lens is adjusted so as not to focus. The presence or absence of deposits can be confirmed from the image thus taken.

Patent Document 2 discloses a method for removing deposits. According to this method, by providing an optical element (low-pass filter) on the sensor unit, it is possible to prevent dust from directly attaching to the sensor unit. Further, the dust attached on the optical element is removed by vibrating the optical element itself.
JP 2001-326848 A Japanese Patent No. 03772793

  Depending on the position of the deposit on the sensor unit (light receiving surface), part of the fluorescence from the DNA chip is blocked by the deposit. In this case, since the luminance value of a part of the DNA chip is uncertain, fluorescence detection may not be performed accurately depending on the sample. For this reason, when there is a deposit on the sensor unit, it is necessary to check whether the deposit interferes with fluorescence detection.

  According to the digital camera described in Patent Document 1, it is possible to detect the deposit on the sensor unit. By applying this technique to the fluorescence detection of a DNA chip, it is possible to detect the position of the deposit. However, Patent Document 1 does not disclose a method for examining whether or not the attached matter hinders fluorescence detection when there is an attached matter and a method for dealing with the method.

  There are some deposits that cannot be removed by the method of removing deposits by vibration described in Patent Document 2. For example, an adherent having adhesiveness has a strong adhesive force to the sensor part, and therefore it is very difficult to remove it simply by vibrating the optical element. Therefore, it is difficult to completely solve the problem that the adhering matter hinders the fluorescence analysis only by applying the method of removing the adhering matter by the vibration to the fluorescence detection of the DNA chip.

  An object of the present invention is to provide an imaging apparatus capable of solving the above-described problems and accurately detecting fluorescence.

In order to achieve the above object, an imaging apparatus of the present invention provides:
An image sensor that includes a light receiving surface and images at least one spot area including a plurality of spots formed on the substrate surface on the light receiving surface;
A detection control unit that detects the deposit on the light receiving surface based on a photographed image obtained by imaging the deposit with the image sensor before performing the main photographing for the inspection images of the plurality of spots. And having
The detection control unit determines whether the deposit affects the shooting of the plurality of spots based on a positional relationship between the plurality of spots on the captured image output from the image sensor and the detected deposit. The main photographing is performed only when there is no influence of the attached matter.

  According to the present invention, since it is possible to confirm the influence of the deposit on the spot, it is possible to create an inspection image without the influence of the deposit. Therefore, fluorescence detection can be performed accurately.

  Next, embodiments of the present invention will be described with reference to the drawings.

(First embodiment)
FIG. 1 is a block diagram showing a schematic configuration of a biochemical reaction analyzer according to the first embodiment of the present invention. Referring to FIG. 1, the processing apparatus of the biochemical reaction analyzer includes a table 13 on which a biochemical reaction cartridge including a chamber serving as a reaction field is placed. The electromagnet 14, the Peltier elements 15 and 16, and the communication unit 26 are arranged on the table 13, and these are connected to the control unit 17 that controls the entire processing apparatus.

  The electromagnet 14 applies electromagnetic force in the biochemical reaction cartridge. The Peltier elements 15 and 16 control the temperature of the biochemical reaction cartridge. Specifically, the Peltier element 15 is used for temperature control during DNA amplification by PCR (polymerase chain reaction). On the other hand, the Peltier element 16 is used for temperature control when the amplified sample DNA and DNA probe are hybridized and for temperature control when the sample DNA not hybridized is washed.

  The communication unit 26 transmits power to the IC chip in the biochemical reaction cartridge and transmits and receives signals. Data of the processing apparatus is stored in the IC chip in the biochemical reaction cartridge through the communication unit 26.

  Electric syringe pumps 18 and 19 and pump blocks 22 and 23 are disposed on both sides of the table 13. The pump block 22 has ten pump nozzles 20 serving as inlets and outlets for discharging or sucking air by the pump 18. The pump block 23 has ten pump nozzles 21 serving as inlets and outlets for discharging or sucking air by the pump 19.

  A plurality of electric switching valves (not shown) are arranged between the electric syringe pumps 18 and 19 and the pump nozzles 20 and 21. The electric syringe pumps 18 and 19 and the electric switching valve are connected to the control unit 17.

  The control unit 17 is connected to an input unit 24 for an inspector to input information and instructions. The controller 17 controls connection and disconnection of the electric syringe pumps 18 and 19 by independently opening and closing the pump nozzles 20 and 21 one by one. The control part 17 can also open and close all the pump nozzles 20 and 21 simultaneously. Moreover, the control part 17 performs the biochemical reaction in a biochemical reaction cartridge by operating the electromagnet 14 and the Peltier elements 15 and 16 suitably.

  A detection unit 28 is provided outside the table 13 and the pump blocks 22 and 23. The detection unit 28 detects the hybridization state of the DNA chip of the biochemical reaction cartridge. Specifically, the detection unit 28 detects a fluorescent substance on the DNA chip. A probe for hybridization is spotted on the DNA chip. In the following description, this probe is referred to as a spot, and a region in which spots are arrayed is referred to as a spot area. The spot area may have a single configuration or a plurality of configurations.

  The detection unit 28 includes a stage 29, a fluorescence detection unit (fluorescence detection device) 30, and a communication unit 31, which are connected to the control unit 17. The stage 29 holds a biochemical reaction cartridge. The stage 29 also holds a surface light emitter. The fluorescence detection unit 30 is mainly composed of an optical device, and measures the intensity of fluorescence from the phosphor. The communication unit 31 transmits power to the IC chip in the biochemical reaction cartridge and transmits / receives a signal to / from the IC chip.

  The cartridge transport unit 27 is connected to the control unit 17. The cartridge transport unit 27 transports the biochemical reaction cartridge from the table 13 to the detection unit 28 in accordance with a command from the control unit 17.

  Next, the configuration of the fluorescence detection unit 30 will be specifically described.

  FIG. 2 shows the configuration of the fluorescence detection unit 30. Referring to FIG. 2, the fluorescence detection unit 30 includes an excitation light projection optical system, a fluorescence imaging unit, a stage 45, and a detection control unit 43.

  The surface light emitter 44 and the biochemical reaction cartridge 1 having a fluorescently labeled DNA array are mounted on the stage 45. The stage 45 can move between a first position where the surface light emitter 44 is disposed at the photographing position and a second position where the biochemical reaction cartridge 1 is disposed at the photographing position. The movement of the stage 45 is controlled by the detection control unit 43.

  The surface light emitter 44 is a flat light source (surface light emitting diode) having a wavelength of around 600 nm. In the first position, the light emitting surface of the surface light emitter 44 is arranged at a position where the imaging lens group is out of focus. The surface controller 44 is turned on and off by the detection control unit 43. In the second position, the DNA array of the biochemical reaction cartridge 1 is disposed at a position where the imaging lens group of the fluorescence imaging unit is in focus.

  The excitation light projection optical system is for exciting the fluorescent material of the DNA chip. The excitation light projection optical system includes a solid-state laser light source 32 that generates laser light having a wavelength of 532 nm, a laser shutter 33, a beam expander 34, and a beam homogenizer 35. The beam expander 34 expands the beam diameter of the laser light to a size corresponding to the range of the measurement region of the DNA chip 12. The beam homogenizer 35 converts a laser beam, which is a Gaussian beam, into a flat-top light beam having a uniform intensity. The laser beam emitted from the beam homogenizer 35 is applied to the DNA array of the biochemical reaction cartridge 1.

  The fluorescence imaging unit includes a fluorescence filter 36, an imaging lens group 38 having a variable diaphragm 37, an imaging element 39, a shutter 40, an imaging unit 41, and a cleaning unit 42. The fluorescent filter 36 transmits light in a predetermined wavelength range including the wavelength of fluorescence from the DNA array and the wavelength of light from the surface light emitter 44, and blocks other light. The fluorescence from the DNA array passes through the fluorescence filter 36 and reaches the sensor part (on the light receiving surface) of the image sensor 39 via the imaging lens group 38. The fluorescence image of the DNA array is formed on the sensor unit of the image sensor 39 by the imaging lens group 38.

  The cleaning unit 42 is incorporated in the image sensor 39, and performs a cleaning process for moving or removing dust and dirt attached to the upper surface of the image sensor 39. FIG. 3 shows a schematic configuration of the cleaning unit 42.

  As shown in FIG. 3, the cleaning unit 42 is incorporated in the image sensor 39. The image sensor 39 is made of a substrate having a sensor portion 39a formed at the center, and an infrared absorbing glass 39b is provided on the substrate so as to cover the sensor portion 39a. The cleaning unit 42 includes two piezoelectric elements 42a provided between the infrared absorbing glass 39 and the substrate, and a piezoelectric element driving unit 42b that drives the piezoelectric elements 42a. The piezoelectric element 42 a is affixed to both ends of the infrared absorption glass 39. When a voltage is applied from the piezoelectric element driving unit 42b to the piezoelectric element 42a, the piezoelectric element 42a is deformed in the thickness direction. By repeating this deformation, the infrared absorbing glass 39b vibrates. Due to this vibration, the deposit on the infrared absorbing glass 39b moves. The infrared absorbing glass 39b may be a low pass filter. The piezoelectric element driving unit 42 b is controlled by the detection control unit 43.

  The detection control unit 43 includes an MPU board 43a, a memory 43b, and an image board 43c. The MPU board 43a controls operations of the excitation light projection optical system, the stage 45, and the fluorescence imaging unit, and transmits / receives data to / from the main device (the control unit 17 in FIG. 1). The image board 43 c performs image processing based on the output signal of the image sensor 39. The memory 43b stores data necessary for fluorescence detection and analysis.

  Next, the operation of the biochemical reaction analyzer will be described in detail.

  Biochemical reactions, such as DNA hybridization, can be performed in the biochemical reaction cartridge 1. The processed biochemical reaction cartridge 1 is transported to the inspection unit 28, and the fluorescence detection unit 30 performs the fluorescence detection process. In performing the fluorescence detection process, the control unit 17 confirms the use of the set biochemical reaction cartridge 1 based on the information received from the IC chip, and determines the number of spot areas of the DNA chip being used and the number of spots. The spot information indicating the arrangement is acquired. The acquired spot information is transmitted from the control unit 17 to the detection control unit 43. The detection control unit 43 stores the received spot information in the memory 43b.

  The fluorescence detection includes first to third fluorescence detection processes. The first fluorescence detection process is a process performed on a sample having a small influence of fluorescence fading, and this process is a basic operation in a normal time. The second and third fluorescence detection processes are processes performed on a sample having a large influence of fluorescence fading.

(1) First fluorescence detection process:
FIG. 4 is a flowchart showing a normal fluorescence detection procedure. FIG. 5 is a diagram for explaining the positional relationship between the deposit and the spot area in the fluorescence detection.

  In step S101, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position. In step S102, the detection control unit 43 performs imaging of the DNA chip in the marker detection mode.

  FIG. 6 is a schematic diagram of a DNA chip to be photographed. As shown in FIG. 6, the DNA chip 300 has a plurality of spot areas 301 in which a plurality of spots are arranged in a matrix. Each of the spot areas 301 includes a marker 302 serving as a reference index arranged at a predetermined spot and a probe 303 arranged at other spots. Since the fluorescence from the marker 302 has a higher luminance than the fluorescence from the probe 303, the marker 302 and the probe 303 can be distinguished from this difference in luminance. Based on the luminance of the fluorescence from the probe 303, the actual hybridization state is determined. In the DNA chip manufacturing process, spots formed on the DNA chip are managed to have a certain size.

  The arrangement of the marker 302 and the probe 303 is the same in each spot area 301, and spot information indicating the positional relationship is stored in the memory 43b. The detection control unit 43 detects a spot corresponding to the marker 302 on a captured image obtained by capturing the spot area 301 with the image sensor 39. And the detection control part 43 specifies the spot corresponding to the probe 303 on a picked-up image from the arrangement | positioning of the detected spot, and the spot information stored in the memory 43b.

  FIG. 7 is a schematic diagram of an image obtained by photographing the DNA chip shown in FIG. Since the luminance of the fluorescence from the marker 302 is relatively strong compared to the fluorescence from the probe 303, the spot of the marker 302 can be easily identified on the image. On the other hand, the luminance of the fluorescence from the probe 303 varies depending on the hybridization state. For the probe 303 with low fluorescence luminance, it is difficult to identify the spot on the image. In this embodiment, all the spots corresponding to the probe 303 can be specified on the image based on the spot position of the marker 302 on the image and the spot information stored in the memory 43b.

  Here, the photographing procedure in the marker detection mode in step S102 will be specifically described. FIG. 8 shows a photographing procedure in the marker detection mode.

  First, the laser light source 32 is turned on (step S1020), the variable diaphragm 37 is opened (step S1021), and the laser shutter 33 is opened (step S1022). Thereby, a laser beam is irradiated to the DNA chip of the biochemical reaction cartridge 1 moved to the photographing position.

  Next, when the shutter 40 is opened (step S1023), the fluorescence from each spot area of the DNA chip enters the sensor unit of the image sensor 39, and charges corresponding to the amount of incident light are accumulated in the image sensor 39 ( Step S1024). After the time set for marker detection elapses (step S1025), charge accumulation in the image sensor 39 is terminated (step S1026), and the shutter 40 and the laser shutter 33 are closed (steps S1027 and S1028). Thereafter, an image signal corresponding to the electric charge accumulated in the image sensor 39 is transferred from the image sensor 39 to the detection control unit 43 (step S1029).

  After photographing in the marker detection mode is performed according to the procedure shown in FIG. 8, the detection control unit 43 extracts a marker on the image transferred from the image sensor 39 in step S104. And the detection control part 43 calculates | requires the position of the spot corresponding to each probe on an image based on the spot position of the marker and the spot information stored in the memory 43b. The detection control unit 43 stores information indicating the determined spot position of each probe in the memory 43b.

  In step S104, the detection control unit 43 moves the biochemical reaction cartridge 1 from the photographing position to the retracted position. In step S105, the detection control unit 43 moves the surface light emitter 44 to the photographing position and lights the surface light emitter 44. In step S106, the detection control unit 43 performs imaging in the dust imaging mode.

  Here, the photographing procedure in the dust photographing mode in step S106 will be specifically described. FIG. 9 shows a photographing procedure in the dust photographing mode.

  First, the variable stop 37 is stopped (step S1060). Next, when the shutter 40 is opened (step S1061), the light from the surface light emitter 44 enters the sensor unit of the image sensor 39, and charges corresponding to the amount of incident light are accumulated in the image sensor 39 (step S1062). ). After the time set for dust photography has elapsed (step S1063), the charge accumulation in the image sensor 39 is terminated (step S1064), and the shutter 40 is closed (step S1065). Thereafter, an image signal corresponding to the electric charge accumulated in the image sensor 39 is transferred from the image sensor 39 to the detection controller 43 (step S1066).

  After shooting in the dust shooting mode is performed according to the procedure shown in FIG. 9, the detection control unit 43 calculates the position and size of dust on the image transferred from the image sensor 39 in step S107. When dust adheres to the sensor unit, the luminance on the image of the part to which the dust adheres decreases. Therefore, it is possible to regard the portion where the luminance is reduced in the image as dust. The detection control unit 43 stores dust information including the calculated dust size and position in the memory 43b. The size of the dust may be replaced with a circle including the entire dust, and the center position of the circle may be the dust position.

  In step S108, the detection control unit 43 determines whether the number of spot areas on the DNA chip is one or more. In this determination, the detection control unit 43 refers to the position information of the spot obtained by photographing in the marker detection mode, and determines the number of spot areas from the position information. When there is one spot area, the process proceeds to step S109, and when there are a plurality of spot areas, the process proceeds to step S130.

  In step S109, the detection control unit 43 checks whether there is a spot that overlaps with dust in the spot area. In this determination, as shown in FIG. 5, when there is no spot overlapping with dust (in the case of “OK”), the image of the spot area can be used as the final image data for fluorescence detection, so step S110. Proceed to If there is a spot overlapping with dust (in the case of “NG”), the image of the spot area cannot be completed, and the process proceeds to step S114.

  In step S110, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. Then, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position in step S111, and performs the main imaging in the microarray imaging mode in step S112.

  Here, the imaging procedure in the microarray imaging mode in step S112 will be specifically described. FIG. 10 shows an imaging procedure in the microarray imaging mode.

  First, the laser light source 32 is turned on (step S1120), the variable diaphragm 37 is opened (step S1121), and the laser shutter 33 is opened (step S1122). Thereby, a laser beam is irradiated to the DNA chip of the biochemical reaction cartridge 1 moved to the photographing position.

  Next, when the shutter 40 is opened (step S1123), the fluorescence from each spot area of the DNA chip enters the sensor unit of the image sensor 39, and charges corresponding to the amount of incident light are accumulated in the image sensor 39 ( Step S1124). After the time set for microarray imaging has elapsed (step S1125), charge accumulation in the image sensor 39 is terminated (step S1126), and the shutter 40 and the laser shutter 33 are closed (steps S1127 and S1128). Thereafter, image data corresponding to the electric charge accumulated in the image sensor 39 is transferred from the image sensor 39 to the detection control unit 43 (step S1129).

  In step S113, the detection control unit 43 sends the image data obtained from the image sensor 39 to the main body (control unit 17). Thereafter, this detection operation is terminated.

  Further, in step S114, the detection control unit 43 confirms whether or not the cleaning by the cleaning unit 42 has been performed from the start of the main detection operation to the present. The detection control unit 43 manages the number of operations of the cleaning unit 42 in the memory 43b, and determines whether or not it is the first cleaning operation based on the number of operations. If it is determined that this is the first cleaning operation, the process proceeds to step S115. If it is determined that it is not the first cleaning operation, the process proceeds to step S118.

  In step S115, the detection control unit 43 sets the number of operations of the cleaning unit 42 to a preset maximum number of operations (initial value). The maximum number of operations can be freely set by the inspector through the input unit 24 shown in FIG. In step S116, the detection control unit 43 causes the cleaning unit 42 to perform a cleaning operation.

  Here, the cleaning operation procedure in step S116 will be specifically described. FIG. 11 shows a cleaning operation procedure. First, the shutter 40 is opened (step S1160). Next, the cleaning unit 42 is operated (step S1161). Finally, the shutter 40 is closed (step S1162).

  When the cleaning operation is performed, in step S117, the detection control unit 43 decreases the value of the number of operations stored in the memory 43b by one. Thereafter, the process returns to step S106 in order to check whether the dust removal is successful.

  In step S118, the detection control unit 43 checks whether or not the value of the number of operations stored in the memory 43b is zero. If the value of the number of operations is not 0, the process proceeds to step S116. If the value of the number of operations is 0, the process proceeds to step S119.

  In step S119, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S120, the detection control unit 43 informs the main body (control unit 17) that dust could not be removed (or moved) by cleaning. Thereafter, this detection operation is terminated.

  Further, in step S130, the detection control unit 43 checks whether or not there is a spot overlapping with dust for each of the plurality of spot areas (spot area 301 shown in FIG. 6). In this determination, as shown in FIG. 5, when there is a spot area where all the spots do not overlap with dust (in the case of “OK”), the image of the spot area may be used as final image data for fluorescence detection. Since it can, it progresses to step S131. If there is no spot area where all the spots do not overlap with dust (in the case of “NG”), the image of the spot area cannot be completed, and the process proceeds to step S136.

  In step S131, the detection control unit 43 stores information (number) indicating a spot area in which all spots do not overlap dust in the memory 43b. In the example shown in FIG. 5, information on the second spot area is stored in the memory 43b.

  In step S132, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. Next, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position in step S133, and performs the main imaging in the microarray imaging mode shown in FIG. 10 in step S134. Then, in step S135, the detection control unit 43 sends image data of an effective spot area (second spot area shown in FIG. 5) from the image data obtained by the actual photographing to the main body (control unit 17). . Thereafter, this detection operation is terminated.

  In step S136, as shown in FIG. 5, the detection control unit 43 sets spots corresponding to the second and third spot areas for spots that overlap dust among the spots constituting the first spot area. Check whether it can be used and complemented. If any one of the corresponding spots in the second and third spot areas does not overlap with dust (in the case of “OK”), the detection control unit 43 determines that complementation is possible, and proceeds to step S137. When the corresponding spots in the second and third spot areas all overlap with dust (in the case of “NG”), the detection control unit 43 determines that complementation is impossible and proceeds to step S114.

  In step S137, the detection control unit 43 complements information indicating a spot that needs to be complemented and information indicating a spot used for complementing the spot (corresponding spots in the second and third spot areas). Information is stored in the memory 43b.

  In step S138, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. Next, the detection control unit 43 moves the biochemical reaction cartridge 1 to the photographing position in step S139, and performs the main photographing in the microarray photographing mode shown in FIG. 10 in step S140. In step S141, the detection control unit 43 refers to the complementary information stored in the memory 43b, collects spots that are not affected by dust from the image data obtained in the actual shooting, and collects the spots as one spot. Send to the main unit as area data. Thereafter, this detection operation is terminated.

  According to the first fluorescence detection process described above, the size and position of each spot in each spot area can be acquired based on the image data captured in the marker detection mode. In addition, the size and position of dust (attachment) can be acquired from image data captured in the dust imaging mode. By comparing the size and position of the spot thus obtained with the size and position of dust (attachment), it is possible to check whether dust (attachment) hinders fluorescence detection.

  In addition, since spots affected by dust (attachment) are complemented by corresponding spots in other areas, an inspection image free from the influence of dust (attachment) can be created. This makes it possible to accurately detect fluorescence.

(2) Second fluorescence detection process:
Depending on the sample, the spot may cause fluorescent fading of the spot, which may affect the fluorescence detection. In this case, since marker photography cannot be performed, individual positions of the spots cannot be determined. In the second fluorescence detection process, fluorescence detection is performed without marker photography.

  FIG. 12 is a flowchart showing a second fluorescence detection processing procedure. FIG. 13 is a diagram for explaining the positional relationship between the deposit and the spot area in the fluorescence detection.

  In step S201, the detection control unit 43 moves the biochemical reaction cartridge 1 from the photographing position to the retracted position. In step S202, the detection control unit 43 moves the surface light emitter 44 to the photographing position and lights the surface light emitter 44. In step S203, the detection control unit 43 performs imaging in the dust imaging mode according to the procedure illustrated in FIG. In step S <b> 204, the detection control unit 43 calculates the position and size of dust on the image transferred from the image sensor 39. The detection control unit 43 stores dust information including the calculated dust size and position in the memory 43b.

  In step S205, the detection control unit 43 determines whether the number of detection target spot areas is one or more. In this determination, the detection control unit 43 refers to spot information indicating the number of spot areas and the spot arrangement of the DNA chip acquired from information received from the IC chip. If there is one spot area, the process proceeds to step S206, and if there are a plurality of spot areas, the process proceeds to step S230.

  In step S206, the detection control unit 43 assumes a virtual spot area based on the spot information, and checks whether the virtual spot area overlaps with dust. The virtual spot area corresponds to the spot area of the DNA chip on the photographed image. In this determination, as shown in FIG. 13, when the virtual spot area does not overlap with dust (in the case of “OK”), it is determined that there is no possibility that the spot overlaps with dust. Therefore, it is determined that the image of the virtual spot area can be used as the final image data for fluorescence detection, and the process proceeds to step S207. When the virtual spot area overlaps with dust (in the case of “NG”), it is determined that the spot may overlap with dust. Therefore, it is determined that the spot area image cannot be completed, and the process proceeds to step S211.

  In step S207, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S208, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position, and in step S209, performs the main imaging in the microarray imaging mode according to the procedure illustrated in FIG.

  In step S210, the detection control unit 43 sends the image data obtained from the image sensor 39 to the main body (control unit 17). Thereafter, this detection operation is terminated.

  In step S211, the detection control unit 43 confirms whether the cleaning unit 42 has performed cleaning from the start of the main detection operation to the present time. The detection control unit 43 manages the number of operations of the cleaning unit 42 in the memory 43b, and determines whether or not it is the first cleaning operation based on the number of operations. If it is determined that this is the first cleaning operation, the process proceeds to step S212. If it is determined that it is not the first cleaning operation, the process proceeds to step S215.

  In step S212, the detection control unit 43 sets the number of operations of the cleaning unit 42 to a preset maximum number of operations (initial value). In step S213, the detection control unit 43 causes the cleaning unit 42 to perform a cleaning operation according to the procedure illustrated in FIG. When the cleaning operation is performed, in step S214, the detection control unit 43 decrements the value of the number of operations stored in the memory 43b by one. Thereafter, the process returns to step S203 in order to check whether the dust removal is successful.

  In step S215, the detection control unit 43 checks whether or not the value of the number of operations stored in the memory 43b is zero. If the value of the number of operations is not 0, the process proceeds to step S213. If the value of the number of operations is 0, the process proceeds to step S216.

  In step S216, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S217, the detection control unit 43 notifies the main body (control unit 17) that the dust could not be removed (or moved) by cleaning. Thereafter, this detection operation is terminated.

  In step S230, the detection control unit 43 assumes a plurality of virtual spot areas based on the spot information acquired from the reception information from the IC chip, and determines whether each of these virtual spot areas overlaps with dust. Investigate. In this determination, as shown in FIG. 13, when there is a virtual spot area that does not overlap with dust (in the case of “OK”), an image corresponding to the virtual spot area is used as final image data for fluorescence detection. The process proceeds to step S231. If there is no virtual spot area that does not overlap with dust (in the case of “NG”), the image of the spot area cannot be completed, and the process proceeds to step S236.

  In step S231, the detection control unit 43 stores information (number) indicating a virtual spot area that does not overlap dust as effective spot area information in the memory 43b. In the example shown in FIG. 13, the information on the second virtual spot area is stored in the memory 43b.

  In step S232, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S233, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position. In step S234, the detection control unit 43 performs main imaging in the microarray imaging mode illustrated in FIG. In step S235, the detection control unit 43 refers to the effective spot area information stored in the memory 43b, extracts the image data of the effective spot area from the image data obtained by the actual photographing, and extracts it from the main body. (Control unit 17). Thereafter, this detection operation is terminated.

  Further, in step S236, the detection control unit 43 can complement spots overlapping with dust with corresponding spots in other virtual spot areas based on the relative positional relationship of dust between the virtual spot areas. Investigate whether there is a possibility of not being able to. Specifically, as shown in FIG. 13, when the relative positions of the area and the dust coincide between the first to third virtual spot areas, the spot overlapping with the dust is replaced with another virtual spot. It may not be possible to supplement with the corresponding spot in the area. When there is even one virtual spot area where the relative position of the area and the dust does not match, there is a possibility that the spot overlapping with the dust can be complemented with the corresponding spot in the other virtual spot area. If there is a possibility that the spot can be complemented, the process proceeds to step S237. If there is a possibility that the spot cannot be complemented, the process proceeds to step S211.

  In step S237, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S238, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position. In step S239, the detection control unit 43 performs main imaging in the microarray imaging mode illustrated in FIG.

  In step S240, the detection control unit 43 extracts each spot of the first to third spot areas from the image data obtained in the actual photographing, and determines the positions of the spots and the dust acquired in step S204. Compare. Then, if there is a spot affected by dust in the first spot area, the detection control unit 43 sets the spot corresponding to the second or third spot area (affected by dust). Complement with no spot). In S241, the detection control unit 43 sends the spot area data for which the spot is complemented to the main body. Thereafter, this detection operation is terminated.

  Hereinafter, the spot complementing process in step S240 will be specifically described.

  FIG. 14 is a schematic diagram showing a minimum dust interval at which dust affects a spot when a spot in the first spot area is complemented with a spot in the second spot area. The image data obtained by the actual photographing includes first to third spot areas that have the same spot alignment direction and are arranged at equal intervals along the alignment direction. From the left in the drawing, the first spot area, the second spot area, and the third spot area are arranged in this order. Each spot area consists of nine spots arranged in 3 rows and 3 columns. Each spot has the same diameter and is arranged at equal intervals. In each spot area, the positions of the spots are represented by numbers 1 to 9 from the upper left to the lower right.

  In FIG. 14, the circular areas indicated by A and B are dust. The dust A is located between the first spot and the second spot in the first spot area, and the outer edge of the dust A is in contact with the outer edges of the first and second spots. . The dust B is located on the left side (first spot area side) of the first spot in the second spot area, and the outer edge of the dust B is in contact with the outer edge of the first spot. The distance between the dusts A and B in this case (the distance between the dust center positions) defines the distance at which the dusts A and B will affect the first spots in the first and second spot areas. This is the minimum dust interval (limit of dust proximity) in the case. That is, the state shown in FIG. 14 is the closest state among the dust intervals in which the dusts A and B affect the first spots in the first and second spot areas.

  When the dust interval is the minimum dust interval, it is determined that the first spot of the first spot area cannot be complemented with the first spot of the second spot area. When the dust interval is smaller than the minimum dust interval, it is determined that the first spot of the first spot area can be complemented with the first spot of the second spot area.

  If it is determined that the first spot in the second spot area cannot be complemented, it is determined whether or not the first spot in the third spot area can be complemented. In the example shown in FIG. 14, since the first spot in the third spot area is not affected by dust, the first spot in the first spot area is complemented with the first spot. It is judged that it is possible.

  FIG. 15 is a schematic diagram showing a maximum dust interval at which dust affects a spot when a spot in the first spot area is complemented with a spot in the second spot area. The image data obtained by the actual photographing includes the same first to third spot areas as those shown in FIG.

  In the example of FIG. 15, the dust A is located on the left side of the first spot area (the side opposite to the second spot area), and the outer edge of the dust A is the first spot area. It touches the outer edge. The dust B is located on the right side (third spot area side) of the first spot in the second spot area, and the outer edge of the dust B is in contact with the outer edge of the first spot. In this case, the distance between the dusts A and B defines the maximum dust distance (the amount of dust) when the distance between the dusts A and B defines the first spot in the first and second spot areas. The limit of distance). That is, the state shown in FIG. 15 is the farthest among the dust intervals at which the dusts A and B affect the first spots in the first and second spot areas.

  When the dust interval is the maximum dust interval, it is determined that the first spot of the first spot area cannot be complemented with the first spot of the second spot area. When the dust interval is larger than the maximum dust interval, it is determined that the first spot of the first spot area can be complemented with the first spot of the second spot area. Further, when the dust interval is in the range of not less than the minimum dust interval and not more than the maximum dust interval, the first spot in the first spot area is supplemented with the first spot in the second spot area. It is judged that it is not possible.

  FIG. 16 is a schematic diagram showing a minimum dust interval at which dust affects a spot when a spot in the first spot area is complemented with a spot in the third spot area. The image data obtained by the actual photographing includes the same first to third spot areas as those shown in FIG.

  In FIG. 16, the circular areas indicated by A, B, and C are dust. The arrangement of the dusts A and B is the same as that shown in FIG. The dust C is located on the left side (second spot area side) of the first spot in the third spot area, and the outer edge of the dust C is in contact with the outer edge of the first spot.

  The distance between the dusts A and C in this case (the distance between the dust center positions) defines the distance at which the dusts A and C will affect the first spots in the first and third spot areas. This is the minimum dust interval (limit of dust proximity) in the case. That is, the state shown in FIG. 16 is the closest state among the dust intervals in which the dusts A and C affect the first spots in the first and third spot areas.

  When the dust interval is the minimum dust interval, it is determined that the first spot of the first spot area cannot be complemented with the first spot of the third spot area. When the dust interval is smaller than the minimum dust interval, it is determined that the first spot of the first spot area can be complemented with the first spot of the third spot area.

  FIG. 17 is a schematic diagram showing the maximum dust interval at which dust affects the spot when the spot of the first spot area is complemented with the spot of the third spot area. The image data obtained by the actual photographing includes the same first to third spot areas as those shown in FIG.

  The arrangement of the dusts A and B is the same as that shown in FIG. The dust C is located between the first spot and the second spot in the third spot area, and the outer edge of the dust C is in contact with the outer edges of the first and second spots. . In this case, the distance between the dusts A and C defines the maximum dust distance (the amount of dust) when the dusts A and C define the distance at which each first spot in the first and third spot areas is affected. The limit of distance). That is, the state shown in FIG. 17 is the farthest among the dust intervals at which the dusts A and C affect the first spots in the first and third spot areas.

  When the dust interval is the maximum dust interval, it is determined that the first spot in the first spot area cannot be complemented with the first spot in the third spot area. When the dust interval is larger than the maximum dust interval, it is determined that the first spot of the first spot area can be complemented with the first spot of the third spot area. Further, when the dust interval is in the range of not less than the minimum dust interval and not more than the maximum dust interval, the first spot in the first spot area is complemented with the first spot in the third spot area. It is judged that it is not possible.

  In the example shown in FIGS. 14 to 17, the dust positional relationship when dust A affects the first spot of the first area spot is shown. Which spot is affected may vary depending on the set state of the cartridge. Since each spot has the same diameter and is arranged at equal intervals, the minimum dust interval and the maximum dust interval are valid for any spot.

  The minimum dust interval dmin in the case where the spot of the first spot area is complemented with the corresponding spot of the second spot area is represented by the following formula, taking the spot size and dust size into consideration. .

dmin = A−S−D1−D2
Here, A is an area interval, S is a spot diameter, D1 is a radius of dust A (first deposit) located in the first spot area, and D2 is dust B (positioned in the second spot area). Radius of the second deposit). When the interval between the dusts A and B is smaller than the minimum dust interval dmin, the detection control unit 43 determines that the dusts A and B do not affect the corresponding spot between the first and second spot areas.

  The maximum dust interval dmax in the case where the spot of the first spot area is complemented with the corresponding spot of the second spot area is expressed by the following equation, taking the spot size and dust size into consideration. become.

dmax = A + S + D1 + D2
When the interval between the dusts A and B is larger than the maximum dust interval dmax, the detection control unit 43 determines that the dusts A and B do not affect the corresponding spot between the first and second spot areas.

  Further, the minimum dust interval dmin when the spot of the first spot area is complemented with the spot of the third spot area is expressed by the following equation, taking the spot size and dust size into consideration. .

dmin = A * 2-S-D1-D3
Here, D3 is the radius of dust C (third deposit) located in the third spot area. When the interval between the dusts A and C is smaller than the minimum dust interval dmin, the detection control unit 43 determines that the dusts A and C do not affect the corresponding spots between the first and third spot areas.

  Further, the maximum dust interval dmax when the spot of the first spot area is complemented with the spot of the third spot area is expressed by the following formula, taking the spot size and dust size into consideration. .

dmax = A × 2 + S + D1 + D3
When the interval between the dusts A and C is larger than the maximum dust interval dmax, the detection control unit 43 determines that the dusts A and C do not affect the corresponding spot between the first and third spot areas.

In the above description, the possibility of complementation is determined based on the relationship between dust and spots in the direction of arrangement of spot areas, but the relationship between dust and spots in a slightly oblique direction with respect to the direction of arrangement of spot areas. It is also possible to consider the possibility of complementation based on. In this case, if the range is expressed by a formula,
[Spot Diameter] + [Dust A Radius] + [Dust B Radius]
It is. If the distance between the dusts A and B is less than or equal to this range for one spot, it is determined that the dust affects the spot. By using this determination method in combination with the determination method based on the minimum dust interval dmin and the maximum dust interval dmax given by the above-described equations, the overlap between dust and spots is determined.

  FIG. 18 shows an example of the determination result according to the degree of dust and spot overlap. The state in which the first spot and the dust A completely overlap has an influence. The state in which the outer edge of the first spot is in contact with the outer edge of the dust A is considered to be a state in which the first spot and the dust A overlap each other, and has an influence. The state in which the first spot and the dust A are completely separated has no influence.

  According to the second fluorescence detection processing described above, an effective spot area that is not affected by dust (attachment) is determined based on the relative positional relationship between the position of dust (attachment) and each virtual spot area. can do. An inspection image free from the influence of dust (attachment) can be created based on the effective spot area. This makes it possible to accurately detect fluorescence.

  When there is no effective spot area, a spot affected by dust (attachment) is complemented with a corresponding spot in another area to acquire the effective spot area. An inspection image free from the influence of dust (attachment) can be created based on the effective spot area.

(3) Third fluorescence detection process:
Here, a fluorescence detection process different from the second fluorescence detection process when performing fluorescence detection without marker imaging will be described.

  The spot areas are not necessarily arranged at equal intervals. In addition, the order of the spots may be different for each spot area. Information such as spot position and spot type (or arrangement) is stored in the IC chip of the cartridge. The control unit 17 transfers the spot information indicating the number of spot areas and the spot arrangement of the DNA chip acquired from the reception information from the IC chip to the detection control unit 43. The detection control unit 43 determines the possibility of spot-dust overlap and spot complementation by superimposing a spot image created based on spot information and indicating a spot arrangement on the dust image.

  FIG. 19 schematically shows a detection area including a template and a dust image. The template 101 is created based on the spot information, and includes first to third spot areas. The size and arrangement of the spots differ between the spot areas. Specifically, the arrangement of spots indicated by numbers 1, 2, and 3 in FIG. 19 differs between spot areas. The detection control unit 43 superimposes the template 101 on the detection area 100 including the dust image, and gradually changes the position of the template 101 on the detection area 100 in the horizontal and vertical directions for each fixed distance. Investigate the positional relationship between spots and dust in each spot area. And the detection control part 43 determines the possibility of the overlap of a spot and dust, or the complement of a spot based on the positional relationship of the spot and dust of each spot area. Here, although a template including three spot areas has been described as an example, the number of spot areas set in the template is determined by information received from the IC chip.

  FIG. 20 is a flowchart showing a third fluorescence detection processing procedure. FIG. 21 is a diagram for explaining the positional relationship between the deposit and the spot area on the template in the fluorescence detection.

  The processing from step S301 to S305 is the same as the processing from step S201 to S205 shown in FIG. In step S305, if there is one spot area, the process proceeds to step S306, and if there are a plurality of spot areas, the process proceeds to step S330.

  In step S306, the detection control unit 43 superimposes the template 101 in which one spot area is set on the detection area 100 as shown in FIG. Determine if the dust does not overlap the spot. If the dust does not overlap the spot, the process proceeds to step S307. If dust overlaps with the spot, the process proceeds to step S311.

  In step S307, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. Next, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position in step S308, and performs main imaging in the microarray imaging mode in step S309 according to the procedure shown in FIG. In step S210, the detection control unit 43 sends the image data obtained from the image sensor 39 to the main body (control unit 17). Thereafter, this detection operation is terminated.

  In step S311, the detection control unit 43 confirms whether the cleaning unit 42 has performed cleaning from the start of the main detection operation to the present. The detection control unit 43 manages the number of operations of the cleaning unit 42 in the memory 43b, and determines whether or not it is the first cleaning operation based on the number of operations. If it is determined that this is the first cleaning operation, the process proceeds to step S312. If it is determined that it is not the first cleaning operation, the process proceeds to step S315.

  In step S312, the detection control unit 43 sets the number of operations of the cleaning unit 42 to a preset maximum number of operations (initial value). In step S313, the detection control unit 43 causes the cleaning unit 42 to perform a cleaning operation according to the procedure shown in FIG. When the cleaning operation is performed, in step S314, the detection control unit 43 decreases the value of the number of operations stored in the memory 43b by one. Thereafter, the process returns to step S303 in order to check whether the dust removal is successful.

  In step S315, the detection control unit 43 checks whether or not the value of the number of operations stored in the memory 43b is zero. If the value of the number of operations is not 0, the process proceeds to step S313. If the value of the number of operations is 0, the process proceeds to step S316.

  In step S316, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S317, the detection control unit 43 notifies the main body (control unit 17) that the dust cannot be removed (or moved) by cleaning. Thereafter, this detection operation is terminated.

  In step S330, the detection control unit 43 superimposes the template 101 on which a plurality of spot areas are set on the detection area 100, as shown in FIG. Check the position. Then, the detection control unit 43 checks whether there is a spot area where the dust does not overlap the spot, regardless of the position on the detection area 100 where the template 101 is located. If there is a spot area where dust does not overlap with the spot, the process proceeds to step S331. If there is no spot area where dust does not overlap with the spot, the process proceeds to step S336.

  In step S331, the detection control unit 43 stores information (number) of the spot area where dust does not overlap with the spot in the memory 43b as effective spot area information. In step S332, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S333, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position. In step S334, the detection control unit 43 performs main imaging in the microarray imaging mode illustrated in FIG. In step S335, the detection control unit 43 refers to the effective spot area information stored in the memory 43b, extracts the image data of the effective spot area from the image data obtained by the actual photographing, and extracts it from the main body. (Control unit 17). Thereafter, this detection operation is terminated.

  In step S336, the detection control unit 43 determines whether spot complementing is possible between a plurality of spot areas. Specifically, as shown in FIG. 21, the detection control unit 43 superimposes the template 101 in which the first to third spot areas are set on the detection area 100 and positions of the spots constituting each spot area. Check the location of dust. Then, the detection control unit 43 can complement the corresponding spot between the first spot area and the second or third spot area regardless of the position of the template 101 on the detection area 100. It is determined whether or not. If spot complement can be performed, the process proceeds to step S337. If spot complement cannot be performed, the process proceeds to step S311.

  In step S337, the detection control unit 43 turns off the surface light emitter 44 and retracts the surface light emitter 44 from the photographing position. In step S338, the detection control unit 43 moves the biochemical reaction cartridge 1 to the imaging position. In step S339, the detection control unit 43 performs main imaging in the microarray imaging mode illustrated in FIG.

  In step S340, the detection control unit 43 extracts each spot of the first to third spot areas from the image data obtained in the actual photographing, and determines the positions of the spots and the dust acquired in step S304. Compare. Then, if there is a spot affected by dust in the first spot area, the detection control unit 43 sets the spot corresponding to the second or third spot area (affected by dust). Complement with no spot). For this complement, the same processing as the complement in step S240 shown in FIG. 12 can be applied. In S341, the detection control unit 43 sends the data of the spot area where the spot is complemented to the main body. Thereafter, this detection operation is terminated.

  According to the third fluorescence detection process described above, the dust is determined based on the positional relationship between the position of dust (attachment) and the spot at each position in the superposition of the image captured in the dust capturing mode and the template. An effective spot area that is not affected by (attachment) can be determined. An inspection image free from the influence of dust (attachment) can be created based on the effective spot area. This makes it possible to accurately detect fluorescence.

  When there is no effective spot area, a spot affected by dust (attachment) is complemented with a corresponding spot in another area to acquire the effective spot area. An inspection image free from the influence of dust (attachment) can be created based on the effective spot area.

  Next, the biochemical reaction cartridge 1 will be described in detail.

  The main body (housing) of the biochemical reaction cartridge 1 is made of a synthetic resin such as polymethyl methacrylate (PMMA), acrylonitrile-butadiene-styrene (ABS) copolymer, polystyrene, polycarbonate, polyester, polyvinyl chloride or the like. ing. These materials are transparent or translucent.

  FIG. 22 shows the configuration of the biochemical reaction cartridge 1. Referring to FIG. 22, a specimen inlet 2 for injecting a specimen such as blood using a syringe or the like is provided at the upper part of the biochemical reaction cartridge 1, and is sealed with a rubber cap. In addition, on both side surfaces of the biochemical reaction cartridge 1, a plurality of nozzle inlets 3 for inserting and applying pressure or depressurization for moving the internal solution are provided and sealed with rubber caps. ing.

  The biochemical reaction cartridge 1 is provided with an IC chip 25. The IC chip 25 includes a nonvolatile storage unit and a communication unit for receiving power from outside and transmitting / receiving signals. Identification information (ID) for identifying the biochemical reaction cartridge 1 is written in the storage unit of the IC chip 25. Further, the type of the biochemical reaction cartridge 1, the procedure of the processing steps, the analysis information for analyzing the result of the biochemical reaction, and the like can be written in the storage unit.

  Usually, the processing device of the biochemical reaction analyzer or the device attached thereto stores information on the procedure of the processing step for each type of the biochemical reaction cartridge 1 in the storage unit. When the type of the biochemical reaction cartridge 1 is written in the IC chip 25, the type is read, and the procedure of the processing process corresponding to the type is selected from the procedure stored in the storage unit, and the process is performed according to the procedure. I do. However, when the type of the biochemical reaction cartridge 1 is not stored in the storage unit, the procedure of the processing process written in the IC chip 25 is read and processing is performed in accordance with the procedure. The data written as the procedure of the processing step may include a temperature condition or the like applied to cause a biochemical reaction.

  FIG. 23 is a plan sectional view of the biochemical reaction cartridge 1. Ten nozzle inlets 3a to 3j are provided on one side surface of the biochemical reaction cartridge 1, and ten nozzle inlets 3k to 3t are provided on the other side surface on the opposite side. The nozzle inlets 3a to 3j communicate with the chambers 5a to 5j through the flow paths 4a to 4j. The nozzle inlets 3k, 3l, 3m, 3o, 3r, and 3t communicate with the chambers 5k, 5l, 5m, 5o, 5r, and 5t through the flow paths 4k, 4l, 4m, 4o, 4r, and 4t, respectively. The flow paths 4a to 4t are air flow paths through which air flows. The chambers 5a to 5t are places where solutions are stored or where reactions occur. The nozzle inlets 3n, 3p, 3q, 3s are spare nozzles, and none of them communicates with the chamber.

  The specimen inlet 2 a communicates with the chamber 7. The chamber 7 communicates with the chambers 5a, 5b, 5c, and 5k through the flow paths 6a, 6b, 6c, and 6k, and communicates with the chamber 8 through the flow path 10. The chamber 8 communicates with the chambers 5 g and 5 o through the flow paths 6 g and 6 o and also communicates with the chamber 9 through the flow path 11. The chamber 9 communicates with the chambers 5h, 5i, 5j, 5r, and 5t via the flow paths 6h, 6i, 6j, 6r, and 6t. The flow path 10 communicates with the chambers 5d, 5e, 5f, 5l, and 5m via the flow paths 6d, 6e, 6f, 6l, and 6m.

A square hole is formed in the bottom surface of the chamber 9. The DNA chip 12 is attached to the square hole so that the probe surface is on the top. The DNA chip 12 is obtained by arranging several tens to several hundreds of thousands of different DNA probes 37 on a solid surface of a glass plate having a size of about 1 square inch (about 645 mm ² ). By using this DNA chip 12 to perform a hybridization reaction with DNA in a specimen, a large number of genes can be examined at once. These DNA probes 37 are regularly arranged in a matrix, and the addresses (positions indicated as what rows and what columns) of the respective DNA probes 37 can be easily taken out as information. Examples of genes to be examined include infectious disease viruses, bacteria, disease-related genes, and individual gene polymorphisms.

  Here, a setting example of each of the chambers 5a to 5t for processing the specimen in the present embodiment will be described. The chamber 5a contains a first hemolytic agent containing EDTA (ethylenediaminetetraacetic acid) that destroys the cell wall, and the chamber 5b contains a second hemolytic agent containing a protein denaturant such as a surfactant. . The chamber 5c contains silica-coated magnetic particles on which DNA is adsorbed. The chambers 5l and 5m accommodate first and second extraction detergents used for DNA purification during DNA extraction, respectively.

  The chamber 5d contains an eluate composed of a low-concentration salt buffer that elutes DNA from magnetic particles. The chamber 5g contains a mixture of chemicals necessary for PCR, that is, a primer, a polymerase, a dNTP solution, a buffer, and Cy3-dUTP (fluorescent label manufactured by Amersham Biosciences) containing a fluorescent agent. In the chambers 5h and 5j, a cleaning agent containing a surfactant for cleaning the sample DNA with the fluorescent substance (fluorescent label) that has not been hybridized and the fluorescent substance (fluorescent label) is accommodated. The chamber 5 i contains alcohol for drying the inside of the chamber 9 including the DNA chip 12.

  The chamber 5e is a chamber for collecting dust other than blood DNA and dust. The chamber 5f is a chamber for storing waste liquids of the first and second extracted cleaning agents from the chambers 5l and 5m. The chamber 5r is a chamber for storing waste liquids of the first and second cleaning agents. The chambers 5k, 5o, and 5t are blank chambers provided to prevent the solution from flowing into the nozzle inlet.

  A liquid specimen such as blood is injected into the biochemical reaction cartridge 1 and set in the processing apparatus. Then, DNA and the like are extracted and amplified inside the biochemical reaction cartridge 1, and hybridization is performed between the amplified sample DNA and the DNA probe 37 of the DNA chip 12 inside the biochemical reaction cartridge 1. To do. On the other hand, the sample DNA with the fluorescent substance (fluorescent label) that has not been hybridized and the fluorescent substance (fluorescent label) can be washed.

  Hereinafter, a method for causing the biochemical reaction of the specimen in the biochemical reaction cartridge 1 will be specifically described.

  First, the examiner inserts a needle of a syringe containing blood as a sample into the sample inlet 2a so as to pass through a rubber cap that closes the sample inlet 2a of the biochemical reaction cartridge 1, and the blood in the syringe is sampled. Injection into the chamber 7 from the inlet 2a. Thereafter, the examiner places the biochemical reaction cartridge 1 on the table 13. The inspector operates a lever (not shown) to move the pump blocks 22 and 23 shown in FIG. 1 in the direction of the arrow shown in FIG. By this movement, the pump nozzles 20 and 21 are inserted into the nozzle inlets 3a to 3t on both side surfaces of the biochemical reaction cartridge 1 so as to penetrate the rubber cap.

  When the inspector inputs an instruction to start an experiment from the input unit 24, the process starts. FIG. 24 is a flowchart for explaining the procedure of the biochemical reaction and the subsequent processing.

  First, in step S <b> 1, the control unit 17 controls the pump nozzles 20 and 21 to open only the nozzle inlets 3 a and 3 k, ejects air from the electric syringe pump 18, and sucks air from the electric syringe pump 19. Thereby, the first hemolytic agent in the chamber 5a is poured into the chamber 7 containing blood. As described above, the pump nozzle 20 is inserted into the nozzle inlet 3a and air is ejected to pressurize, and the pump nozzle 21 is inserted into the nozzle inlet 3k to suck and reduce the pressure of the air in the chamber 5a. The hemolytic agent flows into the chamber 7 containing the blood. This is shown in FIG. 25, which is a cross-sectional view through the chambers 5a, 7, and 5k.

  The pressurization and depressurization of each chamber are controlled by shifting the timing of air supply and suction, whereby the solution can flow smoothly in the cartridge 1. Furthermore, it is possible to flow the solution more smoothly by performing fine control such as linearly increasing the suction of air by the electric syringe pump 19 from the start of the air from the pump 18. For example, depending on the viscosity of the hemolytic agent and the resistance of the flow path, in step S1, the suction of air from the electric syringe pump 19 is started and the ejection of air from the electric syringe pump 18 is started for 10 to 200 milliseconds. Control to start later. According to this control, the solution does not jump out at the beginning of the flowing solution, and the solution flows smoothly. The same applies to the movement of the solution in the following steps.

  In addition, while controlling the supply of air using the electric syringe pumps 18 and 19, only the nozzle inlets 3 a and 3 o are opened, and the electric syringe pumps 18 and 19 alternately repeat the ejection and suction of air. In this way, the solution in the chamber 7 is caused to flow through the flow path 10 and then returned to the agitation to repeat the stirring. Alternatively, stirring is performed while bubbles are generated by continuously ejecting air from the electric syringe pump 19.

  In this way, after performing the flow and stirring step (step S1) of the first hemolytic agent, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the flow and stirring process of the first hemolytic agent, various conditions of the process, and the end time, and the information is stored in the storage unit of the IC chip 25.

  Next, in step S2, only the nozzle inlets 3b and 3k are opened, and the second hemolytic agent in the chamber 5b is poured into the chamber 7 on the same principle as in step S1. And the same stirring as step S1 is performed.

  After performing the second hemolytic agent flow and stirring step (step S2) in this way, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the second hemolytic agent flow and stirring process, various conditions of the process, and the end time, and the information is stored in the storage unit of the IC chip 25.

  In step S3, only the nozzle inlets 3c and 3k are opened, and the magnetic particles in the chamber 5c are poured into the chamber 7 on the same principle as in steps S1 and S2. And the same stirring as step S1 is performed. By this step S3, the DNA obtained by dissolving the cells in steps S1 and S2 adheres to the magnetic particles.

  Thus, after performing the flow and stirring step (step S3) of the magnetic particles, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the flow and stirring processes of the magnetic particles, various conditions of the process, and the end time, and the information is stored in a storage unit (not shown) of the IC chip 25. Is done.

  In step S4, the electromagnet 14 is turned on, only the nozzle inlets 3e and 3k are opened, air is ejected from the electric syringe pump 19, air is sucked from the electric syringe pump 18, and the solution in the chamber 7 is discharged into the chamber 5e. Move to. During this movement, the magnetic particles and DNA are captured at a position above the electromagnet 14 in the flow channel 10. Note that the efficiency of DNA capture is improved by alternately repeating the suction and ejection of air by the electric syringe pumps 18 and 19 to reciprocate the solution between the chambers 7 and 5e twice. If the number of reciprocations is further increased, the capture efficiency can be further increased. However, extra processing time is required.

  As described above, in steps S1 to S4, the DNA in a fluidized state is captured very efficiently using magnetic particles on the small flow path 10 having a width of about 1 to 2 mm and a height of about 0.2 to 1 mm. To do. It should be noted that if the capture target substance is not DNA but RNA or protein, efficient capture can be performed similarly.

  After performing the magnetic particle and DNA capturing step (step S4) as described above, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal indicates the completion of the magnetic particle and DNA capturing process, various conditions of the process, and the end time, and the information is stored in a storage unit (not shown) of the IC chip 25. The

  Next, in step S5, the electromagnet 14 is turned off, and only the nozzle inlets 3f and 3l are opened. Then, air is ejected from the electric syringe pump 19 and air is sucked from the electric syringe pump 18 to move the first extraction cleaning liquid in the chamber 5l to the chamber 5f. At this time, the magnetic particles and DNA captured in step S4 move together with the extraction cleaning liquid to perform cleaning. Further, the electromagnet 14 is turned on, and the magnetic particles, DNA, and extraction cleaning liquid are reciprocated twice between the chamber 5l and the chamber 5f by the same principle as in step S4. Thus, the washed magnetic particles and DNA are collected at a position above the electromagnet 14 in the flow path 10 and the first extraction washing liquid is returned to the chamber 5l.

  In this way, after performing the step of capturing the magnetic particles and DNA (Step S5) after washing with the first extraction washing liquid, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the process of capturing the magnetic particles and DNA after washing with the first extraction washing liquid, the various conditions of the process, and the end time. Stored in the storage unit.

  In step S6, only the nozzle inlets 3f and 3m are opened, and the same process as in step S5 is performed. That is, the second extraction washing liquid in the chamber 5m, the magnetic particles and the DNA are moved, and the magnetic particles and the DNA are further washed and then recovered at a position above the electromagnet 14, and the second extraction washing liquid is used as the second extraction washing liquid. Return to chamber 5m.

  As described above, after performing the step of capturing the magnetic particles and DNA (Step S6) after washing with the second extraction washing liquid, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the process of capturing the magnetic particles and DNA after washing with the second extraction washing liquid, the various conditions of the process, and the end time. Stored in the storage unit.

  Subsequently, with the electromagnet 14 turned on in step S7, only the nozzle inlets 3d and 3o are opened, air is ejected from the electric syringe pump 18, and air is sucked from the electric syringe pump 19. Thereby, the eluate in the chamber 5 d is moved to the chamber 8. Due to the action of the eluate, the magnetic particles and DNA are separated, and only the DNA moves to the chamber 8 together with the eluate, and the magnetic particles remain in the flow path 10.

  In this way, after performing the step of separating the magnetic particles and DNA by flowing the eluate (step S7), a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the process of separating the magnetic particles and DNA by flowing the eluate, the various conditions of the process, and the end time. The information is stored in the storage unit of the IC chip 25. Is done.

  In step S7, DNA extraction and purification are performed. In the embodiment, since the chambers 5l and 5m for storing the extracted cleaning liquid and the chamber 5f for storing the waste liquid after the cleaning are prepared, it is possible to extract and purify the DNA in the cartridge 1.

  Next, in step S8, only the nozzle inlets 3g and 3o are opened, air is ejected from the electric syringe pump 18, and air is sucked from the electric syringe pump 19. Thereby, the PCR agent (for example, a mixed solution of primer, polymerase, dNTP solution, buffer, fluorescent label, etc.) in the chamber 5 g is poured into the chamber 8. Further, only the nozzle inlets 3g and 3t are opened, and the ejection and suction of air by the electric syringe pumps 18 and 19 are alternately repeated, the solution in the chamber 8 is allowed to flow through the flow path 11, and then the operation of returning to it is repeated for stirring. Do. Then, after controlling the Peltier element 15 and holding the solution in the chamber 8 at a temperature of 96 ° C. for 10 minutes, a cycle of 96 ° C. · 10 seconds, 55 ° C. · 10 seconds, 72 ° C. · 1 minute is repeated 30 times. PCR is performed to amplify the eluted DNA.

  Thus, after performing the amplification process (step S8) of the eluted DNA, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the amplification process of the eluted DNA, various conditions of the process, and the end time, and the information is stored in the storage unit of the IC chip 25.

  In step S 9, only the nozzle inlets 3 g and 3 t are opened, air is ejected from the electric syringe pump 18, air is sucked from the electric syringe pump 19, and the solution in the chamber 8 is moved to the chamber 9. Further, the Peltier element 16 is controlled to hold the solution in the chamber 9 at 45 ° C. for 2 hours to perform hybridization. At this time, the ejection and suction of air by the electric syringe pumps 18 and 19 are alternately repeated, the solution in the chamber 9 is moved to the flow path 6t, and the subsequent return operation is repeated to perform the hybridization while stirring. .

  After performing the hybridization step (step S9) in this way, a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the hybridization process, various conditions of the process, and the end time, and the information is stored in the storage unit of the IC chip 25. In this example, the chamber 9 is a reaction field for hybridization.

  Next, in step S10, while maintaining the temperature at 45 ° C., only the nozzle inlets 3h and 3r are opened, air is ejected from the electric syringe pump 18, and air is sucked from the electric syringe pump 19. Accordingly, the solution in the chamber 9 is moved to the chamber 5r, and the first cleaning liquid in the chamber 5h is poured into the chamber 5r through the chamber 9. Thus, the first cleaning liquid in the chamber 5h is inserted by inserting the pump nozzle 20 into the nozzle inlet 3h and ejecting air to pressurize it, and inserting the pump nozzle 21 into the nozzle inlet 3r and sucking air to reduce the pressure. Flows into the chamber 5r through the chamber 9. This is shown in FIG. 26, which is a cross-sectional view through the chambers 5h, 9, 5r. By alternately repeating the suction and ejection of the electric syringe pumps 18 and 19, this solution is reciprocated twice between the chambers 5h, 9, and 5r, and finally returned to the chamber 5h. In this way, the fluorescently labeled sample DNA and the fluorescent label that have not been hybridized are washed.

  Thus, after performing the cleaning process with the first cleaning liquid (step S10), a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the first cleaning process, various conditions of the process, and the end time, and the information is stored in the storage unit of the IC chip 25.

  Further, in step S11, while maintaining the temperature at 45 ° C., only the nozzle inlets 3j and 3r are opened, and the same process as in step S10 is performed. That is, the second washing solution in the chamber 5j is poured into the chamber 5r through the chamber 9 to further wash the DNA, and finally the solution is returned to the chamber 5j.

  In this way, after performing the cleaning step with the second cleaning liquid (step S11), a signal is transmitted from the communication unit 26 toward the communication unit of the IC chip 25. This signal represents the completion of the cleaning process by the second cleaning liquid, various conditions of the process, and the end time, and the information is stored in the storage unit of the IC chip 25.

  In this embodiment, the chambers 5h and 5j for storing the first and second cleaning liquids and the chamber 5r for storing the waste liquid after the cleaning are prepared, so that the DNA chip is provided in the biochemical reaction cartridge 1 as described above. It is possible to perform 12 washings.

  In step S12, only the nozzle inlets 3i and 3r are opened, air is ejected from the electric syringe pump 18, air is sucked from the electric syringe pump 19, and the alcohol in the chamber 5i is moved through the chamber 9 to the chamber 5r. . Thereafter, only the nozzle inlets 3i and 3t are opened, air is ejected from the electric syringe pump 18, and air is sucked from the electric syringe pump 19 to dry the inside of the chamber 9.

  In this way, after performing the alcohol flow and drying step (step S12), a signal is transmitted from the communication unit 26 to the communication unit of the IC chip 25. This signal represents the completion of the alcohol flow and drying process, various conditions of the process, and the end time, and the information is stored in the storage unit of the IC chip 25.

  Through the steps S1 to S12 described above, the biochemical reaction (for example, DNA hybridization) of the specimen can be performed in the biochemical reaction cartridge 1.

  In the present embodiment, the nozzle inlets 3a to 3t are concentrated on the two surfaces of the cartridge 1, that is, both side portions. Therefore, the shape and arrangement of the electric syringe pumps 18 and 19, the electric switching valve, the pump blocks 22 and 23 incorporating the pump nozzle, and the like can be simplified. Furthermore, the pump nozzles 20 and 21 can be inserted by a simple operation of simultaneously sandwiching the biochemical reaction cartridge 1 by the pump blocks 22 and 23 while securing necessary chambers and flow paths. Accordingly, the configuration of the pump blocks 22 and 23 can be simplified. Further, by arranging the nozzle inlets 3a to 3t so as to be all linearly arranged at the same height, the heights of the flow paths 4a to 4t connected to the nozzle inlets 3a to 3t are all the same, and the flow path 4a. Production of ˜4t is facilitated.

  Further, in the processing apparatus of the biochemical reaction analyzer shown in FIG. 1, the pump blocks 22 and 23 can be configured to be n times longer so that n biochemical reaction cartridges 1 can be used simultaneously. In that case, n biochemical reaction cartridges 1 can be arranged in series, and necessary steps can be simultaneously performed on each of the n biochemical reaction cartridges 1. Therefore, the biochemical reaction can be performed simultaneously in a large number of biochemical reaction cartridges, while the configuration is extremely simple.

  After the processing steps described above (steps S1 to S12), in step S13, the inspector operates a lever (not shown) to move the pump blocks 22 and 23 away from the biochemical reaction cartridge 1. Accordingly, the pump nozzles 20 and 21 are detached from the nozzle inlets 3 a to 3 t of the biochemical reaction cartridge 1. In step S <b> 14, the biochemical reaction cartridge 1 is transported from the table 13 to the detection unit 28 using the cartridge transport unit 27. In step S <b> 15, the hybridized DNA captured by the DNA chip 12 is detected by the fluorescence detection unit 30. The detection result is transmitted from the communication unit 31 toward the communication unit of the IC chip 25 and stored in the storage unit of the IC chip 25. In this way, the transition (including the passage of time) and various conditions of each step in steps S1 to S12 and the detection result of the DNA chip 12 that has passed through each step are stored in the IC chip 25 of the biochemical reaction cartridge 1. The details of this fluorescence detection step (step S15) are as described above.

  Finally, in step S16, the control unit 17 analyzes the fluorescence detected pattern. When the biochemical reaction cartridge 1 is of a type that is not stored in the processing apparatus in advance, the analysis information written in the IC chip 25 is read in analyzing the detection pattern, and based on the analysis information. Analyze.

  Here, the principle of fluorescence detection and analysis in this embodiment will be described. For example, when the biochemical reaction cartridge 1 and the DNA chip 12 are for detecting an infectious disease, several infectious diseases can be detected at a time depending on how the DNA probe 37 is set. When the DNA chip 12 in which the DNA probes 37 are arranged in a 5 × 5 matrix is taken as an example, patterns when infectious diseases A to E are individually detected are shown in FIGS. It can be set to be 5 ways. In FIGS. 27A to 27E, black circles indicate a state in which the target is captured by hybridization with the DNA probe 37 and the fluorescent substance (fluorescent label) attached to the target emits fluorescence. . White circles indicate a state in which the target is not hybridized with the DNA probe 37 and is not captured, and there is no fluorescent label.

  In the example shown in FIGS. 27A to 27E, all the DNA probes 37 included in the same column are set to hybridize with DNA existing when infected with the same infection. And it sets so that it may respond | correspond to the DNA of an infectious disease different for every row | line | column. Therefore, when the detection result of the pattern of FIG. 27A is obtained, infection with the infectious disease A is recognized. Similarly, when the detection results of the patterns shown in FIGS. 27B to 27E are obtained, infections to infectious diseases B to E are recognized, respectively. The infection determination method based on such a detection pattern is included in the analysis information stored in advance in the control unit 17.

  As described above, in order to accurately perform the target sample analysis based on the sequence pattern of the DNA probe 37 to which the fluorescent substance is attached, it is important to accurately detect the fluorescence in step S15.

(Second Embodiment)
FIG. 28 is a schematic diagram showing a schematic configuration of a cleaning unit used in the biochemical reaction analyzer according to the second embodiment of the present invention. The biochemical reaction analyzer of this embodiment is the same as the biochemical reaction analyzer of the first embodiment except that the cleaning unit is different.

  Referring to FIG. 28, the cleaning unit includes a blower 200 including a blower port 201. The blower 200 is incorporated in the detection unit so that the compressed air ejected from the blower port 201 hits the sensor part of the image sensor 39. The blower 200 is used for the cleaning process in the flow of operations described in the first embodiment (see FIGS. 4, 12, and 20). Since the compressed air ejected from the air blowing port 201 exists in the sensor unit of the image sensor 39, the deposit can be blown off.

(Third embodiment)
FIG. 29 is a schematic diagram showing a schematic configuration of a cleaning unit used in the biochemical reaction analyzer according to the third embodiment of the present invention. The biochemical reaction analyzer of this embodiment is the same as the biochemical reaction analyzer of the first embodiment except that the cleaning unit is different.

  Referring to FIG. 29, the cleaning unit includes a wiper 54 for electrostatic adsorption, and is incorporated in the detection unit. The wiper 54 has a support part that supports one end of the wiper part 54 and a guide part for reciprocating the support part in one direction. A wiper standby area 54b is provided at one end of the guide portion. As the support portion moves along the guide portion, the wiper portion 54 moves in parallel with the surface of the sensor portion of the image sensor 39.

  FIG. 30 is a block diagram showing the configuration of the control device for the wiper 54. The control device includes an electrostatic chuck wiper control unit 51, a dust position storage unit 52, a wiper driving unit 53, a static electricity generation unit 55, and a static electricity holding member moving unit 56.

  The electrostatic chuck wiper controller 51 controls the entire operation of the electrostatic chuck wiper 54. The dust position information obtained by the detection control unit 43 is transferred from the detection control unit 43 to the electrostatic suction wiper control unit 51. The electrostatic suction wiper control unit 51 stores the dust position information supplied from the detection control unit 43 in the dust position storage unit 52. The wiper drive unit 53 moves the support unit along the guide unit. The static electricity generator 55 generates static electricity. The static electricity generated by the static electricity generation unit 55 is held by the static electricity holding member.

  In accordance with an instruction from the electrostatic attraction wiper control unit 51, the static electricity holding member moving unit 56 packs the static electricity holding member in a state where static electricity is held in the wiper standby area 54b. The wiper portion 54a packed with the static electricity holding member is in a state where static electricity is held from the tip to the root. The wiper 54 scans above the image sensor 39 by the wiper driving unit 53 and adsorbs dust electrostatically.

  The electrostatic suction wiper control unit 51 determines the scan position based on the dust position information stored in the dust position storage unit 52. Then, the electrostatic suction wiper control unit 51 issues an operation instruction to the wiper driving unit 53 so that the range corresponding to the determined scan position is scanned by the wiper unit 54a. After scanning, the wiper 54 returns to the wiper standby area 54b. Then, the electrostatic suction wiper control unit 51 operates the static electricity holding member moving unit 56 to return the static electricity holding member to the static electricity generation unit 55. At this time, the electrostatically attracted dust is removed from the electrostatic holding member.

  As described above, the electrostatic suction wiper control unit 51 specifies the area of the deposit on the sensor unit (light receiving surface) of the image sensor 39 based on the dust position information from the detection control unit 43, and sets the area on the area. On the other hand, control is performed such that dust removal processing by the wiper is performed with priority. With this control, it is possible to remove the deposits more reliably, and the effect that the time required for removing the deposits is shortened can be obtained. In the flow of operations described in the first embodiment (see FIGS. 4, 12, and 20), the removal of deposits by the wiper 54 is used for the cleaning process.

It is a block diagram which shows the structure of the biochemical reaction analyzer which is the 1st Embodiment of this invention. It is a block diagram which shows the fluorescence detection unit of the biochemical reaction analyzer shown in FIG. It is a schematic diagram which shows the cleaning part of the fluorescence detection unit shown in FIG. It is a flowchart which shows the procedure of the 1st fluorescence detection process performed in the fluorescence detection unit shown in FIG. It is a figure for demonstrating the positional relationship of the deposit | attachment and spot area in the 1st fluorescence detection process shown in FIG. It is a schematic diagram which shows the structure of a DNA chip. It is a schematic diagram which shows the image obtained at the time of marker detection. It is a flowchart which shows the marker detection operation | movement in the fluorescence detection unit shown in FIG. It is a flowchart which shows the dust imaging | photography operation | movement in the fluorescence detection unit shown in FIG. 3 is a flowchart showing a microarray imaging operation in the fluorescence detection unit shown in FIG. It is a flowchart which shows the dust cleaning operation | movement in the fluorescence detection unit shown in FIG. It is a flowchart which shows the procedure of the 2nd fluorescence detection process performed in the fluorescence detection unit shown in FIG. It is a figure for demonstrating the positional relationship of the deposit | attachment and spot area in the 2nd fluorescence detection process shown in FIG. It is a schematic diagram which shows the minimum dust space | interval which dust affects a spot in the case of complementing the spot of a 1st spot area with the spot of a 2nd spot area. It is a schematic diagram which shows the maximum dust space | interval which dust influences a spot in the case of complementing the spot of a 1st spot area with the spot of a 2nd spot area. It is a schematic diagram which shows the minimum dust space | interval which dust affects a spot in the case of complementing the spot of a 1st spot area with the spot of a 3rd spot area. It is a schematic diagram which shows the maximum dust space | interval which dust influences a spot in the case of complementing the spot of a 1st spot area with the spot of a 3rd spot area. It is a figure for demonstrating the determination result according to the overlap condition of dust and a spot. It is a schematic diagram which shows the detection area containing a template and a dust image. It is a flowchart which shows the procedure of the 3rd fluorescence detection process performed in the fluorescence detection unit shown in FIG. It is a figure for demonstrating the positional relationship of the deposit | attachment and spot area in the 3rd fluorescence detection process shown in FIG. It is a perspective view of the biochemical reaction cartridge of the biochemical reaction analyzer shown in FIG. FIG. 23 is a plan sectional view of the biochemical reaction cartridge shown in FIG. 22. It is a flowchart which shows the process process in the biochemical reaction analyzer shown in FIG. It is a longitudinal cross-sectional view of a part of the chamber of the biochemical reaction cartridge shown in FIG. It is a longitudinal cross-sectional view of the other chamber of the biochemical reaction cartridge shown in FIG. It is a schematic diagram which shows the example of the fluorescent substance detection pattern of a DNA chip. It is a schematic diagram which shows the structure of the cleaning part of the fluorescence detection unit of the biochemical reaction analyzer which is the 2nd Embodiment of this invention. It is a schematic diagram which shows the structure of the cleaning part of the fluorescence detection unit of the biochemical reaction analyzer which is the 3rd Embodiment of this invention. It is a block diagram which shows the structure of the control apparatus of the cleaning part shown in FIG.

Explanation of symbols

1 Biochemical Reaction Cartridge 32 Laser Light Source 33 Laser Shutter 34 Beam Expander 35 Beam Homogenizer 36 Fluorescent Filter 37 Variable Aperture 38 Imaging Lens Group 39 Imaging Element 40 Shutter 41 Imaging Unit 42 Cleaning Unit 43 Detection Control Unit

Claims (13)

An image sensor that includes a light receiving surface and images at least one spot area including a plurality of spots formed on the substrate surface on the light receiving surface;
A detection control unit that detects the deposit on the light receiving surface based on a photographed image obtained by imaging the deposit with the image sensor before performing the main photographing for the inspection images of the plurality of spots. And having
The detection control unit determines whether the deposit affects the shooting of the plurality of spots based on a positional relationship between the plurality of spots on the captured image output from the image sensor and the detected deposit. An image pickup apparatus that determines whether or not the image is taken and performs the main photographing only when there is no influence of the attached matter. The spot area has a reference index for specifying the position of the spot constituting the spot area,
The detection control unit identifies each position of the plurality of spots based on a captured image obtained by imaging the reference index with the image sensor, and relative to the detected position and the detected deposit The imaging device according to claim 1, wherein it is determined whether or not the attached matter affects photographing of the plurality of spots based on a positional relationship.   The detection control unit assumes a virtual spot area corresponding to the spot area on the photographed image, and based on a relative positional relationship between the virtual spot area and the detected deposit, The imaging apparatus according to claim 1, wherein it is determined whether or not shooting of a plurality of spots is affected.   The detection control unit creates a template that defines the arrangement of the plurality of spots on the photographed image for the spot area, and converts the template into a photographed image obtained by imaging the deposit with the image sensor. Superimposing and changing the position of the template on the photographed image at a certain distance, and based on the positional relationship between the plurality of spots and the deposit at each position, the deposit is used to photograph the plurality of spots. The imaging apparatus according to claim 1, wherein it is determined whether or not to affect the imaging apparatus.   The detection control unit, when there are a plurality of the spot areas, if there is an effective spot area in the plurality of spot areas where the deposit does not overlap any of the plurality of spots, performs the main shooting, 2. The effective spot area according to claim 1, wherein when there is no effective spot area, the effective spot area is obtained by complementing a spot overlapping the deposit with another corresponding spot between at least two areas of the plurality of spot areas. Imaging device. Each of the plurality of spot areas has a reference index for specifying the position of the spot constituting the spot area,
6. The detection control unit according to claim 5, wherein the detection control unit specifies each position of the plurality of spots for the plurality of spot areas based on a captured image obtained by imaging the reference index with the imaging element. Imaging device.   The detection control unit assumes a plurality of virtual spot areas corresponding to the plurality of spot areas on the photographed image, and is based on a relative positional relationship between these virtual spot areas and the deposit on the photographed image. The imaging apparatus according to claim 5, wherein the effective spot area is determined. The plurality of spot areas are composed of first and second spot areas having the same spot arrangement direction and arranged in the arrangement direction.
The area interval is A, the spot diameter is S, the radius of the first deposit located in the first spot area is D1, and the radius of the second deposit located in the second spot area is D2. The minimum dust spacing dmin at which the first and second deposits will affect the corresponding spots between the first and second spot areas,
dmin = A−S−D1−D2
Given in
When the distance between the first and second deposits is smaller than the minimum dust interval dmin, the detection control unit detects that the first and second deposits are between the first and second spot areas. The imaging apparatus according to claim 7, wherein it is determined that the corresponding spot is not affected. The plurality of spot areas are composed of first and second spot areas having the same spot arrangement direction and arranged in the arrangement direction.
The area interval is A, the spot diameter is S, the radius of the first deposit located in the first spot area is D1, and the radius of the second deposit located in the second spot area is D2. When the maximum dust spacing dmax at which the first and second deposits will affect the corresponding spot between the first and second spot areas,
dmax = A + S + D1 + D2
Given in
When the distance between the first and second deposits is greater than the maximum dust interval dmax, the detection control unit detects that the first and second deposits are between the first and second spot areas. The imaging apparatus according to claim 7, wherein it is determined that the corresponding spot is not affected. The plurality of spot areas are composed of first to third spot areas having the same spot arrangement direction and arranged at equal intervals along the arrangement direction,
The area interval is A, the spot diameter is S, the radius of the first deposit located in the first spot area is D1, and the radius of the second deposit located in the third spot area is D2. The minimum dust spacing dmin at which the first and second deposits will affect the corresponding spot between the first and third spot areas,
dmin = A * 2-S-D1-D2
Given in
When the distance between the first and second deposits is smaller than the minimum dust interval dmin, the detection control unit detects that the first and second deposits are between the first and third spot areas. The imaging apparatus according to claim 7, wherein it is determined that the corresponding spot is not affected. The plurality of spot areas are composed of first to third spot areas having the same spot arrangement direction and arranged at equal intervals along the arrangement direction,
The area interval is A, the spot diameter is S, the radius of the first deposit located in the first spot area is D1, and the radius of the second deposit located in the third spot area is D2. The maximum dust spacing dmax at which the first and second deposits will affect the corresponding spots between the first and third spot areas,
dmax = A × 2 + S + D1 + D2
Given in
When the distance between the first and second deposits is larger than the maximum dust interval dmax, the detection control unit detects that the first and second deposits are between the first and third spot areas. The imaging apparatus according to claim 7, wherein it is determined that the corresponding spot is not affected.   The detection control unit creates a template that defines the arrangement of the plurality of spots on the captured image for the plurality of spot areas, and captures the template with the imaging element to capture the deposit. The image is superimposed on an image, and the position of the template on the photographed image is changed at a certain distance, and the effective spot area is determined based on a positional relationship between the plurality of spots and the deposit at each position. 5. The imaging device according to 5. A sample imaging method for imaging, on the light receiving surface, a plurality of spot areas each formed of a plurality of spots, each of which is a sample, using an imaging element having a light receiving surface.
Before performing main imaging for inspection images for the plurality of spots, the deposit on the light receiving surface is detected based on a captured image obtained by imaging the deposit with the imaging element,
Based on the positional relationship between the plurality of spots on the captured image output from the image sensor and the detected deposit, it is determined whether the deposit affects the shooting of the plurality of spots,
A specimen imaging method in which the main imaging is performed only when the attached matter does not affect imaging of the plurality of spots.

Images