Plate with chemical or biological reaction wells and method for multiple imaging of such plate using an imaging system

Abstract

The present invention provides a plate (1; 2) comprising an array of pores (11; 21) for carrying out chemical or biological reactions, wherein each of the pores (11; 21) comprises a reaction chamber having at least one opening (111; 211) on a surface (12; 22) of the plate (1; 2). The array of pores (11; 21) is composed of a plurality of adjacent pore blocks (13; 23), wherein each pore block (13; 23) is composed of a plurality of adjacent rows of pores, and wherein at least one blank portion (14; 24) is provided between the rows of pores in each pore block (13; 23). Here, the blank portion (14; 24) is specifically a portion of the surface (12; 22) of the plate (1; 2) and has no pore opening (111; 211). Furthermore, the present invention provides a method for multiple imaging of such a plate (1; 2) using an imaging system.

Description

[0001] This application is a divisional application of Chinese patent application No. 201710664941.9 (filed on August 7, 2017, entitled "A plate having chemical or biological reaction pores and a method for multiple imaging of such a plate using an imaging system"). Technical Field

[0002] In general, this invention relates to plates comprising wells for carrying out chemical or biological reactions, such as multi-well plates, which are in the form of microplates, microplates, or microwell plates, and are generally also referred to as well plates. The invention also relates to methods for repeatedly imaging such well plates for studying chemical or biological reactions occurring within the wells. In particular, this invention relates to improved well plates that can be used as disposable items and improved methods for measuring reaction results within the wells of well plates. Background Technology

[0003] For many biological, biochemical, diagnostic, or therapeutic applications, it is necessary to accurately determine the amount or concentration of a substance or compound in a sample, such as in polymerase chain reaction (PCR), which includes real-time PCR or digital polymerase chain reaction (dPCR). Most of these applications typically take the form of chemical, biochemical, and / or biological assays, targeting the immobilization of biological materials such as peptides and nucleic acids, cells, or tissues in a reaction chamber and the performance of one or more reactions with the immobilized material, followed by quantitative and / or qualitative analysis processes, such as luminescence assays. Recent developments have improved the efficiency of these analytical processes, such as computer-controlled autofocusing of reaction chambers and microscope stage positioning, which have been developed to facilitate repeated imaging of the biological materials within these chambers.

[0004] To analyze a variety of biological samples, well plates, or more specifically, multi-well plates, have been and still are widely used as standard tools in analytical research and clinical diagnostic testing laboratories. These multi-well plates are typically designed for single use only. More specifically, a multi-well plate is simply a plate, preferably a flat plate, comprising multiple reaction chambers in the form of wells or cavities, serving as test tubes for biological samples. The multi-well plate can be made of any suitable type of available material, such as glass, plastic, quartz, and silicon, and typically provides 6, 24, 96, 384, 1536, or even more sample wells, usually arranged in a 2:3 rectangular matrix. The standardization of the multi-well plate format, particularly in terms of its well arrangement, offers significant advantages because it allows the use of standardized laboratory equipment, such as robotic manipulation devices, automated sample handling devices, sample dispensers, and multi-well plate readers or reaction observation devices. Optical detection is the most common method for measuring reactions, especially for well arrays representing multiple different reactions, particularly for readers or observation devices.

[0005] However, due to the possibility of using multi-well plates with more or less an infinite number of sample wells, associating multiple observed wells with the reactions occurring within each well becomes increasingly cumbersome. One method to achieve this individual correlation is to arrange the wells in a predetermined sequence, such as a long single row, and to find the specific desired well by simply counting them. Another method to identify the desired well among multiple wells is by utilizing specific markers such as reference points, also known as reference marks, reference symbols, or simply references, which associate each well with a combination of a reference assigned to a row of wells in the well array and a reference assigned to a column of wells in the well array. As an example of the use of such reference marks, US 2016032230A1 describes a multi-well plate with a well array in which micro-holes are disposed at the bottom of the wells, and refers to known prior art and the appendix. Figure 3 The preferred embodiment shown describes that reference marks are used to identify each hole. Here, the perforated plate 9 shown includes 96 holes and consists of 8 rows and 12 columns of holes 91, wherein each row is assigned a letter character represented by reference numeral 92, such as A, B, C, etc., and a number represented by reference numeral 93, such as 1, 2, 3, etc., is assigned to each column of the plurality of holes 91, thereby clearly identifying each hole 91. For example, the hole in the upper left corner of the perforated plate 9 includes the assigned reference marks "A" and "1", that is, the combination "A1".

[0006] In the examples described above in the known prior art, each hole 91 has a circular cross-section. However, in recent years it has become clear that a hexagonal shape, at least at the level of the porous plate surface, can increase the hole distribution density on the porous plate, see Appendix. Figure 4Furthermore, as already described, the number of pores in known multi-well plates has increased to over 96, enabling increasingly more analytical processes to be performed on multiple samples in parallel. Now, to enable automated control of pore arrays with such a high number of pores, imaging devices such as cameras, including a so-called field of view of 94, can be used (see...). Figure 4 The field of view, also known as FOV or imaging area, typically constitutes the angular size of the camera's cone of view, and is composed of... Figure 4 The dashed lines in the diagram indicate rectangles or squares.

[0007] To target portions or areas in the aperture array that exceed the camera's field of view (FOV), i.e., areas not fully positioned within the aperture array. Figure 4 The apertures within the aperture array are rectangular or square, and imaging can capture multiple spatially offset images, segmentally imaging the entire array area. However, it is important to be able to identify how the multiple images captured by the camera are correlated with each other, i.e., how they should be stitched together, so as not to miss any apertures in the aperture plate or to avoid double-counting apertures, thus complicating the measurement results. Essentially, each aperture on the aperture array must be directly identifiable, which again requires identifying each image representing a specific FOV of the camera. For this purpose, reference markers 95 are typically used for positioning to identify apertures covered by the corresponding FOV 94, see [reference]. Figure 4 The reference marks used are in Figure 4 The symbols "F1", "F2", and "F3" are used to denote these features, and they can be any machine-readable structure located outside the aperture array. At least one reference marker must be present within any image, i.e., within any field of view (FOV), to serve as a reference for all apertures in that image. For example, US8367016B2 discloses a complex structure of a so-called microfluidic device with varying depths and heights, where the blank spaces between or around the apertures are necessary for the arrangement and differentiation of the corresponding reference markers.

[0008] Therefore, the drawback of reference markers as additional physical structures is that they require additional process steps in manufacturing the corresponding disposable orifice plates, making the plates more expensive and complex. Furthermore, reference markers consume valuable physical space and cannot be used to provide additional holes on the actual orifice plate. Therefore, reserving space on the plate, which implicitly also requires reserving valuable space in the camera's field of view (FOV), significantly reduces the usability and development potential of the orifice plate. Additionally, reference markers may actually interfere with the functionality of the orifice plate, such as the microfluidic properties in the case of microfluidic plates. Moreover, including reference markers located outside the relevant area (i.e., the area covering the actual holes to be captured) in the FOV of the imaging device requires either an FOV significantly larger than the relevant area, or a relevant area significantly smaller than the FOV; both of these approaches render the orifice plate imaging method less effective. Summary of the Invention

[0009] Therefore, there is a great need for an improved aperture plate and an improved method for multiple imaging of such a plate to avoid the above-mentioned drawbacks.

[0010] To address the above, the present invention provides a plate, preferably a multi-well plate, comprising a well array for chemical or biological reactions such as real-time PCR or dPCR. Here, the term "well array" refers to the entirety of all the wells disposed in the plate. Each well includes a reaction chamber for receiving a sample, wherein each well includes at least one opening disposed on the surface of the plate for access to the reaction chamber. Alternatively, each well may also include several openings, such as one opening on each surface of the plate. Furthermore, according to the present invention, the well array consists of multiple adjacent well blocks, which may also be referred to as sub-arrays, wherein each well block consists of multiple adjacent rows of wells. In other words, the wells are arranged in rows, and the rows of wells can be grouped into so-called blocks. Here, rows and blocks should not be understood as actual rows or blocks with clearly separated or boundary distances from adjacent rows or blocks, but rather as virtual rows or blocks in multiple wells being divided into virtual segments or portions combined together so that only a portion of the well array, i.e., a virtual well block, can be monitored. Furthermore, according to the plate of the invention, each hole block has at least one blank portion located between rows of holes, i.e., one or more blank portions, wherein the portion constituting the blank portion on the surface of the plate has no hole opening. In other words, each hole block presents a corresponding hole opening on the plate surface associated with a segment in the hole array, and within each hole block, between rows of holes, a certain area of ​​the plate surface does not present a hole opening, which may also be referred to as "omitted hole opening" or "omitted hole," meaning that the surface in this area is preferably left without cavities, i.e., untreated or unprocessed. The blank portion or "omitted hole" may also be referred to as an interference or defect in hole openings that are otherwise uniformly distributed throughout the entire plate surface, wherein each hole block can provide one blank portion, or alternatively, more than one blank portion can be provided, wherein reasonable space "waste" is taken into account. In addition, according to a further preferred configuration, all hole blocks in the hole array on the plate may include the same number of holes and / or blank portions. Additionally, the plate may include an integrated fluid distribution system implemented as a jet orifice plate for delivering liquid into each orifice, such as an infusion porous plate having a bioreactor array integrated into the porous plate structure, etc.

[0011] The advantage of providing at least one blank portion in each hole block is that the positional information of the holes can be directly encoded in the corresponding hole block, wherein each blank portion preferably serves as a reference for spatially encoding the position of each block on the board, without the need to set corresponding reference marks at the edge of the board surface, etc. This makes it possible to extend the hole arrangement or distribution directly to the edge of the board, which greatly maximizes the effective space on the board surface for providing holes, and thus maximizes the number of holes in the hole array of the board. Of course, it should be understood that a certain minimum edge may be maintained between the board and the outermost holes due to manufacturing requirements.

[0012] Essentially, a camera or other type of imaging device used to capture an image of each block, or in effect, the human eye, can point its field of view (FOV) at a segment of holes. By identifying blank areas at a certain location, it is possible to identify a particular hole block using the blank areas at specific locations within the corresponding block—that is, by interpreting the spatial information provided by the location of the blank areas. This interpreted information is then sufficient to directly identify each hole within each hole block, for example, to determine the local location of the hole blocks covered by the field of view, i.e., the offset, rotation, scaling, etc., of the hole blocks in the x and / or y directions in the xy plane. Further preferably, the hole blocks in the plate of the present invention comprise the same dimensions, particularly in terms of their length and width, such that each block is appropriately sized for monitoring, measuring, and / or simply capturing images of the corresponding hole block using the FOV of the imaging device.

[0013] According to a preferred configuration of the plate of the invention, in each hole block, the hole opening substantially covers the entire surface of the plate except for the blank areas. The advantage of this configuration is that the entire space provided by the plate can be utilized in a productive and beneficial manner, wherein the possibility of maintaining the positioning of the hole array can be achieved without requiring space-consuming reference markers.

[0014] Further preferably, the blank portion of each aperture block is eccentrically arranged within the corresponding block. Thus, information encoded by the location of the blank portion can not only be used to clearly identify the corresponding block and distinguish it from other blocks, but also to identify the rotational positioning of the corresponding block, for example, when the plate has rotated compared to its normal position. Here, for better understanding, it should be noted that even if each blank portion is located at the same position within each block, it can still be used to identify the respective blocks, because a “coarse” identification can be performed by detecting the position of the imaging device’s own FOV relative to the plate, and a “fine” identification of the FOV to be aligned with the corresponding aperture block can be performed using the blank portion and its target position, which can also be at the center of the corresponding block. However, by eccentrically locating the blank portion, the monitored aperture blocks can be identified in a more simplified manner. Further preferably, the eccentric arrangement of the at least one blank portion in each block may require the blank portion to be offset relative to the block center in the longitudinal and / or lateral directions of the plate.

[0015] Furthermore, according to a further preferred configuration of the plate of the present invention, the position of at least one blank portion in a block differs from the position of at least one blank portion in an adjacent block. Additionally, each block can include several blank portions, such as two blank portions, wherein the position of the blank portions and / or the distance between the blank portions can vary depending on the block. These features make it significantly easier to distinguish between blocks. Furthermore, when these features are implemented in the plate of the present invention, more information can be encoded because each other piece of information—besides the position of the blank portion in the case of a single blank portion—such as the number of blank portions, the distance between two or more blank portions in a block, the arrangement of several blank portions relative to each other, etc., can also be associated with other encoded information. For example, for a predetermined monitoring result of a hole in a hole block, it becomes possible to directly encode the monitoring result information in the corresponding block using these additional features. Now, regarding a specific arrangement with more than one blank portion, such as when each hole block has two blank portions, one blank portion can be positioned centrally, while the other blank portion can be positioned off-center in the longitudinal and / or lateral directions of the plate. Alternatively, both blank sections can be positioned offset from the block center in the longitudinal and / or lateral directions of the plate, wherein the two blank sections can be separated from each other by more than one aperture opening in the longitudinal and / or lateral directions of the plate. This specific number and / or arrangement of blank sections as described above makes it easier for the imaging device or the human eye to identify the aperture block compared to other aperture blocks, and also improves the feasibility of determining the local location of the corresponding aperture block covered by the FOV, i.e., the offset, rotation, scaling, etc. of the aperture block along the x and / or y directions in the xy plane.

[0016] According to a further preferred configuration of the plate of the invention, the blank portion in each hole block can occupy a predetermined area on the surface, which is similar to or more preferably the same as the area of ​​the plate surface occupied by the hole opening. The advantage of this configuration is that, during plate production, a blank portion can be easily provided in each hole block simply by omitting the hole at a possible location for each blank portion. Therefore, the blank portion can be identified as an "omitted hole." Here, although it is conceivable that each blank portion could in practice be marked, such as a printed symbol, letter, or number, or have a coating with a certain color or shade, during plate production, for the sake of a fast and simple manufacturing process typically for disposable plates, it is preferable that the blank portions have no markings, marks, or labels, such as reference marks or notched markings, etc.

[0017] Further preferably, the at least one blank portion of each hole block is specifically arranged away from the edge of the corresponding hole block, i.e., at a certain distance from that edge. For example, at least one hole opening is provided between each blank portion and the nearest edge of the corresponding hole block (which is the same as the corresponding edge of the hole array and therefore the corresponding edge of the plate of the present invention), thereby constituting the distance between the edge and the blank portion. This specific positioning of at least one blank portion on the plate of the present invention improves the visibility of the blank portion on the plate surface within the hole block, i.e., within the FOV, resulting in a faster and more reliable method of identifying the blank portion. Furthermore, when several rows of holes are provided within the hole block, for example, offset or offset from each other by, for example, half the hole opening size / diameter, the corresponding free area between the plate edge and an offset row end will not be confused with the blank portion according to the present invention.

[0018] In a further preferred configuration of the plate of the present invention, the cross-sectional area of ​​the opening of each hole may have a circular shape, an elliptical shape, or a polygonal shape such as a hexagon. By utilizing the polygonal shape of the hole openings, and particularly the hexagonal shape, the hole openings can be arranged with a smaller distance between them, thus increasing the distribution density of the hole openings on the plate of the present invention. Therefore, the number of holes in the hole array of the plate can be further maximized.

[0019] According to a further aspect of the invention, a method for repeatedly imaging the aforementioned plate using an imaging system is provided. Here, the imaging system includes a holder for the plate according to the invention, an imaging device for capturing an image of each hole block of the plate according to its FOV, a processing unit communicating with the imaging device, and a memory unit operatively coupled to the processing unit. For example, the plate may be a porous plate with 96 holes, the processing unit may be implemented by a central processing unit (CPU), and the memory unit may be implemented by a RAM or flash memory device connected to the processing unit and the imaging device. Furthermore, the holder and / or the imaging device may move relative to each other, preferably in an automated manner, and the memory unit includes instructions for capturing an image of each hole block, said instructions being pre-stored in the memory unit. Here, the movement of the holder and / or the imaging device relative to each other is preferably a parallel movement of these components in a certain increment or continuously along one direction, requiring a fixed holder and a movable imaging device, a movable holder and a fixed imaging device, or a combination of a movable holder and a movable imaging device, wherein the last combination is advantageous for achieving a faster imaging process.

[0020] Now, when executed by the processing unit, the instructions of the method of the present invention cause the processing unit to perform the following steps: capturing an image of a first hole block using an imaging device; moving the imaging device and / or plate disposed on the holder relative to each other; identifying adjacent hole blocks using the imaging device with at least one blank portion on the surface of the plate; moving the holder and / or imaging device until the adjacent block is within the FOV of the imaging device; and capturing an image of the adjacent hole block using the imaging device, preferably in this order. Using the above method, it becomes possible for an imaging device, such as a camera, for capturing an image of each block to point its FOV at a segment of holes, and by identifying blank portions disposed on the plate, a hole block can be identified using the blank portions specifically positioned in the corresponding block, i.e., by interpreting the spatial information provided by the location of the blank portions. Thus, using the interpreted information, the processing unit can clearly identify whether the FOV is aligned with the desired hole block, or whether the imaging device and / or plate need to be further moved relative to each other to allow the imaging device to capture the desired image. In the method described, the term "capture image" can be understood as simply taking a picture of the FOV of the imaging device and storing it in a memory unit without performing any analysis on the picture, or alternatively, it can be understood as monitoring / observing the FOV of the imaging device and directly analyzing / interpreting the details of the observation, i.e., the response results of the apertures observed in the corresponding aperture blocks, such as the response results in the form of luminescence measurement results.

[0021] Here, the use of blank areas is also to enable clear identification of each individual hole within the corresponding hole block covered by the FOV. Therefore, in a preferred configuration of the method according to the invention, the step of capturing the image may include identifying the position of each hole within the FOV of the imaging device, assigning each hole a so-called global identifier, such as an index and / or coordinates for clearly identifying the position of the corresponding hole, based on a predetermined geometric model of the plate, in conjunction with the at least one blank area, and measuring each hole in the image. A measurement value table corresponding to the assigned holes in the plate is then filled hole-to-hole, in which case the measurement result / value of each hole, obtained successively hole-to-hole, is stored in a memory unit corresponding to the assigned global identifier. With this preferred configuration, a measurement result is obtained for each hole in the image, the measurement result is stored in the measurement value table, and then the image is deleted. Alternatively, as previously explained, each step of capturing an image may include simply taking an image and storing it in a memory unit, wherein the method then further includes: combining the stored images of each hole block into a combined image of the hole array by matching multiple images with each other using blank portions, which is also referred to in the art as “stitching”; and further includes measuring each hole in the combined image and storing each measurement result. Here, the stitching process is known in the imaging field as a process of combining multiple photographic images using overlapping FOVs to produce segmented images, wherein the stitching process is typically performed using specific computer software. Therefore, the step of measuring each hole requires completely filling the measurement value table corresponding to the holes assigned in the plate. In addition, with this alternative configuration, overlapping holes and therefore overlapping measurement results may occur. In order to obtain only a single measurement result for each hole, such measurements of overlapping holes can be averaged into a single average measurement result. Using the two aforementioned alternatives to the method of the present invention, each hole can be measured individually, either directly during imaging of the entire plate or after imaging of the entire plate, wherein the at least one blank portion of the plate significantly improves the identification of each hole and the alignment of each hole block with the FOV of the imaging device.

[0022] In short, the specific inventive concept of this invention is to use one or more blank portions in the orifice plate in the sense of omitting the holes to make each hole easier to identify, that is, to assign a certain measurement result to the corresponding hole, while maximizing the use of the space on such plate used to provide the holes, and improving the operation of the imaging system by simplifying the positioning between the area of ​​the hole to be measured and the FOV of the imaging device of the imaging system.

[0023] This invention is not limited to the specific methods and reagents described herein, as they can be varied. While any methods and materials similar to or equivalent to those described herein may be used in the practice of this invention, preferred methods and materials are described herein. Furthermore, the terminology used herein is for describing specific embodiments only and is not intended to limit the scope of the invention.

[0024] In the specification and claims, singular nouns that themselves contain multiple nouns are used unless the context clearly indicates otherwise. Similarly, the words “comprising,” “including,” and “covering” should be interpreted inclusively rather than exclusively. Likewise, unless the context clearly indicates otherwise, the word “or” is intended to include “and.” The terms “multiple,” “multi-multiple,” or “majority” refer to two or more.

[0025] Advantages of the present invention

[0026] Using the plate and method proposed in this invention, it becomes possible to significantly maximize the number of holes in the plate by directly encoding the positional information of the holes in the hole array through arranging some regions without holes in the array, i.e., the aforementioned blank portions, also referred to as "omitted holes". Identifying these blank regions becomes possible by imaging the hole array with bright / dark field illumination, and then, through image analysis, their dimensions can be measured and the resulting "coded information" can be interpreted. This interpreted information is sufficient to directly identify each hole and determine the local positioning of the array on the image, i.e., x, y-shift, rotation, scaling, etc.

[0027] The hole location identification system proposed in this invention is particularly important for micro-hole arrays requiring multiple imaging sessions, including local scanning and subsequent stitching, or at least data reconstruction. These arrays require careful processing to prevent confusion between areas that have been sequentially detected, to avoid double-counting of overlapping rows, and / or to avoid missing lateral hole rows. By providing these blank areas in a highly irregular manner, i.e., “omitted” holes, each local image includes its own very specific self-identifying mark or fingerprint, preventing users from confusing images and mislocating parts of the images relative to each other, thus avoiding the aforementioned situations. Furthermore, the hole location identification system of this invention can easily identify possible double rows or broken rows, i.e., those hole rows covered only by a single image or a single FOV portion.

[0028] Furthermore, setting up positioning structures within the aperture array no longer requires obtaining an area significantly larger than the relevant region—that is, larger than the actual aperture array. This makes the imaging process more efficient.

[0029] The following examples are intended to illustrate various preferred embodiments of the present invention. Therefore, the specific modifications discussed below should not be construed as limiting the scope of the invention. It will be apparent to those skilled in the art that various equivalents, modifications, and improvements can be made without departing from the scope of the invention; therefore, it should be understood that these equivalent embodiments should be included in this application. Attached Figure Description

[0030] Other aspects and advantages of the invention will become clear from the following description of specific embodiments illustrated in the accompanying drawings, in which:

[0031] Figure 1 A cross-sectional view of a perforated plate according to a first preferred embodiment of the present invention is shown, with the blank portion aligned and having table precision;

[0032] Figure 2 A cross-sectional view of a perforated plate according to a second preferred embodiment of the present invention is shown, with the blank portions of the unique pattern aligned;

[0033] Figure 3 A top view of a perforated plate according to the prior art is shown;

[0034] Figure 4 A cross-sectional view of an orifice plate according to other prior art is shown. Detailed Implementation

[0035] exist Figure 1 The diagram provides a cross-sectional view of a perforated plate 1 according to a first preferred embodiment of the invention, from which the alignment of blank portions and the accuracy of the worktable can be demonstrated. Specifically, the area of ​​the perforated plate 1 shown (only a portion of the entire plate 1) illustrates a plurality of holes 11 arranged in an array on the plate 1. Here, as shown, the corresponding hexagonal openings 111 of the holes 11 are arranged at maximum density on the surface 12 of the plate 1, such that only a minimal edge 121 remains between the outermost hole 11 of each row of holes and the actual end 122 of the plate 1. Here, "row of holes" refers only to a virtual row of holes 11, and thus to a row along the vertical direction, i.e., in... Figure 1The holes 11 are arranged in a single row from top to bottom, with ten holes 11 in a "long" row and nine holes 11 in every other row, or nine holes 11 in a "short" row. This arrangement is due to the fact that the opening 111 of each hole 11 is a hexagonal cross-section combined with the desired maximum density of holes 11 in the plate 1. Thus, each "short" row of holes provides a slightly larger edge 121 between the outermost hole 11 of the row and the actual end 122 of the plate 1; however, this does not change the fact that the omission of reference marks, which is feasible by the present invention, still allows for efficient use of the space provided by the surface 12 of the plate 1. Furthermore, as mentioned above, the multiple rows of holes constitute a hole block 13, which is, of course, only a virtual block 13, as explained above, without any visible boundaries. Here, in the first preferred embodiment, Figure 1 The aperture block 13 shown has six rows of apertures. The field of view 3 of the imaging device (not shown) substantially overlaps with the aperture block 13 and also covers a small portion of the adjacent rows of apertures at the edge of the block 13 in order to fully cover all six rows of apertures in the aperture block 13.

[0036] Now, as a global identifier (see explanation above), a blank portion 14 is provided in the hole block 13 monitored by the field of view 3. In adjacent hole blocks shown, additional blank portions 14 can be seen, with all blank portions 14 in all hole blocks 13 of plate 1 used to distinguish different blocks 13 from one another. Even though the blank portions 14 are always located at the same off-center position in each block 13, a “coarse” identification can be performed by detecting the position of the field of view 3 relative to plate 1, roughly determining the position of plate 1 or its (not shown) holder relative to the imaging device, thereby establishing a suitable positioning and thus identifying the holes. Thus, using the blank portions 14, a “fine” identification of the field of view 3 and its contents can be performed; for example, a hole located above the blank portion 14 in the vertical direction can be assigned “Blank portion above 1”, a hole below the blank portion 14 can be assigned “Blank portion below 1”, “Blank portion below 2”, and so on. Therefore, in the field of view 3, each hole 11 can be identified relative to the blank portion 14, and adjacent hole blocks 13 can also be identified with each other by means of the blank portion 14, because when the image is captured by the imaging device, only a single blank portion 14 is aligned with a certain position in the field of view 3.

[0037] exist Figure 2 The image shows a cross-sectional view of a perforated plate 2 according to a second preferred embodiment of the invention, illustrating a distinctive pattern in the blank areas. Specifically, the area of ​​the perforated plate 2 shown is only a portion of the entire plate 2, illustrating a plurality of holes 21 arranged in an array within the plate 2. Here, similar to... Figure 1In the first preferred embodiment shown, the hexagonal openings 211 of the holes 21 are arranged at maximum density on the surface 22 of the plate 2, such that only a similarly minimal edge 221 remains between the outermost hole 21 of each hole row and the actual end 222 of the plate 2. Similarly, the multiple virtual hole rows of the plate 2 also constitute virtual hole blocks 23, wherein the hole blocks 23 are as follows: Figure 2 The image shows six rows of holes. The field of view 3 of the imaging device is the same as that in the first preferred embodiment, substantially coinciding with the hole block 23, and also covering a small portion of the adjacent hole rows at the edge of the block 23, so as to fully cover all six holes of the hole block 23.

[0038] Now, as a global identifier, the combination of two adjacent blank portions 24 is set in the block 23 monitored by the field of view 3. Other combinations of two blank portions 24 can be seen in adjacent illustrated aperture blocks, wherein the different combinations of blank portions 24 differ from each other in that the blank portions 24 include different distances between the two blank portions 24. Figure 2 In addition to the combination of two directly adjacent blank portions 24 in the block 23 monitored by field of view 3, another block is shown with a combination of two blank portions 24 having an opening 211 in the middle, and another combination of two blank portions 24 having two openings 211 in the middle is also shown. Here, even if the distance between the blank portions 24 is only magnified in the vertical direction shown in the figure (which is consistent with the lateral direction of plate 2), the distance between the blank portions 24 can also be provided in the horizontal direction shown in the figure (which is consistent with the longitudinal direction of plate 2). Here, similarly, all combinations of blank portions 24 in the virtual blocks of plate 2 are used to distinguish different blocks 23 from each other. Even if the combination of blank portions 24 is always set at the same off-center position in each block 23, “coarse” identification and “fine” identification can be performed as explained with reference to the first preferred embodiment. Therefore, in field of view 3, each hole 21 can be identified relative to the corresponding combination of blank portions 24, and adjacent hole blocks 23 can also be identified from each other by different combinations of blank portions 24. In the second preferred embodiment, the position of the blank portion 24 and / or the distance between blank portions 24 in the combination of blank portions 24 can vary depending on the block, which significantly enhances the distinguishability between different blocks. Furthermore, the combination of blank portions 24 can encode more information, such as the local positioning of the corresponding hole block covered by the field of view 3, i.e., the displacement, rotation, scaling, etc. of the hole block 23 in the x-direction and / or y-direction in the xy-plane of the plate 2.

[0039] While the invention has been described with reference to preferred embodiments thereof, it should be understood that this specification is for illustrative purposes only. Therefore, it is intended that the invention be limited only by the scope of the appended claims.

[0040] This disclosure relates to the following implementation plan:

[0041] 1. A plate (1; 2) comprising an array of pores (11; 21) for carrying out chemical or biological reactions, each of the pores (11; 21) comprising a reaction chamber having at least one opening (111; 211) on a surface (12; 22) of the plate (1; 2), and the array of pores (11; 21) comprising a plurality of adjacent pore blocks (13; 23), each pore block (13; 23) comprising a plurality of adjacent rows of pores, wherein at least one blank portion (14; 24) is provided between the rows of pores in each pore block (13; 23), the blank portion (14; 24) being a portion of the surface (12; 22) of the plate (1; 2) and having no pore opening (111; 211).

[0042] 2. The plate (1; 2) according to item 1, wherein the opening (111; 211) substantially covers the entire surface (12; 22) of the plate (1; 2) except for the blank portion (14; 24) in each hole block (13; 23).

[0043] 3. The plate (1; 2) according to item 1 or 2, wherein the blank portion (14; 24) is eccentrically arranged in each corresponding hole block (13; 23).

[0044] 4. The plate (1; 2) according to item 3, wherein the eccentric arrangement of the at least one blank portion (14; 24) comprises the blank portion (14; 24) in each block (13; 23) being offset in the longitudinal and / or lateral directions of the plate (1; 2).

[0045] 5. The plate (1; 2) according to any one of the preceding items, wherein the blank portion (14; 24) in each hole block (13; 23) is a predetermined area on the surface (12; 22) and the area occupied is similar to, preferably the same as, the area occupied by the opening (111; 211) of each hole (11; 21).

[0046] 6. The plate (1; 2) according to any one of the preceding items, wherein the blank portion (14; 24) is free from any markings, identifiers or labels, such as reference marks or notched marks.

[0047] 7. The board (2) according to any one of the preceding items, wherein the position of the at least one blank portion (24) of a block (23) is different from the position of the at least one blank portion (24) of an adjacent block.

[0048] 8. The board (2) according to any one of the preceding items, wherein each block (23) includes a plurality of blank portions (24), preferably including two blank portions (24), wherein the position of the blank portions (24) and / or the distance between the blank portions (24) varies with different blocks (23).

[0049] 9. The plate (1; 2) according to any one of the preceding items, wherein each block (13; 23) includes the same number of holes (11; 21) and / or blank portions (14; 24).

[0050] 10. The board (1; 2) according to any one of the preceding items, wherein each blank portion (14; 24) serves as a reference for spatially encoding the position of each block (13; 23) on the board (1; 2).

[0051] 11. The plate (1; 2) according to any one of the preceding items, wherein the at least one blank portion (14; 24) is arranged away from the edge of the corresponding hole block (13; 23), and / or wherein the hole blocks (13; 23) in the plate (1; 2) comprise the same size, the size of each block (13; 23) being appropriately determined so that the field of view (31; 32) of the imaging device can capture an image of each block (13; 23).

[0052] 12. The plate (1; 2) according to any one of the preceding items, wherein the cross-sectional area of ​​the opening (111; 211) of each hole (11; 21) is a shape selected from the group consisting of circles, ellipses and preferably hexagonal polygons.

[0053] 13. The plate (1; 2) according to any one of the preceding items further includes an integrated fluid distribution system.

[0054] 14. A method for repeatedly imaging a plate (1; 2) according to any one of the preceding claims using an imaging system, said imaging system comprising:

[0055] Holder for the plates (1; 2);

[0056] An imaging device for capturing images of each hole block (13; 23) in the plate (1; 2) corresponding to its field of view (3);

[0057] A processing unit that communicates with the imaging device; and

[0058] A memory cell operatively connected to the processing unit, wherein,

[0059] The holder and / or the imaging device are movable relative to each other, and

[0060] The memory unit includes instructions stored therein for capturing the image of each hole block (13; 23).

[0061] When the instruction is executed by the processing unit, it causes the processing unit to perform the following steps:

[0062] The imaging device is used to capture an image of the first aperture block (13; 23);

[0063] The imaging device and / or the plates (1; 2) are moved relative to each other;

[0064] The imaging device is used to identify adjacent hole blocks by means of at least one blank portion (14; 24) in the surface (12; 22) of the plate (1; 2);

[0065] Move the holder and / or the imaging device until the adjacent block is within the field of view (3) of the imaging device; and

[0066] The imaging device is used to capture images of the adjacent hole blocks.

[0067] 15. The method according to item 14, wherein, or

[0068] Each step of capturing an image includes: (i) identifying the position of each hole (11; 21) in the field of view (3) of the imaging device, and assigning a global identifier, preferably an index and / or coordinate, to each hole (11; 21) based on a predetermined geometric model of the plate (1; 2) in conjunction with the at least one blank portion (14; 24); (ii) measuring each hole (11; 21) in the image; and (iii) storing each measurement result in correspondence with the assigned global identifier; or

[0069] Each step of capturing an image includes taking an image and storing the image, and the method further includes: combining the stored images of each hole block (13; 23) into a combined image of the holes (11; 21) by matching the plurality of images with each other using the blank portions (14; 24); and measuring each hole (11; 21) in the combined image and storing each measurement result.

Claims

1. A plate (1; 2) comprising an array of pores (11; 21) for carrying out chemical or biological reactions, each of the pores (11; 21) comprising a reaction chamber having at least one opening (111; 211) on a surface (12; 22) of the plate (1; 2), and the array of pores (11; 21) comprising a plurality of adjacent pore blocks (13; 23), each pore block (13; 23) comprising a plurality of adjacent rows of pores, wherein, At least one blank portion (14; 24) is provided between the rows of holes in each hole block (13; 23), the blank portion (14; 24) being part of the surface (12; 22) of the plate (1; 2) and having no hole opening (111; 211), wherein each block (23) includes a plurality of blank portions (24), wherein the position of the blank portions (24) and / or the distance between the blank portions (24) varies with the block (23).

2. The plate (1; 2) according to claim 1, wherein, The openings (111; 211) substantially cover the entire surface (12; 22) of the plate (1; 2) except for the blank portions (14; 24) in each hole block (13; 23).

3. The plate (1; 2) according to claim 1 or 2, wherein, The blank portions (14; 24) are eccentrically arranged in each corresponding hole block (13; 23).

4. The plate (1; 2) according to claim 3, wherein, The eccentric arrangement of the at least one blank portion (14; 24) includes the blank portion (14; 24) in each block (13; 23) being offset in the longitudinal and / or lateral directions of the plate (1; 2).

5. The plate (1; 2) according to any one of the preceding claims, wherein, The blank portion (14; 24) in each hole block (13; 23) is a predetermined area on the surface (12; 22), and the area occupied is similar to, preferably the same as, the area occupied by the opening (111; 211) of each hole (11; 21).

6. The plate (1; 2) according to any one of the preceding claims, wherein, The blank areas (14; 24) have no markings, signs or labels, such as reference marks or notched marks.

7. The plate (2) according to any one of the preceding claims, wherein, The position of the at least one blank portion (24) of a block (23) is different from the position of the at least one blank portion (24) of an adjacent block.

8. The plate (2) according to any one of the preceding claims, wherein, Each block (23) includes two blank sections (24).

9. The plate (1; 2) according to any one of the preceding claims, wherein, Each block (13; 23) includes the same number of holes (11; 21) and / or blank areas (14; 24).

10. The plate (1; 2) according to any one of the preceding claims, wherein, Each blank portion (14; 24) serves as a reference for spatially encoding the position of each block (13; 23) on the plate (1; 2).

11. The plate (1; 2) according to any one of the preceding claims, wherein, The at least one blank portion (14; 24) is arranged away from the edge of the corresponding hole block (13; 23), and / or, wherein the hole blocks (13; 23) in the plate (1; 2) comprise the same size, the size of each block (13; 23) being appropriately determined so that the field of view (31; 32) of the imaging device can capture an image of each block (13; 23).

12. The plate (1; 2) according to any one of the preceding claims, wherein, The cross-sectional area of ​​the opening (111; 211) of each hole (11; 21) is a shape selected from the group consisting of circles, ellipses, and preferably hexagonal polygons.

13. The plate (1; 2) according to any one of the preceding claims further includes an integrated fluid distribution system.

14. A method for using an imaging system to image a plate (1) according to any one of the preceding claims; 2) A method for multiple imaging, wherein the imaging system comprises: Holder for the plates (1; 2); An imaging device for capturing images of each hole block (13; 23) in the plate (1; 2) corresponding to its field of view (3); A processing unit that communicates with the imaging device; and A memory cell operatively connected to the processing unit, wherein, The holder and / or the imaging device are movable relative to each other, and The memory unit includes instructions stored therein for capturing the image of each hole block (13; 23). When the instruction is executed by the processing unit, it causes the processing unit to perform the following steps: The imaging device is used to capture an image of the first aperture block (13; 23); The imaging device and / or the plates (1; 2) are moved relative to each other; The imaging device is used to identify adjacent hole blocks by means of at least one blank portion (14; 24) in the surface (12; 22) of the plate (1; 2); Move the holder and / or the imaging device until the adjacent block is within the field of view (3) of the imaging device; and The imaging device is used to capture images of the adjacent hole blocks.

15. The method according to claim 14, wherein, or Each step of capturing an image includes: (i) identifying the position of each hole (11; 21) in the field of view (3) of the imaging device, and assigning a global identifier, preferably an index and / or coordinate, to each hole (11; 21) based on a predetermined geometric model of the plate (1; 2) in conjunction with the at least one blank portion (14; 24); (ii) measuring each hole (11; 21) in the image; and (iii) storing each measurement result in correspondence with the assigned global identifier; or Each step of capturing an image includes taking an image and storing the image, and the method further includes: combining the stored images of each hole block (13; 23) into a combined image of the holes (11; 21) by matching the plurality of images with each other using the blank portions (14; 24); and measuring each hole (11; 21) in the combined image and storing each measurement result.

Images