Sub-pixel Line Scanning

Abstract

Sub-pixel line scanning. The slide scanning device includes multiple line sensors (112a, 112b, 112c), each including multiple pixel sensors. Each line sensor is offset from an adjacent line sensor by a percentage of the length of each pixel sensor, and each line sensor offset generates a line image of the same field of view. For each of the multiple locations on the specimen, the processor combines the line images of the same field of view generated by the multiple line sensors at their respective offsets to generate multiple sub-pixels for each of at least a subset of pixels in the line image of the same field of view, and generates an upsampled line image of the location including the multiple sub-pixels. The processor then combines the upsampled line images of each of the multiple locations on the specimen to form an image.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 914,879, filed October 14, 2019, which is incorporated by reference herein as if set forth in its entirety.

[0002] FIELD OF THEINVENTION This application relates generally to whole slide imaging, and more particularly to sub-pixel scanning of specimens on microscope slides. [Background technology]

[0003] Current pixel shifting techniques improve resolution by shifting the image sensor in length increments that are smaller than the width of a pixel. For example, to sample a subpixel that is 1 / 4 the pixel size, a first image containing the subpixel is captured, the image sensor is shifted half a pixel to the left, a second image containing the subpixel is captured, the image sensor is shifted half a pixel up, a third image containing the subpixel is captured, the image sensor is shifted half a pixel to the right, and a fourth image containing the subpixel is captured. The intensities in these four images are then combined to produce the subpixel. Summary of the Invention [Means for solving the problem]

[0004] In one embodiment, a slide scanning device is disclosed that includes a stage for supporting a microscope slide having a specimen thereon, a plurality of line sensors, an objective lens, and at least one hardware processor, each line sensor of the plurality of line sensors including a plurality of pixel sensors, each line sensor of the plurality of line sensors being offset in a longitudinal direction of the line sensor from an adjacent one of the plurality of line sensors by a percentage of a length of each pixel sensor, and an objective lens sequentially presenting the same field of view of the specimen to each of the plurality of line sensors, thereby providing a plurality of pixel sensors at each of a plurality of positions on the specimen. For each location, each line sensor of the multiple line sensors senses a same field of view for the location and generates a line image of the same field of view for the location at each offset of the line sensors, and the at least one hardware processor combines, for each location of the multiple locations on the specimen, the line images of the same field of view generated by the multiple line sensors at their respective offsets to generate a plurality of sub-pixels for at least each of a pixel subset in the line image of the same field of view, and generates an upsampled line image of the location including the generated plurality of sub-pixels, and combines the upsampled line images of each location of the multiple locations on the specimen to form an image. The multiple line sensors may consist of N line sensors, each line sensor of the multiple line sensors being offset from an adjacent line sensor such that the ratio of the length of each pixel sensor is 1 / N. For each location of the multiple locations on the specimen, the line image of the same field of view may include line images for N offsets from zero to (N-1) / N. For each location of the multiple locations on the specimen, combining the line images of the same field of view may include summing, for at least each of the pixel subsets, intensity values ​​for pixels from each line image at their respective offsets.The at least one hardware processor may combine the upsampled line images for each of the multiple locations on the specimen to form a plurality of image strips, and may align each image strip of the multiple image strips with at least one adjacent image strip of the multiple image strips to form a continuous digital image.

[0005] In one embodiment, receiving image data from a plurality of line sensors, each line sensor of the plurality of line sensors including a plurality of pixel sensors, each line sensor of the plurality of line sensors being offset in a longitudinal direction of the line sensor from an adjacent one of the plurality of line sensors by a percentage of the length of each pixel sensor; Controlling an objective lens to sequentially provide the same field of view of the specimen to each of the line sensors of the plurality of line sensors, such that for each of the plurality of positions on the specimen, each of the line sensors of the plurality of line sensors senses the same field of view of the position and generates a line image of the same field of view of the position at each offset of the line sensors; For each of the multiple locations on the specimen, combine the line images of the same field of view generated by the multiple line sensors at their respective offsets to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, and generate an upsampled line image of the location including the generated sub-pixels; and The upsampled line images for each of multiple locations on the specimen are combined to form an image. A method is disclosed that includes using at least one hardware processor for:

[0006] In one embodiment, a non-transitory computer readable medium is disclosed having instructions stored thereon that, when executed by a processor, cause the processor to: receiving image data from a plurality of line sensors, each line sensor of the plurality of line sensors including a plurality of pixel sensors, each line sensor of the plurality of line sensors being offset in a longitudinal direction of the line sensor from an adjacent one of the plurality of line sensors by a percentage of the length of each pixel sensor; Controlling an objective lens to sequentially provide the same field of view of the specimen to each of the line sensors of the plurality of line sensors, such that for each of the plurality of positions on the specimen, each of the line sensors of the plurality of line sensors senses the same field of view of the position and generates a line image of the same field of view of the position at each offset of the line sensors; For each of the multiple locations on the specimen, combine the line images of the same field of view generated by the multiple line sensors at their respective offsets to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, and generate an upsampled line image of the location including the generated sub-pixels; and The upsampled line images for each of multiple locations on the specimen are combined to form an image. Have them carry out the procedure.

[0007] In one embodiment, a slide scanning device is disclosed, the slide scanning device including a stage supporting a microscope slide having a specimen thereon, a line scan camera, an objective lens, and at least one hardware processor, the line scan camera including a two-dimensional array of pixel sensors, the two-dimensional array including columns parallel to a first axis and rows parallel to a second axis orthogonal to the first axis, the objective lens sequentially providing a same field of view of the specimen to each of a plurality of rows in the two-dimensional array, such that for each of a plurality of locations on the specimen, each of the plurality of rows senses a same field of view of the location and generates a line image of the same field of view of the location, and the at least one hardware processor is configured to, for each of a plurality of locations on the specimen, sense a line image of the same field of view of the location, and and controlling one or more of the objective lens and the line scan camera such that a field of view of the specimen provided to the multiple rows in the two-dimensional array moves across the multiple rows in the two-dimensional array at a non-zero angle relative to the first axis and the second axis, such that each row in the multiple rows senses the same field of view at an offset equal to a different percentage of the length of each pixel sensor, combining line images of the same field of view generated by the multiple rows in the two-dimensional array at each respective offset to generate a plurality of sub-pixels for each of at least a subset of pixels in the line image of the same field of view and generate an upsampled line image of the location including the generated plurality of sub-pixels, and combining the upsampled line images of each location of the multiple locations on the specimen to form an image. The stage may be a motorized stage, and controlling one or more of the stage, the objective lens, and the line scan camera may include controlling the motorized stage to move relative to the objective lens. The multiple rows may consist of N rows, and the angle relative to the first axis is equal to the arctangent of 1 / N. For each of a plurality of locations on the specimen, the line image of the same field of view can include line images for N offsets ranging from zero to (N-1) / N.

[0008] In one embodiment, receiving image data from a line scan camera, the line scan camera including a two-dimensional array of pixel sensors, the two-dimensional array including columns parallel to a first axis and rows parallel to a second axis orthogonal to the first axis; controlling an objective lens to sequentially provide the same field of view of the specimen to each of the plurality of rows in the two-dimensional array, such that for each of the plurality of locations on the specimen, each of the plurality of rows senses the same field of view at the location and generates a line image of the same field of view at the location; For each of a plurality of locations on the specimen, controlling one or more of a stage, an objective lens, and a line scan camera, whereby a field of view of the specimen provided to a plurality of rows in the two-dimensional array is moved across the plurality of rows in the two-dimensional array at a non-zero angle relative to a first axis and a second axis, whereby each row in the plurality of rows senses the same field of view at an offset equal to a different percentage of a length of each pixel sensor, combining line images of the same field of view generated by the plurality of rows in the two-dimensional array at each respective offset to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, and generating an upsampled line image of the location including the generated plurality of sub-pixels; and The upsampled line images for each of multiple locations on the specimen are combined to form an image. A method is disclosed that includes using at least one hardware processor for:

[0009] In one embodiment, a non-transitory computer readable medium is disclosed having instructions stored thereon that, when executed by a processor, cause the processor to: receiving image data from a line scan camera, the line scan camera including a two-dimensional array of pixel sensors, the two-dimensional array including columns parallel to a first axis and rows parallel to a second axis orthogonal to the first axis; controlling an objective lens to sequentially provide the same field of view of the specimen to each of the plurality of rows in the two-dimensional array, such that for each of the plurality of locations on the specimen, each of the plurality of rows senses the same field of view at the location and generates a line image of the same field of view at the location; For each of a plurality of locations on the specimen, controlling one or more of a stage, an objective lens, and a line scan camera, whereby a field of view of the specimen provided to a plurality of rows in the two-dimensional array is moved across the plurality of rows in the two-dimensional array at a non-zero angle relative to a first axis and a second axis, whereby each row in the plurality of rows senses the same field of view at an offset equal to a different percentage of a length of each pixel sensor, combining line images of the same field of view generated by the plurality of rows in the two-dimensional array at each respective offset to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, and generating an upsampled line image of the location including the generated plurality of sub-pixels; and combining the upsampled line images for each of a plurality of locations on the specimen to form an image; Have them carry out the procedure.

[0010] Other features and advantages of the present invention will become readily apparent to those of ordinary skill in the art after consideration of the following detailed description and accompanying drawings.

[0011] The structure and operation of the present invention can be understood from consideration of the following detailed description and the accompanying drawings, in which like reference numerals refer to like parts. [Brief description of the drawings]

[0012] [Figure 1A]FIG. 2 illustrates an array of offset line sensors according to a first embodiment. [Figure 1B] 1B illustrates the relationship between various components of a digital imaging device including the sensor of FIG. 1A, according to one embodiment. [Diagram 2] FIG. 4 shows a sensor according to a second embodiment. [Figure 3A] FIG. 1 illustrates stacking of pixels to form sub-pixels, according to an embodiment. [Figure 3B] FIG. 1 illustrates stacking of pixels to form sub-pixels, according to an embodiment. [Figure 4] FIG. 2 illustrates a process for generating sub-pixel resolution for a digital image according to an embodiment. [Figure 5A] FIG. 2 illustrates a processor-enabled device that may be used in connection with various embodiments described herein, according to an embodiment. [Figure 5B] FIG. 2 illustrates a line scan camera having a linear array according to one embodiment. [Figure 5C] FIG. 2 illustrates a line scan camera having three linear arrays according to one embodiment. [Figure 5D] FIG. 1 is a block diagram illustrating a line scan camera having multiple linear arrays according to one embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Generally, the resolution of a digital imaging device is limited by the pixel size of the sensor and the resolution of the imaging optics. However, certain embodiments disclosed herein provide a digital imaging device (e.g., a digital slide scanner) that utilizes pixel shifting to efficiently capture images at high resolution while utilizing standard imaging optics at a reasonable cost. This resolution is higher than would otherwise be captured by the size of the pixel generating elements in the image sensor. Furthermore, the disclosed approach overcomes the field of view limitations typically associated with the required pixel resolution of digital slide scanners, thereby providing a solution that results in faster scanning, especially in line scan mechanisms.

[0014] After reading this specification, it will become apparent to those skilled in the art how to implement the present invention in various alternative embodiments and alternative applications. However, although various embodiments of the present invention are described herein, it is clear that these embodiments are for illustration only and not for limitation. Therefore, the detailed description of various alternative embodiments should not be construed as limiting the scope or breadth of the present invention as set forth in the appended claims.

[0015] 1. Offset line sensor In a first embodiment, the image sensor includes multiple line sensors that are logically offset from one another in the longitudinal direction by a distance equal to a fraction of the length of a pixel. Thus, as each successive line sensor receives light from the same portion of the specimen, it produces a line of image data (also referred to herein as a "line image") that is offset slightly (i.e., by a fraction of the length of a pixel) from the line of image data produced by the preceding line sensor. This offset can be a physical offset of the line sensors in space, although in alternative embodiments, this offset can instead be induced by shifting one line sensor in space by a defined time interval.

[0016] 1A shows a sensor 100 including three offset line sensors 110 according to one embodiment. In a direction orthogonal to the direction of scanning motion, each line sensor of the line sensor 110 is offset from its neighboring line sensor by a percentage of the length of a pixel. The direction of scanning motion represents the direction in which the imaged field of view moves relative to the sensor 100. The scanning motion may be achieved by moving the specimen relative to an optical path provided to the image sensor (e.g., by moving a motorized stage on which the specimen is supported) and / or by moving the optical path relative to the specimen (e.g., by moving an image sensor and / or an objective lens of a scanning device).

[0017] 1A shows one line for each line sensor 110, each line sensor 110 may include a set of multiple line sensors. For example, each line sensor 110 may include a set of three color sensors (e.g., three lines representing a trilinear sensor). Additionally, although sensor 100 is shown with three offset line sensors (i.e., line sensors 110A, 110B, and 110C), sensor 100 may have any number of multiple line sensors 110. In general, if N offset line sensors 110 are used, each line sensor of the N line sensors 110 should be offset from its neighboring line sensor 110 by 1 / N of the length of the pixel sensor 112. It will be understood that each line sensor 110 captures the same line image as each of the other line sensors 110, but is offset by 1 / N of the length of a pixel with respect to the same line image captured by each neighboring line sensor 110. This produces N lines of identical image data for each line image in the whole slide image, but again the image data in each line image is offset by 1 / N of a pixel length from the image data in the line image captured by the adjacent line sensor.

[0018] In the illustrated embodiment with three offset line sensors 110 (i.e., 110A, 110B, and 110C), line sensor 110B is offset from line sensor 110A by 1 / 3 of a pixel length, and line sensor 110C is offset from line sensor 110B by 1 / 3 of a pixel length and from line sensor 110A by 2 / 3 of a pixel length. In an embodiment with two offset line sensors 110, each line sensor would be offset from the other line sensors by half a pixel length. Similarly, in an embodiment with four offset line sensors 110, each line sensor would be offset from its neighboring line sensor by 1 / 4 of a pixel length.

[0019] Although sensor 100 is shown with the line sensor offset to a particular side (i.e., to the right in FIG. 1A ), the offset line sensor may alternatively be offset to the other side (i.e., to the left in FIG. 1A ) without any modifications to the techniques described herein.

[0020] 1B shows how offset pixels are captured by pixel sensor 112 according to an embodiment. Compared to one line sensor with the same optics for low resolution (i.e., native or non-subpixel) imaging, the scanning motion of sensor 100 utilizing N offset line sensors for high resolution (i.e., subpixel) imaging should be N times slower because each line image needs to be captured N times with N different offsets. Thus, in the illustrated embodiment with three line sensors 110, to achieve the same line rate as a sensor with only one line sensor, the scanning motion should be three times slower than the scanning motion of a sensor with only one line sensor.

[0021] 1B shows the logical positions of pixel sensors 112A, 112B, and 112C relative to lens 130 (e.g., an objective lens described elsewhere herein) and specimen 122 on slide 120 at times t1, t2, and t3. As discussed above, times t1, t2, and t3 each take the time it takes one line sensor to capture one line of image data, and the scanning speed of sensor 100 for high resolution imaging may be set three times slower than the scanning speed of a sensor consisting of only one line sensor for low resolution imaging.

[0022] 1B, at time t1, a location x1 of the specimen 122 is within a field of view provided by lens 130, which is at a focal height z1. A view of location x1 on the specimen 122 is provided by lens 130 via an optical path to line sensor 110A, which includes pixel sensor 112A of line sensor 110A. Pixel sensor 112A thus generates a first pixel of image data representative of a pixel-sized portion of the specimen 122 at location x1.

[0023] At time t2, location x1 on specimen 122 remains within the field of view provided by lens 130, which remains at focal height z1. However, the view of location x1 on specimen 122 has moved in the direction of the scanning motion, such that the view of location x1 on specimen 122 is provided by lens 130 through an optical path to line sensor 110B, which includes pixel sensor 112B of line sensor 110B. Pixel sensor 112B therefore generates a second pixel of image data representative of a pixel-sized portion of specimen 122 at location x1. This second pixel is offset from the first pixel by ⅓ of the pixel length.

[0024] At time t3, location x1 on the specimen 122 remains within the field of view provided by lens 130, which remains at focal height z1. However, the view of location x1 on the specimen 122 has moved in the direction of the scanning motion, causing the view of location x1 on the specimen 122 to be provided by lens 130 through an optical path to line sensor 110C, which includes pixel sensor 112C of line sensor 110C. Pixel sensor 112C therefore generates a third pixel of image data representing a pixel-sized portion of the specimen 122 at location x1. This third pixel is offset from the first pixel by ⅔ of a pixel length and offset from the second pixel by ⅓ of a pixel length.

[0025] Thus, in a sensor 100 with three offset line sensors 110, each pixel captured (i.e., representing a pixel-sized portion of the specimen 122) is captured three times at three different offsets (i.e., zero offset, offset by 1 / 3 the pixel length, and offset by 2 / 3 the pixel length). Similarly, in a sensor with two offset line sensors 110, each pixel will be captured twice at two different offsets (i.e., zero offset and offset by 1 / 2 the pixel length). In a sensor with four offset line sensors 110, each pixel will be captured four times at four different offsets (i.e., zero offset, offset by 1 / 4 the pixel length, offset by 2 / 4 the pixel length, and offset by 3 / 4 the pixel length).

[0026] In each case, each offset pixel may be combined in a manner described elsewhere herein to generate N sub-pixels. Thus, in the case of three offset line sensors 110, three sub-pixels will be generated for each pixel. In the case of two offset line sensors 110, two sub-pixels will be generated for each pixel. In the case of four offset line sensors 110, four sub-pixels will be generated for each pixel.

[0027] Although examples using two, three, and four line sensors 110 have been described, it will be understood that the techniques described herein can be extrapolated to any N (e.g., five, ten, etc.) line sensors 110 to result in N subpixels for each pixel. In an embodiment, during each time point (e.g., t1, t2, t3) that the same location (e.g., x1) on the specimen 122 is imaged by one of the N offset line sensors 110, the lens 130 may remain at the same focal height (e.g., z1), thereby producing each pixel at the same focus. As the same location is imaged by each of the N offset line sensors 110 in the sensor 100, the focal height may be adjusted, if appropriate, to maintain optimal focus (e.g., based on a focus map or other autofocus technique).

[0028] In an alternative embodiment, the same effect as sensor 100 with N line sensors 110 can be achieved by using one line sensor 110 to scan each linear portion of the specimen N times while shifting the imaged location on the specimen N-1 times (i.e., between each individual scan of the same linear portion). In such an embodiment, each time the logical location of the specimen is shifted relative to the line sensor 110, it is shifted by a length that is 1 / N of the length of the pixel sensor 112, thereby capturing N line images from an offset of zero to an offset of (N-1) / N of the pixel length. Once the N line images have been generated for the same linear portion, the logical location of the sensor 110 relative to the specimen is moved so that the next linear portion can be imaged N times, starting from a zero offset and ending at an offset of (N-1) / N of the pixel length.

[0029] 2. Angled Scanning Motion In an alternative second embodiment, the scanning motion follows an angled trajectory relative to the image sensor. In other words, instead of an array of multiple offset line sensors, the image sensor can include one or more sensors that are coplanar (i.e., not offset), but scan at an angled trajectory. Thus, a standard image sensor can be adapted to obtain the same offset line image as the offset line sensor in the first embodiment.

[0030] 2 illustrates a sensor 200 scanning in an angled trajectory, according to one embodiment. As shown, the sensor 200 includes a line scan camera having a plurality of pixel sensors 212 arranged in a two-dimensional array having rows 210 and columns. Alternatively, the sensor 200 can include an area scan camera.

[0031] In embodiments in which a line scan camera is used, the sensor 200 may include a time delay integration (TDI) line scan camera. The Piranha XL™ manufactured by Teledyne DALSA Inc., Waterlo, Ontario, Canada, is an example of a TDI line scan camera that may be used as a line scan camera in such embodiments. A TDI line scan camera includes multiple (e.g., 24, 32, 48, 64, 96, etc.) stages of line sensors, each capturing the same line image. The intensity data from each line image is then summed to provide an output line image with a much better signal-to-noise ratio (SNR). For example, the line images captured by row 210A of pixel sensors 212, row 210B of pixel sensors 212 through row 210Z of pixel sensors 212 will be integrated in this manner to generate one output line image.

[0032] However, in embodiments utilizing a TDI line scan camera, the TDI line scan camera may be switched from TDI mode to area mode. In area mode, the line images produced by rows 210 are not summed into one output line image. Rather, in area mode, each line image represents a different line of image data at a different location on the specimen.

[0033] The movement of the location on the specimen imaged by the sensor 200 relative to the sensor 200 follows a direction at an angle θ with respect to an X-axis that is perpendicular to the longitudinal direction of each row 210 and parallel to the longitudinal direction of the columns of the sensor 200. The angle θ is N -1 (i.e., θ=arctan(1 / N)), where N is the number of sub-pixels desired for each pixel. To maintain the same line rate as a sensor 200 moving parallel to the X-axis and not implementing the sub-pixel techniques described herein, the speed of the scanning motion should be: v1=N * v0 *cosθ where v0 represents the velocity of a sensor moving parallel to the X-axis and not capturing each pixel at N offsets.

[0034] As the sensor 200 images positions on the specimen along the angled trajectory, a relative movement between the sensor 200 and the specimen is set such that each set of N rows is used to capture the same line of image data. For example, in the illustrated embodiment where N=3, rows 210A, 210B and 210C are each used to capture a line image at the same position x1 along the X-axis (e.g., at times t1, t2 and t3, respectively). Similarly, rows 210X, 210Y and 210Z are used to capture a line image at the same position x2 along the X-axis, where x2>x1. The line images generated by each subset of N rows 210 represent the same linear portion of the specimen, but are offset at N different positions. In other words, the output is the same as that in the first embodiment. In particular, for each position on the specimen imaged by the image sensor, N line images are generated that are offset by 1 / N of the pixel length from the line images captured by each adjacent line sensor 110 or row 210, respectively. For N=3, three line images will be generated for each location on the specimen, including a first line image with zero offset, a second line image with an offset of 1 / 3 of the pixel length, and a third line image with an offset of 2 / 3 of the pixel length.

[0035] In particular, the sensor 200 captures fewer line images than would otherwise be captured if each row 210 were used to capture a different linear portion of the specimen. In particular, if the sensor 200 includes M rows 210 (e.g., an M-stage TDI line scan camera), the sensor 200 outputs M / N line images at a time, rather than the M line images that would be output if each row 210 was used to capture a different linear portion of the specimen.

[0036] 3. Subpixel Generation Figures 3A and 3B show how three offset pixels from an offset line image can be used to generate sub-pixels that are 1 / 3 the length of the pixel, according to two alternative embodiments. While Figures 3A and 3B show the use of three offset pixels to generate sub-pixels that are 1 / 3 the length of the pixel, it should be clear how this technique can be used with any N offset pixels to divide a pixel into N sub-pixels, each 1 / N of the pixel's length.

[0037] FIG. 3A illustrates how rectangular pixels can be used to generate a combined image pixel 300. Each line sensor 110 generates a line image 140. Thus, for example, line sensor 110A generates line image 140A, line sensor 110B generates line image 140B, and line sensor 110C generates line image 140C. It will be understood that FIG. 3B only illustrates a partial segment of each line image 140. In the illustrated embodiment, each line image 140 includes rectangular image pixels 142. The length of the image pixels 142 in the direction of movement may be controlled by adjusting the scan speed. As illustrated, when the rectangular pixels 142 from each line image 140 are combined, the combination results in a square image sub-pixel 300. Combining the rectangular pixels 142 may include summing the intensity values ​​of a portion of each pixel 142, and the sum of the intensity values ​​is used as the sub-pixel 300.

[0038] The embodiment shown in FIG. 3A uses rectangular pixels to generate the square sub-pixel 300, while the embodiment shown in FIG. 3B uses square pixels to generate the rectangular sub-pixel 300. As shown in FIG. 3B, at time t1, the pixel sensor 112A or 212A generates a first square pixel with a zero offset. Then, at time t2, the pixel sensor 112B or 212B generates a second square pixel with an offset of 1 / 3 the length of the pixel sensor 112 or 212. Finally, at time t3, the pixel sensor 112C or 212C generates a third square pixel with an offset of 2 / 3 the length of the pixel sensor 112 or 212. The overlapping portions of the first pixel, the second pixel, and the third pixel are combined to generate the rectangular sub-pixel 300. For example, combining these pixels may include summing the intensity values ​​of the first pixel, the second pixel, and the third pixel, and the sum of the intensity values ​​is used as the sub-pixel 300. To obtain a square sub-pixel 300 using such an embodiment, the same sub-pixel operation may be repeated in an orthogonal direction.

[0039] This summation of pixels into sub-pixels 300 may be repeated for each set of offset pixels (i.e., collectively representing one pixel of the image data) captured by each pixel sensor 112 or 212, thereby generating N sub-pixels for each pixel of the image data, thereby upsampling the resolution of the hole slide image by a factor of N. In the example illustrated herein, where N=3, three sub-pixels are generated for each pixel of the image data, generating an upsampled image having three times the resolution.

[0040] 4 illustrates a process 400 for generating sub-pixel resolution for a digital image (e.g., a whole slide image) using the pixel shifting techniques of the first or second embodiments described herein, according to an embodiment. Process 400 may be referred to as "demosaicing" and may be implemented as software and / or hardware in a digital imaging device (e.g., as software stored in memory 565 and executed by processor 555 of device 550). Process 400 may be performed after scanning of the specimen (i.e., generating a line image using sensor 100 or 200) or in parallel with scanning of the specimen.

[0041] At step 410, it is determined whether all line images, each representing a location within a region of interest on the specimen (e.g., a portion of the specimen or the entire specimen or slide), have been acquired. If line images representing additional locations remain to be acquired (i.e., "no" at step 410), process 400 proceeds to step 420. Otherwise, if all line images have been acquired (i.e., "yes" at step 410), process 400 proceeds to step 450.

[0042] In step 420, the current position is changed to the next position and a line image is acquired for this next position. It will be appreciated that at the start of process 400, in step 420, this next position represents the starting position from which the line image is acquired.

[0043] At step 430, N offset line images of the current position are obtained. As described elsewhere herein, each line image represents an image of the same position but offset by increments of 1 / N of the pixel length. Collectively, the N offset line images represent the current position at offsets from zero to (N-1) / N of the pixel length.

[0044] In step 440, each of the N offset line images obtained in step 430 are stacked to result in N sub-pixels for each pixel in the stacked line image. Each pixel in the offset line image may be stacked as described elsewhere herein (e.g., in connection with Figures 3A and 3B). After step 440, process 400 returns to step 410.

[0045] If, in step 410, it is determined that all line images representing the entire region of interest to be imaged on the specimen have been acquired, then process 400 proceeds to step 450. In step 450, the acquired line images are combined to form an image strip or image tile. The resolution of the resulting image strip or image tile is N times the resolution of the image strip or image tile that was not upsampled using the subpixels generated in step 440.

[0046] In step 460, the upsampled image strips or image tiles are aligned to form a continuous digital image (eg, a whole slide image).

[0047] In step 470, one or more filters are applied to the successive digital images, for example to reduce noise (e.g., edge effects caused by "stitching" image strips or image tiles), and process 400 ends.

[0048] 4. Exemplary Digital Imaging Device 5A is a block diagram illustrating an exemplary processor-enabled device 550 that can be used in connection with various embodiments described herein. In the illustrated embodiment, the device 550 is presented as a digital imaging device (also referred to herein as a digital slide scanner, scanner system, or scanning system) that includes one or more processors 555, one or more memories 565, one or more motion controllers 570, one or more interface systems 575, one or more movable stages 580 each supporting one or more glass slides 585 carrying one or more specimens 590, one or more illumination systems 595 for illuminating the specimens, one or more objective lenses 600 each defining an optical path 605 moving along an optical axis, one or more objective lens positioners 630, optional one or more epi-illumination systems 635 (which may be included in, for example, a fluorescent scanner system), one or more focusing optics 610, one or more line scan cameras 615, and / or one or more area scan cameras 620 each defining a separate field of view 625 on the specimen 590 and / or glass slide 585. The various elements of digital imaging device 550 are communicatively coupled via one or more communications buses 560. Although there may be one or more of each of the various elements of digital imaging device 550, to simplify the following description, these elements will be described in the singular unless the plural is necessary to convey the appropriate information. Alternative forms of digital imaging device 550 may also be used as will be understood by those skilled in the art.

[0049] The one or more processors 555 can include, for example, a central processing unit ("CPU") and a separate graphics processing unit ("GPU") capable of processing instructions in parallel, or the processor 555 can include a multi-core processor capable of processing instructions in parallel. Additional, separate processors can also be provided to control specific components or to perform specific functions, such as image processing. For example, the additional processors can include auxiliary processors for managing data input, auxiliary processors for performing floating point operations, application-specific processors (e.g., digital signal processors) with architectures suitable for high speed execution of signal processing algorithms, slave processors (e.g., back-end processors) subordinate to the main processor, and additional processors for controlling the line scan camera 615, the stage 580, the objective lens 600, and / or a display (not shown). Such additional processors can be separate, individual processors or can be integrated with the processor 555.

[0050] Memory 565 provides storage of data and instructions for programs that may be executed by processor 555. Memory 565 may include one or more volatile and / or non-volatile computer-readable storage media for storing data and instructions, such as random access memory (RAM), read only memory (ROM), hard disk drives, removable storage drives, and / or the like. Processor 555 may be configured to execute instructions stored in memory 565 and to communicate with various elements of digital imaging device 550 via communication bus 560 to perform the overall functionality of digital imaging device 550.

[0051] The one or more communication buses 560 may include a communication bus 560 configured to transmit analog electrical signals and / or a communication bus 560 configured to transmit digital data. Thus, communications from the processor 555, the motion controller 570 and / or the interface system 575 via the one or more communication buses 560 may include electrical signals and / or digital data. The processor 555, the motion controller 570 and / or the interface system 575 may also be configured to communicate with one or more of the various elements of the digital imaging device 550 via wireless communication links.

[0052] Motion control system 570 is configured to precisely control and adjust the XYZ movement of stage 580 (e.g., via objective positioner 630) and / or objective 600. Motion control system 570 may also be configured to control the movement of any other moving parts within digital imaging device 550. For example, in a fluorescent scanner embodiment, motion control system 570 may be configured to adjust the movement of optical filters, etc. in epi-illumination system 635.

[0053] The interface system 575 enables the digital imaging device 550 to interact with other systems and with a human operator. For example, the interface system 575 may include a user interface (e.g., a graphical user interface) to provide information directly to the operator and / or to allow direct input from the operator. The interface system 575 may be configured to facilitate communication and data transfer between the digital imaging device 550 and one or more local external devices (e.g., printers, removable storage media, etc.) directly connected thereto and / or one or more remote external devices (e.g., image servers, operator stations, user stations, management servers, etc.) connected to the digital imaging device 550 via a network.

[0054] The illumination system 595 may be configured to illuminate a portion of the specimen 590. For example, the illumination system 595 may include a light source and illumination optics. The light source may be a variable intensity halogen light source with a concave reflector to maximize light output and a KG-1 filter to suppress heat. The light source may be any type of arc lamp, laser, or other light source. In an embodiment, the illumination system 595 illuminates the specimen 590 in a transmission mode such that the line scan camera 615 and / or the area scan camera 620 sense light energy transmitted through the specimen 590. Alternatively or in combination, the illumination system 595 may be configured to illuminate the specimen 590 in a reflection mode such that the line scan camera 615 and / or the area scan camera 620 sense light energy reflected from the specimen 590. Overall, the illumination system 595 is configured to be suitable for examination of the microscope specimen 590 in any known mode of an optical microscope.

[0055] In an embodiment, the digital imaging device 550 optionally includes an epi-illumination system 635 that optimizes the digital imaging device 550 for fluorescence scanning. Fluorescence scanning is the scanning of a specimen 590 that contains fluorescent molecules, which are photon-sensitive molecules that can absorb light at a specific wavelength (excitation). These photon-sensitive molecules also emit light at longer wavelengths (emission). The efficiency of this photoluminescence phenomenon is very low, so the amount of light emitted is often very low. This low amount of emitted light typically hampers conventional techniques for scanning and digitizing the specimen 590, such as transmission mode microscopy. Advantageously, in an embodiment of the fluorescence scanner system of the digital imaging device 550, the use of a line scan camera 615 that includes multiple line sensor arrays (e.g., a time delay integration ("TDI") line scan camera) increases the light sensitivity of the line scan camera 615 by exposing the same area of ​​the specimen 590 to each line sensor array of the multiple line sensor arrays of the line scan camera 615. This is particularly useful when scanning weakly fluorescent specimens, which emit little light.

[0056] Thus, in an embodiment of the fluorescent scanner system, the line scan camera 615 is preferably a monochrome TDI line scan camera. Monochrome images are ideal in fluorescent microscopy because they provide a more accurate representation of the actual signals from the various channels present on the specimen 590. As will be appreciated by those skilled in the art, the fluorescent specimen 590 may be labeled with multiple fluorescent dyes that emit light at different wavelengths, also referred to as "channels."

[0057] Additionally, because the low and high end signal levels of the various fluorescent specimens 590 present a wide range of wavelengths for the linescan camera 615 to sense, it is desirable for the linescan camera 615 to similarly have a wide range of low and high end signal levels that it can sense. Thus, in the fluorescent scanner embodiment, the linescan camera 615 used in the digital imaging device 550 is a monochrome 10 bit 64 linear array TDI linescan camera. It should be noted that various bit depths of the linescan camera 615 can be employed for use with the fluorescent scanner embodiment of the digital imaging device 550.

[0058] In an embodiment, the movable stage 580 is configured for precise XY movement under the control of the processor 555 or the motion controller 570. The movable stage 580 may be configured for Z movement under the control of the processor 555 or the motion controller 570. The movable stage 580 may be configured to position the specimen 590 at a desired location during image capture by the line scan camera 615 and / or the area scan camera 620. The movable stage 580 may be configured to accelerate the specimen 590 to a substantially constant velocity in the scanning direction and then maintain the substantially constant velocity during image capture by the line scan camera 615. In an embodiment, the digital imaging device 550 may use a highly accurate and precisely calibrated XY grid to assist in the positioning of the specimen 590 on the movable stage 580. In an embodiment, the movable stage 580 is a linear motor-based XY stage with high precision encoders used in both the X and Y axes. For example, highly accurate nanometer encoders can be used on axes in the scanning direction and on axes perpendicular to and in the same plane as the scanning direction. Stage 580 can be configured to support a glass slide 585 on which a specimen 590 is disposed.

[0059] The specimen 590 may be anything that can be examined by optical microscopy. For example, a microscope slide 585 is often used as a viewing substrate for samples containing tissues and cells, chromosomes, DNA, proteins, blood, bone marrow, urine, bacteria, beads, biopsy material, or any other type of biological material or substance, dead or alive, stained or unstained, labeled or unlabeled. The specimen 590 may be an array of any type of DNA or DNA-related material, such as cDNA, RNA, or protein, placed on any type of slide or other substrate, including any and all specimens, commonly known as a microarray. The specimen 590 may be a microtiter plate, such as a 96-well plate. Other examples of specimens 590 include integrated circuit boards, electrophoretic recordings, petri dishes, films, semiconductor materials, forensic materials, or machined parts.

[0060] In one embodiment, the objective lens 600 is attached to an objective lens positioner 630, which may use highly accurate linear motors to move the objective lens 600 along an optical axis defined by the objective lens 600. For example, the linear motors of the objective lens positioner 630 may include 50 nanometer encoders. The relative positions of the stage 580 and the objective lens 600 in the XYZ axes are adjusted and controlled in a closed loop manner using a motion controller 570 under the control of the processor 555. The processor 555 uses a memory 565 to store information and instructions, including computer-executable programmed steps, for the overall operation of the digital imaging device 550.

[0061] In an embodiment, the objective 600 is a plan-apochromatic ("APO") infinity corrected objective with a numerical aperture corresponding to the highest spatial resolution desired, where the objective 600 is suitable for transmitted mode illumination microscopy, reflected mode illumination microscopy, and / or epi-mode fluorescence microscopy (e.g., Olympus 40X 0.75NA or 20X 0.75NA). Advantageously, the objective 600 can correct for chromatic and spherical aberrations. If the objective 600 is infinity corrected, the focusing optics 610 can be positioned in the optical path 605 above the objective 600, where the light beam passing through the objective becomes a collimated light beam. The focusing optics 610 focuses the optical signal captured by the objective 600 onto the photoresponsive elements of the line scan camera 615 and / or area scan camera 620, and can include filters, magnifier lenses, and / or similar optical components. The objective lens 600 in combination with the focusing optics 610 provides an aggregate magnification for the digital imaging device 550. In one embodiment, the focusing optics 610 can include a tube lens and an optional 2X magnifier. Advantageously, the 2X magnifier allows the native 20X objective lens 600 to scan the specimen 590 at a magnification of 40X.

[0062] In an embodiment, the line scan camera 615 includes at least one linear array of picture elements ("pixels"). The line scan camera may be monochrome or color. A monochrome line scan camera can have one linear array or multiple linear arrays, while a color line scan camera typically has at least three linear arrays. Any type of linear array or multiple linear arrays can also be used, whether packaged as part of the camera or custom integrated into the imaging electronics module. For example, a color line scan camera with three linear arrays ("red-green-blue" or "RGB") or a monochrome TDI with 96 linear arrays may be used. TDI line scan cameras typically provide a much better signal-to-noise ratio ("SNR") in the output signal by summing intensity data from previously imaged sample areas, which increases the SNR in proportion to the square root of the number of integration stages. TDI line scan cameras include multiple linear arrays. For example, TDI line scan cameras with 24, 32, 48, 64, 96 or more linear arrays are available. Digital imaging device 550 also supports linear arrays manufactured in a variety of formats, including those having 512 pixels, those having 1024 pixels, and those having 4096 pixels or more. Similarly, linear arrays having a variety of pixel sizes can also be used in digital imaging device 550. A notable requirement for selecting any type of line scan camera 615 is that the movement of stage 580 can be synchronized with the line rate of line scan camera 615 to allow stage 580 to move relative to line scan camera 615 during image capture of specimen 590.

[0063] Image data generated by line scan camera 615 may be stored in memory 565 and processed by processor 555 to generate successive digital images of at least a portion of specimen 590. The successive digital images may be further processed by processor 555 and the modified successive digital images may be stored in memory 565.

[0064] In embodiments with two or more line scan cameras 615, at least one of the line scan cameras 615 may be configured to function as a focusing sensor operating in combination with at least one of the line scan cameras 615 configured to function as an imaging sensor. The focusing sensor may be logically located in the same optical path as the imaging sensor, or the focusing sensor may be logically located before or after the imaging sensor with respect to the scanning direction of the digital imaging device 550. In such embodiments in which at least one line scan camera 615 functions as a focusing sensor, image data generated by the focusing sensor may be stored in memory 565 and processed by processor 555 to generate focus information that enables digital imaging device 550 to adjust the relative distance between specimen 590 and objective lens 600 to maintain focus on specimen 590 during scanning.

[0065] In operation, the various components of the digital imaging device 550 and the programmed modules stored in the memory 565 enable automated scanning and digitization of a specimen 590 placed on a glass slide 585. The glass slide 585 can be securely positioned on the movable stage 580 of the digital imaging device 550 for scanning of the specimen 590. Under the control of the processor 555, the movable stage 580 accelerates the specimen 590 to a substantially constant velocity for sensing by the line scan camera 615, where the velocity of the stage 580 is synchronized with the line rate of the line scan camera 615. After scanning of the strip of image data, the movable stage 580 decelerates and brings the specimen 590 to a substantially complete stop. The movable stage 580 then moves orthogonally to the scanning direction to position the specimen 590 for scanning of a subsequent strip of image data (e.g., an adjacent strip). Additional strips are scanned until an entire portion of the specimen 590 or the entire specimen 590 has been scanned.

[0066] For example, during digital scanning of the specimen 590, successive digital images of the specimen 590 may be acquired as multiple successive fields of view, and these successive digital images are combined to form an image strip. Multiple adjacent image strips are similarly combined with each other to form a successive digital image of a portion or the entire specimen 590. Scanning of the specimen 590 may include acquisition of vertical image strips or horizontal image strips. Scanning of the specimen 590 may be from top to bottom, bottom to top, or both (bidirectional), and may begin at any point on the specimen 590. Alternatively, scanning of the specimen 590 may be from left to right, right to left, or both (bidirectional), and may begin at any point on the specimen 590. Furthermore, multiple image strips need not be acquired adjacently or consecutively. Furthermore, the resulting image of the specimen 590 may be an image of the entire specimen 590, or an image of only a portion of the specimen 590.

[0067] In one embodiment, computer-executable instructions (e.g., programming modules or software) are stored within memory 565 and, when executed, enable digital imaging device 550 to perform the various functions described herein. As used herein, the term "computer-readable storage medium" is used to refer to any medium used to store and provide computer-executable instructions to digital imaging device 550 for execution by processor 555. Examples of these media include memory 565 and any removable or external storage medium (not shown) communicatively coupled to digital imaging device 550 directly or indirectly, for example, via a network (not shown).

[0068] 5B illustrates a line scan camera 615 having a linear array 640, which may be implemented as a charge-coupled device ("CCD") array. The linear array 640 includes a plurality of individual pixels 645. In the illustrated embodiment, the linear array 640 includes 4096 pixels 645. In alternative embodiments, the linear array 640 may include more or fewer pixels 645. For example, common formats for linear arrays include 512 pixels 645, 1024 pixels 645, and 4096 pixels 645. The pixels 645 are arranged in a linear fashion to define a field of view 625 of the linear array 640. The size of the field of view 625 varies depending on the magnification of the digital imaging device 550.

[0069] 5C shows a line scan camera 615 having three linear arrays, each of which may be implemented as a CCD array. The three linear arrays are combined to form a color array 650. In one embodiment, different color intensities (e.g., red, green, or blue) are detected by each linear array in the color array 650. The color image data from each individual linear array in the color array 650 is combined to form a field of view 625 of color image data.

[0070] FIG. 5D shows a line scan camera having multiple linear arrays, each of which may be implemented as a CCD array. Collectively, these multiple linear arrays form a TDI array 655. Advantageously, a TDI line scan camera may provide a much better SNR in its output signal by summing intensity data from previously imaged sample areas, which increases the SNR in proportion to the square root of the number of linear arrays (also called integration stages). TDI line scan cameras can include a larger number of linear arrays. For example, common formats of TDI line scan cameras include 24 linear arrays, 32 linear arrays, 48 ​​linear arrays, 64 linear arrays, 96 linear arrays, 120 linear arrays, and many more.

[0071] The above description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles described herein can be applied to other embodiments without departing from the spirit or scope of the present invention. It should therefore be understood that the description and drawings presented herein represent the presently preferred embodiments of the present invention, and therefore represent the subject matter broadly contemplated by the present invention. It should also be understood that the scope of the present invention fully encompasses other embodiments that may become apparent to those skilled in the art, and thus is not limited in scope.

Claims

1. 1. A slide scanning device, comprising: a plurality of line sensors, an objective lens, and at least one hardware processor; the plurality of line sensors are configured to generate a plurality of line images of a specimen, each line sensor of the plurality of line sensors including a plurality of pixel sensors, each line sensor of the plurality of line sensors being offset in a longitudinal direction of the line sensor from an adjacent one of the plurality of line sensors by a percentage of a length of each pixel sensor, each pixel sensor of the plurality of pixel sensors having a defined shape that is elongated along the longitudinal direction of the line sensor; the objective lens is configured to sequentially provide the same field of view of the specimen to each line sensor of the plurality of line sensors; The at least one hardware processor, for each of a plurality of locations on the specimen, configured to combine the line images of the same field of view to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, the defined shape having a dimension such that the line images, when combined, generate square shaped sub-pixels; configured to generate an upsampled line image of the location including the generated plurality of sub-pixels; and combining the upsampled line images for each of the plurality of locations on the specimen to form an image. Slide scanning device.

2. the plurality of line sensors is comprised of N line sensors, each line sensor of the plurality of line sensors being offset from an adjacent line sensor, the proportion of the length of each pixel sensor being 1 / N; 2. The slide scanning device of claim 1.

3. for each of the plurality of locations on the specimen, the line images of the same field of view include line images for N offsets ranging from zero to (N-1) / N.

3. The slide scanning device of claim 2.

4. and for each of the plurality of locations on the specimen, combining the line images of the same field of view includes, for each of the at least a subset of pixels, summing intensity values ​​for pixels from each of the line images at their respective offsets.

4. The slide scanning device of claim 3.

5. The at least one hardware processor further comprises: configured to combine the upsampled line images for each of the plurality of locations on the specimen to form a plurality of image strips; configured to align each image strip of the plurality of image strips with at least one adjacent image strip of the plurality of image strips to form a continuous digital image.

2. The slide scanning device of claim 1.

6. 1. A method comprising using at least one hardware processor, the at least one hardware processor comprising: receiving a plurality of line images of a specimen from a plurality of line sensors configured to generate line images, each line sensor of the plurality of line sensors including a plurality of pixel sensors, each line sensor of the plurality of line sensors being offset in a longitudinal direction of the line sensor from an adjacent one of the plurality of line sensors by a percentage of a length of each pixel sensor, each pixel sensor of the plurality of pixel sensors having a defined shape that is elongated along the longitudinal direction of the line sensor; controlling an objective lens configured to sequentially provide the same field of view of the specimen to each line sensor of the plurality of line sensors; For each of the plurality of locations on the specimen, combining the line images of the same field of view to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, the defined shape having dimensions such that when the line images are combined they generate square shaped sub-pixels; generating an upsampled line image of the location containing the generated plurality of sub-pixels; combining the upsampled line images for each of the plurality of locations on the specimen to form an image. method.

7. A non-transitory computer readable medium having instructions stored thereon that, when executed by a processor, cause the processor to: receiving a plurality of line images of a specimen from a plurality of line sensors configured to generate line images, each line sensor of the plurality of line sensors including a plurality of pixel sensors, each line sensor of the plurality of line sensors being offset in a longitudinal direction of the line sensor from an adjacent one of the plurality of line sensors by a percentage of a length of each pixel sensor, each pixel sensor of the plurality of pixel sensors having a defined shape that is elongated along the longitudinal direction of the line sensor; controlling an objective lens configured to sequentially provide the same field of view of the specimen to each line sensor of the plurality of line sensors; For each of the plurality of locations on the specimen, combining the line images of the same field of view to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, the defined shape having dimensions such that when the line images are combined they generate square shaped sub-pixels; generating an upsampled line image of the location containing the generated plurality of sub-pixels; combining the upsampled line images for each of the plurality of locations on the specimen to form an image. To carry out Non-transitory computer-readable medium.

8. The instructions further cause the processor to: combining the upsampled line images for each of the plurality of locations on the specimen to form a plurality of image strips; aligning each image strip of the plurality of image strips with at least one adjacent image strip of the plurality of image strips to form a continuous digital image; To carry out The non-transitory computer readable medium of claim 7.

9. the plurality of line sensors is comprised of N line sensors, each line sensor of the plurality of line sensors being offset from an adjacent line sensor, the proportion of the length of each pixel sensor being 1 / N; The non-transitory computer readable medium of claim 7.

10. for each of the plurality of locations on the specimen, the line images of the same field of view include line images for N offsets ranging from zero to (N-1) / N.

10. The non-transitory computer readable medium of claim 9.

11. and for each of the plurality of locations on the specimen, combining the line images of the same field of view includes, for each of the at least a subset of pixels, summing intensity values ​​for pixels from each of the line images at their respective offsets. The non-transitory computer readable medium of claim 10.

12. 1. A slide scanning device, comprising: a stage for supporting a microscope slide having a specimen thereon, a line scan camera, an objective lens, and at least one hardware processor; the line scan camera includes a two-dimensional array of pixel sensors, the two-dimensional array including columns parallel to a first axis and rows parallel to a second axis orthogonal to the first axis, each pixel sensor of the plurality of pixel sensors having a defined shape that is elongated; the objective lens is configured to sequentially provide the same field of view of the specimen to each row of a plurality of rows in the two-dimensional array; The at least one hardware processor, for each of a plurality of locations on the specimen, configured to control one or more of the stage, the objective lens, and the line scan camera such that the field of view of the specimen provided to the multiple rows in the two-dimensional array is moved across the multiple rows in the two-dimensional array at a non-zero angle relative to the first axis and the second axis, such that each row in the multiple rows senses the same field of view at an offset equal to a different percentage of a length of each pixel sensor; configured to combine the line images of the same field of view to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, the defined shape having a dimension such that the line images, when combined, generate square shaped sub-pixels; configured to generate an upsampled line image of the location including the generated plurality of sub-pixels; and combining the upsampled line images for each of the plurality of locations on the specimen to form an image. Slide scanning device.

13. the stage is a motorized stage, and controlling one or more of the stage, the objective lens, and the line scan camera includes controlling the motorized stage to move relative to the objective lens.

13. The slide scanning device of claim 12.

14. the plurality of rows comprises N rows, and the angle relative to the first axis is equal to the arctangent of 1 / N; 13. The slide scanning device of claim 12.

15. for each of the plurality of locations on the specimen, the line images of the same field of view include line images for N offsets ranging from zero to (N-1) / N.

15. The slide scanning device of claim 14.

16. 1. A method comprising using at least one hardware processor, the at least one hardware processor comprising: receiving image data from a line scan camera, the line scan camera including a two-dimensional array of pixel sensors including columns parallel to a first axis and rows parallel to a second axis orthogonal to the first axis, each pixel sensor of the pixel sensors having a defined shape that is elongated; controlling an objective lens configured to sequentially provide the same field of view of the specimen to each of a plurality of rows in the two-dimensional array; For each of the plurality of locations on the specimen, controlling one or more of a stage, the objective lens, and the line scan camera such that the field of view of the specimen provided to the plurality of rows in the two-dimensional array is moved across the plurality of rows in the two-dimensional array at a non-zero angle relative to the first axis and the second axis, such that each row in the plurality of rows senses the same field of view at an offset equal to a different fraction of a length of each pixel sensor; combining the line images of the same field of view to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, the defined shape having dimensions such that when the line images are combined they generate square shaped sub-pixels; generating an upsampled line image of the location containing the generated plurality of sub-pixels; combining the upsampled line images for each of the plurality of locations on the specimen to form an image. method.

17. A non-transitory computer readable medium having instructions stored thereon that, when executed by a processor, cause the processor to: receiving image data from a line scan camera, the line scan camera including a two-dimensional array of pixel sensors, the two-dimensional array including columns parallel to a first axis and rows parallel to a second axis orthogonal to the first axis; controlling an objective lens configured to sequentially provide the same field of view of the specimen to each of a plurality of rows in the two-dimensional array; For each of the plurality of locations on the specimen, controlling one or more of a stage, the objective lens, and the line scan camera such that the field of view of the specimen provided to the plurality of rows in the two-dimensional array is moved across the plurality of rows in the two-dimensional array at a non-zero angle relative to the first axis and the second axis, such that each row in the plurality of rows senses the same field of view at an offset equal to a different fraction of a length of each pixel sensor; combining the line images of the same field of view to generate a plurality of sub-pixels for each of at least a subset of pixels in the line images of the same field of view, the defined shape of each pixel sensor of the plurality of pixel sensors having a dimension such that the line images, when combined, generate square shaped sub-pixels; generating an upsampled line image of the location containing the generated plurality of sub-pixels; combining the upsampled line images for each of the plurality of locations on the specimen to form an image. To carry out Non-transitory computer-readable medium.

18. the stage is a motorized stage, and controlling one or more of the stage, the objective lens, and the line scan camera includes controlling the motorized stage to move relative to the objective lens.

20. The non-transitory computer readable medium of claim 17.

19. the plurality of rows comprises N rows, and the angle relative to the first axis is equal to the arctangent of 1 / N; 20. The non-transitory computer readable medium of claim 17.

20. for each of the plurality of locations on the specimen, the line images of the same field of view include line images for N offsets ranging from zero to (N-1) / N.

20. The non-transitory computer readable medium of claim 19.

Images