Combined imaging of assays

Abstract

A combined imaging system includes a housing having a base and a cover having a closed position against the base and having an open position. The combined imaging system further includes a contact area image sensor. When the cover is in the closed position, the cover blocks ambient light for the contact area image sensor. The imaging device also includes a camera. The camera includes a lens, and a field of view of the camera encompasses at least a portion of an imaging area of the contact area image sensor when the cover is in the open position. The device is particularly useful for capturing chemiluminescent images of the electrophoretic assay results, and for capturing colorimetric images of the same results, such that a non-chemiluminescent protein standard can be localized relative to a chemiluminescent analyte of interest.

Description

This application is a divisional application of the invention patent application with the international application date of 2018-12-13, the international application number of PCT / US2018 / 065539, the application number entering the Chinese national phase of 201880080533.1, and the title of "Combined Imaging of Measurement". Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 599,424, filed on December 15, 2017, and entitled “Combination Imaging of Assays,” the entire disclosure of which is hereby incorporated by reference into this application for all purposes. Background Art

[0002] Electrophoresis is a technique used in molecular biology and other disciplines to detect the presence of proteins or other analytes in a mixture. Typically, after some preparatory steps, the mixture is placed in the "wells" of a gel, such as an agarose or polyacrylamide gel. For protein determination, the gel is subjected to an electric field, which causes the proteins to migrate through the gel. The rate at which a particular protein in a mixture migrates through the gel depends on the molecular weight of the protein. Proteins with smaller molecular weights tend to migrate faster than proteins with larger molecular weights. Over time, different proteins are separated because they travel different distances through the gel.

[0003] Proteins can be labeled with antibodies so that the protein of interest emits light by chemiluminescence. In certain applications, such as in the well-known Western blotting technique, proteins are transferred to a membrane, such as polyvinylidene fluoride (PVDF) or nitrocellulose membrane to form a blot. Historically, (after several incubation steps) the blot was placed in contact with film of approximately the same size as the blot. Chemiluminescence exposes portions of the membrane so that the pattern of protein separation is permanently recorded on the membrane. Recently, electronic imaging is replacing film for this purpose.

[0004] In any case, one or more "lanes" of the gel are usually reserved for a standard mixture of proteins having a set of known molecular weights ("protein standards"). The standard mixture is separated simultaneously with the mixture being assayed so that the protein standards can provide an indication of the distance a protein of a given molecular weight has traveled through the gel. This method provides a visual calibration of the assay.

[0005] In many assays, protein standards are visible to the naked eye but are not chemiluminescent, and therefore their positions may not be recorded on film or using an electronic sensor that records chemiluminescence. In existing systems, users may use chemiluminescent substances to track the positions of protein standards on the blot so that the positions of protein standards can be recorded on film or electronically. Alternatively, after the film is exposed and developed, the user can mark the positions of protein standards on the film with a standard pen. Both methods are inconvenient.

[0006] In another technique called "gel documentation" or "geldoc," the gel can be imaged directly without transferring the proteins to a membrane.

[0007] Chemiluminescent protein standards are available but are much more expensive than non-chemiluminescent protein standards. Summary of the invention

[0008] According to one aspect, a combined imaging system includes a housing having a base and a cover, the cover having a closed position against the base and having an open position. The combined imaging system further includes a contact area image sensor. When the cover is in the closed position, the cover shields the contact area image sensor from ambient light. The imaging device also includes a camera. The camera includes a lens, and when the cover is in the open position, the field of view of the camera covers at least a portion of the imaging area of ​​the contact area image sensor. In some embodiments, the camera is mounted in the cover. In some embodiments, the system further includes a controller configured to: capture a first digital image using the contact area image sensor, and capture a second digital image using the camera. In some embodiments, the controller is further configured to combine the first digital image and the second digital image into a composite digital image. In some embodiments, the system further includes a light source controlled by the controller, wherein the light source provides illumination for the second digital image. The light source may be mounted in the cover. In some embodiments, the system does not include a light source for providing illumination for the second digital image, and the second digital image is captured using ambient light. In some embodiments, the first digital image records the intensity of light emitted by chemiluminescence of a target placed on the contact area image sensor, and the second digital image records the intensity of light reflected from the target. The target can be a blot carrying proteins labeled to glow by chemiluminescence and also carrying non-chemiluminescent protein standards. In some embodiments, the system further comprises a lid sensor that senses whether the lid is in a closed position or an open position. In some embodiments, the contact area image sensor is a color sensor. In some embodiments, the camera is a color camera.

[0009] According to another aspect, a method of reading the results of an electrophoretic assay includes placing an output medium of the electrophoretic assay on a contact area image sensor of a combined imaging device and closing a cover of the combined imaging device, thereby blocking ambient light from reaching the contact area image sensor. The method further includes capturing a first digital image of the output medium using the contact area image sensor. The first digital image indicates the intensity of light emitted from the output medium by chemiluminescence. The method further includes opening the cover, and capturing a second digital image of the output medium using a camera mounted in the cover. When the cover is in the open position, the field of view of the camera encompasses at least a portion of the output medium, and the second digital image indicates the intensity of light reflected from the output medium. The first digital image and the second digital image are combined into a composite digital image. In some embodiments, the output medium is a blot carrying a protein labeled to emit light by chemiluminescence and the blot carries a protein standard that is non-chemiluminescent but visible in the second digital image; and combining the first digital image and the second digital image into a composite digital image includes combining the first digital image and the second digital image into a digital image in which both the chemiluminescence of the labeled protein and the non-chemiluminescent protein standard are shown. In some embodiments, the first digital image is captured before the second digital image is captured; or the second digital image is captured before the first digital image is captured. In some embodiments, the output medium is a film. In some embodiments, the combined imaging device does not include a light source for providing illumination for the second digital image, and capturing the second digital image includes capturing the second digital image using ambient light. In some embodiments, the method further includes providing supplemental light to the output medium using a light source in the combined imaging device, and capturing the second digital image includes capturing the second digital image using the supplemental light. In some embodiments, the method further includes digitally adjusting the size of at least one of the first digital image and the second digital image so that the first digital image and the second digital image have the same size. In some embodiments, the method further includes removing distortion from at least one of the first digital image and the second digital image. In some embodiments, the method further includes sensing whether the lid is in the closed position or the open position, and instructing a user of the imaging device to open or close the lid. In some embodiments, the method further includes placing the gel on the contact area image sensor, and capturing one or more images of the gel using the contact area image sensor, the camera, or both.

[0010] According to another aspect, a combined imaging system includes: a housing having a base and a cover, the cover having a closed position against the base and an open position; and a contact area image sensor. When the cover is in the closed position, the cover shields the contact area image sensor from ambient light. The system further includes: a phosphorescent region in the cover, the phosphorescent region corresponding to an area of ​​the contact area image sensor when the cover is in the closed position; and a shutter for covering the phosphorescent region.

[0011] According to another aspect, a method of reading the results of an electrophoretic assay includes: placing an output medium of the electrophoretic assay on a contact area image sensor of a combined imaging device; covering a phosphorescent area in a cover of the combined imaging device; and capturing a first digital image of the output medium using the contact area image sensor. The first digital image indicates the intensity of light emitted from the output medium by chemiluminescence, and the first digital image is captured with the cover of the combined imaging device closed, thereby blocking ambient light from reaching the contact area image sensor. The method further includes uncovering the phosphorescent area in the cover of the combined imaging device, and capturing a second digital image of the output medium using the contact area image sensor. The second digital image indicates the intensity of light transmitted from the phosphorescent area through the output medium, and the second digital image is captured with the cover of the combined imaging device closed, thereby blocking ambient light from reaching the contact area image sensor. The method further includes combining the first digital image and the second digital image into a composite digital image. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Shown is a typical blot after protein separation and several incubation steps according to an embodiment of the present invention.

[0013] Figure 2 An imaging device according to an embodiment of the present invention is shown in a closed position.

[0014] Figure 3 In the open position Figure 2 imaging device.

[0015] Figure 4 1. A diagram showing a method of positioning a target according to an embodiment of the present invention. Figure 2 imaging device.

[0016] Figure 5 Shown in a closed position according to an embodiment of the present invention Figure 2 Imaging equipment and example chemiluminescent digital images.

[0017] Figure 6 The embodiment of the present invention is shown in the open position. Figure 2 The imaging device and example colorimetric digital images.

[0018] Figure 7 The transformation of a digital image into a corrected image with perspective distortion removed is shown according to an embodiment of the present invention.

[0019] Figure 8 The construction of a composite digital image according to an embodiment of the present invention is shown.

[0020] Fig. 9 The embodiment of the present invention is shown Figure 2 A schematic block diagram of an imaging device and a computer system connected to the imaging device.

[0021] Fig.10 A flow chart of a method according to an embodiment of the present invention is shown.

[0022] Fig.11 Imaging devices according to other embodiments of the present invention are shown in an open position. Detailed description of the invention

[0023] Figure 1 A typical blot 100 after separation of proteins according to an embodiment of the present invention is shown. One lane 101 of the blot is reserved for protein standards 102a-102f. Protein standards 102a-102f have been separated in direction 103, with smaller molecular weight protein standards 102f further away from edge 104 than larger molecular weight protein standards 102a.

[0024] A sample of the mixture to be assayed has been separated in lanes 105-110, resulting in protein bands 111 and 112 in each of lanes 105-110. (The lane divisions shown in dashed lines are for illustration only and do not appear on the blot.) Protein band 111 corresponds approximately to the molecular weight of protein standard 102b, and protein band 112 corresponds approximately to the molecular weight of protein standard 102e. Because the molecular weights of standards 102b and 102e are known, their presence provides information about the molecular weights of the proteins at bands 111 and 112 to help identify the proteins in bands 111 and 112.

[0025] like Figure 1 As shown, the proteins in bands 111 and 112 emit light via chemiluminescence, while protein standards 102a-102f do not emit light.

[0026] Figure 2 An imaging device 200 according to an embodiment of the present invention is shown in a closed position. Figure 3 The imaging device 200 is shown in an open position.

[0027] Reference Figure 2 and Figure 3 In both figures, the imaging device 200 includes a base portion 201 and a cover 202. The cover 202 is Figure 2 is shown in the closed position, while in Figure 3 The contact area image sensor 301 is arranged in the base 201 . The contact area image sensor 301 can be of the type described in, for example, the following patent applications: U.S. Patent Application Publication No. 2015 / 0172526, published on June 18, 2015, by Swihart et al. and entitled “Non-Destructive Read Operations with Dynamically Growing Images”; U.S. Patent Application Publication No. 2016 / 0006910, published on January 7, 2016, by Uri et al. and entitled “Contact Imager”; U.S. Patent Application Publication No. 2016 / 0028976, published on January 28, 2016, by Ran et al. and entitled “Digital Masking Pixels with Masked Pixels”; U.S. Patent Application Publication No. 2016 / 0028976, published on January 19, 2017, and entitled “Contact Imaging Devices for Fluorescence Imaging”; U.S. Patent Application Publication No. 2017 / 0016829 to Swihart et al., entitled "Contact Imaging Device for Fluorescence Applications"; all disclosures of these patent applications are hereby incorporated herein by reference for all purposes.

[0028] The contact area image sensor 301 can be, for example, a charge coupled device (CCD) sensor, a complementary metal oxide semiconductor (CMOS) sensor, or another suitable type of sensor. Typically, such sensors utilize the property of certain semiconductor materials, namely that when the material is struck by light, free electrons proportional to the light intensity are generated. The sensor is divided into specific photosensitive areas, called "pixels". In order to capture an image, the pixels are reset and then exposed for an exposure time. At the end of the exposure time, the amount of charge accumulated in each pixel is measured and converted into a numerical value. The array of these numerical values ​​can be referred to as a "digital image", where each value in the array represents the brightness of the light falling on the corresponding pixel.

[0029] In a CCD sensor, the accumulated charge is transferred from the sensor to a charge amplifier, whose output is digitized for each pixel. In a CMOS sensor, the accumulated charge can be read directly from each pixel without transferring the charge. In some sensors, different pixels are sensitive to different light bands, allowing for color imaging.

[0030] In this context, a "contact" sensor is one that receives light directly from a location on a target that contacts the sensor surface at a 1:1 magnification, without any intermediate variable magnification optics. (Other types of optical components may be present between the contact surface and the photosensitive semiconductor layer, as described in more detail below.) This sensing is analogous to making a "contact print" in film photography, where a photographic negative is placed in direct contact with photographic paper and exposed to light. The image formed on the paper is exactly the size of the negative.

[0031] Reference again Figure 3 , the area of ​​contact area image sensor 301 is preferably slightly larger than a typical footprint, for example, about 7×10 centimeters. In other embodiments, contact area image sensor 301 may be about 5×7 inches, 8×10 inches, or 9×12 inches, or another suitable size. Contact area image sensor 301 preferably includes thousands or even millions of pixels that are small enough so that the digital image captured by contact area image sensor 301 provides a high-resolution representation of the object placed on the sensor. For example, each pixel may be about 130 square microns, or another suitable size. A 7×10 centimeter sensor with 130 micron pixels would have a total of about 414,000 pixels.

[0032] The imaging device 200 also includes a camera 302 mounted in the cover 202. The camera 302 preferably includes a lens 303 and another electronic image sensor (in Figure 2 and 3 ). Lens 303 has a field of view 304, which is visible when cover 202 is in Figure 3 304 encompasses at least a portion of the contact area image sensor 301, and preferably encompasses all of the contact area image sensor 301, when the lid 202 is in the open position. The field of view 304 is the area visible to the sensor in the camera 302 through the lens 303. The imaging device 200 preferably includes a mechanism for indicating when the lid 202 is in a particular open position, such as a rotation stop, detent, or other mechanism. The camera 302 can be designed to cooperate with the base 201, the lid 202, and the contact area image sensor 301 to ensure that the field of view of the camera 302 encompasses some or all of the contact area image sensor 301 when the lid 202 is in the open position.

[0033] The imaging device 200 may optionally include a light source 305, which may include, for example, one or more light emitting diodes (LEDs) or other suitable light emitting devices. The light emitted by the light source 305 may be broadband light, white light, narrowband light, monochromatic light, or may have another suitable wavelength distribution.

[0034] Optionally, one or more fiducial markers 306 may be placed on the base 201 at locations within the field of view 304 of the camera 302. A lid sensor 307 may be present, allowing automatic detection of whether the lid 202 is in its closed or open position.

[0035] although Figure 3 The camera 302 and light source 305 are shown mounted in the cover 202, but this is not required and one or both of these components may be mounted differently, such as suspended from the contact area image sensor 301 by some other structure.

[0036] The camera 302 is capable of photographing a target on the contact area image sensor 301 from above by capturing light reflected from the target and forming an image of the target on the sensor within the camera 302. Images taken with reflected light may be referred to as "colorimetric" images, as compared to "chemiluminescent" images taken using the contact area image sensor 301 using only light emitted by the target through chemiluminescence. The reflected light may be from ambient room light, or may be provided by a light source 305, or may be a combination of ambient light and artificial light. Using a light source 305 may be preferred so that the quality and uniformity of the image captured by the camera 302 is not subject to variations in ambient room light. The light source 305 may be designed to cooperate with the base 201, the lid 202, and the contact area image sensor 301 so that when the lid 202 is in the open position, an area of ​​the contact area image sensor 301 is illuminated by the light source 305.

[0037] Figure 4-Figure 8 The steps of using the imaging device 200 are shown. Figure 4 In FIG. 4 , lid 202 has been opened and a target 401 in the form of a blot similar to blot 100 is placed on contact area image sensor 301. Target 401 includes lanes 402 of non-luminescent protein standards and a plurality of locations 403 that emit light by chemiluminescence, indicating the presence of a particular protein that has been separated in the experiment. Figure 4 Only the top surface of target 401 is visible, but chemiluminescence is emitted from both sides and some of the light is directed downward toward contact area image sensor 301.

[0038] Once the target 401 is in place, the lid 202 is closed, as shown in FIG. Figure 5When the cover 202 is in the closed position, the cover 202 blocks ambient light from the contact area image sensor 301. With the cover 202 in the closed position, a digital image 501 is captured using the contact area image sensor 301.

[0039] Generating the digital image 501 from the output of the contact area image sensor 301 may be accomplished in any suitable manner. For example, the imaging device 200 may include a controller that performs all necessary conversions and calculations and stores the digital image 501 in a standard image file format such as JPEG (Joint Photographic Experts Group), TIFF (Tagged Image File Format), GIF (Graphics Interchange Format), PNG (Portable Network Graphics), or any other suitable standardized or proprietary format. In other embodiments, the signals may be passed from the imaging device 200 to a suitable computer system that converts the signals and generates the digital image file. Any feasible architecture and division of tasks may be used.

[0040] Digital image 501 uses the following convention: background areas (where no chemiluminescence is detected) are shown in white, while areas where chemiluminescence is detected (corresponding to the protein of interest) are shown in black. The opposite convention may be used, or the areas may be distinguished in any other suitable manner, such as using grayscale, color, false color, or other distinguishing techniques.

[0041] It is noteworthy that the leftmost portion of digital image 501, corresponding to protein standard lane 402 of target 401, does not indicate any light detected. This is because the protein standards are not chemiluminescent and do not generate light.

[0042] It will be appreciated that the above description of image capture using the contact area array sensor 301 is somewhat simplified. Other techniques may be utilized to improve the quality of the chemiluminescent image, such as compensating for dark current and temperature variations across the contact area array sensor 301, as described in U.S. Patent Application Publication No. 20126 / 0028976 to Ran et al., and non-destructive reading of intermediate images to help determine when to end exposure and reduce noise as discussed in U.S. Patent Application Publication No. 2015 / 0172526 to Swihart et al., both of which have been previously incorporated herein by reference.

[0043] Figure 6The imaging device 200 is shown with the lid 202 again in the open position. In this position, another digital image 601 is captured using the camera 302, either by ambient light or using light emitted from a light source such as the light source 305, or by using a combination of light sources. Due to the tilted angle at which the camera 302 observes the contact area image sensor 301, the target 401 appears as a perspective distorted image 601. However, because the physical relationship of the camera 302 to the target 401 is known, the perspective distortion can be digitally eliminated by simple image processing. In addition, if fiducial markers are used, they can appear in the image 601 and provide additional cues for digitally reversing the perspective distortion. Also in the image 601, the protein standard is visible in the lane 402.

[0044] Figure 7 The transformation of uncorrected image 601 with perspective distortion removed to corrected camera image 701 is shown. In addition, image 701 is preferably scaled to have the same or nearly the same pixel size as image 501 captured using contact area image sensor 301. In this example, pixel 702 in image 601 has been mapped to pixel 703 in image 701. Similarly, pixel 704 in image 601 has been mapped to pixel 703 in image 701. Other pixels in image 601 are mapped to corresponding pixels in image 701 based on their positional relationship to pixels 702 and 704. It may be preferred that the sensor in camera 302 has significantly more pixels than contact area array sensor 301 so that perspective distortion correction does not introduce objectionable "jaggies" or other noticeable image artifacts.

[0045] Other image transformations may also be performed, such as: smoothing the brightness of the image to compensate for non-uniformities in the illumination used to capture image 601, contrast enhancement, etc. The end result is that image 701 is the same size as image 501 and displays the protein standards in lane 402. However, proteins of interest in other lanes may not be visible in digital image 701 because the chemiluminescent light emission is faint relative to the ambient or artificial light used to capture colorimetric image 601.

[0046] In other embodiments, for example, if camera 302 is suspended above contact area image sensor 301 using a fixed structure, rather than mounted in cover 202, image processing may be simplified because camera 302 is able to capture images without perspective distortion.

[0047] Finally, if Figure 8As shown, digital image 501 (captured chemiluminescently using contact area array sensor 301) and digital image 701 (captured colorimetrically using camera 302) are combined into composite digital image 801. For example, if digital images use the convention that darker areas represent protein standards or proteins of interest, digital image 801 can be constructed by selecting, for each pixel, the darker of the corresponding pixels in images 501 and 701.

[0048] Although the above examples are described in the context of reading a blot (such as a protein blot), embodiments of the present invention may also be used for direct gel recording. In gel recording, the electrophoresis gel is read directly without the step of transferring the separated proteins and protein standards to the membrane. The gel itself can be placed on the contact area image sensor 301 and imaged colorimetrically using ambient light, light from a light source 305, or a combination of the two. In either case, the membrane or gel can be considered as the output medium of the electrophoresis assay because the membrane or gel indicates the results of the assay. In addition to or in place of the contact area image sensor 301, a camera 302 can also be used to image the gel.

[0049] Fig. 9 A schematic diagram of an imaging device 200 and a computer system 901 connected to the imaging device 200 according to an embodiment of the present invention is shown.

[0050] Imaging device 200 includes contact area image sensor 301, some aspects of which are described above. More details are given in Fig. 9 For example, the contact area image sensor 301 may include a panel layer 902 on top of a photosensitive semiconductor layer 903. The panel layer may include a bundle of parallel optical fibers whose axes are arranged vertically. The optical fiber may be a gradient refractive index lens or a simple optical fiber. The panel layer 902 has the function of transmitting light entering at the top of the optical fiber to the bottom end of the optical fiber, so that the image formed at the top of the optical fiber is translated downward to the bottom end of the optical fiber. The bottom side of the panel layer 902 is substantially in contact with the photosensitive semiconductor layer 903. This arrangement can provide protection for the photosensitive semiconductor layer 903 and its associated circuitry, and allows an image to be formed on the photosensitive semiconductor layer 903 without the use of other optical devices such as a zoom lens. The top of the panel layer 902 forms a platen for the imaging device, and the target is directly on it.

[0051] The camera 302 forms its image in a different way. In the camera 302, the lens 303 projects the image of the pressure plate onto the electronic array light sensor 904. The electronic array light sensor 904 can be, for example, a CMOS sensor, a CCD sensor, or another sensor. The electronic array light sensor 904 also includes thousands or millions of pixels, but the pixels in the electronic array light sensor 904 are preferably much smaller than the pixels of the contact area image sensor 301. For example, the electronic array light sensor 904 can include as few as 200,000 pixels or as many as several million pixels, or another suitable number. The width of each pixel can be approximately 1 to 6 microns, or other suitable dimensions. The electronic array light sensor 904 can be a color sensor, meaning that different pixels are sensitive to different wavelengths of light, thereby enabling the camera 302 to distinguish between colors.

[0052] Controller 905 is coupled to various components of imaging device 200, including contact area image sensor 301, light source 305, lid sensor 307, and electronic array light sensor 904. Controller 905 is coupled to computer system 901 via any suitable interface, such as a universal serial bus (USB) interface or another interface. Computer system 901 can provide instructions to imaging device 200 regarding when to capture chemiluminescence and colorimetry, etc., and can provide a user interface to accept instructions from a system user and present results to the user. Computer system 901 can cooperate with imaging device 200 to provide image processing for exposure determination, distortion correction, or other functions. Computer system 901 preferably includes a processor and a stored program that, when executed by the processor, causes computer system 901 to perform its specified functions.

[0053] In other embodiments, image processing and the like may be performed by a controller 905 within the imaging device 200. Any suitable division of labor between the imaging device 200 and the computer system 901 may be used. In other embodiments, the imaging device 200 may be a stand-alone system including a user interface and a display so that the assay may be read without the need for an external computer system. In that case, the results may be stored on a removable storage medium for transmission to other devices, or the imaging device 200 may include a network interface for sending the results to a remote server. The network interface may also be used for other functions, such as downloading software updates and other functions.

[0054] Fig.10 A flow chart of a method 1000 according to an embodiment of the present invention is shown. In step 1001, an output medium of an electrophoresis assay is placed on a contact area image sensor of an imaging device. For example, the output medium may be a membrane onto which proteins have been transferred.

[0055] At step 1002, a cover of the imaging device is closed, thereby blocking ambient light from reaching the contact area image sensor. At step 1003, a first digital image of the output medium is captured using the contact area image sensor. The first digital image indicates the intensity of light emitted from the output medium by chemiluminescence, and may be referred to as a "chemiluminescent" image.

[0056] At step 1004, the lid is opened. At step 1005, a second digital image is captured using a camera, which may be mounted in the lid. When the lid is in the open position, the field of view of the camera encompasses at least a portion of the output medium. The second digital image indicates the intensity of light reflected from the output medium.

[0057] In step 1006, the first digital image and the second digital image are combined into a composite digital image. Although the above example has described capturing the chemiluminescent image before the colorimetric image, this is not required. The images can be captured in any order. The terms "first digital image" and "second digital image" as used herein are intended to distinguish between the two digital images and do not convey any temporal relationship.

[0058] Fig.11 A combined imaging device 1100 according to a further embodiment of the invention is shown. The combined imaging device 1100 comprises a base 1101, a cover 1102 and a contact area image sensor 1103, similar to those described above with respect to the other embodiments.

[0059] The combined imaging device 1100 also includes a phosphorescent region 1104 in the cover 1102. When the cover 1102 is closed, the phosphorescent region 1104 corresponds to the area of ​​the contact area image sensor 1103. The phosphorescent region 1104 can be, for example, a sheet of phosphorescent material embedded in the cover 1102. A shutter 1105 can be moved to cover or uncover the phosphorescent region 1104. The shutter 1105 can be a mechanical shutter as shown, or can be an electronic shutter or another shutter. When the shutter 1105 is closed, the phosphorescent region 1104 can be used as a backlight for the contact area image sensor 1103, thereby achieving a combination of electroluminescent and colorimetric imaging.

[0060] To read the results of an electrophoretic assay using the combined imaging device 1100, the user ensures that the phosphorescent regions 1104 are exposed to light long enough to "charge" them with light, so that the phosphorescent regions 1104 spontaneously luminesce for a certain period of time. The user then places the output medium of the assay (e.g., a blot) on the contact area image sensor 1103 and closes the lid 1102. The phosphorescent regions 1104 generate light to backlight the output medium. A first image is captured using the contact area image sensor 1103. Any protein standards in the output medium are visible in the image.

[0061] The user then closes shutter 1105, thereby blocking light from phosphorescent region 1104 from reaching contact area image sensor 1103. With lid 1102 closed, a second image of light emitted from the output medium via chemiluminescence is captured using contact area image sensor 1103. The chemiluminescent analyte of interest will be visible in the second image. The first image and the second image can be combined into a composite image showing the protein standard and the analyte of interest.

[0062] Although the process of capturing the phosphorescence image first is described above, the images can be captured in any order. The order can be selected based on the expected exposure time of the two images, the amount of time that the phosphorescent region 1104 can emit sufficient light, and the amount of time that the chemiluminescent reaction at the analyte of interest will be bright enough for robust detection.

[0063] In the appended claims, the terms "a" or "an" are intended to mean "one or more". The term "comprise" and variations thereof (such as "comprises" and "comprising" when preceding the recitation of steps or elements are intended to mean that the addition of other steps or elements is optional and is not excluded. The invention has now been described in detail for purposes of clarity and understanding. However, one skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A combined imaging system, comprising: a housing having a base; a contact area image sensor located in the base of the housing; a camera comprising a lens, wherein a field of view of the camera encompasses at least a portion of an imaging area of ​​the contact area image sensor, and wherein the camera is configured to generate a colorimetric; as well as A controller configured to: capturing a first digital image using the contact area image sensor; capturing a second digital image using the camera; and The first digital image and the second digital image are combined into a composite digital image.

2. The combined imaging system according to claim 1, characterized in that: Also included is a light source controlled by the controller, wherein the light source provides illumination for the second digital image.

3. The combined imaging system according to claim 1, characterized in that: The system does not include a light source for providing illumination for the second digital image, and wherein the second digital image is captured using ambient light.

4. The combined imaging system according to any one of claims 1 to 3, characterized in that: The first digital image records the intensity of light emitted by chemiluminescence of a target placed on the contact area image sensor; and The second digital image records the intensity of the light reflected from the target.

5. The combined imaging system according to claim 4, characterized in that: The target is a blot carrying proteins labeled to glow by chemiluminescence and also carrying non-chemiluminescent protein standards.

6. The combined imaging system according to any one of claims 1 to 3, characterized in that: The contact area image sensor is a color sensor.

7. The combined imaging system according to any one of claims 1 to 3, characterized in that: The camera is a color camera.

8. A method for reading the result of an electrophoresis assay, the method comprising: placing the output medium of the electrophoretic assay on a contact area image sensor of a combined imaging device; closing a cover of the combined imaging device, thereby blocking ambient light from reaching the contact area image sensor; capturing a first digital image of the output medium using the contact area image sensor, the first digital image indicating the intensity of light emitted from the output medium by chemiluminescence; opening the lid; capturing a second digital image of the output medium using a camera suspended above the contact area image sensor, the camera having a field of view encompassing at least a portion of the output medium when the lid is in the open position, wherein the second digital image includes a colorimetric image and indicates an intensity of the light reflected from the output medium; as well as The first digital image and the second digital image are combined into a composite digital image.

9. The method according to claim 8, characterized in that: The output medium is a blot carrying proteins labeled to glow by chemiluminescence and the blot carrying protein standards that are non-chemiluminescent but visible in the second digital image; as well as Combining the first digital image and the second digital image into a composite digital image includes combining the first digital image and the second digital image into a digital image in which both the chemiluminescent labeled protein and the non-chemiluminescent protein standard are shown.

10. The method according to claim 8 or claim 9, characterized in that: capturing the first digital image before capturing the second digital image; or The second digital image is captured before capturing the first digital image.

11. The method according to any one of claims 8 or 9, characterized in that The output medium is a membrane.

12. The method according to any one of claims 8 or 9, characterized in that The combined imaging device does not include a light source for providing illumination for the second digital image, and wherein capturing the second digital image includes capturing the second digital image using ambient light.

13. The method according to any one of claims 8 or 9, characterized in that Further comprising providing supplemental light to the output medium using a light source in the combined imaging device, wherein capturing the second digital image comprises capturing the second digital image using the supplemental light.

14. The method according to any one of claims 8 or 9, characterized in that Further comprising digitally resizing at least one of the first digital image and the second digital image such that the first digital image and the second digital image have the same size.

15. The method according to any one of claims 8 or 9, characterized in that Further comprising removing distortion from at least one of the first digital image and the second digital image.

16. The method according to any one of claims 8 or 9, characterized in that Further including: placing a gel on the contact area image sensor; as well as One or more images of the gel are captured using the contact area image sensor, the camera, or both.

17. A combined imaging system comprising: a housing having a base; contact area image sensor; a light source configured to illuminate an imaging area of ​​the contact area image sensor; as well as A controller configured to: capturing a first digital image using the contact area image sensor; capturing a second digital image during illumination with the light source; and The first digital image and the second digital image are combined into a composite digital image.

18. The combined imaging system of claim 17, wherein: The first digital image records the intensity of light emitted by chemiluminescence of a target placed on the contact area image sensor; and The second digital image records the intensity of the light reflected from the target.

19. The combined imaging system of claim 18, wherein: The target is a blot carrying proteins labeled to glow by chemiluminescence and also carrying non-chemiluminescent protein standards.

20. The combined imaging system according to any one of claims 17 to 19, characterized in that: The contact area image sensor is a color sensor.

21. The combined imaging system according to any one of claims 17 to 20, characterized in that: Also included is a camera comprising a lens, wherein a field of view of the camera encompasses at least a portion of the imaging area, and wherein the camera is configured to generate a colorimetric image.

22. The combined imaging system of claim 21, wherein: The camera is a color camera.

23. A combined imaging system comprising: a housing having a base and a cover, the cover having a closed position against the base and having an open position; a contact area image sensor, wherein when the cover is in the closed position, the cover shields the contact area image sensor from ambient light; a lid sensor configured to sense whether the lid is in the closed position or the open position; and A controller configured to: capturing a first digital image using the contact area image sensor; determining, based on the lid sensor, that the lid is in the open position; capturing a second digital image with the lid in the open position; and The first digital image and the second digital image are combined into a composite digital image.

24. The combined imaging system of claim 23, wherein: Also included is a visible light source, wherein the light source provides illumination for the second digital image.

25. The combined imaging system of claim 24, wherein: The light source is mounted in the cover.

26. The combined imaging system according to any one of claims 23 to 25, characterized in that: The first digital image records the intensity of light emitted by chemiluminescence of a target placed on the contact area image sensor; and The second digital image records the intensity of the light reflected from the target.

27. The combined imaging system of claim 26, wherein: The target is a blot carrying proteins labeled to glow by chemiluminescence and also carrying non-chemiluminescent protein standards.

28. The combined imaging system according to any one of claims 23 to 27, characterized in that: The contact area image sensor is a color sensor.

29. The combined imaging system according to any one of claims 23 to 28, characterized in that: Also included is a camera mounted in the cover, the camera comprising a lens, wherein a field of view of the camera encompasses at least a portion of the imaging area when the cover is in the open position, and wherein the camera is configured to generate a colorimetric image when the cover is in the open position.

30. The combined imaging system of claim 29, wherein: The camera is a color camera.

31. The combined imaging system of claim 29, wherein: The second digital image is generated using the camera.

32. A combined imaging system comprising: a housing having a base; a camera comprising a lens, wherein a field of view of the camera encompasses at least a portion of an imaging area of ​​the base, and wherein the camera is configured to generate a colorimetric image; one or more fiducial markers located in the base and within the field of view of the camera; and A controller configured to: capturing a first digital image; capturing a second digital image using the camera; and The first digital image and the second digital image are combined into a composite digital image.

33. The combined imaging system of claim 32, wherein: The control is configured to digitally reverse perspective distortion in the second digital image.

34. The combined imaging system of claim 33, wherein: The perspective distortion is reversed based at least in part on a known physical relationship between the camera and the imaging area.

35. The combined imaging system according to any one of claims 32 to 34, characterized in that: A contact area image sensor is also included.

36. The combined imaging system of claim 35, wherein: The first digital image is captured using the contact area image sensor.

37. The combined imaging system of claim 36, wherein: Further comprising scaling the second digital image to have the same size as the first digital image.

38. The combined imaging system of claim 37, wherein: Scaling the second digital image to have the same size as the first digital image includes scaling the first digital image to have the same pixel size as the first digital image.

39. The combined imaging system according to any one of claims 32 to 38, characterized in that: Also included is a light source controlled by the controller, wherein the light source provides illumination for the second digital image.

40. The combined imaging system of claim 32, wherein: The system does not include a light source for providing illumination for the second digital image, and wherein the second digital image is captured using ambient light.

41. The combined imaging system according to any one of claims 32 to 40, characterized in that: The first digital image records the intensity of light emitted by chemiluminescence of a target placed on the contact area image sensor; and The second digital image records the intensity of the light reflected from the target.

42. The combined imaging system of claim 41, wherein: The target is a blot carrying proteins labeled to glow by chemiluminescence and also carrying non-chemiluminescent protein standards.

43. The combined imaging system of any one of claims 32 to 42, wherein: The camera is a color camera.

Images