WO2018148471A2 - Optics, device, and system for assaying - Google Patents

Optics, device, and system for assaying Download PDF

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Publication number
WO2018148471A2
WO2018148471A2 PCT/US2018/017504 US2018017504W WO2018148471A2 WO 2018148471 A2 WO2018148471 A2 WO 2018148471A2 US 2018017504 W US2018017504 W US 2018017504W WO 2018148471 A2 WO2018148471 A2 WO 2018148471A2
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WO
WIPO (PCT)
Prior art keywords
sample
optical
optical assembly
light
imaging
Prior art date
Application number
PCT/US2018/017504
Other languages
English (en)
French (fr)
Other versions
WO2018148471A3 (en
Inventor
Stephen Y. Chou
Wei Ding
Ji QI
Jun Tian
Yufan ZHANG
Wei Dong
Original Assignee
Essenlix Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Essenlix Corporation filed Critical Essenlix Corporation
Priority to CN202310507084.7A priority Critical patent/CN116794819A/zh
Priority to CN201880020973.8A priority patent/CN111465882B/zh
Priority to EP18751754.5A priority patent/EP3580597A4/en
Priority to US16/483,700 priority patent/US10972641B2/en
Priority to JP2019543054A priority patent/JP7177073B2/ja
Priority to CA3053009A priority patent/CA3053009A1/en
Priority to US16/484,998 priority patent/US20200078792A1/en
Priority to JP2019544049A priority patent/JP2020508043A/ja
Priority to CA3053295A priority patent/CA3053295A1/en
Priority to CN201880024948.7A priority patent/CN111194409A/zh
Priority to PCT/US2018/018405 priority patent/WO2018152351A1/en
Priority to EP18753608.1A priority patent/EP3583423A4/en
Priority to US16/485,347 priority patent/US10966634B2/en
Priority to CN201880025156.1A priority patent/CN111448449A/zh
Priority to US16/485,126 priority patent/US11523752B2/en
Priority to PCT/US2018/018521 priority patent/WO2018152422A1/en
Priority to CA3053301A priority patent/CA3053301A1/en
Priority to JP2019544634A priority patent/JP7107953B2/ja
Priority to PCT/US2018/018520 priority patent/WO2018152421A1/en
Publication of WO2018148471A2 publication Critical patent/WO2018148471A2/en
Publication of WO2018148471A3 publication Critical patent/WO2018148471A3/en
Priority to US17/179,319 priority patent/US11463608B2/en
Priority to US17/896,973 priority patent/US20220407988A1/en
Priority to US17/980,400 priority patent/US20230077906A1/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/84—Systems specially adapted for particular applications
    • G01N21/8483—Investigating reagent band
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G01N21/6458—Fluorescence microscopy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/84—Systems specially adapted for particular applications
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/0008—Microscopes having a simple construction, e.g. portable microscopes
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0052—Optical details of the image generation
    • G02B21/0076—Optical details of the image generation arrangements using fluorescence or luminescence
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/06—Means for illuminating specimens
    • G02B21/08—Condensers
    • G02B21/12—Condensers affording bright-field illumination
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/16—Microscopes adapted for ultraviolet illumination ; Fluorescence microscopes
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/24—Base structure
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B7/00—Mountings, adjusting means, or light-tight connections, for optical elements
    • G02B7/02—Mountings, adjusting means, or light-tight connections, for optical elements for lenses
    • G02B7/023—Mountings, adjusting means, or light-tight connections, for optical elements for lenses permitting adjustment
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
    • H04N23/00—Cameras or camera modules comprising electronic image sensors; Control thereof
    • H04N23/50—Constructional details
    • H04N23/51—Housings
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
    • H04N23/00—Cameras or camera modules comprising electronic image sensors; Control thereof
    • H04N23/50—Constructional details
    • H04N23/55—Optical parts specially adapted for electronic image sensors; Mounting thereof
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
    • H04N23/00—Cameras or camera modules comprising electronic image sensors; Control thereof
    • H04N23/56—Cameras or camera modules comprising electronic image sensors; Control thereof provided with illuminating means
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
    • H04N23/00—Cameras or camera modules comprising electronic image sensors; Control thereof
    • H04N23/57—Mechanical or electrical details of cameras or camera modules specially adapted for being embedded in other devices
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
    • H04N23/00—Cameras or camera modules comprising electronic image sensors; Control thereof
    • H04N23/60—Control of cameras or camera modules
    • H04N23/67—Focus control based on electronic image sensor signals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other

Definitions

  • the present invention is related to devices and methods of performing biological and chemical assays, and computational imaging.
  • the present invention provides, among other thing, devices and methods for simple, fast, and sensitive assaying, including imaging.
  • FIG. 1 -A, 1-B and 1 -C are the schematic illustration of system testing sample in fluorescent illumination mode, according to some embodiments of the present invention.
  • FIG. 2-A, 2-B and 2-C are the schematic illustration of system testing sample in bright- field illumination mode, according to some embodiments of the present invention.
  • FIG. 3 is the schematic exploded view of optical adaptor device in system and system 20, according to some embodiments of the present invention.
  • FIG. 4 is the schematic sectional view showing details of system testing sample in bright- field illumination mode, and particularly of device, according to some embodiments of the present invention.
  • FIG. 5 is the schematic sectional view showing details of system testing sample in fluorescent illumination mode, and particularly of device, according to some embodiments of the present invention.
  • FIG. 6-A and FIG. 6-B is the schematic sectional viewing showing the design to make lever stop at the pre-defined position when being pulled outward from the device, according to some embodiments of the present invention.
  • FIG. 7 is the schematic illustration of the structure of the sample slider holding the QMAX device, according to some embodiments of the present invention.
  • FIG. 8 is the schematic illustration of the moveable arm switching between two pre-defined stop positions, according to some embodiments of the present invention.
  • FIG.9 is the schematic illustration of how the slider indicates if QMAX device is inserted in right direction, according to some embodiments of the present invention.
  • FIG. 10-A, 10-B and 10-C are the schematic illustration of system for smartphone colorimetric reader, according to some embodiments of the present invention.
  • FIG. 11 is the schematic exploded view of optical adaptor device in system, according to some embodiments of the present invention.
  • FIG. 12 is the schematic sectional view showing details of system reading a colorimetric card, and particularly of device, according to some embodiments of the present invention.
  • FIG. 13-A, 13-B and 13-C are the schematic illustrations of system for smartphone colorimetric reader, according to some embodiments of the present invention.
  • FIG. 14 is the schematic exploded view of optical adaptor device in system, according to some embodiments of the present invention.
  • FIG. 15-A, 15-B and 15-C are the schematic views showing details of system reading a colorimetric card, and particularly of device, according to some embodiments of the present invention.
  • Fig. 16-A shows a tomography device that consists of an imaging sensor, a lens, and a QMAX structure, according to some embodiments of the present invention.
  • Fig. 16-B shows an example of the pillar array pattern of the letter E.
  • Fig. 16-C shows the thin lens model, which explains the effect of focal distance on the captured image.
  • Fig. 16-D shows a captured image of the example pillar array in Fig. 16-B by the imaging sensor.
  • Fig. 16-E shows the diagram of phase image retrieval based scheme.
  • Fig. 17-A shows analyte detection and localization workflow, which consists of two stages, training and prediction, according to some embodiments of the present invention.
  • Fig. 17-B shows the process to remove one item from an ordered list, according to some embodiments of the present invention.
  • Fig. 18-A shows an embodiment of a QMAX device used for cell imaging.
  • optical adaptor for bright-field and fluorescent microscopy imaging attached to a smartphone one embodiment of optical adaptor for colorimetric measurement attached to a smartphone using tilted fiber end face as light source; one embodiment of optical adaptor for colorimetric measurement attached to a smartphone using side-illumination of a ring-shape fiber as light source; one embodiment of device and methods of tomography; one embodiment of machine learning assisted assay and imaging; one embodiment of device and methods of tissue staining and cell imaging; one embodiment of dual-lens imaging system.
  • Bright-field and fluorescent microscopy are very powerful techniques to let people examine some property of a sample, which have wide applications in health monitoring, disease diagnostic, science education and so on.
  • the taking microscopy images requires, however, expensive microscope and experienced personnel which common people have limited access to.
  • the bright-field microscopy images only give very limited information of the sample.
  • the present invention that is described herein address this problem by providing a system comprising an optical adaptor and a smartphone.
  • the optical adaptor device fits over a smartphone converting it into a microscope which can take both fluorescent and bright-field images of a sample.
  • This system can be operated conveniently and reliably by a common person at any location.
  • the optical adaptor takes advantage of the existing resources of the smartphone, including camera, light source, processor and display screen, which provides a low-cost solution let the user to do bright-field and fluorescent microscopy.
  • the optical adaptor device comprises a holder frame fitting over the upper part of the smartphone and an optical box attached to the holder having sample receptacle slot and illumination optics.
  • their optical adaptor design is a whole piece including both the clip-on mechanics parts to fit over the smartphone and the functional optics elements. This design has the problem that they need to redesign the whole-piece optical adaptor for each specific model of smartphone.
  • the optical adaptor is separated into a holder frame only for fitting a smartphone and a universal optical box containing all the functional parts. For the smartphones with different dimensions, as long as the relative positions of the camera and the light source are the same, only the holder frame need to be redesigned, which will save a lot of cost of design and manufacture.
  • the optical box of the optical adaptor comprises: a receptacle slot which receives and position the sample in a sample slide in the field of view and focal range of the smartphone camera; a bright-field illumination optics for capturing bright-field microscopy images of a sample; a fluorescent illumination optics for capturing fluorescent microscopy images of a sample; a lever to switch between bright-field illumination optics and fluorescent illumination optics by sliding inward and outward in the optical box.
  • the receptacle slot has a rubber door attached to it, which can fully cover the slot to prevent the ambient light getting into the optical box to be collected by the camera.
  • a rubber door attached to it, which can fully cover the slot to prevent the ambient light getting into the optical box to be collected by the camera.
  • its sample slot is always exposed to the ambient light which won't cause too much problem because it only does bright-field microscopy.
  • the present invention can take the advantage of this rubber door when doing fluorescent microscopy because the ambient light would bring a lot of noise to the image sensor of the camera.
  • fluorescent illumination optics enables the excitation light to illuminate the sample partially from the waveguide inside the sample slide and partially from the backside of the sample side in large oblique incidence angle so that excitation light will nearly not be collected by the camera to reduce the noise signal getting into the camera.
  • the bright-field illumination optics in the adaptor receive and turn the beam emitted by the light source so as to back-illuminated the sample in normal incidence angle.
  • the optical box also comprises a lens mounted in it aligned with the camera of the smartphone, which magnifies the images captured by the camera.
  • the images captured by the camera can be further processed by the processor of smartphone and outputs the analysis result on the screen of smartphone.
  • a slidable lever is used.
  • the optical elements of the fluorescent illumination optics are mounted on the lever and when the lever fully slides into the optical box, the fluorescent illumination optics elements block the optical path of bright-field illumination optics and switch the illumination optics to fluorescent illumination optics. And when the lever slides out, the fluorescent illumination optics elements mounted on the lever move out of the optical path and switch the illumination optics to bright-field illumination optics.
  • the lever comprises two planes at different planes at different heights.
  • two planes can be joined together with a vertical bar and move together in or out of the optical box. In some embodiments, two planes can be separated and each plane can move individually in or out of the optical box.
  • the upper lever plane comprises at least one optical element which can be, but not limited to be an optical filter.
  • the upper lever plane moves under the light source and the preferred distance between the upper lever plane and the light source is in the range of 0 to 5mm.
  • Part of the bottom lever plane is not parallel to the image plane. And the surface of the non-parallel part of the bottom lever plane has mirror finish with high reflectivity larger than 95%.
  • the non-parallel part of the bottom lever plane moves under the light source and deflects the light emitted from the light source to back-illuminate the sample area right under the camera.
  • the preferred tilt angle of the non-parallel part of the bottom lever plane is in the range of 45 degree to 65 degree and the tilt angle is defined as the angle between the non-parallel bottom plane and the vertical plane.
  • Part of the bottom lever plane is parallel to the image plane and is located under and 1 mm to 10mm away from the sample.
  • the surface of the parallel part of the bottom lever plane is highly light absorptive with light absorption larger than 95%. This absorptive surface is to eliminate the reflective light back-illuminating on the sample in small incidence angle.
  • a stopper design comprising a ball plunger and a groove on the lever is used in order to stop the lever at a predefined position when being pulled outward from the adaptor. This allow the user to use arbitrary force the pull the lever but make the lever to stop at a fixed position where the optical adaptor's working mode is switched to bright-filed illumination.
  • a sample slider is mounted inside the receptacle slot to receive the QMAX device and position the sample in the QMAX device in the field of view and focal range of the smartphone camera.
  • the sample slider comprises a fixed track frame and a moveable arm:
  • the frame track is fixedly mounted in the receptacle slot of the optical box.
  • the track frame has a sliding track slot that fits the width and thickness of the QMAX device so that the QMAX device can slide along the track.
  • the width and height of the track slot is carefully configured to make the QMAX device shift less than 0.5mm in the direction perpendicular to the sliding direction in the sliding plane and shift less than less than 0.2mm along the thickness direction of the QMAX device.
  • the frame track has an opened window under the field of view of the camera of smartphone to allow the light back-illuminate the sample.
  • a moveable arm is pre-built in the sliding track slot of the track frame and moves together with the QMAX device to guide the movement of QMAX device in the track frame.
  • the moveable arm equipped with a stopping mechanism with two pre-defined stop positions. For one position, the arm will make the QMAX device stop at the position where a fixed sample area on the QMAX device is right under the camera of smartphone. For the other position, the arm will make the QMAX device stop at the position where the sample area on QMAX device is out of the field of view of the smartphone and the QMAX device can be easily taken out of the track slot.
  • the moveable arm switches between the two stop positions by a pressing the QMAX device and the moveable arm together to the end of the track slot and then releasing.
  • the moveable arm can indicate if the QMAX device is inserted in correct direction.
  • the shape of one corner of the QMAX device is configured to be different from the other three right angle corners.
  • the shape of the moveable arm matches the shape of the corner with the special shape so that only in correct direction can QMAX device slide to correct position in the track slot.
  • FIG. 1 -A, 1-B and 1-C is the schematic illustration of system 19 testing sample in fluorescent illumination mode.
  • FIG. 1 -B and 1 -C are the exploded views of system 19, shown from the front and rear sides respectively.
  • System 19 comprises a smartphone 1 ; an optical adaptor device 18 fitting over the upper part of smartphone 1 ; a sample slide 5, inserted into receptacle slot 4 of device 18 so that the sample on sample slide 5 is positioned within the field of view and focal range of camera module 1C in smartphone 1.
  • a lever 8 is fully pressed into device 18 so that system 19 operates in fluorescent illumination mode.
  • a rubber door 16 attached to device 18 covers receptacle slot 4 after sample slide 5 is in so as to prevent the ambient light getting into receptacle slot 4 to affect the test.
  • the software (not shown) installed in smartphone 1 analyzes the image collected by camera module 1C while light source 1 L in smartphone 1 is emitting light, in order to get some property of the sample, and outputs the results to a display screen 1f in smartphone 1.
  • FIG. 2-A, 2-B and 2-C is the schematic illustration of system 20 testing sample in bright- field illumination mode.
  • FIG. 2-B and 2-C are the exploded views of system 20, shown from the front and rear sides respectively.
  • System 20 comprises a smartphone 1 ; an optical adaptor device 18 fitting over the upper part of smartphone 1 ; a sample slide 5, inserted into receptacle slot 4 of device 18 so that the sample on sample slide 5 is positioned within the field of view and focal range of camera module 1C in smartphone 1.
  • a lever 8 is pulled outward from device 18 and stopped by a stopper (not shown) at a pre-designed position in device 18 so that system 20 operates in bright-field illumination mode.
  • FIG. 3 is the schematic exploded view of optical adaptor device 18 in system 19 and system 20.
  • Device 18 comprises a holder case 2 fitting over the upper part of smartphone 1 ; an optical box 3 attached to case 2 including a receptacle slot 4, an optics chamber 3C, track 6b and 6t allowing lever 8 to slide in, and a rubber door 16 inserted into trench 4s to cover receptacle slot 4.
  • An optics insert 7 is fitted into the top of optics chamber 3C with an exit aperture 7L and an entrance aperture 7C in it aligning with light source 1 L and camera 1C (shown in FIG. 2-B) in smartphone 1.
  • a lens 11 is mounted in entrance aperture 7C in optics insert 7 and configured so that the sample in sample slide 5 inserted into receptacle slot 4 is located within the working distance of the camera 1 C (shown in FIG. 2-B and 1-B). Lens 11 serves to magnify the images of the sample captured by camera 1 C (shown in FIG. 2-B and 1 -B).
  • a long-pass optical filter 12 is mounted on top of lens 11 in entrance aperture 7C.
  • a pair of right angle mirrors 13 and 14 are mounted on the bottom of optics chamber 3C and configured so that mirror 13 and mirror 14 are aligned with light source 1 L and camera 1C (shown in FIG. 2-B and 1 -B) respectively.
  • Mirror 13 and mirror 14 whose operation as bright-field illumination optics in device 18 is described below in FIG. 4.
  • Lever 8 comprise two level bars: the upper-level bar comprises a band-pass optical filter 15 mounted in slot 8a, and the lower-level bar comprises a light absorber 9 mounted on the horizontal plane 8b and a reflective mirror 10 mounted on the tilted plane 8c.
  • the optical filter 15, light absorber 9 and mirror 10 whose operation as fluorescent illumination optics in device 18 is described below in FIG. 5.
  • the upper-level bar of lever 8 slides along track 6t in box 3 and lower- level bar 8b and 8c slides along track 6b in box 3.
  • Lever 8 stops at two different positions in box 3 to switch between bright-field illumination optics and fluorescent illumination optics.
  • Lever 8 is fully inserted into box 3 to switch device 18 to work with fluorescent illumination optics.
  • Ball plunger 17 is mounted on the sidewall of track 6t to stop lever 8 at a pre-defined position when lever 8 being pulled outward from box 3 to switch device 18 to work with bright-field illumination optics.
  • FIG. 4 is the schematic sectional view showing details of system 20 testing sample in bright-field illumination mode, and particularly of device 18. This figure illustrates the functionality of the elements that were described above with reference to FIG.3.
  • Lever 8 (shown in FIG. 3) is pulled outward from device 18 and stopped by stopper 17 (shown in FIG. 3) at a pre-defined position so that mirror 13 and mirror 14 is exposed to and aligned with camera 1C and light source 1 L.
  • Light source 1 L emits light beam BB1 away from smartphone 1.
  • Beam BB1 is deflected by mirror 14 by 90 degrees to beam BB2 which is further deflected by mirror 13 by 90 degrees to beam BB3.
  • Beam BB3 back-illuminates the sample in sample slide 5 in normal incidence angle.
  • Lens 11 creates a magnified images of the sample on the image sensor plane of camera 1 C. Smartphone 1 captures and processes the image to get some property of the sample.
  • FIG. 5 is the schematic sectional view showing details of system 19 testing sample in fluorescent illumination mode, and particularly of device 18. This figure illustrates the functionality of the elements that were described above with reference to FIG. 3.
  • Lever 8 (shown in FIG. 3) is fully inserted into device 18 so that light absorber 9 and tilted mirror 10 are under the view of camera 1C and light source 1 L, and block the light path between light source 1 L and the pair of mirrors of 13 and 14.
  • band-pass optical filter 15 is right under the light source 1 L.
  • Light source 1 L emits light beam BF1 away from smartphone 1.
  • Optical filter 15 allows beam BF1 with specific wavelength range which matches the excitation wavelength of the fluorescent sample in sample slide 5 to go through.
  • Part of beam BF1 illuminates on the edge of transparent sample slide 5 and couples to waveguide beam BF3 travelling in sample slide 5 and illuminates the sample area under the lens 11. Part of beam BF1 illuminates on mirror 10. Tilted mirror 10 deflects beam BF1 to beam BF2 and back-illuminates the sample area in sample slide 5 right under lens 11 in large oblique angle. The remaining part of beam BF1 with large divergence angle (i.e., beam BF4) illuminates on absorber 9 and get absorbed so that no reflected light of beam BF4 gets into the camera 1C in small incidence angle.
  • beam BF4 large divergence angle
  • the light coming from the sample area under the lens 11 goes through the lens 11 and is filtered by long-pass filter 12 so that only light in a specify wavelength range that is emitted by the fluorescent sample in sample slide 5 gets into camera 1 C to form an image.
  • Smartphone 1 captures and processes the image to get some property of the sample.
  • Rubber door 16 is inserted into device 18 to cover sample slide 5 to prevent ambient light getting into device 18 to affect the test.
  • FIG. 6-A and FIG. 6-B is the schematic sectional viewing showing the design to make lever 8 stop at the pre-defined position when being pulled outward from the device 18.
  • Ball plunger 17 is mounted in the sidewall of track slot 6t, and a groove 8g is drilled on the sidewall of lever 8 with the shape matching the shape of the ball in ball plunger 17.
  • the ball in ball plunger 17 in pressed into its body by the sidewall of lever 8 so that lever 8 can slide along the track 6t.
  • FIG. 6-B when the groove 8g on lever 8 reach to the position of ball plunger 17, the ball in ball plunger 17 jump into groove 8g to stop lever 8.
  • FIG. 7 is the schematic illustration of the structure of the sample slider holding the QMAX device.
  • the sample slider comprises a track frame having a track slot to let QMAX device slide along it, a moveable arm pre-built in the track slot moving together with QMAX device to guide its movement.
  • the moveable arm equipped with a stopping mechanism to make QMAX device stop at two pre-defined stop positions.
  • the width and height of the track slot is carefully configured to make the QMAX device shift less than 0.5mm in horizontal direction perpendicular to the sliding direction and shift less than less than 0.2mm along the thickness direction of the QMAX device.
  • FIG. 8 is the schematic illustration of the moveable arm switching between two pre-defined stop positions.
  • the QMAX card can stop at either position 1 where sample area is out of field of view of smartphone camera for easily taking out the QMAX device from the slider or position 2 where sample area is right under the field of view of smartphone camera for capturing image.
  • FIG.9 is the schematic illustration of how the slider indicates if QMAX device is inserted in right direction.
  • the shape of one corner of the QMAX device is configured to be different from the other three right angle corners.
  • the shape of the moveable arm matches the shape of the corner with the special shape so that only in correct direction can QMAX device slide to correct position in the track slot. If the QMAX device is flipped or inserted from the wrong side, the part of the QMAX device outside the slider is longer that when the QMAX device is correctly inserted.
  • both fluorescent image and bright-field images are available, one can employ the knowledge of the fluorescent image to process the bright-field image, or employ the knowledge of the bright-field image to process the fluorescent image, or collectively process two images.
  • the field-of-view of the fluorescent image and bright-field image can be different; thus, the two images are not spatially aligned, pixel-to-pixel.
  • An image registration finds a geometric transform that relates the spatial position from one image to another.
  • Various image registration algorithms can be used for aligning a fluorescent image and bright-field image, including but not limited to, feature-point based, cross-correlation based, Fourier alignment based, etc.
  • the image registration outputs a geometric transform that maps the spatial position (coordinate) of one image to another.
  • An optical adaptor comprising:
  • the holder frame is configured to removably fit over a mobile device and align the optical box to a camera and an illumination source integrated in the mobile device; wherein the optical box comprises sample receptacle slot and illumination optics.
  • An optical system comprising:
  • a QMAX card which comprises a first plate and a second, wherein the first plate and the second compresses a liquid sample into a layer of uniform thickness of less than 200 urn;
  • a slider that configured to accommodate the QMAX card and to be asserted into the optical box.
  • the holder frame comprises a holder case that is configured to be replaceable with other holder cases having a different size for different mobile devices.
  • optical box of the optical adaptor comprises:
  • a receptacle slot that is configured to receive and position the QMAX card in a
  • a bright-field illumination optics that is configured to capture bright-field microscopy images of the sample
  • a fluorescent illumination optics that is configured to capture fluorescent microscopy images of a sample
  • fluorescent illumination optics by sliding inward and outward in the optical box.
  • optical box further comprises a lens mounted in it and aligned with the camera of the mobile device, which magnifies the images captured by the camera.
  • images captured by the camera are further processed by processors of mobile device and outputs the analysis result on a screen of mobile device.
  • C21 The adaptor or system of any prior embodiments, wherein the preferred tilt angle of the non-parallel part of the bottom lever plane is in the range of 45 degree to 65 degree and the tilt angle is defined as the angle between the non-parallel bottom plane and the vertical plane.
  • C22. The adaptor or system of any prior embodiments, wherein part of the bottom lever plane is parallel to the image plane and is located under and 1 mm to 10mm away from the sample.
  • C23. The adaptor or system of any prior embodiments, wherein the surface of the parallel part of the bottom lever plane is highly light absorptive with light absorption larger than 95%.
  • C31 The adaptor or system of any prior embodiments, wherein the shape of one corner of the QMAX device is configured to be different from the other three right angle corners.
  • C31 The adaptor or system of any prior embodiments, wherein the shape of the moveable arm matches the shape of the corner with the special shape so that only in correct direction can QMAX device slide to correct position in the track slot.
  • C34 The adaptor or system of any prior embodiments, wherein the frame track has an opened window under the field of view of the camera of smartphone to allow the light back-illuminate the sample.
  • C35 The adaptor or system of any prior embodiments, wherein the moveable arm is pre-built in the sliding track slot of the track frame and moves together with the QMAX device to guide the movement of QMAX device in the track frame.
  • Colorimetric assay is a very powerful technique having wide applications in health monitoring, disease diagnostic, chemical analysis and so on.
  • the key factor to get the accurate colorimetric assay result is to accurately quantify the color change.
  • the color change of a colorimetric test strip is analyzed by comparing the color change with a standard color card. But this comparison is accomplished by human's eye and can be easily influenced by the environment light condition, which limits the accuracy of quantifying the color change.
  • the present invention that is described herein address this problem by providing a system comprising an optical adaptor and a smartphone.
  • the optical adaptor device fits over a smartphone converting it into a colorimetric reader which can provide a consistent and uniform illumination to illuminate the front surface of the colorimetric test card and capture the image of the sample to analyze the color change.
  • the optical adaptor takes advantage of the existing resources of the smartphone, including camera, light source, processor and display screen, which provides a low-cost solution to accurately quantify the color change of a colorimetric assay.
  • the optical adaptor device comprises a holder frame fitting over the upper part of the smartphone and an optical box attached to the holder having sample receptacle slot and illumination optics.
  • their adaptor design is a whole piece including both the clip-on mechanics parts to fit over the smartphone and the functional elements. This design has the problem that they need to redesign the whole-piece adaptor for each specific model of smartphone.
  • the optical adaptor is separated into a holder frame only for fitting a smartphone and a universal optical box containing all the functional parts. For the smartphones with different dimensions, as long as the relative positions of the camera and the light source are the same, only the holder frame need to be redesigned, which will save a lot of cost of design and manufacture.
  • the optical box of the optical adaptor comprises: a receptacle slot which receives and position the colorimetric sample in the field of view and focal range of the smartphone camera; an illumination and imaging optics to create uniform and consistent illumination on the sample independently of any external conditions and capture the sample image.
  • the sample area under the camera is uniformly illuminated. But for all common smartphones, there is always a distance between the light source and the camera. When the sample is placed very close to the camera of smartphone, without additional illumination optics, the area can be uniformly front-illuminated by the light source is right under the light source but not within the field of view of the camera.
  • a tilted large-core optical fiber is used to turn the light beam emitted from the light source to uniformly illuminate the sample area right under the camera.
  • both end faces of the optical fiber are made to have matte finish to serve as the diffuser so that the end face towards the sample can become an area light source to generate more uniform illumination on the sample.
  • the optical box also comprises a lens mounted in it aligned with the camera of the smartphone, which makes the sample within the focal range of the camera.
  • the images captured by the camera will be further processed by the processor of smartphone to analyze the color change and outputs the analysis result on the screen of smartphone.
  • a sample slider is mounted inside the receptacle slot to receive the QMAX device and position the sample in the QMAX device in the field of view and focal range of the smartphone camera.
  • the sample slider comprises a fixed track frame and a moveable arm:
  • the frame track is fixedly mounted in the receptacle slot of the optical box.
  • the track frame has a sliding track slot that fits the width and thickness of the QMAX device so that the QMAX device can slide along the track.
  • the width and height of the track slot is carefully configured to make the QMAX device shift less than 0.5mm in the direction perpendicular to the sliding direction in the sliding plane and shift less than less than 0.2mm along the thickness direction of the QMAX device.
  • the frame track has an opened window under the field of view of the camera of smartphone to allow the light back-illuminate the sample.
  • a moveable arm is pre-built in the sliding track slot of the track frame and moves together with the QMAX device to guide the movement of QMAX device in the track frame.
  • the moveable arm equipped with a stopping mechanism with two pre-defined stop positions. For one position, the arm will make the QMAX device stop at the position where a fixed sample area on the QMAX device is right under the camera of smartphone. For the other position, the arm will make the QMAX device stop at the position where the sample area on QMAX device is out of the field of view of the smartphone and the QMAX device can be easily taken out of the track slot.
  • the moveable arm switches between the two stop positions by a pressing the QMAX device and the moveable arm together to the end of the track slot and then releasing.
  • the moveable arm can indicate if the QMAX device is inserted in correct direction.
  • the shape of one corner of the QMAX device is configured to be different from the other three right angle corners.
  • the shape of the moveable arm matches the shape of the corner with the special shape so that only in correct direction can QMAX device slide to correct position in the track slot.
  • FIG. 10-A, 10-B and 10-C are the schematic illustration of system 10 for smartphone colorimetric reader. Particularly, FIG. 10-B and 10-C are the exploded views of system 10, shown from the front and rear sides respectively.
  • System 10 comprises a smartphone 1 ; an optical adaptor device 13 fitting over the upper part of smartphone 1 ; a colorimetric test card 137, inserted into receptacle slot 136 of device 13 so that the sample area on the sample card 137 is positioned within the field of view and focal range of camera module 1 C in smartphone 1.
  • the software installed in smartphone 1 analyzes the image collected by camera module 1C while light source 1 L in smartphone 1 is emitting light, in order to analyze the color change of the colorimetric test, and outputs the results to a display screen 1f in smartphone 1.
  • FIG. 11 is the schematic exploded view of optical adaptor device 13 in system 10.
  • FIG. 13 comprises a holder case 131 fitting over the upper part of smartphone 1 ; an optical box 132 attached to case 131 including a receptacle slot 136, an optics chamber 132C.
  • An optics insert 134 is fitted into the top of optics chamber 132C with an exit aperture 134L and an entrance aperture 134C in it aligning with light source 1 L and camera 1C (shown in FIG. 10-B) in smartphone 1.
  • a lens 133 is mounted in entrance aperture 134C in optics insert 134 and configured so that the sample area on colorimetric sample card 137 inserted into receptacle slot 136 is located within the working distance of the camera 1 C (shown in FIG. 10-B).
  • a large-core optical fiber 135 is mounted in the exit aperture 134L with tilted angle. Both end faces of fiber 135 are made to have matte finish. Fiber 135 whose operation as the illumination optics in device 13 is described below in FIG. B3.
  • FIG. 12 is the schematic sectional view showing details of system 10 reading a colorimetric card, and particularly of device 13. This figure illustrates the functionality of the elements that were described above with reference to FIG. 11.
  • Light source 1 L emits light beam B1 away from smartphone 1.
  • Beam B1 is coupled into the fiber 135 through the first end face and travels along the direction of fiber 135 and is emitted out from the second end face to become beam B2.
  • Beam B2 illuminates the sample area of colorimetric sample card 137 right under the camera 1C from front side to create uniform illumination. Because the end faces of fiber 135 are made to be matte and diffusive finish, beam B2 can be regarded as emitting from an area light source, which helps to create a more uniform illumination.
  • the tilt angle in which the fiber 135 is mounted is set to make the central tray of beam B2 illuminates on the area on the sample card 137 right under the camera.
  • Lens 11 creates an image of the sample area on the image sensor plane of camera 1 C.
  • Smartphone 1 captures and processes the image to analyze the color information in the image to quantify the color change of the colorimetric assay.
  • Colorimetric assay is a very powerful technique having wide applications in health monitoring, disease diagnostic, chemical analysis and so on.
  • the key factor to get the accurate colorimetric assay result is to accurately quantify the color change.
  • the color change of a colorimetric test strip is analyzed by comparing the color change with a standard color card. But this comparison is accomplished by human's eye and can be easily influenced by the environment light condition, which limits the accuracy of quantifying the color change.
  • the present invention that is described herein address this problem by providing a system comprising an optical adaptor and a smartphone.
  • the optical adaptor device fits over a smartphone converting it into a colorimetric reader which can provide a consistent and uniform illumination to illuminate the front surface of the colorimetric test card and capture the image of the sample to analyze the color change.
  • This system can be operated conveniently and reliably by a common person at any location.
  • the optical adaptor takes advantage of the existing resources of the smartphone, including camera, light source, processor and display screen, which provides a low-cost solution to accurately quantify the color change of a colorimetric assay.
  • the optical adaptor device comprises a holder frame fitting over the upper part of the smartphone and an optical box attached to the holder having sample receptacle slot and illumination optics.
  • their adaptor design is a whole piece including both the clip-on mechanics parts to fit over the smartphone and the functional elements. This design has the problem that they need to redesign the whole-piece adaptor for each specific model of smartphone.
  • the optical adaptor is separated into a holder frame only for fitting a smartphone and a universal optical box containing all the functional parts. For the smartphones with different dimensions, as long as the relative positions of the camera and the light source are the same, only the holder frame need to be redesigned, which will save a lot of cost of design and manufacture.
  • the optical box of the optical adaptor comprises: a receptacle slot which receives and position the colorimetric sample in the field of view and focal range of the smartphone camera; an illumination and imaging optics to create uniform and consistent illumination on the sample independently of any external conditions and capture the sample image.
  • the sample area under the camera is uniformly illuminated.
  • the light source is always a point source and mounted next to the camera with some distance, which means the light source is not central symmetric relative to the camera. This causes the problem that, when the sample is placed very close to the camera of smartphone, without the help of additional illumination optics, the illumination pattern on the front surface of a sample in the field of view of the camera will have a gradient intensity change in a linear direction. Hence, it is desirable to create a light source with large emitting area and central symmetric to the camera.
  • a plastic side-emitting fiber ring is put around the smartphone camera to make the fiber ring central symmetric relative to the camera. And the two end faces of the fiber ring are mounted towards the light source of the smartphone. This will convert the original single point light source to infinite number of small light sources having nearly equal luminous intensity distributed on a circle with equal distance from the smartphone camera.
  • the light emitted from the side wall of the ring fiber further goes through a diffusive film to increase the emitting area and make the illumination more even.
  • the sample area right under the camera is uniformly front-illuminated by the designed illumination optics based on side-emitting fiber ring.
  • the receptacle slot has a rubber door attached to it, which can fully cover the slot to prevent the environmental light getting into the optical box to result in change of the illumination condition.
  • the optical box also comprises a lens mounted in it aligned with the camera of the smartphone, which makes the sample within the focal range of the camera.
  • the images captured by the camera will be further processed by the processor of smartphone to analyze the color change and outputs the analysis result on the screen of smartphone.
  • a sample slider is mounted inside the receptacle slot to receive the QMAX device and position the sample in the QMAX device in the field of view and focal range of the smartphone camera.
  • the sample slider comprises a fixed track frame and a moveable arm:
  • the frame track is fixedly mounted in the receptacle slot of the optical box.
  • the track frame has a sliding track slot that fits the width and thickness of the QMAX device so that the QMAX device can slide along the track.
  • the width and height of the track slot is carefully configured to make the QMAX device shift less than 0.5mm in the direction perpendicular to the sliding direction in the sliding plane and shift less than less than 0.2mm along the thickness direction of the QMAX device.
  • the frame track has an opened window under the field of view of the camera of smartphone to allow the light back-illuminate the sample.
  • a moveable arm is pre-built in the sliding track slot of the track frame and moves together with the QMAX device to guide the movement of QMAX device in the track frame.
  • the moveable arm also called “lever” equipped with a stopping mechanism with two predefined stop positions. For one position, the arm will make the QMAX device stop at the position where a fixed sample area on the QMAX device is right under the camera of smartphone. For the other position, the arm will make the QMAX device stop at the position where the sample area on QMAX device is out of the field of view of the smartphone and the QMAX device can be easily taken out of the track slot.
  • the moveable arm switches between the two stop positions by a pressing the QMAX device and the moveable arm together to the end of the track slot and then releasing.
  • the moveable arm can indicate if the QMAX device is inserted in correct direction.
  • the shape of one corner of the QMAX device is configured to be different from the other three right angle corners.
  • the shape of the moveable arm matches the shape of the corner with the special shape so that only in correct direction can QMAX device slide to correct position in the track slot.
  • the radius of the side illunmring fiber is 10mm
  • the diameter of ring fiber can be at least 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 40 mm, 50 mm, 60 mm, 80 mm, or 100 mm, or in a range between any of the two values;
  • the diameter of the cross-section of the ring fiber can be at least 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3 mm, 4 mm, 5 mm, 6 mm, 8 mm, or 10 mm, or in a range between any of the two values.
  • the external imager lens has a diameter of 6mm
  • the diameter of the imager lens can be at least 2 mm, 3mm, 4 mm, 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 40 mm, or 50 mm, or in a range between any of the two values.
  • the ring fiber can be used in combination with micro-lens array or be replace by a micro-lens array;
  • optical assembly comprises a light diffuser plate between the sample and the ring fiber, wherein the light diffusive plate has an aperture configured to aligned with the camera.
  • the length of one side of the diffusive plate can be at least 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 40 mm, 50 mm, 100 mm, 150 mm, or 200 mm, or in a range between any of the two values
  • the thickness of the diffusive plate can be at least 2 mm, 3mm, 4 mm, 5 mm, 10 mm, 15 mm, or 20 mm, or in a range between any of the two values.
  • the distance between the diffusive plate and ring fiber can be at least 1 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 40 mm, 50 mm, 100 mm, or in a range between any of the two values.
  • the optical assembly of claim 2, wherein the distance between the sample and ring fiber can be at least 2mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 40 mm, 50 mm, 100 mm, 150 mm, 200 mm, or in a range between any of the two values.
  • first planar plane on the moveable arm and the light source can be at least 0.5mm, 2 mm, 4 mm, 8 mm, 10 mm, 20 mm, 50 mm, 100 mm or in a range between any of the two values.
  • first planar plane and the second planar plane of the moveable arm can be at least 5mm, 10 mm, 15 mm, 20 mm, 40 mm, 100 mm, 200mm, or in a range between any of the two values.
  • the optical assembly of claim 5, wherein the distance that the moveable arm needs to move to switch between different positions can be at least 1 mm, 5 mm, 15 mm, 20 mm, 40 mm, 100 mm, or in a range between any of the two values.
  • the second planar plane is connected to a tilted plane, wherein a mirror is mounted on the tilted plane 5.
  • the preferred tilt angle of the tilted plane can be at least 10 degree, 30 degree, 60 degree, 80 degree, or in a range between any of the two values, and the tilt angle is defined as the angle between the second planar plane and tilted plane.
  • FIG. 13-A, 13-B and 13-C are the schematic illustrations of system 10 for smartphone colorimetric reader. Particularly, FIG. 13-B and FIG. 13-C are the exploded views of system 10, shown from the front and rear sides respectively.
  • System 10 comprises a smartphone 1 ; an optical adaptor device 13 fitting over the upper part of smartphone 1 ; a colorimetric sample card 138, inserted into receptacle slot 137 of device 13 so that the sample area on the sample card 138 is positioned within the field of view and focal range of camera module 1 C in smartphone 1.
  • a rubber door 139 attached to device 18 covers receptacle slot 137 after sample card 138 is in so as to prevent the ambient light getting into optical adaptor 13 to affect the test.
  • the software (not shown) installed in smartphone 1 analyzes the image collected by camera module 1 C while light source 1 L in smartphone 1 is emitting light, in order to analyze the color change of the colorimetric test, and outputs the results to a display screen 1f in smartphone 1.
  • FIG. 14 is the schematic exploded view of optical adaptor device 13 in system 10.
  • Device 13 comprises a holder case 131 fitting over the upper part of smartphone 1 ; an optical box 132 attached to case 131 including a receptacle slot 137, an optics chamber 132C and a rubber door 139 inserted into trench 137s to cover receptacle slot 137.
  • An optics insert 134 is fitted into the top of optics chamber 132C with an exit aperture 134L and an entrance aperture 134C in it aligning with light source 1 L and camera 1 C (shown in FIG. 13-B) in smartphone 1.
  • a lens 133 is mounted in entrance aperture 134C in optics insert 134 and configured so that the sample area on colorimetric sample card 138 inserted into receptacle slot 137 is located within the working distance of the camera 1C (shown in FIG. 13-B).
  • a side-emitting optical fiber ring 135 is mounted in optics insert 134 configured to make the camera 1 C in the center of the fiber ring 135. Both end faces of optical fiber ring 135 are mounted in exit aperture 134L facing the light source 1 L.
  • a light diffuser film 136 is put under the optical fiber ring 135 and has a hole opened for the aperture of lens.
  • Optical fiber ring 135 whose operation as the illumination optics in device 13 is described below in FIG. 15-A-c.
  • FIG. 15-A, 15-B and 15-C are the schematic views showing details of system 10 reading a colorimetric card, and particularly of device 13.
  • FIG. 15-A is the sectional view showing details of device 13.
  • FIG. 15-B and FIG. 15-C are the schematic views only showing the configuration of the optics elements in device 13. These figures illustrate the functionality of the elements that were described above with reference to FIG. 14.
  • the light emitted from light source 1 L is coupled into side-emitting optical fiber ring 135 from the two end faces of fiber ring 135 and travels inside along the ring.
  • Beam B1 is emitted out from the side wall of fiber ring and go through the diffuser film 136.
  • Beam B1 illuminates the sample area of colorimetric sample card 138 right under the camera 1C from front side to create uniform illumination.
  • the illuminated sample area absorbs part of beam B1 and reflects the beam B1 to beam B2.
  • Beam B2 is collected by lens 133 and gets into camera 1 C
  • Lens 133 creates an image of the sample area on the image sensor plane of camera 1 C.
  • Smartphone 1 captures and processes the image to analyze the color information in the image to quantify the color change of the colorimetric assay.
  • a tomography device that reconstructs a sliceable virtual three-dimensional copy of a biological specimen with the highest resolution of nanoscale is disclosed.
  • the device consists of an imaging sensor, a lens, and a QMAX device, as in Fig. 16-A.
  • the QMAX device has a periodic pillar array.
  • a biological specimen is contained in the QMAX device.
  • An index-matching liquid can be used to reduce the scattering of light, and reduce heterogeneities of refractive index throughout the specimen.
  • the QMAX structure enhances the detection sensitivity of six (or more) orders of magnitude.
  • the pillar array has a metallic disk on top of each pillar.
  • the metallic disk provides a calibration signal for both spatial and height calibration for images captured by the imaging sensor.
  • the shape of the metallic disk can be designed to facilitate a fast calibration.
  • the shape of the metallic disk can be like the letter E; such a pillar array is illustrated in Fig. 16-B.
  • the captured image goes through an object detection.
  • the object detection scheme can be a template matching, an optical character recognition, a shape detection, or other schemes that are used in the field.
  • the object detection retrieves the orientation of the detected pattern, which in the example of Fig. 16-B is the letter E.
  • orientation parameter spatial calibration is achieved through a two-dimensional geometric transform.
  • the focus degree measures the focus level either the whole image or every image pixel.
  • a wide variety of algorithms and operators have been pro- posed in the literature to measure the focus degree, such as gradient-based, Laplacian-based, wavelet-based, statistics-based, Cosine transform/Fourier transform based, etc.
  • the focus degree of the pillar array captured at different focus planes can be pre- measured and stored in a look up table.
  • Fig. 16-D shows a captured image of the example pillar array in Fig. 16- B
  • we compute the focus degree of the newly captured image refer the focus degree to the look up table, and find its corresponding focal plane location.
  • the goal of tomography is to reconstruct a three-dimensional volume of a biological specimen through several projections of it.
  • An end-to-end tomography system includes light source, imaging, and three-dimensional reconstruction.
  • the light captured by the imaging sensor can be refracted from the specimen, emitted from the specimen, etc.
  • the imaging part captures projection on the imaging sensor.
  • the projections can be captured at different focus distance, different angles, from different illumination, etc.
  • the lens moves towards or backward the QMAX structure at a stepsize or a multiple of stepsize.
  • the value of the stepsize and the movement of the lens can be controlled by hardware or software through an application program interface.
  • the image sensor records the captured image.
  • the specimen is rotated and optical images are captured that approximate straight-line projections through it.
  • the specimen is rotated to a series of angular positions, and an image is captured at each orientation.
  • the apparatus is carefully aligned to ensure that the axis of rotation is perpendicular to the optical axis, so that projection data pertaining to each plane is collected by the imaging sensor.
  • the focal plane can be positioned halfway between the axis of rotation and the QMAX card closest to the lens. This means that every image contains both focused data from the front half of the specimen (the half closest to the lens), and out-of-focus data from the back half of the specimen.
  • the focused data will be utilized for three-dimensional volume reconstruction, while the out-of-focus data will not be used.
  • a band-pass filter can be equipped to select the focused data.
  • Optical projection tomography is performed using standard tomographic algorithms. Due to the position of the focal plane relative to the axis of rotation, two images taken 180 degrees apart from each other will be focused on different parts of the specimen. Limiting the back- projection to the region corresponding to the focused part of the specimen improves the quality of the results. As data is accumulated for the various orientations through the specimen, a semi- disc mask, which acts as a band-pass filter, can be rotated to ensure that only focused data is back-projected.
  • phase images can be captured at different illumination. Quantitative phase images from time-dependent interference patterns induced by the frequency shifting of a reference beam relative to the sample beam can be obtained.
  • a galvanometer-mounted tilting mirror can be used to vary the angle of illumination.
  • a laser beam passes through two acousto-optic modulators which shift the frequency of the laser beam.
  • a second beam splitter recombines the specimen and reference laser beams, forming an interference pattern which is captured at the imaging sensor.
  • Phase images are then calculated by applying phase-shifting interferometry. For near-plane wave illumination of a thin specimen with small index contrast, the phase of the transmitted field is to a good approximation equal to the line integral of the refractive index along the path of beam propagation. Therefore, the phase image can simply be interpreted as the projection of refractive index.
  • various imaging filters can be used during image captures, for the purpose of (including but not limited to):
  • signal enhancement thereby portion or whole of the captured image is enhanced
  • signal transformation thereby portion or whole of the captured image is transformed into another representation, such as frequency representation, multi-scale representation, etc.
  • Captured images can be enhanced through filtering, such as contrast enhancement, color enhancement, noise reduction, etc. It can increase the dynamic range of pixel intensities, adjust color temperature, boost the signal to noise ratio, etc.
  • Captured images can be transformed into another representation, which can be more suitable for the three-dimension reconstruction. It can be transformed into a different format (8 bit to 16 bit, integer to floating point, etc.), different color space (RGB to HSV, etc.), different domain (spatial domain to frequency domain, etc.), etc.
  • Portion of captured images can be replaced by another portion (or transformation of another portion) of captured images. It can be a spatial region, which is replaced by the transformation of another region, such as a reflective extension around the boundary, etc. It can be a frequency subband, which is replaced by the transformation of another frequency subband, such as the high frequency subband is replaced by an estimation from the low frequency subband, etc.
  • the three-dimensional volume reconstruction can employ a phase image retrieval scheme, a back-projection scheme, non-linear approximation scheme, optimization scheme, etc.
  • the focus degrees of these images When several images are captured at different focus distances, we compute the focus degrees of these images, and list these focus degrees as a vector. Then we refer the vector with the look up table, and find their corresponding focal plane distances. The corresponding can be distance based, correlation based, or other criteria to select the best match.
  • FIG. 16-E A diagram of phase image retrieval based scheme is shown in Fig. 16-E. It consists of four components:
  • the second component, phase retrieval is through a quantitative phase imaging technique, based on the transport of intensity (TIE) equation.
  • TIE transport of intensity
  • ⁇ indicates the intensity gradient which can be computed from the multi-focal images
  • k is the wave number
  • ⁇ is the sample phase distribution
  • the TI E equation could be solver using fast Fourier transform, discrete cosine transform; see for example, "Boundary-artifact-free phase retrieval with the transport of intensity equation: fast solution with use of discrete cosine transform", C. Zuo, Q. Chen, and A. Asundi, Optics Express, Vol. 22, No. 8, April 2014.
  • the phase image ⁇ is retrieved from the TI E equation.
  • the height of the biological specimen can be computed, with a known refractive index.
  • the three-dimensional volume of the biological specimen can be reconstructed.
  • the back-projection algorithm is commonly used in three-dimensional reconstruction in tomography. It includes Fourier transform base algorithm, filtered back projection algorithm, back projection and filtering algorithm, and iterative algorithm.
  • Fourier transform base algorithm When the position of the focal plane relative to the axis of rotation differs, two images taken 180 degrees apart from each other will be focused on different parts of the specimen. To compensate, a half-plane adjusted back projection algorithm can be employed. Thus, limiting the back-projection to the region corresponding to the focused part of the specimen will improve the quality of the results.
  • a semi-disc mask can be rotated to ensure that only focused data is back-projected.
  • a procedure based on the filtered back- projection method can be applied.
  • a discrete inverse Radon transform is applied to every ⁇ - ⁇ slice in the beam rotation direction, with x, the coordinate in the tilt direction and ⁇ , the relative angle of laser beam direction to the optic axis of the objective lens.
  • the x values is divided by cos ⁇ .
  • an iterative constraint method can be applied.
  • the resulting three-dimensional volume can be blurred.
  • a ramp filter can be used to remove or reduce the blurriness.
  • various imaging filters can be used for three-dimensional volume reconstruction, for (including but not limited to):
  • portion of the image or image volume is replaced by another portion of the captured image, or by the representation of another portion of the captured image;
  • a device for sample imaging comprising a QMAX device and an imager, wherein:
  • the QMAX device comprises: a first plate, a second plate, and spacers, wherein:
  • the plates are movable relative to each other into different configurations; ii. one or both plates are flexible; iii. each of the plates has, on its respective inner surface, a sample contact area for contacting a deformable sample; iv. one or both of the plates comprise the spacers that are fixed with a
  • the spacers have a predetermined substantially uniform height and a
  • one of the configurations is an open configuration, in which: the two plates are separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates; and wherein another of the configurations is a closed configuration which is configured after the sample deposition in the open configuration; and in the closed configuration: at least part of the sample is compressed by the two plates into a layer of uniform thickness, wherein the uniform thickness of the layer is confined by the inner surfaces of the two plates and is regulated by the plates and the spacers; and
  • the imager is configured to capture an image of signals emanating from at least part of the layer of uniform thickness.
  • a system for tomography comprising a QMAX device, an imager, a holder, and a control device, wherein:
  • the QMAX device comprises: a first plate, a second plate, and spacers, wherein: i. the plates are movable relative to each other into different configurations; ii. one or both plates are flexible; iii. each of the plates has, on its respective inner surface, a sample contact area for contacting a deformable sample; iv. one or both of the plates comprise the spacers that are fixed with a respective plate; v. the spacers have a predetermined substantially uniform height and a
  • one of the spacers is inside the sample contact area; wherein one of the configurations is an open configuration, in which: the two plates are separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates; and
  • another of the configurations is a closed configuration which is configured after the sample deposition in the open configuration; and in the closed configuration: at least part of the sample is compressed by the two plates into a layer of uniform thickness, wherein the uniform thickness of the layer is confined by the inner surfaces of the two plates and is regulated by the plates and the spacers;
  • the imager comprises an image sensor and a lens, wherein:
  • the lens is configured to focus signals emanating from at least part of the layer of uniform thickness and project the focused signals to the image sensor, and ii. the image sensor is configured to capture images of said focused signals;
  • the holder is configured to adjust relative position between the QMAX device and the imager
  • control device comprises hardware and software for controlling and/or deducing the position adjustment made by the holder, and receiving and reconstructing said images into a three-dimensional volume.
  • DBB1 A system for tomography, comprising a QMAX device, an imager, a holder, and a control device, wherein:
  • the QMAX device comprises: a first plate, a second plate, and spacers, wherein: i. the plates are movable relative to each other into different configurations; ii. one or both plates are flexible; iii. each of the plates has, on its respective inner surface, a sample contact area for contacting a deformable sample; iv. one or both of the plates comprise the spacers that are fixed with a respective plate; v. the spacers have a predetermined substantially uniform height and a
  • one of the spacers is inside the sample contact area; wherein one of the configurations is an open configuration, in which: the two plates are separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates; and
  • another of the configurations is a closed configuration which is configured after the sample deposition in the open configuration; and in the closed configuration: at least part of the sample is compressed by the two plates into a layer of uniform thickness, wherein the uniform thickness of the layer is confined by the inner surfaces of the two plates and is regulated by the plates and the spacers;
  • the imager is capable of changing the focal plane and comprises an image sensor and a lens, wherein:
  • the lens is configured to focus signals emanating from at least part of the layer of uniform thickness and project the focused signals to the image sensor, and ii. the image sensor is configured to capture images of said focused signals; iii. the lens is a single lens or a compound lens consisting several lenses;
  • At least one element lens in the lens is moveable to change the distance from the image sensor to change the focal plane of the imager;
  • the moveable lens can be driven by stepper motor and/or electromagnetic force, which is computerized or manually controlled.
  • control device comprises hardware and software for controlling and/or deducing the position adjustment made by the holder, and receiving and reconstructing said images into a three-dimensional volume.
  • a method of tomography comprising the steps of:
  • conformable pressing generates a substantially uniform pressure on the plates over the at least part of the sample, and the pressing spreads the at least part of the sample laterally between the sample contact surfaces of the plates, and wherein the closed configuration is a configuration in which the spacing between the plates in the layer of uniform thickness region is regulated by the spacers;
  • step (d) adjusting relative position between the QMAX device and imager, repeating step (c);
  • a conformable pressing is a method that makes the pressure applied over an area is substantially constant regardless the shape variation of the outer surfaces of the plates;
  • DCC1 A method to take images at different focal planes, comprising steps of:
  • QMAX device further comprises a dry reagent coated on one or both plates that stains the sample.
  • DA22 The device of any prior embodiment, wherein:
  • one or both plate sample contact areas comprise one or a plurality of binding sites that each binds and immobilizes a respective analyte; or ii. one or both plate sample contact areas comprise, one or a plurality of storage sites that each stores a reagent or reagents; wherein the reagent(s) dissolve and diffuse in the sample during or after step (c), and wherein the sample contains one or plurality of analytes; or iii. one or a plurality of amplification sites that are each capable of amplifying a signal from the analyte or a label of the analyte when the analyte or label is 500 nm from the amplification site; or iv. any combination of i to iii.
  • the imager further comprises a light source that provides light for illumination or excitation of the layer of uniform thickness for the imaging.
  • the light source is selected from the group consisting of: LED, laser, incandescent light, and any combination thereof.
  • the imager further comprises a light source providing light illuminating said layer of uniform thickness for the imaging, wherein the light source is selected from the group consisting of: incandescent light, LED, CFL, laser, and any combination thereof.
  • the imager further comprises a light source providing excitation light that excites fluorescence emission from said layer of uniform thickness for the imaging, wherein the light source is a LED and/or a laser.
  • DB5. The system of any prior embodiment, wherein the holder is capable of adjusting the relative position of the lens to the QMAX device along its optical axis to change focal plane position of the lens.
  • DB6 The system of any prior embodiment, wherein the holder is capable of adjusting the relative position between the lens and the QMAX device to change imaging angle, wherein the imaging angle is an angle between focal plane of the lens and the layer of uniform thickness.
  • the imager further comprises a light source providing illumination light for the imaging, and wherein the holder is capable of adjusting the relative position between the light source and the QMAX device to change angle of incidence of the illumination light, wherein the angle of incidence is the angle between the illumination light and a line perpendicular to the layer of uniform thickness.
  • control device comprises hardware and software for sending a command that defines the position adjustment to the holder, and wherein the holder is configured to receive said command and make the adjustment with no more than 10% deviation.
  • control device comprises hardware and software for sending a command that defines the position adjustment to the holder, and wherein the holder is configured to receive said command and make the adjustment with no more than 1 % deviation.
  • control device comprises hardware and software for receiving an input that defines the position adjustment and converting the input into the command for the holder to make the adjustment.
  • DB11 The system of any prior embodiment, wherein the system further comprises a plurality of calibration pillars, and wherein:
  • said plurality of calibration pillars are placed between the sample contact areas of the two plates at the closed configuration, and have different heights from one another, which are all smaller than the uniform height of the spacers;
  • the control device comprises hardware and software for: (a) calculating a focus score for each of said images; and (b) deducing a focus plane position at which each of said images is captured by comparing said focus score with a look-up table, wherein the focus score is a matrix of focus degrees calculated for each pixel of a captured image, wherein the look-up table is predetermined and comprises a row of pre-determined focus plane positions along said common optical axis and a corresponding row of calibration focus scores, each of the calibration focus scores is calculated based on an image of the calibration pillars captured at the corresponding pre-determined focus plane.
  • DB12 The system of any prior embodiment, wherein said images are captured at different focal planes along a common optical axis, and wherein the control device comprises hardware and software for: (a) generating a phase image for a biological entity in said at least part of the layer, wherein the phase image is a phase distribution calculated based on wavelength of an illuminating light used for imaging, at least part of said images that contain signals from the biological entity, and the focus plane positions at which said images are respectively captured; and (b) estimating a thickness of the biological entity based on the phase image and a refractive index of the sample, wherein the biological entity is a part or entirety of said at least part of the layer.
  • control device comprises hardware and software for reconstructing said at least part of the images into a three-dimensional volume of the biological entity based on the estimated thickness.
  • DB14 The system of any prior embodiment, wherein said images are captured at different imaging angles, wherein the control device comprises hardware and software for: (1) knowing or deducing the imaging angle for each of said images; and (2) reconstructing said images into a three-dimensional volume based on the known/deduced imaging angels using a back-projection algorithm, and wherein the imaging angle is an angle between focal plane of the lens and the layer of uniform thickness.
  • DB15 The system of any prior embodiment, wherein said images are captured at different angels of incidence of illumination light
  • the control device comprises hardware and software for: (1) knowing or deducing the angle of incidence for each of said images; and (2) reconstructing said images into a three-dimensional volume based on the known/deduced angle of incidence using a back-projection algorithm, and wherein the angle of incidence of the illumination light is the angle between the illumination light and a line perpendicular to the layer of uniform thickness.
  • DB16 The system of any or embodiments DB14 - DB15, wherein the back-projection algorithm is selected from the group consisting of: Fourier transform base algorithm, filtered back- projection algorithm, back-projection and filtering algorithm, iterative algorithm, and any combination thereof.
  • control device further comprises hardware and software for reconstructing said at least part of the images into a three- dimensional volume, wherein during three-dimensional volume reconstruction, the images and the three-dimensional volume are filtered by software for: (1) signal selection, where portion of the image or image volume is selected; (2) signal enhancement, where portion or whole of the image or image volume is enhanced; (3) signal transformation, where portion or whole of the image or image volume is transformed into another representation, such as frequency representation, multi-scale representation, etc.; (4) signal replication, where portion of the image or image volume is replaced by another portion of the captured image, or by the representation of another portion of the captured image; or any combination of (1) - (4)
  • DC2 The method of embodiment DC1 , further comprising: before step (c), staining the sample with a dye.
  • DC3. The method of any prior method embodiment, wherein during the step (b), the conformable pressing is by human hand.
  • DC4 The method of any prior method embodiment, wherein the conformable pressing of step (d) is provided by a pressured liquid, a pressed gas, or a conformal material.
  • step (d) comprises adjusting the relative position of the lens to the QMAX device along its optical axis to change focal plane position of the lens.
  • step (d) comprises adjusting the relative position between the lens and the QMAX device to change imaging angle, wherein the imaging angle is an angle between focal plane and the layer of uniform thickness.
  • the imager further comprises a light source providing illumination light for the imaging
  • the adjusting step (d) comprises adjusting the relative position of the light source to the QMAX device to change angle of incidence of the illumination light, wherein the angle of incidence is the angle between the illumination light and a line perpendicular to the layer of uniform thickness.
  • DC8 The method of any prior method embodiment, wherein the adjusting step (d) is performed manually.
  • DC9 The method of any prior method embodiment, wherein the adjusting step (d) is performed through a control device operably coupled to a holder, wherein the control device comprises hardware and software for receiving an input that defines the position adjustment and sending a command to the holder, and wherein the holder is configured to receive said command and make the adjustment with a deviation no more than 10%.
  • step (d) is performed through a control device operably coupled to a holder, wherein the control device comprises hardware and software for receiving an input that defines the position adjustment and sending a command to the holder, and wherein the holder is configured to receive said command and make the adjustment with a deviation no more than 1 %.
  • DC1 1. The method of any prior method embodiment, wherein said images are captured at different focal planes along a common optical axis, and wherein the reconstructing step (e) comprises: (i) calculating a focus score for each of said images; and (ii) deducing a focal plane position at which each of said images is captured by comparing said focus score with a look-up table, wherein the focus score is a matrix of focus degrees calculated for each pixel of a captured image, wherein the look-up table is predetermined and comprises a row of predetermined focal plane positions along said common optical axis and a corresponding row of calibration focus scores, each of the calibration focus scores is calculated based on an image of the calibration pillars captured at the corresponding pre-determined focal plane.
  • the reconstructing step (e) comprises: (i) generating a phase image for a biological entity in said at least part of the layer, wherein the phase image is a phase distribution calculated based on the wavelength of an illuminating light used for imaging, at least part of said images that contain signals from the biological entity, and the focal plane positions at which said images are captured; and (ii) estimating a thickness of the biological entity based on the phase image and a refractive index of the sample, wherein the biological entity is a part or entirety of said at least part of the layer.
  • step (e) further comprises reconstructing said at least part of the images into a three-dimensional volume of the biological entity based on the estimated thickness.
  • the reconstructing step (e) comprises: (i) knowing or deducing the imaging angle for each of said images; and (ii) reconstructing said images into a three- dimensional volume based on the known/deduced imaging angels using a back-projection algorithm, and wherein the imaging angle is an angle between focal plane of the lens and the layer of uniform thickness.
  • the reconstructing step (e) comprises: (i) knowing or deducing the angle of incidence for each of said images; and (ii) reconstructing said images into a three-dimensional volume based on the known/deduced angle of incidence using a back-projection algorithm, and wherein the angle of incidence of the illumination light is the angle between the illumination light and a line perpendicular to the layer of uniform thickness.
  • DC16 The method of any of embodiments DC14 - DC15, wherein the back-projection algorithm is selected from the group consisting of: Fourier transform base algorithm, filtered back-projection algorithm, back-projection and filtering algorithm, iterative algorithm, and any combination thereof.
  • the back-projection algorithm is selected from the group consisting of: Fourier transform base algorithm, filtered back-projection algorithm, back-projection and filtering algorithm, iterative algorithm, and any combination thereof.
  • DC17 The method of any prior method embodiment, wherein the sample is a biological sample selected from the group consisting of: cells, tissues, bodily fluids, stool, and any combination thereof.
  • the sample is an environmental sample from an environmental source selected from the group consisting of a river, lake, pond, ocean, glaciers, icebergs, rain, snow, sewage, reservoirs, tap water, drinking water, etc.; solid samples from soil, compost, sand, rocks, concrete, wood, brick, sewage, the air, underwater heat vents, industrial exhaust, vehicular exhaust and any combination thereof.
  • sample is a foodstuff sample selected from the group consisting of: raw ingredients, cooked food, plant and animal sources of food, preprocessed food, partially or fully processed food, and any combination thereof.
  • DC20 The method of any prior method embodiment, wherein the sample is blood, and the biological entity is red blood cells, white blood cells, and/or platelets.
  • a blood test readout selected from the group consisting of: mean corpuscular volume (MCV), hematocrit, Red cell distribution width (RDW), mean platelet volume (MPV), platelet distribution width (PDW), immature platelet fraction (IPF), and any combination thereof.
  • a device for biological analyte detection and localization comprising a QMAX device, an imager, and a computing unit, is disclosed.
  • a biological sample is suspected on the QMAX device.
  • the count and location of an analyte contained in the sample are obtain by the disclosure.
  • the imager captures an image of the biological sample.
  • the image is submitted to a computing unit.
  • the computing unit can be physically directly connected to the imager, connected through network, or in-directly through image transfer.
  • the disclosed analyte detection and localization employ machine learning deep learning.
  • a machine learning algorithm is an algorithm that is able to learn from data.
  • a more rigorous definition of machine learning is "A computer program is said to learn from experience E with respect to some class of tasks T and performance measure P, if its performance at tasks in T, as measured by P, improves with experience E.” It explores the study and construction of algorithms that can learn from and make predictions on data - such algorithms overcome following strictly static program instructions by making data driven predictions or decisions, through building a model from sample inputs.
  • Deep learning is a specific kind of machine learning based on a set of algorithms that attempt to model high level abstractions in data.
  • the input layer receives an input, it passes on a modified version of the input to the next layer.
  • the layers are not made of neurons but it can help to think of it that way), allowing the algorithm to use multiple processing layers, composed of multiple linear and non-linear transformations.
  • the disclosed analyte detection and localization workflow consists of two stages, training and prediction, as in Fig. 17-A. We describe training and prediction stages in the following paragraphs. Training
  • Convolutional neural network a specialized kind of neural network for processing data that has a known, grid-like topology. Examples include time-series data, which can be thought of as a 1 D grid taking samples at regular time intervals, and image data, which can be thought of as a 2D grid of pixels. Convolutional networks have been tremendously successful in practical applications. The name “convolutional neural network” indicates that the network employs a mathematical operation called convolution. Convolution is a specialized kind of linear operation. Convolutional networks are simply neural networks that use convolution in place of general matrix multiplication in at least one of their layers.
  • Training data are annotated for the analyte to be detect.
  • Annotation indicates whether or not an analyte presents in a training data.
  • Annotation can be done in the form of bounding boxes which fully contains the analyte, or center locations of analytes. In the latter case, center locations are further converted into circles covering analytes.
  • training data When the size of training data is large, it presents two challenges: annotation (which is usually done by person) is time consuming, and the training is computing expensive. To overcome these challenges, one can partition the training data into patches of small size, then annotate and train on these patches, or a portion of these patches.
  • Annotated training data is fed into a convolutional neural network for model training.
  • the output is a model that can be used to make pixel-level prediction on an image.
  • FCN fully convolutional network
  • Other convolutional neural network architecture can also be used, such as TensorFlow.
  • the training stage generates a model that will be used in the prediction stage.
  • the model can be repeatedly used in the prediction stage for input images.
  • the computing unit only needs access to the generated model. It does not need access to the training data, nor the training stage has to be run on the computing unit.
  • a detection component is applied to the input image, which is followed by a localization component.
  • the output of the prediction stage is the count of analytes contained in the sample, along with the location of each analyte.
  • an input image along with the model generated from the training stage, is fed into a convolutional neural network.
  • the output of the detection stage is a pixel-level prediction, in the form of a heatmap.
  • the heatmap can have the same size as the input image, or it can be a scaled down version of the input image.
  • Each pixel in the heatmap has a value from 0 to 1 , which can be considered as the probability (belief) whether a pixel belongs to an analyte. The higher the value, the bigger the chance it belongs to an analyte.
  • the heatmap is the input of the localization component.
  • One embodiment of the localization algorithm is to sort the heatmap values into a one- dimensional ordered list, from the highest value to the lowest value. Then pick the pixel with the highest value, remove the pixel from the list, along with its neighbors. Iterate the process to pick the pixel with the highest value in the list, until all pixels are removed from the list.
  • heatmap heatmap ⁇ D // remove D from the heatmap
  • heatmap is a one-dimensional ordered list, where the heatmap value is ordered from the highest to the lowest. Each heatmap value is associated with its corresponding pixel coordinates.
  • the first item in the heatmap is the one with the highest value, which is the output of the pop(heatmap) function.
  • One disk is created, where the center is the pixel coordinate of the one with highest heatmap value.
  • all heatmap values whose pixel coordinates resides inside the disk is removed from the heatmap.
  • the algorithm repeatedly pops up the highest value in the current heatmap, removes the disk around it, till the items are removed from the heatmap.
  • each item has the knowledge of the proceeding item, and the following item.
  • the localization algorithm is complete.
  • the number of elements in the set loci will be the count of analytes, and location information is the pixel coordinate for each s in the set loci.
  • Another embodiment searches local peak, which is not necessary the one with the highest heatmap value. To detect each local peak, we start from a random starting point, and search for the local maximal value. After we find the peak, we calculate the local area surrounding the peak but with smaller value. We remove this region from the heatmap and find the next peak from the remaining pixels. The process is repeated only all pixels are removed from the heatmap.
  • Example of present invention EA1. A method of deep learning for data analysis, comprising:
  • the image is taken by an imager connected to the QMAX device, wherein the image includes detectable signals from an analyte in the test sample;
  • annotated data set is from samples that are the same type as the test sample and for the same analyte
  • a system for data analysis comprising:
  • the QMAX device is configured to compress at least part of a test sample into a layer of highly uniform thickness
  • the imager is configured to produce an image of the sample at the layer of uniform thickness, wherein the image includes detectable signals from an analyte in the test sample;
  • the computing unit is configured to:
  • annotated data set is from samples that are the same type as the test sample and for the same analyte; and training and establishing the detection model by convolution; and iii. (c) analyzing the 2-D data array to detect local signal peaks with signal list process, or local searching process; and
  • Fig. 18-A shows an embodiment of a generic QMAX device, that have or not have a hinge, and wherein Q: quantification; M: magnifying; A: adding reagents; X: acceleration; also known as compressed regulated open flow (CROF)) device.
  • the generic QMAX device comprises a first plate 10 and a second plate 20.
  • panel (A) shows the perspective view of a first plate 10 and a second plate 20 wherein the first plate has spacers. It should be noted, however, that the spacers also are fixed on the second plate 20 (not shown) or on both first plate 10 and second plate 20 (not shown).
  • Panel (B) shows the perspective view and a sectional view of depositing a sample 90 on the first plate 10 at an open configuration.
  • Panel (C) illustrates (i) using the first plate 10 and second plate 20 to spread the sample 90 (the sample flow between the inner surfaces of the plates) and reduce the sample thickness, and (ii) using the spacers and the plate to regulate the sample thickness at the closed configuration of the QMAX device.
  • the inner surfaces of each plate have one or a plurality of binding sites and or storage sites (not shown).
  • the spacers 40 have a predetermined uniform height and a predetermined uniform inter-spacer distance. In the closed configuration, as shown in panel (C) of Fig. 18-A, the spacing between the plates and the thus the thickness of the sample 90 is regulated by the spacers 40. In some embodiments, the uniform thickness of the sample 90 is substantially similar to the uniform height of the spacers 40. It should be noted that although Fig. 18-A shows the spacers 40 to be fixed on one of the plates, in some embodiments the spacers are not fixed. For example, in certain embodiments the spacers is mixed with the sample so that when the sample is compressed into a thin layer, the spacers, which is rigid beads or particles that have a uniform size, regulate the thickness of the sample layer.
  • Fig. 18-A shows an embodiment of a QMAX device used for cell imaging.
  • the device comprises a first plate 10, a second plate 20, and spacers 40.
  • the plates are movable relative to each other into different configurations, one or both plates are flexible.
  • Each of the plates has, on its respective inner surface, a sample contact area (not indicated) for contacting a staining liquid 910 and/or a tissue sample 90 suspected of containing a target analyte.
  • the second plate 20 comprises the spacers 40 that are fixed to its inner surface 21.
  • the spacers 40 have a predetermined substantially uniform height and a predetermined inter-spacer distance, and at least one of the spacers is inside the sample contact area.
  • Fig. 18-A panels (A) and (B) illustrate one of the configurations, an open configuration. As shown in the figure, in the open configuration, the two plates are partially or entirely separated apart, the spacing 102 between the plates is not regulated by the spacers 40, and the staining liquid 910 and the sample 90 are deposited on the first plate 10. It should be noted, the staining liquid 910 and the sample 90 can also be deposited on the second plate 20 or both plates.
  • Fig. 18-A panel (C) depicts another of the configurations of the two plates, a closed configuration.
  • the closed configuration is configured after the deposition of the staining liquid 910 and the sample 90 in the open configuration, as shown in panel (B).
  • at least part of the sample 90 is between the two plates and a layer of at least part of staining liquid 910 is between the at least part of the sample 90 and the second plate 20, wherein the thickness of the at least part of staining liquid layer is regulated by the plates, the sample 90, and the spacers 40, and has an average distance between the sample surface and the second plate surface is equal or less than 250 ⁇ with a small variation.
  • the sample can dried thereon at the open configuration, and wherein the sample comprises bodily fluid selected from the group consisting of: amniotic fluid, aqueous humour, vitreous humour, blood (e.g., whole blood, fractionated blood, plasma or serum), breast milk, cerebrospinal fluid (CSF), cerumen (earwax), chyle, chime, endolymph, perilymph, feces, breath, gastric acid, gastric juice, lymph, mucus (including nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, exhaled breath condensates, sebum, semen, sputum, sweat, synovial fluid, tears, vomit, urine, and any combination thereof.
  • bodily fluid selected from the group consisting of: amniotic fluid, aqueous humour, vitreous humour, blood (e.g., whole blood, fractionated blood, plasma or serum
  • the sample contact area of one or both of the plates is configured such that the sample can dried thereon at the open configuration, and the sample comprises blood smear and is dried on one or both plates.
  • the sample is a solid tissue section having a thickness in the range of 1 - 200 urn, and the sample contact area of one or both of the plates is adhesive to the sample.
  • the sample is paraffin-embedded. In some embodiments, the sample is fixed.
  • the staining liquid is a pure buffer solution that does not comprise particularly component capable of altering the properties of the sample.
  • the staining liquid comprises fixative capable of fixing the sample.
  • the staining liquid comprises blocking agents, wherein the blocking agents are configured to disable non-specific endogenous species in the sample to react with detection agents that are used to specifically label the target analyte.
  • the staining liquid comprises deparaffinizing agents capable of removing paraffin in the sample.
  • the staining liquid comprises permeabilizing agents capable of permeabilizing cells in the tissue sample that contain the target analyte.
  • the staining liquid comprises antigen retrieval agents capable of facilitating retrieval of antigen.
  • the staining liquid comprises detection agents that specifically label the target analyte in the sample.
  • the sample contact area of one or both plates comprise a storage site that contains blocking agents, wherein the blocking agents are configured to disable nonspecific endogenous species in the sample to react with detection agents that are used to specifically label the target analyte.
  • the sample contact area of one or both plates comprise a storage site that contains deparaffinizing agents capable of removing paraffin in the sample.
  • the sample contact area of one or both plates comprise a storage site that contains permeabilizing agents capable of permeabilizing cells in the tissue sample that contain the target analyte.
  • the sample contact area of one or both plates comprise a storage site that contains antigen retrieval agents capable of facilitating retrieval of antigen. In some embodiments, the sample contact area of one or both plates comprise a storage site that contains detection agents that specifically label the target analyte in the sample. In some embodiments, the sample contact area of one or both of the plates comprise a binding site that contains capture agents, wherein the capture agents are configured to bind to the target analyte on the surface of cells in the sample and immobilize the cells.
  • the detection agent comprises dyes for a stain selected from the group consisting of: Acid fuchsin, Alcian blue 8 GX, Alizarin red S, Aniline blue WS, Auramine O, Azocarmine B, Azocarmine G, Azure A, Azure B, Azure C, Basic fuchsine, Bismarck brown Y, Brilliant cresyl blue, Brilliant green, Carmine, Chlorazol black E, Congo red, C.I.
  • a stain selected from the group consisting of: Acid fuchsin, Alcian blue 8 GX, Alizarin red S, Aniline blue WS, Auramine O, Azocarmine B, Azocarmine G, Azure A, Azure B, Azure C, Basic fuchsine, Bismarck brown Y, Brilliant cresyl blue, Brilliant green, Carmine, Chlorazol black E, Congo red, C.I.
  • the detection agent comprises antibodies configured to specifically bind to protein analyte in the sample.
  • the detection agent comprises oligonucleotide probes configured to specifically bind to DNA and/or RNA in the sample.
  • the detection agent is labeled with a reporter molecule, wherein the reporter molecule is configured to provide a detectable signal to be read and analyzed.
  • the signal is selected from the group consisting of:
  • luminescence selected from photoluminescence, electroluminescence, and
  • electrochemiluminescence ii. light absorption, reflection, transmission, diffraction, scattering, or diffusion; iii. surface Raman scattering; iv. electrical impedance selected from resistance, capacitance, and inductance; v. magnetic relaxivity; and vi. any combination of i-v.
  • the devices and methods of the present invention are useful for conducting immunohistochemistry on the sample.
  • tissue sample is fixed (e.g., in paraformaldehyde), optionally embedding in wax, sliced into thin sections that are less then 100 urn thick (e.g., 2 urn to 6 urn thick), and then mounted onto a support such as a glass slide. Once mounted, the tissue sections may be dehydrated using alcohol washes of increasing concentrations and cleared using a detergent such as xylene.
  • a detergent such as xylene.
  • a primary and a secondary antibody may be used.
  • the primary antibody binds to antigen of interest (e.g., a biomarker) and is unlabeled.
  • the secondary antibody binds to the primary antibody and directly conjugated either to a reporter molecule or to a linker molecule (e.g., biotin) that can recruit reporter molecule that is in solution.
  • the primary antibody itself may be directly conjugated either to a reporter molecule or to a linker molecule (e.g., biotin) that can recruit reporter molecule that is in solution.
  • Reporter molecules include fluorophores (e.g., FITC, TRITC, AMCA, fluorescein and rhodamine) and enzymes such as alkaline phosphatase (AP) and horseradish peroxidase (HRP), for which there are a variety of fluorogenic, chromogenic and chemiluminescent substrates such as DAB or BCIP/NBT.
  • fluorophores e.g., FITC, TRITC, AMCA, fluorescein and rhodamine
  • enzymes such as alkaline phosphatase (AP) and horseradish peroxidase (HRP), for which there are a variety of fluorogenic, chromogenic and chemiluminescent substrates such as DAB or BCIP/NBT.
  • the tissue section is incubated with a labeled primary antibody (e.g. an FITC-conjugated antibody) in binding buffer.
  • a labeled primary antibody e.g. an FITC-conjugated antibody
  • the primary antibody binds directly with the antigen in the tissue section and, after the tissue section has been washed to remove any unbound primary antibody, the section is to be analyzed by microscopy.
  • the tissue section is incubated with an unlabeled primary antibody that binds to the target antigen in the tissue. After the tissue section is washed to remove unbound primary antibody, the tissue section is incubated with a labeled secondary antibody that binds to the primary antibody.
  • the tissue sample may be stained with another dye, e.g., hematoxylin, Hoechst stain and DAPI, to provide contrast and/or identify other features.
  • another dye e.g., hematoxylin, Hoechst stain and DAPI
  • the present device may be used for immunohistochemical (IHC) staining a tissue sample.
  • the device may comprise a first plate and a second plate, wherein: the plates are movable relative to each other into different configurations; one or both plates are flexible; each of the plates has, on its respective surface, a sample contact area for contacting a tissue sample or a IHC staining liquid; the sample contact area in the first plate is smooth and planner; the sample contact area in the second plate comprise spacers that are fixed on the surface and have a predetermined substantially uniform height and a
  • predetermined constant inter-spacer distance that is in the range of 7 ⁇ to 200 ⁇ ;
  • one of the configurations is an open configuration, in which: the two plates are completely or partially separated apart, the spacing between the plates is not regulated by the spacers; and wherein another of the configurations is a closed configuration which is configured after a deposition of the sample and the IHC staining liquid in the open configuration; and in the closed configuration: at least part of the sample is between the two plates and a layer of at least part of staining liquid is between the at least part of the sample and the second plate, wherein the thickness of the at least part of staining liquid layer is regulated by the plates, the sample, and the spacers, and has an average distance between the sample surface and the second plate surface is equal or less than 250 ⁇ with a small variation.
  • the device may comprise a dry IHC staining agent coated on the sample contact area of one or both plates. In some embodiments, the device may comprise a dry IHC staining agent coated on the sample contact area of the second plate, and the IHC staining liquid comprise a liquid that dissolve the dry IHC staining agent.
  • the device of claim 1 wherein the thickness of the sample is 2 urn to 6 urn.
  • the devices and methods of the present invention are useful for conducting H&E stain and special stains.
  • Hematoxylin and eosin stain or haematoxylin and eosin stain is one of the principal stains in histology. It is the most widely used stain in medical diagnosis and is often the gold standard; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed "H&E section", "H+E section", or "HE section”. A combination of hematoxylin and eosin, it produces blues, violets, and reds.
  • the "special stain” terminology is most commonly used in the clinical environment, and simply means any technique other than the H & E method that is used to impart colors to a specimen. This also includes immunohistochemical and in situ hybridization stains. On the other hand, the H & E stain is the most popular staining method in histology and medical diagnosis laboratories.
  • the dry binding site may comprise a capture agent such as an antibody or nucleic acid.
  • the releasable dry reagent may be a labeled reagent such as a fluorescently-labeled reagent, e.g., a fluorescently-labeled antibody or a cell stain such Romanowsky's stain, Leishman stain, May-Grunwald stain, Giemsa stain, Jenner's stain, Wright's stain, or any combination of the same (e.g., Wright-Giemsa stain).
  • a stain may comprise eosin Y or eosin B with methylene blue.
  • the stain may be an alkaline stain such as haematoxylin.
  • the special stains include, but not limited to, Acid fuchsin, Alcian blue 8 GX, Alizarin red S, Aniline blue WS, Auramine O, Azocarmine B, Azocarmine G, Azure A, Azure B, Azure C, Basic fuchsine, Bismarck brown Y, Brilliant cresyl blue, Brilliant green, Carmine, Chlorazol black E, Congo red, C.I.
  • the devices and methods of the present invention are useful for conducting in situ hybridization (ISH) on histological samples.
  • ISH in situ hybridization
  • ISH In situ hybridization
  • tissue in situ
  • CTCs circulating tumor cells
  • In situ hybridization is used to reveal the location of specific nucleic acid sequences on chromosomes or in tissues, a crucial step for understanding the organization, regulation, and function of genes.
  • the key techniques currently in use include: in situ hybridization to mRNA with oligonucleotide and RNA probes (both radio-labelled and hapten-labelled); analysis with light and electron microscopes; whole mount in situ hybridization; double detection of RNAs and RNA plus protein; and fluorescent in situ hybridization to detect chromosomal sequences.
  • DNA ISH can be used to determine the structure of chromosomes. Fluorescent DNA ISH (FISH) can, for example, be used in medical diagnostics to assess chromosomal integrity.
  • RNA ISH RNA in situ hybridization
  • CTCs circulating tumor cells
  • the detection agent comprises nucleic acid probes for in situ hybridization staining.
  • the nucleic acid probes include, but not limited to, oligonucleotide probes configured to specifically bind to DNA and/or RNA in the sample.
  • Also provided is a system for rapidly staining and analyzing a tissue sample using a mobile phone comprising:
  • Also provided is a method for rapidly staining and analyzing a tissue sample using a mobile phone comprising: (a) depositing a tissue sample and a staining liquid on the device of the system described above, and placing the two plate into a closed configuration;
  • the plates are movable relative to each other into different configurations
  • one or both plates are flexible
  • each of the plates has, on its respective surface, a sample contact area for contacting a tissue sample or a IHC staining liquid;
  • the sample contact area in the first plate is smooth 5 and planner
  • the sample contact area in the second plate comprise spacers that are fixed on the surface and have a predetermined substantially uniform height and a predetermined constant inter-spacer distance that is in the range of 7 ⁇ to 200 ⁇ ;
  • At least part of the sample is between the two plates and a layer of at least part of staining liquid is between the at least part of the sample and the second plate, wherein the thickness of the at least part of staining liquid layer is regulated by the plates, the sample, and the spacers, and has an average distance between the sample surface and the second plate surface is equal or less than 250 ⁇ with a small variation.
  • the spacers regulating the layer of uniform thickness i.e., the spacers that are spacing the plates away from each other in the layer
  • the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 10 MPa, e.g., at least 15 MPa or at least 20 MPa, where the filling factor is the ratio of the spacer area that is in contact with the layer of uniform thickness to the total plate area that is in contact with the layer of uniform thickness.
  • the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 550 GPa-um, e.g., 100 to 300 GPa-um.
  • the fourth power of the inter-spacer-distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD 4 /(hE), is equal to 5 or less than 10 6 um 3 /GPa, e.g., less than 10 5 um 3 /GPa, less than 10 4 um 3 /GPa or less than 10 3 um 3 /GPa.
  • one or both plates comprise a location marker either on a surface of or inside the plate, that provide information of a location of the plate, e.g., a location that is going to be analyzed or a location onto which the section should be deposited.
  • one or both plates may comprise a scale marker, either on a surface of or inside the plate, that provides information of a lateral dimension of a structure of the section and/or the plate.
  • one or both plates comprise an imaging marker, either on surface of or inside the plate, that assists an imaging of the sample. For example, the imaging marker could help focus the imaging device or direct the imaging device to a location on the device.
  • the spacers can function as a location marker, a scale marker, an imaging marker, or any combination of thereof.
  • the inter-spacer distance may substantially periodic.
  • the spacers may be in a regular pattern and the spacing between adjacent spacers may be approximately the same.
  • the spacers are pillars with a cross- sectional shape selected from round, polygonal, circular, square, rectangular, oval, elliptical, or any combination of the same and, in some embodiments, the spacers may have a substantially flat top surface, wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1.
  • the minimum lateral dimension of spacer is less than or substantially equal to the minimum dimension of an analyte in the sample.
  • the minimum lateral dimension of spacer is in the range of 0.5 urn to 100 urn, e.g., in the range of 2 urn to 50 urn or 0.5 urn to 10 urn.
  • the spacers have a pillar shape and the sidewall corners of the spacers have a round shape with a radius of curverture at least 1 urn, e.g., at least 1.2 urn, at least 1.5 urn or at least 2.0 urn.
  • the spacers may have any convenient density, e.g., a density of at least 1000/mm 2 , e.g., a density of at least 1000/mm 2 , a density of at least 2000/mm 2 , a density of at least 5,000/mm 2 or a density of at least 10,000/mm 2 .
  • At least one of the plates may be transparent, thereby allowing the assay to be read optically.
  • at least one of the plates may be made of a flexible polymer, thereby allowing the sample to be efficiently spread by compressing the plates together.
  • the pressure that compresses the plates, the spacers are not compressible and/or, independently, only one of the plates is flexible.
  • the flexible plate may have a thickness in the range of 20 urn to 200 urn, e.g., 50 urn to 150 urn. As noted above, in the closed position, the thickness of the layer of uniform thickness may have a small variation.
  • the variation may be less than 10%, less than 5% or less than 2%, meaning that the thickness of the area does not exceed +/- 10%, +/- 5% 5 or +/- 2% of the average thickness.
  • first and second plates are connected and the device can be changed from the open configuration to the closed configuration by folding the plates.
  • first and second plates can be connected by a hinge and the device can be changed from the open configuration to the closed configuration by folding the plates such that the device bends along the hinge.
  • the hinge may be a separate material that is attached to the plates or, in some cases, the plates may be integral with the plates.
  • the device may be capable of analyzing the section very rapidly. In some cases, the analysis may be done in 60 seconds or less, in 30 seconds, in 20 seconds or 15 less or in 10 seconds or less.
  • the system may additionally comprise (d) a housing configured to hold the sample and to be mounted to the mobile communication device.
  • the housing may comprise optics for facilitating the imaging and/or signal processing of the sample by the mobile communication device, and a mount configured to hold the optics on the mobile communication device.
  • an element of the optics of the device e.g., a lens, filter, mirror, prism or a beamsplitter, may be movable) such that the sample may be imaged in at least two channels.
  • the mobile communication device may be configured to communicate test results to a medical professional (e.g., an MD), a medical facility (e.g., a hospital or testing lab) or an insurance company.
  • the mobile communication device may be configured to communicate information on the subject (e.g., the subject's age, gender, weight, address, name, prior test results, prior medical history, etc.) with the medical professional, medical facility or insurance company.
  • the mobile communication device may be configured to receive a prescription, diagnosis or a
  • the mobile communication device may send assay results to a remote location where a medical professional gives a diagnosis.
  • the diagnosis may be communicated to the subject via the mobile communication device.
  • the mobile communication device may contain hardware and software that allows it to (a) capture an image of the sample; (b) analyze a test location and a control location in in image; and (c) compare a value obtained from analysis of the test location to a threshold value that characterizes the rapid diagnostic test.
  • the mobile communication device communicates with the remote location via a wireless or cellular network.
  • the mobile communication device may be a mobile phone.
  • the system may be used in a method that comprises (a) sample on the device of the system; (b) assaying the sample deposited on the device to generate a result; and (c) communicating the result from the mobile communication device to a location remote from the mobile communication device.
  • the method may comprise analyzing the results at the remote location to provide an analyzed result; and communicating the analyzed result from the remote location to the mobile communication device.
  • the analysis may be done by a medical professional at a remote location.
  • the mobile communication device may be done by a medical professional at a remote location.
  • the communication device may receive a prescription, diagnosis or a recommendation from a medical professional at a remote location.
  • this method may comprise obtaining a device as described above, depositing the section onto one or both pates of the device; placing the plates in a closed configuration and applying an external force over at least part of the plates; and analyzing the sample in the layer of uniform thickness while the plates are the closed configuration.
  • this method may comprise:
  • each plate has a sample contact surface that is substantially planar, one or both plates are flexible, and one or both of the plates comprise spacers that are fixed with a respective sample contacting surface, and wherein the spacers have:
  • conformable pressing either in parallel or sequentially, an area of at least one of the plates to press the plates together to a closed configuration, wherein the conformable pressing generates a substantially uniform pressure on the plates over the at least part of the sample, and the pressing spreads the at least part of the sample laterally between the sample contact surfaces of the plates, and wherein the closed configuration is a configuration in which the spacing between the plates in the layer of uniform thickness region is regulated by the spacers;
  • the filling factor is the ratio of the spacer contact area to the total plate area; wherein a conformable pressing is a method that makes the pressure applied over an area is substantially constant regardless the shape variation of the outer surfaces of the plates; and wherein the parallel pressing applies the pressures on the intended area at the same time, and a sequential pressing applies the pressure on a part of the intended area and gradually move to other area.
  • this method may comprise: removing the external force after the plates are in the closed configuration; imaging the section in the layer of uniform thickness while the plates are the closed configuration.
  • the inter-spacer distance may in the range of 20 urn to 200 urn or 5 urn to 20 urn.
  • the product of the filling factor and the Young's modulus of the spacer is 2 M Pa or larger.
  • the surface variation is less than 30 nm.
  • the imaging and counting may be done by: i. illuminating the section in the layer of uniform thickness; ii. taking one or more images of the section using a CCD or CMOS sensor.
  • the external force may be provided by human 5 hand, e.g. , by pressing down using a digit such as a thumb, or pinching between a thumb and another digit such as a forefinger on the same hand.
  • one or more of the plates may comprises a dry reagent coated on one or both plates (e.g. , a binding agent, a staining agent, a detection agent or an assay reactant).
  • a dry reagent coated on one or both plates e.g. , a binding agent, a staining agent, a detection agent or an assay reactant.
  • the layer of uniform thickness sample may a thickness uniformity of up to +1-5%, e.g., up to +1-2% or up to +/-1 %.
  • the spacers are pillars with a cross-sectional shape selected from round, polygonal, circular, square, rectangular, oval, elliptical, or any combination of the same. F-6. Examples of Present Invention
  • a device for analyzing a tissue sample comprising:
  • the plates are movable relative to each other into different configurations; ii. one or both plates are flexible; iii. each of the plates has, on its respective inner surface, a sample contact area for contacting a staining liquid and/or a tissue sample suspected of containing a target analyte; iv. one or both of the plates comprise the spacers that are fixed with a
  • the spacers have a predetermined substantially uniform height and a predetermined inter-spacer distance; and vi. at least one of the spacers is inside the sample contact area; wherein one of the configurations is an open configuration, in which: the two plates are partially or entirely separated apart, the spacing between the plates is not regulated by the spacers, and the staining liquid and the sample are deposited on one or both of the plates;
  • another of the configurations is a closed configuration, which is configured after the deposition of the staining liquid and the sample in the open configuration, and in the closed configuration: at least part of the sample is between the two plates and a layer of at least part of staining liquid is between the at least part of the sample and the second plate, wherein the thickness of the at least part of staining liquid layer is regulated by the plates, the sample, and the spacers, and has an average distance between the sample surface and the second plate surface is equal or less than 250 ⁇ with a small variation.
  • a device for analyzing a tissue sample comprising:
  • the plates are movable relative to each other into different configurations; ii. one or both plates are flexible; iii. each of the plates has, on its respective inner surface, a sample contact area for contacting a transfer solution and/or a tissue sample suspected of containing a target analyte; iv. one or both of the plates comprise stain agent that is dried on the
  • one or both of the plates comprise the spacers that are fixed with a
  • the spacers have a predetermined substantially uniform height and a predetermined inter-spacer distance; and vii. at least one of the spacers is inside the sample contact area; wherein one of the configurations is an open configuration, in which: the two plates are partially or entirely separated apart, the spacing between the plates is not regulated by the spacers, and the staining liquid and the sample are deposited on one or both of the plates;
  • another of the configurations is a closed configuration, which is configured after the deposition of the staining liquid and the sample in the open configuration, and in the closed configuration: at least part of the sample is between the two plates and a layer of at least part of transfer solution is between the at least part of the sample and the second plate, wherein the thickness of the at least part of transfer solution layer is regulated by the plates, the sample, and the spacers, and has an average distance between the sample surface and the second plate surface is equal or less than 250 ⁇ with a small variation.
  • a method for analyzing a tissue sample comprising the steps of:
  • the plates are movable relative to each other into different configurations; ii. one or both plates are flexible; iii. each of the plates has, on its respective inner surface, a sample contact area for contacting the staining liquid and/or the tissue sample; iv. one or both of the plates comprise the spacers that are fixed with a
  • the spacers have a predetermined substantially uniform height and a predetermined inter-spacer distance; and vi. at least one of the spacers is inside the sample contact area; (c) depositing the staining liquid and the tissue sample on one or both of the plates when the plates are in an open configuration,
  • the open configuration is a configuration in which the two plates are partially or entirely separated apart, the spacing between the two plates is not regulated by the spacers, and the sample and the staining liquid are deposited on one or both of the plates;
  • the pressing comprises conformable pressing, either in parallel or sequentially, an area of at least one of the plates to press the plates together to the closed configuration, wherein the conformable pressing generates a substantially uniform pressure on the plates over the at least part of the sample, and the pressing spreads the at least part of the sample laterally between the inner surfaces of the plates;
  • another of the configurations is the closed configuration, which is configured after the deposition of the staining liquid and the sample in the open configuration, and in the closed configuration: at least part of the sample is between the two plates and a layer of at least part of staining liquid is between the at least part of the sample and the second plate, wherein the thickness of the at least part of staining liquid layer is regulated by the plates, the sample, and the spacers, and has an average distance between the sample surface and the second plate surface is equal or less than 250 ⁇ with a small variation;
  • a method for analyzing a tissue sample comprising the steps of:
  • the plates are movable relative to each other into different configurations; ii. one or both plates are flexible; iii. each of the plates has, on its respective inner surface, a sample contact area for contacting a staining liquid and/or a tissue sample suspected of containing a target analyte; iv. one or both of the plates comprise stain agents that are coated on the respective sample contact area and configured to, upon contacting a transfer solution, dissolve in the transfer solution and stain the tissue sample; v. one or both of the plates comprise the spacers that are fixed with a
  • the spacers have a predetermined substantially uniform height and a predetermined inter-spacer distance; and vii. at least one of the spacers is inside the sample contact area;
  • the open configuration is a configuration in which the two plates are partially or entirely separated apart, the spacing between the two plates is not regulated by the spacers, and the sample and the staining liquid are deposited on one or both of the plates;
  • the pressing comprises conformable pressing, either in parallel or sequentially, an area of at least one of the plates to press the plates together to the closed configuration, wherein the conformable pressing generates a substantially uniform pressure on the plates over the at least part of the sample, and the pressing spreads the at least part of the sample laterally between the inner surfaces of the plates;
  • another of the configurations is the closed configuration, which is configured after the deposition of the staining liquid and the sample in the open configuration, and in the closed configuration: at least part of the sample is between the two plates and a layer of at least part of staining liquid is between the at least part of the sample and the second plate, wherein the thickness of the at least part of staining liquid layer is regulated by the plates, the sample, and the spacers, and has an average distance between the sample surface and the second plate surface is equal or less than 250 ⁇ with a small variation;
  • the device of embodiment FA1 wherein one or both of the plates is configured such that the sample can dried thereon at the open configuration, and wherein the sample comprises bodily fluid selected from the group consisting of: amniotic fluid, aqueous humour, vitreous humour, blood (e.g., whole blood, fractionated blood, plasma or serum), breast milk, cerebrospinal fluid (CSF), cerumen (earwax), chyle, chime, endolymph, perilymph, feces, breath, gastric acid, gastric juice, lymph, mucus (including nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, exhaled breath condensates, sebum, semen, sputum, sweat, synovial fluid, tears, vomit, urine, and any combination thereof.
  • bodily fluid selected from the group consisting of: amniotic fluid, aqueous humour, vitreous humour
  • the staining liquid has a viscosity in the range of 0.1 to 3.5 mPa S. FA3.
  • the sample contact area of one or both of the plates is configured such that the sample can dried thereon at the open configuration, and wherein the sample comprises blood smear and is dried on one or both plates.
  • the sample contact area of one or both of the plates is adhesive to the sample, and wherein the sample is a tissue section having a thickness in the range of 1 - 200 urn.
  • FA5. The device of embodiment FA4, wherein the sample is paraffin-embedded.
  • FA6. The device of any of embodiment, wherein the sample is fixed.
  • the staining liquid comprises fixative capable of fixing the sample.
  • the staining liquid comprises blocking agents, wherein the blocking agents are configured to disable non-specific endogenous species in the sample to react with detection agents that are used to specifically label the target analyte.
  • the staining liquid comprises deparaffinizing agents capable of removing paraffin in the sample.
  • permeabilizing agents capable of permeabilizing cells in the tissue sample that contain the target analyte.
  • the staining liquid comprises antigen retrieval agents capable of facilitating retrieval of antigen.
  • the staining liquid comprises detection agents that specifically label the target analyte in the sample.
  • sample contact area of one or both plates comprise a storage site that contains blocking agents, wherein the blocking agents are configured to disable non-specific endogenous species in the sample to react with detection agents that are used to specifically label the target analyte.
  • sample contact area of one or both plates comprise a storage site that contains permeabilizing agents capable of permeabilizing cells in the tissue sample that contain the target analyte.
  • sample contact area of one or both plates comprise a storage site that contains antigen retrieval agents capable of facilitating retrieval of antigen.
  • sample contact area of one or both plates comprise a storage site that contains detection agents that specifically label the target analyte in the sample.
  • the detection agent comprises dyes for a stain selected from the group consisting of: Acid fuchsin, Alcian blue 8 GX, Alizarin red S, Aniline blue WS, Auramine O, Azocarmine B, Azocarmine G, Azure A, Azure B, Azure C, Basic fuchsine, Bismarck brown Y, Brilliant cresyl blue, Brilliant green, Carmine, Chlorazol black E, Congo red, C.I.
  • the detection agent comprises antibodies configured to specifically bind to protein analyte in the sample.
  • the detection agent comprises oligonucleotide probes configured to specifically bind to DNA and/or RNA in the sample.
  • the detection agent is labeled with a reporter molecule, wherein the reporter molecule is configured to provide a detectable signal to be read and analyzed.
  • luminescence selected from photoluminescence, electroluminescence, and
  • electrochemiluminescence ii. light absorption, reflection, transmission, diffraction, scattering, or diffusion; iii. surface Raman scattering; iv. electrical impedance selected from resistance, capacitance, and inductance; v. magnetic relaxivity; and vi. any combination of i-v. FA23.
  • the sample contact area of one or both of the plates comprise a binding site that contains capture agents, wherein the capture agents are configured to bind to the target analyte on the surface of cells in the sample and immobilize the cells.
  • the depositing step (c) comprises depositing and drying the sample on one or both of the plates before depositing the remaining of the staining liquid on top of the dried sample, and wherein the sample comprises bodily fluid selected from the group consisting of: amniotic fluid, aqueous humour, vitreous humour, blood (e.g., whole blood, fractionated blood, plasma or serum), breast milk, cerebrospinal fluid (CSF), cerumen (earwax), chyle, chime, endolymph, perilymph, feces, breath, gastric acid, gastric juice, lymph, mucus (including nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, exhaled breath condensates, sebum, semen, sputum, sweat, synovial fluid, tears, vomit, urine, and any combination thereof.
  • bodily fluid selected from the group consisting of: amniotic fluid, aqueous
  • the depositing step (c) comprises depositing and drying the sample on one or both of the plates before depositing the remaining of the staining liquid on top of the dried sample, and wherein the sample comprises blood smear and is dried on one or both plates.
  • the depositing step (c) comprises depositing and attaching the sample to one or both of the plates before depositing the staining liquid on top of the sample, wherein the sample contact area of one or both of the plates is adhesive to the sample, and wherein the sample is a tissue section having a thickness in the range of 1 - 200 Dm.
  • FB5. The device of embodiment FA4, wherein the sample is paraffin-embedded.
  • FB6 The method of any of embodiment, wherein the sample is fixed.
  • the staining liquid comprises fixative capable of fixing the sample.
  • the staining liquid comprises blocking agents, wherein the blocking agents are configured to disable non-specific endogenous species in the sample to react with detection agents that are used to specifically label the target analyte.
  • permeabilizing agents capable of permeabilizing cells in the tissue sample that contain the target analyte.
  • the staining liquid comprises antigen retrieval agents capable of facilitating retrieval of antigen.
  • the staining liquid comprises detection agents that specifically label the target analyte in the sample.
  • FB13 The method of any prior embodiment, wherein the sample contact area of one or both plates comprise a storage site that contains blocking agents, wherein the blocking agents are configured to disable non-specific endogenous species in the sample to react with detection agents that are used to specifically label the target analyte.
  • FB14 The method of any prior embodiment, wherein the sample contact area of one or both plates comprise a storage site that contains deparaffinizing agents capable of removing paraffin in the sample.
  • sample contact area of one or both plates comprise a storage site that contains permeabilizing agents capable of permeabilizing cells in the tissue sample that contain the target analyte.
  • sample contact area of one or both plates comprise a storage site that contains antigen retrieval agents capable of facilitating retrieval of antigen.
  • sample contact area of one or both plates comprise a storage site that contains detection agents that specifically label the target analyte in the sample.
  • the detection agent comprises dyes for a stain selected from the group consisting of: Acid fuchsin, Alcian blue 8 GX, Alizarin red S, Aniline blue WS, Auramine O, Azocarmine B, Azocarmine G, Azure A, Azure B, Azure C, Basic fuchsine, Bismarck brown Y, Brilliant cresyl blue, Brilliant green, Carmine, Chlorazol black E, Congo red, C.I.
  • the detection agent comprises oligonucleotide probes configured to specifically bind to DNA and/or RNA in the sample.
  • FB21 The method of any prior embodiment, wherein the detection agent is labeled with a reporter molecule, wherein the reporter molecule is configured to provide a detectable signal to be read and analyzed.
  • FB22 The device of embodiment FB21 , wherein the signal is selected from the group consisting of:
  • luminescence selected from photoluminescence, electroluminescence, and
  • electrochemiluminescence ii. light absorption, reflection, transmission, diffraction, scattering, or diffusion; iii. surface Raman scattering; iv. electrical impedance selected from resistance, capacitance, and inductance; v. magnetic relaxivity; and vi. any combination of i-v.
  • sample contact area of one or both of the plates comprise a binding site that contains capture agents, wherein the capture agents are configured to bind to the target analyte on the surface of cells in the sample and immobilize the cells.
  • step (e) further comprising: incubating the sample at the closed configuration for a period of time that is longer than the time it takes for the detection agent to diffuse across the layer of uniform thickness and the sample.
  • step (e) further comprising: incubating the sample at the closed configuration at a predetermined temperature in the range of 30 - 75 °C.
  • the staining liquid comprises the transfer solution.
  • Dual camera imaging system is more and more common on state-of-art smartphones, which offers more possibilities of smartphone based imaging.
  • two cameras two different areas of the sample can be imaged at the same time, which is equivalent to a much larger field of view.
  • each camera can be used to do microscopy imaging at a different resolution.
  • one camera can do microscopy with lower resolution but larger field of view to image large objects in sample and the other camera can do microscopy with higher resolution but smaller field of view to image small objects. This is useful when the sample for imaging has mixed small objects and large objects.
  • FIG. 19-A is the schematic illustration of the dual camera imaging system.
  • the dual camera imaging system comprises a mobile computing device (e.g. smartphone) having two built- in camera modules, two external lenses, a QMAX device and light source. Each camera module has an internal lens and an image sensor.
  • the QMAX device is located under the two camera modules.
  • Each external lens is placed between QMAX device and its corresponding internal lens at the appropriate height where the sample in QMAX device can be clearly focused on the image sensor.
  • Each external lens is aligned with its corresponding internal lens.
  • the light captured by the imaging sensor can be refracted from the specimen, emitted from the specimen, etc.
  • the light captured by the imaging sensor covers visible wavelength and can illuminate on the sample in QMAX device from back or top side in a normal or oblique incidence angle.
  • One embodiment is that the dual camera imaging system is used for large FOV imaging.
  • the images taken by both camera have the same scale or optical magnification.
  • the focal length of external lens 1 ⁇ , the focal length of internal lens 1 frn, the focal length of external lens 2 fE2 and the focal length of internal lens 2 fN2 satisfy
  • the distance between two cameras is chosen to an appropriate value so that the FOVs of both cameras have overlap.
  • the letter "A” represents the sample, due to the overlap between the FOVs of two cameras, some part of the letter "A” exist in both the FOV of camera 1 and FOV of camera 2.
  • a further image processing step is used to merge the two images into one large image by matching the same feature shared by the two images taken by camera 1 and camera 2.
  • Dual camera imaging system for dual resolution imaging is used to merge the two images into one large image by matching the same feature shared by the two images taken by camera 1 and camera 2.
  • the lens-based imaging system has the intrinsic drawback that it has the trade-off between the size of FOV and resolution.
  • the resolution of the imaging system need to be sacrificed. This problem is more concerned when the sample has mixed small and large objects with significant different size scale.
  • the FOV need to be large enough, but that will lose the resolution to get the details of the small objects.
  • the dual camera imaging system is used for achieve dual resolution imaging on a same sample, in which camera 1 (or 2) is used for low resolution and large FOV imaging and camera 2 ( or 1) is used for high resolution and small FOV imaging.
  • the resolution of the imaging system depends on the optical magnification and the optical magnification is equal to the ratio of the focal length of the external lens to the focal length of the internal length.
  • camera 1 is used for low resolution imaging and camera 2 is used for high resolution imaging, then the focal length of external lens 1 ⁇ , the focal length of internal lens 1 fm, the focal length of external lens 2 fE2 and the focal length of internal
  • lens 2 fN2 satisfy the relationship:— ⁇ —
  • the FOVs of both cameras can have overlap or no overlap.
  • the sample image taken by camera 1 covers larger FOV and contains more objects in a single FOV but cannot resolve the detail of the small objects.
  • the image taken by camera 2 covers a relatively small FOV and contains fewer objects in a single FOV but has higher resolution that can resolve the details in the small objects.
  • a dual lens imaging device comprising:
  • the housing unit is configured to accommodate the first and second external lenses and the card unit, and to connect the dual length imaging device with a mobile device;
  • the first and the second external lenses are configured to respectively align with two internal lenses in the mobile device;
  • the card unit is configured to accommodate a specimen card, which contains a sample
  • the card unit is positioned between the external lenses and the internal lenses
  • the external lenses are configured to focus illuminating light that is refracted or emitted from the specimen card onto image sensors in the mobile device, allowing the image sensors to capture images of the sample.
  • a dual lens imaging system comprising:
  • the dual lens imaging device of embodiment A1 (a) the dual lens imaging device of embodiment A1 , (b) the mobile device, which comprises hardware and software to capture and process images of the sample through the dual lens imaging device.
  • specimen card is a QMAX card.
  • the device or system of any prior embodiments, wherein the mobile device is a mobile communication device.
  • the mobile device comprises a light source, which provides light to the specimen card.
  • C10 The device or system of any prior embodiment, wherein the two external lenses are configured to image two different locations of a sample area of the Q-Card.
  • C1 1. The device or system of any prior embodiment, wherein the two external lenses are configured to have different size of FoV (field of view from each other).
  • the two external lenses are configured to have different size of FoV (field of view from each other), and wherein the ratio of the two different of FoV is 1.1 , 1.2, 1.5, 2, 5, 10, 15, 20, 30, 50, 100, 200, 1000, or in a range of any value of the two.
  • a preferred ratio is 1.2, 1.5, 2, 5, 10, 20, or in a range of any value of the two.
  • C13 The device or system of any prior embodiment, wherein overlap of FoV of the two external lenses are configured to be around 1 %, 5%, 10%, 20%, 50%, 60%, 70%, 80%, 90%, or a range between any two of these values.
  • An optical adaptor for imaging an sample using a hand-held imaging device that has a light source, a single camera, and a computer processor, comprising:
  • the lever comprises at least one optical element and is configured to be moveable between a first position and a second position, wherein (i) in the first position, said imaging device is capable of imaging a sample in a bright field mode, and (ii) in the second position, said imaging device is capable of imaging the sample in a fluorescence excitation mode.
  • a lens arranged to provide a field of view for the camera; a cavity within the enclosure for receiving the sample and positioning the sample within the field of view of the camera, wherein the lens is positioned to receive light refracted by or emitted by the sample when in the field of view of the camera;
  • the lever comprises at least one optical element and is configured to be moveable between a first position and a second position, wherein (i) in the first position, said imaging device is capable of imaging a sample in a bright field mode, and (ii) in the second position, said imaging device is capable of imaging the sample in a fluorescence excitation mode.
  • An optical adaptor for imaging an sample using a hand-held imaging device that has a light source, a single camera, and a computer processor, comprising:
  • the lever comprises at least one optical element and is configured to be moveable between a first position and a second position, wherein (i) in the first position, said imaging device is capable of imaging a sample in a bright field mode, and (ii) in the second position, said imaging device is capable of imaging the sample in a fluorescence excitation mode, and
  • the lever comprises a first planar region extending along a first plane and a second planar region laterally displaced along a first direction from the first planar region and extending along a second plane, the first plane being disposed at a different height along a second direction from the second plane, the second direction being orthogonal to the first direction.
  • An optical adaptor for imaging an sample using a hand-held imaging device that has a light source, a single camera, and a computer processor, comprising:
  • the lever comprises at least one optical element and is configured to be moveable between a first position and a second position, wherein (i) in the first position, said imaging device is capable of imaging a sample in a bright field mode, and (ii) in the second position, said imaging device is capable of imaging the sample in a fluorescence excitation mode, and
  • the lever comprises a first planar region extending along a first plane and a second planar region laterally displaced along a first direction from the first planar region and extending along a second plane, the first plane being disposed at a different height along a second direction from the second plane, the second direction being orthogonal to the first direction, and
  • first planar region comprises at least one optical element
  • second planar region comprises at least one optical element
  • An optical adaptor for imaging an sample using a hand-held imaging device that has a light source, a single camera, and a computer processor, comprising:
  • the lever comprises at least one optical element and is configured to be moveable between at least three different positions, wherein (i) in a first position, said imaging device is capable of imaging a sample in a bright field mode, (ii) in a second position, said imaging device is capable of imaging the sample in a fluorescence excitation mode, and (iii) in a third position, said imaging device is capable of measuring optical absorption of the sample.
  • a lens configured to provide a field of view for the camera
  • a cavity within the enclosure for receiving the sample and positioning the sample within the field of view of the camera;
  • an aperture within the enclosure wherein the aperture is arranged to receive source light from the light source for illuminating the sample
  • a lever within the cavity wherein the lever comprises at least one optical element and is configured to be moveable between a first position and a second position, wherein (i) in a first position, said imaging device is capable of imaging a sample in a bright field mode, (ii) in a second position, said imaging device is capable of imaging the sample in a fluorescence excitation mode, wherein in the fluorescence excitation mode, the lens is arranged to receive light emitted by the sample when the sample is illuminated by the source light.
  • An optical adaptor for imaging an sample using a smart phone that has a light source, a single camera, and a computer processor, comprising:
  • a lens configured to provide a field of view for the camera
  • the lever comprises at least one optical element and is configured to be moveable between a first position and a second position, wherein (i) in a first position, said imaging device is capable of imaging a sample in a bright field mode, and (ii) in a second position, said imaging device is capable of imaging the sample in a fluorescence excitation mode.
  • a lens configured to provide a microscopic field of view for the camera
  • the moveable arm within the cavity, wherein the moveable arm is configurable to switch between a first position and a second position, wherein when the moveable arm is in the first position, the optical assembly is in a bright field mode, and when the moveable arm is in the second position, the optical assembly is in a fluorescence excitation mode.
  • the enclosure comprises:
  • the optical assembly of embodiments further comprising a first set of one or more optical elements arranged to receive light entering from a first aperture in the enclosure corresponding to the light source and to redirect the light entering from the first aperture along a first pathway toward a second aperture in the enclosure corresponding to the camera to provide bright field illumination of the sample when the moveable arm is in the first position.
  • the first set of one or more optical elements comprises a first right angle mirror and a second right angle mirror, wherein the first right angle mirror and the second right angle mirror are in the first pathway and are arranged to reflect the light from the light source to be normally incident into the camera,
  • the optical assembly of embodiments wherein the light source is a point source to achieve interference imaging of transparent samples via illuminating the sample by a same wavefront.
  • the optical assembly of embodiments further comprising a second set of one or more optical elements mechanically coupled to the movable arm and arranged to receive light entering from the first aperture and redirect the light entering from the first aperture along a second pathway to obliquely illuminate the sample to provide fluorescence illumination of the sample when the moveable arm is in the second position,
  • the second set of one or more optical elements includes a mirror and an optical absorber, wherein the mirror reflects light to obliquely illuminate the sample and the optical absorber absorbs extraneous light from the first aperture that would otherwise pass through the second aperture of the enclosure and overwhelm the camera in the fluorescence excitation mode.
  • the absorber absorbs light that is not incident on the mirror after going through the first aperture, wherein the light absorber is a thin- film light absorber.
  • optical assembly of embodiments further comprising a third set of one or more optical elements arranged to receive light entering from the first aperture and redirect the light entering into the second aperture in the movable arm and going along the first pathway toward a light diffuser on the movable arm to illuminate the sample in normal direction to measure the optical absorption of the sample.
  • the third set of one or more optical elements includes a light diffuser, a first right angle mirror and a second right angle mirror, wherein the first right angle mirror and the second right angle mirror are in the first pathway and are arranged to reflect the light from the light source toward the light diffuser and then to be normally incident into the camera;
  • the optical assembly of embodiments wherein the light diffuser is a semi-opaque diffuser with opacity in the range of 10% to 90%.
  • the optical assembly of embodiments further comprising a rubber door to cover the sample receptacle to prevent ambient light from entering into the cavity.
  • a system comprising: the optical assembly of any of the preceding any embodiments, and
  • a mobile phone attachment comprising a first side configured to couple to the optical assembly and a second opposite side configured to couple to the hand-held electronic device, wherein the hand-held electronic device is a mobile phone.
  • the mobile phone attachment is exchangeable to provide attachment to different sized mobile phones.
  • a size of the mobile phone attachment is adjustable.
  • optical assembly for a hand-held mobile electronic device, the optical assembly comprising:
  • the plurality of optical elements are arranged to receive light entering from a first aperture in the enclosure and to redirect the light entering from the first aperture along a first pathway toward a second aperture in the enclosure;
  • a moveable arm configurable in at least two different positions within the enclosure, a moveable arm configurable in at least three different positions within the enclosure,
  • the moveable arm comprises a light reflector portion to reflect light
  • the moveable arm comprise a light diffuser to homogenize the light and break the coherence of the light
  • the moveable arm comprise an aperture aligned with the entrance aperture in the enclosure
  • the light reflector portion when the moveable arm is in a first position within the enclosure, the light reflector portion is positioned between an entrance aperture in the enclosure and the plurality of optical elements such that the light reflector portion blocks the light entering from the first opening from being incident on the plurality of optical elements, and
  • optical assembly comprising a slot on a side of the enclosure, wherein the slot is arranged to receive a sample substrate such that:
  • the first pathway intersects the sample substrate; and when the sample substrate is fully inserted within the slot and moveable arm is in the first position within the enclosure, light reflected by the light reflector portion is redirected to the sample substrate;
  • the moveable arm comprises a light absorber portion to absorb light that is not incident on the mirror after going through the first aperture.
  • the moveable arm comprises: a first receptacle positioned above the light reflector portion;
  • optical filter seated in the receptacle when the moveable arm is in the first position, the optical filter seated in the receptacle is positioned to receive light entering from the first aperture in the enclosure; and when the moveable arm is in the third position, the optical filter seated in the receptacle is positioned to receive light entering from the first aperture in the enclosure.
  • optical filter seated in the receptacle overlaps a region in which a portion of the sample substrate is located when the sample substrate is fully inserted within the slot.
  • a system comprising:
  • a mobile phone attachment comprising a first side configured to couple to the optical assembly and comprising a second opposite side configured to couple to a mobile phone, wherein a size of the mobile phone attachment is adjustable.
  • An optical assembly attachable to a hand-held electronic device having a light source, a camera, and a computer processor, wherein the optical assembly is configured to enable microscopic imaging of a sample by the camera with illumination of the sample by light from the light source, the optical assembly comprising:
  • a lens configured to provide a microscopic field of view for the camera
  • a receptacle for receiving the sample and positioning the sample within the microscopic field of view
  • an optical fiber configured to receive the light from the light source and to illuminate the receptacle.
  • optical assembly of any embodiments wherein, when the optical assembly is attached to the hand-held electronic device, the lens and the camera define an optical axis, and wherein the optical fiber circumscribes the optical axis.
  • optical assembly of any embodiments wherein the optical fiber is a side-emitting fiber.
  • optical assembly of any embodiments wherein the optical assembly comprises an enclosure defining the receptacle, wherein the ring-shaped fiber sits in a groove of the enclosure, wherein the enclosure comprises an aperture configured to align with the light source and both end faces of the ring-shape fiber to receive light from the light source.
  • the light emits from the side of the ring-shape fiber to illuminate the sample area right under the camera in the optical axis.
  • the optical assembly comprises an enclosure defining the receptacle, wherein the enclosure comprises a first aperture configured to align with the light source, and a first end face of the optical fiber is positioned in the first aperture to receive light from the light source.
  • the enclosure comprises a second aperture configured to align with the camera, and wherein the optical fiber comprises a first end positioned in the first aperture and comprises a second end positioned in the second aperture.
  • at least one of the first end face of the optical fiber and a second end face of the optical fiber is matted.
  • optical assembly of any embodiments wherein when the optical assembly is attached to the hand-held electronic device, the optical fiber is tilted with respect to the light source, and
  • a second end face of the optical fiber is arranged to illuminate a region of the sample located directly beneath the lens.
  • optical assembly of any embodiments wherein the optical assembly comprises an enclosure defining the receptacle, the enclosure comprises a groove, and the optical fiber is arranged in the groove.
  • a lens configured to provide a microscopic field of view for the camera
  • a receptacle for receiving the sample and positioning the sample within the microscopic field of view
  • a wavelength filter positioned between the sample and the camera to pass fluorescence emitted by the sample in response to the oblique illumination.
  • optical assembly of any embodiments wherein the lens is positioned on a front-side of the sample and the mirror is positioned to obliquely illuminate the sample from a back-side of the sample, wherein the oblique angle is larger than a collecting angle of the lens.
  • the optical assembly of any embodiments further comprising an optical absorber positioned on the optical axis adjacent the mirror to absorb light from the light source not reflected by the mirror.
  • any of the preceding any embodiments wherein the sample is supported by a sample holder comprising a planar structure, and wherein the receptacle is configured to position the planar structure to extend partially into a path of illumination light from the light source to couple illumination light into the planar structure.
  • the receptacle is configured to position the planar structure such that the path of illumination light is incident on an edge of the planar structure, wherein the edge extends along a plane that is normal to a plane comprising the field of view.
  • the optical assembly of any embodiments wherein the mirror is arranged to reflect the light to partially obliquely illuminate the sample from a back side of the planar structure and to partially illuminate an edge of the planar structure to couple illumination light into the planar structure.
  • the optical assembly of any embodiments further comprising a rubber door to cover the sample receptacle to prevent ambient light from entering the optical assembly and entering the camera.
  • the optical assembly of any embodiments, wherein the planar structure is configured to waveguide the coupled illumination light to the sample to illuminate the sample and cause the sample to emit fluorescence.
  • the optical assembly of any embodiments further comprising the sample holder, The optical assembly of any embodiments 6, wherein the sample is a liquid sample and the sample holder comprises first and second plates sandwiching the liquid sample.
  • the optical assembly of any embodiments, wherein the light source and the camera are positioned on the same side of the hand-held electronic device and at fixed distance to one another.
  • the hand-held electronic device is a smart phone.
  • An apparatus comprising the optical assembly of any of the preceding any embodiments and the hand-held electronic device.
  • a lens configured to provide a microscopic field of view for the camera
  • a receptacle for receiving the sample and positioning the sample within the microscopic field of view
  • the sample is supported by a sample holder comprising a planar structure, and wherein the receptacle is configured to position the planar structure to extend partially into a path of illumination light from the light source to couple illumination light into the planar structure and cause the sample to emit fluorescence;
  • a wavelength filter positioned between the sample and the camera to pass fluorescence emitted by the sample in response to the illumination.
  • the optical assembly of any embodiments further comprising a rubber door to cover the sample receptacle to prevent ambient light entering the optical assembly through the receptacle.
  • planar structure is configured to waveguide the coupled illumination light to the sample to illuminate the sample and cause the sample to emit the fluorescence.
  • optical assembly of any embodiments further comprising the sample holder,
  • sample is a liquid sample and the sample holder comprises first and second plates sandwiching the liquid sample.
  • optical assembly of any embodiments further comprising a second wavelength filter positioned in the path of the illumination light between the light source and the portion of the sample holder partially extending into the path of the light.
  • optical assembly of any of the preceding any embodiments, wherein the lens, the receptacle, and the wavelength filter are supported in a common optical box and further comprising an exchangeable holder frame for attaching the optical box to the hand-held electronic device.
  • optical assembly of any embodiments wherein the light source and the camera are positioned on the same side of the hand-held electronic device at a fixed distance to one another.
  • the hand-held electronic device is a smart phone.
  • An apparatus comprising the optical assembly of any of the preceding any embodiments and the hand-held electronic device.
  • a first assembly lens configured to provide a first microscopic field of view for the first camera module
  • a second assembly lens configured to provide a second microscopic field of view for the second camera module
  • the first camera module comprises a first internal lens and the second camera module comprises a second internal lens, wherein a first optical magnification provided by the first assembly lens and the first internal lens is the same as a second optical magnification provided by the second assembly lens and the second internal lens.
  • a first ratio of a focal length of the first assembly lens to a focal length of the first internal lens is equal to a second ratio of a focal length of the second assembly lens to a focal length of the second internal lens.
  • a first image resolution provided by the first camera module and the first assembly lens is the same as a second image resolution provided by the second camera module and the second assembly lens.
  • the first camera module comprises a first internal lens and the second camera module comprises a second internal lens, wherein a first optical magnification provided by the first assembly lens and the first internal lens is different from a second optical magnification provided by the second assembly lens and the second internal lens.
  • a first ratio of a focal length of the first assembly lens to a focal length of the first internal lens is less than a second ratio of a focal length of the second assembly lens to a focal length of the second internal lens.
  • a first image resolution provided by the first camera module and the first assembly lens is less than a second image resolution provided by the second camera module and the second assembly lens.
  • optical assembly of any embodiments wherein an amount of overlap of the first microscopic field of view with the second microscopic field of view is between 1 % and 90%.
  • each of the first assembly lens and the second assembly lens is arranged to receive light scattered by or emitted by the sample.
  • a ratio of the angular field of view of the first assembly lens to the angular field of the second assembly lens is between 1.1 and 1000.
  • optical assembly of any of the preceding any embodiments comprising:
  • a first optical filter arranged in a first illumination path to or from the first assembly lens
  • the first optical filter is configured to filter a first range of wavelengths
  • the second optical filter is configured to filter a second range of wavelengths
  • the first range of wavelengths is different from the second range of wavelengths.
  • optical assembly of any of the preceding any embodiments comprising:
  • first polarizer arranged in a first illumination path to or from the first assembly lens
  • second polarizer arranged in a second illumination path to or from the second assembly lens
  • first polarizer and the second polarizer have different polarization dependent light transmission and blocking properties.
  • An apparatus comprising the optical assembly of any of the preceding any embodiments and the hand-held electronic device.
  • the hand-held electronic device is a smart phone.
  • the hand-held electronic device is configured to computationally merge a first image obtained from the first camera module with a second image obtained from the second camera module.
  • An imaging method comprising:
  • each image corresponds to a different object plane within a thickness of the sample
  • the determined information about the corresponding object plane comprises a depth and an orientation of the object plane relative to imaging system.
  • the imaging method of any of the preceding any embodiments, where the computational analyzing of each image comprises determining a degree of defocus of one or more of the reference marks.
  • the imaging method of any embodiments, where the computational analyzing of each image comprises determining a depth for each of multiple ones of the reference marks based on a degree of defocus for each such reference mark and determining a depth and an orientation of the corresponding object plane relative to the imaging system based on the determined depths of the reference marks.
  • references marks are not rotationally symmetric with respect to an axis perpendicular to at least one of the plates.
  • each image comprises determining a rotational orientation of one or more of the reference marks about the axis relative to the imaging system.
  • the imaging method of any embodiments, wherein the a priori knowledge about the reference marks is based on one or more of a shape of each reference mark and a location of each reference mark relative to the plates.
  • the imaging method of any of the preceding any embodiments wherein the acquiring of the multiple images comprises moving one or more components of the imaging system relative to the plates sandwiching the sample.
  • the imaging method of any embodiments, wherein the processing of each acquired image to remove out-of-focus features comprises using a band-pass filter.
  • An imaging apparatus comprising:
  • an imaging system comprising a camera and at least one lens
  • a sample holder for supporting a sample cartridge relative to the imaging system, the sample cartridge comprising two plates are separated from one another by an array of spacers, at least one of which has a reference mark, wherein a sample to be imaged is configured to be compressed between the two plates;
  • a processing and control system coupled to the sample holder and the camera and configured to acquire multiple images of the sample using the imaging system, wherein each image corresponds to a different object plane within a thickness of the sample, and
  • processing and control system is further configured to:
  • the determined information about the corresponding object plane comprises a depth and an orientation of the object plane relative to imaging system.
  • the computational analyzing of each image comprises determining a depth for each of multiple ones of the reference marks based on a degree of defocus for each such reference mark and determining a depth and an orientation of the corresponding object plane relative to the imaging system based on the determined depths of the reference marks.
  • the references marks are not rotationally symmetric with respect to an axis perpendicular to at least one of the plates.
  • the computational analyzing of each image comprises determining a rotational orientation of one or more of the reference marks about the axis relative to the imaging system.
  • the a priori knowledge about the reference marks is based on one or more of a shape of each reference mark and a location of each reference mark relative to the plates.
  • the spacers are pillars.
  • control system is configured to move one or more components of the imaging system relative to the plates sandwiching the sample to acquire the multiple images.
  • each acquired image to remove out-of-focus features comprises using a band-pass filter.
  • the present invention includes a variety of embodiments, which can be combined in multiple ways as long as the various components do not contradict one another.
  • the embodiments should be regarded as a single invention file: each filing has other filing as the references and is also referenced in its entirety and for all purpose, rather than as a discrete independent. These embodiments include not only the disclosures in the current file, but also the documents that are herein referenced, incorporated, or to which priority is claimed.
  • CROF Card or card
  • COF Card or card
  • COF Card QMAX-Card
  • Q-Card CROF device
  • COF device COF device
  • QMAX-device CROF plates
  • COF plates COF plates
  • QMAX-plates are interchangeable, except that in some embodiments, the COF card does not comprise spacers; and the terms refer to a device that comprises a first plate and a second plate that are movable relative to each other into different configurations (including an open configuration and a closed configuration), and that comprises spacers (except some embodiments of the COF card) that regulate the spacing between the plates.
  • X-plate refers to one of the two plates in a CROF card, wherein the spacers are fixed to this plate. More descriptions of the COF Card, CROF Card, and X-plate are given in the provisional application serial nos. 62/456065, filed on February 7, 2017, which is incorporated herein in its entirety for all purposes.
  • the devices, systems, and methods herein disclosed can include or use Q-cards, spacers, and uniform sample thickness embodiments for sample detection, analysis, and quantification.
  • the Q-card comprises spacers, which help to render at least part of the sample into a layer of high uniformity.
  • the structure, material, function, variation and dimension of the spacers, as well as the uniformity of the spacers and the sample layer, are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No.
  • the devices, systems, and methods herein disclosed can include or use Q-cards for sample detection, analysis, and quantification.
  • the Q-card comprises hinges, notches, recesses, and sliders, which help to facilitate the manipulation of the Q card and the measurement of the samples.
  • the structure, material, function, variation and dimension of the hinges, notches, recesses, and sliders are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/426065, which was filed on February 8, 2017, US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can include or use Q-cards for sample detection, analysis, and quantification.
  • the Q-cards are used together with sliders that allow the card to be read by a smartphone detection system.
  • the structure, material, function, variation, dimension and connection of the Q-card, the sliders, and the smartphone detection system are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/426065, which was filed on February 8, 2017, US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the sample contact area of one or both of the plates comprises a compressed open flow monitoring surface structures (MSS) that are configured to monitoring how much flow has occurred after COF.
  • MSS comprises, in some embodiments, shallow square array, which will cause friction to the components (e.g. blood cells in a blood) in a sample.
  • the depth of the MSS can be 1/1000, 1/100, 1/100, 1/5, 1/2 of the spacer height or in a range of any two values, and in either protrusion or well form.
  • the devices, systems, and methods herein disclosed can include or be used in various types of detection methods.
  • the detection methods are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and
  • the devices, systems, and methods herein disclosed can employ various types of labels that are used for analytes detection.
  • the labels are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/426065, which was filed on February 8, 2017, US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can be applied to manipulation and detection of various types of analytes (including biomarkers).
  • the analytes and are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/426065, which was filed on February 8, 2017, US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can employ cloud technology for data transfer, storage, and/or analysis.
  • the related cloud technologies are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/426065, which was filed on February 8, 2017, US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • adapted and “configured” mean that the element, component, or other subject matter is designed and/or intended to perform a given function.
  • the use of the terms “adapted” and “configured” should not be construed to mean that a given element, component, or other subject matter is simply “capable of” performing a given function.
  • subject matter that is recited as being configured to perform a particular function may additionally or alternatively be described as being operative to perform that function.
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PCT/US2018/017504 2017-02-08 2018-02-08 Optics, device, and system for assaying WO2018148471A2 (en)

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Application Number Priority Date Filing Date Title
CN202310507084.7A CN116794819A (zh) 2017-02-08 2018-02-08 用于测定的光学器件、装置和系统
CN201880020973.8A CN111465882B (zh) 2017-02-08 2018-02-08 用于测定的光学器件、装置和系统
EP18751754.5A EP3580597A4 (en) 2017-02-08 2018-02-08 OPTICS, DEVICE AND SYSTEM FOR TESTING
US16/483,700 US10972641B2 (en) 2017-02-08 2018-02-08 Optics, device, and system for assaying
JP2019543054A JP7177073B2 (ja) 2017-02-08 2018-02-08 アッセイ用の光学系、デバイス、およびシステム
CA3053009A CA3053009A1 (en) 2017-02-08 2018-02-08 Optics, device, and system for assaying
EP18753608.1A EP3583423A4 (en) 2017-02-15 2018-02-15 FAST TEMPERATURE CHANGE TEST
JP2019544049A JP2020508043A (ja) 2017-02-15 2018-02-15 急速な温度変化を伴うアッセイ
CA3053295A CA3053295A1 (en) 2017-02-15 2018-02-15 Assay with rapid temperature change
CN201880024948.7A CN111194409A (zh) 2017-02-15 2018-02-15 采用快速温度变化的测定
PCT/US2018/018405 WO2018152351A1 (en) 2017-02-15 2018-02-15 Assay with rapid temperature change
US16/484,998 US20200078792A1 (en) 2017-02-15 2018-02-15 Assay with rapid temperature change
PCT/US2018/018521 WO2018152422A1 (en) 2017-02-16 2018-02-16 Assay with textured surface
CN201880025156.1A CN111448449A (zh) 2017-02-16 2018-02-16 采用纹理化表面的测定
US16/485,126 US11523752B2 (en) 2017-02-16 2018-02-16 Assay for vapor condensates
US16/485,347 US10966634B2 (en) 2017-02-16 2018-02-16 Assay with textured surface
CA3053301A CA3053301A1 (en) 2017-02-16 2018-02-16 Assay with textured surface
JP2019544634A JP7107953B2 (ja) 2017-02-16 2018-02-16 テクスチャ表面を用いたアッセイ
PCT/US2018/018520 WO2018152421A1 (en) 2017-02-16 2018-02-16 Assay for vapor condensates
US17/179,319 US11463608B2 (en) 2017-02-08 2021-02-18 Image-based assay using mark-assisted machine learning
US17/896,973 US20220407988A1 (en) 2017-02-08 2022-08-26 Image-Based Assay Using Mark-Assisted Machine Learning
US17/980,400 US20230077906A1 (en) 2017-02-16 2022-11-03 Assay for vapor condensates

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US201762456504P 2017-02-08 2017-02-08
US201762456598P 2017-02-08 2017-02-08
US201762456590P 2017-02-08 2017-02-08
US62/456,590 2017-02-08
US62/456,504 2017-02-08
US62/456,598 2017-02-08
US201762456904P 2017-02-09 2017-02-09
US201762457133P 2017-02-09 2017-02-09
US62/456,904 2017-02-09
US62/457,133 2017-02-09
US201762459554P 2017-02-15 2017-02-15
US62/459,554 2017-02-15
US201762460075P 2017-02-16 2017-02-16
US201762460062P 2017-02-16 2017-02-16
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PCT/US2018/017713 Continuation WO2018148607A1 (en) 2017-02-09 2018-02-09 Assay using different spacing heights
US17/179,319 Continuation US11463608B2 (en) 2017-02-08 2021-02-18 Image-based assay using mark-assisted machine learning

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