# US 9,436,866 B2 · High sensitivity flat panel microbiology detection and enumeration system

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- Number: US 9,436,866 B2
- Document ID: US9436866B2
- Status: Granted
- Kind: B2
- Application number: 14/449,916
- Filed: 2014-08-01
- Published: 2016-02-04
- Granted: 2016-09-06
- Earliest claimed: 2014-08-01
- Assignees: General Electric Company
- Applicants: General Electric Company
- Inventors: Aaron Judy Couture; Faisal Ahmed Syud; John Brian Hewgley; Yu Zhao
- Web page: https://patentgrep.com/patent/US9436866B2

## CPC

- G06V 20/69: Microscopic objects, e.g. biological cells or cellular parts
- G01N 15/1433: using image recognition
- G01N 15/1434: Optical arrangements
- G01N 21/255: {Details, e.g. use of specially adapted sources, lighting or optical systems}
- G01N 21/6456: {Spatial resolved fluorescence measurements; Imaging}
- G01N 21/76: Chemiluminescence; Bioluminescence
- G06T 7/0012: {Biomedical image inspection}
- G01N 2015/1006: {for cytology}
- G01N 2015/1486: {Counting the particles}
- G06T 2207/10056: Microscopic image
- G06T 2207/10064: Fluorescence image
- G06V: IMAGE OR VIDEO RECOGNITION OR UNDERSTANDING
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- G06T: IMAGE DATA PROCESSING OR GENERATION, IN GENERAL

## Abstract

A flat panel imaging system for imaging cells provided on a cell medium is disclosed. The system includes a housing having a base portion and a lid that collectively form a closed environment to exclude external sources of light, and a flat panel detector encased in the base portion and having an array of pixels each including a photodiode and transistor. The system also includes a first light source that illuminates cells on the cell medium to excite at least a portion of the cells and cause those cells to generate photons that are captured by the array of pixels and a second light source to illuminate cells on the cell medium with a light different from the light from the first light source and that provides for a capturing of photons representative of photons transmitted through the cells on the cell medium.

## Claims

### Claim 1

A flat panel imaging system for imaging cells provided on a cell medium, the flat panel imaging system comprising:
a housing including a base portion and a lid that collectively form a closed environment to exclude external sources of light from entering the housing;
a flat panel detector encased in the base portion, the flat panel detector comprising an array of pixels each including a photodiode and transistor that convert photons received thereby to electrical signals that are representative of the photons impacting individual the respective pixel;
a first light source configured to illuminate the cells on the cell medium with a light that excites at least a portion of the cells and causes those cells to generate photons that are captured by the array of pixels; and
a second light source configured to illuminate the cells on the cell medium with a light different from the light from the first light source, the light from the second light source providing for a capturing of photons by the array of pixels representative of photons transmitted through the cells on the cell medium.

### Claim 2 (depends on 1)

The flat panel imaging system of claim 1 wherein the photons generated by or transmitted through the cells on the cell medium result from one of a chemiluminescence, fluorescence, or colorimetric imaging technique.

### Claim 3 (depends on 1)

The flat panel imaging system of claim 1 wherein the first light source comprises a fluorescent light source configured to output light that excites a fluorescent reagent with which the cells are labeled, so as to cause the at least a portion of the cells to generate photons; and
wherein the second light source comprises a white light source.

### Claim 4 (depends on 1)

The flat panel imaging system of claim 1 further comprising one or more filters positioned between the cell medium and the first and second light sources, the filters comprising at least one of a narrow bandwidth filter, high pass and low pass filters, and a color filter array.

### Claim 5 (depends on 1)

The flat panel imaging system of claim 1 further comprising a transparent protective layer positioned over the array of pixels to provide protection thereto and provide for transmission of photons there through to the array of pixels, with the cell medium being place directly on the transparent protective layer.

### Claim 6 (depends on 1)

The flat panel imaging system of claim 1 further comprising a microscope integrated into the flat panel imaging system.

### Claim 7 (depends on 1)

The flat panel imaging system of claim 1 further comprising a piezoelectric element attached to the flat panel detector that causes a lateral shifting of the array of pixels.

### Claim 8 (depends on 7)

The flat panel imaging system of claim 7 further comprising an image reconstructor configured to process the electrical signals that are representative of the photons received by the array of pixels so as to provide for generation of a digital image of the cells on the cell medium, and wherein the lateral shifting of the array of pixels provides for a sub-pixel image shift between each of a number of images generated by the image reconstructor, thereby providing redundant imaging data between the images.

### Claim 9 (depends on 8)

The flat panel imaging system of claim 8 wherein the image reconstructor is configured to perform a super resolution enhancement of the generated images based on the redundant imaging data.

### Claim 10 (depends on 9)

The flat panel imaging system of claim 9 wherein the super resolution enhancement provides an effective resolution of 1-5 μm for the flat panel detector.

### Claim 11 (depends on 1)

The flat panel imaging system of claim 1 wherein the flat panel detector is sized to accommodate placement of a cell medium of 20×20 cm thereon.

### Claim 12

A method for detecting and enumerating cells in a cell culture using a flat panel imaging system, the method comprising:
providing a cell medium having a plurality of cells thereon;
placing the cell medium on a flat panel detector of a flat panel imaging system, the flat panel detector comprising an array of photodiodes and transistors that collect light generated from or transmitted through the cell medium;
collecting light emitted by cells on the cell medium responsive to an excitation of the cells achieved via one of a chemiluminescence imaging technique and a fluorescence imaging technique, the light emitted by the cells being collected by the array of photodiodes of the flat panel detector and converted to electric charges to generate a first set of light data;
processing the first set of light data to generate a first digital image of the cells;
collecting light transmitted through the cells on the cell medium responsive to illumination of the cells by a light source integrated into the flat panel imaging system, the light transmitted through the cells being collected by the array of photodiodes of the flat panel detector and converted to electric charges to generate a second set of light data; and
processing the second set of light data to generate a second digital image of the cells.

### Claim 13 (depends on 12)

The method of claim 12 further comprising tagging locations at which light emitted by cells responsive to one of the chemiluminescence imaging technique and the fluorescence imaging technique is received by the flat panel detector as containing a marked cell, the tagged locations containing a marked cell being determined from the first digital image of the cells.

### Claim 14 (depends on 13)

The method of claim 13 further comprising obtaining a high resolution image of the marked cells using a microscope integrated into the flat panel imaging system.

### Claim 15 (depends on 12)

The method of claim 12 further comprising determining a total cell count of the cells on the cell medium from the second digital image of the cells.

### Claim 16 (depends on 12)

The method of claim 12 wherein collecting light emitted by cells on the cell medium responsive to an excitation of the cells achieved via one of a chemiluminescence imaging technique and a fluorescence imaging technique comprises illuminating the cells on the cell medium using a fluorescent light source integrated into the flat panel imaging system and that excites a fluorescent reagent with which the cells are labeled.

### Claim 17 (depends on 16)

The method of claim 16 further comprising performing one or more filtering operations during an image acquisition, the one or more filtering operations including at least one of:
filtering the light from the fluorescent light source from the light emitted by the cells, so to provide for collection of only the light emitted by the cells by the array of photodiodes of the flat panel detector; and
filtering light collected by the array of photodiodes to provide for the capture of color information in a colorimetric imaging technique.

### Claim 18 (depends on 12)

The method of claim 12 wherein collecting light transmitted through the cells on the cell medium responsive to illumination of the cells by a light source further comprises transilluminating the gel sample using a white light source.

### Claim 19 (depends on 12)

The method of claim 12 further comprising:
activating a piezoelectric element coupled to the flat panel detector to cause a sub-pixel lateral shift thereof during acquisition of a first set of light data from which a respective first digital image is generated;
comparing each of a number of generated first digital images that include a sub-pixel lateral shift, thereby providing redundant imaging data between the images; and
performing a super resolution enhancement of the generated first digital images based on the redundant imaging data.

### Claim 20

A flat panel imaging system for detecting and enumerating cells microbial cells provided on a cell medium, the flat panel imaging system comprising:
a housing including a base portion and a lid that collectively form a closed environment to exclude external sources of light from entering the housing;
a flat panel detector encased in the base portion, the flat panel detector comprising an array of pixels each including a photodiode and transistor that convert photons received thereby to electrical signals that are representative of the photons impacting individual the respective pixel;
a fluorescent light source configured to illuminate the cells on the cell medium so as to excite at least a portion of the cells and cause those cells to generate photons that are captured by the array of pixels;
a white light source configured to illuminate the cells on the cell medium, with photons transmitted through the cells being captured by the array of pixels; and
an image reconstructor configured to process the electrical signals that are representative of the photons received by the array of pixels so as to provide for generation of a digital image of the cells on the cell medium, wherein the image reconstructor is configured to:
generate a first image of the microbial cells that captures cells that are excited responsive to illumination with the fluorescent light, the first image tagging locations at which photons generated by cells excited responsive to illumination with the fluorescent light as containing a marked cell; and
generate a second image of the microbial cells that captures cells through which photons are transmitted when illuminated by the white light source, the second image providing a total cell count of the microbial cells on the cell medium.