# US 2021/0239589 A1 · Method for examining a liquid which contains at least one cell and/or at least one particle

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- Number: US 2021/0239589 A1
- Document ID: US20210239589A1
- Status: Published application
- Kind: A1
- Application number: 17/049,611
- Filed: 2019-02-04
- Published: 2021-08-05
- Earliest claimed: 2018-04-23
- Assignees: cytena GmbH
- Applicants: cytena GmbH
- Inventors: Jonas SCHÖNDUBE; Lena LAUTSCHAM
- Web page: https://patentgrep.com/patent/US20210239589A1

## CPC

- G01N 15/0227: using imaging; using holography
- G01N 15/1433: using image recognition
- G01N 15/1434: Optical arrangements
- G01N 21/645: {Specially adapted constructive features of fluorimeters}
- G02B 21/0076: {arrangements using fluorescence or luminescence}
- G01N 15/01: specially adapted for biological cells, e.g. blood cells (investigating sedimentation of particle suspensions in blood G01N15/05)
- G01N 2015/1006: {for cytology}
- G01N 2015/144: {Imaging characterised by its optical setup}
- G01N 2015/1493: {Particle size}
- 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)
- G02B: OPTICAL ELEMENTS, SYSTEMS OR APPARATUS

## Abstract

The invention relates to a method for examining a liquid which contains at least one cell and/or at least one particle using a first and a second measurement signal emanating from a liquid region, wherein the method has the following steps: a. reading the first measurement signal and analysing the first measurement signal and b. using the analysed first measurement signal to determine whether the second measurement signal was detected and completely read, whether the detected second measurement signal was completely read, or whether the reading of the detected second measurement signal was completely read, or whether the reading of the detected second measurement signal (20) was interrupted.

## Claims

### Claim 1

A method for automatically examining a liquid (4) which contains at least one cell (3) and/or at least one particle using a first and a second measurement signal (15, 20) emanating from a liquid region (6), wherein the method has the following steps:
a. reading the first measurement signal (15) and analysing the first measurement signal (15) and
b. using the analysed first measurement signal (15) to determine whether the second measurement signal (20) was detected and completely read, whether the detected second measurement signal was completely read, or whether the reading of the detected second measurement signal (20) was completely read, or whether the reading of the detected second measurement signal (20) was interrupted.

### Claim 2 (depends on 1)

The method according to claim 1, wherein
a. the first measurement signal (15) is analysed as to whether at least one cell (3) and/or at least one particle is arranged in the liquid region (6) and/or
b. the first measurement signal (15) is analysed as to whether a predetermined number of cells and/or particles is arranged in the liquid region and/or
c. for determining whether at least one cell (3) and/or at least one particle is arranged in the liquid region (6), an optical property of the liquid region (6) is determined based on the first measurement signal (15) or the first measurement signal (15) is used to generate a bright field image and, to determine whether at least one cell (3) and/or one particle is arranged in the liquid region (6), an optical property of the liquid region (6) is determined based on the bright field image and/or
d. the second measurement signal (20) is not detected and read if no cells (3) and/or no particles are arranged in the liquid region (6) and/or if the predetermined number of cells and/or particles is not arranged in the liquid region (6) and/or
e. reading the second measurement signal (20) is interrupted if no cells (3) and/or no particles are arranged in the liquid region (6) and/or if the predetermined number of cells and/or particles is not arranged in the liquid region.

### Claim 3

(canceled)

### Claim 4

(canceled)

### Claim 5 (depends on 2)

The method according to claim 2, wherein
a. the second measurement signal (20) is detected and read if at least one cell (3) and/or one particle is arranged in the liquid region (6) and/or if the predetermined number of cells (3) and/or particles is arranged in the liquid region (6) and/or
b. the second measurement signal (20) is completely read if at least one cell (3) and/or one particle is arranged in the liquid region (6) and/or if the predetermined number of cells (3) and/or particles is arranged in the liquid region (6).

### Claim 6 (depends on 5)

The method according to claim 5, wherein the detected second measurement signal (20) is analysed to determine whether
a. the liquid region (6) does not fluoresce and/or a cell (3) contained in the liquid region (6) does not fluoresce and/or a particle contained in the liquid region (6) does not fluoresce and/or whether
b. the liquid region (6) fluoresces and/or a cell (3) contained in the liquid region (6) fluoresces and/or a particle contained in the liquid region fluoresces.

### Claim 7 (depends on 1)

The method according to claim 1, wherein
a. the liquid region (6) is illuminated with a first illuminating light (8) and then the first measurement signal (15) emanates from the liquid region (6) and/or
b. the liquid region (6) is illuminated with a second illuminating light (19) and then the second measurement signal (20) emanates from the liquid region (6).

### Claim 8 (depends on 7)

The method according to claim 7, wherein
a. the liquid region (6) is illuminated again with the first illuminating light (8) if no cells (3) and/or no particles are arranged in the liquid region (6) and/or if the predetermined number of cells and/or particles is not arranged in the liquid region (6) and/or
b. the second illuminating light (19) is then only emitted if a cell (3) and/or a particle is arranged in the liquid region (6) and/or if the predetermined number of cells and/or particles is arranged in the liquid region (6) and/or
c. the liquid region (6) is illuminated simultaneously by the first illuminating light (8) and the second illuminating light (19) and/or
d. the liquid region (6) is illuminated with the second illuminating light (19) while determining whether a cell (3) and/or a particle is arranged in the liquid region (6) and/or whether the predetermined number of cells and/or particles is arranged in the liquid region (6) and/or
e. simultaneously, the liquid region (6) begins to be illuminated with the first illuminating light (8) and the second illuminating light (19).

### Claim 9

(canceled)

### Claim 10

(canceled)

### Claim 11

A method for automatically examining a liquid (4) which contains at least one cell (3) and/or at least one particle using a first and second measurement signal (15, 20) emanating from a liquid region (6), wherein
a. the second measurement signal (20) is read and analysed in order to determine whether at least one cell (3), in particular one single cell, and/or at least one particle, in particular one single particle, is arranged in the liquid region (6), and
b. the first measurement signal (15) is read and analysed in order to determine a property of the cell (3) and/or the particle if a cell (3) and/or a particle is arranged in the liquid region (6), wherein reading the second measurement signal (20) takes longer than reading the first measurement signal (15) and/or analysing the second measurement signal (20) takes longer than analysing the first measurement signal (15).

### Claim 12 (depends on 11)

The method according to claim 11, wherein
a. the second measurement signal (20) is analysed in order to determine the position of at least one cell (3) and/or at least one particle in the liquid region (6) and/or
b. the second measurement signal (20) is analysed as to whether a fluorescent cell (3) and/or a fluorescent particle is arranged in the liquid region (6) and/or
c. the second measurement signal (20) is analysed as to whether a predetermined number of fluorescent cells (3) and/or particles is arranged in the liquid region (6) and/or
d. the second measurement signal (20) is used to generate a fluorescence image and in that the fluorescence image is used to determine whether a fluorescent cell (3) and/or a fluorescent particle is arranged in the liquid region (6) and/or whether the predetermined number of fluorescent cells (3) and/or particles is arranged in the liquid region (6).

### Claim 13

(canceled)

### Claim 14 (depends on 11)

The method according to claim 11, wherein
a. the liquid region (6) is illuminated with a first illuminating light (8) and then the first measurement signal (15) emanates from the liquid region (6) and/or
b. the liquid region (6) is illuminated with a second illuminating light (19) and then the second measurement signal (20) emanates from the liquid region (6).

### Claim 15 (depends on 14)

The method according to claim 14, wherein
a. the liquid region (6) is illuminated again with the second illuminating light (19) if no fluorescent cells (3) and/or no fluorescent particles are arranged in the liquid region (6) and/or
b. the liquid region (6) is illuminated again with the second illuminating light if the predetermined number of fluorescent cells and/or fluorescent particles is not arranged in the liquid region.

### Claim 16 (depends on 11)

The method according to claim 11, wherein a detected further second measurement signal (20) is read and analysed if no cells (3) and/or no particles are arranged in the liquid region (6) and/or if the predetermined number of fluorescent cells (3) and/or fluorescent particles is not arranged in the liquid region.

### Claim 17 (depends on 14)

The method according to claim 14, wherein
a. the illumination of the liquid region (6) with the second illuminating light (19) is terminated if a fluorescent cell (3) and/or a fluorescent particle is arranged in the liquid region (6) and/or if the predetermined number of fluorescent cells (3) and/or fluorescent particles is arranged in the liquid region and/or
b. the first illuminating light (8) is emitted after it has been determined that a fluorescent cell (3) and/or a fluorescent particle is arranged in the liquid region (6) and/or after it has been determined that the predetermined number of fluorescent cells (3) and/or fluorescent particles is arranged in the liquid region and/or
c. the first illuminating light is emitted while determining whether a fluorescent cell (3) and/or a fluorescent particle is arranged in the liquid region (6) and/or while determining whether the predetermined number of fluorescent cells (3) and/or fluorescent particles is arranged in the liquid region.

### Claim 18 (depends on 1)

The method according to claim 1, wherein
a. the liquid (4), in particular the liquid region (6), is arranged in a dispenser (2) and/or can be dispensed by the dispenser (2), in particular, a dispensing process is controlled based on the first and/or second measurement signal (15, 20) and/or a liquid dispensing is performed using a drop-on-demand methodology, and/or
b. a storage location is determined and, after determining the storage location, the liquid (4) to be dispensed, in particular into a container of a carrier (10), is dispensed and/or
c. a storage location of the liquid (4) to be dispensed depends on the fluorescent light and/or depends on whether the cell (3) and/or the particle fluoresces and/or
d. a carrier (10) has a plurality of containers, wherein a container, in particular a first group of containers, is intended for receiving a liquid (4), which contains a fluorescent cell (3) and/or a fluorescent particle, and a further container, in particular a second group of containers, is intended for receiving a liquid (4), which contains no fluorescent cells (3) and/or no fluorescent particles, and the liquid, which contains at least one fluorescent cell (3) and/or at least one fluorescent particle, is supplied from the dispenser (2) into the container, in particular a container of the first group, and/or the liquid, which contains no fluorescent cells (3) and/or no fluorescent particles, is supplied from the dispenser (2) into another container, in particular a container of the second group, and/or
e. depending on the first measurement signal and/or the second measurement signal, the liquid to be dispensed is fed into a container of the carrier (10) or into a reject container and/or
f. the dispensing process depends on whether at least one other cell and/or at least one other particle is arranged in another liquid region and/or a predetermined number of other cells and/or other particles is arranged and/or
g. the dispensing process depends on whether one other fluorescent cell and/or one other fluorescent particle is arranged in another liquid region and/or a predetermined number of other fluorescent cells and/or other fluorescent particles is arranged.

### Claim 19

(canceled)

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22

(canceled)

### Claim 23 (depends on 1)

The method according to claim 1, wherein
a. the first measurement signal (15) is an optical signal, in particular a bright field light, and/or
b. the second measurement signal (20) is an optical signal, in particular a fluorescent light, and/or
c. the first measurement signal (15) and the second measurement signal (20) result from different measurement methods.

### Claim 24 (depends on 23)

The method according to claim 23, wherein
a. the bright field light is used to generate a bright field image and/or
b. the fluorescent light is used to generate a fluorescence image.

### Claim 25 (depends on 24)

The method according to claim 24, wherein
a. the bright field image and the fluorescence image are compared with one another and/or
b. the bright field image and the fluorescence image are compared with one another in order to determine the position of the cell and/or the particle and/or
c. the bright field image and the fluorescence image are compared with one another in order to determine the position and/or the size of a fluorescent substance of the cell and/or of the particle.

### Claim 26 (depends on 1)

A device (1) for carrying out the method according to claim 1.

### Claim 27 (depends on 26)

The device (1) according to claim 26, wherein the device (1) has a dispenser (2) for dispensing a liquid (4), which contains at least one cell (3) and/or one particle, and an optical detection device (5), which has a first light source (7) for radiating the first illuminating light (8) for illuminating the at least one liquid region (6) of the dispenser (2), a second liquid region (18) for radiating the second illuminating light (19) for illuminating the at least one liquid region (6) of the dispenser (2), at least one detection means, at least one readout device and at least one analysis device (17).

### Claim 28 (depends on 27)

The device (1) according to claim 27, wherein
a. the optical detection device (5) has a plurality of detection means, wherein a first detection means (14) detects the first measurement signal (15) and a second detection device (21) detects the second measurement signal (20) and/or
b. the optical detection device has a plurality of readout devices, wherein a first readout device reads the detected first measurement signal and a second readout device reads the detected second measurement signal and/or
c. the analysis device (17) determines on the basis of the first measurement signal (15) whether at least one cell and/or a particle is arranged in the liquid region (6) and/or whether a predetermined number of cells and/or particles is arranged in the liquid region (6) and/or
d. the analysis device (17) determines on the basis of the second measurement signal (20) whether no fluorescent cells (3) and/or no fluorescent particles are arranged in the liquid region (6) or whether one single fluorescent cell and/or one single fluorescent particle is arranged in the liquid region or whether a plurality of fluorescent cells and/or a plurality of fluorescent particles are arranged in the liquid region and/or
e. the optical detection device (5) has at least one imaging device for generating at least one image, in particular a bright field image and/or a fluorescence image, or
f. the optical detection device (5) has a plurality of imaging devices, wherein a first imaging device (16) produces at least one first image, in particular a bright field image, and a second imaging device (22) produces at least one second image, in particular a fluorescence image.

### Claim 29

(canceled)

### Claim 30

(canceled)

### Claim 31 (depends on 27)

The device (1) according to claim 27, wherein
a. the optical detection device (5) has a lens (12) which is arranged such that its optical axis (13) is transverse, in particular perpendicular, to a dispensing direction (R) of the liquid (4) and/or
b. the device (1) has a control device (28) and a displacement device (29) for displacing the dispenser (2) and/or a carrier (10) for receiving the dispensed liquid (4), wherein the control device (28) controls the displacement device (29) based on the first and/or second measurement signal (15, 20) and/or
c. a deflection device for deflecting a liquid dispensed from the dispenser and/or a suction device for suctioning away a liquid dispensed from said dispenser and/or
d. the first illuminating light (8) and the first measurement signal (15) have a common beam path at least in parts and/or
e. the second illuminating light (19) and the second measurement signal (20) have a common beam path at least in parts and/or
f. the first illuminating light (8) and the second illuminating light (19) have a common beam path at least in parts.

### Claim 32

(canceled)

### Claim 33

(canceled)

### Claim 34

(canceled)