CN1590982A - Cell automatic optical detecting system - Google Patents
Cell automatic optical detecting system Download PDFInfo
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- CN1590982A CN1590982A CN 03157951 CN03157951A CN1590982A CN 1590982 A CN1590982 A CN 1590982A CN 03157951 CN03157951 CN 03157951 CN 03157951 A CN03157951 A CN 03157951A CN 1590982 A CN1590982 A CN 1590982A
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Abstract
The present invention relates to an automatic optical detection system for cell. Said system is characterized by that it has a phase difference microphotographic device, which can implement plane movement on the operation platform, and can support the transparent sample bearing platform over the phase difference microphotographic device. The above-mentioned driving device is controlled by automatic control system, according to the requirement said driving device can be used to drive the phase difference microphotographic device and make it be moved to a fixed point under the transparent sample bearing platform, and the enlarging, focusing and photographic actions of phase difference microphotographic device can be controlled by said control system, and the image shot by said microphotographic device can be stored in the data storage device.
Description
(1) technical field
Relevant a kind of automated optical monitoring (the automatic optical inspection of the present invention; AOI) system, and particularly relevant a kind of cell automatic optical detecting system.
(2) background technology
Hybridoma cell mainly is the production that is used for monoclonal antibody, and it is generally merged mutually with the cell (for example B cell in the spleen) that can produce antibody by cancer cell of bone marrow and produces.This is that the growth of cancer cell then can be uncontrolled, is easy to grow in nutrient culture media because B cell (B lymphocyte) is difficult for growing in nutrient culture media.So if the continuous forever characteristic of growing of cancer cell, utilize the Fusion of Cells method to import and can produce in the B cell of useful antibody, then can obtain the B cell line of permanent growth in nutrient culture media, this is the hybridoma cell strain.After the hybridoma cell strain is passed through the process of screening (screening) and individual plantization (cloning) again, the hybridoma cell strain that can obtain producing monoclonal antibody (monoclonal antibody).
In general, contain 100,000,000 B cells in the spleen approximately, and the big appointment of the Fusion of Cells of a success produces 500-1000 hybridoma cell.Then, how are the upgrowth situation of necessary these hybridoma cells of monitoring and viability, and whether monitoring has the pollution of virus, bacterium and mould.Then, the ability that the hybridoma cell of surviving must utilize immunoassay to screen its manufacture order strain antibody, the hybridoma cell that has the survival of 1/500-5/10 to get off approximately can produce antibody.Next, carry out the separation of hybridoma cell and the step of hyperplasia (propagation), with these hybridoma cells of individual plantization.Single hybridoma cell strain can produce a large amount of same antibody at single epitope (epitope or antigenic determinant).Can produce antibody that the hybridoma cell strain of antibody produced in order to ensure each is individual plantization, must earlier these hybridoma cells be separated, and guarantees that each population of cells is bred out by single cell.
In the process of this screening and individual plantization, its main bottleneck is monitoring and these hybridoma cells in raised growth of individual plantization.The mode of carrying out of monitoring utilizes phasic difference microscope (invertedmicroscope) to come the growth characteristics of hybridoma cell are carried out the routine inspection for being dependent on the operator at present.But the efficient of this mode and correctness must be dependent on operator's experience, skill and subjective judgement ability fully, and these can change along with the different operating person.
And the length of monitoring time also be very crucial a bit, this is because the hybridoma cell strain must be cultivated under the environment of carbon dioxide.But when monitoring, the hybridoma cell strain must be shifted out outside the growing environment of carbon dioxide, if the overlong time that monitoring is spent, viability for the hybridoma cell strain has quite bad influence with growth, and has also increased the contamination by micro chance simultaneously.Therefore the step that general several cellular incubation grooves in only can grab sample 96 groove cellular incubation dishes are monitored is treated time outside carbon dioxide environment in the hope of reducing the hybridoma cell strain.
In the individual plant process, the present mode of carrying out mainly is subject to utilizes cell culture fluid to dilute the program of hybridoma cell strain.In this program, carry out cell count and whether assess cell survival with cell counter (heamacytometer) and phasic difference microscope earlier, again hybridoma cell dilution is dispersed in the 96 groove cellular incubation dishes, until in theory with statistics go up have only a hybridoma cell in each cellular incubation groove till.And then utilize and manually determine the survival situation of the hybridoma cell in each cellular incubation groove and the degree of individual plantization with vision.In general, whether the hybridoma cell that the operator of denominator will detect a dish 96 groove cellular incubation dishes individual plantizations all, need the time more than 60 minutes just can finish.Therefore this whole process is very to expend operator's muscle power and eyesight.And when using the phasic difference microscope to observe hybridoma cell in the 96 groove cellular incubation dishes, may rock because of the vibration in the operating process and move the position of hybridoma cell in the cellular incubation groove, thereby cause in the counting of hybridoma cell and the mistake in the identification.So generally, known is not suitable for use in a large amount of fast productions of monoclonal antibody in monitoring in the hybridoma cell production and individual plant program.
(3) summary of the invention
Therefore the purpose of this invention is to provide a kind of cell automatic optical detecting system, obtaining the upgrowth situation of hybridoma cell rapidly objectively, and don't can interfere with the cultivation of hybridoma cell.
Another object of the present invention provides a kind of cell automatic optical detecting system, after having detected the upgrowth situation of hybridoma cell, utilize artificial intelligence or computer software to assist and estimate the nutrient solution that needs how many volumes, hybridoma cell could be diluted in each the cellular incubation groove on the 96 groove cellular incubation dishes and have only a hybridoma cell.
Another purpose of the present invention provides a kind of cell automatic optical detecting system, after hybridoma cell being diluted to each cellular incubation groove, utilize the image automatic recognition system in artificial intelligence or the computer to judge whether to have only a hybridoma cell in each cellular incubation groove automatically.
According to above-mentioned purpose of the present invention, a kind of automatic optical detecting system of cell is proposed, this automatic optical detecting system comprises following assembly at least.This automatic optical detecting system has an operating platform, disposes drive unit in this operating platform.The phasic difference photomicrographic device is configured on the drive unit.Above-mentioned phasic difference photomicrographic device is that the installation camera lens place with camera installs and amplifies optical lens and form with the contrast camera lens.In addition, also have a support to be positioned on the operating platform, in order to above the phasic difference photomicrographic device, to support the transparent sample carrying platform.This automatic optical detecting system also has automatic control system and data memory device.Automatic control system can drive the fixed point of phasic difference photomicrographic device to transparent sample carrying platform below according to required accessory drive, and control bit differs the action of amplification, focusing and the photography of photomicrographic device; And data memory device is in order to store the captured image of camera.
According to a preferred embodiment of the present invention, this automatic optical detecting system is also configurable light source, the institute's light requirement when photographing for the phasic difference photomicrographic device.Also can be equipped with a display device in addition, in order to show the captured image of phasic difference photomicrographic device.The image automatic recognition system can also be equipped with in addition,, in order to the cell number in each the cellular incubation groove in the automatic identification transparent sample carrying platform.
From the above, cell automatic optical detecting system provided by the present invention can utilize automatic control system to come control bit to differ moving of photomicrographic device and the sample on the transparent sample carrying platform is carried out the action that image amplifies, focuses and photograph, image can be stored again then, even also can utilize the image automatic recognition system to carry out the counting of cell.Therefore whole testing process can be accomplished without any letup, and the time that cell sample is treated outside culture environment drops to minimum, in order to avoid influence the upgrowth situation of cell sample, and can obtain correct sentence read result.
(4) description of drawings
For above-mentioned and other purposes of the present invention, characteristics and advantage can be become apparent, a preferred embodiment cited below particularly, and conjunction with figs. is elaborated as follows:
Fig. 1 is the structural representation according to a kind of cell automatic optical detecting system of a preferred embodiment of the present invention.
(5) embodiment
As mentioned above, the invention provides a kind of cell automatic optical detecting system, known monitor the upgrowth situation of hybridoma cell and the counting of hybridoma cell with pure manpower to replace.In addition, this cell automatic optical detecting system can also be assisted the volume of the required nutrient solution of decision dilution hybridoma cell, and discerns the cell number in each cellular incubation groove.Therefore the present invention can be applied in a large amount of fast productions of monoclonal antibody.
Please refer to Fig. 1, it is the structural representation according to a kind of cell automatic optical detecting system of a preferred embodiment of the present invention.In this system, integrated phasic difference photomicrographic device, driving element and computer etc., detect cell growth condition and Cytometric purpose to reach robotization.
Because being placed in the 96 groove cellular incubation dishes, cultivates general hybridoma cell, so when detecting, need observe the upgrowth situation of hybridoma cell in each cellular incubation groove in regular turn.Therefore in Fig. 1, drive unit 130 is installed in the operating platform 100, is used for mobile phasic difference photomicrographic device 110 to aim at each cellular incubation groove in the 96 groove cellular incubation dishes one by one.In this embodiment, drive unit 130 has comprised motor 132, driving-belt 134 and gear 136.Phasic difference photomicrographic device 110 is installed in (not shown on the figure) on the chain-wales, to utilize after any known mechanical means and driving-belt 134 link, utilize working in coordination between motor 132, driving-belt 134 and the gear 136, just can differ photomicrographic device 110 moving about front and back on the surface level by control bit.
Above-mentioned phasic difference photomicrographic device 110 is that the installation camera lens place with camera 112 installs and amplifies optical lens 116 and form with contrast camera lens 118, in order to the hybridoma cell upgrowth situation in every groove of observing in the 96 groove cellular incubation dishes.Amplify the image that optical lens 116 can magnocell, and contrast camera lens 118 can make resolution improve, in order to the automatic identification of image.Phasic difference photomicrographic device 110 is basically except having the optical lens of amplification 116 and contrasting the camera lens (contrast lens) 118, also has automatic focusing mechanism 114, in order to adjusting focal length, so also it doesn't matter even this segment distance has a little change according to the distance between phasic difference photomicrographic device 110 and the 96 groove cellular incubation dishes.
Camera 112 for example can be a digital camera, in order to and computer 140,142 between come the transmission of digital image data, and viewed amplifier digital image can be shown on screen 144.Computer 140,142 for example can be seated in cupboard 150 the insides, allows the operating platform 100 can be placed on it, and screen 144 also can be seated on the cupboard 150 by support 152.
Above-mentioned computer 140 for example can be the main frame of automatic optical detecting system, internal storage the Control Software of automatic optical detecting system, action with accessory drive 130 comes the position of mobile phasic difference photomicrographic device 110 to required observation, and control bit differs the focusing amplification of photomicrographic device 110 and the action of taking pictures.And computer 142 for example can be the servomechanism of depositing image database and other Relational databases, storing the image that a large amount of phasic difference photomicrographic devices 110 are taken, and can assist to estimate the volume that in the individual plant process, will dilute the required nutrient solution of hybridoma cell according to captured image.In addition, also the image automatic recognition system can be installed in the computer 142, automatically discern the cell number in each cellular incubation groove, after assisting to determine that cell dilution step in the individual plant process is finished, whether have only a hybridoma cell in each cellular incubation groove.In addition, the function of computer 140,142 also can be incorporated in the computer, or also can be dispersed on several the computers, is not limited to use two computers to finish automatic control and image processing storage and the work of discerning.
In addition, also the substitute of 96 groove cellular incubation dishes 160 can be placed on the position identical, place cell counter on it again, to carry out the counting of the hybridoma cell in the cell counter with 96 groove cellular incubation dishes 160.
On support 154, be provided with support 158 again, in order to settle phasic difference photomicrographic device 110 required light source 170 when the observation.Light source 170 for example can be yellow red light source (yellow-red lightsource), in order to the photography of general visible-range.Light source 170 also for example can be the light source of certain specific band, as blue light, so that fluorescence flag on the cell (fluorescence marker) or phosphorescence flag (phosphorescence marker) are luminous, allow phasic difference photomicrographic device 110 be caught image again.
Therefore in the time will using above-mentioned cell automatic optical detecting system to detect the upgrowth situation of hybridoma cell,, be placed on the support platform 156 as long as 96 groove cellular incubation dishes are taken out in the culture environment of hybridoma cell.Utilize computer 140 to come accessory drive 130 that phasic difference photomicrographic device 110 is moved to the position that desire is observed then, utilize computer 140 to control the focal length that automatic focusing mechanism 114 is adjusted phasic difference photomicrographic devices 110 again.Last computer 140 control bits differ photomicrographic device 110 and carry out the shooting of hybridoma cell image, the digitized video of taking the photograph are sent in the computer 142 store, and utilize the image automatic recognition system to carry out Cytometric work.Because whole process is all automation process, so can just can finish cell monitoring and Cytometric work in a short period of time.For example in 20 minutes, just can determine the hybridoma cell number in the every groove in the 96 groove cellular incubation dishes, and the artificial interpretation of error rate is much lower.Like this, this 96 groove cellular incubation dish can be sent in the culture environment of hybridoma cell again soon again.In the so short time, can drop to the testing process interference that growth is caused to hybridoma cell minimum.
The operator can watch these hybridoma cell images that stores at leisure one by one on screen 144 then, writes down the upgrowth situation of hybridoma cell in each cellular incubation groove, to carry out follow-up screening step.The operator can also utilize the image automatic recognition system, or is learnt the number of the hybridoma cell in each groove by these hybridoma cell images on the screen.So in carrying out the individual plant process, can utilize these information, using computer 142 to estimate will be diluted to these hybridoma cells when having only a hybridoma cell in each cellular incubation groove, how many nutrient solution volumes of required dilution usefulness is, and can learn after the cell dilution step whether have only a cell in each cellular incubation groove.
By the invention described above preferred embodiment as can be known, use the present invention and can obtain the upgrowth situation of hybridoma cell rapidly objectively, and don't can interfere with the cultivation of hybridoma cell.The present invention also can utilize the result of gained after the upgrowth situation that detected hybridoma cell and the individual plant situation, utilize the software of computer inside to assist and estimate the nutrient solution that needs how many volumes, hybridoma cell could be diluted in each the cellular incubation groove on the 96 groove cellular incubation dishes and have only a hybridoma cell.In addition, after hybridoma cell being diluted to each cellular incubation groove, utilize the image automatic recognition system in the computer inside to judge whether to have only a hybridoma cell in each cellular incubation groove automatically.
Though the present invention discloses as above with a preferred embodiment; yet it is not in order to limit the present invention; any person skilled in the art person without departing from the spirit and scope of the present invention; change and replace when making various equivalence, so protection scope of the present invention is when looking being as the criterion that accompanying Claim defines.
Claims (10)
1. cell automatic optical detecting system comprises at least:
One operating platform;
One drive unit is configured in this operating platform;
One phasic difference photomicrographic device is configured on this drive unit, and this phasic difference photomicrographic device is driven by this drive unit and moves with plane on this operating platform;
One support is positioned on this operating platform to support a transparent sample carrying platform in the top of this phasic difference photomicrographic device;
One automatic control system drives the fixed point of this phasic difference photomicrographic device to this transparent sample carrying platform below according to this drive unit of required control, and the action of controlling amplification, focusing and the photography of this phasic difference photomicrographic device; And
One data memory device is in order to store the captured image of this camera.
2. cell automatic optical detecting system as claimed in claim 1 is characterized in that this drive unit comprises a motor, a driving-belt and a gear at least.
3. cell automatic optical detecting system as claimed in claim 1 is characterized in that this phasic difference photomicrographic device comprises a digital camera at least, and this digital camera is equipped with one at least and amplifies optical lens, a contrast camera lens and an automatic focusing mechanism.
4. cell automatic optical detecting system as claimed in claim 1 is characterized in that this transparent sample carrying platform comprises one 96 groove cellular incubation dishes at least.
5. cell automatic optical detecting system as claimed in claim 1 is characterized in that this automatic control system and this data memory device are installed in the computer at least.
6. cell automatic optical detecting system as claimed in claim 1 is characterized in that, also comprises an image automatic recognition system with the cell number in each the cellular incubation groove in identification and this transparent sample carrying platform of calculating.
7. cell automatic optical detecting system as claimed in claim 6 is characterized in that this automatic control system, this data memory device and this image automatic recognition system are installed in the computer at least.
8. cell automatic optical detecting system as claimed in claim 1 is characterized in that also comprising the top that a light source is configured in this transparent sample carrying platform, for this phasic difference photomicrographic device photography time institute's light requirement.
9. cell automatic optical detecting system as claimed in claim 1 is characterized in that also comprising a display device, in order to the image that shows that this camera is captured.
10. cell automatic optical detecting system as claimed in claim 9 is characterized in that this display device comprises a screen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03157951 CN1590982A (en) | 2003-09-01 | 2003-09-01 | Cell automatic optical detecting system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03157951 CN1590982A (en) | 2003-09-01 | 2003-09-01 | Cell automatic optical detecting system |
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| CN1590982A true CN1590982A (en) | 2005-03-09 |
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| CN 03157951 Pending CN1590982A (en) | 2003-09-01 | 2003-09-01 | Cell automatic optical detecting system |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102289066A (en) * | 2011-08-12 | 2011-12-21 | 北京航空航天大学 | Automatic microscopic imaging system for multicellutar culture course |
| CN103031248A (en) * | 2012-12-26 | 2013-04-10 | 綦迎成 | Direct bacterium viewer |
| CN109709346A (en) * | 2018-12-07 | 2019-05-03 | 英华达（上海）科技有限公司 | Automatic cytological analytical equipment and its operating method |
| CN111065726A (en) * | 2017-09-07 | 2020-04-24 | 康宁股份有限公司 | Optical system for cell culture monitoring and analyte measurement |
-
2003
- 2003-09-01 CN CN 03157951 patent/CN1590982A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102289066A (en) * | 2011-08-12 | 2011-12-21 | 北京航空航天大学 | Automatic microscopic imaging system for multicellutar culture course |
| CN103031248A (en) * | 2012-12-26 | 2013-04-10 | 綦迎成 | Direct bacterium viewer |
| CN111065726A (en) * | 2017-09-07 | 2020-04-24 | 康宁股份有限公司 | Optical system for cell culture monitoring and analyte measurement |
| CN109709346A (en) * | 2018-12-07 | 2019-05-03 | 英华达（上海）科技有限公司 | Automatic cytological analytical equipment and its operating method |
| CN109709346B (en) * | 2018-12-07 | 2022-08-02 | 英华达（上海）科技有限公司 | Automated cell analysis device and method of operating the same |
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