CN105181649A - Novel label-free pattern recognition cytometer method - Google Patents
Novel label-free pattern recognition cytometer method Download PDFInfo
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Abstract
The invention discloses a novel label-free pattern recognition cytometer method. The method comprises steps as follows: a to-be-tested label-free cell solution is prepared and introduced into a micro-fluid channel, or a cell suspension chip is prepared; transmitting laser excites to-be-tested cells to form scattered light distributed in three-dimensional space, the scattered light passes through an optical imaging system or does not pass through any optical imaging system and is detected by a two-dimensional CMOS (complementary metal oxide semiconductor) detector, and two-dimensional light scattering patterns corresponding to the to-be-tested cells are obtained; the obtained two-dimensional light scattering patterns are transmitted to a pattern recognition and classification system, and the system automatically learns the two-dimensional light scattering patterns belonging to different types of known cells and performs label-free and automatic recognition on unknown cells. Recognition results trigger corresponding devices, and a label-free and automatic cell counting or cell classification function is realized. With the adoption of the method, complex fluorescent staining is not required to be performed on cells, and recognition, counting and classification of the to-be-tested cells can be realized in an automatic and label-free manner, operation is convenient and quick, the analysis cost is significantly reduced, and the application range is wide.
Description
Technical field
The present invention relates to cell classification identification, particularly utilize and exempt from the light scattering drawing information that labeled cell instrument obtains cell, then pattern-recognition is carried out to light scattering pattern, realize exempting from mark, automatic cytological counting or classification feature.
Background technology
Conventional flow cytometer can be used for analysis and the sorting of cell.In general, conventional flow cytometer need carry out dyeing process to cell, and fluorescent dye or other biological mark may produce certain impact to cell, particularly in active somatic cell functional study.Secondly, light path needed for fluorescence measurement is complicated, and this directly increases instrument cost, and fluorescence measurement needs to calibrate instrument, and complicated operation, needs professional.Finally, in later stage signal transacting, overlapped owing to may exist between fluorescence emission spectrum, need to carry out the operations such as complementary color, and existing streaming cell instrument is in later stage cell classification identification, can only according to predetermined physics, the corresponding cell subsets of chemical feature parameter ranges identification, lack automatic machine learning and carry out the function of Classification and Identification, particularly exempting from mark, automatic cytological Classification and Identification.
The examination of cervical carcinoma is mainly by means of cervical cytological examination and HPV immune detection clinically.For cervical cytological examination, first from the cervical cell that cervical tissue collection comes off, to be dyeed, film-making, then carried out artificial diagosis under the microscope by clinicopathologia doctor.Experienced doctor can differentiate the normal and cancerous tumor cell of uterine neck comparatively accurately, sometimes may need to carry out HPV detect and Biopsy under Colposcopy to make a definite diagnosis.Cervical cytological examination process steps is complicated, length consuming time, and artificial diagosis needs doctor to have abundant clinical experience, and diagosis result has stronger subjectivity.HPV detect and Biopsy under Colposcopy accuracy rate high but more difficult popularize.
Summary of the invention
The invention discloses a kind of Novel free marking mode identification cell instrument method, exempt from the basis of the two-dimentional light scattering pattern of labeled cell or cell aggregation group in acquisition, pattern-recognition is carried out to scattering pattern, reaches the object exempting from mark, automatic cytological counting and Classification and Identification.The method, in sample process, overcomes the shortcoming that conventional flow cytometer needs to carry out fluorescent dye, achieves the sample process exempting to mark; Light path system overcomes the shortcoming that conventional flow cytometer light path is complicated, cost is high; In signal transacting, novelty have employed pattern-recognition to carry out the automatic classification identification of scattering pattern.The organic integration of above technology achieves the innovation on cell sorting method.In result of use, this innovative approach can be used for the quick identification of cell aggregation group quantity, also achieves the uterine neck HeLa cell of normal cervical cell and canceration and exempts from marker recognition.
A kind of Novel free marking mode identification cell instrument method, concrete scheme comprises the following steps:
Make and to be measuredly exempt from labeled cell solution and import in microchannel or make cell suspension chip;
The light that LASER Light Source sends is coupled into optical fiber through four times of object lens, and fiber optic conduction laser also excites the unicellular or many cells gathering groups in microchannel or cell suspension, distributes in three-dimensional scattered light;
Scattered light, through optical imaging system, is detected by two-dimentional cmos detector and obtains two-dimentional light scattering pattern corresponding to cell to be measured;
Or scattered light, without the need to through optical imaging system, is detected by two-dimentional cmos detector and obtains two-dimentional light scattering pattern corresponding to cell to be measured;
The two-dimentional light scattering pattern obtained transfers to pattern recognition classifier system, and this system, by carrying out machine learning to the two-dimentional light scattering pattern of known different cell category, realizes unmarked, robotization identification to unknown cell;
Recognition result is used for triggering and exempts from marking mode identification cell instrument automatic cytological counting or cellular classification system.
Further, the device that two-dimentional light scattering pattern acquisition is corresponding comprises: light-source system, excites the scattered light of tested cell for generation of LASER Light Source; Two dimension light scattering pattern detection register system, the scattered light of tested cell collected in record; Pattern recognition classifier system, carries out automatic classification identification by data processing and machine learning; Cell count or cellular classification system, comprise digital counter and mechanical type sorter.
Further, scattered light is through optical imaging system, when obtaining two-dimentional light scattering pattern corresponding to cell to be measured, mobile adjustment three-D displacement platform is needed to find laser convergent point, make LASER Light Source can enter in optical fiber with optimum coupling state after four times of object lens, the other end of optical fiber as probe for exciting the unicellular or cell aggregation group in microchannel or cell suspension.
Further, the scattered light that the cell in microchannel in solution to be measured is produced by laser excitation, through optical imaging system or without optical imaging system;
Through optical imaging system, in microchannel or cell suspension, cell to be measured is produced scattered light by laser excitation, and this scattered light is by ten times of object lens observations, adjust ten times of object lens, observe the original image of cell, these object lens are defocused, CMOS dimension sensor obtains scattered light pattern.
Without optical imaging system, namely without any need for optical imaging lens, scattered light, through a physical pore size, directly forms two-dimentional light scattering pattern in CMOS plane.
Further, algorithm for pattern recognition adopts and strengthens AdaBoost algorithm, to the N number of two-dimentional light scattering pattern detected, select the pattern training of N-1 known classification, obtain the Weak Classifier of one group of pattern-recognition, then with the combination of this Weak Classifier, original N number of pattern is tested, select the strongest Weak Classifier combination by loop test, finally obtain the high-accuracy to cell classification identification to be measured.
Further, said method is used for the classification of yeast cells cluster group.
Further, said method is used for the classification of normal cervix cell and canceration cervical cell.
Beneficial effect of the present invention:
(1) the Novel free marking mode identification cell instrument device of the present invention's proposition is easy, overcomes the shortcomings such as conventional flow cytometer light path complexity, apparatus expensive, complex operation, can easy quick acquisition two dimension light scattering pattern.
(2) the unmarked technology that adopts of the present invention, overcoming conventional flow cytometer needs to carry out fluorescent dye to cell, thus may cause the problem that cell sample damages, and fluorescent dye can be avoided the cell particularly interference that causes of living cells function.
(3) the Novel free marking mode identification cell instrument that the present invention proposes can realize exempting from mark, mechanized classification identification to cell or cell mass, namely reaches the Classification and Identification to cell to be measured by the algorithm for pattern recognition of robotization.
(4) the Novel free marking mode identification cell instrument generalization ability of the present invention's proposition is strong, can be widely used in the Classification and Identification of different cell.
(5) analytic process of the present invention is workable, can choose the Weak Classifier composition strong classifier of appropriate number, improve recognition accuracy as much as possible.After obtaining strong classification, operating personnel only need input detected image just can obtain Classification and Identification result automatically.
(6) proposed by the inventionly exempt from mark, automatic mode identification cell art, can be used for exciting corresponding physical counters or sorter, realize the counting to cell, sorting function.
(7) the invention provides a kind of novel determination methods of carrying out the differentiation of cell mass quantity.
(8) the invention provides a kind of novel determination methods of carrying out the HeLa cell classification of normal cervix cell and canceration.
Accompanying drawing explanation
Fig. 1 is structure and the schematic diagram of apparatus of the present invention,
The single yeast cells simulation drawing of Fig. 2 (a)-Fig. 2 (d) and the contrast of experiment scatter diagram;
The former figure of Fig. 3 (a)-Fig. 3 (d) varying number yeast cells gathering groups, scatter diagram contrast;
Fig. 4 (a)-Fig. 4 (d) normal cervix cell and the former figure of HeLa cell, scatter diagram contrast;
In Fig. 1: 1, LASER Light Source, 2, four times of object lens, 3, fiber coupler, 4, microchannel or cell suspension chip, 5, ten times of object lens or physical pore size, 6, two-dimentional cmos detector, 7, pattern recognition system, 8 categorizing systems;
Table 1 varying number yeast cells gathering groups classification results;
Table 2 normal cervix cell and HeLa cell classification result.
Embodiment:
Below in conjunction with accompanying drawing, the present invention is described in detail:
As shown in Figure 1, a kind of Novel free marking mode identification cell instrument is formed primarily of light-source system, two-dimentional light scattering pattern detection register system, data processing categorizing system.Wherein light-source system comprises LASER Light Source 1, four times of object lens 2, fiber coupler 3, microchannel or cell suspension chip 4; Two dimension light scattering pattern detection register system comprises ten times of object lens or physical pore size 5, two-dimentional cmos detector 6; Data processing categorizing system component analysis system comprises pattern recognition system 7, categorizing system 8.
Two-dimentional light scattering pattern detection system of the present invention comprises light scattering activating system that is unicellular and cell aggregation group, micro-fluidic or cell suspension chip system, and two-dimentional light scattering pattern obtains system.Data processing categorizing system of the present invention adopts algorithm for pattern recognition to carry out the late time data process of two-dimentional light scattering pattern, achieves to exempt from mark, mechanized classification identification to unicellular and cell mass.AdaBoost machine learning algorithm during the present invention identifies in mode is example, but is not limited to the identification using this specific mode identification method to carry out cell light scattering pattern.The present invention does not rely on traditional fluorescent dye and manual sort, by the pattern-recognition to scattering pattern, achieves and exempts from mark, mechanized classification identification to varying number yeast cells group and cervical cell different pathological status.Range of application of the present invention extends to physiology, the pathological analysis of general biological cell.Novel free marking mode identification cell instrument method disclosed in this invention, without the need to carrying out complicated fluorescent dye to cell, can exempt to mark, robotization realizes the classification of cell to be measured, identification, and the counting in later stage, sorting etc., simple and efficient to handle, result accurately and reliably, significantly reduces analysis cost, has wide range of applications.
The detailed description of concrete operation step is carried out below in conjunction with accompanying drawing 1 couple of the present invention:
Step one: prepare cell solution to be measured, the method according to different cell obtain solutions to be measured is not quite similar.
Step 2: cell solution to be measured is imported microchannel 4 or makes cell suspension chip 4.
Step 3: open LASER Light Source 1, LASER Light Source 1 adopts 532nm wave-length green laser diode pumping solid laser (DPSS).Diode pumping solid laser has that longevity of service, efficiency are high, consume energy low, the significant advantage such as thermal effect is little, volume is little.In order to ensure diameter be 1.0mm laser beam can be coupled into diameter 105 μm to greatest extent, numerical aperture (NA) is in the optical fiber of 0.22, the present invention selects numerical aperture to be that four times of object lens 2 of 0.1 are to improve coupling efficiency.
Step 4: constantly mobile adjustment calibration laser coupling mechanism makes LASER Light Source after four times of object lens 2, can enter optical fiber one end in fiber coupler 3 with optimum coupling state.The optical fiber other end of fiber coupler 3 as probe for exciting cell in microchannel 4 or cell suspension chip 4 or cell mass.
Step 5: in laser excitation microchannel 4 or cell suspension chip 4, cell to be measured produces scattered light.First observed by object lens, moving fiber removes positioning cells, until cell to be measured is in the centre of laser beam and can excites side scattered light completely.
Step 6: the two-dimentional light scattering pattern obtaining cell to be measured.Adjust ten times of object lens 5, make the cell image in the visual field the most clear, what at this time obtain is the original image of cell.The image that the present invention will obtain is not the imaging of cell own, but its two-dimensional scattering optical pattern formed.On focusing basis, according to identical direction and identical distance adjustment object lens, namely carry out " defocusing ", at this time will form two-dimentional light scattering pattern in cmos image sensor 6 plane.Cmos image sensor of the present invention is of a size of 22.3 × 14.9mm, and recording pixel is approximately 17,900,000.Adopt cmos image sensor to have integrated level high, power consumption is little, and cost is low, easily and the advantage such as other chip integration.Or cell scattering light, without any optical imaging system, namely without any lens, also by means of physical pore size 5, cmos detector 6 plane can will form two-dimentional light scattering pattern.
Step 7: the two-dimentional light scattering pattern collected by the cmos image sensor 6 of acquisition is conveyed into pattern recognition system 7.
Step 8: the scattering pattern of acquisition is carried out standardization, is unified into 220 × 220 pixels.Scattering pattern using forestland recognizer after standardization carries out Classification and Identification.
Step 9: in pattern recognition system 7, as the case may be, can use corresponding pattern-recognition to calculate and carries out Classification and Identification.The present invention is for AdaBoost algorithm, to the N number of scattering pattern detected, use the method for leave-one-out, select the pattern training of N-1 known classification wherein, then with the N number of pattern stayed, the combination of this Weak Classifier is debugged, thus obtain one group of Weak Classifier combination.Then, by original N-1 training sample one of them with the N number of pattern change originally to stay, from and training obtain one group of Weak Classifier.Obtain multilayer Weak Classifier according to such method, choose the multilayer Weak Classifier of respective numbers, by the classification results of Weak Classifier is complementary thus effectively combine, build a strong sorter.The number of the multilayer Weak Classifier comprised of this strong classifier, can make classification results optimum.When training sample is abundant, final sorter can be obtained by single training and encapsulate, thus meet Classification and Identification requirement.
Step 10: by pattern recognition system automatic learning cell two dimension to be measured light scattering pattern, realize exempting from mark, robotization identification to unknown cell.Recognition result triggers corresponding categorizing system 8 device, realizes exempting from marking, the cell count of robotization or cell classification function.
Embodiment 1
Configure the yeast soln that concentration is suitable, use device of the present invention to obtain the two-dimentional light scattering pattern of yeast soln, experimental result and theoretical modeling result are carried out contrast verification.Fig. 2 illustrates theoretical modeling result Fig. 2 (a) of the two-dimensional scattering pattern that single yeast cells is formed and the contrast of Fig. 2 (b) and experimental result Fig. 2 (c) and Fig. 2 (d).Yeast is unicellular microorganism, and cell dia is approximately 3-6 μm, and the scatter diagram of experiment presents two kinds of different aspect graphs 2 (c) and Fig. 2 (d).In simulation, yeast cells is assumed that the spheric grain with different-diameter, and refractive index is 1.42, incident wavelength 532nm, and surrounding medium refractive index is that in 1.334, Fig. 2 (a), cell dia elects 3.8 μm as, and in (b), diameter is 5.0 μm.As can be observed from Figure, experimental result and theoretical modeling result are striped quantity or fringe position coincide all mutually, can verify the accuracy of apparatus of the present invention.
Embodiment 2
Use device of the present invention, from 60 groups of yeast cells gathering groups, obtain 60 corresponding gathering groups two dimension light scattering patterns.Wherein, there is the pattern that 30 groups are 3 yeast cells and assemble, other 30 groups of patterns being 4 yeast cells and assembling.The size of each scattering pattern is 220 × 220 pixels, and through normalized, as Fig. 3 (a)-Fig. 3 (d).
The present invention uses AdaBoost method to carry out leave-one-out experiment.Concrete implementation step is: to the light scattering pattern training of 59 known classification (3 yeast cells are assembled or 4 yeast cells gatherings), obtain the Weak Classifier of one group of pattern-recognition, then with the 60th pattern, this Weak Classifier is tested.The correct number (CN) of record test data, calculates accuracy (AR) by formula AR=CN/TN.TN represents the quantity of all two-dimentional light scattering patterns.As shown in table 1, research finds that respective change occurs AR when the number of plies of Weak Classifier increases.The present invention uses 3 layers of Weak Classifier, can obtain maximum accuracy 86.7%.Be wherein 93.3%, 4 yeast cells gathering groups AR for 3 yeast cells gathering groups AR be 80%.
Table 1 yeast cells gathering groups classification results
Embodiment 3
Apparatus of the present invention are used for the Classification and Identification of normal cervix cell and canceration cervical cell (HeLa cell).For the Classification and Identification of cervical cell, marking mode identification cell instrument method of exempting from of the present invention is utilized to obtain 92 two-dimentional light scattering patterns altogether, wherein 54 is normal cervix cell light scattering pattern, 38 is HeLa cell light scattering pattern, and result is as shown in Fig. 4 (a)-Fig. 4 (d).When utilizing AdaBoost method to carry out pattern-recognition, train Weak Classifier with 91 scattering patterns, the 92nd is used for testing.As shown in table 2, research finds that the accuracy rate AR of the classification when the Weak Classifier number of plies is 7 reaches maximal value 90.2%, and wherein the accuracy AR of normal cervix cell is the accuracy AR of 90.7%, HeLa cell is 89.5%.The cervical cell of normal cervix cell and canceration is under the observation of 400 power microscopes, and their profiles are similar, but its inner structure there occurs change.The pattern of two dimension light scattering comprises the information of cell interior change, and exempting from marking mode identification cell instrument can this two classes cell of Classification and Identification of robotization.In the present invention, the cervical cell Classification and Identification accuracy of 90.2% shows that exempting from marking mode identification cell instrument has good potential applicability in clinical practice.
Table 2 cervical cell classification results
Above-mentioned by reference to the accompanying drawings to the description that the specific embodiment of the present invention is carried out; not limiting the scope of the invention; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Claims (8)
1. a Novel free marking mode identification cell instrument method, is characterized in that, comprise the following steps:
Make and to be measuredly exempt from labeled cell solution and import in microchannel or make cell suspension chip;
The light that LASER Light Source sends is coupled into optical fiber through four times of object lens, and fiber optic conduction laser also excites the unicellular or many cells gathering groups in microchannel or cell suspension, distributes in three-dimensional scattered light;
Scattered light, through optical imaging system, is detected by two-dimentional cmos detector and obtains two-dimentional light scattering pattern corresponding to cell to be measured;
Or scattered light, without the need to through optical imaging system, is detected by two-dimentional cmos detector and obtains two-dimentional light scattering pattern corresponding to cell to be measured;
The two-dimentional light scattering pattern obtained transfers to pattern recognition classifier system, and this system, by carrying out machine learning to the two-dimentional light scattering pattern of known different cell category, realizes unmarked, robotization identification to unknown cell;
Recognition result is used for triggering and exempts from marking mode identification cell instrument automatic cytological counting or cellular classification system.
2. a kind of Novel free marking mode identification cell instrument method as claimed in claim 1, is characterized in that, two-dimentional light scattering pattern obtains corresponding device and comprises: light-source system, excites the scattered light of tested cell for generation of LASER Light Source; Two dimension light scattering pattern detection register system, the scattered light of tested cell collected in record; Pattern recognition classifier system, carries out automatic classification identification by data processing and machine learning; Cell count or cellular classification system, comprise digital counter and mechanical type sorter.
3. a kind of Novel free marking mode identification cell instrument method as claimed in claim 1, it is characterized in that, scattered light is through optical imaging system, when obtaining two-dimentional light scattering pattern corresponding to cell to be measured, mobile adjustment three-D displacement platform is needed to find laser convergent point, make LASER Light Source can enter in optical fiber with optimum coupling state after four times of object lens, the other end of optical fiber as probe for exciting the unicellular or cell aggregation group in microchannel or cell suspension.
4. a kind of Novel free marking mode identification cell instrument method as claimed in claim 1, it is characterized in that, in microchannel or cell suspension, cell to be measured is produced scattered light by laser excitation, this scattered light is by ten times of object lens observations, adjust ten times of object lens, observe the original image of cell, these object lens are defocused, CMOS dimension sensor obtains scattered light pattern.
5. a kind of Novel free marking mode identification cell instrument method as claimed in claim 1, it is characterized in that, the scattered light that cell in microchannel in solution to be measured is produced by laser excitation, without optical imaging system, namely without any need for optical imaging lens, scattered light, through a physical pore size, directly forms two-dimentional light scattering pattern in CMOS plane.
6. a kind of Novel free marking mode identification cell instrument method as claimed in claim 1, it is characterized in that, algorithm for pattern recognition adopts and strengthens AdaBoost algorithm, to the two-dimentional light scattering pattern of the N number of unicellular or cell aggregation group detected, select the pattern training of N-1 known classification, obtain the Weak Classifier of one group of pattern-recognition, then with the N number of pattern originally stayed, this Weak Classifier is tested, comprised the strong classifier of some quantity Weak Classifiers by test acquisition one.
7. a kind of Novel free marking mode identification cell instrument method as claimed in claim 1, is characterized in that, said method is used for the classification of yeast cells gathering groups.
8. a kind of Novel free marking mode identification cell instrument method as claimed in claim 1, is characterized in that, said method is used for the classification of normal cervix cell and canceration cervical cell.
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| CN113155713A (en) * | 2021-05-28 | 2021-07-23 | 山东大学 | Label-free high-content video flow cytometer based on transfer learning and method |
| CN114418995A (en) * | 2022-01-19 | 2022-04-29 | 生态环境部长江流域生态环境监督管理局生态环境监测与科学研究中心 | Cascade algae cell statistical method based on microscope image |
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