CN104614332A - Quantitative measurement method of cell DNA under redyeing environment - Google Patents
Quantitative measurement method of cell DNA under redyeing environment Download PDFInfo
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- CN104614332A CN104614332A CN201510052983.8A CN201510052983A CN104614332A CN 104614332 A CN104614332 A CN 104614332A CN 201510052983 A CN201510052983 A CN 201510052983A CN 104614332 A CN104614332 A CN 104614332A
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Abstract
The invention provides a quantitative measurement method of cell DNA under redyeing environment. The quantitative measurement method of the cell DNA under the redyeing environment comprises the following steps: firstly dyeing a slide carrying cast-off cells by using a plurality of same pure dyes; subsequently carrying out multispectral imaging on a multispectral imaging system which is not put into the slide to obtain a spectral image with incident intensity, then sequentially inserting slides which are dyed by pure dyes to calculate the absorbancy of the dyes; measuring absorbancy images of all the dyes and then integrating the absorbancy images into a matrix X in a formula as y=Xc+e; calculating to obtain a model as M=(XtX)-1Xt; and measuring an absorption spectrum image y(lambda) by using to-be-analyzed cells which are dyed by using the redyeing dyes and the multichannel imaging system, then calculating relative concentrations of various dyes on the cell according to the model M and the formula as c=My and calculating the relative content of DNA in the cell according to Feulgen dye concentration which is in direct ratio with the content of DNA in the cell. The method can be used for stripping Feulgen dyeing and Papanicolaou dyeing and can also be used for simultaneously carrying out quantitative measurement of DNA in the cell and quantitative analysis of cellular morphology.
Description
Technical field
The present invention relates to cast-off cells plate coating checking method, especially relate to muti-spectrum imaging and cell component quantitative analysis method, belong to cell dyeing technical field of imaging.
Background technology
Cervical carcinoma is one of gynaecology's malignant tumour occurred frequently, is the key improving cervical carcinoma cure rate and survival rate to the early diagnosis of cervical carcinoma and canceration.The most frequently used screening methods of cervical cancer of current China is TBS classification, early diagnosis of cancer needs the cell selecting a few canceration from up to ten thousand cells, this method needs doctor to carry out long-time artificial diagosis examination, increases working strength and the personal error of doctor greatly.
The existing a large amount of report of diagnosis of precancerous lesions of uterine cervix is carried out, at North America and European cell DNA image quantitative analysis diagnostic method as one of a kind of routine clinical detection method with cell DNA image quantitative analysis diagnostic method.At home, many big cities also start to carry out cervical carcinoma screening with full-automatic DNA quantified system analysis.Much research shows, DNA quantitative cytology diagnostic method diagnosis aspect in early days has greater advantages.
There are two kinds of methods at present in conjunction with TBS and DNA quantitative check.
One cell smear is first done DNA dyeing, carry out cervical carcinoma screening with full-automatic DNA image quantified system analysis, find after can obtaining cancer cell, DNA dyeing is faded with chemical reagent again, and then do pap staining and redye, facilitate doctor directly to check the cancer cell checked out.Shortcoming is complicated operation, and the cancer cell found likely comes off in the process of fading.
Another method does 2 cell smears, a pap staining does TBS classification, a full-automatic DNA quantified system analysis of Fu Ergen (Feulgen) tint applications does DNA content and measures, can once draw materials in clinical practice, film-making simultaneously, coloured differently, two kinds of technology detect simultaneously, can realize having complementary advantages, can accuracy rate of diagnosis be significantly improved.Shortcoming is the abnormal cell that DNA quantified system analysis is found out, and doctor cannot carry out TBS classification by the cellular morphology be familiar with.Doctor also carefully must reexamine the microslide of an other pap staining, and search cancerous tumor cell confirms.
Summary of the invention
The present invention proposes one and redye cell DNA method for quantitative measuring under environment, cell DNA can be carried out quantitatively and morphometry simultaneously; After the cancer cell simultaneously found out in instrument DNA quantitative scanning, doctor can carry out the cast-off cells TBS that doctor is familiar with easily in position and check.
Object of the present invention carrys out specific implementation by the following technical programs:
One redyes cell DNA method for quantitative measuring under environment, comprises the following steps:
Step a, the slide being loaded with cast-off cells to be dyeed respectively with multiple single pure dye;
Step b, first carry out multispectral imaging to the multi-optical spectrum imaging system not putting into dyeing glass slide, obtain the spectrum picture Io (λ) of incident intensity, wherein λ is optical wavelength;
The slide of step c, insertion pure dye dyeing successively again obtains spectrum picture I (λ), calculates the absorbance x of dyestuff accordingly
i(λ)=log (Io (λ)/I (λ));
Steps d, repetition step c, measure the absorbance image x of all dyestuffs
i(λ), then comprehensively sensitivity matrix X is become, X=[x
1, x
2... x
n];
Step e, calculate model M=(X
tx)
-1x
t;
Step f, redye cell to be analyzed together with all dyestuffs in step a, under the slide being loaded with the cell to be analyzed contaminated is placed in microscope, its absorption spectrum image y (λ) is measured with multi-optical spectrum imaging system, the relative concentration of dyestuff is calculated, c=(c according to formula c=My
1, c
2, c
3... c
n), be the concentration that dyestuff is to be measured; Before dyeing, cell nuclear dna produces the aldehyde radical with reducing action after dilute acid hydrolysis, described aldehyde radical is combined with Fu Ergen dyestuff, the concentration of Fu Ergen dyestuff is proportional to nuclear DNA content, thus calculates endonuclear DNA content according to the concentration of Fu Ergen dyestuff.
The spectrum segment of described multi-optical spectrum imaging system is more than or equal to dyestuff number, to calculate the relative concentration of dyestuff.
The spectrum segment of described multi-optical spectrum imaging system adopts the spectrum segment of 480nm-680nm.
On the basis of the spectrum segment of setting, spectrum picture acquisition interval is 10-100nm.
Described multi-optical spectrum imaging system, comprises object lens, imaging lens, video camera and computing machine, the light path between described object lens and imaging lens is provided with electric tuning light filter.
Described camera placements is in the rear end of imaging lens, and the imaging data of described video camera docks with described computing machine.
Further, described multi-optical spectrum imaging system also comprises controller, in order to control the position in the light path of described electric tuning light filter between described object lens and described imaging lens.
Described controller docks with described computing machine, and accepts the instruction of described computing machine, and then controls the action of described electric tuning light filter.
Feulgen's stain and pap staining can be peeled off by the method that the present invention proposes.Cell DNA can be carried out quantitatively and morphometry simultaneously; The cancer cell simultaneously found out after instrument DNA quantitative scanning, doctor can carry out the cast-off cells TBS that doctor is familiar with easily in position and check.
Accompanying drawing explanation
According to drawings and embodiments the present invention is described in further detail below.
Fig. 1 uses dyestuff spectral curve, and can find out that Yihong, BG, Fu Ergen dyestuff exist overlapping at the absorption spectrum of visible light wave range, when therefore redying, Yihong and BG can disturb the quantitative measurment of Fu Ergen dye strength;
Fig. 2 is the multi-spectral imager structural drawing that the present invention adopts;
Fig. 3 is that we use liquid crystal tunable filter optical filtering curve;
Fig. 4 redyes cell at 530nm wave band imaging effect figure, the light absorption in main reflection Yihong;
Fig. 5 redyes cell at 580nm wave band imaging effect figure, the light absorption of main reflection Fu Ergen;
Fig. 6 redyes cell at 50nm wave band imaging effect figure, the light absorption of main reflection BG;
Fig. 7 redyes the design sketch that cell adopts the rear only surplus Fu Ergen dyestuff of inventive method stripping herein, cytoplasm has slight remaining be there is dispersion because of optical system, although we have taken the measure reducing dispersion.This also can find out from Fig. 4-6, and Fig. 5 is the most clear, but Fig. 4 and Fig. 6 exists fuzzy;
Fig. 8 redyes the cell DNA exponential distribution figure that rear employing the present invention records;
Fig. 9 is the same routine cell DNA exponential distribution figure only recorded with feulgen's stain.
Embodiment
As shown in Figure 1, use dyestuff spectral curve, can find out that Yihong, BG, Fu Ergen dyestuff exist overlapping at the absorption spectrum of visible light wave range.
The theory diagram of the muti-spectrum imaging instrument that we build as shown in Figure 2.The white light that light source 1 sends illuminates the cast-off cells on microslide 2 after dyeing, cast-off cells are positioned in the focus of micro objective 3, the light of the point therefore on cast-off cells, directional light is being become after micro objective 3, be imaged on the target surface of video camera 7 through microscope imaging mirror 6 by cell image again, this is general microscopical principle of work.The system that we build inserts an electric tuning light filter 4 (can be acousto-optic tunable filter AOTF and liquid crystal tunable filter) between micro objective 3 and microscope imaging mirror 6, computing machine 8 sends control signal as required, and control electric tuning light filter 4 by needing the light of wave band by the controller 5 of electric tuning light filter, what now video camera collects is exactly the spectrum picture of this wave band.Regulable control electric tuning light filter 4 successively, obtains the micro-multispectral image of cell.
With electric tuning light filter is placed between microscope imaging mirror and CCD different by general multi-optical spectrum imaging system, electric tuning light filter 4 is placed between micro objective 3 and microscope imaging mirror 6 by we.We know, when adopting parallel light path between micro objective 3 and microscope imaging mirror 6, distance (light path) change between micro objective 3 and microscope imaging mirror 6 does not affect microscopical imaging.Electric tuning light filter 4 is thick optical body, different dispersive powers is had to different wavelength, therefore when just electric tuning light filter is placed between microscope imaging mirror and CCD, different wave length focus is different, be difficult to know imaging simultaneously, and our scheme does not have this problem, therefore contribute to the stripping algorithm implementing the present invention's proposition.
First, the smear of the cast-off cells single pure dye redyed is dyeed respectively.Start multi-optical spectrum imaging system, first carry out multispectral imaging to the system not putting into dyeing glass slide, obtain incident intensity spectrum picture Io (λ), wherein λ is optical wavelength; And then the slide inserting pure dye dyeing successively obtains spectrum I (λ), can calculate the absorbance x of dyestuff accordingly
i(λ)=log (Io (λ)/I (λ)); Measure the absorbance image x of all dyestuffs
i(λ) (I=1 – N, N are the sum of dyestuff), then combines the matrix X in composite formula (3).Then model M=(X is calculated
tx)
-1x
t.(X represents matrix, X
trepresent this matrix transpose, X
-1representative is by this matrix inversion)
After this, cell to be analyzed can be redyed with all dyestuffs, under the slide being loaded with the cell to be analyzed contaminated is placed in microscope, its absorbance image y (λ) is measured with multi-optical spectrum imaging system, then calculate the relative concentration of various dyestuff according to formula (4), then can be calculated the DNA content of cell by the concentration of Fu Ergen dyestuff.
As long as the spectrum segment of multispectral imaging is more than or equal to dyestuff number, just can calculate the relative concentration of dyestuff, but the number suitably increasing spectrum segment can improve the precision of measurement.
Consider that short-wave band light signal strength is less, noise is large, and the absorption of each dyestuff is all less after 700nm.We have employed the spectrum segment of 480nm-680nm, and every 10nm gathers a spectrum picture.
Fig. 3 redyes to use dyestuff spectral curve, calculates model M=(X accordingly
tx)
-1x
t.
Fig. 4-6 redyes cell 530, and 580 and 650nm wave band imaging effect figure, can find out that all dyestuffs all have absorption, and overlap at three wave bands;
Fig. 7 redyes cell to adopt inventive method herein to peel off the design sketch of rear only surplus Fu Ergen dyestuff, and can find out to only have on nucleus have absorption, it is the absorption of Fu Ergen dyestuff;
Fig. 8 redyes the cell DNA exponential distribution histogram that rear employing the present invention records;
Fig. 9 is the same routine cell DNA exponential distribution histogram only recorded with feulgen's stain; Can find out that the same routine cell of cell DNA exponential sum adopting the present invention to record when redying only records DNA exponential distribution figure with feulgen's stain substantially identical, illustrating and adopt the inventive method, Yihong and the impact of BG in DNA measure spectrum section (580nm) can be deducted when redying well.
DNA quantitative cytology mainly judges physiological status and the pathological change of cell by the mensuration of DNA content in nucleus.Fu Ergen DNA dyeing is the colouring method of the single-minded display DNA (deoxyribonucleic acid) of a kind of energy, and the shade after nuclear targeting is relevant with DNA content.According to Lambert-Beer law, monochromatic absorbance is proportional to the content of material, and the content of material is more, and absorb light more, the transmission of light is lower, and Lambert-Beer law expression formula is:
A＝-lg(I/I
0)＝εbC (1)
In formula, I
0for parallel, the even incident homogeneous beam intensity that wavelength is λ; I is through the beam intensity after target; A is luminosity degree; ε is the molar absorptivity of component to be measured; B is light path; C is the substance withdrawl syndrome of component to be measured.
The quality of human normal diploid cell DNA is about 7.18pg, utilize the method for Lambert-Beer law and image procossing to measure the integral optical density of whole cell, and the DNA content of cell to be measured can be obtained by the ratio of integral optical density and normal cell integral optical density.
The bus dyeing that what TBS classification adopted is Yihong, the dyestuff such as BG, haematoxylin carries out, feature is that nucleus and the display of cytoplasm form are clear, has abundant color information.But we find out from accompanying drawing 1, the absorption spectrum of Yihong, BG and the absorption spectrum of Fu Ergen dyestuff also exist overlap.Traditional DNA quantitative test uses the monochromatic light of a specific band (being generally 580nm), in this spectrum segment, when redying, the absorption of Yihong, BG is superimposed upon above the absorption optical density measurements of Fu Ergen simultaneously, therefore cannot correct measurement cell DNA content.
Favourable turn can be there is in employing multispectral imaging then problem.Multispectral imaging is a kind of novel imaging technique, obtains being a three-dimensional data, can obtain the image of cell for specific wave band, and any point for cell then can obtain an absorption spectrum.
According to spectral theory, on cell, the absorption spectrum y (λ) of any point can indicate by following linear adduction mathematical model:
y＝c
1x
1+c
2x
2+…+c
nx
n+e (2)
In formula: y represents the spectrum vector redying dyestuff, x
i(i=1,2 ... n) be the spectrum of single pure dye, notice that different materials should have different spectrum vectors, so x
i(i=1,2 ... n) be the vector of mutual linear independence; E is error vector, e=[e
1, e
2... e
n], be generally Normal Distribution etc. variance white noise error; N is dyestuff kind number, c=(c
1, c
2, c
3... c
n) be unknown parameter to be measured, if be the relative concentration of dyestuff. adopt matrix representation, above formula can be rewritten as:
y＝Xc+e (3)
In formula: X=[x
1, x
2... x
n], can be described as sensitivity matrix, c=(c
1, c
2..., c
n) be unknown solve for parameter vector, or be called concentration vector to be measured.The curve of spectrum of dyestuff is as shown in Figure 1:
Surveying vector and actual to measure vector error minimum by making to be estimated, namely making
be tending towards minimum, order
Notice in above formula, only have c to be unknown quantity, therefore the minimum of f (c) can be obtained to its differentiate.Because
In the derivation of above formula, because of
be a scalar, therefore have
therefore can obtain above formula differentiate:
Make above formula equal zero, can obtain immediately,
X
tXc＝X
ty
That is
Make M=(X
tx)
-1x
t
Then c=My
So far, above formula shows: by the spectrum matrix X Modling model M of pure dye, and the composite absorption spectrum y recorded from multispectral imaging calculates the relative concentration of various dyestuff.
Claims (10)
1. redye a cell DNA method for quantitative measuring under environment, it is characterized in that, the method comprises the following steps:
Step a, the slide being loaded with cast-off cells to be dyeed respectively with multiple single pure dye;
Step b, first carry out multispectral imaging to the multi-optical spectrum imaging system not putting into dyeing glass slide, obtain the spectrum picture Io (λ) of incident intensity, wherein λ is optical wavelength;
The slide of step c, insertion pure dye dyeing successively again obtains spectrum picture I (λ), calculates the absorbance x of dyestuff accordingly
i(λ)=log (Io (λ)/I (λ));
Steps d, repetition step c, measure the absorbance image x of all dyestuffs
i(λ), then comprehensively sensitivity matrix X is become, X=[x
1, x
2... x
n];
Step e, calculate model M=(X
tx)
-1x
t;
Step f, redye cell to be analyzed together with all dyestuffs in step a, under the slide being loaded with the cell to be analyzed contaminated is placed in microscope, measure its absorption spectrum image y (λ) with multi-optical spectrum imaging system, y=[y
1, y
2... y
n], then calculate the relative concentration of dyestuff according to formula c=My, c=(c
1, c
2, c
3... c
n), be the concentration that dyestuff is to be measured;
Before dyeing, cell nuclear dna produces the aldehyde radical with reducing action after dilute acid hydrolysis, described aldehyde radical is combined with Fu Ergen dyestuff, the concentration of Fu Ergen dyestuff is proportional to nuclear DNA content, thus calculates endonuclear DNA content according to the concentration of Fu Ergen dyestuff.
2. one as claimed in claim 1 redyes cell DNA method for quantitative measuring under environment, and it is characterized in that, the spectrum segment of described multi-optical spectrum imaging system is more than or equal to dyestuff number, to calculate the relative concentration of dyestuff.
3. one as claimed in claim 2 redyes cell DNA method for quantitative measuring under environment, and it is characterized in that, the spectrum segment of described multi-optical spectrum imaging system adopts the spectrum segment of 480nm-680nm.
4. one as claimed in claim 3 redyes cell DNA method for quantitative measuring under environment, and it is characterized in that, on the basis of the spectrum segment of setting, spectrum picture acquisition interval is 10-100nm.
5. the one as described in any one of Claims 1-4 redyes cell DNA method for quantitative measuring under environment, it is characterized in that, described multi-optical spectrum imaging system, comprises object lens, imaging lens, video camera and computing machine, the light path between described object lens and imaging lens is provided with electric tuning light filter.
6. one as claimed in claim 5 redyes cell DNA method for quantitative measuring under environment, and it is characterized in that, described camera placements is in the rear end of imaging lens, and the imaging data of described video camera docks with described computing machine.
7. the one as described in claim 5 or 6 redyes cell DNA method for quantitative measuring under environment, it is characterized in that, also comprises controller, in order to control the position in the light path of described electric tuning light filter between described object lens and described imaging lens.
8. one as claimed in claim 7 redyes cell DNA method for quantitative measuring under environment, and it is characterized in that, described controller docks with described computing machine, and accepts the instruction of described computing machine, and then controls the action of described electric tuning light filter.
9. the one as described in any one of claim 1 to 8 redyes cell DNA method for quantitative measuring under environment, and it is characterized in that, the sequencing of step a, step b is adjustable.
10. the one as described in any one of claim 1 to 8 redyes cell DNA method for quantitative measuring under environment, it is characterized in that, can peel off feulgen's stain and pap staining by the method that the present invention proposes.
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