CN107003240A - The discriminating conduct of tumor locus, the condition discriminating apparatus of tumor locus - Google Patents
The discriminating conduct of tumor locus, the condition discriminating apparatus of tumor locus Download PDFInfo
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
Abstract
The method and apparatus that the present invention realizes the discrimination that can more accurately carry out tumor locus than ever from the sample comprising the connective tissue containing the material with autofluorescence.The intensity distribution of the first light received with light transmissive first optical filter of the first band of the peak wavelength by the fluorescence for making to be sent comprising porphyrin in the fluorescence from sample is obtained respectively, pass through the light intensity distributions for making more to receive by light transmissive second optical filter of the second band of short wavelength side than first band, each image information corresponding with the light intensity distributions by making more to lean on light transmissive 3rd optical filter of the 3rd wave band of long wavelength side to receive than first band, based on these image informations, the generation image information corresponding with the intensity distribution for the fluorescence that the first smooth mesoporphyrin class is sent, the discrimination of tumor locus and non-tumor locus is carried out based on the image information.
Description
Technical field
The present invention relates to the discriminating conduct of tumor locus and the condition discriminating apparatus of tumor locus.
Background technology
Japan in recent years has welcome quick aging society, and cancer patient's number has increased trend.Particularly, in stomach
In the cancer in digestive system such as cancer and colorectal cancer, breast cancer, lymphatic metastasis is one of important Prognostic Factors, therefore, is being determined
The aspect of the treatment method of patient, it is very important that the presence or absence of lymphatic metastasis is diagnosed exactly.Sentinel lymph node refer to from
The lymph node that the cancer cell that primary tumor leaves is reached at first.Reach sentinel lymph node cancer cell quantity be initially it is limited,
Therefore, sentinel lymph node is investigated, if the transfer of cancer cell is few, it is considered that basic do not turn from sentinel lymph node
Move to the lymph node of end.
As a kind of method of quick diagnosis in art, as disclosed in Patent Document 1, commanded including Digestive
In wide spectrum including domain, application carries out Fluirescence observation using 5-ALA (5-ALA) for the detection of cancer
Method.5-ALA is one kind of the amino acid existed in organism, and it is water solubility, can orally, be partly administered.From
External to when using 5-ALA, in normal cell, tachymetabolism is ferroheme, but in cancer cell, active due to metabolic enzyme
Difference and optionally accumulate the protoporphyrin IX (PpIX) as metabolite.Here, ferroheme does not observe fluorescence, the opposing party
Face, PpIX is fluorescent material, therefore, by being detected to the light, can carry out the discrimination of tumor locus and non-tumor locus.
Prior art literature
Patent document
Patent document 1：International Publication No. 2013/002350
The content of the invention
Invent problem to be solved
But, in the organism of people, lymph node is existed with wrapping up by connective tissue, these connective tissue (fat, collagens
Albumen etc.) in indigo plant~green wavelength region send strong autofluorescence under the exciting light of blueness.The wave band of the autofluorescence with
The wave band of the above-mentioned fluorescence from PpIX has overlapping.
Fig. 1 is to show representational collagen and FAD (Flavin Adenine Dinucleotide, flavin adenine
Dinucleotides) as the material with autofluorescence contained in human organism fluorescence spectrum figure.Collagen exists
There is the peak value of fluorescence near 500nm, long wavelength side is more being leaned on than the peak wavelength, fluorescence intensity smoothly declines.In addition,
FAD has the peak value of fluorescence near 530nm, is more leaning on long wavelength side than the peak wavelength, fluorescence intensity smoothly declines.It is right
For any one material, near wavelength 650nm, although less than the fluorescence intensity under peak wavelength, but confirm tool
There is a certain degree of fluorescence intensity.
Fig. 2 is the fluorescence spectrum for showing to include Auto- fluorescence substance and PpIX sample as above-mentioned collagen, FAD
The figure of one.In Fig. 2, (a) shows the single fluorescence spectrums of PpIX, and (b) shows the fluorescence from Auto- fluorescence substance
Spectrum, (c) shows the fluorescence spectrum of actual measurement.It should be noted that in Fig. 2, by (a), (b), (c) each with mark
Graphics overlay obtained from the value of standardization is patterned is on same figure, in (a), (b), (c) each other, the longitudinal axis of figure
The magnitude relationship of value may not be consistent.
As shown in Fig. 2 (a), PpIX fluorescence spectrum has peak value near wavelength 635nm.Therefore, be free of in the sample
In the case of having Auto- fluorescence substance, by carrying out light splitting detection to the light from the light that sample is sent near wavelength 635nm
And its intensity distribution is investigated, the high position of the intensity can be characterized as tumor locus, more specifically, would indicate that more than rule
The position for determining the fluorescence intensity of threshold value is characterized as tumor locus.
But, Auto- fluorescence substance is actually contained in the sample, therefore, to the wavelength from the light that sample is sent
When light near 635nm carries out light splitting detection, the fluorescence from Auto- fluorescence substance shown in Fig. 2 (b) can be overlapping.Therefore, exist
Also fluorescence intensity near wavelength 635nm is observed in the position for not accumulating PpIX.The intensity of fluorescence from Auto- fluorescence substance
It is different according to the position of the tissue extracted as sample, also with individual difference.Therefore, according to by wavelength 635nm
The position that neighbouring fluorescence intensity exceedes defined threshold is characterized as the method for tumor locus, although not accumulating PpIX sometimes then,
Because the intensity of the fluorescence from Auto- fluorescence substance is high, it is also possible to which non-tumor locus is characterized as tumor locus by mistake.
That is, for the tumour that tumor locus is recognized in clinical practice, is particularly covered by the connective tissue of lymph node etc.
Position is, it is necessary to exclude the method for the autofluorescence produced by Inner sources property tissue.It is an object of the invention to realize can from comprising
Containing collagen, FAD so with autofluorescence material connective tissue sample in more accurately carry out than ever
The method and apparatus of the discrimination of tumor locus.
Method for solving problem
The present invention is a kind of discriminating conduct of tumor locus, and it is in the examination comprising tumor locus and autofluorescence position
Porphyrin that the above-mentioned tumor locus of sample is accumulated irradiation exciting light and to exciting after the fluorescence that is sent of above-mentioned porphyrin enter
The discriminating conduct of the tumor locus of row detection, it is characterised in that have：
The step of above-mentioned exciting light is to excite above-mentioned porphyrin (a) is irradiated to said sample；
Obtain in the light that expression said sample is sent by the peak value ripple for the fluorescence for making to be sent comprising above-mentioned porphyrin
The step of first image information of the intensity distribution for the first light that light transmissive first optical filter of long first band is received
(b)；
Obtain the second ripple by making more to lean on short wavelength side than above-mentioned first band in the light that expression said sample is sent
The step of second image information of the intensity distribution for the second light that light transmissive second optical filter of section is received (c)；
Obtain the 3rd ripple by making more to lean on long wavelength side than above-mentioned first band in the light that expression said sample is sent
The step of three image information of the intensity distribution for the 3rd light that light transmissive 3rd optical filter of section is received (d)；
Based on above-mentioned second image information and above-mentioned 3rd image information, generation with above-mentioned first light from above-mentioned autologous glimmering
The step of intensity distribution of the fluorescence that light position is sent corresponding four image information (e)；
Based on above-mentioned first image information and above-mentioned 4th image information, generation and above-mentioned porphyrin institute in above-mentioned first light
The step of intensity distribution of the fluorescence sent corresponding five image information (f)；With
The step of discrimination of tumor locus and non-tumor locus is carried out based on above-mentioned 5th image information (g).
There is the spectrum for the fluorescence that porphyrin is sent the fluorescence intensity at peak wavelength steeply to rise, than its peak value
The tendency that wavelength more drastically declines by long wavelength side and short wavelength side fluorescence intensity.On the other hand, what is contained in organism is autologous
The fluorescence spectrum of fluorescent material has fluorescence intensity with the tendency smoothly reduced towards long wavelength side from peak wavelength.
Exemplified with representational collagen and FAD as Auto- fluorescence substance in Fig. 1, but it is known also showed that in other materials it is big
Cause identical tendency.
Therefore, from the light that sample is sent, from the light (the second light) after the second filter transmission and saturating from the 3rd optical filter
Light (the 3rd light) after penetrating largely is made up of the fluorescence from Auto- fluorescence substance, though comprising porphyrin sent it is glimmering
Light, is also only limitted to a few part.Moreover, as described above, the fluorescence spectrum of Auto- fluorescence substance has than peak wavelength more
The tendency smoothly reduced by long wavelength side.Therefore, by the intensity distribution for representing the second light the second image information and represent the
3rd image information of the intensity distribution of three light, can be generated in the first band between second band and the 3rd wave band
Fluorescence intensity distribution (step (e)) from Auto- fluorescence substance.
The first image information obtained in step (b) is distributed for the fluorescence intensity of first band, corresponding to from autologous
The fluorescence of the fluorescent material intensity distribution overlapping with the fluorescence that porphyrin is sent.Therefore, based on the generation in step (e)
The 4th image information and the first image information, can generate the intensity distribution of the fluorescence sent with porphyrin it is corresponding
Five image informations (step (f)).Then, the discrimination of tumor locus and non-tumor locus is carried out based on the 5th image information, by
This can based on the fluorescence intensity substantially subtracted after the fluorescence from Auto- fluorescence substance, i.e. substantially porphyrin sent it is glimmering
Luminous intensity carries out the discrimination of tumor locus and non-tumor locus.Thereby, it is possible to more accurately carry out tumor locus than ever
Distinguish.
It should be noted that " porphyrin " in this specification refers to the compound that substituent is carried on porphyrin ring, make
For one kind of porphyrin, such as in addition to PpIX, also exist by Protoporphyrinses such as the PpIX light-protoporphyrins (PPp) generated.
In addition, in this specification, " second band that short wavelength side is more leaned on than first band " can constitute second band
Lower limit than constitute first band lower limit more by short wavelength side and constitute second band higher limit than constitute first wave
The higher limit of section more leans on the situation of short wavelength side.That is, as long as above-mentioned condition is set up, then first band can be one with second band
Part has overlapping.
Similarly, in this specification, " the 3rd wave band that long wavelength side is more leaned on than first band " can constitute the 3rd ripple
The lower limit of section is than constituting the lower limit of first band more by long wavelength side and constituting the higher limit of the 3rd wave band than constituting first
The higher limit of wave band more leans on the situation of long wavelength side.That is, as long as above-mentioned condition is set up, then first band and the 3rd wave band can be
A part has overlapping.
In the above method, as more specifically one, above-mentioned steps (e) can be based in above-mentioned second image information
The intensity distribution of shown above-mentioned second light be standardized using the value corresponding with the wavelength width of above-mentioned second band and
Obtained value and the intensity distribution of above-mentioned 3rd light shown in above-mentioned 3rd image information is utilized and above-mentioned 3rd wave band
The step of value is to generate above-mentioned four image information obtained from the corresponding value of wavelength width is standardized, above-mentioned steps
(f) the step of can including calculating the difference value of above-mentioned first image information and above-mentioned 4th image information.
It should be noted that in above-mentioned, as the value corresponding with the wavelength width of second band, such as can be used
The value of the full width at half maximum (FWHM) of two optical filters.Similarly, as the value corresponding with the wavelength width of the 3rd wave band, for example, it can use
The value of the full width at half maximum (FWHM) of 3rd optical filter.
The intensity distribution of second light is showed in the form of the intensity distribution of the light after the second filter transmission.Here, such as
It is upper described, it is included in the light sent from the second light after the second filter transmission corresponding to said sample in second band
The light of wavelength components.Therefore, by the way that the intensity distribution of the second light is entered using the value corresponding with the wavelength width of second band
Row standardization, can approx calculate the intensity distribution of the fluorescence under the central wavelength of second band.
Similarly, the 3rd is included in the light sent from the 3rd light after the 3rd filter transmission corresponding to said sample
The light of wavelength components in wave band.Therefore, by the way that the intensity distribution of the 3rd light is utilized into relative with the wavelength width of the 3rd wave band
The value answered is standardized, and can approx calculate the intensity distribution of the fluorescence under the central wavelength of the 3rd wave band.
By using the relevant information of the intensity distribution after being standardized with above-mentioned two, it can calculate included in first band
In a wavelength under fluorescence simulation intensity.But, the value is only included in a ripple in first band
The simulation intensity of fluorescence under long, therefore, corresponding to using as the fluorescence from Auto- fluorescence substance and included in first
The fluorescence of wavelength components in wave band is believed obtained from the value corresponding with the wavelength width of first band is standardized
Breath.Thus, for example by implementing the processing such as anti-standardization to the value, calculating as from Auto- fluorescence substance with can simulating
The fluorescence intensity distribution of fluorescence and the wavelength components included in first band.The information relevant with the intensity distribution of the light is corresponding
In the 4th image information.Above-mentioned processing is performed in step (e).
As described above, the 4th image information is represented with simulating in the light that sample is sent from coming after first band transmission
The information being distributed from the fluorescence intensity of Auto- fluorescence substance.On the other hand, the first image information is to represent the light that sample is sent
In from the strong of the state overlapping with the fluorescence from Auto- fluorescence substance of the fluorescence that is sent of porphyrin after first band transmission
Spend the information of distribution.Therefore, performed in step (f) and calculate the first image information and the place of the difference value of the 4th image information
Reason, thus, it is possible to the intensity distribution that generates the fluorescence with being sent based on the porphyrin after being transmitted from first band it is corresponding the
Five image informations.
It should be noted that above-mentioned porphyrin can also be set as into Protoporphyrins.Particularly by above-mentioned Protoporphyrins
In the case of being set as protoporphyrin IX, it is the wave band for including 635nm that can make above-mentioned first band, and above-mentioned second band is center
Wavelength is more than 580nm and below 620nm wave band, and above-mentioned 3rd wave band is that centre wavelength is more than 640nm and below 690nm
Wave band.
Furthermore, it is possible to make above-mentioned second band be that centre wavelength is more than 600nm and below 620nm wave band.In addition, can
So that it is more than 640nm and below 670nm wave band that above-mentioned 3rd wave band, which is centre wavelength,.
By using such method, even in near 635nm the peak value with spectrum come from protoporphyrin IX
(PpIX) the fluorescence state overlapping with the fluorescence from Auto- fluorescence substances such as collagens from the case that sample is sent,
Fiveth image information corresponding with the fluorescence intensity from PpIX can be generated.By being swollen based on the 5th image information
Knurl position and the discrimination of non-tumor locus, can more accurately carry out the discrimination of tumor locus than ever.
In addition, the present invention is a kind of condition discriminating apparatus of tumor locus, it is to including tumor locus and autofluorescence portion
Porphyrin irradiation exciting light that the above-mentioned tumor locus of the sample of position is accumulated and to exciting after above-mentioned porphyrin sent
The condition discriminating apparatus for the tumor locus that fluorescence is detected, it is characterised in that
Have：
Send above-mentioned exciting light light source portion,
The light accepting part for the light that reception is sent from said sample,
Light transmissive first optical filter for the first band of the peak wavelength of fluorescence for making to be sent comprising above-mentioned porphyrin,
Make than above-mentioned first band more by short wavelength side second band light transmissive second optical filter,
Make than above-mentioned first band more by long wavelength side the 3rd wave band light transmissive 3rd optical filter and
Intensity based on the light received in above-mentioned light accepting part carries out calculation process and carries out tumor locus and non-tumour portion
The arithmetic processing section of the discrimination of position,
Above-mentioned light accepting part receive received in the light that said sample is sent by above-mentioned first optical filter the first light, on
State and pass through in the light that the second light and said sample received in the light that sample is sent by above-mentioned second optical filter is sent
The 3rd light that above-mentioned second optical filter is received, above-mentioned calculation process is output to by the information relevant with the intensity distribution of each light
Portion,
Above-mentioned arithmetic processing section
The intensity distribution of the second image information and above-mentioned 3rd light of expression based on the intensity distribution for representing above-mentioned second light
The 3rd image information, the intensity distribution for generating fluorescence with being sent in above-mentioned first light from above-mentioned autofluorescence position is corresponding
The 4th image information,
Based on the first image information and above-mentioned 4th image information of the intensity distribution for representing above-mentioned first light, generation with it is upper
The 5th corresponding image information of the intensity distribution of the fluorescence that above-mentioned porphyrin is sent in the first light is stated, based on the 5th image
Information carries out the discrimination of tumor locus and non-tumor locus.
According to the device of above-mentioned composition, even in the overlapping fluorescence from porphyrin from the fluorescence that sample is sent and come
, also can be after arithmetic processing section generates and substantially subtracts the fluorescence from Auto- fluorescence substance from the fluorescence of Auto- fluorescence substance
Fluorescence intensity, corresponding the 5th image information of distribution for the fluorescence intensity that i.e. substantially porphyrin is sent, based on the 5th
Image information carries out the discrimination of tumor locus and non-tumor locus, therefore, it is possible to more accurately carry out tumor locus than ever
Distinguish.
Here, above-mentioned arithmetic processing section can be with
Based on the wavelength width phase utilized the intensity distribution shown in above-mentioned second image information with above-mentioned second band
Value obtained from corresponding value is standardized and the intensity distribution shown in above-mentioned 3rd image information is utilized and above-mentioned the
Value obtained from the corresponding value of the wavelength widths of three wave bands is standardized, generates above-mentioned 4th image information,
Above-mentioned the is generated by the processing comprising above-mentioned first image information and the calculus of differences of above-mentioned 4th image information
Five image informations.
It should be noted that above-mentioned porphyrin can also be set as into Protoporphyrins.Now, set by above-mentioned Protoporphyrins
In the case of being set to protoporphyrin IX, it is the wave band for including 635nm that can make above-mentioned first band, and above-mentioned second band is middle cardiac wave
A length of more than 580nm and below 620nm wave band, above-mentioned 3rd wave band are that centre wavelength is more than 640nm and below 690nm
Wave band.
Furthermore, it is possible to make above-mentioned second band be that centre wavelength is more than 600nm and below 620nm wave band.In addition, can
So that it is more than 640nm and below 670nm wave band that above-mentioned 3rd wave band, which is centre wavelength,.
In addition, on the basis of above-mentioned composition, the light path that said apparatus can be between said sample and above-mentioned light accepting part
On, any one filter in above-mentioned first optical filter, above-mentioned second optical filter and above-mentioned 3rd optical filter is set with possessing switching
The optical filter switching part of mating plate.
Invention effect
According to the discriminating conduct of the tumor locus of the present invention and device, can substantially it exclude from the glimmering of Auto- fluorescence substance
The influence of light, therefore, it is possible to more accurately carry out the discrimination of tumor locus than ever.
Brief description of the drawings
Fig. 1 is the figure for showing collagen and FAD Autofluorescence.
Fig. 2 is the figure of one of the fluorescence spectrum for showing the sample comprising Auto- fluorescence substance and PpIX.
Fig. 3 is the figure of one of the outward appearance for schematically showing tumor locus condition discriminating apparatus.
Fig. 4 is the block diagram of one of the Inner Constitution for schematically showing tumor locus condition discriminating apparatus.
Fig. 5 is the figure for the fluorescence spectrum for showing PpIX.
Fig. 6 is one of the spatial distribution for showing the fluorescence that the sample from a certain position is sent.
Fig. 7 is that collagen, FAD and PpIX each fluorescence spectrum are standardized using peak value and makes its overlapping and obtains
The figure arrived.
Fig. 8 is to schematically show the fluorescence intensity from PpIX actually contained from the fluorescence that sample is sent with passing through
The figure of the relation of the fluorescence intensity from PpIX of computing presumption.
Fig. 9 is schematically shown from the actual fluorescence intensity Ia after the first filter transmission and reality in the fluorescence
Comprising the fluorescence intensity Ib from PpIX relation figure.
Figure 10 be schematically shown on embodiment 1-9 actually contain from the fluorescence that sample is sent from PpIX's
The figure of the relation of fluorescence intensity and the fluorescence intensity from PpIX estimated by computing.
Figure 11 is the relation of the central wavelength lambda 2, the central wavelength lambda 3 of the 3rd optical filter and S/N ratios that show the second optical filter
Figure.
Figure 12 is the map for illustrating the content of checking.
Figure 13 is to irradiate the fluoroscopic image photo and fluorescence intensity profile that are received after exciting light in light accepting part to orifice plate.
Figure 14 be with based on irradiating the 5th figure that is generated in the fluoroscopic image that light accepting part is received after exciting light to orifice plate
As information corresponding fluoroscopic image photo and fluorescence intensity profile.
Figure 15 be the average value of the respective fluorescence intensities of Figure 13 and Figure 14 is mapped respectively according to PpIX concentration and
Obtained figure.
Embodiment
[device composition]
Refer to the attached drawing is illustrated to the composition of the tumor locus condition discriminating apparatus of the present invention.It should be noted that in each figure,
The size of figure may not be consistent than with actual size ratio.
Fig. 3 is the figure of one of the outward appearance for schematically showing said apparatus.In addition, Fig. 4 be schematically show it is above-mentioned
The block diagram of one of the Inner Constitution of device.It should be noted that Fig. 3 and Fig. 4 are show tumor locus condition discriminating apparatus one
Figure.
As shown in figure 3, tumor locus condition discriminating apparatus 1 (it is following, be properly termed as sometimes " device 1 ") possess clamper installing port
11 and display part 12.Clamper installing port 11 is the sample that sample 2 (not shown in figure 3, with reference to Fig. 4) is contained for installation
With the mechanism of clamper 10.In addition, display part 12 corresponds to display using tumor locus condition discriminating apparatus 1 to tumor locus and non-swollen
The monitor of result obtained from knurl position is distinguished.It should be noted that here, showing in tumor locus condition discriminating apparatus
The composition of display part 12 is provided with 1 main body, but it is also possible to using display part 12 is not provided with the main body of device 1 and at it
His monitor shows the composition of discrimination results.
Sample 2 is biopsy material (such as life comprising sentinel lymph node of the object as the discrimination for carrying out tumor locus
Thing tissue).The biopsy material implements defined disposal in advance so that as long as will accumulate porphin at the position comprising tumor locus
Quinoline class.As one, the biopsy material can be to the biopsy material extractd after 5-ALA to human body.
As shown in figure 4, device 1 possess light source portion 21, optical filter 22, dichronic mirror 23, object lens 24, optical filter switching part 25,
Light accepting part 26, arithmetic processing section 27.It should be noted that in the example of fig. 4, it has been assumed that copy Fig. 3 device 1 is possessed display
The composition in portion 12.
Light source portion 21 such as can the lamp as mercury lamp, xenon lamp, Halogen lamp LED, metal halide lamp and light emitting diode member
Part, laser diode etc. are constituted.Specific wavelength during optical filter 22 has the light for optionally making to project from light source portion 21
Light transmissive function, such as can be constituted by multilayer dielectric film.Here, having with optical filter 22 optionally makes wavelength
The situation of 405nm light transmissive function is illustrated, but in the present embodiment, if with optionally make 385nm with
The light transmissive function of upper and below 425nm specific band.For more generally, as long as optical filter 22 has selectivity
Ground, which is used in, excites the light transmissive function of wave band when tumor locus is included in sample 2 required for the porphyrin accumulated i.e.
Can.
Dichronic mirror 23, which has, makes the light of regulation wave band reflect, make the light transmissive function of miscellaneous stipulations wave band, for example can be with
It is made up of multilayer dielectric film etc..Here, having with dichronic mirror 23 reflects wavelength 405nm light, makes more than wavelength 580nm
The situation of light transmissive function is illustrated.As long as making to select using optical filter 22 it should be noted that the dichronic mirror 23 has
The wavelength gone out light reflection, make to send from sample 2 and included in optical filter switching part 25 described later each optical filter (25a,
25b, 25c) selection wavelength light transmissive function.
Project, reflected from the exciting light 31 of the wavelength 405nm after the transmission of optical filter 22 by dichronic mirror 23 from light source portion 21, led
Enter to object lens 24.Then, the light from object lens 24 after is transmitted from clamper 10, is irradiated on sample 2.Accumulated in sample 2
When having the PpIX of one (it is also one of Protoporphyrins) as porphyrin, PpIX is by wavelength 405nm exciting light 31
Excite, send fluorescence 32.Exciting light 31 is irradiated to sample 2 and the step of PpIX accumulated in sample 2 is excited is corresponded to step
(a)。
Fluorescence 32 is transmitted from clamper 10, with exciting light negative line feed, imported into object lens 24.Then, the fluorescence 32 from point
Look mirror 23 is transmitted and directive optical filter switching part 25.
In present embodiment, set to switching in the light path that optical filter switching part 25 can be between sample 2 and light accepting part 26
Put the first optical filter 25a, the second optical filter 25b and the 3rd optical filter 25c these three optical filters.Each optical filter (25a, 25b,
25c) there is the light transmissive function of optionally making each defined wave band, can be by optical filters such as bandpass filters
Constitute.It it should be noted that the quantity of optical filter is not limited to three, can also be set as that four can be set with light path switching
The composition of optical filter more than individual.
In present embodiment, the first optical filter 25a has the of the peak wavelength for the fluorescence for making to be sent comprising porphyrin
The light transmissive function of one wave band.For example, in the case where using a PpIX of porphyrin as detection object, from PpIX
Fluorescence peak wavelength as shown in Figure 5 near 635nm, therefore using so that comprising the 635nm regulation wave band light select
The first optical filter 25a that the mode transmitted to selecting property is designed.It is used as one, it is possible to use centre wavelength is 632nm, full width at half maximum (FWHM)
For 22nm optical filter.In this case, first band is more than 621nm and below 643nm.
In present embodiment, the second optical filter 25b has the light for the second band for making more to lean on short wavelength side than first band
The function of transmission.More specifically, on by the wave band (second band) of the second optical filter 25b light optionally transmitted, its
Than constituting, the lower limit of first band more leans on short wavelength side to lower limit and its higher limit is more leaned on than constituting the higher limit of first band
Short wavelength side.That is, second band and first band in a part can have overlapping in the range of above-mentioned condition., can as one
To utilize centre wavelength as the optical filter of 620nm, full width at half maximum (FWHM) for 20nm.In this case, second band be more than 610nm and
Below 630nm.
In present embodiment, the 3rd optical filter 25c has the light for the 3rd wave band for making more to lean on long wavelength side than first band
The function of transmission.More specifically, on by the wave band (the 3rd wave band) of the 3rd optical filter 25c light optionally transmitted, its
Than constituting, the lower limit of first band more leans on long wavelength side to lower limit and its higher limit is more leaned on than constituting the higher limit of first band
Long wavelength side.That is, the 3rd wave band and first band in a part can have overlapping in the range of above-mentioned condition., can as one
To utilize centre wavelength as the optical filter of 650nm, full width at half maximum (FWHM) for 20nm.In this case, the 3rd wave band be more than 640nm and
Below 660nm.
Light accepting part 26 is received from each fluorescence being set in after optical filter (25a, the 25b, 25c) transmission of optical filter switching part 25
32.The fluorescence intensity received is output to arithmetic processing section 27 by light accepting part 26 together with the positional information in sample 2.
Arithmetic processing section 27 is based on generating figure from the intensity distribution of each fluorescence after each optical filter (25a, 25b, 25c) transmission
As information.Arithmetic processing section 27 by CPU such as constituting.
First, in the state of optical filter switching part 25 is provided with the first optical filter 25a in light path, will with light accepting part
The information that the intensity of 26 light received is relevant is transported to arithmetic processing section 27 together with the positional information in sample 2.From sample 2
In the fluorescence 32 sent, the light received after the first optical filter 25a transmissions by light accepting part 26 corresponds to " the first light ".At computing
Reason portion 27 generates the image information (the first image information) of the intensity distribution of each position based on first light, storage to inside
In memory cell.The step of generating first image information corresponds to above-mentioned steps (b).
Then, the optical filter set in optical filter switching part 25 in light path is being changed into the second optical filter 25b state
Under, the relevant information of the intensity of the light with being received in light accepting part 26 is transported to computing together with the positional information in sample 2
Processing unit 27.In the fluorescence 32 sent from sample 2, the light correspondence received after the second optical filter 25b transmissions by light accepting part 26
In " the second light ".Arithmetic processing section 27 generates image information (the second image of the intensity distribution of each position based on second light
Information), store into internal memory cell.The step of generating second image information corresponds to above-mentioned steps (c).
Then, the optical filter set in optical filter switching part 25 in light path is being changed into the 3rd optical filter 25c state
Under, the relevant information of the intensity of the light with being received in light accepting part 26 is transported to computing together with the positional information in sample 2
Processing unit 27.In the fluorescence 32 sent from sample 2, the light correspondence received after the 3rd optical filter 25c transmissions by light accepting part 26
In " the 3rd light ".Arithmetic processing section 27 generates image information (the 3rd image of the intensity distribution of each position based on the 3rd light
Information), store into internal memory cell.The step of generating three image informations corresponds to above-mentioned steps (d).
Arithmetic processing section 27 be based on above-mentioned second image information and the 3rd image information, generation with the first light from autologous glimmering
The fluorescence intensity that light position is sent is distributed corresponding image information (the 4th image information).Generate the step of the 4th image information
Suddenly step (e) is corresponded to.As one of specific method, as described below.
First, arithmetic processing section 27 utilizes the wavelength width (such as the second optical filter 25b full width at half maximum (FWHM)) of second band
Intensity distribution to the second light shown in the second image information is standardized.As more specifically one, with second
The full width at half maximum (FWHM) of the value of the intensity of each position of light divided by the second optical filter 25b.
Second image information corresponds to the letter in the distribution of each position from the fluorescence intensity after the second optical filter 25b transmissions
Breath.Here, the second optical filter 25b makes the light for the wavelength components being included in the fluorescence 32 sent from sample 2 in second band saturating
Penetrate.Therefore, the intensity from the fluorescence 32 (the second light) after the second optical filter 25b transmissions detected in light accepting part 26 corresponds to bag
The integrated value of the luminous intensity for each wavelength being contained in the second band.Therefore, by using the light intensity value divided by the second optical filter
25b full width at half maximum (FWHM), calculates the intensity distribution of the light under the central wavelength lambda 2 of second band in the second light in which can simulate.
Then, arithmetic processing section 27 utilizes the wavelength width (such as the 3rd optical filter 25c full width at half maximum (FWHM)) of the 3rd wave band
Intensity distribution to the 3rd light shown in the 3rd image information is standardized.As more specifically one, with the 3rd
The full width at half maximum (FWHM) of the value of the intensity of each position of light divided by the 3rd optical filter 25c.Thus, simulation the 3rd ripple in the 3rd light is calculated
The intensity distribution of light under the central wavelength lambda 3 of section.
Then, the intensity distribution based on being calculated by above-mentioned computing, with the light under the central wavelength lambda 2 of second band
Relevant information and the information relevant with the intensity distribution of the light under the central wavelength lambda 3 of the 3rd wave band, generation the 4th image letter
Breath.4th image information corresponds to the letter for the intensity distribution for simulating the fluorescence sent in the first light from autofluorescence position
Breath.Refer to the attached drawing is illustrated to its reason.
Fig. 6 is show to send from a certain position Z sample 2 one of the spatial distribution of fluorescence 32.Such as refer to Fig. 2 (c)
As illustrated, the fluorescence that the fluorescence and porphyrin that Auto- fluorescence substance sent are sent is overlapped with the fluorescence 32.
In the case where optical filter switching part 25 is provided with the second optical filter 25b, in light accepting part 26, wrapped only in fluorescence spectrum
The light for the wavelength components being contained in second band 62, i.e. the second light are received in light accepting part 26.The light received in light accepting part 26
Amount is provided in the form of the integrated value of the light of the wavelength components included in the second band 62.Therefore, as described above, by inciting somebody to action
The light quantity received in light accepting part 26 is standardized using the wavelength width of second band 62, calculates second band with can simulating
Luminous intensity Iz2 under 62 central wavelength lambda 2.Luminous intensity Iz2 shown in Fig. 6 is a certain position Z luminous intensity, but by
Each position carries out above-mentioned computing, can calculate the light intensity distributions I2 of each position under the central wavelength lambda 2 of second band 62.Need
Illustrate, in the composition of present embodiment, the central wavelength lambda 2 of second band 62 is 620nm.
Similarly, in the case where optical filter switching part 25 is provided with the 3rd optical filter 25c, in light accepting part 26, only fluorescence
Light, i.e. the 3rd light for the wavelength components being included in spectrum in the 3rd wave band 63 is received in light accepting part 26.Connect in light accepting part 26
The light quantity received is provided in the form of the integrated value of the light of the wavelength components included in the 3rd wave band 63.Therefore, as above institute
State, by the way that the light quantity received in light accepting part 26 is standardized using the wavelength width of the 3rd wave band 63, calculate with can simulating
The luminous intensity Iz3 gone out under the central wavelength lambda 3 of the 3rd wave band 63.The light intensity that luminous intensity Iz3 shown in Fig. 6 is a certain position Z
Degree, but by carrying out above-mentioned computing in each position, the luminous intensity of each position under the central wavelength lambda 3 of the 3rd wave band 63 can be calculated
It is distributed I3.It should be noted that in the composition of present embodiment, the central wavelength lambda 3 of the 3rd wave band 63 is 650nm.
In the case where using a PpIX of porphyrin as detection object, as illustrated with reference to fig. 5 as, come from
PpIX fluorescence spectrum has precipitous peak near wavelength 635nm, is 620nm and the in the central wavelength lambda 2 of second band 62
The central wavelength lambda 3 of three wave bands 63 is that compared with the intensity of above-mentioned peak value, intensity is significantly low near 650nm.Accordingly, with respect to by
Transmitted in the fluorescence 32 that light portion 26 is received from the light (the second light) after the second optical filter 25b transmissions and from the 3rd optical filter 25c
Light (the 3rd light) afterwards, can be similar to without being only made up of from PpIX fluorescence the fluorescence from Auto- fluorescence substance.
In addition, for example with reference to as illustrated by Fig. 2, the fluorescence spectrum of Auto- fluorescence substance is shown than peak wavelength
More reduced by the segment smoothing near long wavelength side, the peak wavelength of the fluorescence spectrum more specifically sent in porphyrin
Tendency.In addition, the light intensity distributions of each position under the central wavelength lambda 2 of the second band 62 calculated by above-mentioned computing
The fluorescence intensity distribution of wavelength Xs 2 from Auto- fluorescence substance of the I2 with being sent from sample 2 is approximate.Similarly, above-mentioned fortune is passed through
The light intensity distributions I3 of each position under the central wavelength lambda 3 for the 3rd wave band 63 calculated and calculated comes from certainly with what is sent from sample 2
The fluorescence intensity distribution of the wavelength X 3 of body fluorescent material is approximate.
Therefore, the information based on above-mentioned light intensity distributions I2 and I3, can approx calculate and be come from certainly from what sample 2 was sent
Light intensity distributions I1 of the fluorescence of body fluorescent material under the central wavelength lambda 1 of the first band 61 between λ 2 and λ 3.As
One of computational methods, the fluorescence spectrum from Auto- fluorescence substance is similar to show linearly to be subtracted between wavelength X 2 and λ 3
Few tendency, passes through the light intensity distributions I3 of each position under the light intensity distributions I2 and wavelength X 3 to each position under wavelength X 2
Value carry out pro rate, the light intensity distributions I1 of each position under wavelength X 1 can be calculated.It should be noted that this is only
It is one, can also be by using the fluorescence light from Auto- fluorescence substance between for example defined function pair wavelength X 2 and λ 3
Spectrum carries out the approximate light intensity distributions I1 to calculate each position under wavelength X 1 according to the function.It should be noted that in Fig. 6,
Show with linearly the fluorescence spectrum from Auto- fluorescence substance between wavelength X 2 and λ 3 has been carried out it is approximate in the case of
The light intensity distributions Iz1 estimated at the Z of position position.
The information relevant with light intensity distributions I1 so obtained corresponds to each under the central wavelength lambda 1 of first band 61
The distribution of the luminous intensity of position.Therefore, by using the wavelength width pair of first band 61 letter relevant with light intensity distributions I1
Breath carries out anti-standardization, can obtain the letter relevant with the light intensity distributions of the wavelength components included in first band 61
Breath.The information is received equivalent to being provided with optical filter switching part 25 under the first optical filter 25a situation in light accepting part 26
Fluorescence 32 in corresponding information, i.e. the 4th image information of the intensity distribution of fluorescence that is sent of Auto- fluorescence substance.
Then, arithmetic processing section 27 is based on the first image information generated and the generated by above-mentioned calculation process the 4th
Image information, generation in light accepting part 26 with receiving in the case where optical filter switching part 25 is provided with the first optical filter 25a situation
The corresponding image information (the 5th image information) of the intensity distribution of the fluorescence that the smooth mesoporphyrin class of fluorescence 32, i.e. first is sent.
The step of generating five image informations corresponds to step (f).
As described above, the first image information be in the case where optical filter switching part 25 is provided with the first optical filter 25a situation
The fluorescence and porphyrin sent in the intensity distribution for the fluorescence 32 that light accepting part 26 is received, the fluorescence 32 comprising Auto- fluorescence substance
The fluorescence that class is sent.On the other hand, the 4th image information calculated in step (e) by computing corresponds in optical filter
Switching part 25 is provided with the first optical filter 25a situation that Auto- fluorescence substance is sent out in the fluorescence 32 that light accepting part 26 is received
The intensity distribution of the fluorescence gone out.Therefore, fluorescence of the arithmetic processing section 27 by progress for example shown in the first image information is strong
The computing of the fluorescence intensity distribution shown in the 4th image information is subtracted in degree distribution, can be generated and the first smooth mesoporphyrin class institute
The corresponding information (the 5th image information) of the intensity distribution of the fluorescence sent.
Then, arithmetic processing section 27 is based on the 5th image information generated, and whether the luminous intensity for carrying out each position exceedes
The discrimination of defined threshold.Then, the position that luminous intensity exceedes defined threshold is characterized as tumor locus, by light by arithmetic processing section 27
Position of the intensity below above-mentioned defined threshold is characterized as non-tumor locus.The 5th image information generated by above-mentioned processing is
The wavelength included near the peak wavelength of the fluorescence spectrum of the mesoporphyrin class of fluorescence 32 sent from sample 2, i.e. in first band 61
The light intensity distributions of composition, are the information for approx eliminating the fluorescence from Auto- fluorescence substance.Therefore, by based on this
Five image informations carry out the discrimination of tumor locus and non-tumor locus, compared with the past to be greatly reduced because comprising from autologous
The possibility distinguished by mistake caused by the fluorescence of fluorescent material.
The discrimination processing carried out in arithmetic processing section 27 corresponds to step (g).Arithmetic processing section 27 is by the result of the discrimination
It is output to display part 12.
Coordinate information of the display part 12 based on the tumor locus conveyed from arithmetic processing section 27, shows for example in sample 2
Implement to represent its view data obtained from the mark of tumor locus or colour developing in assigned position on image.In addition, not depositing
, can also be by the presentation of information of the content in display part in the case where being characterized as the region of tumor locus by arithmetic processing section 27
12。
Inspector confirms display part 12 by visual observation, and tumor locus is whether there is thus, it is possible to be informed in sample 2, and
Its Present site can be easily known in the case where there is tumor locus.In addition, by being set as example setting on the device 1
Operation button is put, the clamper 10 for containing sample 2 is installed in device 1 and when this presses the operation button from light source portion 21
The structure of exciting light is projected, the discrimination processing of the tumor locus of sample 2 can be automatically carried out using device 1, can be eliminated by examining
The deviation of judged result caused by the technology for the person of looking into, and also without the judgement of pathologist.
It should be noted that in the above-mentioned methods, optical filter switching part 25 is according to the first optical filter 25a, the second optical filter
25b, the 3rd optical filter 25c order are switched over, and are believed thus in accordance with the first image information, the second image information, the 3rd image
The order of breath obtains information, but this is sequentially not limited to said sequence.
In addition, dichronic mirror 23 is in order in order that device 1 minimizes and is total to the light path part of exciting light 31 and fluorescence 32
What purpose was set, but in the device 1, dichronic mirror 23 is not the composition necessarily needed.In addition, optical filter 22 can be with light source
The integration of portion 21.The composition of device 1 shown in Fig. 4 only one, as long as realizing the composition of identical function, then can enter
The various design alterations of row, this is self-evident.
[filter designs]
Hereinafter, to being recorded as the second optical filter 25b and the preferred conditions of the 3rd optical filter 25c.
As described above, the 5th image information is the peak value ripple of the fluorescence spectrum of the mesoporphyrin class of fluorescence 32 sent from sample 2
The light intensity distributions of the long wavelength components nearby, i.e. included in first band 61, are approx eliminated from autofluorescence thing
The information of the fluorescence of matter.That is, corresponding to being sent to estimate porphyrin according to the intensity distribution of the fluorescence 32 sent from sample 2
Information obtained from the intensity distribution of fluorescence.
But, as described above, the intensity of the fluorescence from Auto- fluorescence substance is according to the tissue extracted as sample
Position and it is different, also with individual difference.Therefore, the fluorescence of Auto- fluorescence substance is included in the fluorescence that porphyrin is sent
In the case of, in order to also ensure that high presumption when the ratio of the fluorescence comprising the Auto- fluorescence substance to change to a certain degree
Precision, it is believed that exist as the second optical filter 25b and the preferred conditions of the 3rd optical filter 25c.Hereinafter, with reference to the reality based on simulation
Example is applied to illustrate the condition.
Fig. 7 is that collagen, FAD and PpIX each fluorescence spectrum are standardized using peak value and makes its overlapping and obtains
The figure arrived.Moreover, using the component ratio of these each spectrum as parameter, generating multiple test spectrals.By the fluorescence of collagen
When spectral function is set to f1, FAD fluorescence spectrum function is set to f2, PpIX fluorescence spectrum function is set into f3, test light
Spectral function Ft is provided by following (number 1).
(number 1)
Ft=af1+bf2+cf3
Here, a=b=0 situation corresponds in test spectral the shape for being free of the fluorescence spectrum from Auto- fluorescence substance
State.On the other hand, the situation of ab ≠ 0 corresponds to the shape for including the fluorescence spectrum from Auto- fluorescence substance in test spectral
State.
Will from the first optical filter 25a transmission after fluorescence 32 actual light intensity degree be set to Ia, will be saturating from the first optical filter 25a
The luminous intensity of the fluorescence from PpIX actually contained in fluorescence 32 after penetrating is set to Ib, the value based on Ia is passed through into above-mentioned computing
The luminous intensity of the fluorescence from PpIX of method presumption is set to Ic.The light intensity of the fluorescence from PpIX actually contained in fluorescence 32
When spending Ib rises, the luminous intensity Ic of the fluorescence from PpIX estimated is also raised, but as described above, the intensity of autofluorescence is deposited
In the individual difference of sample 2.As a result, Ib and Ic is in the relation shown in Fig. 8.
In the case where being free of the fluorescence from autofluorescence from the fluorescence 32 after the first optical filter 25a transmissions, from the
The luminous intensity Ib of the fluorescence from PpIX actually contained in fluorescence 32 after one optical filter 25a transmissions is estimated with the value based on Ia
The fluorescence from PpIX luminous intensity Ic displaying ratio relations.On the other hand, from the fluorescence 32 after the first optical filter 25a transmissions
In the contained fluorescence from autofluorescence light quantity it is higher, luminous intensity Ic is in from the pass with luminous intensity Ib linear deviation
System.Therefore, the luminous intensity Ib of the fluorescence from PpIX actually contained in fluorescence 32 and the fluorescence from PpIX of presumption light
Intensity I c relation is closer to linear, and the presumption precision obtained by above-mentioned computing is higher.
Therefore, in this simulation, by making each leisure of a, b, c in the test spectral function Ft as defined in above-mentioned (number 1)
Change in more than 0.5 and less than 5 scope, multiple test spectrals of autofluorescence of the simulation ground generation comprising 500 kinds of patterns.Need
It is noted that in this simulation, on the first optical filter 25a, it has been assumed that centre wavelength is that 632nm, full width at half maximum (FWHM) are 22nm's
Optical filter.In addition, in the second optical filter 25b and the 3rd optical filter 25c, full width at half maximum (FWHM) is fixed as into 20nm respectively, make the second filter
Various change occurs for the mating plate 25b optical filter 25c of central wavelength lambda 2 and the 3rd central wavelength lambda 3, is thus simulated.
Fig. 9 is simple by the fluorescence 32 after being transmitted from the first optical filter 25a without the above-mentioned computing for being used to estimate
Actual luminous intensity Ia is carried out as the longitudinal axis, using the fluorescence intensity Ib from PpIX actually included in the fluorescence 32 as transverse axis
Scheme obtained from graphical.When understanding that Ib value becomes big, Ia value also becomes big, but relative to same Ib value, Ia value is produced
Relatively large deviation.Shown by Fig. 9 result, a in above-mentioned (number 1) and b value is occurred various become in test spectral function Ft
Even if changing to change the intensity as a result, making what is included in fluorescence 32 to come from of the autofluorescence contained in fluorescence 32 with simulating
PpIX fluorescence intensity Ib value is constant, and actual fluorescence intensity Ia size also generates deviation.
Figure based on Fig. 8 and Fig. 9 is understood, relative to same Ib value, the fluorescence from PpIX estimated by computing
The deviation of intensity I c value is smaller, and presumption precision is higher.
Figure 10 is that the fluorescence from PpIX included in the fluorescence that will be obtained to following embodiment 1-9 by above-mentioned computing is strong
Spend Ic as the longitudinal axis, the fluorescence intensity Ib from PpIX actually included in the fluorescence is patterned as transverse axis and obtained
Figure.
Embodiment 1-9 condition is as described below.It should be noted that as described above, in whole each embodiments and comparing
In example, the second optical filter 25b and the 3rd optical filter 25c full width at half maximum (FWHM) are 20nm, are common.
Embodiment 1：λ 2=620nm, λ 3=650nm
Embodiment 2：λ 2=600nm, λ 3=650nm
Embodiment 3：λ 2=580nm, λ 3=650nm
Embodiment 4：λ 2=620nm, λ 3=670nm
Embodiment 5：λ 2=600nm, λ 3=670nm
Embodiment 6：λ 2=580nm, λ 3=670nm
Embodiment 7：λ 2=620nm, λ 3=690nm
Embodiment 8：λ 2=600nm, λ 3=690nm
Embodiment 9：λ 2=560nm, λ 3=690nm
It can be seen from Figure 10, compared with the Fig. 9 of the figure of embodiment 9 with not carrying out estimating processing figure, deviation is small, but with
Other embodiment 1-8 is compared, and the deviation of Ic value of the value relative to same Ib is maximum.
It should be noted that each embodiment is compared, the deviation of Ic value of the value relative to same Ib, embodiment 1
It is minimum.If it means that each optical filter (25a, 25b, 25c) is constituted with design condition specified in embodiment 1, even if autologous
The intensity of fluorescence changes, and what is included in the fluorescence that will can be also sent by above-mentioned operation method from sample 2 comes from PpIX
Fluorescence intensity be substantially estimated as steady state value.
Embodiment 2, embodiment 3, embodiment 4 and embodiment 7 compared with Example 1, Ic value of the value relative to same Ib
Deviation slightly increase, but it may be said that even in being constituted each optical filter with design condition specified in these each embodiments
In the case of (25a, 25b, 25c), influence of the presumption result to the Strength Changes of autofluorescence is also minimum.
Embodiment 5, embodiment 6 and embodiment 8 are compared with embodiment 2, embodiment 3, embodiment 4 and embodiment 7, Ic value
The deviation of value relative to same Ib further slightly increases, but compared with Example 9, its extent of deviation is small.
Here, as other indexs for evaluating presumption precision, providing S/N ratios.That is, saturating from the first optical filter 25a
In the case that the actual luminous intensity of fluorescence 32 after penetrating is Ia, base during by the fluorescence 32 without the fluorescence from autofluorescence
Included in the luminous intensity Ic1 for the fluorescence from PpIX that Ia value is estimated is with above-mentioned Ic1 and the fluorescence 32 and come from autofluorescence
Fluorescence when the value presumption based on Ia the luminous intensity Ic2 ratio of difference (error) of the fluorescence from PpIX be set to S/N ratios.Should
Value is bigger, can evaluate presumption precision higher.It should be noted that in fact, with each test light for carrying out this time simulation
The whole Ic1 and the root mean square of Ic2 difference that spectral function Ft is calculated carry out specification error.
It should be noted that when computationally stating luminous intensity Ic1, in the test spectral function Ft as defined in above-mentioned (number 1)
In, make a=b=0, c value is changed more than 0.5 and in less than 5 scope, thus the multiple test spectrals of simulation ground generation.
In addition, when computationally stating luminous intensity Ic2, in the test spectral function Ft as defined in above-mentioned (number 1), making each leisure of a, b, c
Change in more than 0.5 and less than 5 scope, thus multiple test lights of autofluorescence of the simulation ground generation comprising 500 kinds of patterns
Spectrum.
Figure 11 be by the second optical filter 25b of appropriate change central wavelength lambda 2, the 3rd optical filter 25c central wavelength lambda 3 simultaneously
And by computing obtain above-mentioned S/N than when, the relation of λ 2 and λ 3 and S/N ratios be patterned obtained from scheme.Need explanation
, Tu11Zhong, the point represented with symbol (b) is corresponding to embodiment 1.Hereinafter, symbol (c) corresponds to embodiment 2, symbol (d)
Corresponding to embodiment 3, symbol (e) corresponds to embodiment 4, and symbol (f) corresponds to embodiment 5, and symbol (g) corresponds to embodiment 6,
Symbol (h) corresponds to embodiment 7, and symbol (i) corresponds to embodiment 8, and symbol (j) corresponds to embodiment 9.
On the extent of deviation of Ic value of the value relative to same Ib, shown in the evaluation result and Figure 11 of the various embodiments described above
S/N than magnitude relationship be consistent.That is, the S/N of embodiment 1, than highest, is about 23.5, on the contrary, the S/N of embodiment 9
It is about 1.5 than minimum.When actually judging tumor locus, being preferably suppressed to the extent of deviation of embodiment 1-8 degree, (S/N ratios are
About more than 6.0) extent of deviation (S/N ratios are about more than 7.0) of embodiment 1-5 and the degree of embodiment 7, is more preferably suppressed to, is entered
One step is preferably suppressed to the extent of deviation (S/N ratios are about more than 10.0) of embodiment 1-3 degree, is still more preferably suppressed to reality
Apply the extent of deviation of the degree of example 1 (S/N ratios are about more than 20.0).
It should be noted that the wavelength width for having obtained the second optical filter 25b and the 3rd optical filter 25c is narrower, then identical
Under the conditions of the more repressed result of above-mentioned extent of deviation.But, in the optical filter using the scope that can be readily available (for example
Wavelength width is more than 10nm and below 30nm) as bandpass filter in the case of, confirm substantially same with the above results
Result.
Based on case above, assuming that PpIX as sample in the case of the porphyrin accumulated, preferably make the second filter
Mating plate 25b central wavelength lambda 2 is more than 580nm and below 620nm, and the central wavelength lambda 3 for preferably making the 3rd optical filter 25c is
More than 640nm and below 690nm.In addition, in above-mentioned, the central wavelength lambda 2 for further preferably making the second optical filter 25b is 600nm
Above and below 620nm, the central wavelength lambda 3 for further preferably making the 3rd optical filter 25c is more than 640nm and below 670nm.
This point that the influence of autofluorescence can be suppressed to the method by using the present invention with reference to other checkings is carried out
Explanation.Figure 12 is the map for illustrating the content of checking.
As shown in figure 12, each 30 μ L of the aqueous solution 71~79 for being mixed with PpIX and FAD are added dropwise in orifice plate 70.The aqueous solution 71
~79 PpIX and FAD concentration are as described below.
The aqueous solution 71：PpIX 0μM、FAD 0μM
The aqueous solution 72：PpIX 0μM、FAD 10μM
The aqueous solution 73：PpIX 0μM、FAD 20μM
The aqueous solution 74：PpIX 0.25μM、FAD 0μM
The aqueous solution 75：PpIX 0.25μM、FAD 10μM
The aqueous solution 76：PpIX 0.25μM、FAD 20μM
The aqueous solution 77：PpIX 0.5μM、FAD 0μM
The aqueous solution 78：PpIX 0.5μM、FAD 10μM
The aqueous solution 79：PpIX 0.5μM、FAD 20μM
Figure 13 is to being received after the above-mentioned illumination wavelength 405nm of orifice plate 70 exciting light 31 in light accepting part 26 using the present apparatus 1
The fluoroscopic image photo and fluorescence intensity profile arrived.In Figure 13, (a) is fluoroscopic image photo, and (b) is distributed for fluorescence intensity
Figure.It should be noted that Figure 13 corresponds to photo and the distribution when optical filter switching part 25 is provided with the first optical filter 25a
Figure.Here, as the first optical filter 25a, in the same manner as above-described embodiment, the centre wavelength is used to be for 632nm, full width at half maximum (FWHM)
22nm optical filter.The image information obtained in Figure 13 corresponds to above-mentioned " the first image information ".
Figure 14 is with switching the first optical filter 25a, the second optical filter 25b, the 3rd optical filter 25c in optical filter switching part 25
And the corresponding fluoroscopic image photo of the 5th image information that is generated after light accepting part 26 receives fluorescence using the above method and
Fluorescence intensity profile.In the same manner as Figure 14, (a) is fluoroscopic image photo, and (b) is fluorescence intensity profile.Need explanation
It is that, here, the first optical filter 25a uses optical filter similar to the above, the second optical filter 25b central wavelength lambda 2 and the 3rd is filtered
Mating plate 25c central wavelength lambda 3 is set as λ 2=600nm, λ 3=650nm in the same manner as above-described embodiment 2.It should be noted that
The full width at half maximum (FWHM) that the full width at half maximum (FWHM) for making the second optical filter 25b is 14nm, make the 3rd optical filter 25c is 13nm.
It should be noted that being to make the thickness of each aqueous solution (71~79) uniform using the purpose of orifice plate 70, dripped for this
Plus the aqueous solution amount also each it is identical.But, generate surface tension near the inwall in the hole filled with the aqueous solution
For relation, compared near the center in hole, thickness is different.The viewpoint of the influence produced from the difference excluded by the thickness
Set out, below, on each aqueous solution (71~79), illustrated based on the data obtained near the center in hole.
According to Figure 13 (b), although being free of PpIX in the aqueous solution 72 and the aqueous solution 73, rule are also confirmed on distribution map
The fluorescence intensity of definite value.This expression detects the fluorescence from FAD in light accepting part 26.
On the other hand, according to Figure 14 (b) corresponding with the 5th image information that the method by the present invention makes, in water
It is almost unconfirmed in the same manner as the aqueous solution 71 to arrive fluorescence in solution 72 and the aqueous solution 73.
In addition, according to Figure 13 (b), the fluorescence intensity of the aqueous solution 74 and the fluorescence intensity of the aqueous solution 75 and the aqueous solution 76 are entered
When row compares, although both PpIX concentration is identical, the aqueous solution 75 and the aqueous solution 76 are confirmed compared with the aqueous solution 74
Fluorescence intensity is higher.Similarly, the fluorescence intensity of the aqueous solution 77 and the fluorescence intensity of the aqueous solution 78 and the aqueous solution 79 are compared
Compared with although both PpIX concentration is identical, the aqueous solution 78 and the aqueous solution 79 are compared with the aqueous solution 77, and the fluorescence confirmed is strong
Du Genggao.This is represented：Increase the fluorescence intensity received because the fluorescence from FAD is overlapping with the fluorescence from PpIX.
On the other hand, it is water-soluble according to Figure 14 (b) corresponding with the 5th image information that the method by the present invention makes
Liquid 74, the aqueous solution 75 and the aqueous solution 76 show the fluorescence intensity of roughly the same degree, similarly, the aqueous solution 77, the aqueous solution 78
The fluorescence intensity of roughly the same degree is shown with the aqueous solution 79.
Figure 15 be the average value of the respective fluorescence intensities of Figure 13 and Figure 14 is mapped respectively according to PpIX concentration and
Obtained figure.Figure 13 corresponds to the value based on " the first image information ", and Figure 14 corresponds to the value based on " the 5th image information ".
It can be seen from Figure 15, even if being identical PpIX concentration, the fluorescence intensity of the first image information also generates big deviation, with
This is relative, and above-mentioned deviation is inhibited as far as possible in the 5th image information generated by the method for the present invention.Thus, according to the present invention
Method, can also generate the image for the fluorescent component for eliminating the Auto- fluorescence substance contained in the samples such as FAD as far as possible,
Therefore, it is possible to using high precision test from the fluorescence intensity using PpIX as the porphyrin of representative.
[other embodiment]
Tumor locus accumulate porphyrin can be protoporphyrin IX (PpIX) beyond material, for example, to from by
In the case that the fluorescence that light-protoporphyrin (PPp), uroporphyrin of PpIX generations etc. are sent carries out light splitting detection, it would however also be possible to employ on
State method.
In this case, as long as optical filter 22 can be selectively employed for exciting the wave band required for the porphyrin
The composition that exciting light 31 is transmitted.As long as making to include the fluorescence that the porphyrin is sent in addition, the first optical filter 25a has
The light transmissive function of the first band of peak wavelength, the second optical filter 25b, which have, to be made than first band more by short wavelength side
The light transmissive function of second band, the 3rd optical filter 25c, which have, makes the 3rd wave band than first band more by long wavelength side
Light transmissive function.
Label declaration
1：Tumor locus condition discriminating apparatus
10：Sample clamper
11：Clamper installing port
12：Display part
21：Light source portion
22：Optical filter
23：Dichronic mirror
24：Object lens
25：Optical filter switching part
25a：First optical filter
25b：Second optical filter
25c：3rd optical filter
26：Light accepting part
27：Arithmetic processing section
31：Exciting light
32：Fluorescence
61：First band
62：Second band
63：3rd wave band
70：Orifice plate
71~79：The aqueous solution
Claims (9)
1. a kind of discriminating conduct of tumor locus, it is in the described swollen of the sample comprising tumor locus and autofluorescence position
Porphyrin that knurl position is accumulated irradiation exciting light and to exciting after swelling of being detected of the fluorescence that is sent of the porphyrin
The discriminating conduct at knurl position, it is characterised in that have：
The step of exciting light is to excite the porphyrin (a) is irradiated to the sample；
Obtain and represent in light that the sample is sent by the peak wavelength of fluorescence that makes to be sent comprising the porphyrin
The step of first image information of the intensity distribution for the first light that light transmissive first optical filter of first band is received (b)；
Obtain and represent in light that the sample is sent by making the second band than the first band more by short wavelength side
The step of second image information of the intensity distribution for the second light that light transmissive second optical filter is received (c)；
Obtain and represent in light that the sample is sent by making the 3rd wave band than the first band more by long wavelength side
The step of three image information of the intensity distribution for the 3rd light that light transmissive 3rd optical filter is received (d)；
Based on second image information and the 3rd image information, from the autofluorescence portion in generation and first light
The step of intensity distribution of fluorescence that position is sent corresponding four image information (e)；
Based on described first image information and the 4th image information, generation is sent with porphyrin described in first light
Fluorescence intensity distribution corresponding five image information the step of (f)；With
The step of discrimination of tumor locus and non-tumor locus is carried out based on the 5th image information (g).
2. the discriminating conduct of tumor locus as claimed in claim 1, it is characterised in that
The step (e) be based on by the intensity distribution of second light shown in second image information utilize with it is described
Value obtained from the corresponding value of the wavelength width of second band is standardized and by shown in the 3rd image information
The intensity distribution of 3rd light is obtained from the value corresponding with the wavelength width of the 3rd wave band is standardized
The step of value is to generate four image information,
The step of step (f) includes calculating the difference value of described first image information and the 4th image information.
3. the discriminating conduct of tumor locus as claimed in claim 1 or 2, it is characterised in that the porphyrin is Protoporphyrins.
4. the discriminating conduct of tumor locus as claimed in claim 3, it is characterised in that
The Protoporphyrins is protoporphyrin IX,
The first band is the wave band for including 635nm,
The second band is the wave band that centre wavelength is more than 580nm and below 620nm,
3rd wave band is that centre wavelength is more than 640nm and below 690nm wave band.
5. a kind of condition discriminating apparatus of tumor locus, it is in the described swollen of the sample comprising tumor locus and autofluorescence position
Porphyrin that knurl position is accumulated irradiation exciting light and to exciting after swelling of being detected of the fluorescence that is sent of the porphyrin
The condition discriminating apparatus at knurl position, it is characterised in that
Have：
Send the exciting light light source portion,
The light accepting part for the light that reception is sent from the sample,
Light transmissive first optical filter for the first band of the peak wavelength of fluorescence for making to be sent comprising the porphyrin,
Make than the first band more by short wavelength side second band light transmissive second optical filter,
Make than the first band more by long wavelength side the 3rd wave band light transmissive 3rd optical filter and
Intensity based on the light received in the light accepting part carries out distinguishing for calculation process, progress tumor locus and non-tumor locus
Other arithmetic processing section,
The light accepting part receives the first light received in the light that the sample is sent by first optical filter, the examination
By described in the light that the second light and the sample received in the light that sample is sent by second optical filter is sent
The 3rd light that second optical filter is received, the arithmetic processing section is output to by the information relevant with the intensity distribution of each light,
The arithmetic processing section
The second image information based on the intensity distribution for representing second light and represent the 3rd light intensity distribution the
Three image informations, generate the intensity distribution of fluorescence with being sent in first light from the autofluorescence position it is corresponding the
Four image informations,
Based on the first image information and the 4th image information of the intensity distribution for representing first light, generation and described the
The 5th corresponding image information of the intensity distribution for the fluorescence that porphyrin is sent described in one light, based on the 5th image letter
Breath, carries out the discrimination of tumor locus and non-tumor locus.
6. the condition discriminating apparatus of tumor locus as claimed in claim 5, it is characterised in that the arithmetic processing section
Based on by the intensity distribution shown in second image information using relative with the full width at half maximum (FWHM) of second optical filter
Value obtained from the value answered is standardized and by the intensity distribution shown in the 3rd image information utilize and the described 3rd
Value obtained from the corresponding value of the full width at half maximum (FWHM) of optical filter is standardized, generates the 4th image information,
5th figure is generated by the processing comprising described first image information and the calculus of differences of the 4th image information
As information.
7. the condition discriminating apparatus of the tumor locus as described in claim 5 or 6, it is characterised in that the porphyrin is Protoporphyrins.
8. the condition discriminating apparatus of tumor locus as claimed in claim 7, it is characterised in that
The Protoporphyrins is protoporphyrin IX,
The first band is the wave band for including 635nm,
The second band is the wave band that centre wavelength is more than 580nm and below 620nm,
3rd wave band is that centre wavelength is more than 640nm and below 690nm wave band.
9. the condition discriminating apparatus of the tumor locus as any one of claim 5~8, it is characterised in that the sample with
In light path between the light accepting part, first optical filter, second optical filter and the described 3rd are set with possessing switching
The optical filter switching part of any one optical filter in optical filter.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014217767A JP6635363B2 (en) | 2014-10-24 | 2014-10-24 | Method for discriminating tumor site, device for discriminating tumor site |
| JP2014-217767 | 2014-10-24 | ||
| PCT/JP2015/079828 WO2016063949A1 (en) | 2014-10-24 | 2015-10-22 | Method for determining tumor sites, and device for determining tumor sites |
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| CN107003240A true CN107003240A (en) | 2017-08-01 |
| CN107003240B CN107003240B (en) | 2020-06-12 |
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| CN201580057659.3A Expired - Fee Related CN107003240B (en) | 2014-10-24 | 2015-10-22 | Method and device for identifying tumor site |
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|---|---|
| JP (1) | JP6635363B2 (en) |
| CN (1) | CN107003240B (en) |
| WO (1) | WO2016063949A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108351302A (en) * | 2015-11-10 | 2018-07-31 | 京都府公立大学法人 | The method of discrimination of tumor locus, the discriminating gear of tumor locus |
| CN110151125A (en) * | 2018-02-12 | 2019-08-23 | 上海交通大学 | A kind of application and method based on nail spontaneous fluorescence intensity as biomarker in the product that preparation occurs for diagnosing |
| CN113646877A (en) * | 2019-03-28 | 2021-11-12 | 浜松光子学株式会社 | Inspection apparatus and inspection method |
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| US20170354357A1 (en) * | 2016-06-11 | 2017-12-14 | Boston Scientific Scimed Inc. | Systems, methods, and devices for monitoring tissue ablation using tissue autofluorescence |
| DE102017203448B9 (en) * | 2017-03-02 | 2021-12-23 | Carl Zeiss Meditec Ag | Microscopy system and microscopy method for quantifying fluorescence |
| USD908881S1 (en) | 2019-01-17 | 2021-01-26 | Sbi Alapharma Canada, Inc. | Handheld endoscopic imaging device |
| US11408825B2 (en) * | 2020-08-28 | 2022-08-09 | Hong Kong Applied Science and Technology Research Institute Company Limited | Forensic detector and the system thereof |
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| CN108351302A (en) * | 2015-11-10 | 2018-07-31 | 京都府公立大学法人 | The method of discrimination of tumor locus, the discriminating gear of tumor locus |
| CN110151125A (en) * | 2018-02-12 | 2019-08-23 | 上海交通大学 | A kind of application and method based on nail spontaneous fluorescence intensity as biomarker in the product that preparation occurs for diagnosing |
| CN113646877A (en) * | 2019-03-28 | 2021-11-12 | 浜松光子学株式会社 | Inspection apparatus and inspection method |
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| CN113646877B (en) * | 2019-03-28 | 2023-08-18 | 浜松光子学株式会社 | Inspection device and inspection method |
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| Publication number | Publication date |
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| WO2016063949A1 (en) | 2016-04-28 |
| CN107003240B (en) | 2020-06-12 |
| JP2016085112A (en) | 2016-05-19 |
| JP6635363B2 (en) | 2020-01-22 |
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