Patent Publication Number: US-2009234234-A1

Title: Biodiagnosis Apparatus

Description:
TECHNICAL ART 
     The present invention relates generally to a bio-diagnosis apparatus, and more particularly to a bio-diagnosis apparatus that lends itself to fluorescent observation and diagnosis of tumors or the like in a living body in general, and the bladder in particular. 
     BACKGROUND ART 
     For the observation of tumors, there has been a method known so far in the art, which makes use of a chemical compound that tends to gather at cancer cells and emits fluorescence upon irradiation with light (see Patent Publication 1). It is said there that not only a fluorescent image but also a direct image is simultaneously observable. Patent Publication 1 shows that the wavelength characteristics of an illumination system and an observation system overlap and are defined for the total transmittance of the whole system. 
     In that case, reflection images of sites other than a fluorescent site are observable through excitation light taken by the overlap of both characteristics slightly in the observation system. 
     Specifically, when 5-ALA (aminolevulinic acid) is used as the fluorescent chemical, the excitation light wavelength is λ e =about 410 nm and the fluorescence wavelength is λ f =630 nm. The florescence wavelength is red and, to observe this fluorescent site in good enough contrast, the background color should preferably be blue, and close to a monochrome. As the background color gets close to white, color contrasts grow unacceptably low. 
     Patent Publication 1 
     Published Translation of PCT No. 11-511369 
     Thus, the florescence wavelength is red and when reflection images of sites other than the fluorescent site are made observable through light excitation light taken in the observation system, there is the self-fluorescence of the living body to be observed among factors affecting the background color. As an optical system is designed without taking care of the self-fluorescence of the living body, it gives rise to a drop of color contrasts. The aforesaid prior art takes aim at making sure brightness contrasts: it says nothing about details of color contrasts. 
     SUMMARY OF THE INVENTION 
     In view of such problems with the prior art as described above, the object of the invention is to provide a biodiagnosis apparatus in which the wavelength characteristics of an illumination system and an observation system overlap to thereby take excitation light in the observation system so that reflection images of sites other than a fluorescent site are observable, and which enables fluorescent observation to be implemented in good enough color contrast. 
     According to one aspect of the invention by which the aforesaid object is achieved, there is provided a bio-diagnosis apparatus harnessing fluorescent reactions of a living body tissue, which comprises a light source, a light source optical system, a light transfer system for guiding illumination light from said light source to the living body, an excitation light filter interposed between said light source and said light transfer system, an image transfer system for guiding light from the living body to an image plane, and an excitation cut filter located in said image transfer system, and in which spectral characteristics of illumination light transmitting through said excitation light filter and transmittance characteristics of said excitation cut filter have an overlapping portion, characterized in that: 
     upon observation of a subject under said bio-diagnosis apparatus, spectral characteristics of a site of the image plane other than a fluorescent site satisfy the following condition (1): 
       0.005 ≦I (λ p +Δ)/ I (λ p )≦0.5  (1) 
     provided that 40≦Δ≦80 nm, where λ p  is a wavelength (nm) at which spectral intensity reaches a maximum, and I(λ p ) is indicative of the then spectral intensity. 
     According to another aspect of the invention, there is provided a biodiagnosis apparatus harnessing fluorescent reactions of a living body tissue, which comprises a light source, a light source optical system, a light transfer system for guiding illumination light from said light source to the living body, an excitation light filter interposed between said light source and said light transfer system, an image transfer system for guiding light from the living body to an image plane, and an excitation cut filter located in said image transfer system, and in which spectral characteristics of illumination light transmitting through said excitation light filter and transmittance characteristics of said excitation cut filter have an overlapping portion, characterized in that: 
     chromaticity coordinates (x, y) for light after transmitting through said excitation cut filter satisfies the following condition (2): 
       0.16≦x≦0.21, 0.04≦y≦0.23  (2) 
     According to yet another aspect of the invention, there is provided a biodiagnosis apparatus harnessing fluorescent reactions of a living body tissue, which comprises a light source, a light source optical system, a light transfer system for guiding illumination light from said light source to the living body, an excitation light filter interposed between said light source and said light transfer system, an image transfer system for guiding light from the living body to an image plane, and an excitation cut filter located in said image transfer system, and in which said light source filter comprises a first transmissive area containing a fluorescence excitation wavelength and a second transmissive area, with transmittance characteristics of said excitation cut filter including said second transmissive area of said light source filter, characterized in that: 
     upon observation of a subject under said bio-diagnosis apparatus, spectral characteristics of a site of the image plane other than a fluorescent site satisfy the following condition (1): 
       0.005≦ I (λ p +Δ)/ I (λ p )≦0.5  (1) 
     provided that 40≦Δ≦80 nm, where λ p  is a wavelength (nm) at which spectral intensity reaches a maximum, and I(λ p ) is indicative of the then spectral intensity. 
     In a preferable embodiment of the invention, said light source comprises a first light source in alignment with said first transmissive area and a second light source filter in alignment with said second transmissive area, and is designed to direct sequentially to the subject light transmitting through said first light source filter and light transmitting through said second light source filter. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is illustrative in schematic of the construction of the biodiagnosis apparatus according to the invention. 
         FIG. 2  is illustrative of the transmittance characteristics of the excitation light filter and excitation cut filter in a prior art biodiagnosis apparatus. 
         FIG. 3  is illustrative of the system performance throughout the conventional biodiagnosis apparatus. 
         FIG. 4  is indicative of the values, as calculated and found, of the wavelength characteristics of the overlapping portion (background site) of the wavelength characteristics of the illumination system and the wavelength characteristics of the observation system in the event that there are the system performance of  FIG. 3 . 
         FIG. 5  is illustrative in schematic of the color contrasts of the fluorescent and background sites in the even that 5-ALA is used as a fluorescent chemical: (a) is indicative of a red fluorescent site against a blue background, and (b) of a red fluorescent site against a white background. 
         FIG. 6  is a spectral intensity distribution for the background site at the upper limit, median and lower limit of the overlapping amount of both characteristics of the illumination and observation systems. 
         FIG. 7  is indicative of the system performance for obtaining spectral characteristics at the upper limit, median and lower limit of the  FIG. 6 , respectively. 
         FIG. 8  is a diagram wherein a spectral intensity distribution for the background site at the upper limit, median and lower limit of  FIG. 6 , respectively, is represented on a chromaticity diagram. 
         FIG. 9  is indicative of the transmittance characteristics of a light source filter in another example of the biodiagnosis apparatus according to the invention. 
         FIG. 10  is indicative of the system performance throughout the biodiagnosis system of the construction of  FIG. 9 . 
         FIG. 11  is indicative of the transmittance characteristics in a modification to  FIG. 9  wherein two light source filters are used. 
         FIG. 12  is illustrative of an exemplary filter switchover mechanism in the event that two light source filters are used as in  FIG. 11 . 
         FIG. 13  is indicative of the transmittance characteristics of an antireflection coat and an excitation light filter in an optical system of the light source unit in the biodiagnosis apparatus of  FIG. 1 . 
         FIG. 14  is indicative of the transmittance characteristics of a prior art IR cut white light filter and an exclusive IR cut filter located in a TV camera head in the biodiagnosis apparatus of  FIG. 15 . 
         FIG. 15  is illustrative in schematic of an arrangement wherein a TV camera system is connected to the biodiagnosis apparatus of the invention for the purpose of taking images. 
     
    
    
     BEST MODE FOR CARRYING OUT THE INVENTION 
     The biodiagnosis apparatus of the invention is now explained with reference to its principles and examples. 
       FIG. 1(   a ) is illustrative in schematic of the construction of the biodiagnosis apparatus of the invention that comprises an exclusive scope (endoscope)  1  capable of being inserted into, for instance, the bladder and a light source unit  2  adapted to send illumination light to an illumination system for the exclusive scope  1  via a light guide cable  3 . The light source unit  2  comprises a lamp  21  such as a xenon lamp, an optical system  22  adapted to condense light from the lamp  21  onto the input end of the light guide cable  3 , and a turret  23  located in an optical path from the lamp  21 . Around the turret  23 , an excitation light filter  24 , a white light filter  25 , an IR cut white light filter  26  and an emergency light (small electric bulb)  27  are selectively disposed, as shown in  FIG. 1(   b ). The excitation light filter  24  is one that has such wavelength characteristics as described later and excites fluorescent reactions; the white light filter  25  is one that transmits light all over the wavelength range to observe an ordinary image; the IR cut white light filter  26  is one that cuts off wavelengths in the infrared range to observe an image with good enough color reproducibility; and the emergency light (small electric bulb)  27  is to make sure the minimum illumination light for removing the exclusive scope  1  out of the living body when the lamp  21  goes off. An optical path through the exclusive scope  1  is provided in it with an excitation cut filter  11  so that an affected site can be directly observed via an eyepiece unit  12 , or it can be observed via a CCD camera mounted to the eyepiece unit  12 , as described later. 
     First, problems with a conventional biodiagnosis apparatus are explained.  FIG. 2(   a ) is indicative of the transmittance characteristics of the excitation light filter  24 , and  FIG. 2(   b ) is indicative of the transmittance characteristics of the excitation cut filter  11 . The excitation light filter  24  and excitation cut filter  11  have such transmittance characteristics; when the turret  23  is turned to insert the excitation light filter  24  in the illumination light path, the whole bio-diagnosis system is going to have such system characteristics as shown in  FIG. 3 , wherein the wavelength characteristics (relative intensity) of an illumination system overlap the wavelength transmittance of an observation system near a wavelength of 440 nm, and fluorescence of a fluorescent site excited by the excitation light of the illumination system is going to occur near a wavelength of 630 nm. 
     As regards the system characteristics of  FIG. 3 ,  FIG. 4  is indicative of the values of the wavelength characteristics, as calculated and found, of a background site (with none of fluorescent emission) that is defined by the overlap of the wavelength characteristics of the illumination system with those of the observation system. The calculated value here is the product of the wavelength characteristics of the illumination system and the wavelength transmittance of the observation system in  FIG. 3 , and the found value is greater than the calculated value especially in a wide range of wavelengths longer than the wavelength of 440 nm. This portion of the background site greater than the calculated value would appear to be caused by the self-fluorescence of the living body. For this reason, if there is a background color selected without taking care of this self-fluorescence of the living body, it will then give rise to a drop of color contrasts between the fluorescent site and the background site. This is the problem with the biodiagnosis apparatus set forth in Patent Publication 1. 
     As can be seen from the foregoing, the background color at the time of fluorescent observations is determined by an excitation light portion taken slightly in the observation system by the overlap of the wavelength characteristics of the illumination system and the observation system, and the self-fluorescence of the living body under observation as well. 
     Here, the excitation light directed on the subject (an affected site in the living body) stays constant, so is the quantity of self-fluorescence emanating out of the living body. The quantity of excitation light taken in the observation system is determined by the amount of overlap of both characteristics of the illumination system and the observation system: the ratio between that quantity of excitation light and the quantity of self-fluorescence is determined by the amount of overlap of both characteristics of the illumination system and the observation system. For this reason, the contrast of the background color, i.e., the color contrast between the fluorescent site and the background site is going to be determined by the amount of overlap of both characteristics of the illumination system and the observation system. 
     For observations in good enough contrasts, of importance is the ratio between the excitation light taken in the observation system and the self-fluorescence of the living body. As the amount of overlap grows large, the self-fluorescence of the living body becomes relatively smaller as compared with the excitation light taken in: the background color gets close to a monochrome. As the amount of overlap becomes small, on the contrary, the self-fluorescence of the living body grows large with respect to excitation light: the background color gets close to white. 
       FIG. 5  is illustrative in schematic of the color contrasts between the fluorescent site and the background site in the event that 5-ALA (aminolevulinic acid) is used as the fluorescent chemical. When there is a red fluorescent site against a blue background site, there is a good color contrast obtained so that the fluorescent site (affected site) is easy to see, as can be seen from  FIG. 5(   a ). As there is a red fluorescent site against a white background as shown in  FIG. 5(   b ), on the contrary, there is no good contrast obtained: the fluorescent site (affected site) is difficult to see, resulting in an increased probability of overlooking. 
     Therefore in the invention, the spectral characteristics of the background site other than the fluorescent site on the image plane upon observation of a subject should satisfy the following condition: 
       0.005≦ I (λ p +Δ)/ I (λ p )≦0.5  (1) 
     provided that 40≦Δ≦80 nm, where λ p  is the wavelength (nm) at which the spectral intensity reaches a maximum, and I(λ p ) is indicative of the then spectral intensity. 
     As the upper limit of 0.5 to condition (1) is exceeded, there is an increase in the proportion of the self-fluorescence of the living body relative to the excitation light taken in by the overlap of characteristics. As a result, the background color gets close to white, giving rise to a drop of color contrasts, which may otherwise make it difficult to see the fluorescent site (affected site), resulting in an increased probability of overlooking. 
     As the lower limit of 0.005 to condition (1) is not reached, on the other hand, there is a decrease in the proportion of the self-fluorescence of the living body relative to the excitation light taken in by the overlap of characteristics, because a lot more excitation light is taken in the observation system. As a result, there is light reflected off sites other than the fluorescent site in addition to the fluorescence from the subject; that is, the background becomes all too bright, giving rise to a drop of brightness contrasts. 
     Especially when 5-ALA is used as the fluorescent chemical, the excitation light wavelength is λ e =410 nm and the fluorescence wavelength is λ f =630 nm. To observe orange or red fluorescence in good enough contrasts, the background color must tend to become a complementary color, or it should preferably be blue. 
       FIG. 6  is indicative of the spectral intensity distributions of the background site at the upper limit, median and lower limit (corresponding to the upper limit, median and lower limit of condition (1), respectively) of the amount of overlap of both characteristics of the illumination system and the observation system, and  FIG. 7(   a ),  7 ( b ) and  7 ( c ) are indicative of the system performances for obtaining the spectral characteristics at the upper limit, median and lower limit of  FIG. 6 , respectively. In  FIG. 7  here, note that each solid line is indicative of the wavelength characteristics (relative intensity) of the illumination system, and each broken line is indicative of the wavelength transmittance of the observation system. 
     The background at the lower limit of  FIG. 6  ( FIG. 7(   c ) is whitish blue, the background at the median ( FIG. 7(   b )) is blue, and the background at the upper limit ( FIG. 7(   a )) is deep blue. 
     The spectral intensity distributions of the background site at the upper limit, median and lower limit (corresponding to the lower limit, median and upper limit of condition (1), respectively) of the amount of overlap of both characteristics of the illumination system and the observation system in  FIG. 6  may also be expressed on a chromaticity diagram (CIE(X, Y)). On  FIG. 8 , chromaticity coordinates (x, y) at the aforesaid upper limit, median and lower limit are plotted. As can be appreciated from  FIG. 8 , it is desired that the chromaticity coordinates for light (on the image plane) after transmitting through the excitation cut filter  11  satisfies the following condition (2). 
       0.16≦x≦0.21, 0.04≦y≦0.23  (2) 
     The range of condition (2) is marked off by a broken line in  FIG. 8 . Exceeding the upper limits of 0.21 and 0.23 to condition (2) causes the background color to get to white, giving rise to a drop of color contrasts between the fluorescent site and the background site. This in turn makes it difficult to view the fluorescent site (affected site), resulting in an increased probability of overlooking. Falling short of the lower limits of 0.16 and 0.04 to condition (2) is not desirable because there is a monochrome with an extremely noticeable blue tint. With visual sensitivity in mind, the background gets dark, giving rise to inconvenience that an image of light reflected off sites other than the fluorescent site is hardly viewable, even when the energy of the excitation light taken in the observation system is the same. 
     To obtain an image of light reflected off sites other than the fluorescent site in an image under observation, a light source filter (located instead of the excitation light filter  24 ) disposed in the illumination light path may be provided with a first transmissive area and a second transmissive area, with such transmittance characteristics as in  FIG. 9 . In this case, the first transmissive area is designed to contain an excitation wavelength for fluorescence (in the case of 5-ALA, the excitation light wavelength is λ e =410 nm), and the second transmissive area is designed to be contained in the transmissive are of the excitation cut filter  11 . 
     With the thus constructed arrangement, the whole biodiagnosis system has such system performances as shown in  FIG. 10 , wherein light transmitting through the second transmissive area is used to obtain a reflection image for the background other than the fluorescent site. 
     In this case, too, it is desired that the spectral characteristics of the background site other than the fluorescent site on the image plane upon observation of the subject satisfies the following condition (1): 
       0.005≦ I (λ p +Δ)/ I (λ p )≦0.5  (1) 
     provided that 40≦Δ≦80 nm, where λ p  is the wavelength (nm) at which the spectral intensity reaches a maximum, and I(λ p ) is indicative of the then spectral intensity. 
     As the upper limit of 0.5 to condition (1) is exceeded, there is an increase in the proportion of the self-fluorescence of the living body relative to the light passing through the second transmissive area. As a result, the background color gets close to white, giving rise to a drop of color contrasts, which may otherwise make it difficult to see the fluorescent site (affected site), resulting in an increased probability of overlooking. 
     As the lower limit of 0.005 to condition (1) is not reached, on the other hand, there is a decrease in the proportion of the self-fluorescence of the living body relative to the light transmitting through the second transmissive area, because the light transmitting through the second transmissive area enters more the observation system. As a result, there is light reflected off sites other than the fluorescent site in addition to the fluorescence from the subject; that is, the background becomes all too bright, giving rise to a drop of brightness contrasts. 
     It is noted that instead of providing the light source filter disposed in the illumination light path with the first and the second transmissive area, two light source filters may be used. The first light source filter with such transmittance characteristics as shown in  FIG. 11  is designed to contain the excitation wavelength for fluorescence as is the case with the aforesaid first transmissive area, and the second light source filter is designed to be contained in the transmissive area of the excitation cut filter  11  as is the case with the aforesaid second transmissive area. 
     Then, the light transmitting through the first light source filter and the light transmitting through the second light source filter are sequentially directed to the subject so that by making use of the afterimage phenomenon of the observer&#39;s eye or field sequential video image pickup, the fluorescent and background sites can be superposed to implement observation in good enough color contrasts. To direct sequentially to the subject the light transmitting through the first light source filter and the light transmitting through the second light source filter, such a turret  30  as shown in  FIG. 12  is located. Around that turret  30  a first light source filter  31  and a second light source filter  32  are disposed in a continuously switchover way to turn that turret  30  continuously or reciprocally. 
     As a light source for the illumination light directed to the subject, a laser that oscillates an excitation light wavelength may be used instead of the light source filter having such transmittance characteristics as shown in  FIG. 9 . Then, light of a wavelength contained in the transmissive area of the excitation cut filter  11  is superposed on the excitation light coming from that laser, or directed sequentially to the subject in an alternate manner. 
     Referring back to the biodiagnosis apparatus of  FIG. 1(   a ), the optical system  22  must not attenuate excitation light transmitting through the excitation light filter  24 ; as can be seen from the wavelength characteristics of  FIG. 13 , it is of importance that an antireflection coating applied onto a lens, etc. in the optical system  22  should have high transmittance with respect to the wavelength transmitting through the excitation light filter  24 . 
       FIG. 15(   a ) is illustrative in schematic of an arrangement wherein a TV camera system is connected to the biodiagnosis apparatus of  FIG. 1(   a ) for imaging purposes. As is the case with  FIG. 1 , the biodiagnosis apparatus itself comprises an exclusive scope (endoscope)  1  capable of being inserted into, for instance, the bladder, and a light source unit  2  for sending illumination light to that exclusive scope  1  via a light guide cable  3 . The light source unit  2  comprises a lamp  21  such as a xenon lamp, an optical system  22  adapted to condense light from the lamp  21  onto the input end of the light guide cable  3 , and a turret  23  located in an optical path from the lamp  21 . Around the turret  23 , an excitation light filter  24 , a white light filter  25 , a conventional IR cut white light filter  26  and an emergency light (small electric bulb)  27  are selectively disposed, as shown in  FIG. 15(   b ). The excitation light filter  24  is one that has such wavelength characteristics as described above and transmits light containing an excitation wavelength; the white light filter  25  is one that transmits light all over the wavelength range to observe an ordinary image; the conventional IR cut white light filter  26  is one that cuts off wavelengths in the infrared range and transmits light in the visible range to observe an image with good color reproducibility, as can be seen from the transmittance characteristics of  FIG. 14  for conventional IR cutting; and the emergency light (small electric bulb)  27  is to make sure the minimum illumination light for pulling the exclusive scope  1  out of the living body when the lamp  21  goes off. An optical path through the exclusive scope  1  is provided in it with an excitation cut filter  11  and an eyepiece unit  12  for the observation of an affected site. 
     And, in the exemplary arrangement here, a TV camera head  40  is mounted on the eyepiece unit  12  of the bio-diagnosis apparatus per se to enable a subject to be electronically imaged. The TV camera head  40  has in it a CCD  41  and an exclusive IR cut filter  42  located on the entrance side of CCD  41 . That exclusive IR cut filter  42  is used instead of an absorption type IR cut filter such as the conventional IR cut filter of  FIG. 14  for the purpose of keeping ordinary color reproducibility as conventional. To this end, a filter with a cutoff frequency shifted to a longer wavelength side is used in such a way as to have no influence on a fluorescent image (fluorescent wavelength λ f =630 nm). 
     Video signals obtained from the TV camera head  40  are forwarded to a camera control unit  43  to display and record taken images, and feedback signals are forwarded from the camera control unit  43  to the light source unit  2  for light control, etc. 
     While the biodiagnosis apparatus of the invention has been described with reference to its principles and some specific examples, it is to be understood that the invention may be modified or changed in various ways. 
     INDUSTRIAL APPLICABILITY 
     The invention provides a biodiagnosis apparatus wherein the wavelength characteristics of an illumination system and an observation system overlap so that a reflection image other than at a fluorescent site can be observed through excitation light taken by that overlap in the observation system. The invention is designed to satisfy condition (1) or (2) so that the fluorescent site can be observed in good enough color contrasts against the background.