US20050027166A1 - Endoscope system for fluorescent observation - Google Patents

Abstract

An endoscope system is disclosed for detecting fluorescent light emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into a living tissue. An illumination system generates illumination light in the wavelength range 600 nm-2000 nm which serves as excitation light for the plurality of fluorescent labeling materials, and a detection system that can separately detect different ones of the plurality of fluorescent light emissions that are emitted at different wavelengths from among the plurality of fluorescent labeling materials is provided. The endoscope system may include a conventional-type endoscope having an insertion section, or a capsule endoscope that wirelessly transmits image data. By superimposing the image data obtained using reflected light in the visible region and fluorescent light emitted by the fluorescent labeling materials, improved diagnostic capabilities are provided.

Description

• This application claims the benefit of priority of JP 2003-172361, filed in Japan on Jun. 15, 2003, and of JP 2004-176198, filed in Japan on Jun. 14, 2004, the subject matters of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
• Prior art endoscopes have conventionally been used in diagnosis and treatment where a fluorescent substance having an affinity to a lesion, such as cancer, has been previously administered into a subject's body and excitation light that excites the fluorescent substance is then irradiated onto tissue of the subject so that fluorescent emissions from the fluorescent substance that deposits at the lesion can be detected.
• For example, Japanese Laid-Open Patent Application H10-201707 describes a prior art endoscope wherein indocyanine green derivative labeled antibodies have been previously introduced into the living tissue. The lesions then emit fluorescent light when excited by infrared light, with the infrared light being readily transmitted by living tissue without damaging the living tissue. This enables the lesions to be observed by detecting the fluorescent light emissions while the light caused by self-fluorescence (autofluorescence) of the living tissues is blocked in order to aid in preventing lesions that are deep inside the living tissue from being overlooked.
• Indocyanine green derivative labeled antibodies attach to human IgG as a fluorescent agent and are excited by excitation light having a peak wavelength of approximately 770 nm. Such labeled antibodies produce fluorescence having a peak wavelength of approximately 810 nm. Japanese Laid-Open Patent Application H10-201707 illuminates living tissue of interest that has previously been administered such a fluorescent agent with light from a light source having wavelengths in the range of approximately 770-780 nm, and then detects light wavelengths that are emitted from the living tissue in the wavelength range of approximately 810-820 nm so as to determine the presence of a lesion.
• It is a well known fact that the earlier cancer is detected in a patient the less invasive the treatment; moreover, the treatment is generally more effective so as to provide improved survivability. Early detection of cancer in patients is a goal embraced by workers in the life science/medical field as well as by the population as a whole. However, cancer cells in the earliest stage show only meager morphologic changes from normal cells, and thus, conventional techniques that focus primary on morphologic changes in cells for determining the presence of cancer are not applicable for detecting cancer in the earliest stage.
• Furthermore, cancer in the earliest stage typically develops several millimeters deep within the surface of living tissue. In addition, living tissue scatters light in a sufficiently intense manner that the living tissue layer above the cancerous region blocks observation of the cancer. This becomes a remarkably adverse factor in solving the problem of detecting cancer in the earliest stage. Of course, the fact that the tissues to be observed are within a living body is also an adverse factor.
• Attempts have been made to develop a technique that combines using infrared light, which can reach deep inside living tissue with the infrared light being minimally scattered or absorbed, with a technology that introduces a plurality of different fluorescent labels into a plurality of different specific proteins. The proteins appear as cancer develops within livihg cells, and such a technique would enable the detection of cancer in its earliest stage and should enable a diagnosis to be made of whether the cancer has become malignant. In addition to endoscopes, diagnosis systems for cancer include CT, MRI, and PET scanning devices. Each of these devices uses a sensor that is externally provided in order to depict in three dimensions the interior regions of a human body and each is a non-invasive organ examination tool. Such devices can detect cancer once the cancerous region has grown to a size of approximately 1 cm or larger. However, the resolution of these devices is not yet sufficient to enable cancer to be detected in its earliest stage or to enable a diagnosis to be made of whether the cancer has become malignant.
• Research in life science such as genomics and proteomics has determined that cancer develops as a pre-cancerous lesion and the lesion gradually grows and transforms into metastatic, infiltrative cancer cells. Cancer is a genetic disease, and it is believed that a succession of genetic mutations causes the cells to become malignant. Gene defects are triggered by the expression (i.e., the presence) of specific proteins in the cell. A diagnosis of malignancy concerning a tumor or cancer can be made only when specific proteins for plural types of cancers are present, or when genes that cause defects are detected.
• According to recent reports, tumors can be diagnosed as being either benign or malignant when several types of proteins that are specifically expressed in cancer cells are detected. The diagnosis of the malignancy of a tumor is assured with improved accuracy if various additional types of proteins are detected. Theoretically, plural cancer-specific proteins in a living body can be labeled with different fluorescent light producing substances. Then, the different fluorescent light producing substances can be detected so as to determine the presence of cancer-specific proteins in order to verify a malignancy.
• Living tissue scatters light in a sufficiently intense manner that illuminated living tissue is difficult to see through. However, living tissue rarely scatters or absorbs significant amounts of light in the near-infrared to infrared range. For this reason, near-infrared and infrared wavelengths of light are often used in lesion diagnosis techniques. Light of this wavelength range is used as the excitation light for the fluorescent labels so that fluorescent labels that are distributed deep inside a living tissue will emit fluorescence, thereby aiding in the detection of cancer at an early stage.
• In the present invention, plural cancer-specific proteins are labeled with different fluorescent light producing substances that fluoresce in the near-infrared to infrared range, and these wavelengths are then detected using an endoscope so as to reveal the presence of cancer-specific proteins in cells that may be several millimeters deep within a living body. It is desirable that the respective fluorescent labels have narrow fluorescent wavelength emissions so that plural fluorescent labels can be introduced and detected, thus increasing the number of types of cancer-specific proteins that can be detected and thereby improving the accuracy of such an endoscopic diagnosis.
• Fluorescent labels that bind to cancer-specific proteins are introduced into living tissues, and plural fluorescent wavelengths are detected so that cancer-specific proteins that correspond to the fluorescent wavelengths can be detected. Thus, plural fluorescent labels can be used for fluorescence detection so that cancer in a patient can be diagnosed as being either benign or malignant at an earlier stage.
• In prior art endoscopes, the wavelength used can be varied only by varying the wavelength of the light source, and thus a technique for separating plural wavelengths in the near-infrared range is not available in the detection component. Therefore, in prior art endoscopes, plural fluorescent wavelengths that emit fluorescence in the near-infrared range when excited by illumination cannot be detected even when such labels have been previously introduced into living tissue that is to be observed.
BRIEF SUMMARY OF THE INVENTION
• The present invention relates to an endoscope system for endoscopic diagnosis of a subject who has been administered, for example, multiple fluorescent labels that emit fluorescence of the near-infrared wavelength range. More specifically, the present invention provides an endoscope system wherein plural fluorescent labels that have been previously introduced into living tissue can be separately detected using wavelengths in the near-infrared range.
BRIEF DESCRIPTION OF THE DRAWINGS
• The present invention will become more fully understood from the detailed description given below and the accompanying drawings, which are given by way of illustration only and thus are not limitative of the present invention, wherein:
• FIG. 1 shows the overall structure of an embodiment of an endoscope system according to the present invention, characterized by having the components that separate and detect plural fluorescent wavelengths positioned within the endoscope tip section of an endoscope that uses an image pickup device (such a combination is sometimes termed an ‘electronic endoscope’ or a ‘video endoscope’);
• FIG. 2 shows in greater detail the structure of the light sourceoptical system2 shown inFIG. 1;
• FIG. 3 is an end view of a turret22 (also shown inFIG. 2) that is provided with two different band pass filters;
• FIG. 4 shows the spectral transmittance of theband pass filter27aofFIG. 3 that transmits primarily visible light (solid line) and of theband pass filter27bofFIG. 3 that transmits primarily near-infrared light (dot-dash line);
• FIG. 5 shows a layout of windows that are provided on arotational disk23 ofFIG. 2;
• FIG. 6 shows exemplary spectral transmittances of optical filters that are attached to the inner windows of the rotational disk shown inFIG. 5;
• FIG. 7 is a schematic illustration that shows the illumination system;
• FIGS.8(a)-8(d) show exemplary spectral intensity profiles of light for sequentially illuminating the living tissue4 (illustrated inFIG. 1);
• FIG. 9 illustrates the spectral reflectance of normal living tissue;
• FIG. 10 shows the spectral transmittance of the excitation cut-off filter34 (shown inFIG. 1);
• FIGS.11(a)-11(d) show the spectral intensities of light entering the objective lens33 (FIG. 1) from living tissue when illumination light as shown in FIGS.8(a)-8(d) is irradiated onto the living tissue after fluorescent labels have been introduced into the living tissue;
• FIG. 12 shows the structure of a two-layer, tunable Fabry-Perot etalon filter;
• FIG. 13 shows the spectral transmittance of the tunable filter structure shown inFIG. 12;
• FIG. 14 is a cross-sectional view of a three-layer, tunable Fabry-Perot etalon filter;
• FIG. 15 is a cross-sectional view of another three-layer, tunable Fabry-Perot etalon filter;
• FIGS.16(a)-16(c) show different spectral transmittances of a tunable filter35 (shown inFIG. 1) that may be used in the endoscope system of the present invention;
• FIGS.17(a)-17(c) show the spectral intensities of the blue, green, and red light, respectively, that has been reflected from living tissue and the fluorescent light emitted by the fluorescent labels (shown in FIGS.11(a)-11(d)) when the light reaches the light receiving surface of the detector36 (FIG. 1) after having been transmitted through thetunable filter35;
• FIG. 17(d) shows the manner that plural fluorescent wavelengths in the infrared range are detected by scanning the transmission band pass wavelength of a tunable filter;
• FIGS.18(a)-18(d) relate to an exemplary design of a two-layer, tunable Fabry-Perot etalon filter, withFIG. 18(a) showing the spectral transmittance of a semi-transmitting coating deposited on the substrate surface that forms an air gap, and FIGS.18(b)-18(d) showing the spectral transmittances of the tunable filter when the air gap distance d (shown inFIG. 12) is 375 nm, 500 nm, and 625 nm, respectively;
• FIGS.19(a)-19(d) relate to an exemplary design of the three-layer, tunable Fabry-Perot etalon filter wherein the wavelength λ of fluorescent light emitted by the fluorescent labels is in the range 950≦λ≦1050 nm;
• FIGS.20(a)-20(c) show the spectral transmittances of the translucent coatings on the surfaces of the first through third substrates of an exemplary three-layer, tunable Fabry-Perot etalon filter, respectively, that face the translucent film;
• FIGS.20(d)-20(f) show the spectral transmittances of the three-layer, tunable Fabry-Perot etalon filter when the wavelength λ of fluorescent light emitted by the fluorescent labels is in the range 950≦λ≦1050 nm;
• FIGS.21(a)-21(c) show exemplary structures of tunable filters that may be provided for use with anobjective lens33, withFIG. 21(a) having a two-layer, tunable Fabry-Perot etalon filter, withFIG. 21(b) having a three-layer, tunable Fabry-Perot etalon filter, and withFIG. 21(c) having two, two-layer, tunable Fabry-Perot etalon filters;
• FIG. 22 is a timing chart for use in explaining the operation of the endoscope of the present invention for color image observation;
• FIG. 23 is a timing chart for use in explaining the operation of the endoscope of the present invention for fluorescence detection and color image observation;
• FIG. 24 shows a timing chart wherein more than three different fluorescent light emitting substances are to be separately detected;
• FIG. 25 is a timing chart for use in explaining the operation of the endoscope of the present invention for fluorescence detection and color image observation based on another operation principle;
• FIG. 26 shows a display image on a monitor;
• FIGS. 27 and 28 show another embodiment of the rotational disk of the light source optical system and with three different band pass filters attached to thewindows29d,29e, and29f, respectively, of the rotational disk, withFIG. 27 showing the structure of arotational disk23bandFIG. 28 showing the spectral transmittances of the three different band pass filters B, G, R;
• FIGS.29(a)-29(c) show the spectral transmittances of another embodiment of a tunable filter, withFIG. 29(a) being the spectral transmittance of a semi-transmitting coating that is deposited on the substrates that form an air gap, withFIG. 29(b) being the spectral transmittance of the tunable filter having an air gap, and withFIG. 29(c) being the spectral transmittance of the tunable filter when the air gap distance is changed to a different distance;
• FIGS.30(a)-30(d) show the spectral intensity of light that is transmitted through thetunable filter35 and reaches the light receiving surface of thedetector36;
• FIGS.31(a)-31(c) show the spectral transmittances of an exemplary two-layer, tunable filter when the air gap distance d is 1800 nm, 2000 nm, and 2200 nm, respectively;
• FIGS.32(a)-32(c) show the spectral transmittances of an exemplary three-layer, tunable filter, withFIG. 32(a) showing the spectral transmittance when d₁=d₂=900 nm, withFIG. 32(b) showing the spectral transmittance when d, =d₂=1000 nm, and withFIG. 32(c) showing the spectral transmittance when d₁=d₂=1100 nm;
• FIG. 33 shows the structure of a charge multiplying, solid-state image pickup element;
• FIG. 34 is a timing chart that illustrates the relative timing of a sensitivity control pulse CMD (Charge Multiplying Detector) and of horizontal transfer pulses S1 and S2 used with the solid-state image pickup element shown inFIG. 33;
• FIG. 35 shows the sensitivity (i.e., the multiplication factor) of the charge multiplying solid-state image pickup element versus the applied voltage to the solid-state image pickup element shown inFIG. 33;
• FIG. 36 is a timing chart for driving the charge multiplying, solid-state image pickup element shown inFIG. 33;
• FIG. 37 is a prior art illustration to show an example of a quantum dot;
• FIG. 38 is a graphical representation to show the excitation and emission spectra of the quantum dot shown inFIG. 37;
• FIG. 39 is a block diagram to show an alternative configuration in part of another embodiment of the present invention;
• FIG. 40 shows the overall structure of another embodiment of an endoscope system according to the present invention, wherein the optical elements for separating and detecting plural fluorescent light sources are located within a separate housing that receives light from the endoscope tip of an endoscope that uses an optical fiber bundle in its observation optics (such a combination is sometimes termed a ‘fiberscope’);
• FIG. 41 illustrates a minor change from that illustrated inFIG. 40;
• FIG. 42 also illustrates a minor modification fromFIG. 40;
• FIG. 43 illustrates another embodiment of the present invention;
• FIG. 44 illustrates an additional embodiment of the present invention;
• FIG. 45 illustrates the spectral transmittance of an infrared transmitting filter that is used for detecting only fluorescent wavelengths;
• FIGS. 46 and 47 show another embodiment of the present invention that uses a capsule endoscope that functions similarly to the endoscope shown inFIG. 1, but outputs its data wirelessly, withFIG. 46 being a side sectional view andFIG. 47 being a front view;
• FIGS.48(a) shows the spectral transmittance of an excitation light cut-off filter34;
• FIGS.48(b)-48(d) show the overall spectral transmittances of the same excitation light cut-off filter when combined with the tunable filters having individual spectral transmittances as shown in FIGS.18(b)-18(d); and
• FIGS.49(a)-49(d) show the spectral transmittances relating to a two-layer, tunable Fabry-Perot etalon filter.
DETAILED DESCRIPTION
• The endoscope system according to the present invention may be used for endoscopic diagnosis of a subject who has been administered plural known fluorescent labels that produce fluorescent light in the near-infrared range, and is characterized by having: an illumination system that includes multiple wavelengths λ in thewavelength range 600 nm≦λ≦2000 nm so as to excite different fluorescent labels; a detection system that includes a wavelength separation element for separating fluorescent wavelengths produced by the fluorescent labels; and a controller that controls the wavelength separation element so as to scan for peak wavelengths of the fluorescence produced by the fluorescent labels.
• The endoscope system shown inFIG. 1 is characterized in that it provides components within the endoscope tip for separating and transmitting plural fluorescent wavelengths so as to enable observations and diagnoses of lesions, such as cancers, using light in the near-infrared range. The wavelength range used is approximately 600-2000 nm, as these wavelengths are not significantly scattered or absorbed when living tissue is illuminated with such wavelengths, and thus these wavelengths reach deep into living tissue and enable a more effective diagnosis of cancer within a living body. A wavelength separation element is controlled so as to scan for the fluorescent emission peaks produced by the fluorescent labels. Such a technique enables high speed separation of fluorescent peak emission wavelengths in the near-infrared range.FIG. 2 shows in greater detail the structure of the light sourceoptical system2 shown inFIG. 1.
• According to a second type of the endoscope system of the present invention, an endoscope system is provided for endoscopic diagnosis of a subject who has previously been administered plural, known fluorescent light emitting labels that produce different fluorescent light emissions in the near-infrared range. The endoscope includes an illumination system for illuminating the subject with wavelengths that include wavelengths in the range 600-2000 nm so as to provide excitation light for the fluorescent labels, a detection system that includes a wavelength separation element for separating the fluorescent light emissions by the different fluorescent substances that comprise the labels, and a controller that controls the wavelength separation element so as to scan for the peak wavelengths of the fluorescent emissions produced by the fluorescent labels, with the detection system and controller being provided in an ocular portion (i.e., the eyepiece portion) of the endoscope.
• In the first and second types of the endoscope system of the present invention discussed above, the illumination system includes a light source that is detachably provided with plural wavelength selective filters that are switched into and out of the light path in order to select at least the following two illumination modes:
• • illumination mode 1—wherein light is emitted only in the visible wavelength range, and
  • illumination mode 2—wherein light is emitted having a wavelength component λ in therange 600≦λ≦2000 nm.
• It is desirable that the voltage for driving the wavelength separation element is changed only during theillumination mode 2.
• In the first and second types of the endoscope system of the present invention as discussed above, it is desirable that a voltage for driving the wavelength separation element is changed n times for n different fluorescent labels. In this way, at least two fluorescent wavelengths can be separated for observation.
• The third type of the endoscope system of the present invention is an endoscope system for endoscopic diagnosis of a subject who has been administered plural known fluorescent labels that, when excited, produce fluorescence in the near-infrared range, characterized by the following: an illumination system for illuminating the subject with at least part of the wavelength range 600-2000 nm including at least part of the excitation wavelengths of the fluorescent labels, a detection system including a wavelength separation element for separating fluorescent wavelengths produced by the plural fluorescent labels, and plural detection elements for detecting individual fluorescent wavelengths separated by the wavelength separation element, wherein the detection system and the plural detection elements are provided at the tip of the endoscope.
• The third type of the endoscope system of the present invention separates fluorescent wavelengths without any control of the wavelength separation element, which simplifies the structure of the endoscope system.
• The fourth type of the endoscope system of the present invention is for endoscopic diagnosis of a subject administered plural known fluorescent labels producing fluorescence in the near-infrared range, characterized by the following: an illumination system for illuminating the subject with at least part of the wavelength range 600-2000 nm including at least part of the excitation light wavelengths of the fluorescent labels, a detection system and including a wavelength separation element for separating fluorescent wavelengths produced by the plural fluorescent labels, and plural detection elements for detecting individual fluorescent wavelengths separated by the wavelength separation element wherein the detection system and the plural detection elements are provided in the eyepiece of the endoscope.
• The fourth type of the endoscope system of the present invention positions the detection system and plural detection elements at the endoscope eyepiece, which enables the distal end of the endoscope to be thin.
• It is desirable in the second and fourth types of the endoscope system of the present invention that an objective optical system be provided at the endoscope tip, that the objective optical system has at least one filter, and a cut-off filter that blocks the excitation light wavelengths of the fluorescent labels. In such a case, visible and infrared components can be transmitted.
• In the third and fourth types of the endoscope system of the present invention, the illumination system includes a light source. The light source is detachably provided with a filter that selectively transmits or reflects at least part of the wavelength range 600-2000 nm. The wavelength separation element separates plural fluorescent wavelengths individually when the filter is inserted. Furthermore, it is desirable in the third and fourth types of the endoscope system of the present invention that the wavelength separation element has an ability to separate at least three fluorescent wavelengths.
• In the first through fourth types of the endoscope system of the present invention, the detection system is further provided with at least one filter which cuts off the wavelengths that excite the fluorescent labels but enables visible and infrared wavelengths of interest to be transmitted.
• The first through fourth types of the endoscope system of the present invention further include an image processing device for merging a fluorescent image and a visible light observation image of the subject, and a monitor for displaying the merged image. The display of a merged fluorescent and visible light observation image allows the simultaneous observation of a fluorescent image and an ordinary observation image. Hence, the fluorescent image and ordinary observation image are obtained with no time lag, enabling the locating of the lesion in a simple and highly accurate manner.
• It is desirable in the first and second types of the endoscope system of the present invention that the fluorescent labels be substances containing InAs nanocrystal. The wavelength separation element of the first through fourth embodiments of the endoscope system of the present invention is preferably an etalon. Using an etalon as a variable spectral transmittance element ensures that the fluorescent wavelengths produced by fluorescent labels are detected even if they have a Gaussian distribution in a narrow wavelength region.
• It is desirable that the wavelength separation element consists of a tunable Fabry-Perot etalon filter comprising three or more aligned translucent substrates. Using three or more aligned translucent substrates enables the separation of fluorescent emissions having at least two wavelength peaks. However, the tunable Fabry-Perot etalon filter may be composed of only two aligned translucent substrates.
• The present invention provides an endoscope system for observation and diagnosis of living tissue within a subject who has previously been administered plural fluorescent labels that emit different fluorescent wavelengths as a result, for example, of being formed of different materials.
• It is desirable that the respective fluorescent labels have narrow fluorescent wavelength properties so that plural fluorescent labels can be introduced so as to increase the number of types of cancer-specific proteins detected for improved accuracy of diagnosis. Quantum dots (Q dots) can be used as the labels described above.
• FIG. 37 is an illustration to show an example of a quantum dot. InFIG. 37, aquantum dot80 has, for example, a semiconductor micro sphere formed of CdSe having a diameter of 2-5 nm as a nucleus, which is coated with ZnS in order to form a shell layer. Hydroxyl groups are attached to the shell layer via a sulfur molecule and thus proteins that target part of the hydroxyl group become bonded to the quantum dot.
• FIG. 38 shows the excitation light spectrum and the emission spectrum of a quantum dot. InFIG. 38, the broken line is the spectral distribution of the excitation light for a quantum dot and the solid line is the spectral distribution of the light emitted by a quantum dot that is formed of CdSe and InP. In order to distinguish different types of quantum dots, the quantum dots may have different particle sizes. As shown inFIG. 38, the excitation light wavelength distribution reaches to 700 nm. The quantum dot emits fluorescence in the near-infrared wavelength range. Quantum dots have the following characteristic fluorescent wavelength emission characteristics as compared to the prior art fluorescent dyes:
• • (1) the full band width of the emission spectrum profile of a quantum dot as measured at 50% of the peak intensity is about 1/200^thof the central wavelength of the spectrum (typically 20-30 nm) and is only about one-third that of a fluorescent dye;
  • (2) the peak wavelengths of the emission spectrum can be relatively flexibly selected in the range of approximately 400-2000 nm depending on the size (diameter) and material of the quantum dot, so as to create different, narrow-wavelength, Gaussian distributions; and
  • (3) the excitation light spectrum is intensified at the shorter wavelengths within the visible to ultraviolet range regardless of the center wavelength of the emission spectrum.
• When used for the detection of a single molecule, the quantum dots have the following advantages over conventional fluorescent dyes:
• • (1) they are very small in size and do not interfere with the movement of target molecules;
  • (2) their emission efficiency is much higher than that of conventional fluorescent dyes and thus, they allow highly sensitive detection of a single molecule; and
  • (3) they are rarely discolored after an extended period of excitation.
• According to these advantages, it is suitable to use fluorescent labels having the properties provided by quantum dots when conducting a single molecule detection analysis.
• The quantum dots characteristically allow for relative flexibility in the selection of plural emission center wavelengths, depending on their particle size and the material used, and they have a narrow half band width emission spectrum. Thus, more types of molecules can be identified in a given usable wavelength range as compared with using conventional fluorescent dyes. Furthermore, quantum dots have a wider excitation light spectrum. Hence, plural different quantum dots can be excited at once using light in the visible and infrared range.
• FIG. 1 shows the entire structure of a first embodiment of the endoscope system according to the present invention. InFIG. 1, anendoscope system1 is formed of alight source system2, anendoscope3, aprocessor5, and amonitor6. This embodiment is characterized by having a structure that separates and detects plural fluorescent wavelengths within the endoscope tip.
• FIG. 2 is an illustration that shows the structure of the light source optical system in thelight source system2 which can be used to detect fluorescent labels such as quantum dots (having, for example, emission spectra as shown inFIG. 38) that have previously been introduced into livingtissue4 to be examined with the endoscope system of the present invention. The light sourceoptical system2 is formed of alight source21, aturret22 provided with plural optical filters, and arotational disk23 provided with plural optical filters that are arranged concentrically. Thelight source21 can be a Xenon lamp that includes light wavelengths in the visible range as well as in the excitation light wavelength range of the fluorescent labels.
• FIG. 3 is an end view of theturret22 shown inFIG. 2. The turret is provided with two different band pass filters. The respective band pass filters have, for example, the spectral transmittances shown inFIG. 4.
• FIG. 4 shows the spectral transmittance of aband pass filter27athat transmits primarily visible light (solid line) and of aband pass filter27bthat transmits primarily near-infrared light (the dot-dash line). Theturret22 is rotated (as shown by the curved arrow R inFIG. 2) around therotation axis25 so as to insert one of the band pass filters into the optical path. Theturret22 is further provided with a mechanism (not shown) that moves theturret22 in a direction orthogonal to the optical axis CL of the light source optical system.
• FIG. 5 shows a layout of windows that are provided on therotational disk23 around therotation axis26. The windows are provided concentrically spaced on the outer and inner regions of the disk. Optical filters are bonded and fixed toinner region windows29a,29b, and29c, respectively. Therotational disk23 is rotated around therotation axis26 at a fixed rotation speed. Therotational disk23 is also moved by a rotational disk moving mechanism (not shown) so as to move therotational disk23 in a direction that is orthogonal to the optical axis CL of the light source optical system2 (as shown by the double-headed arrow S).
• After being moved by the rotational disk moving mechanism to a proper position, therotational disk23 can selectively create plural illumination modes. Table 1 below lists the illumination modes available using the light source optical system of this embodiment. A mode selection mechanism (not shown) is used to automatically select a given combination of the optical filter in theturret22 and the window region formed in therotational disk23, as detailed in Table 1 below.

  	TABLE 1
  	Turret 22	Rotational Disk 23	illumination light

  visible light mode:	27a	29a, 29b, 29c	visible light
  			(B, G, R)
  infrared mode:	27b	28a, 28b, 28c	infrared
  			(excitation light)

• FIG. 6 shows exemplary spectral transmittances of the optical filters attached to the inner windows of therotational disk23, with the band pass filter for transmitting blue light (B) being illustrated by a solid line, the band pass filter for transmitting green light (G) being illustrated by a dot-dash line, and the band pass filter for transmitting red light (R) being illustrated by a dash-dash line. When theturret22 is rotated so as to insert theband pass filter27ainto the optical path, therotational disk23 is operated to sequentially insert theinner windows29a,29b, and29cinto the optical path so as to realize field sequential color illumination suitable for the endoscope system.
• FIG. 7 shows a manner of illumination by the illumination system. Among the light emitted from thelight source21, light mainly in the visible region having wavelengths λ in therange 400≦λ≦650 nm is selectively transmitted through theband pass filter27a(not shown) and separated by the rotational disk into light of the blue B wavelength range, light of the green G wavelength range, and light of the red R wavelength range. Consequently, the three light colors R, G, and B are repeatedly and intermittently emitted. When theturret22 is rotated so as to insert theband pass filter27binto the optical path, therotational disk23 is operated so as to sequentially insert theouter windows28a,28b, and28cinto the optical path.
• In this case, among the light emitted from thelight source21, light mainly in the near-infrared range is selectively transmitted through theband pass filter27b, and then is repeatedly and intermittently transmitted by therotational disk23. Other, non-intermittent, illumination can be achieved by stopping the rotation of the rotational disk so as to keep anysingle window28a,28b, or28cin the optical path, or by retracting the rotational disk from the optical path. As shown inFIG. 1, theillumination lens32, thelight guide fiber31 as well as the reflected light receiving optics may be provided within the endoscope tip. Light produced by thelight source21 is transferred by thelight guide fiber31 so as to illuminate theliving tissue4 through theillumination lens32.
• FIGS.8(a)-8(d) show exemplary spectral intensity distributions of light illuminating theliving tissue4. More specifically, FIGS.8(a)-8(c) show the spectral intensities in arbitrary units (A.U.) of light that sequentially illuminates the living tissue while the visible light mode is selected, andFIG. 8(d) shows the spectral intensity in arbitrary units (A.U.) of light that illuminates the living tissue while the infrared mode is selected.
• FIG. 9 shows the spectral reflectance for normal living tissue. InFIG. 9 the reflection intensity is plotted on the ordinate in arbitrary units (A.U.) and the wavelength (in nm) is plotted on the abscissa. Light in the red and infrared ranges is reflected and/or absorbed less by living tissue and thus reaches deep inside the living tissue as compared with the other visible light. Thus, light in the red and infrared ranges can excite the fluorescent labels wherever they are located within the living tissue, (i.e., on the surface or deep inside) and thus makes a proper excitation light. Taking into account the properties of the fluorescent labels, the excitation light can have a wavelength λ anywhere in therange 600≦λ≦2000 nm.
• As shown inFIG. 1, anobjective lens33 is provided at the endoscope tip, adjacent to theillumination lens32. The light receiving surface of adetector36, such as a CCD, CMOS or another highly sensitive image pickup element, is provided at the image plane of theobjective lens33. An excitation light cut-off filter34 having a fixed transmittance and atunable filter35 having a variable transmittance are provided between theobjective lens33 and thedetector36. Astop37 is provided immediately following theobjective lens33.
• FIG. 10 shows the percentage spectral transmittance of the excitation light cut-off filter34. The excitation light cut-off filter34 transmits visible light and the light in the fluorescent wavelength range of the fluorescent labels, and cuts off the light in the near-infrared range that excites the fluorescent labels. In most cases, the intensity of the fluorescence produced by the fluorescent labels is significantly low, less than 1/1000, in comparison with the intensity of the excitation light. Thus, it is desirable that the excitation light cut-off filter34 has a cut-off performance of OD4 or more, where OD stands for Optical Density and “OD4 or more” means that log₁₀(I/I′)≧4, where I is the intensity of light entering the filter, and I′ is the intensity of light transmitted by the filter.
• Providing a filter having such a cut-off performance prevents the excitation light from reaching the light receiving surface of the detector, and thus allows the detection of only the fluorescence so as to provide good contrast. It is desirable that the excitation light cut-off filter34 be provided on the object side of thetunable filter35. In this way, the excitation light that is reflected by theliving tissue4 is prevented from causing thetunable filter35 to produce self-fluorescence, which can be a source of noise in the detection operation.
• FIGS.11(a)-11(d) show the spectral intensities in arbitrary units (A.U.) of light entering theobjective lens33 from the living tissue when the illumination light shown in FIGS.8(a)-8(d) is irradiated onto living tissue that has had fluorescent labels introduced. The light entering theobjective lens33 includes two different components, namely, the light reflected by the living tissue (hereafter simply termed “reflected light”, the intensity of which is shown by solid lines) and the fluorescence produced by the fluorescent labels (shown using dash-dash lines). In FIGS.11(a)-11(d), although the spectral intensity curves of the reflected light and of the fluorescence are both shown in each figure, the intensity of the fluorescence has been greatly exaggerated for convenience of illustration. More particularly, FIGS.11(a)-11(c) show the spectral intensities of light entering theobjective lens33 from the living tissue while the visible light mode is selected. The fluorescent labels can be excited by light in the visible range. Thus, in addition to the reflected light, fluorescence enters theobjective lens33. For example, when the blue illumination light is irradiated, as shown inFIG. 11(a), the reflected light carrying information from on and near the surface of the living tissue and the fluorescence from the fluorescent labels distributed on and near the surface layer of the living tissue enter theobjective lens33. Likewise, when green illumination light is irradiated, as shown inFIG. 11(b), the reflected light carrying information from the surface to a middle layer of the living tissue and the fluorescence from the fluorescent labels distributed from the surface to the middle layer of the living tissue enter theobjective lens33.
• In addition to the fluorescence shown, the blue and green light induces self-fluorescence of the living tissue and the green to red light enters theobjective lens33. These light components are not shown in the figures. When the red illumination light is irradiated, as shown inFIG. 11(c), the reflected light carrying information from the surface to a relatively deep layer of the living tissue and the fluorescence from the fluorescent labels distributed from the surface to a relatively deep layer of the living tissue enter theobjective lens33.
• FIG. 11(d) shows the spectral intensity of light entering theobjective lens33 from the living tissue while the infrared mode is selected. When the illumination light in the red and near-infrared range having a relatively wide range of wavelengths λ in the range 620≦λ≦830 nm is irradiated, the reflected light carrying information on the deep layer of the living tissue and the fluorescence from the fluorescent labels distributed from the surface to a relatively deep layer of the living tissue all enter theobjective lens33.
• The tunable filter that is used in this embodiment is a band pass filter of the tunable Fabry-Perot etalon type and has a transmittance wavelength range that may be varied. For example, the operation and structure of a two-layer, tunable Fabry-Perot etalon filter will now be described.FIG. 12 shows the structure of such a tunable filter andFIG. 13 shows the spectral transmittance of such a tunable filter.
• As shown inFIG. 12, the tunable band pass filter is formed of twosubstrates35X-1 and35X-2, on the facing surfaces of whichreflective coatings35Y-1 and35Y-2 are formed with an air gap d in-between. Light entering thesubstrate35X-1 is subject to multiple reflections. The air gap distance d is changed so as to modify the peak wavelength transmittance that emerges from thesubstrate35X-2. In other words, when the air gap distance d shown inFIG. 12 is changed, the wavelength of the maximum transmittance is changed from Ta to Tb, as shown inFIG. 13. The air gap distance d can be changed using a Piezo-electric element. The substrates can be made of transparent film and each has the same reflective property as either of thereflective coatings35Y-1 and35Y-2.
• The term ‘reflective coating’ as used herein means a coating that exhibits a high reflectance (and thus low transmittance) to a range of wavelengths that includes the near-infrared range. Such a reflective coating can be formed of multiple laminated metal coatings (such as deposited silver) or from several to a score or more of laminated dielectric coatings. Thetunable filter35 that is provided between theobjective lens33 anddetector36 can distinguish among the different fluorescent labels by detecting specific ranges of wavelengths. The air gap distance is controlled in order to scan for the peak wavelengths of light transmitted through the tunable filter so that plural wavelengths in the near-infrared range can be separated for detection.
• The operation and structure of a three-layer, tunable Fabry-Perot etalon filter35 will now be described.FIG. 14 shows a cross section of such a tunable band pass filter. InFIG. 14,glass substrates35X-1,35X-2, and35X-3 havereflective coatings35a,35b,35c, and35edeposited on their facing surfaces. Thereflective coatings35a,35b,35c, and35eare each formed of laminated metal coatings of, for example, deposited silver, or they may each be formed of several to as many as a score or more of laminated dielectric coatings.
• FIG. 14 further shows air gaps d₁and d₂, cylindrical laminatedpiezoelectric actuator elements71,71 fixed to the peripheries of theglass substrates35X-1,35X-2 and35X-3,reflective coatings35a,35b,35c, and35e, and variablevoltage power sources70,70 for applying voltage to the laminatedpiezoelectric actuator elements71,71. The laminatedpiezoelectric actuator elements71,71 expand or contract in their axial direction (i.e., the horizontal direction ofFIG. 14) in inverse proportion to the applied voltage so as to change the air gap distances d₁and d₂in a known manner. The top andbottom actuator elements71,71 inFIG. 14 independently control the air gaps d₁and d₂.
• The excitation light blocking property of the excitation light cut-off filter34 can also be applied to thetunable filter35. For example, an excitation light blocking (i.e., cut-off) coating can be applied to thesubstrate35X-1 on the surface that is opposite thereflective coating35aso that the excitation light cut-off filter34 can be eliminated, thus saving space between theobjective lens33 and thedetector36.
• FIG. 15 shows a cross section of another three-layer, tunable Fabry-Perot etalon filter in which the substrates are made of translucent film. This leads to reducing the weight, thus reducing the load of the air gap control devices such as the piezoelectric elements. This also contributes to higher response speeds and in saving power. The tunable Fabry-Perot etalon filter may be formed of plural layers that are constructed of substrates and reflective coatings, formed of only translucent films, or formed of a combination of these components so as to achieve a desired effect.
• The endoscope system of the present invention guides the endoscope tip to a subject (living tissue) and enables color image observation of the subject using illumination light in the visible range. Thus, the tunable filter has to transmit the light in the visible range and scan for the fluorescence produced by the plural fluorescent labels in the near-infrared range.
• The spectral transmittance required of a three-layer tunable filter that may be used in the endoscope system of the present invention will now be described with reference to FIGS.16(a)-16(c). It is assumed here that the wavelengths of fluorescence from the fluorescent labels is in the range 900-1100 nm.
• FIG. 16(a) shows an exemplary spectral transmittance of the semi-transmitting coating deposited on the substrate forming an air gap. In this example, the coating exhibits a much reduced transmittance to the wavelengths λ in therange 900 nm≦λ≦1100 nm than to other wavelengths.
• FIG. 16(b) shows the spectral transmittance of a tunable filter having an air gap distance A, with the light being subject to multiple interferences. As a result of multiple interferences of the light rays in the air gap, significantly narrow band pass regions occur in the range 900-1100 nm so as to enable the discerning of fluorescent emissions from the plural fluorescent labels. On the other hand, being scarcely subject to multiple interferences, light in the visible range is transmitted.
• FIG. 16(c) shows the spectral transmittance of a tunable filter having an air gap distance B. Light is also subject to multiple interferences when the air gap distance is the distance B. The transmittance range is shifted according to the air gap distance within the range 900-1100 nm. However, no transmittance changes are observed for light in the visible range. The air gap distance can be changed to modify the transmittance of a desired range of wavelength and to maintain the transmittance of other wavelengths. To this end, the spectral transmittance of the semi-transmitting coating deposited on the substrate forming an air gap should be properly defined. It is desirable to use semi-transmitting coatings made of dielectric multi-layered coatings for obtaining the spectral transmittance described above.
• FIGS.17(a)-17(d) show the spectral intensities of the reflected light from the living tissue and the fluorescence from the fluorescent labels shown in FIGS.11(a)-11(d) after the light has reached the light receiving surface of the detector36 (i.e., after having been transmitted through thetunable filter35 with a spectral transmittance as shown in FIGS.16(a)-16(c)). In FIGS.17(a)-17(d), the intensity is plotted on the ordinate in arbitrary units (A.U.) and the wavelength is plotted on the abscissa in units of nm. Once again, in FIGS.17(a)-17(d), although the spectral intensity curves of the reflected light and of the fluorescence are both shown in each figure, the intensity of the fluorescence has been greatly exaggerated for convenience of illustration.
• Thetunable filter35 transmits light in the visible range regardless of the air gap distance. Light in the blue (B), green (G) and red (R) wavelength ranges (as shown in FIGS.17(a)-17(c), respectively) that is reflected from the living tissue always reaches the light receiving surface of thedetector36. On the other hand, among the light wavelengths in the range 900-1100 nm, light in a wavelength range having a peak near 1000 nm reaches the light receiving surface of thedetector36 when the air gap distance is the distance ‘A’.
• The fluorescence, because it has a significantly lower intensity than the reflected light, can be neglected in the R, G, B color image observation. Among the light entering theobjective lens33 from the living tissue while the infrared mode is selected, light in the near-infrared range that excites the fluorescent labels is cut off by the excitation light cut-off filter34. As shown inFIG. 17(d), only the fluorescence reaches the light receiving surface of thedetector36. The air gap distance may be varied between the positions ‘A’ and ‘B’ so as to repeatedly scan the peak wavelengths in the direction indicated by the arrows. In this way, plural fluorescent wavelengths in the infrared range can be detected.
• FIGS.18(a)-18(d) show the spectral transmittances relating to a two-layer, tunable Fabry-Perot etalon filter that is designed for when the fluorescent emission wavelength peaks are in the wavelength range of 950-1050 nm.FIG. 18(a) shows the spectral transmittance of a semi-transmitting coating deposited on the substrate surfaces that form an air gap. In this case, the spectral transmittance of the semi-transmitting coating satisfies the following conditions:
  T1≧80%  Condition (1)
  T2≦20%  Condition (2)
  where
• • T1 is the average transmittance in the wavelength region of 400 nm≦λ≦650 nm, and
  • T2 is a transmittance in a wavelength band having a lower boundary that is 50 nm shorter than the peak transmittance wavelength of the shortest fluorescence wavelength, and an upper boundary that is 50 nm longer than the peak transmittance wavelength of the longest fluorescence wavelength.
• FIGS.18(b)-18(d) show the spectral transmittances of the tunable filter when the air gap distance d is 375 nm,500 nm, and 625 nm, respectively. A transmission range having a half band width of only 15 nm is established within the wavelength range 900-1100 nm, and an average transmittance of 70% or more is ensured for the visible range.FIG. 18(b) shows the spectral transmittance of the tunable filter with d=375 nm. In this case, the transmission wavelength peak is at 950 nm, and the transmittance is 3% or less in the approximate ranges 900-930 nm and 970-1100 nm.
• FIG. 18(c) shows the spectral transmittance of the tunable filter with d=500 nm. In this case, there is a narrow band width transmission peak at λ=1000 nm. The transmittance is 3% or less in the wavelength ranges 900-980 nm and 1020-1100 nm.FIG. 18(d) shows the spectral transmittance of the tunable filter with d=625 nm. In this case, the transmission wavelengths have a peak at 1050 nm, and the transmittance is 3% or less in the wavelength ranges 900-1030 nm and 1070-1100 nm.
• An appropriate spectral transmittance of the tunable filter for separating plural fluorescent wavelengths for detection can be obtained by setting the transmittance of the semi-transmitting coating to be 20% or less in the wavelength range extended by at least 50 nm with respect to the range defined by the shortest fluorescent wavelength peak and the longest fluorescent wavelength peak used. The air gap d is fixed at an appropriate distance for RGB color image observation.
• FIGS.49(a)-49(d) show the spectral transmittances relating to a two-layer, tunable Fabry-Perot etalon filter that is designed for when the fluorescent emission wavelength peaks are in the wavelength range of 950-1050 nm and that has different transmittance properties from those shown in FIGS.18(a)-18(d).FIG. 49(a) shows the spectral transmittance of a semi-transmitting coating deposited on the substrate surfaces that form an air gap. In this case, the spectral transmittance of the semi-transmitting coating satisfies the following conditions:
  T1≧80%  Condition (1)
  T2≦35%  Condition (2′)
  where
• • T1 is the average transmittance in the wavelength region of 400 nm≦λ≦650 nm, and
  • T2 is a transmittance in the wavelength band having a lower boundary that is 50 nm shorter than the peak transmittance wavelength of the shortest fluorescence wavelength, and an upper boundary that is 50 nm longer than the peak transmittance wavelength of the longest fluorescence wavelength.
• FIGS.49(b)-49(d) show the spectral transmittances of the tunable filter when the air gap distance d is 925 nm,1000 nm, and 1075 nm, respectively. A transmission range having a half band width of only 30 nm is established within the wavelength range 900-1100 nm, and an average transmittance of 70% or more is ensured for the visible range.FIG. 49(b) shows the spectral transmittance of the tunable filter with d=925 nm. In this case, the transmission wavelength peak is at 950 nm.
• FIG. 49(c) shows the spectral transmittance of the tunable filter with d=1000 nm. In this case, there is a narrow band width transmission peak at λ=1000 nm.FIG. 49(d) shows the spectral transmittance of the tunable filter with d=1075 nm. In this case, the transmission wavelengths have a peak at 1050 nm.
• The tunable filter having a transmittance property mentioned above has a wider half band width than the tunable filter having the transmittance property shown in FIGS.18(a)-18(d), in the wavelength region of 900 nm-1100 nm. This causes the amount of flourescent light passing through the tunable filter to increase and serves to achieve both separation of the plural fluorescent lights and detection of the brighter flourescent images.
• FIG. 48(a) shows the spectral transmittance properties of the excitation light cut-off filter34. Here the excitation light has a band width ranging from 720 nm to 850 nm which is determined by the half band width of the excitation light used in the light source system.FIG. 48(a) shows the spectral transmittance properties of the excitation light cut-off filter34. FIGS.48(b)-48(d) show the total spectral transmittance properties of the excitation light cut-off filter34 when combined with the tunable filters having individual spectral transmittances as shown in FIGS.18(b)-18(d).
• The excitation light cut-off filter34 of this embodiment satisfies the following Conditions (3)-(5):
  T_Ex1≧90%  Condition (3)
  T_Ex2≦0.01%  Condition (4)
  T_Ex3≧90%  Condition (5)
  where
• • T_Ex1is the average transmittance for 400 nm≦λ≦650 nm,
  • T_Ex2is the average transmittance for 700 nm≦λ≦870 nm,
  • T_Ex3is the average transmittance for 900 nm≦λ≦1100 nm, and
  • λ is the wavelength of light incident onto the filter.
• The excitation light cut-off filter34 passes the wavelength band of 400 nm-650 nm (in which the transmittance is T_EX1) that is used for observing a visible color image composed of R, G and B color components among the light reflected by the living tissue, and cuts off the wavelength band of 700 nm-870 nm (in which the transmittance is T_EX2) that includes the excitation light of the fluorescent label materials. The wavelength band width for T_EX2(700 nm-870 nm) is set to cover the extended wavelength range whose upper limit is 20 nm longer, and whose lower limit is 20 nm shorter, than the wavelength range determined by the filter placed in the light source system. This ensures the blocking of the excitation light that causes noise when detecting the fluorescent light. The excitation light cut-off filter34 has a transmittance T_EX3in the wavelength range that includes the flourescent lights emitted from the fluorescent label materials.
• The excitation light cut-off filter34 when combined with each of the tunable filters having individual spectral transmittances as shown in FIGS.18(b)-18(d) satisfy the following Conditions (6)-(9):
  T3≧60%  Condition (6)
  T4≦0.01%  Condition (7)
  T5≧65%  Condition (8) and
  5 nm≦d5≦35 nm  Condition (9)
  where
• • T₃is the average transmittance within the visible wavelength range of 400 nm≦λ≦650 nm of the illumination light,
  • T4 is the transmittance for the wavelengths within arange 20 nm above and 20 nm below the wavelength range of the excitation light generated by the illumination unit,
  • T5 is the transmittance at the peak transmittance wavelength for an infrared passband in the wavelength range of 950 nm≦λ≦1050 nm,
  • d5 is the infrared passband's full width as measured at 50% of the peak transmittance, and
  • λ is the wavelength of light incident onto the filter.
• Condition (6) ensures that there is sufficient transmittance of the filter(s) used to observe the sample in the visible region. Condition (7) ensures that the excitation light is not detected as noise during the detection of fluorescence emitted from the fluorescent labels by blocking wavelengths within arange 20 nm above and below the wavelength range of the excitation light. Conditions (8) and (9) ensure that the fluorescence wavelengths will be sufficiently transmitted by the filter(s) used to detect the fluorescence. Thus, Conditions (6)-(9) ensure that a sufficient brightness of observation light within the visible region is obtained while at the same time ensuring that the detected fluorescent light from the fluorescent labels can be separated and detected when the fluorescent labels emit fluorescence in the wavelength range 950 nm≦λ≦1050 nm.
• FIGS.19(a)-19(d) show spectral transmittances that relate to an exemplary design of a three-layer, tunable Fabry-Perot etalon filter when the fluorescent wavelengths of the fluorescent labels lie approximately in the range 950-1050 nm. This exemplary design is intended to improve the resolution obtainable in the infrared region as compared with the spectral transmittances (shown in FIGS.18(b)-18(d)) exhibited by the two-layer, tunable Fabry-Perot etalon filter discussed above. The semi-transmitting coatings deposited on the substrates forming the air gaps of the three-layer, tunable filter have the same spectral transmittance as shown inFIG. 18(a) for the two-layer, tunable filter.
• The air gap distances can be controlled in various ways. One way is to maintain the relationship that d₁is equal to d₂, the other way is to maintain the relationship that d₁is not equal to d₂.
• FIG. 19(a) shows the spectral transmittance when d, equals 375 nm and d₂equals 625 nm, which is an example that the air gap distances are controlled by the relation that d₁not be equal to d₂. As can be seen in the figure, there is a transmission peak centered at 800 nm, and the transmittance in the wavelength range 900-1100 nm is 0.3% or less. As one would expect, the transmittance shown for any given wavelength inFIG. 19(a) is equal to the product of the transmittances shown in FIGS.18(b) and18(d) for that same wavelength.
• FIG. 19(b) shows the spectral transmittance when both d, and d₂equal 375 nm. As one would expect in this case, the spectral transmittance at any given wavelength is the square of the transmittance at the same wavelength for the spectral transmittance curve shown inFIG. 18(b). In this situation, there is a transmission peak having roughly the same maximum transmission as inFIG. 19(a), but the peak is now centered at 950 nm in the wavelength range 900-1100 nm, and the half band width is reduced to about 7.5 nm. In addition, the transmittances in the ranges 900-930 nm, and 970-1100 nm are each 0.1% or less.
• FIG. 19(c) shows the spectral transmittance when d, equals 500 nm and d₂equals 500 nm.FIG. 19(d) shows the spectral transmittance when d, equals 625 nm and d₂equals 625 nm. FIGS.19(b)-19(d) are examples in which the air gap distances are controlled by the relation that d, equal d₂. As can be seem from comparing FIGS.19(b)-19(d), the transmission peak in the wavelength range 900-1100 nm, is moved to longer wavelengths by changing the value of d, or d₂.
• The two air gap distances should not be identical for good R, G, B color image observation. For example,FIG. 19(a) illustrates the spectral transmittance of the tunable filter when d₁=375 nm and d₂=625 nm.
• FIGS.20(a)-20(f) show the spectral transmittances of an exemplary three-layer, tunable Fabry-Perot etalon filter when the fluorescences from the fluorescent labels lie within the approximate range of 950-1050 nm. In this exemplary design, the middle substrate among the three substrates is made of translucent film.FIG. 20(b) shows the spectral transmittance of the translucent film, and FIGS.20(a) and20(c) show the spectral transmittances of the translucent coatings on the surfaces of the first and third substrates, respectively, that face the translucent film.
• By using different spectral transmittances in the range 900-1100 nm, the resolution of the tunable filter in the near-infrared range can be appropriately defined. FIGS.20(d)-20(f) show the spectral transmittances of the tunable filter when the two air gaps have the air gap distances d₁and d₂as given in Table 2 below.

  	TABLE 2
  	FIG. 20(d)	FIG. 20(e)	FIG. 20(f)

  d1(nm)	500	562.5	625
  d2(nm)	500	625	750
  peak transmission wavelength (nm)	1000	1056	1097

• In this exemplary design, the etalons having different transmittances are independently controlled so as to realize a low transmittance for the non-transmitting range and a larger half band width for the transmitting wavelength range within the range 900-1100 nm. This results in improving the S/N ratio when fluorescent dyes having low light emission efficiencies but larger light emission spectral width are used as fluorescent labels.
• Exemplary structures for providing the tunable filter within the endoscope optical system will now be described.FIG. 21(a) shows an exemplary structure in which a two-layer, tunable Fabry-Perot etalon filter is provided within anobjective lens33. InFIG. 21(a), theobjective lens33 is formed of, in order from the object side, alens33a, an excitation light cut-off filter34, abiconvex lens33b, atunable filter35, adoublet33c, and adetector36 having a light receiving surface.
• Thetunable filter35 includestransparent substrates35Z-1 and35Z-2, and translucent coatings are deposited on the surfaces thereof that form an air gap d. Apiezoelectric element72 is provided between thetransparent substrates35Z-1 and35Z-2. Thepiezoelectric element72 also serves as an aperture diaphragm.
• FIG. 21(b) shows an embodiment in which a three-layer, tunable Fabry-Perot etalon filter is provided in theobjective lens33 shown inFIG. 21(a). In this case, thetunable filter35 comprisestransparent substrates35Z-1,35Z-2, and35Z-3, on the surfaces of which that form air gaps d₁and d₂translucent coatings are deposited.Piezoelectric elements72 and73 are provided between thetransparent substrates35Z-1 and35Z-2 and between thetransparent substrates35Z-2 and35Z-3, respectively.
• Thepiezoelectric elements72 and73 are independently controlled. Thepiezoelectric element72 also serves as an aperture diaphragm. It is desirable that the angle of incidence of light to the translucent coating (as measured from the surface normal) not be large when the tunable filter is provided in the objective optical system as shown here. In the figure, the angle of incidence of the axial marginal light is less than or equal to 1°.
• FIG. 21(c) shows an embodiment in which a pair of two-layer, tunable Fabry-Perot etalon filters are provided in theobjective lens33. InFIG. 21(c), theobjective lens33 comprises, in order from the object side, aconcave lens33a, an excitation light cut-off filter34, abiconvex lens33b, a tunable filter35-1, adoublet33c, a tunable filter35-2, and adetector36 with a light receiving surface. The tunable filters35-1 and35-2 can have either the same transmittance property or different transmittance properties.
• Where there is not enough space to provide a three-layer, tunable Fabry-Perot etalon filter in the objective optical system, a combination of two-layer, tunable Fabry-Perot etalon filters can be used to obtain an equivalent transmittance property and an improved freedom of optical design, as shown inFIG. 21(c). Furthermore, it is not necessary to provide the tunable filter in the objective optical system when the endoscope is a fiberscope. For example, the tunable filter can instead be provided in the eyepiece lens or in a television camera system connected to the eyepiece lens. In addition, the excitation light cut-off filter34 can be provided immediately before the light receiving surface of thedetector36.
• FIGS. 22 and 23 are timing charts for use in explaining the operation of the endoscope of the present invention, withFIG. 22 being the timing chart for color image observation, andFIG. 23 being the timing chart for fluorescence detection and color image observation.FIG. 25 is a timing chart for use in explaining the operation of the endoscope of the present invention for fluorescence detection and color image observation based on another operation principle.
• The operation of the endoscope for color image observation shown inFIG. 22 will now be described. In the light source optical system shown inFIG. 1, theband pass filter27aof the turret22 (shown inFIG. 3) that primarily transmits the visible light is inserted in the optical path. In this state, theinner windows29a,29b, and29cof therotational disk23 shown inFIG. 5 are sequentially inserted in the optical path so as to sequentially transmit B, G, or R light intermittently. Here, a period of time during which therotational disk23 rotates one time is termed one frame.
• An explanation will now be provided wherein it is assumed that anobjective lens33 as shown inFIG. 21(a) is used as the objective optical system and that a two-layer, tunable Fabry-Perot etalon filter having the spectral transmittance as shown in FIGS.18(b)-18(d) is provided in the insertion section of an endoscope tip used as thetunable filter35. It is further assumed that the air gap has a distance d=d(V₀) when a driving voltage V₀is applied to thepiezoelectric element72 of thetunable filter35, and that the transmission wavelength range of thetunable filter35 IR(_V0) varies in the range 950-1050 nm, depending on the air gap distance d(V₀).
• It is unnecessary to scan thetunable filter35 during color image observation. The driving voltage applied to thepiezoelectric element72 per frame is maintained at V₀and the air gap distance is maintained at d=d(V₀). Thus, the B, G, R light reflected by the living tissue and the fluorescence produced by the fluorescent labels reach the light receiving surface of thedetector36. In the timing chart, the B,G,R light reflected by the living tissue are indicated by RF_B, RF_G, and RF_Rand the fluorescence produced by the fluorescent labels is indicated by F_IR(V0).
• The control of the endoscope system is simplified for color image observation. V₀can be changed to scan the wavelengths in accordance with the wavelengths of the illumination light B, G, or R and the transmittance of the tunable filter.
• Light received by the detector36 (the image pickup element) is subject to photo-electric conversion to produce image signals for R, G, and B color components, which are then supplied to aprocessor5. Theprocessor5 processes signals and displays color images of the living tissue on amonitor6. During the operation for color image observation shown inFIG. 22, thedetector36 receives the fluorescence along with the reflected light. However, the intensity of the fluorescence F_IR(V0)is significantly low and therefore the influence of the fluorescence on the production of color images can be neglected.
• The operation of the endoscope shown inFIG. 23 is described hereafter. The endoscope used has the same structure as the one inFIG. 22. The timing chart inFIG. 23 shows the alternate operation of the fluorescence detection and the color image observation. In this case, theband pass filter27aof theturret22 is inserted in the optical path during the first frame and theband pass filter27bis inserted in the optical path during the following frame.
• During the first frame, the rotational disk and tunable filter operate as described with reference toFIG. 22 and thedetector36 sequentially receives RF_B+F_IR(V0), RF_G+F_IR(V0), RF_R+F_IR(V0). On the other hand, during the following frame, theouter windows28a,28b, and28cof therotational disk23 are sequentially inserted in the optical path and, thus, the excitation light in the near-infrared range illuminates the living tissue intermittently. A driving voltage V₁is applied to thepiezoelectric element72 and the air gap has a distance d=d(V₁) while thewindow28ais inserted in the optical path. Consequently, thedetector36 receives F_IR(V1).
• A driving voltage V₂is then applied to thepiezoelectric element72 so that the air gap has a distance d=d(V₂) while thewindow28bis inserted in the optical path. Consequently, thedetector36 receives F_IR(V2). A driving voltage V₃is then applied to thepiezoelectric element72 so that the air gap has a distance d=d(V₃) while thewindow28cis inserted in the optical path. Consequently, thedetector36 receives F_IR(V3).
• In this way, three different fluorescent wavelengths can be detected in a frame. When more than three different fluorescent wavelengths should be detected, the driving voltages applied to thepiezoelectric element72 can be further altered in another frame.FIG. 24 shows a timing chart in such a case. For example, driving voltages V₁-V₃can be sequentially applied to thepiezoelectric element72 while the windows28a-28care rotated sequentially into the optical path, and driving voltages V₄-V₆can be sequentially applied to thepiezoelectric element72 while the windows28a-28care next sequentially rotated into the optical path.
• The rotation cycles of theturret22 androtational disk23 and the driving voltage of thepiezoelectric element72 are controlled in a synchronous manner per frame. Control is executed by, for example, afilter control circuit51 shown inFIG. 1. According to the timing chart inFIG. 23, color images and fluorescent information of the living tissue can be concurrently displayed on themonitor6 after theprocessor5 processes the images.
• FIG. 25 shows a timing chart for use in explaining the operation of the endoscope when theobjective lens33 shown inFIG. 21(b) is used as the objective optical system provided in the endoscope tip. Thetunable filter35 has the transmittance properties as shown in FIGS.19(b)-19(d). The differences from the timing chart inFIG. 23 will now be described.
• Two air gaps d₁and d₂of thetunable filter35 are independently controlled. During the first frame, different driving voltages are applied to thepiezoelectric elements72 and73 so that d, does not equal d₂. Then, during the next frame, three different driving voltages V₁, V₂and V₃are sequentially applied to thepiezoelectric elements72 and73 when the rotational disk has a window in the light path such that, at any instant during the following frame, the air gaps d₁and d₂are identical. For example, d₁(V₁)=d₂(V₁) where d₁=d₂so as to transmit F_IR(V1)while thewindow28ais in the optical path, and d₁(V₂)=d₂(V₂) where d₁=d₂so as to transmit F_IR(V2)while thewindow28bis in the optical path.
• The method for creating images will now be described with reference toFIG. 1. Aprocessor5 includes afilter control circuit51, apre-processor circuit52, an A/D converter53, an imagesignal processing circuit54, and a D/A converter55. Thefilter control circuit51 controls theturret22 in the light sourceoptical system2 for positioning the band pass filters27aand27bin the optical path. It also controls therotational disk23 for positioning the outer and inner windows in the optical path.
• Thefilter control circuit51 further controls the voltage applied to the piezoelectric elements provided in thetunable filter35 so as to control the air gap d of thetunable filter35 and thus, shifts the transmission wavelength range as described with reference toFIG. 13. The filter control circuit supplies thepre-processor circuit52 with control signals. Thepre-processor circuit52 adjusts the image signals supplied from thedetector36 by adjusting the gain of an amplifier that receives the detected image signals and by adjusting the white balance of color images using a white balance correction circuit.
• Image signals from thepre-processor circuit52 are supplied to the A/D converter53 where analog signals are converted to digital signals. The digital signals converted by the A/D converter53 are supplied to the imagesignal processor circuit54 and stored in an image memory.
• Subsequently, they are subject to image processing, such as image enhancing and noise elimination, and display controls for concurrent display of a fluorescent image, a color image, and a character image. The imagesignal processing circuit54 further executes the process for displaying a fluorescent image overlapped with a color light image or for normalizing the fluorescent intensity by calculation between color and fluorescent images. This provides a fluorescent image that is easy to identify along with a color image. The digital signals from the imagesignal processing circuit54 are supplied to the D/A converter55 where they are converted to analog signals. The analog signals are supplied to themonitor6 which displays individual images.
• Thefilter control circuit51 controls the transmission wavelength range of fluorescence so that the fluorescent peak wavelengths are calculated or counted and the displayed image (monitor6) is provided in pseudo-colors according to the count or counted fluorescence and the associated fluorescent labels.
• Table 3 below lists an example of the display of five different fluorescent labels detected at a point Pi (Xi, Yi) in a lesion.

  	TABLE 3
  	Fluorescent Label No:	1	2	3	4	5
  	P1(X1, Y1):		∘	∘	∘	∘
  	P2(X2, Y2):		∘	∘
  	P3(X3, Y3):	∘

• The coordinate X₁, Y₁, for example, is a point on the monitor shown inFIG. 26. The fluorescent labels P₁(X₁, Y₁), P₂(X₂, Y₂), and P₃(X₃, Y₃) can be displayed in different colors. For example, P₁can be displayed in yellow, P₂can be displayed in red, and P₃can be displayed in green, depending on the number and type of fluorescent labels obtained, or their combination. These can represent the degree of malignancy of the lesion by color, allowing a highly advanced diagnosis.
• FIG. 26 shows concurrent display of a color image overlapped with a fluorescent image on themonitor6. The color image presents the morphology of the lesion and the fluorescent image presents the functional information (information on the degree of malignancy) of the lesion. As shown inFIG. 26, concurrent display allows for the diagnosis of the location and the malignancy of the lesions.
• The image processing described above ensures the observation of a current condition, such as a cancer of a lesion, without error. Theprocessor5 calculates or counts the fluorescent peak wavelength signals and refers to a table of corresponding proteins to the fluorescent peak wavelengths in a memory of theprocessor5 to identify the protein present in the living body and stores the identified protein in the memory as data. Thus, individual in vivo protein data can be read from the memory and compared with the data in the table of corresponding proteins to reference fluorescent peak wavelengths.
• FIGS. 27 and 28 show another embodiment of the rotational disk of the light source optical system and of the band pass filter attached to thewindows29d,29e, and29fof the rotational disk. Only the differences from the rotational disk and band pass filter shown inFIGS. 5 and 6 will now be described.
• FIG. 27 shows the structure of arotational disk23bandFIG. 28 shows the spectral transmittance of the band pass filter. As shown inFIG. 27, therotational disk23bhas threewindows29d,29e, and29f, in which are mounted a blue (B) filter (not shown), a green (G) filter (not shown), and a red (R) filter (not shown), respectively. As shown inFIG. 28, the B, G, and R filters transmit light in the near-infrared range in addition to transmitting light in the blue, green, and red wavelengths, respectively.
• Table 4 below lists the possible combinations of the band pass filter provided on theturret22 and the windows provided in therotational disk23b.

  	TABLE 4
  	Turret 22	Rotational Disk 23b	Illumination Light

  visible light mode:	27a	29d, 29e, 29f	visible light
  			(B, G, R)
  infrared mode:	27b	29d, 29e, 29f	infrared
  			(excitation light)

• Only the B, G, or R light is transmitted and irradiated onto the living tissue while theband pass filter27athat is provided on theturret22 is inserted in the optical path. The excitation light in the near-infrared range is irradiated onto the living tissue while theband pass filter27bis inserted in the optical path. In this way, the rotational filter can be down-sized, thereby enabling the entire light source device to be made smaller. Furthermore, with the filter control mechanism being simplified, the production cost of the light source device can be reduced.
• Another embodiment of the structure of the tunable filter is described with reference to FIGS.29(a)-29(c). In FIGS.29(a)-29(c), the transmittance is plotted on the ordinate and the wavelength is plotted on the abscissa. Here, it is assumed that the fluorescent wavelengths from the fluorescent labels are in the range 950-1050 nm.FIG. 29(a) shows the spectral transmittance of the semi-transmitting coating deposited on the substrates forming an air gap. In this structure, the spectral transmittance of the semi-transmitting coating is characterized by a constantly low transmittance over the entire range of wavelengths in use.
• On the other hand, due to interference effects, the spectral transmittance of the tunable filter periodically has passbands as shown inFIG. 29(b), at least in the wavelength range 400-1100 nm. The transmittance peaks occur at wavelengths λ according to the following equation:
  2 n_dd cos α=mλ  Equation (1)
  where
• • n_dis the refractive index of the air gap,
  • d is the thickness of the air gap,
  • α is the angle of incidence of light onto the tunable filter, as measured from the surface normal,
  • m is the interference order, and
  • λ is the wavelength of a passband peak transmittance.
• FIG. 29(c) shows the spectral transmittance when the air gap distance is changed from a distance A to a distance B, where both the distance A and the distance B are sufficient for the light to be subject to multiple interferences. As shown inFIG. 29(c), the wavelengths of the peak transmittance are shifted, but the peak transmittance amplitudes remain substantially constant. The semi-transmitting coating having the spectral transmittance property as shown inFIG. 29(a) can be made of a metal coating formed of deposited silver and aluminum layers, or the coating can be a dielectric, multi-layered coating.
• Light having the spectral intensity properties as shown in FIGS.11(a)-11(c) enters theobjective lens33 and a portion of this light is transmitted through thetunable filter35 and reaches the light receiving surface of thedetector36. The light that reaches the receiving surface of thedetector36 has the spectral intensity properties shown FIGS.30(a)-30(d). In the FIGS.30(a)-(d), the intensity is plotted in arbitrary units (A.U.) on the ordinate and the wavelength (in nm) is plotted on the abscissa.
• As mentioned above, the tunable filter of this exemplary structure has a discrete property in which the transmission wavelengths in the visible range periodically have peaks. This allows partial, narrow ranges of wavelengths among the reflected light from the living tissue to transmit through the tunable filter. The transmission wavelengths of the tunable filter can be scanned so as to subdivide the light into narrow ranges of wavelengths. This allows fine analysis of data concerning the living tissue that is carried by the light that has been reflected from the living tissue. Needless to say, the tunable filter can be operated to detect plural fluorescent wavelengths in the near-infrared range.
• FIGS.31(a)-31(c) show the spectral transmittance for an exemplary design of a two-layer, tunable Fabry-Perot etalon filter. In this exemplary design, it is assumed that the fluorescence emitted by the fluorescent labels is in the range 950-1050 nm. FIGS.31(a),31(b) and31(c) show the spectral transmittance of the tunable filter when the air gap distance d is 1800, 2000, and 2200 nm, respectively.
• The reflectance of the reflective coating deposited on the substrates forming the air gap is 90% or more for the light entering the tunable filter at an incident angle of 0° (as measured from the surface normal). As can be seen in FIGS.31(a)-31(c), the air gap distance d can be changed so as to scan the narrow band width passband of the tunable filter at least in the wavelength range 900-1100 nm.
• FIGS.32(a)-32(c) show the spectral transmittance of an exemplary design of a three-layer, tunable Fabry-Perot etalon filter. In this exemplary design, it is assumed that the fluorescence emitted by the fluorescent labels is in the range 950-1050 nm. This exemplary design is intended to increase the bandwidth of the passbands within the infrared range so as to improve the S/N ratio of the fluorescent detection.
• Furthermore, the reflective coating can have a lower reflectance so as to facilitate manufacture of the coating, thus improving the production yield in manufacturing the tunable filter. With a three-layer design of the tunable filter, the reflective coating needs to have a reflectance of only 80% or more. The air gap distances d₁and d₂can be maintained identical while being increased or decreased so that the maximum transmissions of the passbands in the wavelength range 900-1100 nm are maintained high and the transmissions in the non-transmission range are lowered.
• FIG. 32(a) shows the spectral transmission when d, =d₂=900 nm. Likewise,FIG. 32(b) shows the spectral transmission when both d₁and d₂equal 1000 nm, andFIG. 32(c) shows the spectral transmission when both d, and d₂equal 1100 nm. Compared with FIGS.31(a)-31(c), it can be seen that the width of the passbands in the transmission wavelength range 900-1100 nm are increased.
• The detector (light receiving part)36 will now be described. Thedetector36 generally consists of a CCD, CMOS, or highly sensitive image pickup element. Highly sensitive image pickup elements can be preferably used in the present invention particularly because very weak light, such as fluorescence, is detected.FIGS. 33-36 show an embodiment in which a charge multiplying solid-state image pickup element is used as a highly sensitive image pickup element.
• FIG. 33 is an illustration of the structure of a charge multiplying solid-state image pickup element.
• FIG. 34 is a timing chart of a sensitivity control pulse CMD (Charge Multiplying Detector) and of the horizontal transfer pulses S1 and S2.
• FIG. 35 shows the sensitivity (i.e., the multiplication factor) of the charge multiplying solid-state image pickup element of the CMD versus the applied voltage.
• FIG. 36 is a timing chart for driving the charge multiplying solid-state image pickup element. The various signals (a)-(j) can be decoded using Table 5 below.

  TABLE 5
  Signal	Meaning or Operation
  (a)	action of the rotational filter during
  	the ordinary light observation mode
  (b)	vertical transfer pulses P1, P2 during
  	the ordinary light observation mode
  (c)	horizontal transfer pulses S1, S2 during
  	the ordinary light observation mode
  (d)	sensitivity control signal for the CMD
  	during the ordinary light observation mode
  (e)	CCD output signal (exposure/cut-off) during
  	the ordinary light observation mode
  (f)	action of the rotational filter during the
  	special light observation mode
  (g)	vertical transfer pulses P1, P2 during
  	the special light observation mode
  (h)	sensitivity control pulses for the CMD
  	during the fluorescent light observation mode
  (i)	sensitivity control pulses for the CMD
  	during the fluorescent light observation mode
  (j)	CCD output signal during one cycle of the
  	fluorescent light observation mode

• The solid-state image pickup element (hereinafter referred to as a CCD) is provided with a charge multiplying part between the horizontal transfer path and an output amplifier or at individual pixels in the element. An intensive pulse electric field is applied to the charge multiplying part from the processor so that signal charges acquire energy from the electric field and collide with electrons in the valence band. This causes impact ionization at first and then produces new signal charges (secondary electrons). The charge multiplying part may be implemented using, for example, a charge multiplying solid-state image pickup element as described in U.S. Pat. No. 5,337,340, entitled “Charge Multiplying Detector (CMD) Suitable for Small Pixel CCD Image Sensors”, the disclosure of which is hereby incorporated by reference.
• For example, the pulses may be applied to produce secondary electrons in a chain reaction avalanche effect. Pulses with relatively low voltage compared to those for an avalanche effect are applied to produce a pair of electron-positive holes in the impact ionization. When the charge multiplying part is provided before the output amplifier in a CCD, the pulse voltage value (amplitude) or pulse number applied can be controlled in a lump so as to multiply the number of signal charges in an arbitrary manner.
• On the other hand, when the charge multiplying parts are provided to individual pixels, the pulse voltage value (amplitude) or pulse number applied can be controlled pixel-by-pixel so as to multiply the number of signal charges in an arbitrary manner. The CCD in this embodiment is an FFT (Full Frame Transfer) type monochrome CCD in which the charge multiplying part is mounted between the horizontal transfer path and the output amplifier.
• Referring toFIG. 33, the CCD includes animage area60 of the light receiving part, an OB (Optical Black)part61, ahorizontal transfer path62, adummy63, acharge multiplying part64, and anoutput amplifying part65. Thecharge multiplying part64 includes a number of cells, with the number of cells being in the range from approximately equal to the number ofhorizontal transfer paths62 to twice the number ofhorizontal transfer paths62. The CCD may be an FT (Frame Transfer) type having a charge storage part.
• The signal charges produced at individual pixels of theimage area60 are transferred to thehorizontal transfer path62 one horizontal line at a time according to vertical transfer pulses P1 and P2 and are then transferred from thehorizontal transfer path62 to thedummy63 and to thecharge multiplying part64 according to horizontal transfer pulses S1 and S2. When a sensitivity control pulse CMD is applied to individual cells forming thecharge multiplying part64, the charge is sequentially multiplied in being transferred from one cell to another as far as to theoutput amplifying part65. Theoutput amplifying part65 converts the charge from thecharge multiplying part64 to a voltage so as to produce an output signal.
• The sensitivity multiplication rate obtained by thecharge multiplying part64 is modified by changing the voltage value (amplitude) of the sensitivity control pulse CMD to thecharge multiplying part64 from the CCD driving circuit. Thecharge multiplying part64 executes charge multiplication at every cell. The sensitivity multiplication rate obtained by thecharge multiplying part64 is characterized in that the charge multiplication starts when the applied voltage exceeds a certain threshold Vth and the sensitivity is exponentially multiplied thereafter, as shown inFIG. 35.
• The CCD driving circuit varies the voltage value (amplitude) of the sensitivity control pulse CMD shown inFIG. 36(i) based on the data supplied by the sensitivity control circuit, and outputs the sensitivity control pulse CMD that is synchronized with the horizontal transfer pulses S1 and S2, shown inFIG. 36(h), in phase to the CCD. In this manner the CCD driving circuit changes the voltage value (amplitude) of the sensitivity control pulse CMD signal that is applied to thecharge multiplying part64 so as to achieve a desired sensitivity multiplication rate. Using an image pickup element as described above as thedetector36 enables the detection of the fluorescence, which is significantly weaker than the reflected light, with a high S/N ratio.
• FIG. 39 is a block diagram to show the configuration of another embodiment of the present invention. In this embodiment, a dichroic prism is used in place of the tunable filter described with reference toFIG. 12 as the wavelength separation element for separating the fluorescent wavelengths produced by the fluorescent labels. InFIG. 39, the near-infrared wavelengths transmitted through the excitation light cut-off filter are separated by the dichroic prism into individual wavelengths, which are individually detected by a CCD. In the embodiment shown inFIG. 39, the reflected light from a subject and the fluorescence are imaged by an eyepiece lens provided at the tip of alight guide fiber132. The images are transferred to the rear end surface via thelight guide fiber132 and supplied to acamera head100 attached to the endoscope by animaging lens121. Light entering thecamera head100 is separated into infrared and visible light components by adichroic mirror122. The infrared component reflected by thedichroic mirror122 enters a firstdichroic prism125 via an excitation light cut-off filter123.
• The excitation light cut-off filter123 eliminates the excitation light component and transmits the fluorescent component in the infrared range. The firstdichroic prism125 separates the incident light into three specific fluorescent wavelengths and leads them to CCDs124a,124b, and124c, respectively. TheCCDs124a,124b, and124cdetect different fluorescent wavelengths. In this way, the image of the fluorescent components produced by the fluorescent labels can be detected by theCCDs124a,124b, and124c.
• The lengths and number of components of wavelengths separated by the firstdichroic prism125 can be determined by the optical property of the prism in an arbitrary manner. InFIG. 39, as described above, the excitation light cut-off filter123 blocks the excitation light wavelengths and transmits the fluorescent wavelengths. The firstdichroic prism125 and CCDs124a-124ccorrespond to a detection means including the wavelength separation element for separating fluorescent wavelengths produced by plural fluorescent labels and plural detection elements for detecting individual fluorescent wavelengths separated by the wavelength separation element.
• The visible light component transmitted through thedichroic mirror122 is supplied to a seconddichroic prism129 and a camera that includes threeCCDs126,127 and128. The seconddichroic prism129 separates the incident light into red (R), green (G), and blue (B) components and leads them to CCDs126,127, and128, respectively. In this way, ordinary visible image (ordinary optical image) components can be obtained by theCCDs126,127, and128. CCDs124a-124cand CCDs126-128 are synchronously driven by a CCD driving circuit (not shown).
• Electric signals from the CCDs124a-124cand CCDs126-128 are supplied to apre-process circuit152 of theprocessor5bwhere adjustments are made for gain by an amplifier and for white balance of visible light images by a white-balance correction circuit, which are not shown. Then, the signals are supplied to an A/D converter153 where analog signals are converted to digital signals. The digital signals from the A/D converter153 are supplied to an imagesignal processing circuit154 and temporarily stored in an image memory. Subsequently, they are subject to image processing, such as image enhancing and noise elimination, and display controls for concurrent display of a fluorescent image, a color image, and character information.
• The imagesignal processing circuit154 further executes a process for displaying a fluorescent image overlapped with an ordinary optical image or a process that normalizes the fluorescent image using data of the color and fluorescent images. This provides a fluorescent image that is easy to identify when presented with an ordinary image. The digital signals from the imagesignal processing circuit154 are supplied to a D/A converter155 where they are converted to analog signals. The analog signals are supplied to themonitor160 for display.
• On the monitor, several choices are available: two images, ordinary light and fluorescent, may be displayed concurrently side-by-side in the same size or in different sizes; two images may be overlapped; or processed images of fluorescent and ordinary light images may be displayed. Thus, a fluorescent image and an ordinary observation image can be viewed simultaneously. Therefore, the fluorescent image and ordinary observation image may be obtained with no time lag, enabling the locating of a lesion in a simple and highly accurate manner, which is a significant advantage in facilitating a proper diagnosis.
• The excitation light cut-off filter123, a firstdichroic prism125, threeCCDs124a,124b, and124c, and a detection means that includes a wavelength separation element for separating fluorescent wavelengths produced by plural fluorescent labels and plural detection elements for detecting individual fluorescent wavelengths separated by the wavelength separation element are provided at the eyepiece of an endoscope. In other embodiments of the present invention, these members can be provided at the tip of an endoscope.
• An excitation light cut-off filter123 having the transmittance shown inFIG. 10 may be used as a means for eliminating the excitation light component while transmitting the fluorescent components in the infrared range. In the exemplary structure ofFIG. 39, the firstdichroic prism125 serves as a wavelength separation element that automatically separates fluorescent wavelengths without any controls, which simplifies the structure of the endoscope.
• With the transmittance being separated by wavelengths, theprocessor5bcalculates or counts the fluorescent peak wavelengths and displays images in pseudo-colors according to the count obtained. With the transmitted light being separated by wavelengths, the fluorescent peak wavelengths are calculated or counted and reference is made to a table of the corresponding proteins which exhibit a similar profile of fluorescent peak wavelengths in a memory (not-shown) of theprocessor5bso as to identify the protein present in the living body and to store this information as data in the memory.
• In this way, images may be displayed in pseudo-colors, depending on the count, and the current condition of a lesion, such as whether it is cancerous, can be reliably diagnosed. Furthermore, individual in vivo protein data can be read from memory and compared with data in a table of corresponding proteins by referencing the peak transmittance wavelengths in the fluorescence.
• The fluorescent wavelengths of quantum dots used as fluorescent labels can be made to have a desired Gaussian distribution by adjusting the materials and outer diameters of the quantum dots, as shown inFIG. 38. For example, for a blue series, Cd Se nano-crystals can be used with diameters of 2.1, 2.4, 3.1, 3.6, or 4.6 nm. For a green series, InP nano-crystals can be used with diameters of 3.0, 3.5, or 4.6 nm. For a red series, InAs nano-crystals can be used having diameters of 2.8, 3.5, 4.6, or 6 nm.
• As described above, the present invention allows the use of quantum dots as fluorescent labels (tags) made from CdSe, InP, or InAs and having various diameters depending on the number of living subjects (proteins) to be identified, and with diameters in the range 2.1-6.0 nm. The quantum dots having plural different diameters are synthesized so as to have hydrophilicity, antibody properties, and to be bio-compatible. In addition, the materials and the outer diameters may be selected so as to provide optimized spectral properties regarding infrared excitation light and infrared fluorescence.
• The quantum dots are used as fluorescent labels in this embodiment. However, materials that are excited with red or near-infrared light which reaches the deep portion of the living tissue and materials that emit fluorescent light lying in the near-infrared region are also applicable as fluorescent label materials in the diagnostics using the endoscope system according to the present invention. The fluorescent labels (tags), such as the quantum dots, that are excited with red or near-infrared light which reaches the deep portion of the living tissue and that emit fluorescent light lying in the near-infrared region may be introduced into living tissue and then irradiated by excitation light so as to cause fluorescence in the near-infrared wavelength range. This allows the detection of cancer in the earliest stage even deep inside living tissue. In this way, the present invention enables fluorescent labels that have been introduced into living tissue to be used to diagnose cancer in its earliest stage.
• FIGS. 40-42 show alternative embodiments of the entire structure of the endoscope system according to the present invention wherein the structure that separates and detects plural fluorescent wavelengths is positioned other than in the endoscope tip. As the individual components are numbered identically with those ofFIG. 1, only the differences will be now be described.FIG. 40 shows the overall structure of a second embodiment of an endoscope system according to the present invention, characterized by having the components that separate and detect plural fluorescent wavelengths within the endoscope tip of the type that uses an optical fiber (fiberscope). Whereas inFIG. 1 the optical elements including the excitation light cut-off filter34 are positioned just after theobjective lens33, inFIG. 40 a fiber bundle (a so-called image guide fiber bundle) is arranged just after the objective lens, and an ocular lens is provided at the exit side of the fiber bundle. The detection optical elements, which have a similar structure to those inFIG. 1, may be arranged in a separate housing from that which houses the insertion section and ocular lens.
• FIG. 41 illustrates a minor change from that illustrated inFIG. 40. Whereas inFIG. 40 the excitation light cut-off filter34 is arranged within the ocular lens, inFIG. 41 it is arranged outside the ocular lens by being positioned within the insertion section between the optical fiber bundle and the ocular;
• FIG. 42 also illustrates a minor modification fromFIG. 40. InFIG. 40 the optical elements are arranged at the exit side of an ocular lens so as to be outside the insertion section. On the other hand, inFIG. 42, the housing of the optical elements is united with the fiber scope (i.e., all optical elements are arranged within the insertion section). Whereas inFIG. 40 the optical elements for separating and detecting plural fluorescent light sources are arranged at the exit side of the ocular lens, inFIG. 42 these same optical elements are united within the housing of the fiberscope (i.e., all optical elements are arranged in the housing of the insertion portion of the endoscope);
• FIG. 43 shows another embodiment of the present invention. Only the differences with regard toFIG. 43 will be described as compared toFIG. 39. In this embodiment, atunable filter35 and adetector36 are used as inFIG. 1 as a wavelength separation element for separating fluorescent wavelengths emitted by the fluorescent labels in lieu of using adichroic prism125 and the threeCCDs124a,124b, and124cshown inFIG. 39. Furthermore, acolor CCD202 is used in lieu of the seconddichroic prism129 for detecting visible light components and the plural-circuit-board camera that uses the threeCCDs126,127, and128. Thus, the number of CCDs used at the camera head can be significantly reduced and this not only makes for a more compact design but also the endoscope has reduced cost. Also with this structure, the same detection ability of visible and fluorescent light as the endoscope system having the structure shown inFIG. 39 can be obtained. Thecolor CCD202 can be replaced by a monochrome CCD. In such a case, thelight source unit2 emits the light in a sequential manner as inembodiment 1.
• FIG. 44 shows another embodiment of the present invention. Again, only the differences relative to the structure shown inFIG. 1 will be described. In this embodiment, an endoscopeoptical system3 that utilizes two observation optical systems, one observation optical system for detecting only wavelengths of light in a band that corresponds to an emitted fluorescence, and a second observation optical system for detecting only visible light.
• The observation optical system for detecting only visible light is formed of an objective lens200, a visible light transmitting filter203, and a CCD201. The visible light transmitting filter203 is different from the visiblelight transmitting filter27aonly in terms of its outer diameter.
• The observation optical system for detecting only wavelengths corresponding to those of an emitted fluorescence is different from that ofFIG. 1 in that it uses aninfrared transmitting filter204 having a spectral transmittance as shown inFIG. 45 in lieu of using the excitation light cut-off filter34 shown inFIG. 1. Thedetector36 detects only wavelengths corresponding to an emitted fluorescence. Thus, thedetector36 can be a highly sensitive detector that detects only infrared light. The morphology (i.e., structure) of an observation site is obtained by using a CCD201 that detects visible light components. Thedetector36 can be a photo-electric sensor made, for example, of PbS that is highly sensitive to infrared wavelengths instead of visible wavelengths (the latter are normally detected with an image pickup element that uses, for example, a CCD). This allows for improved S/N in the detection of fluorescent components, which are significantly weaker than the light emitted in the visible region. The endoscope system of this embodiment enables one to observe a visible image and a fluorescent image simultaneously by irradiating illumination lights for visible observation and for fluorescent observation at the same time. In this case, the structure of the illuminationoptical system2 is simplified.
• FIGS. 46 and 47 show another embodiment of the present invention. In this embodiment, the function of the endoscope system described with regard toFIG. 1 is realized in a capsule endoscope. InFIG. 46, the same items have been labeled with the same reference numbers and thus only the differences will be discussed.
• InFIG. 46, acapsule endoscope apparatus300 includes light emitting elements301-304 (such as LED's), alens33 for collecting light that has been reflected from a living body (e.g. an examination subject) or fluorescence, an excitation light cut-off filter34, atunable filter35 and adetector36. Thelens33 has an optical axis CL. Thelight emitting elements301 to304 are asymmetrically provided in relation to the optical axis CL.
• Thecapsule endoscope apparatus300 also comprises acontrol circuit305, apower source306 such as a capacitor and a battery, acoil307 that is electrically connected to thepower source306, amagnet308, andantenna309, and atransmitter310. Atransparent cover311 transmits the emitted light from the light emitting elements301-304 so as to illuminate the living body and introduces the reflected light or fluorescence into thelens33. Acase312 is also shown. When themagnet308 is magnetized by externally provided magnetic field lines, thecoil307 generates electric current due to magnetic induction so as to charge the capacitor or battery of thepower source306. Themagnet308 serves as an energy source to move thecapsule endoscope apparatus300 using externally provided electromagnetic waves. Theantenna309 transmits detection signals of thedetector36 to an external unit. Thetransmitter310 transmits information on the current position of thecapsule endoscope apparatus300 to an external unit that, together with theendoscope apparatus300, forms a capsule endoscope system.
• Theexternal unit313 has a transmission/reception antenna314 and amonitor315. It also has a control circuit, not shown. The transmission/reception antenna314 receives signals transmitted from theantenna309 andtransmitter310 of thecapsule endoscope apparatus300. It also transmits electromagnetic waves or magnetic energy to themagnet308. Themonitor315 displays images that are formed based on the detection signals of thedetector36 transmitted from theantenna309.
• FIG. 47 is an end view of the front end of the capsule endoscope apparatus as viewed from a position on the optical axis. Thelight emitting elements301,302, and303 emit blue, green, and red light, respectively. Thelight emitting element304 emits infrared light having wavelengths including part of the wavelength range from 600 to 2000 nm that comprises the excitation light wavelength of the fluorescent labels. A different detection system from that used in the endoscope system shown inFIG. 1 is used for detecting the wavelengths of reflected visible light versus fluorescence from a living body.
• The endoscope apparatus shown inFIG. 1 uses band pass filters having different properties and that are provided in the light sourceoptical system2 for selecting the wavelengths of the illumination light that illuminates the living body tissue. In this embodiment, as shown inFIG. 47, multiple light emitting elements having different wavelengths, such as LED's, are used in lieu of using the light sourceoptical system2. Thecontrol circuit305 is used to intermittently energizemultiple LEDs301 to304 that emit different wavelengths sequentially so as to utilize the same illumination system as the light sourceoptical system2. In this manner, the capsule endoscope system of the present invention can separately detect visible light that is reflected by the living tissue versus fluorescence that is emitted by the fluorescent labels. In addition, by using a capsule endoscope that employs wireless technology in lieu of, for example, using an insertion-type endoscope as shown inFIG. 1 (i.e., one that is hard-wired) the pain experienced by a patient during an endoscopic examination can be reduced.
• The present invention enables the user to provide advanced (i.e., early) diagnosis including diagnosis of the malignancy of lesions using an endoscope system than previously available in prior art endoscope systems. Using quantum dots for fluorescent markers in conjunction with the endoscope system of the present invention allows for more than one hour of endoscopic observation, as the fluorescence from quantum dots has a prolonged emission time period and is bright. Moreover, the fluorescence emitted by quantum dots has a narrow wavelength range, Gaussian distribution, and thus is suitable for detection by an tunable filter, such as a Fabry-Perot etalon type, band pass filter.
• The invention being thus described, it will be obvious that the same may be varied in many ways. For example, the combinations of the excitation light cut-off filters and tunable filter(s) are not restricted those described above. And, as is apparent from the various embodiments discussed above, many modifications are allowed in the endoscopic system used while practicing the basic concept of the invention. Thus, variations from the specific embodiments discussed above are not to be regarded as a departure from the spirit and scope of the invention. Rather, the scope of the invention shall be defined as set forth in the following claims and their legal equivalents. All such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims (43)

1. An endoscope system for detecting fluorescent light emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into a living tissue, comprising:

an endoscope that has an elongated insertion section and an eyepiece section;

an illumination system for generating illumination light that includes an excitation light for said plurality of fluorescent labeling materials;

a detection system that includes an optical element having a transmission wavelength that can be varied so as to separate fluorescent light emissions that are emitted at different wavelengths from among the plurality of fluorescent labeling materials, said optical element located in the eyepiece section; and

a controller that controls the transmission wavelength of said optical element so as to scan for different fluorescent light emissions.

2. An endoscope system for detecting fluorescent light emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into a living tissue, comprising:

an endoscope that has an elongated insertion section;

an illumination system for generating illumination light that includes an excitation light for said plurality of fluorescent labeling materials;

a detection system that includes an optical element having a transmission wavelength that can be varied so as to separate fluorescent light emissions that are emitted at different wavelengths from among the plurality of fluorescent labeling materials, said optical element located in a distal end part of said elongated insertion section; and

a controller that controls the transmission wavelength of said optical element so as to scan for different fluorescent light emissions.

3. The endoscope system according toclaim 2, wherein said excitation light includes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.

4. An endoscope system for detecting fluorescent light emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into a living tissue, comprising:

an endoscope having an insertion section and an eyepiece section;

an illumination system for generating illumination light that includes an excitation light for the plurality of fluorescent labeling materials;

a detection system that includes an electronic camera head adapted to be optically connected to said eyepiece section and an optical element which separates fluorescent light emissions that are emitted at different wavelengths from among the plurality of fluorescent labeling materials, said optical element located in the camera head; and

a plurality of sensors that receive the respective separated fluorescent light emissions that are emitted at different wavelengths.

5. The endoscope system according toclaim 4, wherein said excitation light includes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.

6. The endoscope system according toclaim 1, the detection system further including a filter that cuts off the excitation light.

7. The endoscope system according toclaim 2, the detection system further including a filter that cuts off the excitation light.

8. The endoscope system according toclaim 2, the detection system further including an objective optical system and a filter that cuts off the excitation light, said objective optical system and said filter located in a distal end portion of the insertion section.

9. The endoscope system according toclaim 4, the detection system further including an objective optical system and a filter that cuts off the excitation light, said objective optical system and said filter located in a distal end portion of the insertion section.

10. The endoscope system according toclaim 1, wherein said optical element is an etalon.

11. The endoscope system according toclaim 2, wherein said optical element is an etalon.

12. The endoscope system according toclaim 1, wherein:

the illumination system comprises a light source device that includes a plurality of wavelength selection filters that are insertable into, and removable from, an optical path of the illumination light; and

the illumination system has at least two illumination modes, namely, mode 1 and mode 2, that are selectable by inserting, and/or removing, one or more of the plurality of filters;

where

in mode 1, illumination light is emitted only within the visible region; and

in mode 2, illumination light having a wavelength component λ within the range 600 nm≦λ≦2000 nm is emitted.

13. The endoscope system according toclaim 12, wherein said optical element has its transmission wavelength varied by changing a voltage applied to said optical element only in mode2.

14. The endoscope system according toclaim 2, wherein:

the illumination system includes a light source device having a plurality of wavelength selection filters that are insertable into, and removable from, an optical path of the illumination light; and

the illumination system has at least two illumination modes, namely, mode1 and mode2, that are selectable by inserting, and/or removing, one or more of the plurality of filters;

where

in mode 1, illumination light is emitted only within the visible region; and

in mode 2, illumination light having a wavelength λ component within the range 600 nm≦λ≦2000 nm is emitted.

15. The endoscope system according toclaim 14, wherein said optical element has its transmission wavelength varied by changing a voltage applied thereto only in the mode2.

16. The endoscope system according toclaim 4, wherein:

the illumination system comprises a light source device that includes a wavelength selection filter that is insertable into, and removable from, an optical path of the illumination light, said wavelength selection filter transmits or reflects, at least a part, wavelengths of illumination light in the range of approximately 600 nm-2000 nm, and

the fluorescence separation optical element is configured so as to separate the fluorescences only when a specified filter is inserted into the illumination light path.

17. An endoscope system for detecting fluorescences in the near-infrared region by a plurality of fluorescent labeling materials that have previously been introduced into a living tissue, comprising:

an illumination system for generating illumination light that includes light for excitation of the plurality of fluorescent labeling materials, or visible light;

a detection system that includes an excitation light cut-off filter, a wavelength separation filter that separates the fluorescences emitted from the plurality of fluorescent labeling materials, and a sensor that detects sequentially each of the separated fluorescences; and

a observation system that includes an objective optical system and an image sensor for receiving an image of an object formed by the objective optical system.

18. The endoscope system according toclaim 17, wherein said excitation light includes wavelengths in the wavelength range of 600 nm≦λ2000 nm.

19. The endoscope system according toclaim 17, wherein the sensor serves as both a fluoresence detector and an image sensor.

20. An endoscope system for detecting fluorescences emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced in a living tissue, comprising:

an illumination system;

an observation system; and

a TV camera unit;

wherein

the illumination system includes a light source device which generates illumination light that includes light for excitation of the plurality of fluorescent labeling materials;

the observation system includes an objective optical system, an image transmitting optical system that transmits an image formed by the objective optical system, and an ocular optical system; and

the TV camera unit includes a coupling optical system adapted to be optically connectable to the ocular optical system for forming an image of the image transmitted by the transmission optical system, an excitation light cut-off filter, a wavelength separation filter that separates the fluorescences emitted from the plurality of fluorescent labeling materials, and an image sensor.

21. The endoscope system according toclaim 20, wherein said excitation light includes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.

22. An endoscope system for detecting fluorescences emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into living tissue, comprising:

an illumination system;

an observation system; and

a TV camera unit;

wherein

the illumination system includes a light source device which generates illumination light that includes light for excitation of the plurality of fluorescent labeling materials;

the observation system includes an objective optical system, an image transmitting optical system that transmits an image formed by the objective optical system, and an ocular optical system that includes an excitation light cut-off filter; and

the TV camera unit includes a coupling optical system adapted to be optically connectable to the ocular optical system for forming an image of the image transmitted by the transmission optical system, a wavelength separation filter that separates the fluorescences emitted from the plurality of fluorescent labeling materials, and an image sensor.

23. The endoscope system according toclaim 22, wherein said excitation light includes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.

24. An endoscope system for detecting fluorescences emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into living tissue, comprising:

an endoscope; and

a light source device;

wherein

the light source device generates illumination light that includes light for excitation of the plurality of fluorescent labeling materials;

the endoscope comprises an objective optical system, an image transmission optical system that transmits an image formed by the objective optical system, a coupling optical system that forms an image of the image transmitted by the transmission optical system, an image sensor, an excitation light cut-off filter, and a wavelength separation filter that separates the fluorescences emitted by the plurality of fluorescent labeling materials; and

both the excitation light cut-off filter and the wavelength separation filter are arranged between the transmission optical system and the image sensor.

25. The endoscope system according toclaim 24, wherein said excitation light includes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.

26. A capsule endoscope apparatus for detecting fluorescences emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into living tissue, the capsule endoscope apparatus comprising:

an illumination unit that includes a red band light source, a green band light source, a blue band light source, and a near-infrared band light source; and

an imaging unit that includes an objective optical system, an excitation light cut-off filter, a transmission wavelength separation filter which separates different fluorescences emitted from different fluorescent labeling materials, and an image sensor.

27. A capsule endoscope system that includes the capsule endoscope apparatus according toclaim 26, wherein

the capsule endoscope apparatus further includes a transmitter; and

a receiver is provided outside the capsule endoscope apparatus for receiving an image signal transmitted by the transmitter.

28. The capsule endoscope system according toclaim 27, and further including an image display device positioned outside the capsule endoscope apparatus that displays an endoscopic image using reflected visible wavelength light and on which marks, that indicate positions where the fluorescences are emitted by the living tissue, are superimposed.

29. The capsule endoscope system according toclaim 28, wherein the displayed marks are different colors, each different color corresponding to a different fluorescent labeling material.

30. An endoscope system for detecting fluorescences emitted by a plurality of different fluorescent labeling materials introduced into living tissue, comprising:

an illumination system; and

an observation system;

wherein

the illumination system includes illumination optics and a light source device that generates at least light for normal observation and light for excitation of the fluorescent labeling materials;

the observation system includes an objective optical system, an excitation light cut-off filter, a wavelength tunable filter, and a detector; and

the wavelength tunable filter is a tunable etalon that has an average transmittance in the visible region that enables a sufficient intensity of light to transmit through the wavelength tunable filter for normal observation, and has a narrow passband in the infrared region with the passband, as well as the passband wavelength peak, being variable in wavelength.

31. An endoscope system for detecting fluorescences emitted by a plurality of fluorescent labeling materials introduced into living tissue, comprising:

an illumination system; and

an observation system;

wherein

the illumination system generates an excitation light for the fluorescent labeling materials;

the observation system includes an objective optical system, an excitation light cut-off filter, a wavelength tunable filter and a detector;

the tunable filter is formed as an etalon that includes a plurality of transparent substrates arranged so as to form a gap therebetween, the surfaces of the substrates that face each other across the gap have semi-transparent films, at least two of which have a spectral transmittance and the following conditions are satisfied:

T1≧80% and

T2≦35%,

where

T1 is the average transmittance in the wavelength region of 400 nm≦λ≦650 nm, and

T2 is a transmittance in the wavelength band having a lower boundary that is 50 nm shorter than the peak transmittance wavelength of the shortest fluorescence wavelength, and an upper boundary that is 50 nm longer than the peak transmittance wavelength of the longest fluorescence wavelength.

32. An endoscope for detecting fluorescence emitted by a plurality of fluorescent labeling materials introduced into living tissue, comprising:

an illumination unit; and

an observation unit;

wherein

the illumination unit generates near-infrared illumination light that includes a wavelength band for excitation of the fluorescent labeling materials;

the observation unit includes an objective optical system, an excitation light blocking filter, a wavelength tunable filter, and a detector;

the combination of the excitation light blocking filter and the tunable filter passes light in the visible region, and has a passband in the infrared region which allows the fluorescence emitted from the fluorescent labeling material that is under observation to pass through;

wherein the spectral transmittance of said combination satisfies the following conditions:

T3≧60%

T4≦0.01%

T5≧65%

5 nm≦d5≦35 nm

where

T3 is the average transmittance within the visible wavelength range of 400 nm≦λ≦650 nm,

T4 is the transmittance for the wavelengths within a range 20 nm above and 20 nm below the wavelength range of the excitation light generated by the illumination unit,

T5 is the transmittance at the peak transmittance wavelength for an infrared passband,

d5 is the infrared passband's full width as measured at 50% of the peak transmittance, and

λ is the wavelength of light incident onto the filter.

33. The endoscope system according toclaim 30, wherein the tunable etalon includes at least three semi-transparent base substrates.

34. The endoscope system according toclaim 31, wherein the etalon includes at least three semi-transparent base substrates.

35. The endoscope system according toclaim 32, wherein the tunable filter includes at least three semi-transparent base substrates.

36. The endoscope system according toclaim 1, and further comprising an image display device that displays an endoscopic image of the living tissue on which marks, that indicate the positions on the living tissue from which fluorescences are detected, are superimposed.

37. The endoscope system according toclaim 2, and further comprising an image display device that displays an endoscopic image of the living tissue on which marks, that indicate the positions on the living tissue from which fluorescences are detected, are superimposed.

38. The endoscope system according toclaim 4, and further comprising an image display device that displays an endoscopic image of the living tissue on which marks, that indicate the positions on the living tissue from which fluorescences are detected, are superimposed.

39. The endoscope system according toclaim 17, and further comprising an image display device that displays an endoscopic image of the living tissue on which marks, that indicate the positions on the living tissue from which fluorescences are detected, are superimposed.

40. The endoscope system according toclaim 20, and further comprising an image display device that displays an endoscopic image of the living tissue on which marks, that indicate the positions on the living tissue from which fluorescences are detected, are superimposed.

41. The endoscope system according toclaim 22, and further comprising an image display device that displays an endoscopic image of the living tissue on which marks, that indicate the positions on the living tissue from which fluorescences are detected, are superimposed.

42. The endoscope system according toclaim 24, and further comprising an image display device that displays an endoscopic image of the living tissue on which marks, that indicate the positions on the living tissue from which fluorescences are detected, are superimposed.

43. The endoscope according toclaim 1, wherein said excitation light includes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.

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