JP4663258B2 - Endoscope device - Google Patents

Description

  The present invention relates to an endoscope apparatus that uses a plurality of fluorescent labeling substances that emit fluorescence in the near-infrared wavelength region, and performs diagnosis with an endoscope in a state where these substances are administered to an object to be examined.

  Conventionally, a fluorescent substance that has affinity for a diseased tissue such as cancer is administered into the body of a subject to be examined in advance, and the excitation light that excites the fluorescent material is irradiated to detect fluorescence from the fluorescent material accumulated in the diseased tissue. A diagnosis / treatment method using such a conventional endoscope apparatus is known.

  As an example, Patent Document 1 discloses that an indocyanine green derivative-labeled antibody that is excited by infrared light having good permeability through living tissue and emits fluorescence in the visible region is introduced into the diseased tissue. There is described a conventional endoscope apparatus configured to perform fluorescence observation of a diseased tissue while eliminating the influence of autofluorescence, and to prevent oversight of a lesion occurring in a deep portion of a living tissue.

  The excitation / fluorescence characteristics when an indocyanine green derivative-labeled antibody is bound to human IgG as a fluorescent agent are such that the peak wavelength of excitation light is around 770 nm and the peak wavelength of fluorescence is around 810 nm. Based on such knowledge, Patent Document 1 determines the presence or absence of a lesion by irradiating light in the vicinity of 770 to 780 nm from the light source into the body and detecting light in the vicinity of 810 to 820 nm from the body.

  It is well known that the earlier cancer is discovered, the less the physical burden on the patient during treatment (minimally invasive) and the higher the therapeutic effect (improved survival rate). In fact, early detection and treatment of cancer is one major goal in the life science / medical field.

  However, very early cancer cells have few morphological changes with respect to normal cells, and in reality, it is impossible to apply conventional methods that use morphological changes as a powerful indicator for diagnosing the presence or absence of cancer. . At the same time, very early cancer often occurs several millimeters behind the surface of living tissue. Biological tissue is a very strong scatterer against light and is difficult to see through. This is a major factor that cannot solve the problem of detecting very early cancer including the inside of a living body.

There are CT, MRI, PET, and the like as cancer diagnostic apparatuses other than endoscopes. These can visualize the human body three-dimensionally using a sensor installed outside the body, and can examine the organ non-invasively. However, although it is possible to detect cancer that has progressed to a size of about 1 cm or more, there is a problem that the resolution is insufficient to detect very early cancer, and the malignancy of cancer cannot be diagnosed. is there.
JP-A-10-201707

  From the results in the life science field such as genome analysis and proteome research, it has been found that cancer progresses in multiple stages from precancerous lesions to cancer cells with metastasis / invasion ability. Cancer is a genetic disease, and it is said that its malignancy increases with accumulation of genetic mutations. Genetic abnormalities start with the expression of specific proteins that cause genetic abnormalities in the cell, so to evaluate the malignancy of tumors or cancers, the proteins that cause specific proteins or abnormalities in multiple cancers It is impossible without detecting itself.

  A very recent report states that it is possible to determine whether a tumor is malignant or benign by detecting several types of proteins that are specifically expressed in cancer cells. The more types of proteins to be detected, the better the accuracy of tumor malignancy assessment. Theoretically, multiple cancer-specific proteins in vivo can be labeled with different fluorescent wavelengths, and by detecting each fluorescent wavelength, the presence of intracellular cancer-specific proteins can be determined, and the malignancy can be confirmed. it can.

  As described above, biological tissue is a very strong scatterer against light and is difficult to see through. However, in the near-infrared light region to the infrared region, there is little scattering and absorption in the living tissue that is the object to be examined. This is the reason why light in this region is often used in the diagnosis of lesions using light. For detection of early cancer, it is necessary to emit fluorescence from the fluorescent labeling substance distributed in the deep part of the living tissue by using light in this wavelength region as light for exciting the fluorescent labeling substance.

  In addition, if a plurality of cancer-specific proteins are labeled with different fluorescence wavelengths in the near-infrared to infrared region, and each fluorescence wavelength is detected, the presence of intracellular cancer-specific proteins within a few millimeters of the body I understand. In order to increase the kinds of cancer-specific proteins that can be detected by introducing a plurality of fluorescent labeling substances and improve the diagnostic accuracy, it is desirable that the fluorescence wavelength characteristics of each fluorescent labeling substance be as narrow as possible.

  Thus, a cancer-specific protein corresponding to a fluorescence wavelength can be detected by introducing a fluorescent labeling substance that binds to a cancer-specific protein into a living tissue and detecting a plurality of fluorescence wavelengths. Therefore, by performing fluorescence detection using a plurality of fluorescent labeling substances, it becomes possible to discriminate between benign and malignant cancers in the inspected body (living tissue).

  However, in the conventional endoscope apparatus, the wavelength can be changed only on the light source side, and a technique for separating a plurality of wavelengths in the near-infrared wavelength region has not been established on the detection side. For this reason, there is a problem that even if a plurality of fluorescent labeling substances are introduced into a living tissue, a plurality of fluorescent wavelengths cannot be detected in the near infrared wavelength region.

  The present invention has been made in view of the above-described problems, and an object thereof is to introduce a plurality of fluorescent labeling substances into a living body and detect a plurality of fluorescent wavelengths in the near infrared wavelength region. It is providing the endoscope apparatus made into the structure.

In order to achieve the above object, the first endoscope apparatus of the present invention provides a plurality of the plurality of fluorescent labeling substances that emit fluorescence having different wavelengths in the near-infrared wavelength region. An illumination means for irradiating light including the excitation wavelength of the fluorescent labeling substance;
A transmission wavelength separation element for separating the fluorescence wavelength emitted from the fluorescent labeling substance from the light from the object to be inspected;
Detection means for detecting light of the fluorescence wavelength separated by the transmission wavelength separation element, and a peak of spectral transmission characteristics of the transmission wavelength separation element with respect to a range where fluorescence peak wavelengths of the plurality of fluorescent labeling substances exist Control means for controlling to scan
It is characterized by having.

In this case, the transmission wavelength separation element can be provided at a distal end portion or an eyepiece portion of the endoscope apparatus.
Further, the transmission wavelength separation element changes the spectral transmission characteristic by changing the distance of the air gap between the reflective films facing each other, and the distance of the air gap is controlled by the control means. be able to.

The second endoscope apparatus of the present invention is configured to change the excitation wavelengths of the plurality of fluorescent labeling substances with respect to an object to be inspected to which a plurality of fluorescent labeling substances emitting fluorescence having different wavelengths in the near infrared wavelength region are administered. Illumination means for irradiating light including:
A transmission wavelength separation element that separates the fluorescence wavelength emitted by the fluorescent labeling substance from the light from the object to be examined for each fluorescence wavelength of the fluorescent labeling substance;
A plurality of detection means for individually detecting light for each fluorescence wavelength of the fluorescent labeling substance separated by the transmission wavelength separation element;
It is characterized by having.

  In this case, the transmission wavelength separation element can be provided at a distal end portion or an eyepiece portion of the endoscope apparatus.

A third endoscope apparatus according to the present invention is an endoscope apparatus that performs diagnosis with an endoscope in a state where a plurality of known fluorescent labeling substances that emit fluorescence in the near-infrared wavelength region are administered to an object to be examined. Illuminating means including at least a part of the excitation wavelength of the fluorescent labeling substance and irradiating at least a part of the wavelength band of 600 to 2000 nm to the object to be inspected; It has a detection means including a transmission wavelength separation element capable of separating the fluorescence wavelength emitted from the labeling substance, and a means for controlling the transmission wavelength separation element so as to scan the peak wavelength of the fluorescence emitted from the fluorescence labeling substance. And
The third endoscope apparatus of the present invention can separate and transmit a plurality of fluorescent wavelengths in the near-infrared wavelength region on the detection side, so that a lesion such as cancer can be observed. At this time, since a wavelength band of 600 to 2000 nm is used, there is little scattering and absorption in the near-infrared region and excellent depth of penetration, and cancer diagnosis of a living body can be performed effectively. Further, since the transmission wavelength separation element is controlled to scan the peak wavelength of fluorescence emitted from the fluorescent labeling substance, the fluorescence wavelength in the near infrared wavelength region can be separated and observed at high speed.
A fourth endoscope apparatus according to the present invention is an endoscope apparatus that performs diagnosis with an endoscope in a state where a plurality of known fluorescent labeling substances that emit fluorescence in the near-infrared wavelength region are administered to an object to be examined. Including at least part of the excitation wavelength of the fluorescent labeling substance, and illuminating means for irradiating the object to be inspected at least part of the wavelength band of 600 to 2000 nm, provided in the endoscope eyepiece, Detecting means including a transmission wavelength separation element capable of separating a fluorescence wavelength emitted from the fluorescent labeling substance, and means for controlling the transmission wavelength separation element so as to scan a peak wavelength of fluorescence emitted from the fluorescent labeling substance. Features.
In addition to the advantages of the third endoscope apparatus, the fourth endoscope apparatus of the present invention has a configuration in which a means for controlling and a control means are provided in the endoscope eyepiece, and the observation of a living lesion is observed. Can be performed effectively.
In the third endoscope apparatus and the fourth endoscope apparatus of the present invention, the illumination means includes a light source, and a plurality of wavelength selection filters are detachably disposed in the light source, and the wavelength selection filters are switched. Thus, at least the following two illumination modes can be selected.

  Illumination mode 1: a mode in which only light in the visible wavelength band is illuminated, illumination mode 2: a mode in which at least part of the wavelength band of 600 to 2000 nm is illuminated. Further, it is desirable that the driving voltage of the transmission wavelength separation element is changed only in the illumination mode 2.

  Further, in the third endoscope apparatus and the fourth endoscope apparatus of the present invention, the number of times that the drive voltage of the transmission wavelength separation element changes is 2 times or more for n types of fluorescent labeling substances. Desirably n times or less. In this case, at least two wavelengths of fluorescence can be separated and observed.

  The fifth endoscope apparatus of the present invention is an endoscope apparatus that performs diagnosis with an endoscope in a state where a plurality of fluorescent labeling substances that emit fluorescence in the near-infrared wavelength region are administered to an object to be examined. An illumination unit that includes at least a part of the excitation wavelength of the fluorescent labeling substance and irradiates at least a part of the wavelength band of 600 to 2000 nm to the object to be inspected; It has a detection means including a transmission wavelength separation element capable of separating the fluorescence wavelength emitted from the labeling substance, and a plurality of detection elements for individually detecting the fluorescence wavelengths separated by the transmission wavelength separation element.

  In the fifth endoscope apparatus of the present invention, the transmission wavelength separation element separates the fluorescence wavelengths without requiring any control, so that the configuration of the endoscope apparatus can be simplified.

  The sixth endoscopic device of the present invention is an endoscopic device that performs diagnosis with an endoscope in a state where a plurality of fluorescent labeling substances that emit fluorescence in the near-infrared wavelength region are administered to an object to be examined. An illumination unit that includes at least a part of the excitation wavelength of the fluorescent labeling substance and irradiates at least a part of the wavelength band of 600 to 2000 nm to the object to be inspected; It has a detection means including a transmission wavelength separation element capable of separating the fluorescence wavelength emitted from the fluorescent labeling substance, and a plurality of detection elements for individually detecting the fluorescence wavelengths separated by the transmission wavelength separation element.

  In addition to the advantages of the fifth endoscope apparatus, the sixth endoscope apparatus of the present invention has a configuration in which a detection means and a plurality of detection elements are provided in the endoscope eyepiece, Observation can be performed effectively.

  In the fourth endoscope apparatus and the sixth endoscope apparatus of the present invention, an objective optical system is provided at the distal end portion of the endoscope, the objective optical system has at least one filter, and the filter is fluorescent. It is desirable to have a property of blocking the excitation wavelength of the labeling substance. In this case, a visible light component and an infrared light component can be transmitted.

  In the fifth endoscope apparatus and the sixth endoscope apparatus of the present invention, the illumination means includes a light source, and the light source selectively transmits or reflects at least a part of wavelengths in a wavelength band of 600 to 2000 nm. The transmission wavelength separation element separates a plurality of fluorescence wavelengths individually only when the filter to be inserted is detachably disposed and the filter is inserted. In the fifth endoscope apparatus and the sixth endoscope apparatus of the present invention, the separation number i of the fluorescence wavelength by the transmission wavelength separation element is 2 ≦ i ≦ for n types of fluorescent labeling substances. n is desirable.

  In the third to sixth endoscope apparatuses of the present invention, at least one filter is further arranged in the detection means, and this filter has a characteristic of blocking the excitation wavelength of the fluorescent labeling substance. For this reason, visible light components and infrared light components can be transmitted.

  In the third to sixth endoscope apparatuses of the present invention, the endoscope apparatus further displays an image processing apparatus that combines the fluorescent image of the object to be inspected and the visible light observation image, and the combined image. Have a monitor.

  Thus, by combining and displaying the fluorescent image and the visible light observation image, the fluorescent image and the normal observation image can be observed simultaneously. For this reason, since a fluorescence image and a normal observation image without time lag are obtained, positioning of a lesioned part and the like can be performed easily and with high accuracy.

  In the third to sixth endoscope apparatuses of the present invention, the fluorescent labeling substance is preferably a substance containing InAs nanocrystals. In the third and fourth endoscope apparatuses of the present invention, the transmission wavelength separation element is an etalon. Thus, by using an etalon as the spectral transmittance variable element, it is possible to reliably detect the fluorescence wavelength emitted by a fluorescent labeling substance having a Gaussian distribution with a narrow fluorescence wavelength.

  At that time, the spectral transmittance element is more preferably an etalon having a configuration in which three or more semi-transparent substrates are arranged. As a result, it is possible to separate fluorescence wavelengths having at least two peak wavelengths. The etalon can also be configured by arranging two or more semi-transparent substrates.

  As described above, according to the present invention, early detection and diagnosis of a lesion such as extremely early cancer can be performed. Moreover, highly accurate fluorescence detection can be performed.

Example 1
Examples of the present invention will be described below.

  The present invention is an endoscope apparatus for observing and diagnosing a living tissue in a state where a plurality of fluorescent labeling substances having different fluorescence wavelengths are introduced into a subject to be examined.

  In order to increase the diagnostic accuracy by introducing a plurality of fluorescently labeled substances and increasing the types of proteins specific to cancer that can be detected, it is desirable that the fluorescence wavelength characteristics of each fluorescently labeled substance be as narrow as possible. Thus, for example, the use of quantum dots can be considered as such a substance. FIG. 37 shows an example of quantum dots. As shown in FIG. 37, the quantum dot 80 forms a shell layer by coating ZnS on the surface of a semiconductor CdSe microsphere having a diameter of 2 to 5 nm as a nucleus, for example. Hydroxyl groups are adsorbed on the shell layer via sulfur molecules. A part of this hydroxyl group is bonded to a target protein.

  FIG. 38 is a characteristic diagram showing excitation and emission spectra of quantum dots. The broken line is the spectral distribution of the excitation light of the quantum dots, and the solid line is the emission spectral distribution of quantum dots made of CdSe and InP and having different particle diameters. As shown in FIG. 38, the excitation light is distributed to a region of about 900 nm. The quantum dots emit fluorescence in the near infrared wavelength region. The fluorescence wavelength of quantum dots has the following characteristics compared to the wavelength of conventional fluorescent dyes.

  (1) The half width of the emission spectrum is about 1/200 (typically 20 to 30 nm) of the center wavelength, and is about 1/3 that of the fluorescent dye. (2) The peak wavelength of the emission spectrum can be set relatively freely in the range of about 400 to 2000 nm by selecting the size (diameter) and material of the quantum dots. That is, a narrow band Gaussian distribution can be created by setting the material of the quantum dots and adjusting the diameter. (3) Regardless of the position of the central wavelength of the emission spectrum, the intensity of the excitation spectrum increases in the visible light to ultraviolet light region as the wavelength is shorter.

  When used for single molecule detection, quantum dots have the following advantages compared to conventional fluorescent dyes.

  (1) The size is very small and hardly interferes with the movement of the target molecule. (2) The luminous efficiency is much higher than that of conventional fluorescent dyes, and one molecule can be detected with high sensitivity. (3) Almost no fading even if the excitation is continued for a relatively long time.

  Because of these advantages, it is most desirable to use a fluorescent labeling substance having characteristics such as quantum dots for analysis using single molecule detection.

  As described above, the quantum dot has a characteristic that a plurality of emission center wavelengths can be set relatively freely by selecting the particle size and the material, and the half width of the emission spectrum is narrow. For this reason, in the usable wavelength range, it becomes possible to identify many types of molecules as compared with the case of using a conventional fluorescent dye. Furthermore, quantum dots have a wide excitation spectrum, and it is possible to excite a plurality of types of quantum dots at once using light in the visible to near infrared region.

  FIG. 1 is an overall configuration diagram of the present embodiment. The endoscope apparatus 1 includes a light source optical system 2, an endoscope distal end optical system 3, a processor 5, and a monitor 6.

  For example, a fluorescent labeling substance such as a quantum dot having an emission spectrum shown in FIG. 38 is introduced into the living tissue 4 in advance.

  FIG. 2 is a diagram showing a configuration of the light source optical system 2. The light source optical system 2 includes a light source 21, a turret 22 having a plurality of optical filters, and a rotating disk 23 having a plurality of optical filters concentrically. As the light source 21, a xenon lamp including light in a visible light region and a wavelength region including an excitation wavelength of the fluorescent labeling substance is used.

  FIG. 3 is a diagram showing the configuration of the turret 22. Two types of bandpass filters are attached to the turret. An example of transmittance characteristics of each bandpass filter is shown in FIG. The scale on the vertical axis in FIG. 4 represents the transmittance, and the scale on the horizontal axis represents the wavelength. The characteristic of the band filter 27a mainly having the characteristic of transmitting visible light is indicated by a solid line, and the characteristic of the band pass filter 27b having the characteristic of mainly transmitting near infrared light is indicated by a one-dot chain line. . The turret 22 rotates around the rotation shaft 25 and inserts one of the bandpass filters into the optical path. Further, a mechanism (not shown) that moves in a direction perpendicular to the optical axis CL of the light source optical system 2 is provided.

  The rotating disk 23 is provided with windows concentrically spaced around the rotating shaft 26. The layout of the windows arranged on the rotating disk 23 is shown in FIG. Windows are provided on the outer peripheral portion and the inner peripheral portion of the disk substrate, and optical filters are bonded and fixed to the windows 29a, 29b, and 29c on the inner peripheral portion, respectively.

  The rotating disk 23 rotates at a constant rotation speed about the rotating shaft 26. Further, the rotating disk 23 moves perpendicularly to the optical axis CL of the light source optical system 2 by a rotating disk moving mechanism (not shown). A plurality of illumination states can be selectively created by moving the rotary disk 23 to an appropriate position by the rotary disk moving mechanism.

  FIG. 49 shows illumination modes that can be selected by the light source optical system 2 of this embodiment. A mode selection mechanism (not shown) automatically selects the combination of the optical filter arranged on the turret 22 and the window provided on the rotary disk 23 shown in FIG.

  An example of the transmittance characteristic of the optical filter that is bonded and fixed to the window on the inner peripheral portion of the rotating disk 23 is shown in FIG. The vertical scale in FIG. 6 represents the transmittance, and the horizontal scale represents the wavelength. The band-pass filter with the characteristic of transmitting blue light (B) is a solid line, the band-pass filter with the characteristic of transmitting green light (G) is a one-dot chain line, and has the characteristic of transmitting red light (R). The provided bandpass filter is indicated by a dotted line.

  When the turret 22 rotates and the band-pass filter 27a is inserted into the optical path, the rotary disk 23 operates so that the windows 29a, 29b, 29c on the inner periphery are sequentially inserted into the optical path. . As a result, illumination suitable for a field sequential endoscope apparatus is performed.

  FIG. 7 is a diagram schematically showing the illumination method. The light emitted from the light source 21 is selectively transmitted mainly by visible light of 400 to 650 nm by a band pass filter 27a (not shown), and further, by the rotating disk 23, the light having a wavelength belonging to the blue region and the green region. The light is divided into light having a wavelength belonging to and light having a wavelength belonging to the red region. As a result, light of three colors of RGB is repeatedly and repeatedly illuminated.

  When the turret 22 rotates and the band pass filter 27b is inserted into the optical path, the rotating disk 23 operates so that the windows 28a, 28b, and 28c on the outer peripheral portion are sequentially inserted into the optical path. In this case, the light emitted from the light source 21 is selectively transmitted through the bandpass filter 27b mainly for light having a wavelength belonging to the near infrared region. Then, the rotating disk 23 is repeatedly and repeatedly illuminated. Note that illumination other than intermittent illumination can be performed by keeping the rotating disk stationary and always inserting the window 28 into the light source optical path, or by retracting the rotating disk from the optical path.

  An illumination optical system and an objective optical system are disposed at the distal end portion of the endoscope. The light generated by the light source device is transmitted through the light guide fiber 31 and irradiated onto the living tissue 4 through the illumination lens 32. An example of the spectral intensity characteristic of the illumination light applied to the living tissue 4 is shown in FIG. The scale on the vertical axis represents intensity (arbitrary unit), and the scale on the horizontal axis represents wavelength (unit: nm).

  FIGS. 8A to 8C show the spectral intensity characteristics of the illumination light applied to the living tissue when the visible light mode is selected. FIG. 8D shows the spectral intensity characteristics of the illumination light irradiated to the living tissue when the infrared light mode is selected.

  FIG. 9 shows the reflectance characteristics of normal living tissue. The scale on the vertical axis represents the reflectance, and the scale on the horizontal axis represents the wavelength. Light in the red to near-infrared region is less reflected, scattered, or absorbed by living tissue than other visible region light, and has excellent depth reachability to the deep portion of the living tissue. Therefore, the fluorescent labeling substance is most suitable as excitation light in that it can be reliably excited regardless of where it is distributed from the surface layer to the deep layer of the biological tissue. In consideration of the characteristics of the fluorescent labeling substance, the wavelength of the excitation light can be set in an arbitrary region between 600 and 2000 nm.

  As shown in FIG. 1, an objective lens 33 is provided adjacent to the illumination lens 32 at the distal end portion of the endoscope. On the imaging surface of the objective lens 33, a light receiving surface of a detector 36 using a CCD, a CMOS, a high-sensitivity image sensor or the like is disposed. Between the objective lens 33 and the detector 36, a filter 34 having a fixed transmission characteristic and a tunable filter 35 having a variable transmission characteristic are installed.

  FIG. 10 is a graph showing the spectral transmittance characteristics of the filter 34. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength. The filter 34 has a characteristic of transmitting light in the visible region and light in the fluorescent wavelength band of the fluorescent labeling substance and blocking light in the near infrared wavelength band that excites the fluorescent labeling substance. Since the intensity of the fluorescence emitted from the fluorescent labeling substance is often extremely weak as 1/1000 or less compared to the intensity of the excitation light, the excitation light cutting performance of the filter 34 is preferably OD4 or more.

However, OD is an optical density, and is expressed by log ₁₀ (I / I ′) where I is the intensity of light incident on the filter and I ′ is the intensity of light transmitted through the filter. By doing so, the excitation light can be prevented from reaching the light receiving surface of the detector 36, and only the fluorescence can be detected with good contrast.

  Further, the filter 34 is desirably disposed closer to the object side than the tunable filter 35. By arranging in this way, it is possible to prevent the tunable filter 35 from emitting self-fluorescence due to the excitation light reflected by the living tissue 34 and causing detection noise.

  FIG. 11 shows the spectral intensity characteristics of light incident on the objective lens 33 from the biological tissue when the illumination light having the characteristics shown in FIG. 8 is irradiated onto the biological tissue into which the fluorescent labeling substance is introduced. The light incident on the objective lens 33 includes two types of light: illumination light reflected by biological tissue (hereinafter simply referred to as “reflected light”) and fluorescence emitted when a fluorescent labeling substance is excited by the illumination light. The scale on the vertical axis represents intensity (arbitrary unit), and the scale on the horizontal axis represents wavelength (unit: nm).

  In the figure, for convenience, the spectral intensity characteristic curve of reflected light and the spectral intensity characteristic curve of fluorescence are displayed in parallel, but the ratio of the reflected light intensity and the fluorescence intensity is not considered. FIGS. 11A to 11C show the spectral intensity characteristics of light incident on the objective lens 33 from the living tissue when the visible light mode is selected. Since the fluorescent labeling substance has a property of being excited even by light in the visible region, fluorescence is also incident on the objective lens 33 in addition to the reflected light. For example, when blue illumination light is irradiated, as shown in FIG. 11A, the reflected light including information on the extreme surface layer of the living tissue and the fluorescent material distributed on the extreme surface layer of the living tissue. Fluorescence enters the objective lens 33.

  Similarly, when the green illumination light is irradiated, as shown in FIG. 11 (b), the reflected light including the information on the middle layer of the living tissue and the fluorescent material distributed from the surface layer to the middle layer of the living tissue. Fluorescence enters the objective lens 33. In addition to the fluorescence shown here, blue light or green light induces autofluorescence of living tissue, and green to red light is incident on the objective lens 33, but is not displayed in the figure.

  When red illumination light is irradiated, as shown in FIG. 11C, reflected light including information on a relatively deep layer of the living tissue and a fluorescent material distributed from the surface layer of the living tissue to a relatively deep layer. From the light enters the objective lens 33.

  FIG. 11D shows the spectral intensity characteristics of light incident on the objective lens 33 from the living tissue when the infrared light mode is selected. When illumination light in the red to near-infrared region having a relatively wide width of 620 to 830 nm is irradiated, the reflected light including information on the deep layer of the living tissue and the surface layer to the deep layer of the living tissue Fluorescence from the fluorescent material distributed in the light enters the objective lens 33 without any leakage.

  The tunable filter used in the present embodiment is a Fabry-Perot etalon type band-pass filter, and is configured so that the transmission wavelength band can be arbitrarily changed. As an example, the operation and configuration of an etalon having a two-layer structure will be described. FIG. 12 is a configuration diagram of a tunable filter using an etalon having a two-layer structure. FIG. 13 is a graph showing the transmittance characteristics of the tunable filter. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength.

  As shown in FIG. 12, in the tunable filter, reflecting films 35Y-1 and 35Y-2 are formed on the opposing surfaces of the two substrates 35X-1 and 35X-2, and the reflecting films 35Y-1 and 35Y-2 are interposed. Has an air gap d. Then, multi-beam interference is generated in the incident light from the substrate 35X-1 side, and the wavelength of the maximum transmittance of the emitted light from the substrate 35X-2 side is changed by changing the length of the air gap d.

  That is, when the distance of the air gap d is changed, the wavelength of the maximum transmittance is changed from Ta to Tb as shown in FIG. The length of the air gap d can be changed using a piezoelectric element such as a piezoelectric element. Further, the substrate may be made of a transparent film, and the film itself may have the characteristics of the reflective films 35Y-1 and 35Y-2.

  Here, the reflective film refers to a film having a characteristic of high reflectivity (low transmittance) in at least a part of the wavelength region including the near-infrared region. It is composed of dielectric multilayer films laminated from several layers to several tens of layers.

By providing the tunable filter 35 between the objective lens 33 and the detector 36, the fluorescence wavelength emitted by the fluorescent labeling substance can be separated and only light in a specific wavelength band can be detected. In addition, by controlling the length of the air gap and scanning the peak wavelength of the light transmitted through the tunable filter, it is possible to separate and detect a plurality of fluorescence wavelengths in the near infrared region.
(Example 2)
The operation and configuration of a tunable filter 35 using a three-layer etalon will be described. FIG. 14 is a cross-sectional view of a tunable filter 35 using a three-layer etalon. The substrates 35X-1, 35X-2, and 35X-3 are glass substrates. Reference numerals 35a, 35b, 35c and 35e are reflective films deposited on the opposing surfaces of the respective substrates, and are composed of laminated metal films such as silver or dielectric multilayer films laminated in several to several tens of layers. .

  d1 and d2 are air gaps, 71 is a cylindrical laminated piezoelectric actuator element fixed to the outer periphery of the glass substrate and the reflective film, and 70 is a variable voltage power source for applying a voltage to the laminated piezoelectric actuator element 71. is there. The laminated piezoelectric actuator element 71 expands and contracts in the left-right direction (axial direction) in FIG. 14 in inverse proportion to the applied voltage, and the lengths of the air gaps d1 and d2 can be freely changed. Further, the actuator element 71 can independently control the air gaps d1 and d2.

  Note that the excitation light cut characteristics of the filter 34 can be matched to the tunable filter 35. For example, by applying an excitation light cut coat as shown in FIG. 10 to the surface of the substrate 35X-1 opposite to the reflective film 35a, the filter 34 becomes unnecessary, and the space between the objective lens 33 and the detector 36 is eliminated. Can be reduced.

  FIG. 15 shows another configuration example of a tunable filter using a three-layer etalon. In this configuration example, the substrate is made of a translucent film. As a result, the weight can be reduced, the load on the air gap control device such as a piezoelectric element can be reduced, and the response speed can be increased and the power can be saved. In addition, in such an etalon composed of a plurality of layers, a desired effect can be achieved by using either a structure composed of a substrate and a reflective film, a structure composed of a translucent film, or a structure combining both. can do.

  In the endoscope apparatus of the present invention, it is necessary to perform color image observation of a subject using illumination light in the visible region in order to guide the distal end portion of the endoscope to an object to be examined (living tissue).

  Therefore, the tunable filter must have a function of transmitting light in the visible region and scanning peak wavelengths of fluorescence emitted by a plurality of fluorescent labeling substances in the near infrared region.

  The spectral transmission characteristics necessary for the tunable filter used in the endoscope apparatus of the present invention will be described with reference to FIG. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength. Here, it is assumed that the fluorescence wavelength of the fluorescent labeling substance exists between 900 and 1100 nm.

  FIG. 16A is a conceptual diagram showing an example of the spectral transmission characteristics of the semi-transmissive film deposited on the substrate surface forming the air gap. In this example, the transmittance between at least 900 and 1100 nm was set lower than the transmittance in other wavelength regions. At this time, the spectral transmission characteristic of the tunable filter when the air gap distance is A is conceptually shown in FIG. A is a distance at which light can cause multiple interference. In the region between 900 and 1100 nm, only a very narrow band of light is transmitted due to multiple interference in the air gap. In the visible region, the light is transmitted with almost no influence of multiple interference.

  FIG. 16C conceptually shows the spectral transmission characteristics of the tunable filter when the distance of the air gap is changed to B. B is also a distance at which light can cause multiple interference. In the region between 900 and 1100 nm, the transmission band moves as the air gap distance changes, but the transmission characteristics in the visible region do not change.

  In this way, by changing the distance of the air gap, the transmission characteristics in the desired wavelength region are changed and the transmission characteristics in the other wavelength regions are kept almost constant. It is necessary to appropriately set the spectral transmission characteristics of the semi-transmissive film to be deposited. In order to obtain such spectral transmission characteristics, it is desirable to form a semi-transmissive film with a dielectric multilayer film.

  Assuming that the tunable filter 35 has the spectral transmittance characteristic shown in FIG. 16, the reflected light from the living tissue and the fluorescence from the fluorescent labeling substance shown in FIG. FIG. 17 shows the spectral intensity characteristics when the light-receiving surface of the detector 36 is reached. The scale on the vertical axis represents intensity (arbitrary unit), and the scale on the horizontal axis represents wavelength (unit: nm). In the figure, for convenience, the spectral intensity characteristic curve of reflected light and the spectral intensity characteristic curve of fluorescence are displayed in parallel, but the ratio of the reflected light intensity and the fluorescence intensity is not considered.

  Since the tunable filter 35 transmits light in the visible region regardless of the distance of the air gap, as shown in FIGS. 17A to 17C, red (R), green (G), The light of each wavelength band of blue (B) always reaches the light receiving surface of the detector 36.

  On the other hand, in the region between 900 and 1100 nm, the transmission band moves as the air gap distance changes. For example, when the air gap distance is A, light in the wavelength band with a peak of 1000 nm is detected. The light receiving surface of the device 36 is reached. When observing a color image using an RGB image, a very weak fluorescence intensity compared to the intensity of the reflected light can be ignored.

In addition, among the light incident on the objective lens 33 from the living tissue when the infrared light mode is selected, the light in the near-infrared wavelength band that excites the fluorescent labeling substance is blocked by the filter 34, which is shown in FIG. Thus, only the fluorescence reaches the light receiving surface of the detector 36. By appropriately changing the distance of the air gap, the peak of the transmission wavelength can be repeatedly scanned in the direction indicated by the arrow in the figure, so that a plurality of fluorescence wavelengths can be detected in the near infrared wavelength region.
(Example 3)
FIG. 18 shows a specific design example of a tunable filter using a two-layer structure etalon when the fluorescence wavelength of the fluorescent labeling substance exists between 950 and 1050 nm. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength.

  FIG. 18A shows the spectral transmission characteristics of the semi-transmissive film deposited on the substrate surface forming the air gap. In this design example, the spectral transmission characteristics of the semi-transmissive film satisfy the following conditions.

T1 ≧ 80%, where T1 is the average transmittance at 400 nm <λ <700 nm
When the transmittance at 900 nm ≦ λ ≦ 1100 nm is T2, T2 ≦ 20%
Where λ is the wavelength of light incident on the semi-transmissive film.

  The spectral transmission characteristics of the tunable filter when the air gap d is d = 375 nm, 500 nm, and 625 nm are shown in FIGS. In this design example, a transmission band having a half width of 15 nm is formed between 900 and 1100 nm. In the visible region, an average transmittance of 70% or more is ensured.

  FIG. 18B is a diagram showing the spectral transmission characteristics of the tunable filter at d = 375 nm. In this state, there is a transmission wavelength peak at 950 nm. Further, the transmittance between 900 and 930 nm and between 970 and 1100 nm is 3% or less.

  FIG. 18C is a diagram showing the spectral transmission characteristics of the tunable filter at d = 500 nm. In this state, a transmission wavelength peak exists at 1000 nm. Further, the transmittance between 900 and 980 nm and between 1020 and 1100 nm is 3% or less.

  FIG. 18D is a diagram showing the spectral transmission characteristics of the tunable filter at d = 625 nm. In this state, there is a transmission wavelength peak at 1050 nm. Further, the transmittance between 900 and 1030 nm and between 1070 and 1100 nm is 3% or less.

  As described above, among the plurality of fluorescent labeling substances to be administered to the object to be inspected in advance, semi-transmission in a wavelength range that is extended by at least about 50 nm with respect to the range in which the shortest fluorescent peak wavelength and the longest fluorescent peak wavelength exist. By setting the transmittance of the film to 20% or less, it is possible to realize spectral transmission characteristics suitable for a tunable filter that separates and detects a plurality of fluorescence wavelengths. Note that the air gap d is fixed at an appropriate distance when observing a color image using an RGB image.

  53 (a) to 53 (d) correspond to the case where a fluorescence peak exists in the range of 950 to 1050 nm and have transmission characteristics different from those shown in FIGS. 18 (a) to (d). The spectral transmittance characteristics of the designed two-layer etalon are presented.

  FIG. 53A shows the light transmission characteristics of the semi-transmissive film deposited on the surface of the substrate forming the air gap. In this design example, the spectral transmission characteristics of the semi-transmissive film satisfy the following conditions.

When the average transmittance at 400 nm <λ <700 nm is T1, T1 ≧ 80%
When the transmittance at 900 nm ≦ λ ≦ 1100 nm is T2, T2 ≦ 35%
Where λ is the wavelength of light incident on the semi-transmissive film.

  The spectral transmission characteristics of the tunable filter when the air gap d is d = 925 nm, 1000 nm, and 1075 nm are shown in FIGS. In this design example, a transmission band having a half width of 30 nm is formed between 900 and 1100 nm. In the visible region, an average transmittance of 70% or more is ensured.

  FIG. 53B is a diagram showing the spectral transmission characteristics of the tunable filter at d = 925 nm. In this state, there is a transmission wavelength peak at 950 nm. FIG. 53 (c) is a diagram showing the spectral transmission characteristics of the tunable filter at d = 1000 nm. In this state, a transmission wavelength peak exists at 1000 nm. FIG. 53 (d) is a diagram showing the spectral transmission characteristics of the tunable filter at d = 1075 nm. In this state, there is a transmission wavelength peak at 1050 nm.

  As can be seen from comparison with FIGS. 18A to 18D, the spectral transmission characteristics of the semi-transmissive film deposited on the surface of the substrate on which the air gap is formed and the air gap are changed to 900. The half bandwidth of the transmission band formed between ˜1100 nm can be expanded to an appropriate width. This increases the amount of fluorescence that passes through the tunable filter when detecting the fluorescence emitted from the fluorescent labeling substance, so that the fluorescence peak wavelength can be identified and detected brightly.

  FIG. 48A shows the spectral transmittance characteristics of the excitation light cut filter 34 combined to cut the excitation light. 48B to 48D show the total spectral transmission when the excitation cut filter having the characteristics shown in FIG. 48A and the tunable filter shown in FIGS. 18B to 18D are combined. The rate characteristic is shown.

  The excitation light cut filter 34 of the present embodiment exhibits the following characteristics.

TEx1 ≧ 90%, where TEx1 is the average transmittance at 400 nm <λ <650 nm
When the average transmittance at 700 nm <λ <870 nm is TEx2, TEx2 <0.01%
When the transmittance at 900 nm ≦ λ ≦ 1100 nm is TEx3, TEx3 ≧ 90%
Where λ is the wavelength of light incident on the filter.

  The total spectral transmittance characteristics when the excitation light cut filter having the characteristics shown in FIG. 48A and the tunable filters shown in FIGS. 18B to 18D are combined are as follows.

  When the average transmittance in the visible region is T3, T3 ≧ 60%. Thereby, sufficient brightness is obtained to detect light in the visible region.

  When the wavelength region of excitation light for exciting the fluorescent labeling substance is 720 nm ≦ λ ≦ 850 nm, and the transmittance in the wavelength band extended by 20 nm from the wavelength region is T4, T4 ≦ 0.01% Become. Thereby, when detecting the fluorescence from the fluorescent labeling substance, the excitation light can be sufficiently shielded from becoming noise.

  When the peak transmittance is T5 between 950 and 1050 nm, T5 ≧ 65%. Further, when the full width at half maximum for the peak transmittance T5 is d5, 5 nm ≦ d5 ≦ 35 nm. Thereby, when the fluorescence wavelength of the fluorescent labeling substance exists between 950 and 1050 nm, it has sufficient brightness and the fluorescence of the fluorescent label can be separated and detected.

The combination of the excitation cut filter and the tunable filter is not limited to this.
Example 4
FIG. 19 shows a specific design example of a tunable filter using a three-layered etalon when the fluorescence wavelength of the fluorescent labeling substance exists between 950 and 1050 nm. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength.

  The purpose of this design example is to improve the resolution in the near-infrared region with respect to the tunable filter using the etalon having the two-layer structure shown in FIG. Therefore, the spectral transmission characteristics of the semi-transmissive film deposited on the substrate surface on which the air gap is formed are the same as those shown in FIG. 18A, and the following relational expression is used to change the distance between the two air gaps. It was made to satisfy.

d1 = d2
Here, d1 and d2 are air gap distances.

  Thereby, for example, when d1 = 375 nm, a characteristic obtained by multiplying the transmission characteristic shown in FIG. 18B twice is obtained. FIG. 19B is a diagram showing the spectral characteristics of the tunable filter in this state. In the region between 900 and 1100 nm, the peak of the transmission wavelength is present at 950 nm as in FIG. 18B, but the half-value width of the transmission wavelength band is narrowed to about 7.5 nm. Further, the transmittance between 900 and 930 nm and between 970 and 1100 nm is 0.1% or less.

  Similarly, when d1 = 500 nm and 625 nm, the spectral transmission characteristics shown in FIGS. 19C and 19D are obtained, respectively.

  Further, when observing a color image using an RGB image, the distance between the two air gaps may satisfy the following relational expression.

d1 ≠ d2
For example, when d1 = 375 nm and d2 = 625 nm, the characteristics obtained by multiplying the transmission characteristics shown in FIGS. 18B and 18D can be obtained. FIG. 19A shows the spectral characteristics of the tunable filter in this state. In the region between 900 and 1100 nm, the transmittance can be 0.3% or less.
(Example 5)
FIG. 20 shows another specific design example of a tunable filter using a three-layered etalon when the fluorescence wavelength of the fluorescent labeling substance is present between 950 and 1050 nm. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength.

  In this design example, among the three layers of substrates, the intermediate substrate is composed of a translucent film. The spectral transmission characteristics of the translucent film are shown in FIG.

  The spectral transmission characteristics of the semi-transmissive films formed on the surfaces of the first and third layers facing the semi-transparent film are shown in FIGS. 20 (a) and 20 (c), respectively. In this way, the resolution in the near infrared region of the tunable filter can be appropriately set by varying the transmission characteristics in the region between 900 and 1100 nm.

  In addition, the transmission characteristics of the tunable filter when the two air gaps d1 and d2 have the values shown in FIG. 52 are shown in FIGS.

In this design example, by independently controlling etalons having different transmission characteristics, the transmittance of the non-transmissive region in the region between 900 and 1100 nm is lowered and the half-value width of the transmission wavelength band is widened. As a result, the S / N ratio can be improved when a fluorescent dye having low emission efficiency and a wide emission spectrum width is used as a fluorescent label.
(Example 6)
Next, a configuration example in the case where a tunable filter is arranged in the objective optical system is shown. FIG. 21A is a diagram illustrating an example in which a tunable filter using a two-layered etalon is disposed in the objective lens 33.

  The objective lens 33 includes a concave lens 33a, an excitation light cut filter 34, a convex lens 33b, a tunable filter 35, a cemented lens 33c, a detector 36, and a light receiving surface thereof in order from the object side.

  The tunable filter 35 is composed of transparent substrates 35Z-1 and 35Z-2, and a translucent film is deposited on the surface forming the air gap d. A piezoelectric element 72 such as a piezoelectric element is disposed between the transparent substrates 35Z-1 and 35Z-2. The piezoelectric element 72 also serves as an aperture stop.

  FIG. 21B shows an example in which a tunable filter using a three-layer structure etalon is arranged instead of the two-layer structure etalon in the objective lens 33 shown in FIG. In this case, the tunable filter 35 is made of transparent substrates 35Z-1, 35Z-2, and 35Z-3, and a semitransparent film is deposited on each surface that forms the air gaps d1 and d2. Piezoelectric elements 72 and 73 such as piezoelectric elements are disposed between the transparent substrates 35Z-1 and 35Z-2 and between the transparent substrates 35Z-2 and 35Z-3. The piezoelectric elements 72 and 73 are controlled independently. The piezoelectric element 72 also serves as an aperture stop.

  As shown here, when the tunable filter is disposed in the objective optical system, it is desirable to dispose the tunable filter at a position where the incident angle of the light incident on the translucent film does not increase. Here, it arrange | positions so that the incident angle to the semi-transparent film | membrane of an axial marginal ray may be less than 1 degree.

  FIG. 21C is a diagram illustrating an example in which two tunable filters using a two-layer etalon are arranged in the objective lens 33. The objective lens 33 includes a concave lens 33a, an excitation light cut filter 34, a convex lens 33b, a tunable filter 35-1, a cemented lens 33c, a tunable filter 35-2, a detector 36, and a light receiving surface thereof in order from the object side. Yes. The tunable filters 35-1 and 35-2 may have different transmission characteristics, or may have the same transmission characteristics.

  If there is no wide space for arranging a tunable filter using a three-layer etalon in the objective optical system, a plurality of tunable filters using a two-layer etalon are used as shown in FIG. By combining them, transmission characteristics equivalent to using one tunable filter using a three-layer etalon can be obtained, and the degree of freedom in optical design is improved.

When the endoscope is a fiberscope, it is not always necessary to arrange a tunable filter in the objective optical system. For example, it can be placed in an eyepiece or in a TV camera system connected to the eyepiece. Further, the excitation light cut filter 34 may be disposed immediately before the light receiving surface of the detector 36.
(Example 7)
FIG. 22 is a timing chart for explaining the operation of the endoscope apparatus of the present invention during color image observation. FIG. 23 is a timing chart for explaining operations during fluorescence detection and color image observation. FIG. 25 is a timing chart for explaining operations at the time of fluorescence detection and color image observation based on another operation principle.

  First, the timing chart of FIG. 22 will be described. In the light source optical system shown in FIG. 2, a band filter 27a of the turret 22 having a characteristic of transmitting mainly visible light is inserted on the optical path. In this state, the windows 29a, 29b, and 29c on the inner peripheral portion of the rotating disk 23 shown in FIG. 5 are sequentially inserted into the optical path and transmit the BGR light. Irradiated. At this time, a period in which the rotating disk 23 is rotated once is defined as one frame.

  Hereinafter, the objective lens 33 shown in FIG. 21A is used as the objective optical system arranged at the distal end portion of the endoscope, and the tunable filter 35 is made of a two-layer structure etalon having the characteristics shown in FIG. A description will be given assuming that the tunable filter used is used.

The drive voltage applied to the piezoelectric element 72 of the tunable filter 35 is indicated as V0, and the distance of the air gap at this time is indicated as d (V0). In this case, the transmission wavelength band between 950 and 1050 nm in the tunable filter 35 changes depending on the air gap distance d (V0), and therefore is indicated as IR _(V0) .

When observing a color image, it is not necessary to scan the tunable filter 35, so that the drive voltage applied to the piezoelectric element 72 in one frame is maintained at V0 and the distance of the air gap is maintained at d (V0). Therefore, the BGR light reflected by the living tissue and the fluorescence emitted from the fluorescent labeling substance reach the light receiving surface of the detector 36. In the timing chart, the BGR light reflected from the living tissue is indicated as RF _B , RF _G , and RF _R , respectively, and the fluorescence emitted from the fluorescent labeling substance is indicated as F _{IR (V0)} .

  Thus, when observing a color image, the control of the endoscope apparatus can be simplified. Note that wavelength scanning can be performed by changing V0 according to the wavelength characteristics of the illumination lights B, G, and R used and the transmission characteristics of the tunable filter.

The light received by the image sensor is converted into an image signal for each RGB color component by photoelectric conversion, and is input to the processor 5. The processor 5 performs image processing and displays a color image of the living tissue on the monitor 6. In the operation at the time of color image observation shown in FIG. 22, the detector 36 receives fluorescence as well as reflected light. However, the fluorescence intensity F _{IR (V0)} is weak, and the influence of fluorescence can be eliminated when constructing a color image.

  Next, the timing chart of FIG. 23 will be described. The configuration of the endoscope apparatus to be used is the same as that in FIG.

  The timing chart of FIG. 23 shows the operation in the case of performing fluorescence detection and color image observation alternately. In this case, the band pass filter 27a of the turret 22 is inserted on the optical path in the first frame, and the band pass filter 27b is inserted on the optical path in the other one frame that follows.

In the first frame, the rotating disk and the tunable filter operate as described in FIG. 22, and the detector 36 has RF _B + F _{IR (V0)} , RF _G + F _{IR (V0)} , RF _R + F _{IR ( V0)} are sequentially received.

  In another subsequent frame, the windows 28a, 28b, 28c on the outer peripheral portion of the rotating disk 23 are sequentially inserted into the optical path, and the living tissue is irradiated with excitation light in the near infrared region at intervals.

During the period in which the window 28a is inserted in the optical path, the driving voltage V1 is applied to the piezoelectric element 72, and the distance of the air gap at this time is set to d (V1). As a result, the detector 36 receives F _{IR (V1)} . During the period in which the window 28b is inserted in the optical path, the drive voltage V2 is applied to the piezoelectric element 72, and the distance of the air gap at this time is set to d (V2). As a result, the detector 36 receives F _{IR (V2)} . During the period in which the window 28c is inserted in the optical path, the driving voltage V3 is applied to the piezoelectric element 72, and the distance of the air gap at this time is set to d (V3). As a result, the detector 36 receives F _{IR (V3)} .

  Thus, three types of fluorescence wavelengths can be detected in one frame. When it is necessary to detect four or more types of fluorescence wavelengths, the drive voltage applied to the piezoelectric element 72 may be changed in yet another frame. The timing chart of FIG. 24 is an example.

  Further, for example, the drive voltages V1 and V2 can be sequentially applied to the piezoelectric element 72 during a period in which the window 28a is inserted in the optical path.

  Through each frame, the rotation period of the turret 22 and the rotary disk 23 and the drive voltage of the piezoelectric element 72 are controlled in synchronization with each other. Such control is performed by, for example, the filter control circuit 51 shown in FIG. In addition, according to the timing chart of FIG. 23, it is possible to simultaneously display the color image of the living tissue and the fluorescence information on the monitor 6 after the image processing by the processor 5.

  FIG. 25 is a timing chart showing the operation of the endoscope apparatus when the objective lens 33 shown in FIG. 21B is used as the objective optical system arranged at the distal end portion of the endoscope.

  The tunable filter 35 has the transmission characteristics shown in FIG. Hereinafter, differences from the timing chart of FIG. 23 will be described.

  Since the tunable filter 35 can control the two air gaps d1 and d2 independently, by applying different driving voltages to the piezoelectric elements 72 and 73 in the first frame, d1 ( Control is performed so that V0) ≠ d2 (V0). In another subsequent frame, the same drive voltage is applied to the piezoelectric elements 72 and 73. For example, during a period in which the window 28a is inserted in the optical path, control is performed so that d1 (V1) = d2 (V1).

  Next, an image construction method will be described with reference to FIG.

  The processor 5 is provided with a filter control circuit 51, a preprocess circuit 52, an A / D converter 53, a video signal processing circuit 54, and a D / A converter 55. The filter control circuit 51 aligns the bandpass filters 27a and 27b on the optical path for the turret 22 of the light source optical system 2. In addition, the rotating disk 23 is also aligned with the windows installed on the outer peripheral portion and the inner peripheral portion, respectively, on the optical path.

  Further, the filter control circuit 51 controls the voltage applied to the piezoelectric element provided in the tunable filter 35, thereby controlling the air gap d of the tunable filter 35, and the transmission wavelength as described in FIG. Move the band. In addition, a control signal is input to the preprocess circuit 52. The preprocess circuit 52 performs gain adjustment by an amplifier, white balance adjustment of a color image by a white balance correction circuit, and the like on the image signal input from the detector 36.

  The image signal from the preprocess circuit 52 is input to the A / D converter 53 and converted from an analog signal to a digital signal. The converted signal is input to the video signal processing circuit 54, temporarily stored in the image memory, and then displayed for image processing such as image enhancement and noise removal, and simultaneous display of a fluorescent image, a color image, and character information. Control or the like is performed.

  Furthermore, the video signal processing circuit 54 can perform a superimposed display of the fluorescent image and the color light image, and a standardization process of the fluorescence intensity by calculating between the color image and the fluorescent image. Easy fluorescent image is obtained. The digital signal output from the video signal processing circuit 54 is input to the D / A conversion circuit 55 and converted into an analog signal. This analog signal is input to the monitor 6 and each image is displayed on the monitor.

  The filter control circuit 51 calculates or counts the fluorescence peak wavelength by performing variable control of the fluorescence transmission wavelength band, and displays a display image (monitor) according to the count number or the correspondence between the counted fluorescence and the fluorescent labeling substance. 6)) is displayed in pseudo color.

FIG. 51 shows an example of displaying the type of fluorescent label detected at the position P _i (x _i , y _i ) where the lesion is obtained, obtained when five types of fluorescent labels are used. x _i and y _i are positions on the monitor shown in FIG. P ₁ (x ₁ , y ₁ ), P ₂ (x ₂ , y ₂ ), and P ₃ (x ₃ , y ₃ ) depend on the number of fluorescent labels acquired, their types and combinations, for example, P ₁ : yellow display , P ₂ : Red display, P ₃ : Green display can be displayed in different colors, thereby displaying the degree of malignancy of the lesion by color and making a more advanced diagnosis. .

  In FIG. 26, a simultaneous display in which a color image and a fluorescence image are superimposed on the monitor 6 is performed. Morphological information on the lesion is acquired from the color image, and functional information (malignancy information) on the lesion is obtained from the fluorescence image. As shown in FIG. 26, the position and malignancy of the lesion can be diagnosed by simultaneous display.

  By adding such image processing, the current state of a lesion such as cancer can be reliably observed without error. The processor 5 calculates or counts the signal of the fluorescence peak wavelength, refers to a protein table corresponding to the fluorescence peak wavelength in a memory (not shown) provided in the processor 5 and refers to the protein present in the living tissue. And the identified protein is stored in memory as data.

Therefore, individual in vivo protein data can be read from the memory at any time and used for diagnosis or the like in comparison with the protein table data corresponding to the reference fluorescence peak wavelength.
(Example 8)
27 and 28 show another embodiment of the band pass filter attached to the rotating disk of the light source optical system and the windows 29d, 29e and 29f of the rotating disk. Hereinafter, differences from the rotating disk and the bandpass filter shown in FIGS. 5 and 6 will be described.

  FIG. 27 is a diagram illustrating the configuration of the rotating disk 23b, and FIG. 28 is a diagram illustrating the spectral transmittance characteristics of the band-pass filter. As shown in FIG. 27, the rotating disk 23b is provided with blue (B) filters, green (G) filters, and red (R) filters in the windows 29d, 29e, and 29f. As shown in FIG. 28, the B filter, the G filter, and the R filter have characteristics of transmitting light in the near infrared region in addition to transmitting light of blue, green, and red wavelengths, respectively.

  FIG. 50 shows a combination of a bandpass filter on the turret 22 and a window on the rotating disk 23b that can be taken in this case. When the bandpass filter 27a disposed in the turret 22 is inserted on the optical path, only the BGR light is transmitted and irradiated to the living tissue. When the band pass filter 27b is inserted on the optical path, the living tissue is irradiated with excitation light in the near infrared region.

Thereby, since the size of the rotary filter can be reduced, the size of the entire light source device can be reduced. In addition, since the filter control mechanism can be simplified, the manufacturing cost of the light source device can be reduced.
Example 9
Another configuration example of the tunable filter will be described with reference to FIG. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength. Again, it is assumed that the fluorescence wavelength of the fluorescent labeling substance exists between 950 and 1050 nm. FIG. 29A is a conceptual diagram showing the spectral transmittance characteristics of the semi-transmissive film deposited on the substrate surface on which the air gap is formed. In this configuration example, the spectral transmission characteristics of the semi-transmissive film are made flat with low reflectance over the entire wavelength range to be used.

  As a result, the spectral transmittance characteristic of the tunable filter is a transmission characteristic in which a spectral peak periodically appears in a wavelength region of at least 400 to 1100 nm, as shown in FIG. At this time, the distance of the air gap is A. A is a distance at which light can cause multiple interference. Such transmission characteristics are realized by satisfying the following conditional expression.

2n _d dcosθ = mλ
However,
n _d : Refractive index of air gap d: Distance of air gap θ: Incident angle of light beam to tunable filter m: Order of interference λ: Wavelength Spectral transmission when air gap distance is changed from A to B The characteristics are shown in FIG. B is also a distance at which light can cause multiple interference. As shown in FIG. 29 (c), the peak wavelength shifts without changing the period in which the peak of the spectrum appears. Note that the semi-transmissive film having the spectral transmission characteristics shown in FIG. 29A can be formed of a metal coat such as silver or aluminum in addition to the dielectric multilayer film.

  Since the light having the intensity characteristic shown in FIG. 11 is incident on the objective lens 33, the light passing through the tunable filter 35 and reaching the light receiving surface of the detector 36 has the intensity characteristic shown in FIG. The scale on the vertical axis represents intensity (arbitrary unit), and the scale on the horizontal axis represents wavelength (nm).

  Since the tunable filter of this configuration example has a discrete characteristic in which the transmission wavelength region in the visible region has a periodic peak, a part of the narrow wavelength region of the reflected light from the living tissue is used. Only light is transmitted. Further, by scanning the transmission wavelength of the tunable filter, the reflected light can be subdivided and detected in a narrow wavelength region. Thereby, it becomes possible to finely analyze the information of the living tissue contained in the reflected light.

Needless to say, the tunable filter can be operated so as to detect a plurality of fluorescence wavelengths in the near-infrared region.
(Example 10)
FIG. 31 shows a design example of a tunable filter using a two-layer etalon. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength. In this design example, it is assumed that the fluorescence wavelength of the fluorescent labeling substance exists between 950 and 1050 nm. 31A to 31C are diagrams showing the spectral transmission characteristics of the tunable filter when the air gap distance d is set to 1800 nm, 2000 nm, and 2200 nm in order. The reflectance of the reflective film deposited on the substrate surface on which the air gap is formed with respect to a light beam having an incident angle of 0 degree on the tunable filter was 90% on both sides.

FIG. 31 shows that the peak value of the transmittance of the tunable filter can be scanned in the range of at least 900 to 1100 nm by changing the distance d of the air gap.
(Example 11)
A design example of a tunable filter using a three-layer structure etalon is shown in FIG. The scale on the vertical axis represents the transmittance, and the scale on the horizontal axis represents the wavelength. Also in this design example, it is assumed that the fluorescence wavelength of the fluorescent labeling substance exists between 950 and 1050 nm. The purpose of this design example is to widen the half-value width of the spectrum peak in the infrared region in the design example shown in FIG. 31 and to improve the S / N ratio of fluorescence detection.

  Another object of the present invention is to improve the yield when manufacturing a tunable filter by reducing the reflectance of the reflective film so that the film can be easily formed. Therefore, the reflectivity of the reflective film is all 80%. In addition, in order to lower the transmittance of the non-transmission band while keeping the peak value of the transmission wavelength band at least at 900 to 1100 nm, the distance between the air gaps d1 and d2 is varied so as to satisfy the following relational expression.

d ₁ = d ₂
32A is a diagram showing spectral characteristics when d ₁ = d ₂ = 900 nm, FIG. 32B is a diagram showing spectral characteristics when d ₁ = d ₂ = 1000 nm, and FIG. ) Is a diagram showing spectral characteristics when d ₁ = d ₂ = 1100 nm.

Compared to FIGS. 31A to 31C, it can be seen that the half-value width of the transmission wavelength band at 900 to 1100 nm is widened.
(Example 12)
Next, the detector (light receiving unit) will be described. As a detector, a CCD, a CMOS, a high sensitivity image sensor, or the like is generally used. In the present invention, a high-sensitivity image sensor is desirable particularly for detecting weak light such as fluorescence. 33 to 36 show an embodiment using a charge amplification type solid-state imaging device as a high-sensitivity imaging device.

  FIG. 33 is a diagram showing the structure of the charge amplification type solid-state imaging device, FIG. 34 is a timing chart of the sensitivity control pulse φCMD and the horizontal transfer pulses φS1, φS2, and FIG. A graph showing the relationship between the applied voltage [V] (horizontal axis) and the sensitivity amplification factor [times] (vertical axis), FIG. 36 is a timing chart when driving the charge amplification type solid-state imaging device.

  As the charge amplification type solid-state imaging device, for example, a solid-state imaging device with variable sensitivity using the impact ionization phenomenon described in US Pat. No. 5,337,340 can be used.

  The solid-state imaging device (hereinafter simply referred to as a CCD) is provided with a charge amplifying unit between a horizontal transfer path in the device and an output amplifier or for each pixel. Is applied, the signal charge obtains energy from the electric field and collides with electrons existing in the valence band, and a new signal charge (secondary electron) is generated by impact ionization.

  For example, when the avalanche effect is used, secondary electrons are generated in a chain reaction by application of a pulse. However, when impact ionization is used, a set of electrons is applied by applying a relatively low voltage pulse to the avalanche effect. -Only hole pairs are generated.

  In this CCD, when the charge amplifying unit is provided in front of the output amplifier, the number of signal charges can be arbitrarily amplified by controlling the voltage value (amplitude) or the number of pulses of the pulse to be applied.

  On the other hand, when a charge amplifying unit is provided for each pixel, it is possible to arbitrarily amplify the number of signal charges by controlling the voltage value (amplitude) of the pulse to be applied or the number of pulses.

  In the case of the present embodiment, an FFT (Full Frame Transfer) type monochrome CCD in which a charge amplifier is mounted between the horizontal transfer path and the output amplifier is used as the CCD.

  The CCD includes an image area 60 of a light receiving unit, an OB (Optical Black) unit 61, a horizontal transfer path 62, a dummy 63, a charge amplification unit 64, and an output amplifier unit 65. Further, the charge amplifying unit 64 is configured with the number of cells substantially the same as or about twice the number of cells of the horizontal transfer path 62.

  The CCD may be an FT (Frame Transfer) type provided with a charge storage unit.

  The signal charges generated in each pixel of the image area 60 are transferred to the horizontal transfer path 62 for each horizontal line by the vertical transfer pulses ΦP1 and ΦP2, and the dummy 63 and the charges are transferred from the horizontal transfer path 62 by the horizontal transfer pulses ΦS1 and ΦS2. It is transferred to the amplifying unit 64. Then, by applying a sensitivity control pulse φCMD to each cell of the charge amplifying unit 64 composed of a plurality of cells, charges are sequentially amplified one step at a time while being transferred to each cell, and sequentially transferred to the output amplifier unit 65. Is done. The output amplifier unit 65 converts the charge from the charge amplification unit 64 into a voltage and outputs the voltage.

  The sensitivity amplification factor obtained by the charge amplification unit 64 is variable by changing the voltage value (amplitude) of the sensitivity control pulse ΦCMD from the CCD drive circuit to the charge amplification unit 64. The charge amplifying unit 64 amplifies one stage at each cell. As shown in FIG. 35, the sensitivity amplification factor obtained by the charge amplifying unit 64 has characteristics in which charge amplification starts when the voltage exceeds a certain threshold value Vth with respect to the applied voltage, and the sensitivity is exponentially amplified.

  Here, the CCD drive circuit varies the voltage value (amplitude) of the sensitivity control pulse φCMD shown in (i) of FIG. 36 based on the data supplied from the sensitivity control circuit. Then, the CCD drive circuit outputs the sensitivity control pulse φCMD to the CCD in a phase relationship synchronized with the horizontal transfer pulses ΦS1 and ΦS2 shown in FIG.

Thus, in the special light mode, the CCD drive circuit controls the CCD so as to obtain a desired sensitivity amplification factor by changing the voltage value (amplitude) of the sensitivity control pulse ΦCMD applied to the charge amplifier 64. Thus, by using the above-described imaging device as a detector, fluorescence that is weak light can be detected with good S / N.
(Example 13)
FIG. 39 is a block diagram partially showing a configuration according to another embodiment of the present invention. In this example, a dichroic prism is used instead of the tunable filter shown in FIG. 12 or the like as a transmission wavelength separation element capable of separating the fluorescence wavelength emitted from the fluorescent labeling substance. In FIG. 39, near-infrared light that has passed through the excitation light cut filter is separated for each fluorescence wavelength by the dichroic prism, and the fluorescence wavelength is individually detected by the CCD.

  In the example of FIG. 39, an image of reflected light and fluorescence from the object to be inspected is formed on the tip surface (not shown) of the light guide fiber 132. The image is transmitted to the rear end face through the light guide fiber 132 and input to the camera head 100 mounted on the endoscope by the imaging lens 121.

  The light input to the camera head 100 is separated into an infrared light component and a visible light component by the dichroic mirror 122. The infrared light component reflected by the dichroic mirror 122 is incident on the first dichroic prism 125 through the excitation light cut filter 123.

  The excitation light cut filter 123 is set to have a spectral transmission characteristic that removes the excitation light component emitted from the fluorescent labeling substance and transmits the fluorescence component in the infrared light region. The first dichroic prism 125 divides incident light into three specific fluorescence wavelength components and guides them to the CCD 124a, CCD 124b, and CCD 124c, respectively. The CCD 124a, CCD 124b, and CCD 124c individually detect different fluorescence wavelengths. In this way, an image of the fluorescent component emitted from the fluorescent labeling substance can be detected from each CCD.

  In addition, the magnitude | size and the number of components of the fluorescence wavelength isolate | separated by the 1st dichroic prism 125 can be arbitrarily set by the design of the optical characteristic of a prism. In FIG. 39, as described above, the excitation light cut filter 123 removes the excitation light component emitted by the fluorescent labeling substance and transmits the fluorescence component. In addition, the first dichroic prism 125 and the CCDs 124a to 124c each include a detection unit including a transmission wavelength separation element capable of separating the fluorescence wavelengths emitted by a plurality of fluorescent labeling substances, and a fluorescence separated by the transmission wavelength separation element. This corresponds to a plurality of detection elements that individually detect wavelengths.

  The visible light component that has passed through the dichroic mirror 122 is input to a three-plate camera including a second dichroic prism 129 and three CCDs 126, 127, and 128. The second dichroic prism 129 separates incident light into three components of red (R), green (G), and blue (B), and guides them to the CCD 126, CCD 127, and CCD 128, respectively. In this way, a normal visible image (normal light image) component is obtained from the CCDs 126 to 128. The CCDs 124a to 124c and the CCDs 126 to 128 are driven in synchronization by a CCD drive circuit (not shown).

  Electrical signals from the CCDs 124a to 124c and the CCDs 126 to 128 are input to the preprocess circuit 152 of the processor 5b, and gain adjustment by an amplifier (not shown), white balance adjustment of a visible light image by a white balance correction circuit, and the like are performed. Thereafter, each signal is input to the A / D conversion circuit 153 and converted from an analog signal to a digital signal. The digital signal from the A / D conversion circuit 153 is input to the video signal processing circuit 154 and temporarily stored in the image memory, and thereafter, image processing such as image enhancement and noise removal, and simultaneous use of the fluorescence image, the normal image, and the character information. Display control or the like for display is performed.

  In addition, the video signal processing circuit 154 can perform superimposing display of the fluorescent image and the normal light image, and normalization processing of the fluorescent image by calculation between the normal light image and the fluorescent image, together with the normal image, A fluorescent image that is easy to recognize is obtained. The digital signal output from the video signal processing circuit 154 is input to the D / A conversion circuit 155, converted into an analog signal, and displayed on the monitor 160.

  On the monitor, two normal light images and fluorescent images at the same time are displayed side by side with the same size, two with different sizes displayed side by side, two overlaid, or a fluorescent image and a normal image. It is possible to select to display an image that has been subjected to image processing. Accordingly, it is possible to simultaneously observe a fluorescent image and a normal observation image. For this reason, since a fluorescence image and a normal observation image without time lag are obtained, positioning of a lesioned part can be performed easily and with high accuracy, which is very effective for diagnosis.

  Each member of the excitation light cut filter 123, the first dichroic prism 125, the three CCDs 124a, 124b, and 124c shown in FIG. 39, that is, “a transmission wavelength separation element capable of separating the fluorescence wavelengths emitted by a plurality of fluorescent labeling substances. The detection means including and a plurality of detection elements for individually detecting the fluorescence wavelengths separated by the transmission wavelength separation element ”are provided in the eyepiece of the endoscope. In an embodiment of the present invention, each member may be provided at the distal end portion of the endoscope.

  Further, the excitation light cut filter 123 having the transmission characteristics shown in FIG. 10 is used as means for removing the excitation light component emitted from the fluorescent labeling substance and transmitting the fluorescence component in the infrared light region. In the configuration example of FIG. 39, the first dichroic prism 125 as the transmission wavelength separation element automatically performs the separation of the fluorescence wavelength without any control, so that the configuration of the endoscope apparatus is simplified. Can do.

  The processor 5a calculates or counts the peak wavelength of fluorescence by dividing the transmitted light according to wavelength, and displays the pseudo color on the display image according to the count number. Further, by dividing the transmitted light by wavelength, the peak wavelength of fluorescence is calculated or counted, and a fluorescence peak wavelength versus protein table in a memory (not shown) provided in the processor 5a is referred to. A protein in the body is identified and the identified protein is stored in memory as data.

As described above, pseudo color display is performed on the display image in accordance with the number of counts, so that the current state of a lesion such as cancer can be reliably observed without error. In addition, individual in vivo protein data can be read from the memory at any time and used for diagnosis or the like in comparison with the fluorescence peak wavelength as a reference and the data in the protein table.
(Example 14)
FIG. 43 is a diagram showing a configuration according to another embodiment of the present invention. Differences from FIG. 39 will be described. In this example, instead of the dichroic prism and the three CCDs 124a, 124b, and 124c used in FIG. 39, the tunable filter 35 shown in FIG. The detector 36 is used.

  Further, a color CCD 202 is used in place of the three-plate camera composed of the second dichroic prism 129 for detecting the visible light component and the three CCDs 126, 127, and 128.

  As a result, the number of CCDs used in the camera head can be greatly reduced, and thus the cost of the endoscope apparatus can be reduced. Also in this configuration, the visible light and fluorescence detection capabilities similar to those of the endoscope apparatus configured as shown in FIG. 39 can be obtained.

The color CCD 202 may be a monochrome CCD. In that case, the light source device 2 may irradiate light in a frame sequential manner as in the first embodiment.
(Example 15)
FIG. 44 is a diagram showing a configuration according to another embodiment of the present invention. Differences from FIG. 1 will be described. In the present embodiment, the scope optical system 3 is provided with two of an observation optical system that detects only the fluorescence wavelength component and an observation optical system that detects only the visible light component.

  An observation optical system that detects only a visible light component includes an objective lens 200, a visible transmission filter 203, and a CCD 201. The visible transmission filter 203 differs from the visible transmission filter 27a shown in FIG. 3 only in the outer diameter.

  In addition, the observation optical system that detects only the fluorescent component uses an infrared light transmission filter 204 having the characteristics shown in FIG. 45 instead of the fixed filter 34 shown in FIG.

The detector 36 only needs to detect the fluorescent component. Therefore, a high-sensitivity detector specialized in detection sensitivity in the near infrared region can be used as the detector 36. In addition, since the form (structure) of the observation site is obtained by the CCD 201 that detects a visible light component, the detector 36 is not an image pickup device such as a CCD, but a photoelectric conversion device made of PbS or the like having high sensitivity in the near infrared region. (Sensor) can also be used. As a result, the S / N of the detection of the fluorescent component that is weak light can be improved.
(Example 16)
46 and 47 are diagrams showing a configuration according to another embodiment of the present invention. In this embodiment, the function of the (wired) endoscope apparatus shown in FIG. 1 is realized by a capsule endoscope. 46, the same components as those in FIG. 1 are denoted by the same reference numerals.

  The capsule endoscope apparatus 300 includes light emitting elements 301 to 304 using LEDs, a lens 33 that collects reflected light or fluorescence from a living body that is an object to be inspected, a fixed filter 34, a tunable filter 35, A detector 36 is provided. CL is the optical axis of the lens 33, and the light emitting elements 301 to 304 are arranged at positions symmetrical to the lens 33 with respect to the optical axis CL.

  The capsule endoscope apparatus 300 includes a control circuit 305, a power source 306 using a capacitor or a battery, a coil 307 electrically connected to the power source 306, a magnet 308, an antenna 309, and a transmitter 310. Yes. Reference numeral 311 denotes a transparent cover that transmits the light emitted from the light emitting elements 301 to 304 and irradiates the living body, and introduces the reflected light or fluorescence into the lens 33. Reference numeral 312 denotes a case.

  When the magnet 308 is magnetized by external magnetic lines of force, the coil 307 conducts current by magnetic induction to charge the capacitor of the power supply 306 or charge the battery. The magnet 308 serves as an energy source for moving the capsule endoscope apparatus 300 by external electromagnetic waves. The antenna 309 transmits the detection signal of the detector 36 to the external device 313. The transmitter 310 transmits information on the current position of the capsule endoscope apparatus 300 to an external device.

  The external device 313 is provided with a transmission / reception antenna 314, a monitor 315, and a control circuit (not shown). The transmission / reception antenna 314 receives signals transmitted from the antenna 309 and the transmitter 310 of the capsule endoscope apparatus 300. In addition, an electromagnetic wave, that is, magnetic energy is transmitted to the magnet 308. The monitor 315 displays an image formed based on the detection signal of the detector 36 transmitted from the antenna 309.

  FIG. 47 is a cross-sectional view seen from the direction of the optical axis CL. The light emitting element 301 emits blue light, the light emitting element 302 emits green light, and the light emitting element 303 emits red light. The light emitting element 304 emits light having a near-infrared wavelength including a part of the wavelength range of 600 to 2000 nm that is the excitation wavelength of the fluorescent label.

  When the reflected light and fluorescence in the visible region from the living body are detected by wavelength separation, the illumination optical system is different from the endoscope apparatus 1 shown in FIG.

  In the endoscope apparatus shown in FIG. 1, the wavelength of illumination light is selected using a band-pass filter having various characteristics installed in the light source optical system 2, and is irradiated on the living body. In this embodiment, as shown in FIG. 47, instead of the light source optical system 2, light emitting elements such as a plurality of LEDs having different wavelengths are used. A plurality of LEDs 301 to 304 having different wavelengths are lit in time series by the control circuit 305 to realize the same function as the surface sequential method of the light source optical system 2. Thereby, the capsule endoscope apparatus 300 of the present invention has the same function as the endoscope apparatus shown in FIG. 1, and can similarly obtain the reflected light and fluorescence of the visible light by wavelength separation.

As described above, since the wireless capsule endoscope is used, it is not necessary to restrain the patient in the hospital, and the pain of the patient can be reduced.
(Example 17)
FIGS. 40-42 shows the whole structure of Example 17 of the endoscope apparatus of this invention. In the present embodiment, the configuration for separating and detecting a plurality of fluorescence wavelengths is positioned other than the tip of the endoscope.

  The same components as those in FIG. 1 are denoted by the same reference numerals, and only different portions will be described.

  FIG. 40 shows the overall configuration of the present embodiment, which is characterized by having a portion for separating and detecting a plurality of fluorescence wavelengths at the tip of an endoscope (fiber scope) of the type using an optical fiber. In the endoscope apparatus of FIG. 1, the optical element including the excitation light cut filter 34 is disposed immediately after the objective lens, whereas in FIG. 40, a fiber bundle (so-called image guide fiber bundle) is disposed immediately after the objective lens. And the eyepiece is placed on the exit side of the fiber bundle. The detection optical system has a configuration similar to that shown in FIG. 1, and is arranged in a housing separate from the housing including the insertion portion and the eyepiece.

  FIG. 41 shows a slight modification of the configuration shown in FIG. In FIG. 40, the excitation light cut filter 34 is disposed in the eyepiece lens, whereas in FIG. 41, the excitation light cut filter 34 is disposed in the insertion portion between the fiber bundle and the eyepiece lens. Arranged outside.

  FIG. 42 shows a slight modification of the configuration shown in FIG. In FIG. 40, the optical element is disposed on the exit side of the eyepiece so as to be outside the insertion portion. On the other hand, in FIG. 42, the housing of the optical element is integral with the fiberscope (ie, all the optical elements are disposed in the insertion portion). In FIG. 40, optical elements for separating and detecting a plurality of fluorescent lights are arranged outside the eyepiece lens, whereas in FIG. 42, these same optical elements are integrated in the fiberscope housing (ie, all of them are integrated). The optical element is disposed in the housing of the insertion portion of the endoscope).

  As shown in FIG. 38, the fluorescence wavelength of the quantum dots used for the fluorescent labeling substance can create a narrow band Gaussian distribution by adjusting the material and the outer diameter. For example, for the blue series, CdSe nanocrystals are used, and the outer diameters are 2.1 nm, 2.4 nm, 3.1 nm, 3.6 nm, and 4.6 nm. The green series uses InP nanocrystals with outer diameters of 3.0 nm, 3.5 nm, and 4.6 nm. In addition, the red series uses InAs nanocrystals and the outer diameters are 2.8 nm, 3.6 nm, 4.6 nm, and 6 nm.

  Thus, in the present invention, as a fluorescent labeling substance (tag), the outer diameter is in the range of 2.1 to 6.6 nm in which the material is CdSe, InP, InAs, and the outer diameter is adjusted to the number of living bodies (proteins) to be detected. A plurality of quantum dots having different values can be used. Quantum dots having a plurality of outer diameters are synthesized so as to have hydrophilicity, antibody characteristics, and biocompatibility, respectively. As a premise, it is desirable to optimize the material and the outer diameter, and set the spectral characteristics within the conditions of infrared excitation and infrared fluorescence.

  By using quantum dots as described above, a fluorescent labeling substance (tag) can be introduced into a biological tissue, irradiated with excitation light, and fluorescence in the near infrared wavelength region can be extracted. Therefore, it is possible to accurately observe even early cancer that has occurred in the deep part of the living body. Thus, in the present invention, early cancer can be diagnosed using the fluorescent labeling substance introduced into the living tissue.

  The fluorescent labeling substance may be any substance that emits a plurality of different fluorescences in the near infrared region, and is not limited to quantum dots.

  In the present invention, advanced diagnosis such as malignancy diagnosis of a lesion is possible using an endoscope apparatus. Quantum dots have the characteristics that they can be observed for 1 hour or more under a microscope, have a long fluorescence lifetime, and have a bright fluorescence. Note that the fluorescence wavelength emitted from the quantum dots has a narrow band and a Gaussian distribution, and is suitable for characteristics detected by an etalon type bandpass filter.

  The endoscope apparatus of the present invention can be configured as follows, for example.

  (1) The detection unit further includes at least one filter, and the filter has a characteristic of blocking an excitation wavelength of the fluorescent labeling substance. The endoscope apparatus described.

  (2) An endoscope is provided with an objective optical system at the distal end of the endoscope, the objective optical system has at least one filter, and the filter has a characteristic of blocking the excitation wavelength of the fluorescent labeling substance. The endoscope apparatus according to any one of claims 2 to 4.

  (3) The illumination means includes a light source, and a plurality of wavelength selection filters are detachably disposed in the light source, and the wavelength selection filter can be switched to select at least the following two illumination modes. The endoscope apparatus according to claim 1, wherein the endoscope apparatus is configured.

Illumination mode 1: Mode for illuminating only light in the visible wavelength band Illumination mode 2: Mode for illuminating at least a part of the wavelength band of 600 to 2000 nm (4) Only in the illumination mode 2, the transmission wavelength separation element The endoscope apparatus according to (3), wherein the driving voltage is changed.

  (5) The illumination means includes a light source, and a filter that selectively transmits or reflects at least a part of wavelengths in a wavelength band of 600 to 2000 nm is detachably disposed in the light source, and the filter is inserted. 5. The endoscope apparatus according to claim 3, wherein the transmission wavelength separation element is configured to separate a plurality of fluorescence wavelengths only when the endoscope is in a closed state.

  (6) The number of times that the drive voltage of the transmission wavelength separation element changes for n types of fluorescent labeling substances is 2 times or more and n times or less. The endoscope apparatus according to item 4).

  (7) The number of fluorescence wavelength separations i by the transmission wavelength separation element is 2 ≦ i ≦ n with respect to n types of fluorescent labeling substances, 3 or 4 or (5) The endoscope apparatus according to item.

  (8) The endoscope apparatus further includes an image processing device that combines a fluorescent image of a subject to be inspected and a visible light observation image, and a monitor that displays the combined image. 4. The endoscope apparatus according to any one of (1) to (7).

  (9) The endoscope apparatus according to any one of claims 1 to 4, wherein the fluorescent labeling substance is a substance containing InAs nanocrystals.

  (10) The endoscope apparatus according to any one of claims 1 to 4, and (1) to (9), wherein the transmission wavelength separation element is an etalon.

  (11) The endoscope apparatus according to (10), wherein the etalon is configured by arranging three or more semi-transparent substrates.

(12) The endoscope apparatus according to (10), wherein the etalon is configured by arranging two or more translucent substrates.

1 is an overall configuration diagram of Example 1. FIG. 1 is a configuration diagram of a light source optical system in Example 1. FIG. 1 is a configuration diagram of a turret of Example 1. FIG. FIG. 4 is a diagram illustrating an example of transmittance characteristics of each bandpass filter according to the first embodiment. It is a figure which shows the layout of the window arrange | positioned at the rotating disk of Example 1. FIG. 6 is a diagram illustrating an example of transmittance characteristics of the optical filter of Example 1. FIG. 3 is a schematic diagram of an illumination method of Example 1. FIG. It is a figure which shows the example of the spectral intensity characteristic of the illumination light of Example 1. FIG. It is a figure which shows the reflectance characteristic of a biological normal tissue. It is a figure which shows the spectral transmittance characteristic of a filter. It is a figure which shows the spectral intensity characteristic of the light which injects into a objective lens from a biological tissue. It is a block diagram of a tunable filter using an etalon having a two-layer structure. It is a figure which shows the transmittance | permeability characteristic of a tunable filter. 6 is a configuration diagram of a tunable filter using the etalon having a three-layer structure of Example 2. FIG. It is another block diagram of the tunable filter using the etalon of a three-layer structure. It is a figure which shows the spectral transmission characteristic required for a tunable filter. It is a figure which shows the spectral intensity characteristic of the reflected light and fluorescence which permeate | transmitted the tunable filter. FIG. 6 is a diagram illustrating spectral transmission characteristics of a tunable filter according to Example 3. FIG. 6 is a diagram illustrating spectral transmission characteristics of a tunable filter according to Example 4. FIG. 6 is a diagram showing spectral transmission characteristics of a tunable filter of Example 5. 10 is a cross-sectional view of an objective optical system according to Example 6. FIG. 10 is a timing chart illustrating an operation during color image observation according to the seventh exemplary embodiment. 10 is a timing chart showing operations during fluorescence detection and color image observation in Example 7. It is a timing chart in the case of detecting four or more types of fluorescence wavelengths. It is a timing chart which shows the operation | movement at the time of the fluorescence detection based on another operation | movement principle, and a color image observation. It is a figure which shows the lesioned part displayed on the monitor. FIG. 10 is a configuration diagram of a rotating disk according to an eighth embodiment. It is a figure which shows the spectral transmittance characteristic of the band pass filter of Example 8. 10 is a configuration diagram of a tunable filter according to Embodiment 9. FIG. It is a figure which shows the spectral intensity characteristic of the reflected light and fluorescence which permeate | transmitted the tunable filter. It is a figure which shows the spectral transmission characteristic of the tunable filter of Example 10. FIG. FIG. 10 is a diagram showing the spectral transmission characteristics of the tunable filter of Example 11. FIG. 14 is a diagram illustrating a structure of a charge amplification type solid-state imaging element according to Example 12; 14 is a timing chart of sensitivity control pulses and horizontal transfer pulses in Example 12. It is a figure which shows the relationship between the voltage applied to the electric charge amplification part of the electric charge amplification type solid-state image sensor of Example 12, and a sensitivity amplification factor. 18 is a timing chart when driving the charge amplification type solid-state imaging device of Example 12. It is a figure which shows the example of a quantum dot. It is a characteristic view which shows the excitation and emission spectrum of a quantum dot. FIG. 20 is a block diagram partially showing a configuration of Example 13; It is a figure which shows the whole structure of Example 17. FIG. FIG. 20 is a diagram showing a modification of Example 17. FIG. 20 is a diagram showing another modification of the seventeenth embodiment. It is a figure which shows the structure of Example 14. FIG. FIG. 16 is a diagram showing a configuration of Example 15; It is a figure which shows the characteristic of the infrared-light transmissive filter of Example 15. FIG. 16 is a cross-sectional view of a capsule endoscope according to a sixteenth embodiment. It is the figure which looked at the capsule endoscope of Example 16 from the optical axis direction. It is a figure which shows the spectral transmittance characteristic of an excitation light cut filter. 6 is a table showing illumination modes that can be selected by the light source optical system according to the first embodiment. 10 is a table showing combinations of bandpass filters and windows on a rotating disk that can be taken in Example 8; It is an example in the case of displaying the position of a lesioned part and the kind of detected fluorescent label obtained by using five types of fluorescent labels in Example 7. 10 is a table showing a relationship between values of two air gaps d1 and d2 of Example 5 and transmission characteristics of a tunable filter. It is a figure which shows the spectral transmission characteristic in a structure different from the tunable filter of Example 3.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Endoscope apparatus 2 Light source optical system 3 Endoscope tip part 4 Living body 5 Processor 6 Monitor 21 Light source 22 Turret 23 Rotating disk 31 Light guide fiber 32 Illumination lens 33 Objective lens 34 Fixed filter 35 Tunable filter 36 Detector

Claims (7)

For a plurality of fluorescence inspection object labeled substance is administered to emitting fluorescence of different wavelengths in the near infrared wavelength region, illuminating means for irradiating a light including an excitation wavelength of the plurality of fluorescent labels,
A transmission wavelength separation element for separating the fluorescence wavelength emitted from the fluorescent labeling substance from the light from the object to be inspected;
Detection means for detecting light of the fluorescence wavelength separated by the transmission wavelength separation element, and a peak of spectral transmission characteristics of the transmission wavelength separation element with respect to a range where fluorescence peak wavelengths of the plurality of fluorescent labeling substances exist Control means for controlling to scan
An endoscope apparatus characterized by comprising: The endoscope apparatus according to claim 1, wherein the transmission wavelength separation element is provided at a distal end portion of the endoscope apparatus. The endoscope apparatus according to claim 1, wherein the transmission wavelength separation element is provided in an eyepiece portion of the endoscope apparatus. The transmission wavelength separation element changes a spectral transmission characteristic by changing a distance of an air gap between opposing reflective films, and the distance of the air gap is controlled by the control means. The endoscope apparatus according to claim 1. For a plurality of fluorescence inspection object labeled substance is administered to emitting fluorescence of different wavelengths in the near infrared wavelength region, illuminating means for irradiating a light including an excitation wavelength of the plurality of fluorescent labels,
A transmission wavelength separation element that separates the fluorescence wavelength emitted by the fluorescent labeling substance from the light from the object to be examined for each fluorescence wavelength of the fluorescent labeling substance;
A plurality of detection means for individually detecting light for each fluorescence wavelength of the fluorescent labeling substance separated by the transmission wavelength separation element;
An endoscope apparatus characterized by comprising: The endoscope apparatus according to claim 5, wherein the transmission wavelength separation element is provided at a distal end portion of the endoscope apparatus. The endoscope apparatus according to claim 5, wherein the transmission wavelength separation element is provided in an eyepiece portion of the endoscope apparatus.

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