Patent Publication Number: US-2005143627-A1

Title: Fluorescence endoscopy video systems with no moving parts in the camera

Description:
CROSS-REFERENCE TO RELATED APPLICATION  
      This application is a divisional of U.S. patent application Ser. No. 10/050,601, filed Jan. 15, 2002, the benefit of the filing date of which is being claimed under 35 U.S.C. § 120. 
    
    
     FIELD OF THE INVENTION  
      The present invention relates to medical imaging systems in general, and in particular to fluorescence endoscopy video systems.  
     BACKGROUND OF THE INVENTION  
      Fluorescence endoscopy utilizes differences in the fluorescence response of normal tissue and tissue suspicious for early cancer as a tool in the detection and localization of such cancer. The fluorescing compounds or fluorophores that are excited during fluorescence endoscopy may be exogenously applied photo-active drugs that accumulate preferentially in suspicious tissues, or they may be the endogenous fluorophores that are present in all tissue. In the latter case, the fluorescence from the tissue is typically referred to as autofluorescence or native fluorescence. Tissue autofluorescence is typically due to fluorophores with absorption bands in the UV and blue portion of the visible spectrum and emission bands in the green to red portions of the visible spectrum. In tissue suspicious for early cancer, the green portion of the autofluorescence spectrum is significantly suppressed. Fluorescence endoscopy that is based on tissue autofluorescence utilizes this spectral difference to distinguish normal from suspicious tissue.  
      Since the concentration and/or quantum efficiency of the endogenous fluorophores in tissue is relatively low, the fluorescence emitted by these fluorophores is not typically visible to the naked eye. Fluorescence endoscopy is consequently performed by employing low light image sensors to acquire images of the fluorescing tissue through the endoscope. The images acquired by these sensors are most often encoded as video signals and displayed on a color video monitor. Representative fluorescence endoscopy video systems that image tissue autofluorescence are disclosed in U.S. Pat. No. 5,507,287, issued to Palcic et al.; U.S. Pat. No. 5,590,660, issued to MacAulay et al.; U.S. Pat. No. 5,827,190, issued to Palcic et al., U.S. patent application Ser. No. 09/615,965, and U.S. patent application Ser. No. 09/905,642, all of which are herein incorporated by reference. Each of these is assigned to Xillix Technologies Corp. of Richmond, British Columbia, Canada, the assignee of the present application.  
      While the systems disclosed in the above-referenced patents are significant advances in the field of early cancer detection, improvements can be made. In particular, it is desirable to reduce the size, cost, weight, and complexity of the camera described for these systems by eliminating moving parts.  
     SUMMARY OF THE INVENTION  
      A fluorescence endoscopy video system in accordance with the present invention includes an endoscopic light source that is capable of operating in multiple modes to produce either white light, reflectance light, fluorescence excitation light, or fluorescence excitation light with reference reflectance light. An endoscope incorporates a light guide for transmitting light to the tissue under observation and includes either an imaging guide or a camera disposed in the insertion portion of the endoscope for receiving light from the tissue under observation. A compact camera with at least one low light imaging sensor that receives light from the tissue and is capable of operating in multiple imaging modes to acquire color or multi-channel fluorescence and reflectance images. The system further includes an image processor and system controller that digitizes, processes and encodes the image signals produced by the image sensor(s) as a color video signal and a color video monitor that displays the processed video images. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:  
       FIGS. 1A-1B  are block diagrams of a fluorescence endoscopy video system according to one embodiment of the present invention;  
       FIGS. 2A-2B  are block diagrams of a multi-mode light source in accordance with different embodiments of the present invention;  
       FIG. 3  shows a filter wheel and optical filters for the multi-mode light source;  
       FIGS. 4A-4C  illustrate a number of alternative embodiments of a camera that can acquire color and/or fluorescence/reflectance images according to one embodiment of the present invention with optional placement for collimation and imaging optics;  
       FIGS. 5A-5C  illustrate a number of camera beamsplitter configurations;  
       FIGS. 6A-6E  are graphs illustrating presently preferred transmission characteristics of filters utilized for color imaging and fluorescence/reflectance imaging with the camera embodiments shown in  FIGS. 4A-4C ;  
       FIGS. 7A-7B  illustrate additional embodiments of a camera according to the present invention that can acquire color, fluorescence/reflectance, and/or fluorescence/fluorescence images according to an embodiment of the present invention with optional placement for collimation and imaging optics; and  
       FIGS. 8A-8F  are graphs illustrating presently preferred transmission characteristics of filters for color imaging, fluorescence/fluorescence imaging, and fluorescence/reflectance imaging with the camera embodiment shown in  FIGS. 7A-7B . 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       FIG. 1A  is a block diagram of a fluorescence endoscopy video system  50  in accordance with one embodiment of the present invention. The system includes a multi-mode light source  52  that generates light for obtaining color and fluorescence images. The use of the light source for obtaining different kinds of images will be described in further detail below. Light from the light source  52  is supplied to an illumination guide  54  of an endoscope  60 , which then illuminates a tissue sample  58  that is to be imaged.  
      As shown in  FIG. 1A , the system also includes a multi-mode camera  100 , which is located at the insertion end of the endoscope  60 . The light from the tissue is directly captured by the multi-mode camera  100 . With the multi-mode camera  100  located at the insertion end of the endoscope, the resulting endoscope  60  can be characterized as a fluorescence video endoscope, similar to video endoscopes currently on the market (such as the Olympus CF-240L) in utility, but with the ability to be utilized for fluorescence/reflectance and/or fluorescence/fluorescence imaging, in additional to conventional color imaging. Fluorescence/reflectance and fluorescence/fluorescence imaging will be described in detail below. By locating the camera at the insertion end of the endoscope, the inherent advantages of a video endoscope can be obtained: namely, the light available to form an image and the image resolution are improved compared to the case when the image is transmitted outside the body through an endoscope imaging guide or relay lens system.  
      A processor/controller  64  controls the multi-mode camera  100  and the light source  52 , and produces video signals that are displayed on a video monitor  66 . The processor/controller  64  communicates with the multi-mode camera  100  with wires or other signal carrying devices that are routed within the endoscope. Alternatively, communication between the processor/controller  64  and the camera  100  can be conducted over a wireless link.  
       FIG. 1B  is a block diagram of an alternative fluorescence endoscopy video system  50 , which differs from that shown in  FIG. 1A  in that endoscope  60  also incorporates an image guide  56  and the multi-mode camera  100  is attached to an external portion of the endoscope that is outside the body. The light that is collected from the tissue by endoscope  60  is transmitted through the image guide  56  and projected into the multi-mode camera  100 . Other than the addition of the image guide  56  to endoscope  100  and the location of the multi-mode camera  100  at the external end of the endoscope, the system of  FIG. 1B  is identical to that shown in  FIG. 1A .  
       FIG. 2A  shows the components of the light source  52  in greater detail. The light source  52  includes an arc lamp  70  that is surrounded by a reflector  72 . In the preferred embodiment of the invention, the arc lamp  70  is a high pressure mercury arc lamp (such as the Osram VIP R 150/P24). Alternatively, other arc lamps, solid state devices (such as light emitting diodes or diode lasers), or broadband light sources may be used, but a high pressure mercury lamp is currently preferred for its combination of high blue light output, reasonably flat white light spectrum, and small arc size.  
      The light from the arc lamp  70  is coupled to a light guide  54  of the endoscope  60  through appropriate optics  74 ,  76 , and  78  for light collection, spectral filtering and focusing respectively. The light from the arc lamp is spectrally filtered by one of a number of optical filters  76 A,  76 B,  76 C . . . that operate to pass or reject desired wavelengths of light in accordance with the operating mode of the system. As used herein, “wavelength” is to be interpreted broadly to include not only a single wavelength, but a range of wavelengths as well.  
      An intensity control  80  that adjusts the amount of light transmitted along the light path is positioned at an appropriate location between the arc lamp  70  and the endoscope light guide  54 . The intensity control  80  adjusts the amount of light that is coupled to the light guide  54 . In addition, a shutter mechanism  82  may be positioned in the same optical path in order to block any of the light from the lamp from reaching the light guide. A controller  86  operates an actuator  77  that moves the filters  76 A,  76 B or  76 C into and out of the light path. The controller  86  also controls the position of the intensity control  80  and the operation of the shutter mechanism  82 .  
      The transmission characteristics of filters  76 A,  76 B,  76 C, . . . , the characteristics of the actuator  77  mechanism, and the time available for motion of the filters  76 A,  76 B,  76 C, . . . , into and out of the light path, depend on the mode of operation required for use with the various camera embodiments. The requirements fall into two classes. If the light source shown in  FIG. 2A  is of the class wherein only one filter is utilized per imaging mode, the appropriate filter is moved in or out of the light path only when the imaging mode is changed. In that case, the actuator  77  only need change the filter in a time of approximately 1.0 second. The optical filter characteristics of filters  76 A,  76 B . . . are tailored for each imaging mode. For example, optical filter  76 A, used for color imaging, reduces any spectral peaks and modifies the color temperature of the arc lamp  70  so that the output spectrum simulates sunlight. Optical filter  76 B transmits only fluorescence excitation light for use with the fluorescence/fluorescence imaging mode and optical filter  76 C transmits both fluorescence excitation light and reference reflectance light for use with the fluorescence/reflectance imaging mode.  
      A light source  52 A of a second class is illustrated in  FIG. 2B ; only the differences from the light source shown in  FIG. 2A  will be elucidated. The light source  52 A uses multiple filters during each imaging mode. For example, light source filters, which provide red, green, and blue illumination sequentially for periods corresponding to a video frame or field, can be used for the acquisition of a color or a multi-spectral image with a monochrome image sensor, with the different wavelength components of the image each acquired at slightly different times. Such rapid filter changing requires a considerably different actuator than necessitated for the light source  52  of  FIG. 2A . As shown in  FIG. 2B , the filters are mounted on a filter wheel  79  that is rotated by a motor, which is synchronized to the video field or frame rate. The layout of the blue, red and green filters,  79 A,  79 B, and  79 C respectively, in filter wheel  79  are shown in  FIG. 3 .  
      The transmission characteristics of light source filters, the characteristics of the filter actuator mechanism, and the time available for motion of the filters into and out of the light path, for the two different classes of light sources are described in more detail below in the context of the various camera embodiments.  
      Because fluorescence endoscopy is generally used in conjunction with white light endoscopy, each of the various embodiments of the multi-mode camera  100  described below may be used both for color and fluorescence/reflectance and/or fluorescence/fluorescence imaging. These camera embodiments particularly lend themselves to incorporation within a fluorescence video endoscope due to their compactness and their ability to be implemented with no moving parts.  
      In a first embodiment, shown in  FIG. 4A , a camera  100 A receives light from the tissue  58 , either directly from the tissue in the case of a camera located at the insertion end of an endoscope, as shown in  FIG. 1A , or by virtue of an endoscope image guide  56 , which transmits the light from the tissue to the camera, as shown in  FIG. 1B . The light is directed towards a monochrome image sensor  102  and a low light image sensor  104  by a fixed optical beamsplitter  106  that splits the incoming light into two beams. The light beam is split such that a smaller proportion of the light received from the tissue  58  is directed towards the monochrome image sensor  102  and a larger proportion of the incoming light is directed towards the low light image sensor  104 . In this embodiment, the beamsplitter may be a standard commercially available single plate  88 , single cube  89 , or single pellicle design  90 , as shown in  FIGS. 5A-5C . It should be noted that, if the optical path between the tissue  58  and the image sensors contains an uneven number of reflections (e.g., such as from a single component beamsplitter), the image projected onto the sensor will be left-to-right inverted. The orientation of such images will need to be corrected by image processing.  
      In  FIG. 4A , light collimating optics  110  are positioned in front of the beamsplitter  106 , and imaging optics  112  and  114  are positioned immediately preceding the monochrome image sensor  102  and the low light image sensor  104 , respectively. A spectral filter  118  is located in the optical path between the beamsplitter  106  and the low light image sensor  104 . Alternatively, the spectral filter  118  may be incorporated as an element of the beamsplitter  106 .  
       FIG. 4B  illustrates another embodiment of the camera  100 . A camera  100 B is the same as the camera  100 A described above except that the light collimating optics  110  and imaging optics  112  and  114  have been eliminated and replaced with a single set of imaging optics  113  located between the tissue and beamsplitter  106 . The advantage of this configuration is that all imaging is performed and controlled by the same imaging optics  113 . Such a configuration requires all beam paths to have the same optical path length, however, and this restriction must be considered in the design of the beamsplitter  106  and spectral filter  118  that is located in the path to the low light image sensor  104 . In addition, the fact that these optical elements are located in a converging beam path must be considered in specifying these elements and in the design of the imaging optics  113 .  
      The low light image sensor  104  preferably comprises a charge coupled device with charge carrier multiplication (of the same type as the Texas Instruments TC253 or the Marconi Technologies CCD65), electron beam charge coupled device (EBCCD), intensified charge coupled device (ICCD), charge injection device (CID), charge modulation device (CMD), complementary metal oxide semiconductor image sensor (CMOS) or charge coupled device (CCD) type sensor. The monochrome image sensor  102  is preferably a CCD or a CMOS image sensor.  
      An alternative configuration of the camera  100 B is shown in  FIG. 4C . All aspects of this embodiment of this camera  100 C are similar to the camera  100 B shown in  FIG. 4B  except for differences which arise from reducing the width of the camera by mounting both image sensors  102  and  104  perpendicular to the camera front surface. In this alternative configuration, the low light image sensor  104  and the monochrome image sensor  102  are mounted with their image planes perpendicular to the input image plane of the camera. Light received from the tissue  58  is projected by imaging optics  113  through beamsplitter  106  onto the image sensors  102  and  104 . The beamsplitter  106  directs a portion of the incoming light in one beam towards one of the sensors  102 ,  104 . Another portion of the incoming light in a second light beam passes straight through the beamsplitter  106  and is directed by a mirror  108  towards the other of the sensors  102 ,  104 . In addition, a second set of imaging optics  115  is utilized to account for the longer optical path to this second sensor. The images projected onto both sensors will be left-to-right inverted and should be inverted by image processing.  
      The processor/controller  64  as shown in  FIGS. 1A and 11B  receives the transduced image signals from the camera  100  and digitizes and processes these signals. The processed signals are then encoded in a video format and displayed on a color video monitor  66 .  
      Based on operator input, the processor/controller  64  also provides control functions for the fluorescence endoscopy video system. These control functions include providing control signals that control the camera gain in all imaging modes, coordinating the imaging modes of the camera and light source, and providing a light level control signal for the light source.  
      The reason that two separate images in different wavelength bands are acquired in fluorescence imaging modes of the fluorescence endoscopy video systems described herein, and the nature of the fluorescence/reflectance and fluorescence/fluorescence imaging, will now be explained. It is known that the intensity of the autofluorescence at certain wavelengths changes as tissues become increasingly abnormal (i.e. as they progress from normal to frank cancer). When visualizing images formed from such a band of wavelengths of autofluorescence, however, it is not easy to distinguish between those changes in the signal strength that are due to pathology and those that are due to imaging geometry and shadows. A second fluorescence image acquired in a band of wavelengths in which the image signal is not significantly affected by tissue pathology, utilized for fluorescence/fluorescence imaging, or a reflected light image acquired in a band of wavelengths in which the image signal is not significantly affected by tissue pathology consisting of light that has undergone scattering within the tissue (known as diffuse reflectance), utilized for fluorescence/reflectance imaging, may be used as a reference signal with which the signal strength of the first fluorescence image can be “normalized”. Such normalization is described in two patents previously incorporated herein by reference: U.S. Pat. No. 5,507,287, issued to Palcic et al. describes fluorescence/fluorescence imaging and U.S. Pat. No. 5,590,660, issued to MacAulay et al. describes fluorescence/reflectance imaging.  
      One technique for performing the normalization is to assign each of the two image signals a different display color, e.g., by supplying the image signals to different color inputs of a color video monitor. When displayed on a color video monitor, the two images are effectively combined to form a single image, the combined color of which represents the relative strengths of the signals from the two images. Since light originating from fluorescence within tissue and diffuse reflectance light which has undergone scattering within the tissue are both emitted from the tissue with a similar spatial distribution of intensities, the color of a combined image is independent of the absolute strength of the separate image signals, and will not change as a result of changes in the distance or angle of the endoscope  60  to the tissue sample  58 , or changes in other imaging geometry factors. If, however, there is a change in the shape of the autofluorescence spectrum of the observed tissue that gives rise to a change in the relative strength of the two image signals, such a change will be represented as a change in the color of the displayed image. Another technique for performing the normalization is to calculate the ratio of the pixel intensities at each location in the two images. A new image can then be created wherein each pixel has an intensity and color related to the ratio computed. The new image can then be displayed by supplying it to a color video monitor.  
      The mixture of colors with which normal tissue and tissue suspicious for early cancer are displayed depends on the gain applied to each of the two separate image signals. There is an optimal gain ratio for which tissue suspicious for early cancer in a fluorescence image will appear as a distinctly different color than normal tissue. This gain ratio is said to provide the operator with the best combination of sensitivity (ability to detect suspect tissue) and specificity (ability to discriminate correctly). If the gain applied to the reference image signal is too high compared to the gain applied to the fluorescence image signal, the number of tissue areas that appear suspicious, but whose pathology turns out to be normal, increases. Conversely, if the relative gain applied to the reference image signal is too low, sensitivity decreases and suspect tissue will appear like normal tissue. For optimal system performance, therefore, the ratio of the gains applied to the image signals must be maintained at all times. The control of the gain ratio is described in two patent applications previously incorporated herein by reference: U.S. patent application Ser. No. 09/615,965, and U.S. patent application Ser. No. 09/905,642.  
      In vivo spectroscopy has been used to determine which differences in tissue autofluorescence and reflectance spectra have a pathological basis. The properties of these spectra determine the particular wavelength bands of autofluorescence and reflected light required for the fluorescence/reflectance imaging mode, or the particular two wavelength bands of autofluorescence required for fluorescence/fluorescence imaging mode. Since the properties of the spectra depend on the tissue type, the wavelengths of the important autofluorescence band(s) may depend on the type of tissue being imaged. The specifications of the optical filters described below are a consequence of these spectral characteristics, and are chosen to be optimal for the tissues to be imaged.  
      As indicated above, the filters in the light source and camera should be optimized for the imaging mode of the camera, the type of tissue to be examined and/or the type of pre-cancerous tissue to be detected. Although all of the filters described below can be made to order using standard, commercially available components, the appropriate wavelength range of transmission and degree of blocking outside of the desired transmission range for the described fluorescence endoscopy images are important to the proper operation of the system. The importance of other issues in the specification of such filters, such as the fluorescence properties of the filter materials and the proper use of anti-reflection coatings, are taken to be understood.  
       FIGS. 6A-6E  illustrate the preferred filter characteristics for use in a fluorescence endoscopy system having a camera of the type shown in  FIGS. 4A-4C  and light source as shown in  FIG. 2B , that operates in a fluorescence/reflectance imaging mode, or a color imaging mode. There are several possible configurations of fluorescence endoscopy video systems, operating in the fluorescence/reflectance imaging mode including green fluorescence with either red or blue reflectance, and red fluorescence with either green or blue reflectance. The particular configuration utilized depends on the target clinical organ and application. The filter characteristics will now be described for each of these four configurations.  
       FIG. 6A  illustrates the composition of the light transmitted by a blue filter, such as filter  79 A, which is used to produce excitation light in the system light source. This filter transmits light in the wavelength range from 370-460 nm or any subset of wavelengths in this range. Of the light transmitted by this filter, less than 0.001% is in the fluorescence imaging band from 480-750 nm (or whatever desired subsets of this range is within the specified transmission range of the primary and reference fluorescence image filters described below).  
       FIG. 6B  illustrates the composition of the light transmitted by a red filter, such as filter  79 B, which is used to produce red reflectance light in the system light source. This filter transmits light in the wavelength range from 590-750 nm or any subset of wavelengths in this range. Light transmitted outside this range should not exceed 1%.  
       FIG. 6C  illustrates the composition of the light transmitted by a green filter, such as filter  79 C, which is used to produce green reflectance light in the system light source. This filter transmits light in the wavelength range from 480-570 nm or any subset of wavelengths in this range. Light transmitted outside this range should not exceed 1%.  
       FIG. 6D  shows the composition of the light transmitted by a camera spectral filter, such as filter  118 , for defining the primary fluorescence image in the green spectral band. In this configuration, the filter blocks excitation light and red fluorescence light while transmitting green fluorescence light in the wavelength range of 480-570 nm or any subset of wavelengths in this range. When used in a fluorescence endoscopy video system with the light source filter  79 A described above, the filter characteristics are such that any light outside of the wavelength range of 480-570 nm, or any desired subset of wavelengths in this range, contributes no more than 0.1% to the light transmitted by the filter.  
       FIG. 6E  shows the composition of the light transmitted by a camera filter, such as filter  118 , for defining the primary fluorescence image in the red spectral band. In this configuration, the filter blocks excitation light and green fluorescence light while transmitting red fluorescence light in the wavelength range of 590-750 nm or any subset of wavelengths in this range. When used in a fluorescence endoscopy video system with the light source filter  79 A described above, the filter characteristics are such that any light outside of the wavelength range of 590-750 nm, or any desired subset of wavelengths in this range, contributes no more than 0.1% to the light transmitted by the filter.  
      The operation of the preferred embodiment of the fluorescence endoscopy video system will now be described. The cameras  100 A as shown in  FIGS. 4A and 100B  as shown in  FIG. 4B  or  100 C as shown in  FIG. 4C  are capable of operating in color and fluorescence/reflectance imaging modes. A light source of the type shown in  FIG. 2B , that provides a different output every video frame or field is required. In the color imaging mode, the processor/controller  64  provides a control signal to the multi-mode light source  52  that indicates the light source should be operating in the white light mode and provides a synchronizing signal. The light source  52  sequentially outputs filtered red, green, and blue light, synchronously with the video field or frame of the image sensors  102  and  104 . The filtered light from the light source  52  is projected into the endoscope light guide  54  and is transmitted to the tip of the endoscope  60  to illuminate the tissue  58 .  
      The processor/controller  64  also protects the sensitive low light image sensor  104  during color imaging by decreasing the gain of the amplification stage of the sensor. The light reflected by the tissue  58  is collected and transmitted by the endoscope image guide  56  to the camera where it is projected through beamsplitter  106  onto the monochrome image sensor  102 , or the light is directly projected through the camera beamsplitter  106  onto the monochrome image sensor  102  if the sensor is located within the insertion portion of the endoscope. The image projected during each of red, green, and blue illuminations is transduced by the monochrome image sensor  102  and the resulting image signals are transmitted to the processor/controller  64 .  
      Based on the brightness of the images captured, the processor/controller  64  provides a control signal to the multi-mode light source  52  to adjust the intensity control  80  and thereby adjust the level of light output by the endoscope light guide  54 . The processor/controller  64  may also send a control signal to the camera  100 A,  100 B or  100 C to adjust the gain of the monochrome image sensor  102 .  
      The processor/controller  64  interpolates the images acquired during sequential periods of red, green, and blue illumination to create a complete color image during all time periods, and encodes that color image as video signals. The video signals are connected to color video monitor  66  for display of the color image. All of the imaging operations occur at analog video display rates (30 frames per second for NTSC format and 25 frames per second for PAL format).  
      When switching to the fluorescence/reflectance imaging mode, the processor/controller  64  provides a control signal to the multi-mode light source  52  to indicate that it should be operating in fluorescence/reflectance mode. In response to this signal, the light source filter wheel  79  stops rotating and the light source  52  selects and positions the appropriate blue optical filter  79 A continuously into the optical path between the arc lamp  70  and the endoscope light guide  54 . This change from sequentially changing filters to a static filter occurs in a period of approximately one second. Filter  79 A transmits only those wavelengths of light that will induce the tissue  58  under examination to fluoresce. All other wavelengths of light are substantially blocked as described above. The filtered light is then projected into the endoscope light guide  54  and transmitted to the tip of the endoscope  60  to illuminate the tissue  58 .  
      As part of setting the system in the fluorescence/reflectance mode, the processor/controller  64  also increases the gain of the amplification stage of the low light image sensor  104 . The fluorescence emitted and excitation light reflected by the tissue  58  are either collected by the endoscope image guide  56  and projected through the camera beamsplitter  106  onto the low light image sensor  104  and the image sensor  102 , or are collected and directly projected through the camera beamsplitter  106  onto the low light image sensor  104  and the image sensor  102  at the insertion tip of the endoscope  60 . Spectral filter  118  limits the light transmitted to the low light image sensor  104  to either green or red autofluorescence light only and substantially blocks the light in the excitation wavelength band. The autofluorescence image is transduced by the low light image sensor  104 . The reference reflected excitation light image is transduced by the monochrome image sensor  102  and the resulting image signals are transmitted to the processor/controller  64 .  
      Based on the brightness of the transduced images, the processor/controller  64  may provide a control signal to the multi-mode light source  52  to adjust the intensity control  80  and thereby adjust the level of light delivered to the endoscope  60 . The processor/controller  64  may also send control signals to the cameras  100 A,  100 B or  100 C to adjust the gains of the low light image sensor  104  and the monochrome image sensor  102 , in order to maintain constant image brightness while keeping the relative gain constant.  
      After being processed, the images from the two sensors are encoded as video signals by processor/controller  64 . The fluorescence/reflectance image is displayed by applying the video signals to different color inputs on the color video monitor  66 .  
      In order for the combined image to have optimal clinical meaning, for a given proportion of fluorescence to reference light signals emitted by the tissue and received by the system, a consistent proportion must also exist between the processed image signals that are displayed on the video monitor. This implies that the (light) signal response of the fluorescence endoscopy video system is calibrated. The calibration technique is described in two patent applications previously incorporated herein by reference: U.S. patent application Ser. No. 09/615,965, and U.S. patent application Ser. No. 09/905,642.  
      The cameras  100 A,  100 B,  100 C can be operated in a variation of the fluorescence/reflectance mode to simultaneously obtain fluorescence images and reflectance images with red, green, and blue illumination. The operation of the system is similar to that described previously for color imaging, so only the points of difference from the color imaging mode will be described.  
      In this variation of the fluorescence/reflectance mode, instead of changing from sequential red, green, and blue illumination to static blue illumination when switching from color imaging to fluorescence/reflectance imaging, the multi-mode light source  52  provides the same sequential illumination utilized in the color imaging mode, for all imaging modes. Capture and display of the light reflected by the tissue is similar to that described previously for the color imaging mode. However, in addition to the reflectance images captured in that mode, the gain of the amplification stage of the low light image sensor  104  is adjusted to a value that makes it possible to capture autofluorescence images during blue illumination. During red and green illumination, the gain of amplification stage of the low light sensor is decreased to protect the sensor while the image sensor  102  captures reflectance images.  
      In this modified fluorescence/reflectance mode, the camera captures both reflectance and fluorescence images during the blue illumination period, in addition to reflected light images during the red and green illumination periods. As for the color imaging mode, the reflectance images are interpolated and displayed on the corresponding red, green and blue channels of a color video monitor to produce a color image. Like the previously described fluorescence/reflectance mode, a fluorescence/reflectance image is produced by overlaying the fluorescence image and one or more of the reflectance images displayed in different colors on a color video monitor.  
      Since individual reflectance and fluorescence images are concurrently captured, both a color image and a fluorescence/reflectance image can be displayed simultaneously on the color video monitor. In this case, there is no need to utilize a separate color imaging mode. Alternatively, as described for the previous version of fluorescence/reflectance operation, only the fluorescence/reflectance image may be displayed during fluorescence/reflectance imaging and a color image displayed solely in the color imaging mode.  
      Yet another embodiment of this invention will now be described. All points of similarity with the first embodiment will be assumed understood and only points that differ will be described.  
      In this second embodiment, all aspects of the fluorescence endoscopy video system are similar to those of the first embodiment except for the camera and the light source. A camera  100 D for this embodiment of a system is as shown in  FIG. 7A . It differs from the cameras  100 A,  100 B or  100 C as described above in that all imaging modes utilize a single, low light color image sensor  103  (preferably a color CCD with charge carrier multiplication such as the Texas Instruments TC252) and that no beamsplitter is required. Alternatively, the color image sensor  103  may be a three-CCD with charge carrier multiplication color image sensor assembly, a color CCD, a three-CCD color image sensor assembly, a color CMOS image sensor, or a three-CMOS color image sensor assembly.  
      Each of the pixel elements on the low light color sensor  103  is covered by an integrated filter, typically red, green or blue. These filters define the wavelength bands of fluorescence and reflectance light that reach the individual pixel elements. Such mosaic filters typically have considerable overlap between the red, green, and blue passbands, which can lead to considerable crosstalk when imaging dim autofluorescence light in the presence of intense reflected excitation light. Therefore, a separate filter  118  is provided to reduce the intensity of reflected excitation light to the same level as that of the autofluorescence light and, at the same time, pass autofluorescence light.  
      In this embodiment, the primary fluorescence and reference images are projected onto the same image sensor  103 , but, because of the individual filters placed over each pixel, these different images are detected by separate sensor pixels. As a result, individual primary fluorescence and reference image signals can be produced by processor/controller  64  from the single CCD image signal.  
      In  FIG. 7A , light collimating optics  110  is positioned between the tissue  58  and filter  118  and imaging optics  112  is positioned immediately preceding the color image sensor  103 . In an alternative optical configuration, camera  100 E, as shown in  FIG. 7B , eliminates the collimating optics  110  and imaging optics  112  and replaces them with a single imaging optics  113  located between the tissue  58  and filter  118 . The advantage of this configuration is that all imaging is performed and controlled by the same imaging optics  113 . The fact that filter  118  is located in a converging beam path must be considered in specifying that element and in the design of the imaging optics.  
      The operation of a system based on camera  100 D of  FIG. 7A  or  100 E of  FIG. 7B  will now be described. The cameras  100 D and  100 E are capable of operation in the color, fluorescence/fluorescence, and fluorescence/reflectance imaging modes. For a system based on camera  100 D or  100 E, a light source of the type shown in  FIG. 2A , provides steady state output in each imaging mode. As described below, the light transmission specifications of the light source filters  76 A,  76 B, and  76 C, the filter  118 , and the mosaic color filters integrated with the image sensor  103  are selected such that the intensity of the reflected light and fluorescence light at the color image sensor&#39;s active elements results in transduced image signals with good signal-to-noise characteristics and without significant saturation. At the same time these filters have appropriate light transmission specifications for excitation and imaging of the primary fluorescence and for color imaging. The filter transmission characteristics are chosen to provide the desired ratio of relative primary fluorescence to reference light intensity at the image sensor.  
      In the color imaging mode, the processor/controller  64  provides a control signal to the multimode light source  52  that it should be in white light mode. The light source selects and positions the appropriate optical filter  76 A into the optical path between the arc lamp  70  and endoscope light guide  54 . Given the presence of filter  118  in cameras  100 D,  100 E which have reduced transmission for excitation light at blue wavelengths, the light source filter  76 A should incorporate reduced transmission at red and green wavelengths to obtain a balanced color image at image sensor  103  with the proper proportions of red, green, and blue components.  
      Image signals from the color low light sensor  103  are processed by processor/controller  64 . Standard techniques are utilized to produce a color image from a single color sensor: the image signals from pixels having the same filter characteristics are interpolated by processor/controller  64  to produce an image signal, related to the pass band of each element of the mosaic filter (e.g. red, green, and blue), at every pixel location. The resulting multiple images, which when combined produce a color image, are encoded by processor/controller  64  as video signals. The color image is displayed by connecting the video signals to the appropriate inputs of color video monitor  66 .  
      Processor/controller  64  also maintains the overall image brightness at a set level by monitoring the brightness of the image signal at each pixel and adjusting the intensity of the light source output and camera amplifier gains according to a programmed algorithm.  
      When switching to the fluorescence/fluorescence imaging mode, processor/controller  64  provides a control signal to the multi-mode light source  52  to indicate that it should be in fluorescence/fluorescence mode. The light source  52  moves light source filter  76 B into position in the light beam. Filter  76 B transmits excitation light and blocks the transmission of light at the green and red fluorescence detection wavelengths, as described below. The characteristics of light source fluorescence excitation filter  76 B and excitation filter  118 , along with the mosaic filter elements on the color sensor  103 , are such that the intensity of blue light at the color sensor is less than the intensities of red and green autofluorescence at the sensor, and are such that the ratio of the intensity of red autofluorescence to the intensity of green autofluorescence at the color sensor  103  has the appropriate value for optimal differentiation between normal and abnormal tissue. The fluorescence images are processed, as previously described for color imaging, by processor/controller  64  to produce separate images corresponding to each of the pass bands of the mosaic filter (e.g. red, green, and blue). These separate images are encoded as video signals by processor/controller  64 . A composite fluorescence/fluorescence image is displayed on the color video monitor  66  by applying the video signals from red and green pass bands of the mosaic filter to different color inputs of the monitor.  
      When switching to the fluorescence/reflectance imaging mode, processor/controller  64  provides a control signal to the multi-mode light source  52  to indicate that it should be in fluorescence/reflectance mode. The light source  52  moves light source filter  76 C into position in the light beam. Filter  76 C transmits both excitation light and reference light and blocks the transmission of light at fluorescence detection wavelengths, as described below. The characteristics of the light source filter  76 C for fluorescence excitation and the reflectance illumination and the camera filter  118 , along with the mosaic filter on the color sensor  103 , as detailed below, are such that the intensity of reflected excitation light at the color sensor is comparable to the intensity of autofluorescence at the sensor, and should be such that the ratio of the intensity of autofluorescence to the intensity of reflected reference light at the color sensor  103  has the appropriate value. The fluorescence and reflectance images are processed, as previously described for color imaging, by processor/controller  64  to produce separate images corresponding to each of the pass bands of the mosaic filter (e.g. red, green, and blue). These separate images are encoded as video signals by processor/controller  64 . A composite fluorescence/reflectance image is displayed on color video monitor  66  by applying the video signals from the appropriate mosaic filter pass bands (as discussed below) to different color inputs of the monitor.  
      As indicated above, the filters in the light source and camera should be optimized for the imaging mode of the camera, the type of tissue to be examined and/or the type of pre-cancerous tissue to be detected. Although all of the filters described below can be made to order using standard, commercially available components, the appropriate wavelength range of transmission and degree of blocking outside of the desired transmission range for the described fluorescence endoscopy images modes are important to the proper operation of the system. The importance of other issues in the specification of such filters such as the fluorescence properties of the filter materials and the proper use of anti-reflection coatings are taken to be understood.  
      As discussed above, the filters in the light source and camera should be optimized for the imaging mode of the camera, the type of tissue to be examined and/or the type of pre-cancerous tissue to be detected, based on in vivo spectroscopy measurements. The preferred filter characteristics for use in the fluorescence endoscopy video systems with a camera of the type shown in  FIGS. 7A and 7B , operating in a fluorescence/reflectance imaging mode, or a fluorescence/fluorescence imaging mode, are shown in  FIGS. 8A-8F . There are several possible configurations of fluorescence endoscopy video systems, operating in the fluorescence/reflectance imaging mode including green fluorescence with red reflectance, and red fluorescence with green reflectance and red or green fluorescence with blue reflectance. The particular configuration utilized depends on the target clinical organ and application. The filter characteristics will now be described for each of these four configurations.  
       FIGS. 8A-8B  illustrate a preferred composition of the light transmitted by filters for a color imaging mode.  FIG. 8A  illustrates the composition of the light transmitted by the light source filter, such as filter  76 A, which is used to produce light for color imaging. The spectral filter  118  remains in place during color imaging since there are no moving parts in the present camera embodiment. Accordingly, to achieve correct color rendition during color imaging it is necessary for the transmission of light source filter  76 A to be modified, compared to the usual white light transmission for color imaging, such that the light received by the high sensitivity color sensor  103  is white when a white reflectance standard is viewed with the camera. Therefore, to balance the effect of spectral filter  118 , the transmission of filter  76 A in the red and green spectral bands must be less than the transmission in the blue, and the transmission of filter  76 A in the blue must extend to a long enough wavelength that there is an overlap with the short wavelength region of appreciable transmission of filter  118 . Filter  76 A transmits light in the blue wavelength range from 370-480 nm or any subset of wavelengths in this range at the maximum possible transmission. The transmission of Filter  76 A in the green and red wavelength range from 500 nm-750 nm, or any subsets of wavelengths in this range, is preferably reduced by at least a factor of ten compared to the transmission in the blue, in order to achieve a balanced color image at the high sensitivity color sensor  103 , after taking into account the effect of filter  118 .  
       FIG. 8B  shows the composition of the light transmitted by the spectral filter  118 , which is used for all imaging modes. In this configuration, the filter blocks the blue excitation light in the range 370-450 nm while transmitting red and green light in the wavelength range of 470-750 nm or any subsets of wavelengths in this range. When used in a fluorescence endoscopy video system in combination with the light source filter  76 A described above, the filter characteristics are such that the intensity of light captured by high sensitivity color sensor  103  in the wavelength bands transmitted by the different regions of the sensor&#39;s mosaic filter are comparable, when a white reflectance standard is imaged. When used in a fluorescence endoscopy video system for fluorescence/fluorescence imaging in combination with the light source filter  76 B described below, the filter characteristics are such that any light outside of the wavelength range of 470-750 nm (or any desired subset of wavelengths in this range) contributes no more than 0.1% to the light transmitted by the filter.  
       FIG. 8C  illustrates the composition of the light transmitted by a filter, such as filter  76 B, which is used to produce excitation light in the system light source. This filter transmits light in the wavelength range from 370-450 nm or any subset of wavelengths in this range. Of the light transmitted by this filter, preferably less than 0.001% is in the fluorescence imaging band from 470-750 nm (or whatever desired subsets of this range is within the transmission range of the primary and reference fluorescence wavelength bands defined by the transmission of the mosaic filter incorporated in the high sensitivity color sensor  103 ).  
       FIG. 8D  illustrates the composition of the light transmitted by the light source filter, such as filter  76 C, which is used to produce blue excitation light and red reference light for a green fluorescence and red reflectance imaging mode. This filter transmits light in the blue wavelength range from 370-450 nm, or any subset of wavelengths in this range. It also transmits light in the red wavelength range of 590-750 nm, or any subset of wavelengths in this range. The light transmitted in the red wavelength range (or subset of that range) is adjusted, as part of the system design, to be an appropriate fraction of the light transmitted in the blue wavelength range. This fraction is selected to meet the need to match the intensity of the reflected reference light projected on the color image sensor to the requirements of the sensor, at the same time as maintaining sufficient fluorescence excitation. Of the light transmitted by this filter, less than 0.001% is in the green wavelength range of 470-570 nm (or whatever desired subset of this range is specified as the transmission range of the primary fluorescence wavelength band).  
       FIG. 8E  illustrates the composition of the light transmitted by a light source filter which is used to produce excitation light such as filter  76 C described above for a red fluorescence and green reflectance imaging mode. This filter transmits light in the blue wavelength range from 370-450 nm or any subset of wavelengths in this range. It also transmits light in the green wavelength range of 470-570 nm or any subset of wavelengths in this range. The light transmitted in the green wavelength range (or subset of that range) is adjusted, as part of the system design, to be an appropriate fraction of the light transmitted in the blue wavelength range. This fraction is selected to meet the need to match the intensity of the reflected reference light projected on the color image sensor to the requirements of the sensor, at the same time as maintaining sufficient fluorescence excitation. Of the light transmitted by this filter, less than 0.001% is in the red fluorescence imaging wavelength range of 590-750 nm (or whatever desired subset of this range is specified as the transmission range of the primary fluorescence wavelength band).  
       FIG. 8F  illustrates the composition of the light transmitted by a light source filter which is used to produce excitation light such as filter  76 C described above for a red or green fluorescence and blue reflectance imaging mode. This filter transmits light in the blue wavelength range from 370-470 nm or any subset of wavelengths in this range. The light transmitted in the 450-470 nm wavelength range (or subset of that range) is adjusted, as part of the system design, to meet the need to match the intensity of the reflected reference light projected on the color image sensor to the requirements of the sensor and to provide the appropriate ratio of reference reflected light to fluorescence light, at the same time as maintaining sufficient fluorescence excitation. Of the light transmitted by this filter, less than 0.001% is in the fluorescence imaging wavelength range of 490-750 nm (or whatever desired subset of this range is specified as the transmission range of the primary fluorescence wavelength band).  
      The fluorescence endoscopy video systems described in the above embodiments have been optimized for imaging endogenous tissue fluorescence. They are not limited to this application, however, and may also be used for photo-dynamic diagnosis (PDD) applications. As mentioned above, PDD applications utilize photo-active drugs that preferentially accumulate in tissues suspicious for early cancer. Since effective versions of such drugs are currently in development stages, this invention does not specify the filter characteristics that are optimized for such drugs. With the appropriate light source and camera filter combinations, however, a fluorescence endoscopy video system operating in either fluorescence/fluorescence or fluorescence/reflectance imaging mode as described herein may be used to image the fluorescence from such drugs.  
      As will be appreciated, each of the embodiments of a camera for a fluorescence endoscopy video system described above, due to their simplicity, naturally lend themselves to miniaturization and implementation in a fluorescence video endoscope, with the camera being incorporated into the insertion portion of the endoscope. The cameras can be utilized for both color imaging and fluorescence imaging, and in their most compact form contain no moving parts.