Abstract:
A system visually distinguishes diseased tissue from healthy tissue after a treatment is administered to a patient to provide different concentrations of a fluorescent marking substance between the diseased tissue and the healthy tissue. A light source illuminates the tissue with excitation light. A detector detects light returning from the tissue, and a controller characterizes the returning light according to a measured property indicative of the different concentrations. A light projector projects light having a predetermined cue in response to the characterization of the returning light.

Description:
TECHNICAL FIELD 
     The present invention relates in general to optical detection of cancerous tissue with fluorescent markers, and, more specifically, to an optical system for visually highlighting marked tissues for excision by a surgeon. 
     BACKGROUND 
     Fluorescent markers have been used to differentiate between diseased and healthy tissues in connection with applying therapies such as surgical excision. Photodynamic substances have been used with properties that cause them to accumulate in tumor cells so that the fluorescence can be used to detect the cancer cells. One such substance is 5-aminolevulinic acid (5-ala) which is taken up by all cells but which is quickly eliminated by healthy cells but converts to a fluorescent substance protoporphyrin IX in cancer cells. During surgery to remove a tumor, excitation light is provided to the tissues, and the resulting fluorescent areas mark the cancer for removal. Another known photo-sensitizer substance is porfimer sodium, sold as Photofrin® by Axcan Pharma of Birmingham, Ala. 
     Due to the low concentrations of the photo-sensitive substance in the tissues, the amount of fluorescent light produced in the diseased tissues may be low. Thus, it may be difficult for a surgeon to see all the areas containing the marker substance. In surgeries of certain organs, such as the brain, it is desirable to ascertain precise boundaries between cancerous and healthy tissues so that all cancerous tissue can be removed without affecting any healthy tissue. To improve recognition, electronic systems with higher sensitivity than the human eye have been developed for sensing the areas that fluoresce. A sensed image of the fluorescing areas has been presented on a display screen or monitor. However, such systems still have a drawback in that the surgeon must estimate where the areas depicted on the monitor are actually located in the patient when performing the tissue removal. 
     SUMMARY OF INVENTION 
     The present invention has the advantage of providing a direct indication of the cancerous areas present in the patient. After electronically detecting the fluorescing areas, the present invention superimposes a coded image onto the patient that permits easy visual distinction between the cancerous and healthy tissues. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a block diagram showing a first embodiment of a system of the present invention. 
         FIG. 2  illustrates target tissue with healthy and diseased tissue with an indication of the visible marking of diseased tissue obtained by the prior art. 
         FIG. 3  illustrates target tissue with healthy and diseased tissue with an indication of the visible marking of diseased tissue obtained by the present invention. 
         FIG. 4  is a block diagram showing one embodiment of an excitation module of the present invention. 
         FIG. 5  is a block diagram showing one embodiment of a detection module of the present invention. 
         FIG. 6  is a block diagram showing an alternative embodiment of a detection module of the present invention. 
         FIG. 7  is an energy plot showing a spectrum of light obtained from target tissue after excitation. 
         FIG. 8  shows bandwidth windows that can be used to detect whether fluorescing diseased tissue is present. 
         FIG. 9  is a block diagram showing one embodiment of a projection module of the present invention. 
         FIG. 10  is a flowchart of one preferred method of the present invention. 
         FIG. 11  is a block diagram showing an alternative system of the present invention that incorporates all the light generation and reception functions. 
         FIG. 12  is a flowchart of an alternative method of the invention that can be performed by the system of  FIG. 11 . 
     
    
    
     DESCRIPTION OF EMBODIMENTS 
     The present invention is a form of photo dynamic diagnostic (PDD) in which a patient receives a photo-sensitizer substance resulting in a concentration of fluorescent material in diseased cancer cells. Referring to  FIG. 1 , a PDD system  10  is used while treating a patient  11 . Patient  11  has healthy tissue  12  and diseased tissue  13  that are exposed during surgical intervention. A surgeon or other specialist visualizes the tissues using the naked eye  14 . System  10  assists the surgeon by enabling better visualization of diseased tissue  13  within a field of view FOV of system  10 . 
     System  10  includes several interacting modules which may be contained in a single housing  15  or may be separately constructed. A first module  20  includes an excitation source for generating light having a wavelength that excites the fluorescent substance in diseased tissue  13 . When the photo-sensitizer is 5-ala, excitation source module  20  provides blue light with a wavelength of about 420 nM, which may be generated by a blue laser or LED. The blue light may be directed toward patient  11  either directly or through optics such as a lens or a diffuser. 
     A second module  21  comprises a detector that responds to the fluorescent emission of the photo-sensitizer substance on a localized basis across the tissue. As discussed below, the localization may be obtained using a scanning mirror, a CCD imager, or any other known technique to obtain separate measurements for each distinct area of tissue. Detector module  21  is responsive to the emission of red light, e.g., at a wavelength of 640 nM in the case of 5-ala. 
     A third module  22  comprises a projection source that responds to the localized data from detector module  21  in order to illuminate areas where diseased tissue is detected using a much more easily visualized lighting than the weak fluorescent emission from the diseased tissue. Preferably, the projection source light is characterized by a different color, intensity, or other light property, cue, or coding, thereby allowing the surgeon to discern the boundaries of the diseased tissue. In one preferred embodiment, projection source module  22  illuminates diseased tissue  13  using bright green light that is easily seen. Other examples of visual cues or image coding include time-varying intensity or color attributes of the projected light, or image patterns in the projected light. 
     A fourth module  23  may optionally be provided that includes a treating source for directing treating radiation to the spots where diseased tissue  13  is detected. Treating source module  13  may include a red laser that interacts with the marker substance in a manner that causes death of the diseased cells, as known in the art. A push button or other manual control would be provided so that the treating source is only energized when desired by the surgeon. 
     A controller  24  is coupled to modules  20 - 23  in order to coordinate operations and to process and share data. An optional display  25  can be connected to controller  24  in order to generate live images of tissue  12  and  13 . 
       FIG. 2  illustrates the visibility of fluorescent emissions using prior art methods. A patient has healthy tissue  12  and diseased tissues  13  and  27 . All diseased tissues  13  and  27  contain fluorescent marker substance, but only area  28  includes a sufficient concentration to generate red light visible to the naked eye of the surgeon. With the additional projected illumination of the present invention, the surgeon sees green light  29  as shown in  FIG. 3  that directly corresponds to all the diseased tissue. As long as any fluorescent marker remains at a concentration above a threshold, it will be detected by the system of the present invention and the projection source will continue to indicate the location(s) of remaining diseased tissue. 
     Excitation source module  20  is shown in greater detail in  FIG. 4 . A blue LED laser array  30  is powered by an LED power driver  31 . Blue light from array  30  passes through a diffuser  32  for providing even excitation illumination to a target. 
     A first embodiment of detector module  21  is shown in greater detail in  FIG. 5 . Fluorescent and reflected emissions from a target are gathered by optics  35  (such as a lens) and pass through a half mirror  36  to a micro-electro-mechanical system (MEMS) scanner  37 . MEMS scanner  37  includes a scannable mirror  38  that is deflected under control of controller  24  in order to reflect light received from a particular area (i.e., a pixel) of the target back to half mirror  36  and to a beam splitter  40 . Some of the light from the pixel is directed to a photodiode  41  to support the creation of an image on the optional display. Another portion of the light emission received from the tissue pixel is provided by beam splitter  40  through a lens  42  to a spectrometer  43 . Using a fast Fourier transform (FFT) or other known techniques, spectrometer  43  analyzes light received from the tissue pixel in order to determine whether the received light energy at the fluorescent wavelength exceeds a predetermined threshold indicative of the presence of diseased tissue. The resulting determination is provided from spectrometer  43  to controller  24 . 
       FIG. 6  shows an alternative embodiment of detector module  21 ′ in which full images are captured rather than using pixel scanning. Thus, light from the target is gathered by an optical system  45  which may contain a lens  46 . Light passes to a beam splitter  47  directing a first portion of the light to a charge coupled device (CCD)  48  for forming an image that is sent to the (optional) display monitor. Another portion of the incoming light is directed by beam splitter  47  to a CCD  50  through a filter  51 . Likewise, further portions of the light are directed to CCD  52  and  54  through filters  53  and  55 , respectively. Image data from CCD  50 ,  52 , and  54  are provided to controller  24  for analysis in order to determine presence of diseased tissues. Filters  51 ,  53 , and  55  pass different wavelengths at or near the wavelength of the fluorescent emissions in order to detect pixels within the CCD images where the fluorescent emissions exceed a predetermined threshold as described in connection with  FIGS. 7 and 8  below. 
     A spectrum of light reflected/emitted from the tissues while being illuminated by the blue light is shown in  FIG. 7 . The intensity of the light peaks at the fundamental wavelength of the blue illumination source, e.g., about 420 nM. For normal healthy tissue, the intensity of reflected light falls off into and through the red area of the spectrum as shown at  57 . A different spectrum  58  results when diseased tissue containing the fluorescent marker is present. Thus, the spectrum increases to a secondary peak  60  at around a wavelength of 640 nM. The spectrum shown in  FIG. 7  corresponds to an individual pixel or tissue area within the detected image. Each individual pixel has a respective spectrum according to its particular concentration of marker substance. 
     As shown in  FIG. 8 , separate passbands B 1 , B 2 , and B 3 , for measuring the light energy received can be used to detect the presence of a peak in each respective spectrum. When the energy distribution exhibits the peak, then cancerous tissue is detected. Filters  51 ,  53 , and  55 , each correspond to a respective bandwidth B 1 , B 2 , and B 3 , such that B 2  is centered on the peak emission wavelength. The resulting intensities (i.e., magnitudes) at each pixel in the CCD images can be compared in order to detect whether the corresponding peak is present. Thus, if the intensity for bandpass B 2  minus the intensity for bandpass B 1  is greater than zero and the intensity for bandpass B 2  minus the intensity for bandpass B 3  is also greater than zero, then a peak is detected and the corresponding pixel is marked as diseased. Otherwise, the corresponding pixel is marked as healthy. 
     One embodiment of projection source module  22  is shown in greater detail in  FIG. 9 . A green light source  63  such as a green LED or other green laser source is driven by a power driver  64 . Green light is directed to half mirror  65  and reflects to MEMS scanner  66  which has a tiltable mirror  67 . Controller  24  positions mirror  67  according to pixels marked as diseased and activates driver  64  to turn on green source  63  to direct a beam of green light through mirror  65  and an optical system  68  to illuminate a corresponding pixel on the target tissue. Scanning mirror  67  may be controlled using horizontal and vertical trajectories crossing over all pixels, with green source  63  only being activated when crossing the appropriate pixels. 
     One preferred method of the invention will be described in connection with the flowchart of  FIG. 10 . In step  70 , a position calibration is performed in order to align the projection source with the detection module. In one embodiment of the calibration, a pixel of green laser light from the projection source is scanned over a target area while monitoring the position of the resulting image of the green-illuminated pixel in the CCDs of the detector module. A calibration map is generated by the controller that correlates the coordinate spaces of the projector and the detector in order to accurately associate the corresponding pixels. In step  71 , the target area is illuminated with the blue excitation light. In step  72 , a determination is made as to which pixel should be scanned next. In response to the excitation light, tissue containing the marker substance generates a fluorescent emission. Relative energy at the fluorescent wavelength and adjacent wavelengths for the scanned pixel are determined in step  73 . A determination is made in step  74  whether the relative energy levels indicate cancerous tissue. If not, then a return is made to step  71  to illuminate the target area with excitation light and to determine a next pixel to scan. If cancerous tissue is detected, than the corresponding pixel is illuminated with projection light in step  75  (e.g., either a green marker light or illumination by a treating laser). Thus, the green laser may be used to draw a pattern on the tissue corresponding to the areas where red fluorescent emission indicates diseased tissue. 
     An alternative embodiment is shown in  FIG. 11  wherein a PDD system  80  has all the various modules integrated into one unit. Thus, a beam splitter/combiner  81  receives laser light from a blue laser  82 , a red laser  83 , and a green laser  84  and directs it through a pinhole shade  85  or other optical system, and a half mirror  86  to a MEMS scanner  87 . A scannable mirror  88  in MEMS scanner  87  directs the various laser lights through an aperture  90  (which may or may not contain further optics) to a target  91 . A red laser used for photo dynamic therapy (PDT) may preferably correspond to the fluorescent frequency of the marker substance (e.g., 640 nM), but other frequencies may also be used. Beam splitter/combiner  81  may be comprised of a dichroic splitter, as appropriate. 
     Light from target  91  (including any fluorescent emission) passes through half mirror  86  to mirror  88  in MEMS scanner  87 . Light for a presently scanned pixel reflects from mirror  88  to mirror  86  and through pinhole shade  85  into beam splitter/combiner  81 . Some of the light is directed to photodetectors  92  and  93  through filters  94  and  95 , respectively. One of filters  94  and  95  is centered on the fluorescent emission wavelength while the other is at an adjacent bandwidth. Using the device of  FIG. 11 , excitation, detection, projection marking, and treatment are performed on a pixel by pixel basis at a scanning rate sufficient to provide even illumination to the naked eye. Detection of a peak is performed by comparing energy at the bandwidth containing the fluorescent emission wavelength with energy at an adjacent bandwidth, preferably a passband which is below the bandwidth containing the fluorescent emission wavelength. In detecting peaks that correspond to diseased tissue, a predetermined threshold of about 1.3 for the ratio of energy in passband B 2  to the energy in passband B 1  can be used. Alternatively, the incoming light could be further split into another beam in order to compare passbands both below and above the fluorescent wavelength passband. 
       FIG. 12  shows a preferred method utilized by the system of  FIG. 11 . A scan is started in Step  100  (i.e., beginning at a first pixel). With the MEMS scanner set on a current pixel, the blue laser is turned on in Step  101  in order to provide excitation. The return energies in the bandpass windows are measured in Step  102 , and a check is made to determine whether a peak is found for the current pixel in Step  103 . If a peak is found then the green laser light is turned on in Step  104  for a predetermined time of t 1  seconds. If a peak is not found then Step  104  is skipped. 
     In Step  105 , position data is stored in a memory of the controller. Specifically, for each pixel in a scanning area, the stored position data indicates whether a peak was detected. In Step  106 , the scanning MEMS mirror is moved to the next position corresponding to the subsequent pixel. A check is made in Step  107  to determine whether a scan of the full image area has been completed. If not, then a return is made to Step  101  to continue with excitation by the blue laser. If the scan is completed, then a full projection scan of the green laser is performed in step  108  using the latest position data stored in memory. The projection scan may be continued for a time of t 2  seconds, wherein t 2  is greater than t 1 . Thus, a first detection scan is performed while detecting the location of diseased tissue, wherein the detection scan also provides an initial illumination using the green laser of the diseased tissue. Once the full area has been detection scanned, the green laser alone may be scanned in order to ensure a bright image to be seen without interruption by the detection process. Due to the possibility of movement of the tissue or movement of the diagnostic system, periodic re-detection is desirable after the delay of t 2  seconds, wherein t 2  is chosen based on the fastest potential rate of movement that would give rise to the need to perform a re-scan. The value of t 2  may be about 250 ms, for example. 
     Optionally, a step  109  may be performed wherein white light illumination is generated (either by a separate source or by action of the colored sources together) for t 3  seconds to allow natural visualization of the area by the surgeon. Preferably, the while light illuminates the entire field of view of the device rather than just the diseased tissues.