Abstract:
Endoscopic device incorporating diode lasers for use in PDD, PDT and AF applications. Devices according to the invention do not require an external light source, bulb lamp, or light delivery cables. Multiple laser diodes and multiple wavelengths can be employed in continuous or pulsed applications for simultaneous multi-mode diagnostic readout or simultaneous diagnostic readout and treatment.

Description:
FIELD OF THE INVENTION 
       [0001]    The invention relates to devices for photodynamic diagnosis or treatment generally, and specifically to systems and devices incorporating diode lasers for use in PDD, PDT and AF applications. 
       BACKGROUND OF THE INVENTION 
       [0002]    Auto-fluorescence (AF) is the natural emission of light by biological structures such as mitochondria and lysozomes when they have absorbed light. In some medical applications, AF can be used to illuminate structures of interest, or as a diagnostic indicator. For example, cellular AF can be used as an indicator of cytotoxicity. 
         [0003]    Photodynamic Diagnosis (PDD) is another medical application of fluorescence. In PDD, malignant tissue can be differentiated from benign tissue by administering a suitable fluorescence marker. Typically the marker is selected such that it is preferentially absorbed by tumors. Under appropriate diagnostic lighting, the marker can be made to fluoresce, helping to define the borders of the tumor for identification and diagnosis or for removal by a surgeon, for example. In some applications, diagnostic light of varying wavelengths can be used to differentiate tissue without administering a drug. 
         [0004]    Photodynamic Therapy (PDT) is conducted similarly to PDD, except that the drug which is administered and preferentially absorbed by malignant tissue is used in subsequent destruction of that tissue. Typically, PDT applications involve the use of a photosensitizer, a light source, and tissue oxygen. The wavelength of the light source is tuned to excite the photosensitizer in order to produce reactive oxygen species. The combination of these elements leads to the destruction of any tissues which have selectively taken up the photosensitizer and are locally exposed to light from the light source. 
         [0005]    Prior art systems for these applications are known. One example is the Karl Storz D-Light C PDD System. This system incorporates an endoscope, such as a cystoscope used in bladder and urethra examinations. Diagnostic light is supplied to the endoscope from a separate and remote external light source using a light guide, which may be a quartz light guide or a fluid light cable, for instance. The closed end of the light cable is inserted into a socket on the light source. The open end of the light cable is connected to a light post that is a part of the endoscope. 
         [0006]    As is typical for known systems, the light source incorporates a lamp to generate the diagnostic light. In this case, a 300 W Cermax® Lamp is used. The light source is sizeable, measuring 300 mm×164 mm×320 mm, and weighting approximately 11 kg. The lamp is a xenon arc lamp generating incoherent light, which must be replaced after an operating time of 400 hours. The light source is typically housed in a tower, which is a rack mounting system. 
         [0007]    Another known system is disclosed in U.S. Pat. No. 6,640,131 to Irion et al., assigned to Karl Storz GmbH &amp; Co., the content of which is incorporated herein in its entirety. 
         [0008]    Such discrete component systems are complicated, delicate, cumbersome, and require frequent maintenance of the light source. 
         [0009]    Other known approaches to PDT, PDD or AF endoscopy have incorporated light emitting diodes. However, these applications have used diodes at the distal end of the endoscope. Furthermore, these systems have supported limited additional functionality. 
         [0010]    U.S. Pat. No. 7,351,242 to Neuberger et al. discloses an endoscope for PDT having low wattage diodes at the distal end. However, Neuberger et al. does not teach the use of a diode laser incorporated into the proximal end for PDT/PDD applications, does not teach synchronous video and diode pulsing for simultaneous readout of multiple diagnostic modes or treatment, and teaches away from the use of a non-distally located light source. 
         [0011]    U.S. Pat. No. 5,468,238 to Mersch discloses an endoscope having a diode laser at the distal end for cutting or coagulating tissue. However, Mersch does not teach the use of a diode laser incorporated into the proximal end for PDT/PDD applications, does not teach synchronous video and diode pulsing for simultaneous readout of multiple diagnostic modes or treatment, and teaches away from the use of a non-distally located light source. 
         [0012]    US Patent Publication No. 2008/0114419 to Crowley discloses a miniature light device at the distal end of an interventional device, including distally located laser diodes used for PDT. However, Crowley does not teach the use of a diode laser incorporated into the proximal end for PDT/PDD applications, does not teach synchronous video and diode pulsing for simultaneous readout of multiple diagnostic modes or treatment, and teaches away from the use of a non-distally located light source. 
         [0013]    Other known approaches to endoscopic illumination have incorporated light emitting diodes at the proximal end of the endoscope. However, these applications have not been designed for use in PDT, PDD or AF applications, and systems have supported limited additional functionality. 
         [0014]    U.S. Pat. No. 6,730,019 to Irion, assigned to Karl Storz GmbH &amp; Co., discloses an endoscope for multi-color illumination having multiple light emitting diodes at the proximal end, emitting visible light of different colors which is additively mixed to provide faithful full color imaging. The diodes are used for color modulation. However, Irion does not teach the use of non-visible wavelength diodes, PDT applications, or synchronous video and diode pulsing for simultaneous readout of multiple diagnostic modes of treatment. 
         [0015]    US Patent Publication No. 2011/0245603 to Brannon discloses a detachable external visible laser source which can be attached to the proximal end of an endoscope for use as a sighting device for aiming the endoscope. However, Brannon not teach the use of multiple different wavelength laser diodes, non-visible wavelength diodes, PDT, PDD or AF applications, video recording, or synchronous video and diode pulsing for simultaneous readout of multiple diagnostic modes or treatments. 
         [0016]    It is therefore desired to provide a device which addresses these deficiencies. 
       SUMMARY OF THE INVENTION 
       [0017]    Accordingly, it is an object of the present invention to provide a PDD, PDT, and/or AF system which improves the simplicity, ergonomics, and efficiency of the prior systems. 
         [0018]    It is a further object of the present invention to provide a PDD, PDT, and/or AF system which replaces the light source and delivery cable with laser diodes incorporated into the endoscope. 
         [0019]    It is a further object of the present invention to provide a PDD, PDT, and/or AF system incorporating various types of lasers. 
         [0020]    It is a further object of the present invention to provide a PDD, PDT, and/or AF system incorporating a laser diode. 
         [0021]    It is a further object of the present invention to provide a PDD, PDT, and/or AF system adapted for both continuous and pulsed operations. 
         [0022]    It is a further object of the present invention to provide a PDD, PDT, and/or AF system incorporating synchronous video/diode pulsing for simultaneous readout of multiple modes. 
         [0023]    It is a further object of the present invention to provide a PDD, PDT and/or AF system incorporating synchronous video/diode pulsing for simultaneous non-visible wavelength treatment or fluorescence diagnosis and visible wavelength diagnostic readout. 
         [0024]    It is a further object of the present invention to provide a PDD, PDT, and/or AF system incorporating a combination of blue and white diodes in the same system. 
         [0025]    It is a further object of the present invention to provide a PDD, PDT, and/or AF system incorporating a dual- or multiple-wavelength diode. 
         [0026]    These and other objects of the invention are achieved by providing an endoscopy system for photodynamic applications including an endoscope having a distal end and a proximal end; a light source configured to emit light at a wavelength suitable for a photodynamic application and disposed closer to the proximal end than to the distal end; and, a light guide configured to transmit light from the light source to the distal end for illuminating tissue. 
         [0027]    In some implementations, the light source is integral with the endoscope. Optionally, the light source may be incorporated into a unit attached to the endoscope. The light source may include a laser diode, and/or a light emitting diode. 
         [0028]    In some implementations, the system includes focus optics disposed at the distal end. Optionally, the system includes a collimator disposed closer to the proximal end than to the distal end. 
         [0029]    In some implementations, the system includes an imager disposed at the distal end. 
         [0030]    In some implementations, the system includes a solid state image sensor disposed at the distal end. 
         [0031]    In some implementations, the light source includes a dual-wavelength or multi-wavelength diode. 
         [0032]    In some implementations, the light source includes at least two diodes or at least two p-n junctions. Optionally, the light source includes a first diode and a second diode; wherein the first diode is configured to emit light having a first wavelength and the second diode is configured to emit light having a second wavelength different from the first wavelength. 
         [0033]    Optionally, the light source is configured to emit light having both predominantly blue and predominantly white wavelengths. Optionally, the light source is configured to emit both visible and non-visible wavelengths. Optionally, the light source includes a plurality of diodes, each configured to emit light having a different predominant wavelength. Optionally, the light source is configured to emit light at a wavelength suitable for diagnostic observation of tissue. Optionally the light source is configured to emit light at a wavelength suitable for Photodynamic Diagnosis. Optionally, the light source is configured to emit light at a wavelength which when absorbed by a biological structure will cause the biological structure to auto-fluoresce. Optionally, the light source is configured to emit light at a wavelength suitable for producing therapeutic effects in tissue. Optionally, the light emitting diode is configured to emit light at a wavelength suitable for Photodynamic Treatment. 
         [0034]    In some implementations, the light source is configured to emit light at a wavelength which activates a drug. Optionally, the light source is configured to emit light at a wavelength which causes a drug illuminated by the light to produce reactive oxygen species. Optionally, the light source is configured to emit light at a wavelength which causes a drug illuminated by the light to produce free radicals. Optionally, the light source is configured to emit light at a wavelength which causes a drug illuminated by the light to produce singlet oxygen. Optionally, the light source is configured to emit light at a wavelength which causes a drug illuminated by the light to produce reactive oxygen species, wherein the drug is selected from the group consisting of hexaminolevulinate, porfimer sodium, aminolevulinic acid, methyl ester of aminolevulinic acid, Allumera™, Photofrin™, Visudyne™, Foscan™, Metvix™, Hexvix™, and Laserphyrin™, Antrin™, Photochlor™, Photosens™, Photrex™, Lumacan™, Cevira™, Visonac™, BF-200 aminolevulinic acid, Amphinex™ and azadipyrromethene. 
         [0035]    In some implementations, the light source is configured to emit light pulses. Optionally, the light source is configured to emit light pulses which are synchronized with an imager. Optionally, the light source is configured to emit light pulses which are synchronized with image capturing by an imager. Optionally, the light source is configured to emit light pulses wherein at least one of the pulses has a wavelength that is different from at least one other of the pulses. Optionally, the light source is configured to emit light pulses wherein at least one of the pulses has a wavelength in the visible wavelength spectrum and at least one of the pulses has a wavelength that is not in the visible spectrum. Optionally, the light source is configured to emit light pulses wherein at least one of the pulses includes predominantly blue light, and wherein at least one of the pulses includes predominantly white light. Optionally, the light source is configured to emit light pulses which alternate among at least two different wavelengths. Optionally, the light source is configured to emit light pulses which alternate among diagnostic and therapeutic wavelengths. 
         [0036]    In some implementations, the light source is configured to emit light pulses which alternate among at least two different wavelengths, and the pulses are synchronized with an imager such that a first image is produced under illumination under one of the wavelengths; and, a second image is produced under illumination under a different one of the wavelengths. Optionally, an image is not generated under pulses of light having photodynamic wavelengths. 
         [0037]    In some implementations, the system includes an imager configured to produce a first image under illumination by light having a first wavelength and a second image under illumination by light having a second wavelength. 
         [0038]    In some implementations, the system includes an imager configured to produce a first image under illumination by light having a first wavelength and configured not to produce an image under illumination by light having a second wavelength. Optionally, an image is only generated under pulses of light having a wavelength primarily suitable for diagnosis and not primarily suitable for therapy. 
         [0039]    Other objects of the invention are achieved by providing an endoscopy system for photodynamic diagnosis including an endoscope having a distal end and a proximal end; a light source configured to emit light at a wavelength suitable for photodynamic diagnosis and disposed closer to the proximal end than to the distal end; and, a light guide configured to transmit light from the light source to the distal end for illuminating tissue. 
         [0040]    In some implementations, the light source is integral with the endoscope. Optionally, the light source is incorporated into a unit attached to the endoscope. Optionally, the light source includes a laser diode or an LED. 
         [0041]    Further objects of the invention are achieved by providing an endoscopy system for photodynamic treatment including an endoscope having a distal end and a proximal end; a light source configured to emit light at a wavelength suitable for photodynamic treatment and disposed closer to the proximal end than to the distal end; and, a light guide configured to transmit light from the light source to the distal end for illuminating tissue. 
         [0042]    In some implementations, the light source is integral with the endoscope. Optionally, the light source is incorporated into a unit attached to the endoscope. Optionally, the light source includes a laser diode or an LED. 
         [0043]    Other objects of the invention are achieved by providing a method for endoscopic photodynamic diagnosis including providing an endoscope having a distal end and a proximal end; a light source configured to emit light at a wavelength suitable for photodynamic diagnosis disposed closer to the proximal end than to the distal end; and, a light guide configured to transmit light from the light source to the distal end for illuminating tissue. 
         [0044]    In some implementations the method includes applying a photodynamic diagnosis drug to a tissue; illuminating the tissue using the light source via the light guide; and, detecting an image of the illuminated tissue using an imaging device. 
         [0045]    In some implementations, the light source is integral with the endoscope. Optionally, the light source is incorporated into a unit attached to the endoscope. Optionally, the light source includes a laser diode or an LED. 
         [0046]    Other objects of the invention and its particular features and advantages will become more apparent from consideration of the following drawings and accompanying detailed description. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0047]      FIG. 1  is a schematic diagram of an example endoscopy system according to aspects of the invention. 
           [0048]      FIG. 2  is a 3D view illustrating the example endoscopy system as shown in  FIG. 1 , including additional features. 
           [0049]      FIG. 3  is a 3D view illustrating the example endoscopy system as shown in  FIG. 1 , including other additional features. 
           [0050]      FIG. 4  is a flow chart illustrating an example photodynamic diagnosis method using the system of  FIG. 1 , according to aspects of the invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0051]      FIG. 1  is a schematic diagram of an example endoscopy system having a light source according to aspects of the invention. 
         [0052]    The system includes an endoscope  100  having a distal end  105  and a proximal end  110 . A light source  115  is integral with endoscope  100 . In some implementations, light source  115  is a solid state light source, such as a laser diode. Optionally, light source  115  may be detachable or replaceable. A light guide  120 , which may consist of a bundle of optical fibers, for example, passes light from light source  115  to distal end  105  of endoscope  100 . The light emerges from the distal end  105  and can be used to illuminate a tissue region. 
         [0053]    Light reflected or radiating from the illuminated tissue may be detected by a camera  145  or a distal solid state imaging device  155 , depending on the desired implementation. 
         [0054]    In implementations where a camera  145  is located proximally to distal end  105 , an image relaying section  135  may relay light that is reflected or radiated from observed tissues from distal end  105  to the camera  145  or solid state imaging device  155 . In these implementations, image relaying section  135  may include optical fibers, rod-shaped lenses, or other suitable light communication structures. 
         [0055]    In implementations where a solid state imaging device  155  is located at or near the distal end  105 , image relaying section  135  may relay image data from solid state imaging device  155  to proximal end  110 . In these implementations, image relaying section may include a wire or any other suitable medium for communication of data from solid state imaging device  155  to proximal end  110 . 
         [0056]    An image of the tissue region may optionally be viewed with the eye through an ocular  140 . Camera  145  may receive the image via ocular  140 , however, camera  145  may also be configured to receive the image without the use of an ocular. 
         [0057]    Camera  145  or solid state imaging device  155  may communicate the image to a recording device, monitor, and/or analysis system (not shown). 
         [0058]    Endoscope  100  may be of any type or configuration, including flexible/video endoscopes and rigid endoscopes. Example endoscope configurations are discussed herein with respect to  FIGS. 2 and 3 , although other applications of the present invention will be evident to those having skill in the art. 
         [0059]    Light guide  120  may include any suitable structure for communicating light from proximal end  110  to distal end  105 , such as optical fibers, rod lenses, or the like. 
         [0060]    Optional ocular  140  may include an objective lens for viewing an image produced by endoscope  100 , and may be configured to attach optional camera  145  to endoscope  100 . In some implementations where light source  115  is integral with camera  145 , ocular  140  may include structures (not shown) for communicating light from light source  115  to light guide  120 . In some configurations, optional camera  145  may be attached to endoscope  100  without the use of ocular  140 . 
         [0061]    Optional camera  145  may be any suitable image sensing or recording device, and is typically a digital type camera configured to be attached to an endoscope by attachment to an ocular. It will be clear however to those having skill in the art that other types of cameras may be used with endoscope  100 , with or without ocular  140 . For example, in applications involving flexible video endoscopes, camera  145  may be integral with endoscope  100 . 
         [0062]    Optional solid state imaging device  155  may be any suitable solid state imaging sensor known in the art. For example, solid state imaging device  155  may include a charge coupled device (CCD) or CMOS active pixel sensor. Solid state imaging device  155  may be integral with endoscope  100 , and may be disposed at or toward distal end  105 . Optionally, imaging device  155  may be disposed at or toward the proximal end. An image and/or image data may be communicated from the distal end  105  to the proximal end  110  via a suitable communications medium. For example, in implementations where imaging device  155  is distally disposed, image data from the imaging device may be communicated to the proximal end  110  via a wire (not shown). In implementations where imaging device  155  is proximally disposed, light emitted or reflected by the illuminated tissue region may be communicated to imaging device  155  from the distal end using a light guide or rod lens array, for example (not shown). Various implementations may also incorporate focus optics or other optical components, for example. 
         [0063]    Light source  115  may be powered internally or externally and may have at least one solid state light emitting device, such as a laser diode. Light source  115  may operate on a wavelength that is useful for PPD and/or PDT applications, depending upon the desired application. Such wavelengths may be selected based on their resonance with or activation of various substances, for example, tissues, drugs, or other molecules. Examples of drugs used in PDD and PDT applications include Hexaminolevulinate (Cysview®), Porfimer sodium (Photofrin®), Aminolevulinic acid (ALA or Levulan®), Methyl ester of ALA (Metvixia® cream), and other known drugs including Allumera™, Photofrin™, Visudyne™, Foscan™, Metvix™, Hexvix™, and Laserphyrin™, Antrin™, Photochlor™, Photosens™, Photrex™, Lumacan™, Cevira™, Visonac™, BF-200 ALA, Amphinex™ and Azadipyrromethenes. 
         [0064]    The light source  115  may be capable of emitting light at multiple wavelengths. In some implementations, each wavelength may be emitted in a different mode of operation. Light source  115  may also be capable of emitting wavelengths in visible and/or non-visible spectra. Optionally, light source  115  includes multiple solid state light sources, e.g. laser diodes. Optionally, each diode can emit light at a different wavelength. 
         [0065]    The use of solid state light emitting devices such as laser diodes can have the advantage of simplifying the system, resulting in improved ergonomics and efficiency by reducing the size and bulk over existing systems, reducing costs, simplifying cabling, enabling more efficient energy delivery, reducing fragility of the system, and addressing problems relating to short lamp life. 
         [0066]    Optionally, light source  115  and device  100  are configured for continuous and/or pulsed operation. Optionally, light source  115 , and solid state imaging device  155 , camera  145 , or a monitor, recording, or analysis system (not shown), can be synchronized such that images, each produced under a different wavelength, can be displayed and/or recorded by pulsing light source  115  at different wavelengths. Different wavelengths may be pulsed alternately and synchronously with video capture in order to allow simultaneous readout of multiple modes. For example, separate displays or display windows may show images under white light and blue diagnostic light, or under white light and another wavelength which causes fluorescence, for example. This can have the advantage of enabling simultaneous diagnostic observation of tissue under both non-fluorescing and fluorescing conditions, for example. This can also have the advantage of enabling diagnostic observation of tissue under visible non-fluorescing or fluorescing conditions, simultaneously with the application of non-visible wavelengths for PDT, coagulation, cautery, or cutting of tissue. This can have the further advantage of increasing the differentiability between healthy and malignant tissue by highlighting features that are optimally visible under different diagnostic wavelengths without confusion or interference caused by viewing the images additively. 
         [0067]      FIG. 2  illustrates an example endoscopy system incorporating a solid state light source according to aspects of the invention. 
         [0068]    The system includes an endoscope  200  having a distal end  205  and a proximal end  210 . Light source  215  is integral with, and incorporated into device  200 . Optionally, light source  215  is detachable or replaceable. A light guide  220  in the endoscope, which may consist of a fiber bundle, for example, passes light from light source  215  to the distal end  205  of device  200 . The light emerges from the distal end  205  and illuminates a tissue region  225  to be examined. 
         [0069]    Light arriving from the illuminated tissue region  225  is received by solid state imaging device  230 . A signal representing the image detected by device  230  is transmitted by an image relaying section  235  to the proximal end  210 . Image relaying section  235  may be a wire or any other suitable medium for communication of data from solid state imaging device  230  to proximal end  210 . Solid state imaging device  230  may include any suitable solid state image sensor, such as a charge coupled device (CCD) or CMOS active pixel sensor. 
         [0070]    An image of tissue region  225  may be detected using solid state imaging device  230 . Solid state imaging device  230  may communicate the image to a recording device, monitor, and/or analysis system via an output  240 . 
         [0071]    Light source  215  may be similar to light source  115 , as described with respect to  FIG. 1 , and may be useable for PDD and/or PDT applications depending upon the desired implementation. 
         [0072]      FIG. 3  illustrates an example endoscopy system incorporating a solid state light source according to aspects of the invention. 
         [0073]    The system includes an endoscope  300  having a distal end  305  and a proximal end  310 . Light source  315  is integral with device  300 . In other optional implementations, light source  315  may be detachable or replaceable. For example, optional light source  315 ′ is shown incorporated into an external attached camera  350 . In this example, camera  350  is attached to device  300  via an ocular  340 , although those having skill in the art will understand that a camera or other imager may be used without an ocular, without departing from the invention. A light guide  320  in the endoscope, which may consist of a fiber bundle, for example, passes light from light source  315  to the distal end  305  of device  300 . The light emerges from the distal end  305  and illuminates a tissue region  325 . 
         [0074]    Light emitted or reflected by the illuminated tissue region  325  enters a lens  330  of device  300 . The image produced by lens  330  is guided by an image relaying section  335  to the proximal end  310 . Optionally, the image may be detected by a solid state imaging sensor (not shown) proximal to, or in place of lens  330 . 
         [0075]    The image of tissue region  325  may be viewed with the eye through ocular  340 , may be detected by camera  350  or a solid state imaging device (not shown), and/or may be communicated to a recording device, monitor, and/or analysis system (not shown). 
         [0076]    Light source  315  may be similar to light source  115 , as described with respect to  FIG. 1 , and may be useable for PDD and/or PDT applications depending upon the desired implementation. 
         [0077]    Image relaying section  335  may include relay lenses including rod-shaped lenses or may include optical fibers. Image relaying section  335  may also incorporate various combinations of optics for collimation and focus of light. 
         [0078]      FIG. 4  is a flow chart illustrating an example photodynamic diagnosis method  400  using the system of  FIG. 1 , according to aspects of the invention. 
         [0079]    In step  410 , an endoscope is provided having a solid state light source that is configured to emit light at a wavelength suitable for photodynamic diagnosis, and which is disposed closer to a proximal end than to a distal end of the endoscope, and a light guide configured to transmit light from the light source to the distal end for illuminating a tissue region. 
         [0080]    In step  420 , a photo diagnosis drug is applied to a tissue region to be observed. 
         [0081]    In step  430 , the tissue region to be observed is illuminated using the solid state light source. 
         [0082]    In step  440 , an image of the illuminated tissue is detected using an imaging device such as those described with respect to other figures herein, such as a solid state imaging chip or a camera. 
         [0083]    Although the invention has been described with reference to a particular arrangement of parts, features and the like, these are not intended to exhaust all possible arrangements or features, and indeed many modifications and variations will be ascertainable to those of skill in the art.