Abstract:
An instrument for photodynamic therapy applies treatment light from a dye laser, white light, and ultraviolet fluorescence excitation light from an LED onto a lesion and surrounding areas in a time-multiplexed manner. The reflected white light is analyzed in a spectrometer to determine a correction for the dynamic optical spectral properties of the patient&#39;s tissue. Light emitted by fluorescence from the lesion and the surrounding areas is analyzed in another spectrometer, and the results are corrected in a computer, using the correction. An optical switch has been developed for the instrument, using a bistable solenoid and a sled.

Description:
REFERENCE TO RELATED APPLICATION 
       [0001]    The present application claims the benefit of U.S. Provisional Patent Application No. 60/583,786, filed Jun. 30, 2004, whose disclosure is hereby incorporated by reference in its entirety into the present disclosure. 
     
    
     STATEMENT OF GOVERNMENT INTEREST 
       [0002]    The research leading to the present invention was supported by the Roswell Park Cancer Institute/NIH under Grant No. P01 CA55719. The government has certain rights in the invention. 
     
    
     FIELD OF THE INVENTION 
       [0003]    The present invention is directed to photodynamic therapy (PDT) and more particularly to a method and apparatus for accurate, real-time determination of a therapeutic dose delivered by photodynamic therapy. 
       DESCRIPTION OF RELATED ART 
       [0004]    The accurate, real-time determination of therapeutic dose delivered by photodynamic therapy (PDT) is an area of active research and clinical importance. Photosensitizer evolution, including photobleaching and photoproduct formation, and accumulation of endogenous porphyrins provide attractive implicit dose metrics, as these processes are mediated by similar photochemistry as dose deposition and report cellular damage, respectively. Reflectance spectroscopy can similarly report blood volume and hemoglobin oxygen saturation. 
         [0005]    However, the accuracy of known techniques is still not sufficient. In particular, living human tissue has dynamic optical properties which may reduce the accuracy. 
       SUMMARY OF THE INVENTION 
       [0006]    It is an object of the invention to provide real-time in vivo determination of photodynamic therapy dose metrics and tissue optical properties. 
         [0007]    It is another object to correct for the dynamic optical properties of tissue. 
         [0008]    To achieve the above and other objects, the present invention is directed to an apparatus for real-time determination of photodynamic therapy dosimetry in vivo, employing measurements of fluorescence emission spectra corrected for the effects of dynamic tissue optical properties using white light diffuse reflectance. This system accurately measures photosensitizer photobleaching, photoproduct formation, and tissue oxygenation, all of which are useful as dose metrics. 
         [0009]    Compact instrumentation is developed that controls delivery and monitoring of PDT dose. In at least one embodiment, the instrumentation provides 405 nm fluorescence excitation light to two spatially-resolved points on the skin, delivered through fiber-pigtailed LEDs terminated with GRIN microlenses. One point is located inside the PDT target lesion and the other in the perilesion margin. The fluorescence spectra generated from sensitizer, photoproducts, autofluorescence, and various endogenous porphyrins are measured from both points, concurrently with excitation. Emission spectra from these points are corrected for the effects of tissue optical properties with division by white light reflectance spectra delivered through the treatment fiber. Spectral fitting reports fluorophore concentrations and blood oxygenation. This instrumentation employs multimode fiber switches and time multiplexing to deliver the treatment beam at 635 nm, fluorescence excitation beam at 405 nm, and white light interrogation beam while monitoring the aforementioned dose metrics with a pair of thermoelectrically cooled spectrometers. 
         [0010]    The present invention can provide real-time determination of photodynamic therapy dosimetry in vivo during PDT treatment. The fluorescence spectra and white light reflectance are measured from each point during brief interruption of the treatment beam. Emission spectra are corrected for the effects of tissue optical properties with division by white light reflectance spectra, and spectral fitting is used to accurately characterize photosensitizer photobleaching, photoproduct formation, blood volume, and tissue oxygenation, all of which are useful as dose metrics. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS  
         [0011]    Preferred embodiments of the invention will be set forth in detail with reference to the drawings, in which: 
           [0012]      FIG. 1  is a schematic diagram showing an instrument according to a first preferred embodiment of the invention; 
           [0013]      FIG. 2  is a timing chart showing a timing of operation of the instrument of  FIG. 1 ; 
           [0014]      FIG. 3  is a schematic diagram showing an instrument according to a second preferred embodiment of the invention; 
           [0015]      FIGS. 4A and 4B  show a 1×2 fiber optic switch usable in the embodiment of  FIG. 1  or that of  FIG. 3 ; 
           [0016]      FIGS. 5A-5C  show variations of the fiber terminations in the switch of  FIGS. 4A and 4B ; 
           [0017]      FIG. 6  shows a 2×2 fiber optic switch based on the fiber optic switch of  FIGS. 4A and 4B ; 
           [0018]      FIGS. 7A and 7B  show a variation of the switch of  FIGS. 4A and 4B  with a filter which can be moved into or out of the light beam; 
           [0019]      FIGS. 8A and 8B  show a further modification of the switch of  FIGS. 4A and 4B ; 
           [0020]      FIG. 9  is a perspective view showing a bulkhead used in the switch of  FIGS. 8A and 8B ; 
           [0021]      FIG. 10  shows an instrument according to a third preferred embodiment of the present invention; and 
           [0022]      FIG. 11  shows an alternative fiber coupler usable with the embodiment of  FIG. 10 . 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0023]    Preferred embodiments of the present invention will be set forth in detail with reference to the drawings, in which like reference numerals refer to like elements or operational steps throughout. 
         [0024]    An instrument according to a first preferred embodiment of the present invention is shown in  FIG. 1  as  100 . As shown, the instrument includes a treatment laser (such as a dye laser)  102 , a white light source (such as a tungsten halogen or xenon lamp)  104 , fiber optic switches  106 ,  108 , a shutter  110 , two thermoelectrically cooled spectrometers  112 ,  114 , an optical probe  116 , an optical filter  118 , circuitry  120 , housings (not shown), and a computer  122 . The computer  122  and the spectrometers  112 ,  114  communicate through a USB cable connection  124 . Each of the spectrometers  112 ,  114  has reserved auxiliary (AUX) pins on its on-board circuitry. The AUX pins are connected to the LEDs  126 , shutter  110 , and fiber optic switches  106 ,  108  via external circuitry  120 . Transistor-transistor logic (TTL) pulses transmit from the AUX pins to the circuitry  120 . 
         [0025]    In a delivery arm of the instrument  100 , the white light source  104  and treatment laser  102  are coupled via fibers  128  into the 2×1 fiber optic switch  106 . The output of this switch  106  is coupled via a fiber  130  to part of the optical probe  116  and is terminated with a microlens  132 . 
         [0026]    In the detection arm, two more optical fibers  134  terminated with microlenses  136  are in the probe. Each of the two fibers  134  is directed to a housing (not shown) with a dichroic optical filter  138 . The reflection path of the filter housing contains an LED  126 , and the transmission path contains a secondary optical fiber  140 . The secondary optical fibers  140  are connected to the 2×2 optical switch  108 . One of the two outputs of the 2×2 switch  108  is directed to the first spectrometer  112 , and the second output is directed to the optical filter  118  and then to the second spectrometer  114 . 
         [0027]    The treatment area A includes two regions, a target lesion region L and a perilesion margin region M. 
         [0028]    The computer  122  determines which of two states the first fiber optic switch  106  is in and the state of the white light shutter  110 . Depending on the states of the switch  106  and shutter  110 , the light is blocked, white light is transmitted through the treatment fiber  130 , or laser light from the treatment laser  102  is transmitted though the treatment fiber  130 . Light transmitted through the treatment fiber  130  is directed onto the treatment area A, comprising both the lesion region L and the perilesion region M. The treatment areas may have different optical, chemical or physiological properties. 
         [0029]    Light emitted or reflected from the area A is collected by the two optical fibers  134  terminated with microlenses  136 . One of the optical fibers  134  collects primarily from the target lesion region L, and the other fiber  134  collects primarily from the perilesion margin region M. Light may also be generated by the LEDs  126  in the detection arm. Light generated by the LEDs  126  will be reflected off the dichroic mirror  138  and transmitted through the optical fibers  134  and directed through the microlenses  136  onto the corresponding treatment regions L, M. Light omitted or reflected from these regions will be collected by the fibers  134  and directed onto the dichroic mirror  138 . Light that is at a different wavelength from the LED sources  126  will be transmitted through the filter  138 . Light transmitted through the secondary fibers  140  is directed into the 2×2 optical switch  108 . Depending on the state of the 2×2 optical switch  108 , light from either of the two secondary detection fibers  140  can be directed either through another optical filter  118  followed by a spectrometer  114  or directly into a spectrometer  112 . 
         [0030]    Up to three measurements can be made for each of two spatially resolved locations during photodynamic therapy. The laser source is used as a treatment beam. Light from this source is directed into the treatment area and activates photoactive drugs within that area. 
         [0031]    Treatment beam excited fluorescence can be measured. Some of the absorbed laser light may be emitted as fluorescence. By directing collected light through the filtered path of the system before the spectrometer, the fluorescent signal can be evaluated without the spectrometer being optically saturated by the treatment laser. Therefore, with the first switch transmitting the laser and the second switch directing light collected from the treatment area region of interest, spatially resolved fluorescence from that region can be measured. 
         [0032]    In measuring 405 nm excited fluorescence, the fluorescent signals of interest are highly excited by light emitted by the LED sources. By using the first fiber switch and shutter to stop the laser and white sources and using pulses to turn on the LED source, the 405 nm light can be directed onto either treatment region of interest, and excited fluorescence can be collected through that same path and directed by the 2×2 fiber switch directly to the non-filtered spectrometer path. Therefore, a spatially resolved measurement of fluorescence can be made. 
         [0033]    The reflected spectrum of a white light source provides information about tissue optical properties, blood volume, and blood oxygenation. White light can be directed through the first optical switch on the treatment area, and the reflected signal can be collected by the detection arm. Either of the two fibers in the detection path can be directed into the non-filtered spectrometer, and the spatially resolved white light reflectance can be measured. The computer  122  receives detection signals for all types of reflected light and uses the reflected white light to correct the detection signals for the dynamic optical properties of the tissue, particularly the spectral reflectivity. 
         [0034]    During the measurements listed, data are transmitted from the spectrometers into the computer, where characteristics about the treatment regions are stored and analyzed. Analysis of the data from these measurements can be fed back into the system to control the timing of the measurements and the treatment. 
         [0035]    An example of timing is shown in  FIG. 2 . The timing of the light source alternates among the laser, the white light source, and the LED (an ultraviolet source). The corresponding time periods for measurement are fluorescence from the laser, reflectance from the white light, and fluorescence from the LED. With those measurements, it is possible to correct for dynamic tissue optical characteristics. 
         [0036]    A second preferred embodiment, using an optical probe, will now be described. An instrument according to the second preferred embodiment is shown in  FIG. 3  as  300 . Except as noted below, the instrument  300  can be constructed and used like the instrument  100 . 
         [0037]    The optical probe  302  is capable of two-point spatial resolution. A single or plurality of optical fibers  304  can be used in concert with either a single or plurality of MEMS (micro-electro-mechanical systems) scanning mirrors  306  in a housing  308  to scan the treatment area. At each location (pixel) in the scan analogous measurements to those above can be performed. Also, the delivery of the laser, white light, and LED sources may be delivered through the same optical probe that is doing the collection depending on switching configuration. 
         [0038]    Either of the preferred embodiments can use a variety of switches, such as the following. 
         [0039]    Several embodiments of large diameter multimode fiber switches (the switches  106  and  108  of  FIGS. 1 and 3 ) are provided, as illustrated in  FIGS. 4A through 9 . The purpose of the switches is to control the flow of light through the system, as previously disclosed. In addition, some embodiments contain in-line filters which can be moved into or out of the path in order to control the light transmitted through the system. 
         [0040]      FIG. 4A  shows a top view of a 1×2 fiber optic switch  400  in which an optical fiber  402  is mounted on a translating sled  404  that can be translated by a linear actuator (bistable solenoid)  406  by applying a voltage from a voltage source  408  across electrical leads. In this embodiment using a bistable solenoid  406 , a voltage pulse across one set of leads translates the sled  404  into a first position. Permanent magnets within the solenoid  406  latch the device in place so that it is stable and requires no additional electrical source to hold it in place. In this position, the fiber  402  is in close proximity to the fiber  412  and provides optical throughput from the fiber  402  to the fiber  412  (or vice versa). Application of a voltage pulse across a second set of leads (not shown) translates the sled  404  to a second position, as shown in  FIG. 4B , where a second set of permanent magnets holds the sled  404  in place and throughput between the fiber  402  and a fiber  410  is obtained. A precision linear slide (not shown) holds the sled  404  very precisely in two dimensions to reduce fiber alignment errors otherwise imparted by the slop in the axle of the bistable solenoid  406 . 
         [0041]      FIGS. 5A-5C  show a magnified view of the sled  404  and the alignment of the optical fibers  402 ,  410 ,  412 . In  FIG. 5A , the fibers used have polished ends  502  and are coupled by placing them in close proximity. In  FIG. 5B , the fibers are terminated with lenses (GRIN lenses)  504  which collimate the beam and allow efficient coupling at spacing prohibitive for polished fiber coupling. An alternative embodiment of that shown in  FIG. 5B  would include traditional lenses or ball lenses.  FIG. 5C  shows a perspective view of the sled holding an optical fiber. 
         [0042]      FIG. 6  shows a 2×2 switch  600  using the same base components as used for the 1×2 switches of  FIGS. 4A and 4B . In this embodiment, an interconnecting fiber  602  allows either of the two input fibers  604 ,  606  to be connected to either of the two output fibers  608 ,  610  by controlling the positions of the sleds  404  with two bistable solenoids  406 . The basic 1×2 switch can be multiplexed together as in the 2×2 switch to increase number of channels that can be switched. 
         [0043]      FIGS. 7A and 7B  show a removable in-line filter  702  incorporated into a 1×2 switch  700  based on the previous design. In this embodiment, a fiber  704  from the 1×2 switch is coupled to a second fiber  704  with lenses  706 . A filter  702  mounted onto a sled  404  (as previously described) can then be translated into or out of the beam path using a solenoid  406 . In this way, light transmitted through the system can be modified in intensity, spectral content, or polarization depending on filter choice.  FIG. 7A  shows this device with the filter not in the path of the light, and  FIG. 7B  shows this device with the filter in the path of the light. Again, a precision linear guide may be used to improve system repeatability and robustness. 
         [0044]      FIGS. 8A and 8B  show an alternative 1×2 switch embodiment  800  in which two lens-terminated fibers  802 ,  804  are mounted in the switch  800  and aligned to the two input ends of a y-coupled fiber  806 . Switching between throughput of fibers is accomplished by translating a bulkhead  808  with through holes  810 . In  FIG. 8A , the bulkhead  808  is in a first position, and light transmitted through a first fiber  802  travels through a through hole  810  in the bulkhead and is coupled into the output by the y-coupler  806 . Light transmitted through the second fiber  804  is blocked by the bulkhead  808 .  FIG. 8B  shows the device  800  after the bistable solenoid  406  is used to switch the position of the bulkhead  808 . In this state, light transmitted through the first fiber  802  is blocked by the bulkhead  808 , and light transmitted through the second fiber  804  is transmitted through a through hole  810  and is coupled into the output fiber by the y-coupler  806 . A perspective view of the bulkhead  808  with through holes  810  is illustrated in  FIG. 9 . Similarly, this basic switch unit can be multiplexed to achieve a higher number of channels and can also have in-line filters incorporated for additional functionality. 
         [0045]    Use of a precision linear slide to improve throughput repeatability and lifetime and inclusion of coupling optics to improve robustness separates this system from known prior art examples. No prior art incorporating y-couplers and bulkheads with through holes is known. Switches incorporating bistable solenoids can be purchased commercially from Fibersense &amp; Signals Inc., San Jose, Calif., U.S.A. 
         [0046]      FIG. 10  shows a third preferred embodiment of the invention. In the third preferred embodiment, the instrument  1000  can be constructed and used like the instrument  100  of  FIG. 1 , except that additional light sources, such as a fluorescence laser  1002 , are coupled into the system and transmitted through the treatment fiber. Such additional sources may be coupled with multiplexed switches, as described above. In a variation of the third preferred embodiment, sources may be coupled into the system by butt-coupling multiple fiber sources into the treatment source. A known type of coupling is shown in  FIG. 11  as  1100 , in which input fibers  1102  are formed into a fiber bundle  1104  in a housing  1106  and tapered to form a taper region  1108  leading to the output fiber  1110 . In this case, the source fibers used would have smaller diameters than the treatment fiber, and the sources would be switched on and off, or shuttered on and off upstream of the coupling. In this way, multiple sources can be used to interrogate the target tissue without much added complexity. It is an advantage of this embodiment that the sources are transmitted to the tissue surface in the same geometry which simplifies computational analysis and interpretation of resulting measurements. 
         [0047]    While preferred embodiments and variations thereon have been set forth above, those skilled in the art who have reviewed the present disclosure will readily appreciate that other embodiments can be realized within the scope of the invention. For example, wavelengths and other numerical values are illustrative rather than limiting. Therefore, the present invention should be construed as limited only by the appended claims.