DE19639653A1 - Diagnostic apparatus using fluorescence- or light induced- reaction in vivo - Google Patents

Abstract

An apparatus is claimed for in vivo diagnosis by a fluorescence-induced reaction or by a light-induced reaction of a sensitiser in biological tissue. The apparatus has a lamp system (6) to generate an incoherent light in a wavelength of at least 380-680 nm; light-conducting elements (2,5,21) to carry the light to the tissue area (7) requiring diagnosis and/or therapy; and a unit (31,32,4,8) to take, record and transfer a picture. The degree of pure spectral transmission (Tl( lambda )) of the light carrier is matched to the fluorescent excitation spectrum of the photosensiter or the tissue. The degree of pure spectral transmission (Tb( lambda )) of the picture unit is matched to the fluorescent spectrum of the photosensitiser or the tissue. The degree of pure transmission of the light carrier and picture units forming the total system is more than 5 % only in a wavelength range of a maximum of 50 nm of a spectral transmission degree. In other parts of the given wavelength range, it is less than 5.

Description

Technical field

The invention relates to a device for "in Vivo Diagnosis "by means of a body's own or non-body photosensitizer light-induced Reaction in biological tissue.

State of the art

The diagnostic method carried out with such a device is also used in medical terminology as photodynamic diagnosis (PDD) or as fluorescence diagnosis designated. Also known is "Photosensibilisa use gates for photodynamic therapy (PDT). For this purpose, reference is made to WO 93/20810 "to the above not with regard to the explanation of all here expressly described terms and process steps Reference is made.

It has also been suggested to be an endoscopic photodynamic diagnosis and therapy with a Vorrich device with a cryptonio as the light source laser with a wavelength of approx. 410 nm and a Power of more than 200 mWatt is used. The light this laser is clogged with a quartz light guide numerical aperture through an endoscope to the target radiating areas of the human body.  

A light-induced reaction in biological systems trigger, the patient becomes a photosensitizer, which is either a hematoporphyrin backbone like the sub punch Photofrin and Photosan-3, or Delta Amino levulinic acid (ALA), which has recently been used in urology and dermatology is used in a concentration of a few mg / kg body weight. The hematoma porphyrin derivatives are administered intravenously, delta Aminolevulinic acid, however, can be applied locally, d. H. it is used as a solution, for example, in the urinary bladder injected. These substances now accumulate in tumors weave in 2 to 10 times increased concentration. This selective enrichment in the tumor tissue is the decisive factor the basis for photodynamic diagnosis and represents photodynamic therapy.

For diagnosis, the tissue to be examined is approximately 2-12 Hours after administration of photosensitizer (ALA) endoscopically with violet light - with known Vorrich almost exclusively laser light - irradiated. The Porphyrin derivatives that are present in an increased amount in the tumor tissue This light indicates concentration stimulates and then shows a typical red fluorescence through which the tumor can be located.

In addition to fluorescence - caused by one in the tissue Enriched photosensitizer can also be the so-called Auto fluorescence of the tissue is triggered by so-called fluorophores, d. H. endogenous fluorescence fabric comes about.

Radiation is used in photodynamic therapy performed with red laser light, since this light with egg a wavelength of more than 630 nm  the tissue reaches about 5 mm, in contrast to light shorter wavelengths, which is a blatantly lower one possesses depth of penetration. Despite using this optimal wel length is the indication for the photodynamic Thera currently on flat superficial carcinomas limited.

The biophysical course of the light-induced reaction can be assumed as follows:
The photosensitizer stored in the tissue is converted into an excited state by the absorption of a light quantum with defined energy, which is emitted by the respective light source. When irradiated with violet light as part of the photodynamic diagnosis, fluorescence radiation is now emitted when it falls back into the basic state.

In the case of photodynamic therapy in connection with irradiation with red laser light of high power density the transition from the excited form to a meta takes place stable intermediate state from which the energy, which is released by return to the basic state, on mo molecular oxygen is transmitted, which is this energy with formation of excited singlet oxygen takes. This aggressive singlet oxygen destroys in affected tissue by photooxidation cell structures. This cellular damage leads to an equal early collapse of the tumor vascular system complete tumor destruction (more phototoxic Effect).

However, this procedure is dependent on the ver used photosensitizers with certain problems  is liable. When using Photofrin and Photosan-3 as Photosensitizers in photodynamic diagnosis need very complex techni for the fluorescence detection cal devices are used because of annoying egg gene fluorescence components only with the help of very complex com computer-aided image processing techniques and high temp sensitive cameras with low light intensifiers, the fluorescence of the tumor tissue can be detected accordingly.

When using delta-aminolevulinic acid, the in induced fluorescence strong enough to be purely visual can be known. But also by delta aminolevulin acid fluorescence does not lead to an optimal one Quality of the endoscopic image, which is part of the slide to be drawn on. The use of a quartz light guide with a small numerical aperture, as for the light transmission of a laser beam is used, only allows a very poor illumination of the bil of.

By using an additional light guide, the could improve the illumination, so will others Lumen available in the endoscope in such a way right induced that the use of other endoscopic instru ment is severely restricted.

Above all, however, outshines when using known front directions possibly additional introduced into the endoscope Illuminating light that also when using Del ta-aminolevulinic acid comparatively weak fluorescence image.

In addition, in the methods described above for the diagnosis and therapy different light or La  sources necessary, which on the one hand increases costs leaves, and on the other hand the handling of the endoscopic Systems difficult.

Similar problems also occur when implementing the photodynamic diagnosis using a microscope and especially an operating microscope.

Presentation of the invention

The invention has for its object a device for diagnosis by means of a foreign body or body's photosensitizer light-induced or reaction caused by autofluorescence in biolo to develop tissue in such a way that the induced Fluorescence while observing the Adequate illumination of the tissue area - preferably without the use of lasers - can be recognized with high contrast can.

Two preferably alternatively usable Lö according to the invention Solutions to this problem are in claims 1 and 2 specified. Developments of the invention are the subject of claims 3 following.

The solutions given in the two main claims of the object according to the invention are based on the following a basic idea:
The pure transmittance in the light-supplying and bil-generating part of the device according to the invention are selected so that, on the one hand, practically no light with a wavelength λ from the area used for excitation, which naturally has a comparatively high intensity, through the imaging part of the device into the proximal Image plane "arrives", while light with a wavelength λ from the area in which fluorescence occurs can only reach the proximal image plane if it comes from the illuminated tissue area and not from the illumination system. On the other hand, the degrees of re-transmission of the light-supplying and the image-forming part of the device ensure that the illuminated tissue area is so strongly illuminated with light with a wavelength that is neither in the range of the excitation spectrum nor in the range of the fluorescence spectrum that the investigator is due to the in this wavelength range of directly reflected light can perceive details of the illuminated tissue area independently of the fluorescent radiation.

In other words, according to the invention, the image of the Excitation light of the illuminated tissue area simultaneously using fluorescent light and reflected lighting generates light, the two of them contributing to image generation proportions with respect to their wavelength and with respect their intensity is such that they are not "disturb" each other.

The device according to the invention for diagnosis by means of an egg ner by a foreign or body's own photosen sensitizer or light-induced by self-fluorescence A lighting system exhibits a reaction in biological tissue stem with at least one light source to guide a light de Unit that shines the light of the lighting system on the tissue area to be diagnosed, and a imaging unit that is from the tissue area maps incoming light into a proximal image plane. Before directions for the diagnosis of body tissue with the pre  mentioned features are generally known and are in used for example in endoscopy or microscopy.

According to the invention is preferred in claim 1 and even in the solution specified in claim 2 - in au better known per se outside of photodynamic diagnosis Way - uses a broadband light source, the inco inherent light in the wavelength range of at least 380 to 660 nm - preferably from 370 to 780 nm. This broadband light source can be a different spectral distribution like conventional light used in endoscopy have sources. But if the light source also becomes one conventional investigation of - also - with photodynami the diagnosed area can be used , it is preferred if the light source is a conventional one high-performance light source is, as in medical African endoscopy is used. The power consumption the light source is preferably at least 300 watts.

When using "broadband" light sources, the problem has arisen in the past that the light from the light source reflected on the tissue region to be examined outshines the fluorescent light. Therefore, according to the invention, not only the pure transmittance Ti _l (λ) of the light-supplying unit is adapted to the fluorescence excitation spectrum of the photosensitizer and the pure transmittance Ti _b (λ) of the imaging unit is adapted to the fluorescence spectrum of the photosensitizer.

According to the invention in the solution alternative specified in claim 1, the pure transmittance of the entire system consisting of light-supplying unit and imaging unit, which results from the multiplication of the pure transmittances Ti _l (λ) and Ti _b (λ), only in a range of maximum 50 nm has a spectral transmittance of more than 5% and is otherwise less than 5%. In this range of maximum 50 nm, the pure transmittance of the overall system can reach values of 10% and more.

In the alternative specified in claim 2, the spectral pure transmittance Ti _l (λ) of the light-guiding unit in addition to a first pass band, which is adapted to the fluorescence excitation spectrum of the photosensitizer or the tissue, has a second pass band, the wavelengths of which lie between the waves lengths of the fluorescence excitation spectrum and the wavelengths of the fluorescence spectrum. The spectral pure transmittance Ti _b (λ) of the imaging unit has, in addition to a first pass band which is adapted to the fluorescence spectrum of the photosensitizer or the tissue, a second pass band which is in the same wavelength range as the second pass band of the light-supplying Unity lies. The degree of re-transmission of the overall system consisting of light-supplying unit and imaging unit only has a spectral degree of trans mission of more than 5%, which can preferably be 10% and more, only in the second pass band and is otherwise smaller than in the above wavelength range 5%.

Through this formation of the spectral permeability the light supply unit and the imaging unit is achieved that the fluorescent light on the by the Illumination light generated image of the reverse, for example tumor is perceived clearly and with high contrast that can.  

It is preferred if the first and the second Passband of the imaging unit is approximately complete are mental to each other. This gives you a strong one Contrast between the fluorescent image and the illuminated one Background image that continues through an alternating dar position of both images on a monitor can be increased can.

It is further preferred if the intensity of the loading illuminating light and the filters are chosen so that the power arriving at the proximal image plane Light with wavelengths from the second range 10% (and less) to about 100% of the cumulative light output in the er most passband of the imaging unit.

To adapt to the different photosensitizers and / or different diagnostic conditions or to convert the device according to the invention to a therapeutic method, it is further preferred if the transmission properties of the light transmitting and the imaging unit by means of one or more opti shear elements are adjustable.

It is preferred if the setting is such follows that the intensity of the induced fluorescence tes in the same order of magnitude as the total intensity of the reflective part of the light of the lighting systems lies. This takes place in a particularly advantageous manner Adjustment such that the two intensities are approximately are the same.

In any case, the device according to the invention has the Advantage that it is necessary to carry out the photodynamic slide diagnosis while illuminating the observed field  des and the previous and / or subsequent visu sufficient observation of the examined area is sufficient ne single light source to use. Furthermore, can with the device according to the invention also the photodyna mix therapy without changing the light source, d. H. With a single light source. In this Traps become - as already mentioned - the transmission egg properties of the light-transmitting unit to the absorpti adapted spectrum of the photosensitizer.

The optical elements used to adjust the transmis sion properties of light transmitting and imaging The unit used are preferably Filtersy steme in the lighting and observation beam path can be brought in. It is under lighting The beam path from the lamp of the Light source to the light supplying unit, through this one unit, and from this unit to the diagnosing tissue understood area. The optical elements and in particular the filter systems can in principle at any point this beam path can be arranged. Particularly preferred is the arrangement between the lighting system and light supply unit, for example a light fiber bundle. (Without a filter system, the Reintrans degree of mission assumed as 100%.)

Accordingly, the observation beam path is the Beam path from the illuminated tissue area to the image giving unit and from this to the proximal image plane Understood. (Without a filter system, the clean is also here transmittance assumed as 100%).

If the device according to the invention in an endoscope is tegrated, the image plane can both in the endos  Kop in the area of the distal end - for example at Using a distal video chip - as well located in the area of the proximal end. In the latter Trap has the imaging unit next to a lens as an imaging unit, for example, a relay lens system or a flexible fiber bundle as an image transmitting Unity on. When using a relay lens system or a fiber bundle as an image-transmitting unit the fil introduced in the observation beam path ter systems preferred between the "last surface" of the Re lais lens system or the exit surface of the fiber bund dels and the proximal image plane.

When integrating the device according to the invention in one Surgical microscope is part of the imaging one the microscope lens system, for example Subordinate video recorders as image capturing unit can be.

As already stated, it is achieved according to the invention that that of the tissue area to be diagnosed and its Illuminated light reflected the surrounding area Fluorescent light does not outshine. To realize the ses the basic idea of the invention, it is preferred if that in the lighting beam path and that in the Observation beam path each filter system that can be inserted have almost opposite filter characteristics. in the In the case of a device designed according to claim 2 pulls the opposite development of the filter characters of course only on the first passband characteristic in question, but not to the two characteristic relating to th pass band.  

The curves that show the transmission of the two opposite Specify filters depending on the wavelength, intersect - in the configuration according to claim 1 - preferably with a transmission of the individual systems is less than 50%.

In a further embodiment of the invention, this Filters that can be inserted into the lighting beam path min at least two separate filters, one of which is a filter one thermostable interference filter and the other filter is a thermostable heat protection filter (neutral filter).

The properties of these two filters are to be explained below, provided that delta-aminolevulinic acid is used as the photosensitizer. If another photosensitizer is used, the filter properties must be adjusted accordingly:
When using delta-aminolevulinic acid (ALA) it is preferred if the transmission of the illumination beam path through a short-pass filter in the range between 380 and 430 nm is at least 50%. In a particularly preferred embodiment, the transmission between 370 and 440 nm is at least 70% and preferably 95%.

At a wavelength of 445 ± 4 nm or 447 ± 2 nm the transmission is 50%. At longer wavelengths the transmission is much smaller and is typical usually less than 1%.

In a preferred embodiment of the invention the transmission both in the wavelength range between 460 and 600 nm as well as between 720 - preferably 660 nm - and 780 nm below 1%. In the wavelength range in which  mainly fluorescent light is excited, i.e. at Delta aminolevulinic acid in the wavelength range between between 600 and 720, preferably 660 nm, the transmission is sion less than 0.1%.

This characteristic of the filter system results in a light distribution of the illuminating light, which guarantee achieves that of the tissue area to be examined in the wavelength range in which mainly fluorescence light occurs, practically no "non-fluorescent light" is reflected back.

Accordingly, the filter has in the observation beam path (Long pass filter) following characteristics:

T _l (λ = 370-430 nm) <0.1%
T _l (λ = 453 ± 2 nm) = 50%
T _i (λ = 500-1100 nm) = 95%, preferably 98-99%.

The tolerance for the wavelengths of both filters at which the respective transmission is 50%, is preferably ± 2 nm. This design of the filter ensures that the pure transmission of the entire system only in Range between 430 and 460 nm is greater than 5%. The in this range should be preferred not exceed 15%.

The use of optical elements and in particular of filters to influence the beam path trans mission characteristics has the advantage that at for example, by swiveling out the filter White light lighting and observation can be done so that the examiner, for example a doctor the tissue also examined with fluorescence diagnosis rich u. a. judge by color. The color is  for example in the field of ophthalmology ches assessment criterion.

The one in a preferred embodiment of the invention thermostable heat protection filter still used (Neutral filter) can have the following characteristics:

T _l (λ = 370-440 nm) <95%
T _l (λ = 440-700 nm) ≈ 90%
T _l (λ = 700 nm) = 50%
T _l (λ = 720-1100 nm) <1%.

Has the use of a thermostable heat protection filter the advantage that the interference filter during diagnosis is not heated by infrared light. This on heating could possibly be the filter characteristic change and the sensitivity of a camera reduce the light transmission unit destroy because of the high intensity.

In any case, it is preferred if the individual filters only introduced into the respective beam paths if required be given their removal from the beam path not enabled or ver by a monitoring signal is prevented.

As a filter, commercially available filters with the invent according to the intended "almost step-shaped" characters ristik be used, for example known In interference filter, the carrier material of which is quartz.

Known light sources can also be used as light sources and in particular already known from endoscopy Light sources are used that are broadband in the ge named wavelength range emit light. A derar  term light source, the light in sufficient intensity is emitted, for example, a gas discharge lamp and in particular a xenon gas discharge high pressure lamp. In individual cases, the light output of the light source may not be sufficient in addition to one "continuously working" light source a "pulsed" Light source, such as a flash or a laser turned on be set. In particular given in claim 2 NEN alternative solution, it is possible to use a light ner wavelength λ in the first pass band with a La to produce water that is a pulsed laser or a duration line laser can be. The light with wavelengths from the second passband can then be of more or we niger broadband "white light source" originate.

As light-supplying units can - in particular endoscopic applications - commercially available light guides used with at least one fiber, the more advantageous Have a numerical aperture greater than 0.45, because then an efficient light transport to the diagnosis stic area becomes possible.

Such fibers have a core, for example Quartz and a jacket made of a thermostable material on.

In the case of using an optical fiber, it is before moves when the light source, d. H. for example the Gas discharge lamp, a focal spot with a diameter of less than 2 mm, which is characterized by an elliptical Re is generated which has a numerical aperture for the Has light emission of more than 0.45. In this case you get a highly efficient coupling between Be  lighting system and light supply unit, i.e. the Fiber light guide.

Furthermore, a gas discharge lamp can also be used, whose focal spot has a diameter of less than 2 mm using a parabolic reflector and a focus unit is focused. The focusing unit is in In this case, a lens system that at least has an element with an aspherical surface.

In a further preferred embodiment of the invention is the lighting system, i.e. the light source and the optical elements upstream of the light source, such as Filters etc., designed so that the excitation wavelengths according to the photosensitizer used in each case and tunable to the tissue to be diagnosed in each case are. This tuning can be done either by an ent speaking influence of the light source or by means of switched filter, e.g. B. graduated filters or prisms respectively.

So it is u. a. possible, different fabrics areas to stimulate fluorescence.

The device according to the invention enables both visual observation of fluorescence as well as recording the fluorescence image with an image sensor, such as one Video camera or the like

This video camera or unit is in the image plane of the imaging unit arranged. In the case of a distal Arrangement of the video unit is this in the image plane of the Lens of the endoscope arranged. In the case of a proxi paint arrangement of the video unit this is in the picture  level of the image relay unit, i.e. the relay lens system or the fiber bundle arranged. Alternatively, you can the video unit be designed so that it the eyepiece takes picture. When using a microscope as an image unit, the video unit is arranged so that it takes the eyepiece image of the surgical microscope.

The video unit can in particular (at least) one Have CCD recorders. In this case it is possible that the gas discharge lamp has a periodically operating blit Discharge lamp is based on a control and evaluation unit is controlled so that the flash exposure off finally in the light integration phase of the CCD sensor falls. This is a highly effective loading illumination of the area to be examined achieved, wherein the application of the lighting system and the vice exercise with light energy is reduced. With that the Reduced heat or temperature stress on the components.

At the same time, a visual observation of the under searching area or increase the light output it is advantageous if an additional con continuously operating light source is provided.

To control the video signal, it is further preferred if the video unit has a variable exposure setting having; this can ver overexposure in the video image be prevented and you always get a high contrast Image that shows the fluorescence radiation well.

A device according to the invention, which has the features described above, enables visual observation of the fluorescence image by means of the naked eye or a video unit. A particular advantage of the device according to the invention, however, is that the image it generates allows a largely automated evaluation:
For this purpose, the output signal of the video unit is applied to an image processing system. This image processing system can perform a number of manipulations on the image provided by the video unit:
The color images can, for example, be captured via the RGB input channels and transformed into the HSI color space:

(H = Hue (hue)
(S = Saturation)
(I = intensity).

In the HSI room, for example, this is caused by tumors called "fluorescence radiation" by the HSI separation highlighted.

It is also possible that the image processing system electronically a color range in the color shown hides the image to adjust the contrast between different areas. If the machine vision system carries out an RGB acquisition, for example the The blue and / or green channel can be switched on and off. The This procedure has the advantage that when the Blue and / or green channel especially the fluorescence image stands out clearly.

This emphasis is reinforced by the fact that the picture processing system the hidden color channel shutter like in the example shown on a monitor Fades in color image. This results in the Be  trachten a particularly "eye-catching" representation, which in particular simplifies the detection of tumors.

An examination process can proceed as follows:
First, the tissue area to be examined is examined visually. This means that a doctor looks at the area illuminated with "white" light with the eyepiece of an endoscope or a microscope or on a monitor. To switch to photodynamic diagnosis, for example, by means of a foot switch or a switch on the video camera, the short-pass filter and, if appropriate, the thermostable heat protection filter are pivoted into the illumination beam path. At the same time, the green channel and / or the blue channel is switched off periodically. So the doctor sees on the monitor only the fluorescence image (or the "normal" image) and then the superimposition of the fluorescence image with the "normal" image, which is caused by light from the small area in which the transmission of the overall system is not equal to 0 - So either the area of overlap or the second Durchlaßbe rich - is generated. Conversely, the fluorescence image can also be periodically superimposed on the background image (blue channel).

Furthermore, the image processing system can determine the fluorescence contrast value at the individual points of the image for the maximum fluorescence wavelength to determine any tumors. If delta-aminolevulinic acid (ALA) is used as the photosensitizer, the contrast ratio for the wavelength 630 nm to the intensity can be calculated in the range of at most 50 nm in which the overall system has a spectral transmittance of more than 5%:
By comparing the images taken with and without fluorescence excitation - in the simplest case a subtraction of the images - the image processing unit can determine the intensity of the fluorescence radiation and calculate the contrast ratio, so that an accurate localization of any tumors is possible.

The device according to the invention can be used for the most diverse medical examinations:
In addition to the particularly preferred use in endoscopic applications, the device according to the invention can also be used in conjunction with an operating microscope, for example in neurosurgery, colposcopy or ophthalmology.

In any case, however, a device is obtained that in particular the following advantages due to the observation of illuminating light reflected on the fabric at the same time or alternating with the fluorescent light:

• - It is an orientation also about fluorescence negative Tissue possible.
• - The orientation implemented according to the invention is against above pure white light lighting in particular the use of ALA as a photosensitizer partly that he has a strong emphasis on vascular structures follows and there is clear visibility even with diffuse Bleeding into the irrigation fluid.  
• - The threshold function of the blue light suppresses the unspecific red fluorescence of normal tissue.
• - Above all, the detection is really fluorescence positive areas by color contrast and not by intensi contrast - like this with a complete block of the illuminating light would be the case. This especially simplifies image processing.
• - The color contrast obtained according to the invention is - in Ge contrast to the intensity contrast - regardless of the obser distance of observation and from the observation angle. So that will the probability of error is significantly reduced. Dar moreover, there is no need for complex image processing proceed so that in the case of automated detection simple image processing methods for use can come.

Brief description of the drawing

The invention is based on an embodiment example with reference to the drawing be wrote in the show:

Fig. 1 shows schematically an apparatus according to the invention for endoscopic applications,

Fig. 2a shows the filter characteristic of the filters used in the various beam paths,

Fig. 2b, the "total transmission" of a first embodiment, and

FIGS. 3a and b are corresponding views for a second embodiment.

Representation of exemplary embodiments

In Fig. 1, the structure of an inventive device for endoscopic applications is shown schematically. The reference numeral 1 denotes an endoscope, in a known manner, a light guide connection 2 , a stab-shaped part 3 , which can be inserted into a (not shown) human body, and an eyepiece 4 .

The light guide connection 2 is connected via a light guide cable 5 to a light source 6 , which can have a xenon discharge lamp, for example. A z. B. from a fiber bundle of existing light guide 21 in the endoscope 1 directs the light in the light guide connection 2, the light source 6 coupled to the distal end 11 of the endoscope 1 . The light emerging from the distal end 11 illuminates the tissue region 7 to be examined.

The light coming from the tissue area 7 enters a lens 31 of the endoscope 1, which is only shown schematically. The image of the objective 31 is sent through a conductor 32 to the proximal end 12 of the endoscope 1 .

In the exemplary embodiment shown, the image guide 32 has a plurality of relay lens systems, each of which carries out a 1: 1 image and consists of so-called rod lens systems. Alternatively, the image guide 32 can have a fiber imaging system.

The image of the tissue region 7 generated in the proximal image plane 13 can be viewed through the eyepiece 4 with the eye. Alternatively or via a beam splitter in addition to viewing with the eye, the image can be recorded with a video camera 8 . In Fig. 1 the alternative is shown that the video camera 8 is attached directly to the eyepiece 4 .

As far as described above, the structure is at for example by Endosko equipped with a video camera pe of Karl Storz GmbH & Co., Tuttlingen, Germany knows. For the detailed structure, therefore, the well-known En doskope from this manufacturer.

To carry out so-called photodynamic diagnoses, the device shown in FIG. 1 is further developed such that filter systems can be introduced into the illumination beam path and into the observation beam path.

For this purpose, in the embodiment shown in FIG. 1, a filter system 9 is attached to the light output connection 61 of the light source 6 , to which the light guide cable 5 is in turn flanged. The filter system 9 has a thermostable interference filter 91 and a thermally stable heat protection filter 92 , which is intended to substantially reduce the heat applied to the interference filter 91 . A filter 93 is also placed in front of the video camera 8 or the eye with which the image is visually evaluated.

The exposure setting of the video camera 8 and the light output from the light source 6 are controlled by a control and evaluation unit 10 . For example, the control and evaluation unit 10 can synchronize a flash light source with the light integration phase of a CCD chip in the video camera 8 . Furthermore, the control and evaluation unit 10 can regulate the light output from the light source 6 and / or the exposure setting of the video camera.

The output signal of the video camera 8 is also present at the control and evaluation unit 10 . The evaluation unit can in particular have an image processing system that processes the output signal of the video camera in the manner described in the introduction and displays the image processed output signal on a monitor. Of course, the directly from the video camera ra and / or the image processed output signal z. B. stored by means of a video recorder and / or stored in an image database or further processed in another way by means of electronic data processing.

When using a photosensitizer, the tissue area 7 emits both reflected illuminating light and fluorescent light, which is caused by the light-induced reaction of the photosensitizer in biological systems. In order to be able to detect the small proportion of fluorescent light compared to the reflected light and to be able to safely separate from the "non-fluorescent light", especially in the case of a subsequent image processing, a suitably chosen transmission characteristic of the illumination and observation beam path is required. Filters 91 and 93 , which can be inserted into the beam path, serve to set the transmission characteristic during photodynamic diagnosis. Since the filters can be removed again, for example, by swiveling them out of the beam paths, normal observation of the tissue area 7 is also possible without, for example, color falsification.

The characteristics of the filters 91 and 93 for the first embodiment of the invention and for the case in which delta-aminolevulinic acid is used as the photosensitizer will be explained below with reference to FIG. 2. If other photosensitizers are used, the filter characteristics must be adjusted accordingly.

In Fig. 2a the thick curve shows the transmission (in percent) of the filter 91 as a function of the wavelength (in nm), i.e. the so-called pure transmittance Ti (λ), while the thin curve shows the pure transmission Ti ( λ) for the filter 93 . The fluorescence spectrum is also entered in FIG. 2a.

FIG. 2a shows that the pure transmission of the filter 91 is greater than 90% at wavelengths that are less than about 440 nm. At wavelengths that are greater than about 460 nm, the transmission is less than 1%. At about 455 nm, the transmission is 50%. Furthermore, in the exemplary embodiment for an interference filter 91 , which is shown in FIG. 2a, the transmission in the range between 600 and 660 nm - but preferably 720 to 780 nm - in which fluorescence light occurs in an increased manner is particularly low and is in particular less than 0 , 1%, preferably 0.01%. The filter 91 is therefore a short pass filter.

The filter 93 has an almost opposite characteristic:
At wavelengths between 370 and 430 nm, the transmission T _l is less than 0.1%, preferably even by at least an order of magnitude less than 0.1%. At a wavelength of 445 nm, the transmission is 50%. At wavelengths between 500 and 1100 nm, the transmission reaches almost 99% or more.

The transmission curves of the filters 91 and 93 intersect in the exemplary embodiment shown at pass values of more than 60%. However, it is also possible - and especially in the case of weak fluorescence - that the curves intersect at transmission values of 25 to 30%.

Fig. 2b shows the transmission characteristic of the overall system, which is obtained by multiplying the curves of an individual filter 91 and 93 . As you can see, the transmission is only in the range between 440 and 460 nm over 1% and reaches a maximum value of about 50%.

In the above-mentioned alternative, in which the curves intersect at transmission values of 25 to 30%, the maximum value is approximately 12.5%. This means that only a small part of the illuminating light, which is reflected on the tissue area 7 , "reaches" the proximal image plane 13 . The fluorescent light, which is typically emitted at wavelengths λ between 500 and 780 nm, mostly between 600 and 660 nm, reaches the image plane 13 unhindered, since it only has to pass through the long-pass filter 93 , but not through the short-pass filter 91 .

This still allows a visual observation of the tissue area 7 , but the fluorescence component of the detected light can be safely separated from the reflected, shorter-wave light.

FIGS. 3a and 3b show the corresponding curves for the second embodiment of the invention, in which both the water introduced in the illumination beam path filter 91 and the provided in the observation beam path filter 93 nm a second pass band around 490 ± 10 nm to have.

The above wavelength specifications refer to the Use of delta-aminolevulinic acid as photosensitizer sator. When using other photosensitizers Ren or when using the own fluorescence are the wel Lengths at which the individual filters fit change characteristics, adapt accordingly. Unchanged However, the essential property remains that the two complementary filter curves for one Pure transmittance of approx. 50% or less than 50% cut, or that there is a second pass band is. The overall system also remains unchanged only in a narrow range, typically 50 nm, but possibly more or less, is clear is different from zero and in particular is greater than 1%.

If the device according to the invention are also to be used for Thera pie, the filter system 9 must have a wide res filter which does not have a short-pass characteristic, but a medium-pass to long-pass characteristic.

The above description of exemplary embodiments, which relate to the use of using delta Related Aminolevulinic acid as a photosensitizer, be limits the claims and the description baren general inventive idea.

Claims (47)

1. Device for diagnosis by means of a light-induced by a photosensitizer or caused by self-fluorescence reaction in biological tissue "in vivo" with

• an illumination system which has at least one light source with a lamp system ( 6 ) which generates incoherent light in the wavelength range from at least 380 to 680 nm,
• - A light supply unit ( 2 , 5 , 21 ), which directs the light of the lighting system to the tissue area ( 7 ) to be diagnosed and / or treated, and
• an imaging, image-capturing and image-transmitting unit ( 31 , 32 , 4 , 8 ) which images the light coming from the tissue tissue ( 7 ) into a proximal image plane ( 13 ),

wherein the spectral pure transmittance Tl (λ) of the light supplying unit is adapted to the fluorescence excitation spectrum of the photosensitizer or tissue and the spectral pure transmittance Tb (λ) of the imaging unit is adapted to the fluorescence spectrum of the photosensitizer or tissue, and
wherein the pure transmittance of the overall system consisting of light-supplying unit and imaging unit only has a spectral transmittance of more than 5% in a wavelength range of at most 50 nm and is otherwise less than 5% in the above-mentioned wavelength range. 2. Device for diagnosis by means of a light-induced by a photosensitizer or caused by self-fluorescence reaction in biological tissue "in vivo" with

• a lighting system which has at least one light source,
• - A light supply unit ( 2 , 5 , 21 ), which directs the light of the lighting system to the tissue area ( 7 ) to be diagnosed and / or treated, and
• an imaging, image-capturing and image-transmitting unit ( 31 , 32 , 4 , 8 ) which images the light coming from the tissue tissue ( 7 ) into a proximal image plane ( 13 ),

wherein the spectral pure transmittance Ti _l (λ) of the light-supplying unit has a first pass band which is adapted to the fluorescence excitation spectrum of the photosensitizer or of the tissue, and a second pass band whose wavelengths lie between the wavelengths of the fluorescence excitation spectrum and the wavelengths of the fluorescence spectrum lies, and the spectral pure transmittance Tb (λ) of the imaging unit has a first pass band, which is adapted to the fluorescence spectrum of the photosensitizer or the tissue, and a second pass band, which is in the same wavelength range as the second pass band of the light-supplying unit, and
wherein the pure transmittance of the total system consisting of light-supplying unit and imaging unit only has a spectral transmittance of more than 5% in the second pass band and is otherwise less than 5% in the above wavelength range. 3. Device according to claim 2, characterized in that the first and the second Passband of the imaging unit is approximately complete are mental to each other. 4. Device according to one of claims 1 to 3, characterized in that the lighting system several Has light sources, one of which is a broadband Light source is with a lamp system and another has at least one laser system. 5. The device according to claim 4, characterized in that all light sources of lighting system coupled into the light supply unit will. 6. Device according to one of claims 1 to 5, characterized in that the transmission properties the light transmitting and the imaging unit with adjustable by means of one or more optical elements are. 7. The device according to claim 6, characterized in that the transmission properties are set so that the total intensity of the in induced fluorescent light in the same order of magnitude like the total intensity of the directly on the tissue area reflected portion of the light from the lighting system lies. 8. Apparatus according to claim 6 or 7, characterized in that the optical elements are filter systems ( 9 , 91 , 92 , 93 ) which can be introduced into the illumination or the observation beam path. 9. The device according to claim 8, characterized in that in the lighting beam filter system that can be inserted into the observer filter system can be introduced an approx have complementary filter characteristics and esp special approximate edge filters are. 10. The device according to claim 9 in connection with claim characterized in that the two complementary Filter curves with a pure transmittance of the individual sy cut less than 50%. 11. Device according to one of claims 8 to 10, characterized in that the filter system in the lighting beam path has at least two filters which can be brought into the beam path, of which one filter is a thermostable interference filter ( 91 ) and the other filter is a thermostable heat protection filter ( 92 ) and in particular is an interference filter. 12. The apparatus according to claim 11, characterized in that when using delta aminoavulinic acid as the photosensitizer, the thermostable interference filter ( 91 ) has the following transmission properties in the visible range: Tl (λ = 380-430 nm) <50%
Tl (λ = 610-650 nm) <1%, preferably <0.01%. 13. The apparatus according to claim 12, characterized in that the blocking factor of the filter ( 91 ) at a wavelength λ of 630 nm based on the transmission maximum in the pass band at a shaft length of about 407 nm is greater than 1000. 14. The apparatus of claim 12 or 13 in connection with claim 1, characterized in that the thermostable interference filter (short pass filter 91) has the following characteristics: Tl (λ = 370-440 nm) <95%
Tl (λ = 447 nm) = 50%
Tl (λ = 460-600 nm) <1%
Tl (λ = 600-660 nm) <0.1%
Tl (λ = 660-680 nm) <1%. 15. The apparatus of claim 12 or 13 in conjunction with claim 2, characterized in that the thermostable interference filter (short pass filter 91) has the following characteristics: Tl (λ = 370-440 nm) <95%
Tl (λ = 447 nm) = 50%
Tl (λ = 460-480 nm) <1%
Tl (λ = 490 nm) <10% and in particular <30%
Tl (λ = 500-600 nm) <1%
Tl (λ = 600-660 nm) <0.1%
Tl (λ = 660-680 nm) <1%. 16. The apparatus of claim 14 or 15, characterized in that the tolerance for the waves length at which the transmission is 50%, ± 2 nm, be is preferably ± 1 nm.   17. Device according to one of claims 12 to 16, characterized in that the thermostable heat protection filter ( 92 ) has the following characteristic: Tl (λ = 380-440 nm) <95%
Tl (λ = 440-700 nm) <90%
Tl (λ = 700 nm) = 50%
Tl (λ = 720-1100 nm) <1%. 18. Device according to one of claims 9 to 17, characterized in that the thermostable interference filter ( 91 ) is introduced only for the implementation of the diagnostic process in the illumination beam path. 19. Device according to one of claims 1 or 3 to 18, characterized in that the pure transmission of Ge entire system only in the range between 430 and 460 nm is greater than 5%, and a maximum value in this range of no more than about 50%, preferably about 15% -35%. 20. Device according to one of claims 8 to 19, characterized in that the removal of the filter ( 91 , 92 , 93 ) from the beam paths is only possible if a monitoring signal enables this. 21. The device according to one of claims 8 to 20, characterized in that the carrier material of the filter of the filter system quartz or a heat-resistant glass material. 22. Device according to one of claims 1 to 21, characterized in that the light source ( 6 ) has at least one gas discharge lamp. 23. The device according to claim 22, characterized in that the gas discharge lamp a Xenon gas discharge lamp is. 24. Device according to one of claims 1 to 23, characterized in that the light-supplying unit has a light guide ( 21 ) with at least one fiber, the numerical aperture of which is greater than 0.45. 25. The device according to claim 24, characterized in that the core material of the fiber Quartz and the jacket made of a thermostable material stands. 26. The device according to claim 24 or 25, characterized in that the gas discharge lamp of the Be lighting system a focal spot with a diameter of less than 2 mm and an elliptical reflector has a numerical aperture for the light emission of more than 0.45. 27. The apparatus of claim 25 or 26, characterized in that the gas discharge lamp of the Be lighting system a focal spot with a diameter less than 2 mm and a parabolic reflector like that as a focusing unit with a lens system with at least has an aspherical surface. 28. The device according to one of claims 1 to 27, characterized in that the lighting system looks like this is formed that the excitation wavelengths are tunable are.   29. Device according to one of claims 1 to 28, characterized in that a video unit ( 8 ) is arranged in the image plane. 30. The apparatus according to claim 29, characterized in that the video unit ( 8 ) has a CCD image recorder, and that the gas discharge lamp ( 6 ) is a periodically operating flash discharge lamp, the flash exposure phase of which controls a control and evaluation unit ( 10 ) so that the Flash exposure only occurs in the light integration phase of the CCD sensor. 31. The device according to claim 30, characterized in that the lighting system additional Lich has a continuously operating light source. 32. Device according to one of claims 29 to 31, characterized in that the video unit is a variable Exposure setting has. 33. Device according to one of claims 29 to 32, characterized in that the output signal of the video unit is applied to an image processing system ( 10 ). 34. Device according to claim 33, characterized in that the image processing system fades out a range of hues in the displayed color image. 35. The apparatus of claim 34, characterized in that the image processing system in the case of RGB processing, the blue and / or green channel switches on and off to increase contrast.   36. Apparatus according to claim 34 or 35, characterized in that the image processing system the hidden color range shutter-like in that the color picture. 37. Device according to one of claims 34 to 36, characterized in that the image processing system performs an HSI transformation. 38. Device according to one of claims 34 to 37, characterized in that the image processing system the contrast value to determine any tumors individual parts of the image for the maximum fluorescence world length calculated. 39. Device according to claim 38, characterized in that the image processing system when using delta-aminolevulinic acid as photosensi bilizer the contrast ratio for the wavelength 630 nm to the intensity in the range of maximum 50 nm net, in which the overall system uses a spectral transmission degree of more than 5%. 40. Device according to one of claims 1 to 39, characterized in that the light supply unit and integrated the imaging unit into a microscope are. 41. Device according to claim 40, characterized in that the microscope is a microscope for neurosurgical or ophthalmic examinations gen is.   42. Device according to one of claims 1 to 39, characterized in that the light supply unit and the imaging unit integrated into an endoscope are. 43. Device according to claim 42, characterized in that the active translucent Total cross-sectional area of the light supply unit 4 mm² does not exceed. 44. Device according to claim 42 or 43, characterized in that the light source itself is known endoscopic light source. 45. Device according to claim 44, characterized in that the power consumption of the Light source is at least 300 watts.