WO2004019774A1

WO2004019774A1 - Method and device for the non-invasive determination of the temperature in biological tissue

Info

Publication number: WO2004019774A1
Application number: PCT/DE2003/002800
Authority: WO
Inventors: Georg Schuele; Carsten Framme; Ralf Brinkmann
Original assignee: Medizinisches Laserzentrum Lübeck GmbH
Priority date: 2002-08-30
Filing date: 2003-08-20
Publication date: 2004-03-11
Also published as: DE10240109A1; AU2003263142A1

Abstract

Disclosed are a method and a device for the non-invasive determination of the temperature in a biological tissue, particularly at the fundus of the eye, which is treated with therapeutic radiation, especially laser radiation. According to the inventive method, the modification of the fluorescence of the irradiated tissue is detected via an optical measurement, the absolute temperature values are determined from the test signals, and the therapeutic radiation is optionally controlled in accordance therewith. The fluorescence can relate to the autofluorescence of the tissue or the fluorescence of an injected dye.

Description

Method and device for non-invasive temperature determination on biological tissue

[Description]

The invention relates to a method and a device for the non-invasive determination of the temperature of biological tissue treated with radiation, in particular laser radiation, by means of fluorescence detection.

It is known from DE 101 35 944.6-51 that the tissue temperature during electromagnetic radiation, in particular laser radiation, can be determined non-invasively with the aid of opto-acoustic techniques.

From G. Schule, G. Hüttmann, J. Roider, C. Wirbelauer, R.

Birngruber, R. Brinkmann: Optacustic measurement during μs- irradiation of the retinal pigment epithelium, SPIE, Proc. Vol. 3914: 213-236, 200 it is known to be able to measure the temperatures at the treated fundus in the selective microphotocoagulation at the back of the eye for the treatment of retinal diseases by means of μs laser pulses. The pressure amplitude caused by the first treatment pulse was used to normalize the pressure amplitude to the temperature of the fundus. The increase in pressure and the respective absolute temperatures were determined from the increase in pressure amplitude of the subsequent treatment pulses using the dependence of the temperature on the pressure amplitudes known from calibration measurements. Due to the measurement in principle, however, only the temperatures of the structures absorbing the test radiation can be determined.

From T. Desmettre, S. Soulie-Begu, J. Devoisselle S. ordon: Diode laser-induced thermal damage evaluation on the retina with a liposome dye system, Lasers in Surgery and Medicine 24: 61-68 (1999) is known, that with the help of a specially developed dye, the warming induced at the back of the eye can be detected by fluorescence. The dye used is a thermosensitive liposo, which undergoes a phase transition irreversibly at a certain temperature. The fluorescence of the two phases is different, so that the fluorescence is temperature-proportional in the area of the phase transition. Since the phase transition is irreversible, only the max. Temperature read out, accurate even in the small area around the phase transition. The method cannot therefore be used for on-line temperature control to regulate treatment radiation. In addition, the dye is not clinically approved.

In many areas of ophthalmology, different energy sources, especially lasers, are used for diagnosis and treatment. As a rule, the entire radiated energy is absorbed by the biological tissue and converted into heat, the desired treatment effect being achieved by the resulting increase in temperature. In laser photocoagulation, for example, the retina of the eye is specifically thermally coagulated. The usual irradiations with irradiation times around 100 ms result in temperatures above 60 ° C. In transpupilar thermotherapy (TTT) too, temperature increases are used to achieve vascular occlusion. Photodynamic therapy (PDT) uses a previously injected dye activated by laser radiation on the fundus. The active ingredient only works on the cells to which it is bound. Almost all of the radiated energy in the dye and retina is also absorbed and converted into heat. During the respective irradiation time (pulse duration) with relatively long treatment and radiation pulses in the order of μs to several hundred seconds, the temperature of the treated biological tissue, in particular the back of the eye, can increase, which leads to unintended damage to the retinal areas. A non-invasive real-time temperature determination has not yet been possible with such eye treatments, but would be extremely desirable for the safety of the radiation and to optimize the treatment. The temperature control should be based on the area of the target structure or the area to be protected.

The object of the invention is therefore to create a method and a device for the non-invasive determination of the temperature on the treated biological tissue, in particular in ophthalmology, in which electromagnetic radiation sources are used for the treatment radiation.

This object is achieved in the method by the characterizing features of patent claim 1 and in the device by the characterizing features of patent claims 21 and 22 and by the use according to patent claims ^¬ 27 and 28.

The invention creates a fluorescence-based method and a corresponding device, wherein During the respective irradiation time of the treatment radiation, additional radiation pulses, which are used for fluorescence excitation, are preferably directed at the treated biological tissue with a shorter pulse duration and less energy than with the treatment radiation. The additional radiation pulses can occur essentially at the same time intervals. The excited fluorescence is detected by optical measurement. The temperature increase is determined from a change in the fluorescence, in particular the respective absolute values of the temperature are determined.

However, the treatment radiation itself can also be used for fluorescence excitation.

The natural fluorophores contained in the irradiated, biological tissue are stimulated. When used on the back of the eye, this can be the autofluorescence of lipofuscin, which accumulates as an old pigment in the retinal pigment epithelium, or also of flavins. In other biological tissues, this is typically the autofluorescence of the natural fluorophores, in particular NADH (nicotinamide-adenine-dinncleotide, reduced) and tryptophan.

On the other hand, a fluorescent dye to be injected can also be used for temperature determination. At the back of the eye while the African already for cli ^¬ diagnosis fluorophores used fluorescein and indocyanine green (ICG) are mainly used.

The fluorescence properties of the fluorophores change, in particular the fluorescence intensity, as a function of the temperature increase. The absolute temperature increase can then be determined from this change in fluorescence with the aid of calibration data. A fluorescence measurement signal, which is normalized to the normal body temperature, for example the human body temperature of 37 ° C., is preferably obtained shortly before, when, or immediately after the treatment radiation is switched on by an additional short-term radiation pulse.

Due to the constant monitoring of the temperature even during the respective irradiation time (pulse duration) of the treatment radiation, it is possible to control the treatment radiation as a function of the respectively determined temperature at the irradiation site. In particular, the pulse energy or pulse power of the treatment beam can be controlled in order to obtain the desired temperature at the radiation site.

It is advantageous in the invention that the target tissue can be determined by a suitable choice of the dye, in particular by specific attachment of the dye, if exogenous dyes are used. By selecting the suitable wavelength, natural tissue-specific chromophores can be excited, which means that their temperature increase can be recorded selectively. Using a confocal fluorescence excitation, a temporal and depth resolution and thus a 3-D temperature distribution during irradiation can be achieved in addition to the temporal resolution.

[Examples] The invention is explained in more detail with the aid of the figures.

It shows 1 shows a first exemplary embodiment of a device for carrying out the invention in which the treatment beam source is used for fluorescence excitation;

2 shows a second exemplary embodiment of a device with which the invention can be carried out;

3 shows an autofluorescence change measured on the fundus of the patient during irradiation and already converted into a temperature increase, on which a simulated temperature profile was superimposed;

Fig. 4 shows a temperature-dependent change in fluorescence from

A2E (1μM dissolved in DMSO), the main constituent of the fluorophore lipofuscin, which occurs naturally in the retinal pigment epithelium, the fluorescence intensity changing linearly with the sample temperature; and

5 shows a temperature-dependent change in fluorescence of fluorescein (lμM in H20), which is routinely used as a dye for diagnostics in ophthalmology.

The device shown partially in block diagram in FIGS. 1 and 2 includes a treatment beam source 1, for example a laser beam source, in particular a cw laser. The treatment radiation used for the treatment of the fundus of the eye is generated with the treatment beam source 1. The treatment radiation is processed and via an applicator 9, in particular a slit lamp, via a further optic 8, which preferably An ophthalmic contact glass can be directed onto the fundus, in particular the retina of an eye 5.

The treatment beam source 1 is controlled by a system controller 3. The system control 3 can in particular control the radiation energy and the time period with which the treatment radiation is directed onto the fundus. The signals measured by a fluorescence detector 2 are also evaluated in the system controller 3 and converted into temperature values.

The fluorescence of the fundus, as shown in FIG. 1, can be excited on the one hand with the treatment beam source 1. On the other hand, as shown in FIG. 2, the fluorescence excitation can be carried out with an additionally coupled beam source β.

For this purpose, the device shown in FIG. 2 has the additional beam source 6 used for fluorescence excitation in the form of a pulsed electromagnetic beam source, in particular a pulsed LED or a pulsed laser. The radiation from the additional beam source 6 can be coupled into the beam path of the treatment radiation with the aid of a beam splitter 4. In the exemplary embodiment shown, this coupling takes place after the applicator 9. However, coupling into the treatment radiation can also take place inside or in front of the applicator 9.

As shown in FIGS. 1 and 2, the fluorescent light emitted from the background of the eye is directed to a fluorescence detector 2 with the aid of a beam splitter 7. Its signals are passed on to the system control 3 for evaluation and conversion into absolute temperature values. The absolute values of the temperature can be displayed or for Control or actuation of the treatment beam source 1 can be used.

The fluorescence detector can be designed as a photodiode. A CCD camera or a PMT (photomultiplier) is also suitable for fluorescence measurement. Furthermore, a confocal arrangement with a scanner, such as is known for 3-D fluorescence measurement, for example from DE 198 50 149 AI, can be used. Furthermore, the fluorescence measurement can be spectrally resolved.

FIG. 3 shows that the temperature profile calculated as a function of the irradiation time corresponds to the fluorescence data measured at the fundus of the patient during irradiation.

4 shows the time course of the temperature and the fluorescence of A2E (1 μM dissolved in DMOS (dimethylsuloxide)). It follows that the fluorescence intensity changes linearly and inversely proportional with the sample temperature. A2E is a pyridium bisretenoid that is formed by a Schiff base reaction. It is a main component of retinal lipofuscin and can be produced synthetically.

In the Fig. 5 is the linear temperature dependence of the fluorescence of fluorescence zenzänderung zin (1 uM dissolved in H20) represents ^¬ provided. The fluorescence changes this Farbstof fes prop ^¬ thus also NEN is for temperature determination. [Reference character list]

1 treatment source

2 fluorescence detector 3 system control

4 beam splitters

5 Biolog. Tissue, especially eye

6 beam source for fluorescence excitation

7 beam splitters 8 radiation optics

9 Applicator / slit lamp

Claims

[Claims]

1. A method for non-invasive temperature determination on biological tissue treated with treatment radiation, in particular laser radiation, characterized in that a change in fluorescent light caused by the temperature changes is determined, wherein either a spectral change contains the information of the temperature change and / or the temperature rise from the Total fluorescence intensity change is determined,

and / or the change in the fluorescence decay times is used to determine the temperature.

2. The method according to claim 1, characterized in that the autofluorescence of the irradiated tissue is used for temperature determination.

3. The method according to claim 1, characterized in that an invasively administered fluorophore is used to generate the fluorescent light in the temperature determination.

4. The method according to any one of claims 1 and 2, characterized in that at least one natural fluorophore, in particular NADH and tryptophan and its change in fluorescence is used for temperature determination in biological tissue.

5. The method according to any one of claims 1 and 2, characterized in that in particular on the eye The natural retinal fluorophores lipofuscin and / or flavine and their changes in fluorescence are used to determine the temperature.

6. The method according to any one of claims 1 and 3, characterized in that in particular at the fundus fluorescent and / or ICG and their fluorescence changes are used for temperature determination as dyes.

7. The method according to any one of claims 1 to 6, characterized in that the treatment radiation is simultaneously used for fluorescence excitation.

8. The method according to any one of claims 1 to 6, characterized in that at the same time as the treatment radiation, a further radiation for fluorescence excitation is applied to the radiation surface.

9. The method according to any one of claims 1 to 6 and 8, characterized in that a laser is used for fluorescence excitation.

10. The method according to any one of claims 1 to 6 and 8, characterized in that a pulsed LED is used for fluorescence excitation.

11. The method according to any one of claims 1 to 10, characterized in that an imaging method, in particular a retina scanner at the fundus, is used to determine the fluorescence.

12. The method according to any one of claims 1 to 11, characterized in that before the ^{treatment radiation is} switched on, the fluorescence properties on the normalized body temperature of the irradiated biological tissue.

13. The method according to any one of claims 1 to 11, characterized in that when the treatment radiation is switched on, the fluorescence properties are normalized to the normal body temperature of the irradiated biological tissue.

14. The method according to any one of claims 1 to 11, characterized in that shortly after the treatment radiation is switched on, the fluorescence properties are normalized to the normal body temperature of the irradiated biological tissue.

15. The method according to any one of claims 1 to 14, characterized in that the treatment radiation is controlled as a function of the determined temperature.

16. The method according to any one of claims 1 to 15, characterized in that the fluorescence measurement is carried out with a photodiode.

17. The method according to any one of claims 1 to 15, characterized in that a CCD camera is used for measuring florescence.

18. The method according to any one of claims 1 to 15, characterized in that a photomultiplier is used for the florescence measurement.

19. The method according to any one of claims 1 to 18, characterized in that a confocal arrangement with a scanner for 3-D fluorescence measurement is used.

20. The method according to any one of claims 1 to 15, characterized in that the fluorescence measurement is carried out spectrally resolved.

21. Device for the non-invasive temperature determination of biological tissue, which is treated with radiation, in particular laser radiation, with a predetermined treatment time, characterized by

a treatment beam source (1) for generating the treatment radiation, - a control device (3) which controls the treatment beam source (1) during the predetermined treatment time, an applicator (9) and a radiation optics (8) with which the treatment radiation is directed towards the biological Tissue is directed, a fluorescence detector (2) with which fluorescence excited by the treatment radiation (1) is optically measured, and a system controller (3) which converts the respectively detected measurement signals into a respective one using a calibration curve

Temperature values changes.

22. Device for the non-invasive temperature determination of biological tissue, which is treated with a treatment radiation, in particular laser radiation, with a predetermined treatment time, characterized by a treatment radiation source (1) for generating the treatment radiation, a control device (3), which during the predetermined treatment time controls the treatment beam source (1), an applicator (9) and radiation optics (8) with which the treatment radiation is directed onto the biological tissue, an additional beam source (6) for fluorescence excitation, in particular a laser beam source or LED, which supplies additional radiation pulses via a beam splitter during the treatment time (4) can be coupled into the radiation, a detector (2), with which the excited fluorescence is measured, and a system controller (3), which converts the respectively detected measurement signals with a calibration curve into respective temperature values.

23. The device according to claim 22, characterized in that the radiation pulses of the additional radiation source (6) have a lower energy than the treatment radiation and the pulse duration is shorter than the respectively predetermined ^' irradiation time of the treatment radiation.

24. The device according to claim 22 or 23, characterized in that the pulse duration of the additional radiation pulses or the switch-off time of the treatment radiation is dimensioned smaller by a factor 10 ² or a higher factor than the respective irradiation time of the treatment radiation.

25. Device according to one of claims 21 to 24, characterized in that the treatment beam source

(1) is connected to the system control (3).

26. Device according to one of claims 21 to 25, characterized in that the system controller (3) displays the absolute temperatures.

27. Use of one of the methods according to one of claims 1 to 20 for determining the temperature at the back of the eye, which is treated with treatment radiation, in particular laser radiation.

28. Use of a device according to one of claims 21 to 26 for determining the temperature at the back of the eye, which is treated with treatment radiation, in particular laser radiation.