Device for treating dysplasia, tumours and / or bacterial and viral infections

Abstract

The present invention relates to a device for treating dysplasia, tumours and / or bacterial and viral infections, comprising a first laser (20), at least one second laser (30), a wavelength combiner (40) for combining the radiation emitted from the first laser and the second laser, and an optical supply apparatus (50), wherein the optical supply apparatus is connected to the wavelength combiner and is configured to supply the radiation combined in the wavelength combiner to a treatment region, wherein the first laser (20) is configured to emit narrow-band radiation at a first wavelength from the ranges from 400 nm to 420 nm, preferably 410 nm, 440 nm to 460 nm, preferably 450 nm, 520 nm to 540 nm, preferably 530 nm, 620 nm to 640 nm, preferably 630 nm, 645 nm to 675 nm, preferably 660 nm, 680 nm to 700 nm, preferably 690 nm, 745 nm to 775 nm, preferably 760 nm, 800 nm to 820 nm, preferably 810 nm, 910 nm to 930 nm, preferably 920 nm, 970 nm to 990 nm, preferably 980 nm, 1035 nm to 1100 nm, preferably 1065 nm, 1460 nm to 1490 nm, preferably 1470 nm or 1930 nm to 1950 nm, preferably 1940 nm, and the second laser (30) is configured to emit narrow-band radiation at a second wavelength from the range from 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, particularly preferably 1267 nm.

Description

[0001] Device for the treatment of dysplasia, tumors and / or bacterial and viral infections

[0002] Technical area

[0003] The present invention relates to a device for treating dysplasias, tumors and / or bacterial and viral infections, comprising a first laser, at least one second laser, a wavelength combiner for combining the radiation emitted by the first laser and the second laser, and an optical feed device, wherein the optical feed device is connected to the wavelength combiner and is configured to feed the radiation combined in the wavelength combiner to a treatment area.

[0004] State of the art

[0005] “Dysplasia” is the general term for the abnormal growth or development of cells, which can occur at the microscopic (cellular) or macroscopic (organ) level. Dysplasias at the cellular level include epithelial dysplasias and fibrous dysplasias of bone tissue. Some of these histopathological changes are usually precancerous and can develop into cancerous tissue. These precancerous dysplasias can be treated in several ways. The most modern treatments consist either of lift-off techniques with subsequent excision of the diseased mucosal sections or of thermal techniques in which the mucosa is irradiated with lasers (e.g., CO2 lasers) (see non-patent literature D. Condor, et al., A Review of CO2 Laser-Mediated Therapy for Oral Mucosal Lesions, Appl. Sci., 11, 7744 (2021)).

[0006] The term "tumor" refers to new growths in body tissue (neoplasms) that arise due to dysregulation of cell proliferation. Such neoplasms can affect any type of body tissue and can be benign or malignant. Benign tumors are clearly demarcated from healthy cells, whereas malignant tumors grow into and destroy the surrounding tissue. Despite advances in medical therapy, tumor diseases are one of the most serious medical problems worldwide and new treatment options are urgently needed. Various therapeutic approaches exist today. Current treatment methods include, for example, surgical removal of the tumor, including using laser-based techniques, chemotherapy, therapies with biological agents such as special antibodies, radiation therapy or photodynamic therapy (PDT).

[0007] Laser treatment is used in numerous medical fields for various diseases and is a well-known tool, especially in surgery (see non-patent literature E. Khalkhal, et al., The Evaluation of Laser Application in Surgery: A Review Article, J. Lasers Med. Sci., 10 (Suppl 1), pp. S104-S111 (2019) and non-patent literature DJ Jordan, at al., The Use of LASER and its Further Development in Varying Aspects of Surgery, Open Med. J., 3 (Suppl-3, M2), pp. 288-299 (2016).). In some cases, photodynamic therapy (PDT) is also used, e.g., for dysplasias of the oral cavity, dysplasias of the esophagus (Barrett's esophagus), or dysplasias of the vulva. Typically, PDT requires the systemic or local ingestion or administration of a drug (a photosensitizer, e.g., Photofrin) followed by appropriate light irradiation.The combination of photosensitizer, light, and the oxygen present in all cells generates reactive oxygen species that damage the irradiated abnormal cells. However, PDT is associated with prolonged photosensitivity in the treated patient because some of the photosensitizer accumulates in the skin (see non-patent reference JH Correia, et al., Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions, Pharmaceutics, 13, 1332 (2021)).

[0008] In the case of tumor treatment, large parts of the tissue in the affected area are usually treated or removed, including those surrounding the tumor, in order to minimize the likelihood of tumor recurrence.

[0009] In the case of the treatment of dysplasia, current methods such as surgery, thermal laser ablation or PDT can, for example, remove the mucous membrane and thus the precancerous stage, which might otherwise develop into cancer. However, the associated discomfort is in many cases disproportionate to the comparatively low risk of transformation into cancer, and only a small proportion of patients opt for diagnosis and treatment. These treatments usually also involve the removal of relatively large portions of tissue in the affected area. Dysplasia in the female genital area, e.g. dysplasia of the cervix, is a particularly serious problem. As already mentioned in the general considerations, treatment methods include medication, electrocautery, cryosurgery, laser vaporization and surgery.Cryotherapy involves cooling the cervix to subzero temperatures, damaging the cells through freezing. The main advantage of this method is that it is simple and inexpensive. A significant disadvantage is that it cannot freeze the abnormal cells located deep down, leaving them untreated. Therefore, it is not suitable for treating advanced dysplasia.

[0010] Loop excision is another conventional method in which the tissue is removed using a wire loop. Also known as LEEP (Loop Electrosurgical Excision Procedure), loop excision uses a fine wire loop through which electrical energy is passed to remove the abnormal area of ​​the cervix. Cramping is common during the procedure, and mild bleeding is to be expected. Cone biopsy involves removing a cone of tissue in and around the cervix either surgically or with the help of a laser. This procedure requires anesthesia and is performed in a surgical setting. Mild bleeding and discomfort are common after the procedure. For advanced stages of the disease, hysterectomy is another option, but it can only be performed on women who do not plan to have children in the future.Hysterectomy has the lowest recurrence rate of all treatments, but is a major surgical procedure. Even after a hysterectomy, dysplasia in the vagina can recur, so regular Pap smears are essential even after a hysterectomy. It is particularly unsuitable for women of childbearing age. Laser therapy, for example, uses a carbon dioxide laser to vaporize the abnormal cells. A colposcope is used to direct the laser precisely at the affected area. However, due to the vaporization process, it is an invasive procedure. Healing after laser treatment is much faster than after freezing, as no dead tissue is left behind. Studies on laser treatment show that failure rates are lower with laser than with freezing.Another important advantage is that as the cervix heals, the squamocolumnar junction usually remains visible, allowing for easy later evaluation. Another option for treating cervical dysplasia is PDT, although, as previously mentioned, this is usually associated with a prolonged period of skin photosensitivity. All of these methods are very effective in treating invasive cancers. Although most of these methods are effective to some extent in treating dysplasia, they can unfortunately have a detrimental effect on fertility and the ability to conceive normally. In attempting to enclose all the abnormal tissue and the cervical transformation zone, the cervix may lose the ability to withstand the weight load of a normal pregnancy to term.

[0011] One solution for an incompetent cervix is ​​surgical cerclage, which carries a high risk of failure, infection, and compromised future fertility. Furthermore, ablative techniques can leave microscopic remnants of abnormal tissue. This problem is usually addressed with additional ablative treatments, which further increase cervical damage. These existing treatments for dysplasia, and dysplasia of the female genital region in particular, demonstrate the need to find less invasive methods that are still capable of combating the abnormal cells and that also allow for faster healing of the affected area after treatment. Furthermore, it is becoming clear that it is necessary to find treatments for the early stages of the disease to avoid the need for highly invasive treatments in advanced stages.

[0012] In the case of tumor treatment, current methods, such as surgery or PDT, often achieve the goal of removing the tumor, but they are associated with significant side effects, such as prolonged photosensitivity in patients in the case of PDT. Furthermore, there is no treatment method that allows for easy differentiation between different tissue areas during treatment, for example, combining the destruction of the tumor tissue with a non-destructive treatment in adjacent tissue areas.

[0013] Furthermore, bacterial and viral infections pose one of the greatest challenges in medical practice and are a leading cause of death worldwide. Although a large number of antibacterial (antibiotic) and antiviral treatments are known and numerous compounds with antibiotic and antiviral effects have been identified, there is still a need for new active ingredients, formulations, and therapies that can be used to treat bacterial and viral infections that cannot be successfully treated with existing compounds and therapies. This is especially true given the increasing antibiotic resistance that renders many known antibiotics ineffective against bacterial infections (see non-patent literature DM Lin, et al., "Phage therapy: An alternative to antibiotics in the age of multi-drug resistance," World J. Gastrointest. Pharmacol. Ther., 8, pp. 162-173, 2017).Similar to the increasing resistance to antibiotics, viral resistance to antiviral drugs is currently a cause for concern (see non-patent literature L. Strasfeld et al., "Antiviral Drug Resistance: Mechanisms and Clinical Implications," Infect. Dis. Clin. North Am., 24, pp. 413-437, 2010). Therefore, there is a need for new therapeutic options based on mechanisms other than conventional antibiotics and antivirals. One of these newer therapeutic approaches is antimicrobial photodynamic therapy (aPDT), which can be used not only against bacteria and other microorganisms but also against viruses (see non-patent literature A. Wiehe et al., Trends and targets in antiviral phototherapy, Photochem. Photobiol. Sci., 18, pp. 2565-2612, 2019). Photodynamic therapy (PDT) in general is already being researched and used for a variety of medical applications (see non-patent literature BWHenderson, et al., Photodynamic therapy, basic principles and clinical applications, New York: Marcel Dekker, 1992). Photodynamic therapy uses light and a photosensitizer to achieve the desired medical effect. A large number of naturally occurring and synthetic dyes have been investigated as potential photosensitizers for aPDT and PDT. Perhaps the most extensively studied class of photosensitizers is tetrapyrrolic macrocyclic compounds. Among them, porphyrins and chlorins have been tested for their photodynamic efficacy.

[0014] The photodynamic effect is only observed when the three necessary components—the photosensitizer, the light, and oxygen (present within the cell)—are present simultaneously (cf. non-patent literature BW Henderson, et al., Photodynamic therapy, basic principles and clinical applications, New York: Marcel Dekker, 1992). The selective application of light in PDT limits aPDT, and PDT in general, to the local treatment area, in contrast to the systemic effect of many other drugs and treatments. aPDT has so far been used primarily for localized bacterial infections. Bacteria are generally divided into two main groups, Gram-positive and Gram-negative, based on the different properties and structure of their cell walls. Of these, Gram-negative bacteria, in particular, are the most resistant to antibacterial treatments due to their complex cell walls.Viruses are classified in a number of different ways, depending on the type of genetic information they carry (RNA or DNA viruses) or on their division into enveloped and non-enveloped viruses. A disadvantage of PDT and aPDT is the prolonged photosensitivity of patients, which is caused by the distribution of the photosensitizer throughout the body, specifically its accumulation in the skin.

[0015] For example, WO 94 / 15666 A1, WO 93 / 21842 A1 and US 8,292,935 B2 present light irradiation devices for the treatment of cancer and dysplasia, which, however, were designed for use in combination with photosensitizers during PDT treatment and are unsuitable or oversized, particularly for dysplasia in the early stages.

[0016] US 2015 / 0375194 A1 describes and discloses a quantum dot laser diode for the treatment of tumors and non-tumor diseases such as inflammation in bacterial infections. However, this document does not address dysplasia and the specific conditions of early-stage dysplasia.

[0017] Description of the invention

[0018] Based on the known prior art, it is an object of the present invention to provide an improved device for the treatment of dysplasias, tumors, and / or bacterial and viral infections. In particular, it is an object to provide an improved device for the gentle treatment of dysplasias, tumors, and / or for the treatment of associated tissue changes or tissue damage caused by inflammation, such as bacteria or viruses, and / or epithelializing diseases, or for wound treatment or the regeneration phase of wounds and inflammations; to eliminate or at least mitigate the deficiencies and side effects of existing treatments for tumors and similar diseases or precursors to the development of tumors.At the same time, it is an object of the present invention to provide a device for the gentle treatment of local viral or bacterial infections.

[0019] The task is solved by a device for the treatment of dysplasia, neoplastic

[0020] Diseases and / or local viral or bacterial infections are solved with the features of claim 1. Advantageous further developments emerge from the subclaims, the description and the figures.

[0021] Accordingly, a device for treating dysplasias, tumors and / or inflammations is proposed, comprising a first laser, at least one second laser, a wavelength combiner for combining the radiation emitted by the first laser and the second laser, and an optical feed device, wherein the optical feed device is connected to the wavelength combiner and is configured to feed the radiation combined in the wavelength combiner to a treatment area.According to the invention, the first laser is configured to emit radiation at a narrow-band first wavelength from the ranges of 400 nm to 420 nm, preferably 410 nm, 440 nm to 460 nm, preferably 450 nm, 520 nm to 540 nm, preferably 530 nm, 620 nm to 640 nm, preferably 630 nm, 645 nm to 675 nm, preferably 660 nm, 680 nm to 700 nm, preferably 690 nm, 745 nm to 775 nm, preferably 760 nm, 800 nm to 820 nm, preferably 810 nm, 910 nm to 930 nm, preferably 920 nm, 970 nm to 990 nm, preferably 980 nm, 1035 nm to 1100 nm, preferably 1065 nm, 1460 nm to 1490 nm, preferably 1470 nm or 1930 nm to 1950 nm, preferably 1940 nm, and the second laser is configured to emit radiation at a narrowband second wavelength from the range of 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, particularly preferably 1267 nm.

[0022] The term "narrowband wavelength" refers to monochromatic light, i.e., electromagnetic radiation of a precisely defined wavelength. The "wavelength range" refers to a range of the electromagnetic spectrum. The narrowband wavelengths mentioned above can be selected from the ranges specified above. The term "wavelength ±x nm" refers to a range of 2x the specified wavelength. For example, the term 1065±30 nm refers to the range 1035 nm to 1095 nm. Irradiation of / at “wavelength±x nm” means irradiation with light of a specific wavelength from the range “2x” around the specified central wavelength, such as irradiation with light of one of the wavelengths 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271 or 1272 nm selected from the specified range of 1267±5 nm, ie 1262 to 1272 nm.

[0023] The advantage of combining irradiation with a wavelength from the wavelength ranges of the first laser with the wavelength of the second laser is that this combination can either enhance the direct excitation of oxygen to singlet oxygen by stimulating two oxygen transitions, or that various photoinduced cell biological mechanisms can be activated in parallel. This parallel activation of cell biological mechanisms includes, for example, the direct excitation of oxygen to singlet oxygen combined with photobiomodulation, which can also lead to the generation of singlet oxygen or other reactive oxygen species (ROS); the direct excitation of oxygen to singlet oxygen combined with PDT, photobiomodulation combined with PDT, or photobiomodulation combined with the light-induced activation of stem cells.According to the invention, the wavelength ranges for the first laser are selected so that they can effectively stimulate clinically used photosensitizers.

[0024] Light-mediated treatment with most of the above-mentioned wavelengths can directly excite the oxygen present in cells to form singlet oxygen, or generate singlet oxygen and / or other reactive oxygen species through biochemical mechanisms. Furthermore, irradiation at a wavelength in the range of 1267±5 nm has an immunogenic effect and stimulates the release of cytokines and chemokines, which can modulate the body's immune response.

[0025] Furthermore, tissue can also be directly ablated using laser irradiation. Using this device, for example, tumor tissue can be directly ablated, while tumor cells can be specifically eliminated in peripheral areas of the tumor at lower intensity, thereby reducing damage to the tissue, through direct stimulation of oxygen and the immunomodulatory effect of this laser radiation.

[0026] Furthermore, the reactive oxygen species generated by the light-mediated treatment are capable of directly damaging bacteria and viruses or, through the immunomodulating effect of the laser radiation, enhancing the body's immune response against the pathogens.

[0027] The direct stimulation of oxygen in the tissue makes it possible to eliminate bacteria and viruses, as well as cells from tumors or precancerous lesions. This occurs without overheating the intercellular matrix, allowing it to be preserved and new cells to colonize the matrix and the surface. Deeper in the tissue, at lower radiation intensity and doses, cell proliferation and activity can be stimulated to support the healing process and shorten the recovery time of the treated area. Furthermore, narrowband stimulation makes it possible to increase the proportion of radiation absorption that specifically leads to the stimulation of oxygen and the formation of reactive oxygen species, compared to the proportion of radiation absorption that simply leads to tissue heating.This reduced thermal stress on the tissue preserves the collagen matrix and allows the migration of new cells into the existing matrix, thereby promoting and facilitating the healing process.

[0028] In the case of tumor treatment, to minimize heating of the treated tissue when irradiating the peripheral areas of the tumor, the absorption peak for the formation of reactive oxygen must be targeted as accurately as possible. Bragg gratings allow laser diodes to emit a narrowband, precise wavelength, and such sources are preferred (e.g., 1267±5 nm). Since the absorption peak also depends on the environment, and different environments can exist in the treated area (water, fatty tissue, etc.), it may also be useful to combine two (or more) wavelengths (e.g., 1065±30 nm and 1267±5 nm).

[0029] Furthermore, the provision of radiation based on at least two different wavelengths enables the device to be combined with other light-based treatment methods, such as PDT. The particular advantage of the described device is that the generation of reactive oxygen species at the treatment site occurs indirectly – through excitation of the photosensitizer – and through direct excitation of the oxygen in the treatment area. Such photosensitizers can be approved PDT dyes, such asTemoporfin (excitation at 652 nm), Talaporfin (excitation at 664 nm), Talaporfin sodium (excitation at 664 nm), Padeliporfin (excitation at 753 nm), Verteporfin (excitation at 689 nm), HpD (excitation at 630 nm), Porfimer sodium (excitation at 630 nm), Chlorin e6 (excitation at 665 nm), Fimaporfin (excitation at 650 nm), Redaporfin (excitation at 750 nm), Photochlor (excitation at 665 nm), Protoporphyrin IX (excitation at 630 nm), ALA (as photosensitizer prodrug) (excitation of the formed protoporphyrin IX at 630 nm), IRDye700DX (excitation at 690 nm), methylene blue (excitation at 660 nm), or safranin (excitation at 630 nm). Such photosensitizers can also be endogenous protoporphyrin IX or other endogenous photosensitizers. In addition, there is the immunostimulatory and immunomodulatory effect of light, particularly through the use of an additional second irradiation wavelength, which the described device enables.This allows for greater treatment effectiveness and significantly reduces the amount of photosensitizer used, resulting in reduced side effects of the treatment.

[0030] The combination with another light-based treatment method, such as PDT, also has the advantage that different tissue areas can be treated differently, for example the area of ​​a tumor using a photosensitizer and a suitable wavelength - corresponding to the absorption spectrum of the photosensitizer - and the peripheral areas with laser irradiation of 1267±5 nm, preferably 1267±3 nm, in order to treat the tissue gently or to use the immune-stimulating effect of the light of this wavelength.

[0031] In addition, the combination of two wavelengths in the described device can also be used to stimulate two absorption transitions of oxygen and thus increase the efficiency of the treatment.

[0032] A further advantageous application of the device of the present invention is the use of laser light to activate differentiation of stem cells in the context of stem cell therapy.

[0033] In general, the combination of two wavelengths offers the advantage of simultaneously activating various photoinduced cell biological mechanisms to enhance treatment success in dysplasia, neoplastic diseases, and local viral or bacterial infections. These photo-based mechanisms can be of various natures and include the generation of reactive oxygen species as well as immunostimulatory and immunomodulatory effects of light.

[0034] Furthermore, the device can be used to specifically irradiate and stimulate various tissues (e.g., skin tissue layers, white and brown fat tissue) by utilizing the specific absorption of these tissues, or to reach underlying tissue layers directly through these tissue layers. For example, due to the relatively low light absorption of fat at 1270±30 nm, light irradiation at these wavelengths in particular allows tissue areas, including areas with dysplasia covered (or surrounded) by fat cells, to be particularly well reached and treated with these laser systems and procedures.

[0035] In a preferred embodiment, the second laser has a first laser power of 0.01 to 5 watts, preferably 2 to 4 watts. The low power of the second laser makes it possible to avoid excessive heating of the tissue to be treated, for example, in the peripheral areas of a tumor, and thus avoid unnecessary damage to the collagen tissue. For example, 6-7 diodes with a power of 300 milliwatts (mW) to 400 mW each can be used for one laser.

[0036] A comparatively high power density is often used to eliminate tumor cells, while the power density required for the effective treatment of dysplasia while preserving the collagen matrix tissue is comparatively low.

[0037] By combining irradiation with a wavelength in the range of 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, particularly preferably 1267 nm with the low power density described above, the tumor or dysplasia cells are eliminated - in contrast to existing methods in the case of the treatment of tumors or dysplasias - while the collagen matrix is ​​preserved and the healing process is promoted and facilitated.

[0038] The treatment promotes the migration of new cells into the affected area and prevents scarring. In general, a low dose of laser radiation promotes cell growth and promotes cell division. This contributes to accelerated healing and improved cosmetic and functional results.

[0039] In a preferred embodiment, the first laser has a second laser power of 10 watts to 100 watts and / or 0.01 to 5 watts, preferably 2 to 4 watts. For tissue ablation, higher light outputs and thus higher light doses can be selected. In the case of tumor treatment, a higher radiation intensity of the first laser makes it possible to ablate tumor tissue directly. By combining this with further irradiation using the second laser with a low power density, i.e. with an individually adjustable and controllable power density in the peripheral areas and the wider surroundings of the tumor, damage or side effects can be mitigated or avoided. In this way – in contrast to known methods – the tumor cells can be eliminated while the collagen matrix is ​​preserved, promoting and facilitating the healing process.

[0040] In the case of treating bacterial and / or viral infections, unwanted or infected tissue can be directly ablated with a first, higher laser power, i.e., with a higher irradiation power density using the first laser. With a second, lower laser power, i.e., with a lower irradiation power density using the second laser, bacteria and viruses can be directly damaged and reduced by the immunostimulatory effect of the generated reactive oxygen species.

[0041] In the event that the first laser is also operated at a low laser power in the range of 0.01 to 5 watts, preferably 2 to 4 watts, it is possible, for example, to use the first laser in combination with a photosensitizer to specifically treat dysplasia or tumor tissue by light excitation of the photosensitizer, and with the second laser (at 1267±5 nm, preferably 1267±3 nm) to eliminate remaining cells in the peripheral areas of the tumor or dysplasia tissue through the immune-stimulating effect of the laser light and to stimulate the body's own defenses.

[0042] In a further development, the first laser has a higher laser power and / or power intensity than the second laser. A lower power intensity of the second laser can be used, for example, to treat the peripheral areas of the treatment site with laser irradiation at 1267±5 nm, preferably 1267±3 nm, in a tissue-sparing manner and to utilize the immune-stimulating effect of light at this wavelength.

[0043] In a preferred embodiment, the wavelength combiner comprises an optical fiber bundle, a free-space multiplexer with a dichroic mirror and collimating lenses, or a fused fiber wavelength division multiplexer.

[0044] In a preferred embodiment, the optical feed device is a fiber bundle.

[0045] In a further preferred embodiment, the optical delivery device is a solid optical fiber, in particular a monomode (e.g., quartz-quartz) or multimode (e.g., quartz-polymer) fiber, a hollow-core quartz fiber, or a balloon fiber. The use of a balloon fiber, for example, enables uniform illumination of the area to be treated.

[0046] Furthermore, fiber optic devices such as diffusers, frontally directed illumination probes, balloon catheters and the like can be connected to the first laser and the second laser for the purpose of irradiating the area to be treated.

[0047] In a further preferred embodiment, the optical feed device has at least a partially square (core) cross-section. This makes it possible to irradiate the affected zone, i.e., the area to be treated, with as uniform an intensity as possible. In particular, top-hat radiation intensity distributions can be achieved.

[0048] In a further preferred embodiment, laser devices that generate or amplify vortex photons are used, as this advantageously increases the penetration depth of the light. This allows deeper tissue layers of tumor or dysplasia cells or viruses or bacteria located deeper in the tissue to be reached. In a preferred embodiment, tapered fiber amplifiers are used for this purpose. In further preferred embodiments, such vortex radiation is transmitted via optical fibers with a ring-shaped core. With the help of these embodiments, the penetration depth of the light into the tissue can be increased by approximately 30 percent. In a preferred embodiment, a cooling device for cooling the treatment area and / or a temperature sensor is arranged at a free end of the delivery device.Temperature monitoring and additional cooling can be used to prevent overheating of the treatment area. Temperature monitoring, for example, using sensors that ensure, via a control loop or alarm system, that the temperature or power density remains below a predefined critical value, can contribute to a consistent, low energy input into the tissue.

[0049] In a preferred embodiment, the second laser or the first laser is configured to emit the radiation in pulses, with the respective other laser being configured to emit the radiation continuously. Interrupting the irradiation, for example, the irradiation of the first laser, which provides, for example, laser irradiation, can contribute to the desired homogeneous, low power density. For example, pulsed radiofrequency sources (in the MHz range or higher) can be used. The combination with pulsed laser radiation can also contribute to the direct ablation of tumor tissue. Alternatively, the first laser 20 and the second laser 30 are configured to emit their light radiation in pulses.

[0050] In a further preferred embodiment, the first laser and the second laser are configured to emit radiation continuously. Continuous wave (CW) irradiation can contribute to the desired homogeneous, low power density. Irradiation with continuous light waves (CW) can ensure the desired (homogeneous) low power density continuously. Raman spectroscopy can also be used to characterize the tissue and delineate the zone, i.e., the area to be treated, or the device can be combined with optical coherence tomography (OCT) for diagnosis and treatment monitoring.

[0051] In a preferred embodiment, a control / regulation and computing unit is further included, wherein a control / regulation program can modify individual treatment stages depending on measurement data obtained by means of the control / regulation unit, in particular measurement data of the previous treatment stageZn.

[0052] In a preferred embodiment, the control / regulation unit is configured to suppress the radiation of the first laser or the second laser at least temporarily, in particular to suppress the radiation of the first laser or the second laser alternately. This enables the treatment site to be alternately irradiated with only one wavelength. This can counteract unwanted heating of the treatment site.

[0053] Dysplasias are often associated with viral infections, e.g., HPV (human papillomavirus). The combination of light-induced reactive oxygen species and immune stimulation, as induced by the device of the present invention, is also effective in eliminating viruses and reducing viral load (see non-patent literature A. Wiehe, et al., Trends and targets in antiviral phototherapy, Photochem. Photobiol. Sci., 18, 2565-2612 (2019)). The elimination of viruses through treatment also contributes to the prevention of dysplasia, since dysplasias are partly caused by viruses. The present device and its methods of use are thus also suitable for preventive use in the treatment of precursors to dysplasia (PAP II, see below).

[0054] The described device has been developed for the treatment of dysplasia tissue in various body areas, e.g., dysplasia in the mouth, pharynx, esophagus, genital, or anal region. However, the device can also be used on other tissues. Although the device is particularly advantageous for precancerous lesions such as dysplasia, it can also be used on cancerous lesions as well as inflamed and other diseased tissue. Furthermore, the device can also be used to treat or alleviate diseases or local or systemic viral or bacterial infections. To improve its effectiveness, the described device can also be combined with suitable substances, such as pro-oxidant substances, as described in the non-patent literature DG Choi, et al., Selective Anticancer Therapy Using Pro-Oxidant Drug-Loaded Chitosan-Fucoidan Nanoparticles, Int. J. Mol. Sci., 20, 3220 (2019).

[0055] In dysplasias of the female genital area (vulva, cervix and vagina), the observed tissue changes are classified according to Papanicolaou as follows:

[0056] PAP I: normal findings,

[0057] PAP II: inflammatory / degenerative changes (still normal),

[0058] PAP III: severely inflammatory and / or dysplastic changes, unclear findings, neoplasia (precancerous stage) cannot be ruled out,

[0059] PAP IIID: mild to moderate dysplasia,

[0060] PAP IVA: severe dysplasia, and

[0061] PAP V: Suspected invasive carcinoma (cancer).

[0062] The device described can be used for all stages of PAP II and above, but is particularly suitable for the treatment of stages PAP II and III.

[0063] In one embodiment, the device is used in the treatment of dysplasias and / or proliferative diseases and / or local and / or systemic viral and / or bacterial infections and / or epithelial dysplasias and / or wound healing. In another embodiment, the device is used in the treatment of oral, pharyngeal, nasopharyngeal, esophageal, gastrointestinal, genital, or anal dysplasias. In another embodiment, the device is used for the light-mediated immunomodulation of dysplasias and proliferative diseases. In another embodiment, the device is used for the light-mediated immunomodulation or treatment of cancerous and precancerous lesions.

[0064] Short description of the characters

[0065] Preferred further embodiments are explained in more detail in the following description of the figures. They show:

[0066] Figure 1 schematically shows a device for laser irradiation using a combination of two irradiation wavelengths; Figure 2 schematically shows a device for laser irradiation, cooling, and temperature control using a combination of two irradiation wavelengths;

[0067] Figure 3 shows schematically a device for low power density laser irradiation equipped with a balloon fiber, with a combination of two irradiation wavelengths;

[0068] Figure 4 shows schematically a device for laser irradiation with low power density at a combination of two irradiation wavelengths, with a wavelength combiner in the form of an optical system in free space;

[0069] Figure 5a schematically shows a device for low power density laser irradiation with a combination of two irradiation wavelengths with a fused single-mode wavelength division multiplexer (WDM) with single-mode fibers;

[0070] Figure 5b is a sectional view of the device according to Figure 5a;

[0071] Figure 6a schematically shows a device for low power density laser irradiation with a combination of two irradiation wavelengths with a fused multimode wavelength division multiplexer (WDM) with multimode fibers;

[0072] Figure 6b is a sectional view of the device according to Figure 6a;

[0073] Figure 7a shows schematically a device for laser irradiation with low power density using a combination of two irradiation wavelengths with a delivery device of GTWave technology;

[0074] Figure 7b is a sectional view of the device according to Figure 7a;

[0075] Figure 8a schematically shows a device for laser irradiation with low power density in a combination of two irradiation wavelengths with a feed device in the form of a fiber bundle; and

[0076] Figure 8b is a sectional view of the device according to Figure 8a.

[0077] Detailed Description of Preferred Embodiments Preferred embodiments are described below with reference to the figures. Identical, similar, or equivalent elements in the different figures are provided with identical reference numerals. To avoid redundancies, a repeated description of some of these elements is omitted.

[0078] In the embodiments according to Figures 1 to 3, a first laser 20 can provide irradiation with low light power at a wavelength in a range of 400-540 nm or 620-1950 nm. Preferably, the first laser 20 provides narrowband irradiation at a wavelength from the ranges 410±10 nm, 450±10 nm, 530±10 nm, 630±10 nm, 660±15 nm, 690±10 nm, 760±15 nm, 810±10 nm, 920±10 nm, 980±10 nm, 1065±30 nm, 1470±10 nm, or 1940±10 nm.

[0079] Furthermore, in the embodiments according to Figures 1 to 3, a second laser 30 provides NIR radiation at a wavelength of 1267±5 nm, preferably 1267±3 nm.

[0080] This makes it possible to treat different tissue areas of the treatment area differently, for example the area of ​​a tumor using a photosensitizer and a suitable wavelength - corresponding to the absorption spectrum of the photosensitizer - and the peripheral areas with laser irradiation of 1267±5 nm in order to treat these areas in a tissue-sparing manner or to use the immune-stimulating effect of the light at this wavelength.

[0081] The devices described herein can also be combined with a Raman or OCT device for diagnosis or therapy monitoring. The laser systems can operate in both continuous wave and pulsed laser modes.

[0082] Figure 1 shows the schematic structure of a device 1 for treating dysplasias, tumors, and / or bacterial and viral infections, combining two irradiation wavelengths. The device 1 comprises a first laser 20 and a second laser 30, wherein the first laser 20 can emit narrowband radiation from a wavelength range of 400–540 nm and 620–1950 nm, respectively, and the second laser 30 can emit narrowband radiation at a wavelength in the range of 1267±5 nm (1262 nm to 1272 nm), preferably 1267±3 nm (1264 nm to 1270 nm).

[0083] The wavelength ranges from which the first laser 20 can be selected are in particular the following: 400 nm to 420 nm, preferably 410 nm, 440 nm to 460 nm, preferably 450 nm, 520 nm to 540 nm, preferably 530 nm, 620 nm to 640 nm, preferably 630 nm, 645 nm to

[0084] 675 nm, preferably 660 nm, 680 nm to 700 nm, preferably 690 nm, 745 nm to 775 nm, preferably

[0085] 760 nm, 800 nm to 820 nm, preferably 810 nm, 910 nm to 930 nm, preferably 920 nm, 970 nm to

[0086] 990 nm, preferably 980 nm, 1035 nm to 1100 nm, preferably 1065 nm, 1460 nm to 1490 nm, preferably 1470 nm or 1930 nm to 1950 nm, preferably 1940 nm.

[0087] The device 1 further comprises a wavelength combiner 40 for combining the wavelengths emitted by the first laser 20 and the second laser 30 and an optical delivery device 50 for delivering the combined radiation to the area to be treated.

[0088] For the first and second lasers of Figures 1 to 8a, the laser irradiation of the first laser 20 occurs optionally at low or high power density and the laser irradiation of the second laser 30 occurs at low power density, with a combination of the irradiation wavelengths of the first laser 20 and second laser 30. Low power density in this context means 0.01-10 watts, preferably 0.01 to 5 watts, particularly preferably 2 to 4 watts, depending on the size of the irradiated area.

[0089] The wavelength combiner 40 is formed by an optical fiber bundle. Alternatively, a free-space multiplexer comprising a dichroic mirror and collimating lenses or a fused fiber wavelength division multiplexer (WDM) can be used as the wavelength combiner.

[0090] In the embodiment shown in Figure 1, the optical feed device 50 for the combined light supply to the area to be treated is formed by a fiber bundle. Alternatively, the optical feed device 50 can be a solid optical fiber. The optical fiber can be a monomode (SM) fiber (e.g. quartz-quartz), a multimode (MM) fiber (e.g. quartz-polymer), a hollow-core quartz fiber or a balloon fiber. In order to irradiate the affected zone, i.e. the area to be treated, with the most uniform intensity possible, it can be advantageous to design the fiber used for the feed device at least partially with a square cross-section or core cross-section, which leads to a top-hat radiation intensity distribution.

[0091] The cooling device 60 shown in Figure 2 and the temperature sensor 70 can be combined with a corresponding temperature control (not shown) to prevent overheating of the area to be treated. The cooling device 60 is arranged at the exit surface or at a free end 52 of the delivery device 50 in such a way that it can exert a cooling effect on the surface to be irradiated. Cooling agents such as those used in known laser treatments can be used.

[0092] Figure 2 shows a device 1 comprising a first laser 20, a second laser 30, and a feed device 50 connected to the first laser 20 and second laser 30, wherein a cooling device 60 and a temperature sensor 70 are arranged at the end of the feed device 50 directed towards the area to be treated. The laser irradiation of the first laser takes place optionally at low or high power density, the laser irradiation of the second laser at low power density, with a combination of the irradiation wavelengths of the first and second lasers. Low power density in this context means 0.01-10 watts, preferably 0.01 to 5 watts, particularly preferably 2 to 4 watts, depending on the size of the irradiated area. The possible wavelengths of the first laser 20 and the second laser 30 correspond to those of the first and second lasers according to Figure 1.

[0093] The device 1 further comprises a wavelength combiner 40 for combining the wavelengths emitted by the first laser 20 and the second laser 30 and an optical delivery device 50 for delivering the combined radiation to the area to be treated.

[0094] Figure 3 shows a device 1 that enables laser irradiation with low power density and cooling and temperature control, with a combination of two irradiation wavelengths emanating from a first laser 20 and a second laser 30. In Figure 3, the optical feed device 50 for the combined light supply to the area to be treated is formed by a balloon fiber, which enables uniform illumination of the area to be treated. The possible wavelengths of the first laser 20 and the second laser 30 correspond to those of the first and second lasers according to Figure 1. The device 1 further comprises a wavelength combiner 40 for combining the wavelengths emanating from the first laser 20 and the second laser 30 and an optical feed device 50 for feeding the combined radiation to the area to be treated.

[0095] Figures 4, 5a, 6a, 7a and 8a show devices 1 for the treatment of dysplasias, tumors and / or bacterial and viral infections with different wavelength combiners 40. The first laser 20 comprises a light source which provides irradiation with a wavelength from the ranges 400 - 540 nm or 620 - 1950 nm, in particular 400 nm to 420 nm, preferably 410 nm, 440 nm to 460 nm, preferably 450 nm, 520 nm to 540 nm, preferably 530 nm, 620 nm to 640 nm, preferably 630 nm, 645 nm to 675 nm, preferably 660 nm, 680 nm to 700 nm, preferably 690 nm, 745 nm to 775 nm, preferably 760 nm, 800 nm to 820 nm, preferably 810 nm, 910 nm to 930 nm, preferably 920 nm, 970 nm to 990 nm, preferably 980 nm, 1035 nm to 1100 nm, preferably 1065 nm, 1460 nm to 1490 nm, preferably 1470 nm or 1930 nm to 1950 nm, preferably 1940 nm.

[0096] The second laser 30 comprises a light source with a wavelength in the range 1267±5 nm (1262 nm to 1272 nm), preferably 1267±3 nm (1264 nm to 1270 nm). The two lasers 20, 30 are connected to or directed towards a beam combiner, i.e., a wavelength combiner 40. Connected to the wavelength combiner 40 is a feed device 50 in the form of an optical feed cable, which delivers the combined beams (of, for example, 690±10 nm and 1267±5 nm) to the treatment area. The feed device 50 can comprise a quartz-quartz fiber, a quartz-polymer fiber, a hollow-core fiber, or a balloon fiber.

[0097] The different design of the wavelength combiners 40 in the embodiments according to Figures 4 to 8b will be discussed below.

[0098] According to Figure 4, the first laser 20 and the second laser 30 have a free-space output. The wavelength combiner 40 forms an optical system in free space, which includes a collimating lens 42, 42' and a focusing lens 43 as well as a dichroic mirror 44 and a highly reflective (HR) mirror 45. The radiation from the first laser 20 is guided via a first collimating lens 42 to the highly reflective (HR) mirror 45. From the highly reflective (HR) mirror 45, the radiation is guided via the dichroic mirror 44 to the focusing lens 43. The radiation from the second laser 30 is guided via a second collimating lens 42' and via the dichroic mirror 44 to the focusing lens 43, where it is combined with the radiation from the first laser 20. The combined radiation, i.e.the light of the two ewavelengths, are finally introduced into the delivery device 50, which guides them to the site to be treated.

[0099] According to Figures 5a and 5b, the first laser 20 and the second laser 30 have a fiber-coupled output. The wavelength combiner 40 shown in Figure 5a, i.e., the coupler, is formed by a fused single-mode wavelength division multiplexer (WDM) comprising single-mode fibers, for example, a quartz-quartz fiber. Figure 5b shows an enlarged sectional view through the wavelength combiner 40.

[0100] According to Figures 6a and 6b, the first laser 20 and the second laser 30 have a fiber-coupled output. The wavelength combiner 40 shown in Figure 6a is formed by a fused multimode wavelength division multiplexer (WDM) comprising multimode fibers, for example, a quartz-polymer fiber. Figure 6b shows an enlarged sectional view through the wavelength combiner 40.

[0101] According to Figures 7a and 7b, the first laser 20 and the second laser 30 have a fiber-coupled output. The wavelength combiner 40 shown in Figure 7a comprises an array of single-mode or multimode fibers drawn in a polymer layer and having an optical contact (GTWave technology). Figure 7b shows an enlarged sectional view through the wavelength combiner 40.

[0102] According to Figures 8a and 8b, the first laser 20 and the second laser 30 have a fiber-coupled output. The wavelength combiner 40 shown in Figure 8a is formed by a fiber bundle for combining the radiation. Figure 8b shows an enlarged sectional view through the wavelength combiner 40.

[0103] Where applicable, all individual features presented in the embodiments may be combined and / or exchanged without departing from the scope of the invention.

[0104] List of reference symbols

[0105] 1 device

[0106] 20 First laser

[0107] 30 Second laser 40 Wavelength combiner

[0108] 41 fiber bundles

[0109] 42, 42' collimation lens

[0110] 43 Focusing lens

[0111] 44 Dichroic mirror 45 High-reflective (HR) mirror

[0112] 46 fiber wavelength division multiplexers

[0113] 50 feeding device

[0114] 51 Balloon fiber

[0115] 52 Free end 60 Cooling device

[0116] 70 Temperature sensor

Claims

AMENDED CLAIMS received by the International Bureau on 11 March 2025 (11.03.2025) 1. A device (1) for treating dysplasias, tumors, and / or bacterial and viral infections, comprising a first laser (20); at least one second laser (30); a wavelength combiner (40) for combining the radiation emitted by the first laser and the second laser; and an optical feed device (50), wherein the optical feed device is connected to the wavelength combiner and is configured to feed the radiation combined in the wavelength combiner to a treatment area.characterized in that the first laser (20) is configured to emit monochromatic radiation at a first wavelength from the ranges of 400 nm to 420 nm, preferably 410 nm, 440 nm to 460 nm, preferably 450 nm, 520 nm to 540 nm, preferably 530 nm, 620 nm to 640 nm, preferably 630 nm, 645 nm to 675 nm, preferably 660 nm, 680 nm to 700 nm, preferably 690 nm, 745 nm to 775 nm, preferably 760 nm, 800 nm to 820 nm, preferably 810 nm, 910 nm to 930 nm, preferably 920 nm, 970 nm to 990 nm, preferably 980 nm, 1035 nm to 1100 nm, preferably 1065 nm, 1460 nm to 1490 nm, preferably 1470 nm or 1930 nm to 1950 nm, preferably 1940 nm, and the second laser (30) is configured to emit monochromatic radiation at a second wavelength from the range of 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, particularly preferably 1267 nm, and wherein the optical feed device (50) comprises a fiber bundle; 2. Device (1) according to claim 1, characterized in that the second laser (30) has a first laser power of 0.01 to 5 watts, preferably 2 to 4 watts.

3. Device (1) according to claim 1 or 2, characterized in that the first laser (20) has a second laser power of 10 watts to 100 watts and / or of 0.01 to 5 watts, preferably 2 to 4 watts. AMENDED SHEET (ARTICLE 19) 4. Device (1) according to one of the preceding claims, characterized in that the first laser (20) has a greater laser power than the second laser (30).

5. Device (1) according to one of the preceding claims, characterized in that the wavelength combiner (40) comprises an optical fiber bundle (41); a free-space multiplexer comprising a dichroic mirror (44), a high-reflection (HR) mirror (45) and collimating lenses (42, 42'), and / or at least one focusing lens (43); or a fused fiber wavelength division multiplexer (46).

6. Device (1) according to one of claims 1 to 5, characterized in that the optical feed device (50) is a solid optical fiber, in particular comprising a monomode or multimode fiber, a hollow-core quartz fiber or a balloon fiber (51).

7. Device (1) according to one of the preceding claims, characterized in that the optical feed device (50) has at least partially a square or other polygonal cross-section.

8. Device (1) according to one of the preceding claims, characterized in that a cooling device (60) for cooling the treatment area and / or a temperature sensor (70) is arranged at a free end (52) of the feed device (50).

9. Device (1) according to one of the preceding claims, characterized in that the second laser (30) or the first laser (20) is configured to emit the radiation in pulses and the respective other laser is configured to emit the radiation continuously; or that the first laser (20) and the second laser (30) are configured to emit their light radiation in pulses, or that the first laser (20) and the second laser (30) are configured to emit the radiation continuously. AMENDED SHEET (ARTICLE 19) 10. Device (1) according to one of the preceding claims, characterized in that a control / regulation unit is included, wherein a control / regulation program can modify individual treatment stages depending on measurement data obtained by means of the control / regulation unit, in particular measurement data of previous treatment stages.

11. Device (1) according to the preceding claim, characterized in that the control unit is configured to suppress the radiation of the first laser (20) or the second laser (30) at least temporarily, in particular to suppress the radiation of the first laser (20) or the second laser (30) alternately. AMENDED SHEET (ARTICLE 19)

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