Apparatus for treating dysplasia, neoplasia, and / or bacterial and viral infections

Abstract

This invention relates to an apparatus for treating dysplasia, tumors, and / or bacterial and viral infections, comprising a first laser (20), at least one second laser (30), a wavelength combiner (40) for combining radiation emitted by the first and second lasers, and an optical transmission device (50), wherein the optical transmission device is connected to the wavelength combiner and configured to transmit the radiation combined in the wavelength combiner to a treatment area, wherein the first laser (20) is configured to emit radiation from a first narrowband wavelength within the following ranges: 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. The second laser 30 is configured to emit radiation from a second narrowband wavelength in the range of 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, particularly preferably 1267 nm. The wavelength range is 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, particularly preferably 1267 nm.

Description

Technical Field

[0001] The present invention relates to an apparatus for treating dysplasia, tumors and / or bacterial and viral infections, comprising a first laser, at least one second laser, a wavelength combiner for combining radiation emitted by the first and second lasers, and an optical transmission device, wherein the optical transmission device is connected to the wavelength combiner and configured to transmit the radiation combined in the wavelength combiner to a treatment area. Background Technology

[0002] "Atypical hyperplasia" is a general term for abnormal growth or development of cells, which can occur at the microscopic (cellular) or macroscopic (organ) level. Cellular-level atypical hyperplasia includes epithelial atypical hyperplasia and osteofibrous atypical hyperplasia. Some of these histopathological changes are often precancerous lesions and can develop into cancerous tissue. These precancerous atypical hyperplasias can be treated in different ways. The most modern treatments either involve dissection techniques followed by resection of the diseased mucosal segment, or thermal techniques, in which a laser (e.g., a CO2 laser) is used to irradiate the mucosa (see non-patent literature D. Condor et al., A Review of CO2 Laser-Mediated Therapy for Oral Mucosal Lesions, Appl. Sci., 11, 7744 (2021)).

[0003] The term "tumor" refers to a new growth (malformation) in body tissue caused by abnormal regulation during cell proliferation. This malformation can involve any type of body tissue and can be benign or malignant. Benign tumors are clearly demarcated from healthy cells, while malignant tumors grow into and damage surrounding tissues. Despite advances in medical treatment, cancer remains one of the most serious medical problems worldwide, urgently requiring new treatment options. Various treatment methods exist today. Current treatments include surgical removal of tumors, especially using laser-based technologies, chemotherapy, therapies utilizing bioactive substances such as specific antibodies, radiation therapy, or photodynamic therapy (PDT).

[0004] Laser therapy is used in multiple medical fields for a wide variety of diseases, and is a 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 et 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)). Photodynamic therapy (PDT) is also used in some cases, such as in oral dysplasia, esophageal dysplasia (Barrett's esophagus), or vulvar dysplasia. Typically, PDT requires systemic or local administration of a drug (photosensitizer, such as Photofrin), followed by appropriate light irradiation. The combination of photosensitizers, light, and oxygen, which is present in all cells, generates reactive oxygen species that damage the abnormal cells irradiated. However, PDT is associated with prolonged photosensitivity in treated patients because a portion of the photosensitizer accumulates in the skin (see non-patent literature JHCorreia et al., Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions, Pharmaceutics, 13, 1332 (2021)).

[0005] In the case of cancer treatment, a large portion of the tissue in the surrounding area is usually treated or removed in order to minimize the possibility of tumor recurrence.

[0006] In the treatment of dysplasia, current methods such as surgery, thermal laser ablation, or photodynamic therapy (PDT) can remove the mucosa and thus eliminate precancerous lesions that might otherwise develop into cancer; however, in many cases, the associated pain is disproportionate to the relatively low risk of transformation into cancer, and only a small percentage of patients decide to undergo diagnosis and treatment. In these treatments, a relatively large portion of the tissue in the affected area is usually also removed.

[0007] A particularly serious problem is dysplasia of the female reproductive region, such as cervical dysplasia. As already mentioned in the general considerations, treatment methods exist, including medication, electrocautery, cryosurgery, laser vaporization, and surgery. In cryotherapy, the cervix is ​​cooled to sub-zero temperatures, thereby damaging the cells through freezing. The main advantage of this method is its simplicity and low cost. The main disadvantage is that it cannot freeze abnormal cells located deep within the tissue, thus leaving these cells untreated. Therefore, it is not suitable for treating advanced dysplasia.

[0008] Snare excision is another routine method in which tissue is removed using a wire snare. In snare excision, also known as LEEP (Loop Electrosurgical Excision Procedure), a thin wire snare is used through which electrical energy is passed to remove abnormal areas of the cervix. Spasms are common during the intervention, and minor bleeding should be anticipated. In cervical conization, cone-shaped tissue inside and around the cervix is ​​removed through surgical intervention or with the aid of a laser. This procedure requires anesthesia and is performed in a surgical setting. Minor bleeding and discomfort are common post-operatively. Hysterectomy is another option in the advanced stages of the disease; however, it is only performed on women who do not wish to have children in the future. Hysterectomy has the lowest recurrence rate of all treatments but is a major surgical intervention. Even after a hysterectomy, dysplasia may reappear in the vagina, making regular Pap smears essential even after the procedure. Importantly, it is not suitable for women of childbearing age. In laser treatment, a laser, such as a carbon dioxide laser, is used to vaporize the degenerated cells. With the aid of a colposcope, the laser is precisely aimed at the relevant area. However, it involves an invasive procedure due to the vaporization process. Healing after laser treatment is much faster than after cryotherapy because no necrotic tissue is left behind. Studies on laser treatment have shown that the failure rate is lower than that of cryotherapy. Another important advantage is that the squamous-columnar junction usually remains visible during cervical healing, making subsequent evaluation easier.

[0009] Another option for treating cervical dysplasia is photodynamic therapy (PDT), however, as already mentioned, it is often associated with prolonged photosensitivity of the skin. All of these methods are highly effective in treating invasive cancer types. While most of these methods are effective to some extent in treating dysplasia, unfortunately, they can have adverse effects on fertility and normal fertility desires. When attempting to completely remove the abnormal tissue and the transformation zone of the cervical mucosa, the cervix may lose its ability to bear the weight of a normal pregnancy up to full term.

[0010] The solution for dysfunctional cervix is ​​surgical cerclage, which carries a high risk of failure, infection, and impaired future fertility. Furthermore, ablation techniques may leave tiny remnants of abnormal tissue. This problem is usually addressed with additional ablation treatment, further increasing cervical damage. These existing treatments for dysplasia, particularly in the female reproductive region, indicate a need for less invasive methods that still combat abnormal cells and promote faster healing of the affected area after treatment. Moreover, it is clear that treatments for early stages of the disease are needed to avoid the need for highly invasive procedures as the disease progresses.

[0011] In the context of cancer treatment, while current methods (such as surgery or phototherapy) often achieve the goal of tumor removal, they are accompanied by considerable side effects, such as prolonged photosensitivity in patients during phototherapy. Furthermore, there is a lack of treatment methods that allow for differentiation between different tissue areas during treatment in a simple manner, i.e., combining invasive treatment of tumor tissue with non-invasive treatment of adjacent tissue areas.

[0012] Furthermore, bacterial and viral infections are among the greatest challenges in medical practice and constitute one of the leading causes of death worldwide. Although a vast array of antibacterial (antibiotic) and antiviral therapies are known, and many compounds with antibiotic and antiviral activity have been identified, new active substances, formulations, and therapies are still needed for bacterial and viral infections that cannot be successfully treated with known compounds and therapies. This is particularly relevant in the context of increasing antibiotic resistance, which 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 antibiotic resistance, the current resistance of viruses to antiviral drugs is also 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, new treatment options are needed, based on mechanisms different from traditional antibiotics and antivirals. One of these newer treatments 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, 2565-2612, 2019). General photodynamic therapy (PDT) has been investigated or applied in a wide range of medical applications (see non-patent literature B.W. Henderson et al., Photodynamic therapy, basic principles and clinical applications, New York: Marcel Dekker, 1992). Photodynamic therapy (PDT) utilizes light and photosensitizers to achieve desired medical effects. A large number of naturally occurring and synthetic dyes have been investigated as potential photosensitizers for aPDT and PDT. Perhaps the most studied class of photosensitizers is tetrapyrrole macrocyclic compounds. Among them, porphyrins and dihydroporphyrins have primarily been tested for their photodynamic efficacy.

[0013] Photodynamic effects are observed only when all three necessary components—a photosensitizer, light, and oxygen (which are present in the cells)—are present simultaneously (see non-patent literature BW Henderson et al., Photodynamic therapy, basic principles and clinical applications, New York: Marcel Dekker, 1992). In PDT, photoselective application confines aPDT and general PDT to the local treatment area, unlike the systemic effects of many other drugs and treatments.

[0014] To date, aPDT has primarily been used for locally restricted bacterial infections. Bacteria are generally classified into two main categories based on the different characteristics and structures of their cell walls: Gram-positive bacteria and Gram-negative bacteria. Among them, Gram-negative bacteria, in particular, are the most resistant to antimicrobial therapy due to their complex cell walls. Viruses, on the other hand, exist in a range of different classifications, depending on the type of genetic information they possess (RNA or DNA viruses) or by being divided into enveloped and non-enveloped viruses. A drawback of both PDT and aPDT is the prolonged photosensitivity experienced by patients, caused by the distribution of the photosensitizer in the body, especially its accumulation in the skin.

[0015] For example, light irradiation devices for treating cancer and dysplasia are described in WO 94 / 15666 A1, WO 93 / 21842 A1 and US 8,292,935 B2. However, these devices are designed for use in combination with photosensitizers during PDT treatment and are either unsuitable or too large for early-stage dysplasia.

[0016] US 2015 / 0375194 A1 describes and discloses a quantum dot laser diode for treating inflammation in both oncological and non-oncological conditions, such as bacterial infections. However, this text does not discuss specific conditions related to dysplasia and early-stage dysplasia. Summary of the Invention

[0017] Based on known prior art, the objective of this invention is to provide an improved device for treating dysplasia, tumors, and / or bacterial and viral infections. In particular, the objective is to provide an improved device for the gentle treatment of dysplasia, tumors, and / or for treating tissue changes or tissue damage associated with inflammation (e.g., also caused by bacteria or viruses) and / or epithelialization diseases, or for wound treatment or the regenerative phase of wounds and inflammation; to eliminate or at least reduce the imperfections and side effects of existing treatments for tumors and similar diseases or precancerous lesions developing from tumors. Simultaneously, the objective of this invention is to provide a device for the gentle treatment of local viral or bacterial infections.

[0018] This task is solved by a device having the features of claim 1 for treating dysplasia, neoplastic diseases, and / or localized viral or bacterial infections. Advantageous improvements are derived from the dependent claims, the description, and the drawings.

[0019] Accordingly, an apparatus for treating dysplasia, tumors and / or inflammation is proposed, comprising a first laser, at least one second laser, a wavelength combiner for combining radiation emitted by the first and second lasers, and an optical transmission device, wherein the optical transmission device is connected to the wavelength combiner and configured to transmit the radiation combined in the wavelength combiner to a treatment area. According to the invention, a first laser is configured to emit radiation from a first narrowband wavelength within the following ranges: 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. nm, and the second laser is configured to emit radiation from a second narrowband wavelength in the range of 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, and particularly preferably 1267 nm.

[0020] The term "narrowband wavelength" refers to monochromatic light, that is, electromagnetic radiation with a precisely defined wavelength. A wavelength range refers to a range from the electromagnetic spectrum. The aforementioned narrowband wavelength can be selected from the range given above. The expression "wavelength ± x nm" means a range of 2x around a given wavelength. For example, the expression 1065 ± 30 nm refers to the range from 1035 nm to 1095 nm. Irradiation with "wavelength ± x nm" means irradiation with light within a specific wavelength range of "2x" around a given average wavelength, such as, for example, irradiation with light selected from one of the wavelengths 1262 nm, 1263 nm, 1264 nm, 1265 nm, 1266 nm, 1267 nm, 1268 nm, 1269 nm, 1270 nm, 1271 nm, or 1272 nm within the given range of 1267 ± 5 nm (i.e., 1262 nm to 1272 nm).

[0021] The advantage of combining irradiation with a wavelength selected from the wavelength range used for the first laser and the wavelength of the second laser is that this combination can either enhance the direct excitation of oxygen to singlet oxygen by exciting two transitions of oxygen, or it can activate various different photoinduced cell biological mechanisms in parallel. Such parallel activation of cell biological mechanisms includes, for example, a combination of direct oxygen excitation to singlet oxygen and photobiomodulation, which can also lead to the generation of singlet oxygen or other reactive oxygen species (ROS); a combination of direct oxygen excitation to singlet oxygen and photodynamic therapy (PDT); a combination of photobiomodulation and PDT; or a combination of photobiomodulation and photoinduced activation of stem cells. According to the invention, the wavelength range used for the first laser is selected such that it can effectively excite clinically used photosensitizers.

[0022] By utilizing light-mediated therapy at most of the aforementioned wavelengths, oxygen present in cells can be directly excited into singlet oxygen, or singlet oxygen and / or other reactive oxygen species can be generated through biochemical mechanisms. Furthermore, irradiation at wavelengths in the 1267±5 nm range has immunogenic effects and stimulates the release of cytokines and chemokines, thereby modulating the body's immune response.

[0023] Furthermore, laser irradiation can also be used to directly remove tissue. With this device, for example, tumor tissue can be directly removed, and tumor cells can be selectively eliminated in the periphery of the tumor by direct oxygen stimulation and the immunomodulatory effects of the laser radiation, while maintaining low-intensity tissue protection.

[0024] In addition, reactive oxygen species generated through photo-mediated therapy can directly damage bacteria and viruses, or enhance the body's immune response against pathogens through the immunomodulatory effect of laser radiation.

[0025] Here, direct oxygen stimulation within the tissue can also eliminate bacteria, viruses, and cells associated with tumors or precancerous lesions. This occurs without overheating the intercellular matrix, thus preserving its integrity and allowing new cells to colonize the matrix and its surface. Deeper within the tissue, at low intensities and doses of radiation, cell proliferation and activity can be stimulated to support the healing process and shorten recovery time in the treated area.

[0026] Furthermore, narrow-band excitation enhances the share of radiation absorbed that specifically induces oxygen excitation and the formation of reactive oxygen species, compared to the share of radiation absorbed that results in pure tissue heating. This lower thermal load on the tissue preserves the collagen matrix and allows new cells to migrate into the existing matrix, thereby promoting and simplifying the healing process.

[0027] To minimize the heating of the treated tissue during irradiation of the tumor periphery in tumor treatment, it is essential to target the absorption peaks that generate reactive oxygen species as effectively as possible. Laser diodes, using Bragg gratings, can emit precise wavelengths in a narrow band, and such light sources (e.g., 1267 ± 5 nm) are preferred. Since absorption peaks are also environmentally dependent, and different environments (water, adipose tissue, etc.) may exist in the treatment area, it may also be meaningful to mix two (or more) wavelengths (e.g., 1065 ± 30 nm and 1267 ± 5 nm).

[0028] Furthermore, by providing radiation based on at least two different wavelengths, this device can be combined with other light-based treatment methods, such as phototherapy (PDT). A particular advantage of this device is that the generation of reactive oxygen species at the treatment site is achieved both indirectly through the excitation of a photosensitizer and directly through the excitation of oxygen in the treatment area. This photosensitizer can be a permissible PDT dye, such as, for example, temopofen (excited at 652 nm), tarapofen (excited at 664 nm), tarapofen sodium (excited at 664 nm), padeporfen (excited at 753 nm), vertepofen (excited at 689 nm), HpD (excited at 630 nm), porphyrin sodium (excited at 630 nm), dihydroporphyrin e6 (excited at 665 nm), femtopofen (excited at 650 nm), radopofen (excited at 750 nm), photosensitive dihydroporphyrin (excited at 665 nm), protoporphyrin IX (excited at 630 nm), ALA (as a photosensitizer precursor) (protoporphyrin IX formed by excitation at 630 nm), IRDye700DX (excited at 690 nm), methylene blue (excited at 660 nm), or safranin (excited at 630 nm). Furthermore, this photosensitizer can also be endogenous protoporphyrin IX or other endogenous photosensitizers. In addition, there are photoimmunostimulatory and immunomodulatory effects, especially by employing an additional second irradiation wavelength, which is achieved by the device. This results in a more potent therapeutic effect and a significant reduction in the amount of photosensitizer used, accompanied by a reduction in therapeutic side effects.

[0029] Furthermore, combining it with another light-based treatment method (such as PDT) has the advantage that different tissue regions can be treated in different ways, such as tumor regions with the help of photosensitizers and appropriate wavelengths (corresponding to the absorption spectrum of the photosensitizers) and peripheral regions with laser irradiation at 1267±5 nm, preferably 1267±3 nm, so as to treat these tissues in a protective manner or to take advantage of the immunostimulatory effect of light at that wavelength.

[0030] Alternatively, the combination of two wavelengths in the device can be used to excite two absorption transitions of oxygen and thus enhance the therapeutic effect.

[0031] Another advantageous application of the device of the present invention is the use of laser to activate the differentiation of stem cells within the scope of stem cell therapy.

[0032] Very generally, the combination of two wavelengths offers the advantage of simultaneously activating a variety of different light-induced cell biological mechanisms to improve therapeutic success rates in dysplasia, neoplastic diseases, and localized viral or bacterial infections. These light-based mechanisms can be of different natures and include the generation of reactive oxygen species as well as photostimulatory and immunomodulatory effects.

[0033] Furthermore, the device can be used to specifically irradiate and excite various tissues, taking full advantage of their specific absorption (e.g., skin tissue layers, white and brown adipose tissue), or to penetrate directly through these tissues to reach the underlying tissue layers. Thus, for example, since fat absorbs relatively little light at 1270 ± 30 nm, irradiation with light, especially at these wavelengths, can reach tissue areas covered (or surrounded) by fat cells and associated with atypical hyperplasia particularly well, and these tissue areas can be treated using these laser systems and methods.

[0034] In a preferred embodiment, the second laser has a first laser power of 0.01 watts to 5 watts, preferably 2 watts to 4 watts. The low power of the second laser prevents overheating of the tissue to be treated, for example, in the periphery of a tumor, thus avoiding unnecessary damage to collagen tissue. Here, for example, six to seven diodes with powers of 300 milliwatts (mW) to 400 mW can be used for the laser.

[0035] For the elimination of tumor cells, a fairly high power density is often used, while the power density required for the effective treatment of dysplasia while preserving the collagen matrix tissue is relatively low.

[0036] By using irradiation with wavelengths selected from 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, and particularly preferably 1267 nm, in combination with the aforementioned low power density (as opposed to existing methods in the treatment of tumors or dysplasia), tumor cells or dysplastic cells were cleared, while the collagen matrix was preserved and the healing process was promoted and simplified.

[0037] The treatment promotes the migration of new cells to the affected area and prevents scarring. Typically, low-dose laser radiation promotes cell growth and division. This helps accelerate healing and produces better cosmetic and functional results.

[0038] In a preferred embodiment, the first laser has a second laser power of 10 watts to 100 watts and / or 0.01 watts to 5 watts, preferably 2 watts to 4 watts. Higher optical power and thus a higher optical dose can be selected for tissue removal. In the case of tumor treatment, the higher radiation intensity of the first laser allows for direct removal of tumor tissue. By combining this with further irradiation using a second laser at a low power density—that is, with further irradiation at a separately coordinated and controllable power density in the peripheral region of the tumor and the wider surrounding environment—damage or side effects can be reduced or avoided. Therefore, tumor cells can be cleared, contrary to known methods, while preserving the collagen matrix and promoting and simplifying the healing process.

[0039] In the treatment of bacterial and / or viral infections, using a higher first laser power, i.e., using a higher power density of irradiation with a first laser, it is possible to directly remove unwanted or infected tissue. At a lower second laser power, i.e., using a lower power density of irradiation with a second laser, bacteria and viruses can be directly damaged, and the bacteria and viruses can be reduced through the immunostimulatory effect of the generated reactive oxygen species.

[0040] When the first laser is operating at a low laser power in the range of 0.01 watt to 5 watts, preferably 2 watts to 4 watts, for example, the first laser can be used in combination with a photosensitizer to selectively treat atypical proliferative tissue or tumor tissue by photoexcitation of the photosensitizer, and a second laser (at 1267±5 nm, preferably 1267±3 nm) can be used to clear cells remaining in the edge region of tumor or atypical proliferative tissue through the immunostimulatory effect of the laser, and stimulate the body's own defense.

[0041] In one improved embodiment, the first laser has a greater laser power and / or power intensity than the second laser. The lower power intensity of the second laser can, for example, be used to irradiate the edge region of the treatment site with a laser at 1267±5 nm, preferably 1267±3 nm, to protect the tissue, and can also be used to utilize the immunostimulatory effect of light at that wavelength.

[0042] In a preferred embodiment, the wavelength combiner includes: an optical fiber bundle; a free-space multiplexer with a dichroic mirror and a collimating lens; or a fused fiber wavelength division multiplexer.

[0043] In a preferred improvement, the optical transmission device is an optical fiber bundle.

[0044] In another preferred embodiment, the optical transmission device is a solid optical fiber, particularly a single-mode fiber (e.g., quartz-quartz) or a multimode fiber (e.g., quartz-polymer), a hollow quartz fiber, or a balloon fiber. The use of a balloon fiber can, for example, achieve uniform illumination of the treatment area.

[0045] In addition, to achieve the purpose of irradiating the surface to be treated, fiber optic devices such as diffusers, forward-guided illumination probes, and balloon catheters can be connected to the first laser and the second laser.

[0046] In another preferred improvement, the optical transmission device has at least a square (fiber core) cross-section. This allows for the illumination of the relevant area, i.e., the area to be treated, with the most uniform intensity possible. In particular, this results in a flat-topped emission intensity distribution.

[0047] In another preferred improvement, laser devices are used that generate or amplify vortex photons, which advantageously increases the depth of light penetration. This allows light to reach deeper tissue layers containing tumor cells or atypical proliferating cells, or to reach deeper viruses or bacteria located within the tissue. In a preferred embodiment, a tapered fiber amplifier is used for this purpose. In another preferred embodiment, the transmission of this vortex radiation is achieved via an optical waveguide with a ring core. With the help of these embodiments, the depth of light penetration into the tissue can be increased by approximately 30%. In a preferred embodiment, a cooling device and / or temperature sensor for cooling the treatment area is arranged at the free end of the transmission device. Temperature monitoring and additional cooling can be used to prevent overheating of the treatment area. Temperature monitoring, for example, using a sensor system, can help to deliver lower, uniform, and continuous energy to the tissue, which, through a control loop or alarm system, ensures that the temperature or power density is kept below a predetermined critical value.

[0048] In a preferred embodiment, either the second laser or the first laser is configured to emit radiation in a pulsed manner, wherein a correspondingly other laser is configured to emit radiation continuously. Interruption of irradiation, such as interruption of irradiation by the first laser providing the irradiation, can help achieve the desired uniform low power density. For example, a pulsed high-frequency source (in the MHz range or higher) can be used. Combination with pulsed laser radiation can also help to directly remove tumor tissue. Alternatively, the first laser 20 and the second laser 30 are configured to emit their light radiation in a pulsed manner.

[0049] In another preferred embodiment, the first laser and the second laser are configured to continuously emit radiation. Continuous wave irradiation (CW) can help achieve the desired uniform low power density. By utilizing continuous light wave (CW) irradiation, the desired (uniform) low power density can be continuously ensured.

[0050] Similarly, Raman spectroscopy can be used to characterize tissues and define areas, i.e., areas to be treated, or the device can be combined with optical coherence tomography (OCT) for diagnostic and therapeutic control.

[0051] In a preferred embodiment, a control / adjustment and calculation unit is also included, wherein the control / adjustment program can modify each treatment stage based on measurement data obtained by means of the control / adjustment unit, particularly measurement data from one or more previous treatment stages.

[0052] In a preferred embodiment, the control / adjustment unit is configured to at least temporarily suppress the radiation from the first or second laser, particularly to alternately suppress the radiation from the first or second laser. This allows for the treatment site to be irradiated with only one wavelength alternately. This, in turn, prevents undesirable heating of the treatment site.

[0053] Atypical hyperplasia is often associated with viral infections, such as HPV (human papillomavirus). The combination of photoinduced reactive oxygen species and immune stimulation induced by the device of this invention is also effective in eliminating the virus and reducing viral load (see, for this purpose, non-patent literature A. Wiehe et al., Trends and targets in antiviral phototherapy, Photochem. hotobiol. Sci., 18, 2565-2612 (2019)). Clearing the virus through this treatment also helps prevent atypical hyperplasia, as it is partially caused by the virus. This device and its method of use are therefore also suitable for prophylactic applications to treat the precursor stage of atypical hyperplasia (PAPII, see below).

[0054] The device is designed to treat dysplastic tissues in various body regions, such as the oral cavity, pharynx, esophagus, genitals, or anus. However, it can also be applied to other tissues. While the device demonstrates advantages specifically for precancerous lesions like dysplasia, it can also be applied to cancerous lesions as well as inflamed and other diseased tissues. Furthermore, the device can be used to treat or alleviate diseases or local or systemic viral or bacterial infections. To improve efficacy, the device can also be combined with suitable substances, such as pro-oxidants, 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 cases of dysplasia in the female reproductive regions (vulva, cervix, and vagina), the observed tissue changes are classified according to the Papanicolaou classification as follows: PAP I: Normal result. PAP II: Inflammatory / degenerative changes (still within the normal range). PAP III: Severe inflammatory and / or dysplastic changes, indeterminate results, and neoplasia (precancerous lesion) cannot be ruled out. PAP IIID: Mild to moderate dysplasia PAP IVA: Severe dysplasia, and PAP V: Suspected invasive carcinoma (cancer).

[0056] The device can be used in all stages from PAP II onwards, however it is specifically designed for treatment stages PAPII and III.

[0057] In one improved embodiment, the device is used in the treatment of dysplasia and / or proliferative diseases and / or local and / or systemic viral and / or bacterial infections and / or epithelial dysplasia and / or wound healing. In another embodiment, the device is used in the treatment of dysplasia of the oral cavity, pharynx, nasopharynx, esophagus, gastrointestinal tract, reproductive organs, or anus. In one improved embodiment, the device is used for light-mediated immunomodulation of dysplasia and proliferative diseases. In another embodiment, the device is used for light-mediated immunomodulation or treatment of cancerous lesions and precancerous lesions. Attached Figure Description

[0058] Other preferred embodiments are further illustrated by the following description with reference to the accompanying drawings. In the drawings: Figure 1 The diagram illustrates a device for laser irradiation in combination of two irradiation wavelengths. Figure 2 The diagram schematically illustrates a device for laser irradiation, cooling, and temperature control when two irradiation wavelengths are combined. Figure 3 The diagram schematically illustrates a device for low-power-density laser irradiation in a combination of two irradiation wavelengths, equipped with a spherical fiber. Figure 4 The schematic diagram illustrates a device for low-power-density laser irradiation when two irradiation wavelengths are combined, which has a wavelength combiner in the form of an optical system in free space; Figure 5a The diagram schematically illustrates a device for low power density laser irradiation in a combination of two irradiation wavelengths, which includes a fused single-mode wavelength division multiplexer (WDM) comprising a single-mode fiber. Figure 5b Showing according to Figure 5a A cross-sectional view of the equipment; Figure 6a The diagram schematically illustrates a device for low-power-density laser irradiation in a combination of two irradiation wavelengths, which includes a fused multimode wavelength division multiplexer (WDM) comprising multimode fiber. Figure 6b Showing according to Figure 6a A cross-sectional view of the equipment; Figure 7a The diagram schematically illustrates a device for low-power-density laser irradiation in a combination of two irradiation wavelengths, which features a transmission device with GTWave technology. Figure 7b Showing according to Figure 7a A cross-sectional view of the equipment; Figure 8a The diagram schematically illustrates an apparatus for low-power-density laser irradiation in a combination of two irradiation wavelengths, comprising a transmission device in the form of an optical fiber bundle; and Figure 8b Showing according to Figure 8a A cross-sectional view of the equipment. Detailed Implementation

[0059] Preferred embodiments are described below with reference to the accompanying drawings. Here, identical, similar, or functionally equivalent elements are given the same reference numerals in different drawings. To avoid redundancy, some repeated descriptions of these elements are omitted.

[0060] According to Figures 1 to 3In some embodiments, the first laser 20 can provide low-power illumination with wavelengths in the range of 400 nm to 540 nm or 620 nm to 1950 nm. Preferably, the first laser 20 provides narrowband illumination with wavelengths in the ranges of 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.

[0061] In addition, according to Figures 1 to 3 In one embodiment, the second laser 30 provides NIR radiation at a wavelength of 1267±5 nm, preferably 1267±3 nm.

[0062] This allows for the treatment of different tissue regions in different ways. For example, the tumor region can be treated with a photosensitizer and a suitable wavelength (corresponding to the absorption spectrum of the photosensitizer), while the peripheral region can be irradiated with a laser at 1267±5 nm to treat the tissue in a protective manner or to utilize the immunostimulatory effect of the light at that wavelength.

[0063] The device described in this article can also be combined with Raman or OCT devices used for diagnostic or therapeutic control. The laser system can operate not only in CW laser mode but also in pulsed laser mode.

[0064] Figure 1 A schematic structure of a device 1 for treating dysplasia, tumors, and / or bacterial and viral infections is shown, wherein two irradiation wavelengths are combined. Device 1 includes a first laser 20 and a second laser 30, wherein the first laser 20 can emit narrowband radiation from a wavelength range of 400 nm to 540 nm or 620 nm to 1950 nm, and wherein the second laser 30 can emit narrowband radiation from a wavelength range of 1267 ± 5 nm (1262 nm to 1272 nm), preferably 1267 ± 3 nm (1264 nm to 1270 nm).

[0065] The wavelength range available for selection of the first laser 20 is particularly the following ranges: 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.

[0066] The device 1 also includes a wavelength combiner 40 for combining wavelengths emitted by the first laser 20 and the second laser 30, and an optical device 50 for transmitting the combined radiation to the area to be treated.

[0067] Applicable to Figures 1 to 8a The first laser and the second laser are such that, when the irradiation wavelengths of the first laser 20 and the second laser 30 are combined, the laser irradiation of the first laser 20 can optionally be achieved with a low power density or a high power density, and the laser irradiation of the second laser 30 is achieved with a low power density. In this context, low power density means 0.01 watts to 10 watts, preferably 0.01 watts to 5 watts, particularly preferably 2 watts to 4 watts, depending on the size of the irradiated area.

[0068] The wavelength combiner 40 is formed from a bundle of optical fibers. Alternatively, a free-space multiplexer including a dichroic mirror and a collimating lens or a fused fiber wavelength division multiplexer (WDM) can be used as the wavelength combiner.

[0069] exist Figure 1 In the illustrated embodiment, the optical transmission device 50 for transmitting combined light to the treatment area is formed of a bundle of optical fibers. Alternatively, the optical transmission device 50 may be a solid optical fiber. The optical fiber may be a single-mode (SM) fiber (e.g., quartz-quartz), a multimode (MM) fiber (e.g., quartz-polymer), a hollow quartz fiber, or a spherical fiber. In order to irradiate the relevant area, i.e., the treatment area, with the most uniform intensity possible, it may be advantageous to at least partially implement the optical fiber used for the transmission device with a square cross-section or a core cross-section, which results in a flat-top emission intensity distribution.

[0070] Figure 2The cooling device 60 and temperature sensor 70 shown can be combined with a corresponding temperature adjustment device (not shown) to prevent overheating of the area to be treated. The cooling device 60 is arranged on the exit surface or free end 52 of the transmission device 50, i.e., it can apply a cooling effect to the surface to be irradiated. Coolants such as those used in known laser treatments can be used.

[0071] Figure 2 A device 1 is shown, comprising a first laser 20, a second laser 30, and a transmission device 50 connected to the first laser 20 and the second laser 30. A cooling device 60 and a temperature sensor 70 are arranged on the end of the transmission device 50 pointing towards the area to be treated. In the case of a combination of irradiation wavelengths of the first and second lasers, the laser irradiation of the first laser can optionally be achieved with either a low power density or a high power density, while the laser irradiation of the second laser is achieved with a low power density. In this context, low power density means 0.01 watts to 10 watts, preferably 0.01 watts to 5 watts, particularly preferably 2 watts 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... Figure 1 The possible wavelengths of the first and second lasers.

[0072] The device 1 also includes a wavelength combiner 40 for combining wavelengths emitted by the first laser 20 and the second laser 30, and an optical transmission device 50 for transmitting the combined radiation to the area to be treated.

[0073] Figure 3 A device 1 is shown that can achieve laser irradiation with low power density, as well as cooling and temperature control, when two irradiation wavelengths are combined by a first laser 20 and a second laser 30. Figure 3 In this process, the optical transmission device 50 for transmitting combined light to the area to be treated is formed of 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 specified in the original text. Figure 1 The device 1 also includes a wavelength combiner 40 for combining the wavelengths emitted by the first laser 20 and the second laser 30, and an optical transmission device 50 for transmitting the combined radiation to the area to be treated.

[0074] Figure 4 , Figure 5a , Figure 6a , Figure 7a and Figure 8aA device 1 with different wavelength combiners 40 is shown for treating dysplasia, tumors and / or bacterial and viral infections. The first laser 20 includes a light source capable of utilizing wavelengths from 400 nm to 540 nm or 620 nm to 1950 nm, particularly 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. nm, preferably irradiation with wavelengths in the range of 1940 nm.

[0075] The second laser 30 includes a light source having wavelengths in the range of 1267±5 nm (1262 nm to 1272 nm), preferably 1267±3 nm (1264 nm to 1270 nm). The two lasers 20 and 30 are connected to or pointed to a beam combiner, i.e., a wavelength combiner 40. A transmission device 50 in the form of an optical transmission cable is connected to the wavelength combiner 40, ensuring that the combined beams (e.g., 690±10 nm and 1267±5 nm) are transmitted to the treatment area. The transmission device 50 may include quartz-quartz fiber, quartz-polymer fiber, hollow fiber, or balloon fiber.

[0076] The following will discuss based on Figures 4 to 8b Different design schemes of the wavelength combiner 40 in the implementation.

[0077] according to Figure 4The first laser 20 and the second laser 30 have free-space output ends. A wavelength combiner 40 is formed in free space as an optical system, comprising collimating lenses 42 and 42', a focusing lens 43, a dichroic mirror 44, and a high-reflectance (HR) mirror 45. Here, the radiation from the first laser 20 is guided via the first collimating lens 42 to the high-reflectance (HR) mirror 45. The radiation from the high-reflectance (HR) mirror 45 is guided by the dichroic mirror 44 to the focusing lens 43. The radiation from the second laser 30 is similarly guided via the second collimating lens 42' and the dichroic mirror 44 to the focusing lens 43, where it merges with the radiation from the first laser 20. The combined radiation, i.e., light of two wavelengths, is finally introduced into a transmission device 50, which guides the combined radiation to the treatment site.

[0078] according to Figure 5a and Figure 5b The first laser 20 and the second laser 30 have fiber-coupled output ends. Figure 5a The wavelength combiner 40 shown is formed by a fused single-mode wavelength division multiplexer (WDM) that includes single-mode optical fiber, such as quartz-quartz fiber. Figure 5b An enlarged cross-sectional view of the wavelength combiner 40 is shown.

[0079] according to Figure 6a and Figure 6b The first laser 20 and the second laser 30 have fiber-coupled output ends. Figure 6a The wavelength combiner 40 shown is formed by a fused multimode wavelength division multiplexer (WDM) that includes multimode optical fiber, such as quartz-polymer optical fiber. Figure 6b An enlarged cross-sectional view of the wavelength combiner 40 is shown.

[0080] according to Figure 7a and Figure 7b The first laser 20 and the second laser 30 have fiber-coupled output ends. Figure 7a The wavelength combiner 40 shown includes an array of single-mode or multimode fibers that are drawn in a polymer layer and have optical contacts (GTWave technology). Figure 7b An enlarged cross-sectional view of the wavelength combiner 40 is shown.

[0081] according to Figure 8a and Figure 8b The first laser 20 and the second laser 30 have fiber-coupled output ends. Figure 8a The wavelength combiner 40 shown is formed from a bundle of optical fibers used to combine radiation. Figure 8b An enlarged cross-sectional view of the wavelength combiner 40 is shown.

[0082] Within the applicable scope, all individual features shown in the embodiments may be combined and / or substituted with each other without departing from the scope of the invention.

[0083] List of reference numerals

[0084] 1 Equipment

[0085] 20 First Laser

[0086] 30 Second laser

[0087] 40-wavelength beam combiner

[0088] 41 Fiber bundle

[0089] 42' collimating lens

[0090] 43 Focusing lens

[0091] 44 Dichroic mirror

[0092] 45 High Reflectance (HR) Mirror

[0093] 46 Fiber Wavelength Division Multiplexer

[0094] 50 Transmission devices

[0095] 51-cell balloon fiber

[0096] 52 Free end

[0097] 60 Cooling device

[0098] 70 Temperature Sensor Claims (as amended under Article 19 of the Treaty) 1. A device for treating dysplasia, tumors, and / or bacterial and viral infections (1), said device comprising: First laser (20); At least one second laser (30); A wavelength combiner (40) for combining radiation emitted by the first laser and the second laser; and An optical transmission device (50) is connected to the wavelength combiner and configured to transmit radiation combined in the wavelength combiner to the treatment area. Its features are, The first laser (20) is configured to emit monochromatic radiation of a first wavelength from the following ranges: 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. nm, and the second laser (30) is configured to emit monochromatic radiation of 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 delivery device (50) includes a bundle of optical fibers. 2. The device (1) according to claim 1, wherein the second laser (30) has a first laser power of 0.01 watt to 5 watts, preferably 2 watts to 4 watts. 3. The 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 0.01 watts to 5 watts, preferably 2 watts to 4 watts. 4. The device (1) according to any one of the preceding claims, characterized in that the first laser (20) has a greater laser power than the second laser (30). 5. The device (1) according to any 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. The device (1) according to any one of claims 1 to 5, characterized in that the optical transmission device (50) is a solid optical fiber, especially including single-mode or multi-mode optical fiber, hollow quartz optical fiber or spherical optical fiber (51). 7. The device (1) according to any one of the preceding claims, characterized in that the optical transmission device (50) has at least a square or other polygonal cross-section. 8. The device (1) according to any one of the preceding claims, characterized in that a cooling device (60) and / or a temperature sensor (70) for cooling the treatment area are arranged on the free end (52) of the transmission device (50). 9. The device (1) according to any one of the preceding claims, characterized in that the second laser (30) or the first laser (20) is configured for pulsed emission of radiation, while correspondingly another laser is configured for continuous emission of radiation; or the first laser (20) and the second laser (30) are configured for pulsed emission of their light radiation, or The first laser (20) and the second laser (30) are configured to emit radiation continuously. 10. The device (1) according to any one of the preceding claims, characterized in that it includes a control / adjustment unit, wherein the control / adjustment program is capable of modifying each treatment stage based on measurement data obtained by means of the control / adjustment unit, especially measurement data from one or more previous treatment stages. 11. The device (1) according to the preceding claim, characterized in that the control / adjustment unit is configured to at least temporarily suppress the radiation of the first laser (20) or the second laser (30), and in particular to alternately suppress the radiation of the first laser (20) or the second laser (30).

Claims

1. A device for treating dysplasia, tumors, and / or bacterial and viral infections (1), said device comprising: First laser (20); At least one second laser (30); A wavelength combiner (40) is used to combine the radiation emitted by the first laser and the second laser; as well as An optical transmission device (50) is connected to the wavelength combiner and configured to transmit radiation combined in the wavelength combiner to the treatment area. Its features are, The first laser (20) is configured to emit radiation from a first narrowband wavelength within the following ranges: 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. nm, and the second laser (30) is configured to emit radiation from a second narrowband wavelength in the range of 1262 nm to 1272 nm, preferably 1264 nm to 1270 nm, particularly preferably 1267 nm.

2. The device (1) according to claim 1, characterized in that, The second laser (30) has a first laser power of 0.01 watt to 5 watts, preferably 2 watts to 4 watts.

3. The 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 0.01 watts to 5 watts, preferably 2 watts to 4 watts.

4. The device (1) according to any one of the preceding claims, characterized in that, The first laser (20) has a greater laser power than the second laser (30).

5. The device (1) according to any one of the preceding claims, characterized in that, The wavelength combiner (40) includes: an optical fiber bundle (41); a free-space multiplexer including 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. The device (1) according to any one of the preceding claims, characterized in that, The optical transmission device (50) includes an optical fiber bundle.

7. The device (1) according to any one of claims 1 to 5, characterized in that, The optical transmission device (50) is a solid optical fiber, particularly including single-mode or multi-mode optical fiber, hollow quartz fiber or spherical fiber (51).

8. The device (1) according to any one of the preceding claims, characterized in that, The optical transmission device (50) has at least a square or other polygonal cross-section.

9. The device (1) according to any one of the preceding claims, characterized in that, A cooling device (60) and / or a temperature sensor (70) for cooling the treatment area are arranged on the free end (52) of the transmission device (50).

10. The device (1) according to any one of the preceding claims, characterized in that, The second laser (30) or the first laser (20) is configured for pulsed emission of radiation, while the other laser is configured for continuous emission of radiation; or the first laser (20) and the second laser (30) are configured for pulsed emission of their light radiation, or The first laser (20) and the second laser (30) are configured to emit radiation continuously.

11. The device (1) according to any one of the preceding claims, characterized in that... It includes a control / adjustment unit, wherein the control / adjustment program is capable of modifying each treatment stage based on measurement data obtained by means of the control / adjustment unit, especially measurement data from one or more previous treatment stages.

12. The device (1) according to the preceding claim, characterized in that, The control / adjustment unit is configured to at least temporarily suppress the radiation of the first laser (20) or the second laser (30), and in particular to alternately suppress the radiation of the first laser (20) or the second laser (30).

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