Illumination devices for inducing biological effects

Abstract

A phototherapy device is disclosed for irradiating tissues, such as those within a patient's body cavity, with light to induce various biological effects. These biological effects may include at least one of the following: inactivation and / or inhibition of the growth of one or more pathogens, upregulation of local immune responses, increase of endogenous nitric oxide reserves, release of nitric oxide from endogenous reserves, and induction of anti-inflammatory effects. The biological effects may also include upregulation and downregulation of inflammatory immune response molecules within the target tissue. The wavelength of light is selected based on the expected biological effects on one or more of the target tissue type and target pathogens. Whether using light of a single wavelength or light of multiple wavelengths, phototherapy can provide a variety of pathogenic biological effects. A device for phototherapy is disclosed that provides a light dose to induce biological effects on various target pathogens and tissues with enhanced efficacy and reduced cytotoxicity.

Description

[0001] Related application statement

[0002] This application claims the benefit of U.S. Patent Application Serial No. 17 / 173,457, filed February 11, 2021, which is a continuation-in-part of U.S. Patent Application Serial No. 17 / 162,259, filed January 29, 2021, which is a continuation-in-part of U.S. Patent Application Serial No. 17 / 117,889, filed December 10, 2020. This application also claims the benefit of U.S. Patent Application Serial No. 17 / 162,283, filed January 29, 2021, which is a continuation-in-part of U.S. Patent Application Serial No. 17 / 117,889, filed December 10, 2020. The disclosures of the above applications are incorporated herein by reference in their entirety.

[0003] U.S. Patent Application Serial No. 17 / 117,889 claims the following benefits: U.S. Provisional Patent Application Serial No. 63 / 123,631, filed December 10, 2020; U.S. Provisional Patent Application Serial No. 63 / 075,010, filed September 4, 2020; U.S. Provisional Patent Application Serial No. 63 / 074,970, filed September 4, 2020; U.S. Provisional Patent Application Serial No. 63 / 065,357, filed August 13, 2020; and U.S. Provisional Patent Application Serial No. 62 / 991,903, filed March 19, 2020, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0004] The subject matter of this disclosure generally relates to apparatus and methods for irradiating tissue with light (e.g., phototherapy) to induce one or more biological effects. Furthermore, methods and apparatus for delivering light as a therapeutic treatment of tissue in contact with or infected by a pathogen are also disclosed. Background Technology

[0005] Viral infections pose a significant challenge to human health, particularly respiratory infections from the Orthomyxoviridae family (e.g., influenza) and the Coronaviridae family (e.g., SARS-CoV-2). Furthermore, DNA viruses, including those from the Papillomaviridae family (e.g., human papillomavirus (HPV)), are extremely prevalent, causing low-risk cutaneous papillomas and high-risk mucosal epithelial papillomas. Human papillomavirus (HPV) infection is currently the most common sexually transmitted disease (STD).

[0006] Various phototherapies (including low-level phototherapy (LLLT) and photodynamic therapy (PDT)) have been publicly reported or claimed to provide a variety of health-related medical benefits, including but not limited to: promoting hair growth; treating skin or tissue inflammation; promoting tissue or skin healing or regeneration; promoting wound healing; pain management; reducing wrinkles, scars, stretch marks, varicose veins, and spider veins; treating cardiovascular diseases; treating erectile dysfunction; treating microbial infections; treating hyperbilirubinemia; and treating various oncological and non-oncological diseases or conditions.

[0007] Various mechanisms by which phototherapy provides therapeutic benefits include: increasing circulation (e.g., by increasing the formation of new capillaries); stimulating collagen production; stimulating the release of adenosine triphosphate (ATP); promoting porphyrin production; reducing the excitability of nervous system tissues; regulating fibroblast activity; increasing phagocytosis; inducing thermal effects; stimulating tissue granulation and connective tissue projection; reducing inflammation; and stimulating the release of acetylcholine.

[0008] It has also been proposed that phototherapy stimulates cells to produce nitric oxide. This is attributed to various biological functions of nitric oxide, including its role as a signaling messenger, cytotoxin, anti-apoptotic agent, antioxidant, and microcirculation regulator. Nitric oxide is thought to relax vascular smooth muscle, dilate blood vessels, inhibit platelet aggregation, and regulate T cell-mediated immune responses.

[0009] Nitric oxide is produced by various cell types in tissues and is formed from the conversion of the amino acid L-arginine to L-citrulline and nitric oxide, mediated by the enzymatic action of nitric oxide synthase (NOS). NOS is an NADPH-dependent enzyme that catalyzes the following reactions:

[0010]

[0011] In mammals, three distinct genes encode NOS isoenzymes: neuronal (nNOS or NOS-I), cytokine-induced (iNOS or NOS-II), and endothelial (eNOS or NOS-III). iNOS and nNOS are soluble and primarily found in the cytosol, while eNOS is membrane-associated. Many cells in mammals synthesize iNOS in response to inflammatory conditions.

[0012] The upregulation of inducible nitric oxide synthase expression in the skin and subsequent nitric oxide production in response to radiation stress have been documented. Nitric oxide plays a major antioxidant role in the high levels produced in response to radiation.

[0013] Nitric oxide is a free radical capable of diffusing across cell membranes and into various tissues; however, it is highly reactive, with a half-life of only a few seconds. Due to its unstable nature, nitric oxide rapidly reacts with other molecules to form more stable products. For example, in blood, nitric oxide is rapidly oxidized to nitrite, which is then further oxidized by oxyhemoglobin to nitrate. Nitric oxide also reacts directly with oxyhemoglobin to form methemoglobin and nitrate. Nitric oxide is also endogenously stored in various nitrosochemical structures, including nitrosoglutathione (GSNO), nitrosoalbumin, nitrosohemoglobin, and numerous nitrosocysteine ​​residues on other key blood / tissue proteins. The term "nitroso" is defined as a nitrosated compound (nitrosothiol (RSNO) or nitrosamine (RNNO)) that has undergone S- or N-nitrosation. Examples of nitrosated compounds include GSNO, nitrosoalbumin, nitrosohemoglobin, and proteins containing nitrosocysteine ​​residues. Metal nitroso (M-NO) complexes are another type of endogenously stored cyclic nitric oxide, most commonly found in ferrous nitroso complexes within the body; however, metal nitroso complexes are not limited to complexes with iron-containing metal centers, as nitrosation also occurs at heme groups and copper centers. Examples of metal nitroso complexes include cytochrome c oxidase (CCO-NO) (exhibiting two heme and two copper binding sites), cytochrome c (exhibiting heme center binding), and nitrosohhemoglobin (exhibiting heme center binding in both hemoglobin and methemoglobin), representing endogenous storage of nitric oxide. Summary of the Invention

[0014] This disclosure relates to apparatus and methods for irradiating tissue (e.g., within a mammal and / or within a body cavity of a patient) with light, wherein the light may include at least one property that exerts or induces at least one biological effect within or on the tissue. The biological effect may include at least one of inactivating and inhibiting the growth of one or more combinations of microorganisms and pathogens, including but not limited to viruses, bacteria, fungi, and other microorganisms. The biological effect may also include one or more of upregulating a local immune response, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, releasing nitric oxide from endogenous nitric oxide storage, and inducing anti-inflammatory effects. The wavelength of the light may be selected based on at least one expected biological effect on the target tissue and on one or more target microorganisms or pathogens. In some aspects, the wavelength of the light may include visible light within any number of wavelength ranges based on the expected biological effect. Further aspects relate to irradiating tissue with light using light of a single peak wavelength or a combination of light having more than one peak wavelength, targeting multiple microorganisms and / or multiple pathogens for biological effects. Devices and methods for phototherapy are disclosed, which provide light doses to enhance efficacy and reduce cytotoxicity-induced biological effects against various targeted pathogens and tissues. The light dose can include various combinations of irradiance, wavelength, and exposure time, and can be applied continuously or intermittently via multiple pulsed exposures.

[0015] Due to their relative cost, both economically and in terms of patient health and well-being, there is a great need for novel treatments that inhibit or eradicate viral infections in tissues, particularly mucosal epithelial surfaces such as the cervix, mouth, nose, throat, and anus. Therefore, this article provides such treatments and devices.

[0016] Phototherapy has attracted widespread attention as a treatment method for various diseases and conditions. This article discloses a device for delivering phototherapy to inhibit or eradicate viral infections and its usage. The power output is specified as milliwatts per square centimeter (mW / cm²). 2 The irradiance of light, expressed as , has been proposed to be measured at a specific wavelength for a threshold time exceeding a given duration to produce irradiance in joules per square centimeter (J / cm²). 2 The treatment dose (J / cm³) is indicated by this expression, which is effective for inactivating viruses or treating viral infections while maintaining the viability of epithelial tissue. These treatments can be tailored to the specific tissue being treated and to various fluids in the medium, such as blood, sputum, saliva, cervical fluid, and mucus. Total dose for treating infection (J / cm³) 2 It can be used to treat infection while minimizing damage to specific tissues by dispersing individual doses in multiple administrations, each lasting for seconds or minutes, and multiple doses can be administered over days or weeks.

[0017] In one aspect, an illumination device includes: at least one light source arranged to illuminate tissue within a body cavity, the light configured to induce a biological effect, the biological effect including at least one of altering the concentration of one or more pathogens within the body cavity and altering the growth of one or more pathogens within the body cavity; a light guide configured to receive light from the at least one light source; and a light guide locator configured to fix the light guide to provide light to tissue within the body cavity. In some embodiments, the biological effect includes altering the concentration of one or more pathogens within the body cavity and altering the growth of one or more pathogens within the body cavity. In some embodiments, the one or more pathogens include at least one of viruses, bacteria, and fungi. In some embodiments, the one or more pathogens include the Coronaviridae family. In some embodiments, the Coronaviridae family includes SARS-CoV-2. In some embodiments, the biological effect further includes at least one of upregulating a local immune response within the body cavity, stimulating at least one of enzymatic production of nitric oxide to increase endogenous nitric oxide storage, and releasing nitric oxide from endogenous nitric oxide storage. In some embodiments, the biological effect includes inactivating one or more pathogens in a cell-free environment within the body cavity. In some embodiments, the biological effect includes inhibiting the replication of one or more pathogens in a cell-associated environment within the body cavity.

[0018] In some embodiments, the light guide locator includes a mouthpiece configured to engage one or more surfaces of a user's oral cavity. In some embodiments, the mouthpiece includes one or more bite guards for protecting and securing the light guide. In some embodiments, the lighting device further includes a tongue depressor configured to depress the user's tongue to provide light to the oropharynx. In some embodiments, the tongue depressor is formed from a portion of the light guide. In some embodiments, the lighting device further includes a housing comprising at least one light source, wherein the light guide and the light guide locator are configured to be detachably attached to the housing. In some embodiments, the lighting device further includes a port configured to charge the lighting device and access at least one of the data stored in the lighting device.

[0019] In some embodiments, the light includes a first optical characteristic comprising a peak wavelength in the range of 410 nanometers (nm) to 440 nm. In some embodiments, irradiating the light onto tissue within a body cavity comprises applying light at a concentration of 0.5 joules per square centimeter (J / cm²). 2 Up to 100 J / cm 2 The light dose is within the range. In some embodiments, irradiating tissue within a body cavity with light includes applying a light dose with a phototherapy index in the range of 2 to 250, where the phototherapy index is defined as the dose concentration that reduces tissue viability by 25% divided by the dose concentration that reduces the cellular percentage of one or more pathogens by 50%.

[0020] In another aspect, a lighting device includes: at least one light source arranged to illuminate tissue of a user's oropharynx to induce a biological effect, the biological effect including at least one of altering the concentration of one or more pathogens and altering the growth of one or more pathogens; and a mouthpiece configured to engage with one or more surfaces of a user's oral cavity to provide light to the oropharynx. In some embodiments, the biological effect includes altering the concentration of one or more pathogens and altering the growth of one or more pathogens. In some embodiments, the one or more pathogens include at least one of viruses, bacteria, and fungi. In some embodiments, the one or more pathogens include members of the Coronaviridae family. In some embodiments, the Coronaviridae family includes SARS-CoV-2.

[0021] In some embodiments, the biological effect further includes at least one of upregulating a local immune response, stimulating the enzymatic production of nitric oxide to increase endogenous nitric oxide storage, and releasing at least one of nitric oxide from endogenous storage. In some embodiments, the mouthpiece is configured to dilate the user's oral cavity. In some embodiments, the illumination device further includes a light guide configured to receive light from at least one light source. In some embodiments, the mouthpiece is configured to be detachably attached to the light guide. In some embodiments, the mouthpiece includes one or more mouthguards for protecting and securing the light guide. In some embodiments, a portion of the light guide forms a tongue depressor configured to depress the user's tongue to deliver light to the oropharynx. In some embodiments, the peak wavelength of the light is in the range of 410 nm to 440 nm, and irradiating the oropharyngeal tissue with light includes applying 0.5 J / cm². 2 Up to 100J / cm 2 The light dose is within the range. In some embodiments, one or more pathogens include the Coronaviridae family, and irradiating the oropharyngeal tissue with light includes applying a light dose with a phototherapy index in the range of 2 to 250, whereby the phototherapy index is defined as the dose concentration that reduces tissue viability by 25% divided by the dose concentration that reduces the cellular percentage of one or more pathogens by 50%.

[0022] In another aspect, an illumination device includes: at least one light source; a communication module; and a driving circuit associated with the communication module and the at least one light source, the driving circuit being configured to: receive at least one parameter from a server via the communication module, and control the at least one light source to irradiate mammalian tissue with light to induce at least one biological effect. In some embodiments, the at least one parameter includes one or more of the following: light duration, intensity, peak wavelength, or peak wavelength range. In some embodiments, the at least one parameter includes one or more of the following: optics, locators, light source locators, and light guide locators for identifying the illumination device used to irradiate mammalian tissue. In some embodiments, mammalian tissue includes one or more of the following: ear canal, nasal cavity, oral cavity, oropharyngeal region, larynx, larynx, pharynx, oropharynx, trachea, esophagus, lung, endothelial tissue, and gastrointestinal tissue. The illumination device may further include at least one of the following: a camera and a sensor for collecting data from the mammalian tissue. In some embodiments, the communication module is configured to transmit data from the mammalian tissue to a server. In some embodiments, the data from the mammalian tissue includes one or more of the following: images of the mammalian tissue and sensor data of the mammalian tissue.

[0023] In another aspect, a method includes: accessing data associated with mammalian tissue; generating at least one parameter based on the data associated with mammalian tissue; and sending the at least one parameter to an illumination device capable of irradiating the mammalian tissue with light based on the at least one parameter to induce at least one biological effect. In some embodiments, the at least one parameter includes one or more of the following: light duration, intensity, peak wavelength, or peak wavelength range. In some embodiments, the at least one parameter includes one or more of the following: optics, locators, light source locators, and light guide locators for identifying the illumination device used to irradiate mammalian tissue. In some embodiments, mammalian tissue includes one or more of the following: ear canal, nasal cavity, oral cavity, oropharyngeal region, larynx, larynx, pharynx, oropharynx, trachea, esophagus, lung, endothelial tissue, and gastrointestinal tract tissue. In some embodiments, generating the at least one parameter includes inferring characteristics of the mammalian tissue based on a comparison of data associated with the mammalian tissue with data corresponding to previously determined characteristics of the mammalian tissue.

[0024] In another aspect, a system includes: an illumination device comprising at least one light source arranged to irradiate light onto mammalian tissue; and a server communicating with the illumination device via a network, wherein the server is configured to provide the illumination device with at least one parameter to irradiate light onto mammalian tissue to induce at least one biological effect. In some embodiments, the at least one parameter includes one or more of the following: duration of light, intensity, peak wavelength, or peak wavelength range. In some embodiments, the at least one parameter includes one or more of the following: optics, locators, light source locators, and light guide locators for identifying the illumination device used to irradiate mammalian tissue. In some embodiments, mammalian tissue includes one or more of the following: ear canal, nasal cavity, oral cavity, oropharyngeal region, larynx, larynx, pharynx, oropharynx, trachea, esophagus, lungs, endothelial tissue, and gastrointestinal tract tissue. The network may include at least one of the following: intranet, Internet, wide area network (WAN), local area network (LAN), personal area network (PAN), power line communication (PLC), and cellular network.

[0025] In some embodiments, the server includes an artificial intelligence library in which data corresponding to previously identified mammalian tissue features is input. In some embodiments, the server includes a server-side application configured to collect usage data from other lighting devices and add the usage data to the artificial intelligence library. In some embodiments, the server-side application is configured to: infer features of mammalian tissue based on a comparison between the data collected from the mammalian tissue and the data in the artificial intelligence library corresponding to previously identified mammalian tissue features; and provide at least one parameter to the lighting device.

[0026] In some embodiments, the data collected from mammalian tissue may include one or more measurements of the mammalian tissue. In some embodiments, the data collected from mammalian tissue includes one or more images of the mammalian tissue. One or more images may include at least one of visible light images, infrared images, ultraviolet images, images measuring light within a predetermined wavelength range, and images measuring light within two or more different predetermined wavelength ranges. In some embodiments, the data collected from mammalian tissue includes sensor data of the mammalian tissue. The illumination device may further include at least one of a camera and a sensor, and the data collected from the mammalian tissue is captured by at least one of the camera and sensor of the illumination device. In some embodiments, the data collected from mammalian tissue further includes other tissue diagnostics provided separately from the illumination device. In some embodiments, previously identified mammalian tissue features include at least one of the following: present pathogens, diseases, cancerous lesions, precancerous lesions, tumors, polyps, effusions, and inflammation. In some embodiments, the system may further include a computing device communicating with a server and the illumination device. The computing device may include one or more of a laptop computer, tablet computer, desktop computer, another server, cellular phone, personal digital assistant (PDA), multimedia player, embedded system, wearable device, smartwatch, smart glasses, and game console. In some embodiments, at least one biological effect includes at least one of the following: inactivation of one or more pathogens in a cell-free environment; inhibition of replication of one or more pathogens in a cell-associated environment; upregulation of local immune responses; stimulation of enzymatic production of nitric oxide to increase endogenous nitric oxide storage; release of nitric oxide from endogenous nitric oxide storage; and induction of anti-inflammatory effects. In some embodiments, the lighting device is configured to communicate with a server via at least one of wired and wireless connections. In some embodiments, the lighting device includes a rechargeable power source configured to receive power from an external power source. In some embodiments, the external power source is configured to provide power in response to human movement. In some embodiments, the external power source includes solar energy.

[0027] In another aspect, an illumination device includes: a housing forming a mouthpiece for placement in a user's mouth; at least one light source disposed within the housing to illuminate mammalian tissue; and an electrical module disposed within the housing, the electrical module including drive circuitry configured to drive the at least one light source. In some embodiments, the housing includes at least one optical port configured to transmit light from the at least one light source to mammalian tissue. In some embodiments, the at least one optical port is a continuous portion of the housing. In some embodiments, the at least one optical port is a discontinuous element attached to the housing. In some embodiments, the at least one optical port includes increased transmittance for light of one or more wavelengths supplied to the at least one light source compared to other portions of the housing. In some embodiments, the at least one optical port forms a lens for the at least one light source. In some embodiments, the lens includes an outer surface forming an outwardly curved shape relative to the at least one light source. In some embodiments, the lens includes an outer surface forming an inwardly curved shape relative to the at least one light source. The illumination device may further include at least one of a camera and a sensor. In some embodiments, the illumination device is configured to communicate with a server via a network, and the server is configured to provide the illumination device with at least one parameter to illuminate mammalian tissue to induce at least one biological effect. In some embodiments, the mouthpiece includes an upper surface configured to receive the user's upper teeth during operation and a lower surface configured to receive the user's lower teeth, wherein the thickness of the housing between the upper and lower surfaces is in the range of 1 mm to 50 mm.

[0028] In another aspect, an illumination device includes: a housing forming a mouthpiece for placement within a user's mouth; an electrical module attached to the housing, the electrical module including at least one light source arranged to illuminate a mammal and drive circuitry configured to drive the at least one light source; and a light guide within the housing configured to propagate light from the at least one light source through the housing. In some embodiments, the housing includes at least one optical port configured to transmit light from the light guide to mammalian tissue. In some embodiments, the at least one optical port is a continuous portion of the housing. In some embodiments, the at least one optical port is a discontinuous element attached to the housing. In some embodiments, compared with other portions of the housing, the at least one optical port includes increased transmittance for light of one or more wavelengths provided by the at least one light source. In some embodiments, the at least one optical port forms a lens for light propagation within the light guide. In some embodiments, the lens includes an outer surface forming an outwardly curved shape relative to the light guide. In some embodiments, the lens includes an outer surface forming an inwardly curved shape relative to the light guide. The illumination device may further include at least one of a camera and a sensor. In some embodiments, the lighting device is configured to communicate with a server via a network, and the server is configured to provide the lighting device with at least one parameter to direct light onto mammalian tissue to induce at least one biological effect. In some embodiments, the mouthpiece includes an upper surface configured to receive the user's upper teeth during operation and a lower surface configured to receive the user's lower teeth, wherein the thickness of the housing between the upper and lower surfaces is in the range of 1 mm to 50 mm.

[0029] In another aspect, a method includes: providing an illumination device configured to emit light having optical properties, the illumination device including a light source, a light guide configured to receive light from the light source, and a light guide locator configured to fix at least a portion of the light guide within a user's oral cavity; and irradiating tissue accessible from the user's oral cavity with light to induce a biological effect, wherein the biological effect includes altering a local immune response within the tissue. The tissue may include upper respiratory tract tissue. In some embodiments, the local immune response includes an inflammatory immune response. In some embodiments, altering the local immune response includes upregulating and downregulating at least one of inflammatory immune response molecules. In some embodiments, the inflammatory immune response molecules include cytokines. In some embodiments, the cytokines include one or more of interleukin-1α (IL-1α) molecules, interleukin-1β (IL-1β) molecules, and interleukin-6 (IL-6) molecules. In some embodiments, upregulating and downregulating at least one of the inflammatory immune response molecules includes upregulating one or more of IL-1α and IL-1β molecules while downregulating IL-6 molecules. The method may further include upregulating and downregulating inflammatory immune response molecules without increasing the expression of caspase-3 or lactate dehydrogenase B (LDH-B) proteins. In some embodiments, the optical properties include a peak wavelength in the range of 385 nm to 450 nm, or in the range of 410 nm to 440 nm, or a radiant flux in the range of 5 mW to 5000 mW. The radiant flux is configured to provide 5 mW / cm² to the tissue. 2 Up to 200mW / cm 2 Irradiance within a certain range. In some embodiments, irradiating tissue includes applying 0.5 joules per square centimeter (J / cm²). 2 Up to 100 J / cm 2 The light dose. In some embodiments, the light dose is 2 J / cm². 2 Up to 50J / cm 2 Within the scope of [specific range]. In some embodiments, the biological effect further includes inactivating one or more pathogens in a cell-free environment in vivo and inhibiting the replication of one or more pathogens in a cell-associated environment in vivo. In some embodiments, the one or more pathogens include at least one of viruses, bacteria, and fungi. The biological effect may further include stimulating at least one of the enzymatic production of nitric oxide to increase endogenous nitric oxide storage and release nitric oxide from endogenous nitric oxide storage.

[0030] In another aspect, a method includes: providing a light source configured to emit light comprising optical properties; and irradiating mammalian tissue in vivo with the light to induce a biological effect, wherein the biological effect comprises upregulating and downregulating inflammatory immune response molecules within the tissue. In some embodiments, the inflammatory immune response molecules comprise cytokines. In some embodiments, the cytokines comprise one or more of interleukin-1α (IL-1α) molecules, interleukin-1β (IL-1β) molecules, and interleukin-6 (IL-6) molecules. In some embodiments, upregulating and downregulating the inflammatory immune response molecules comprises upregulating one or more of IL-1α and IL-1β molecules while downregulating IL-6 molecules. The method may further comprise upregulating and downregulating the inflammatory immune response molecules without increasing the expression of caspase-3 or lactate dehydrogenase B (LDH-B) proteins. In some embodiments, the optical properties comprise a peak wavelength in the range of 385 nm to 450 nm or in the range of 410 nm to 440 nm. In some embodiments, irradiating mammalian tissue comprises administering light at a concentration of 0.5 joules per square centimeter (J / cm²). 2 Up to 100 J / cm 2 Within a certain range of light doses. In some embodiments, the biological effects further include inactivating one or more pathogens in a cell-free environment in vivo and inhibiting the replication of one or more pathogens in a cell-associated environment in vivo.

[0031] On the other hand, any of the foregoing aspects, and / or the various individual aspects and features as described herein, may be combined to obtain additional advantages. Any of the various features and elements disclosed herein may be combined with one or more other disclosed features and elements, unless otherwise indicated herein.

[0032] After reading the following detailed description of preferred embodiments in conjunction with the accompanying drawings, those skilled in the art will understand the scope of this disclosure and implement its additional aspects. Attached Figure Description

[0033] The accompanying drawings, which are incorporated in and form part of this specification, illustrate various aspects of this disclosure and, together with the specification, serve to explain the principles of this disclosure.

[0034] Figure 1 This is a block diagram of an exemplary lighting device for increasing the concentration of unbound nitric oxide in living tissue, according to some embodiments.

[0035] Figure 2 It is based on some implementation methods Figure 1 Another block diagram of an exemplary lighting device.

[0036] Figure 3 It is a spectrum showing the intensity of nitric oxide modulated light versus wavelength according to some embodiments.

[0037] Figure 4 It is a spectral graph showing the intensity of light increased by an exemplary endogenous storage and the intensity of light released by an exemplary endogenous storage according to some embodiments, relative to wavelength.

[0038] Figure 5A It shows the reaction sequence of nitric oxide (NO) generated by iNOS catalytic photoactivation, followed by the combination of NO with CCO.

[0039] Figure 5B The diagram shows how arginine reacts with oxygen and NADPH to release unbound nitric oxide, reduce NADPH to NADP, and convert arginine to citrulline in the presence of NOS1 / nNOS, NOS2 / iNOS, and NOS3 / eNOS.

[0040] Figure 5C It is a graph showing the enzymatic production of nitric oxide (in keratinocytes) 24 hours after 10 minutes of irradiation when exposed to light of various wavelengths, expressed as a percentage of cells expressing iNOS.

[0041] Figure 6A This is a graph showing the relationship between the release of nitric oxide (µmol / s) from the GSNO photoreceptor and time (minutes) when exposed to blue, green, and red wavelengths.

[0042] Figure 6B It is a diagram showing nitric oxide attaching to the photoreceptor CCO to form a complex CCO-NO, and then releasing NO from the complex upon exposure to endogenous storage release light.

[0043] Figure 7 It is based on some implementation methods Figure 1 Another block diagram of an exemplary lighting device.

[0044] Figure 8 This is a display based on some implementation methods. Figure 7 The exemplary spectrum of intensity versus wavelength of nitric oxide modulated light is shown.

[0045] Figure 9 According to some embodiments, it includes an additional light emitter. Figure 1 Another block diagram of an exemplary lighting device.

[0046] Figure 10 According to some implementation methods, it includes a camera sensor. Figure 1 Another block diagram of an exemplary lighting device.

[0047] Figure 11This is another block diagram of an exemplary lighting device including an additional light emitter and a camera sensor, according to some embodiments.

[0048] Figure 12 This is based on some implementation methods. Figure 1 Another block diagram of an exemplary lighting device, the size of which is substantially suitable for use within a body cavity.

[0049] Figure 13 According to some embodiments, it includes a light guide for guiding nitric oxide-modulated light into a body cavity. Figure 1 Another block diagram of an exemplary lighting device.

[0050] Figure 14 It is based on some implementation methods Figure 13 A side view of an exemplary handheld structure of an exemplary lighting device.

[0051] Figure 15 It is based on some implementation methods Figure 14 A front view of an exemplary handheld construction.

[0052] Figure 16 It is based on some implementation methods Figure 13 A side view of an exemplary handheld structure of an exemplary lighting device.

[0053] Figure 17 It is based on some implementation methods Figure 16 A perspective view of the various components of an exemplary handheld construction.

[0054] Figure 18 It is based on some implementation methods Figure 16 A front view of an exemplary handheld construction.

[0055] Figure 19 It is based on some implementation methods Figure 13 A perspective view of an exemplary handheld structure of an exemplary lighting device.

[0056] Figure 20 It is based on some implementation methods Figure 13 A partially transparent view of an exemplary handheld structure of an exemplary lighting device.

[0057] Figure 21A This is a schematic front view of at least a portion of an exemplary lighting device for delivering nitric oxide modulated light into tissue within a patient's cavity, according to one embodiment.

[0058] Figure 21B This is a schematic front view of at least a portion of a light-emitting device according to one embodiment, the light-emitting device including a concave light-emitting surface for delivering nitric oxide-modulated light to the cervical tissue of a patient.

[0059] Figure 21C The illustration shows insertion into the vaginal cavity to deliver nitric oxide-modulated light to the patient's cervical tissue. Figure 21B The device.

[0060] Figure 21D This is a schematic front view of at least a portion of a light-emitting device according to another embodiment, the light-emitting device including a probe for delivering nitric oxide-modulated light to a patient's cervical tissue defining a light-emitting surface.

[0061] Figure 21E The illustration shows the insertion into the vaginal cavity. Figure 21D The device, in which a probe portion of a light-emitting surface is inserted into the cervical opening to deliver nitric oxide-modulated light to the patient's cervical tissue.

[0062] Figure 22A This is a perspective view of an exemplary linear light guide according to at least one embodiment.

[0063] Figure 22B This is a perspective view of an exemplary bent light guide according to at least one embodiment.

[0064] Figure 23A This is a side view of an exemplary linear light guide according to at least one embodiment.

[0065] Figure 23B This is a side view of an exemplary bent light guide according to at least one embodiment.

[0066] Figure 23C This is a side view of an exemplary tapered light guide according to at least one embodiment.

[0067] Figure 23D This is a side view of an exemplary upward-conical light guide according to at least one embodiment.

[0068] Figure 23E This is a side view of an exemplary bent light guide with a 90-degree bend, according to at least one embodiment.

[0069] Figure 24A This is a side view of an exemplary bent light guide having multiple bends according to at least one embodiment.

[0070] Figure 24B This is a side view of an exemplary spherical light guide according to at least one embodiment.

[0071] Figure 24C This is a side view of an exemplary bent light guide according to at least one embodiment.

[0072] Figure 25A This is a side view of an exemplary tapered light guide according to at least one embodiment.

[0073] Figure 25B It is based on at least one embodiment. Figure 25A A front view of an exemplary tapered light guide.

[0074] Figure 25C It is based on at least one embodiment. Figure 25A A top view of an exemplary tapered light guide.

[0075] Figure 26A This is a side view of an exemplary split light guide according to at least one embodiment.

[0076] Figure 26B It is based on at least one embodiment. Figure 26A A front view of an exemplary split light guide.

[0077] Figure 26C It is based on at least one embodiment. Figure 26A A top view of an exemplary split light guide.

[0078] Figure 27A It is a perspective view of an exemplary light guide having a circular cross-sectional area and a circular surface according to at least one embodiment.

[0079] Figure 27B It is a perspective view of an exemplary light guide having a hexagonal cross-sectional area and hexagonal surfaces according to at least one embodiment.

[0080] Figure 27C It is a perspective view of an exemplary light guide having an elliptical cross-sectional area and an elliptical surface according to at least one embodiment.

[0081] Figure 27D It is a perspective view of an exemplary light guide having a rectangular cross-sectional area and a rectangular surface according to at least one embodiment.

[0082] Figure 27E It is a perspective view of an exemplary light guide having a pentagonal cross-sectional area and a pentagonal surface according to at least one embodiment.

[0083] Figure 27F It is a perspective view of an exemplary light guide having an octagonal cross-sectional area and an octagonal surface according to at least one embodiment.

[0084] Figure 27G It is a perspective view of an exemplary light guide having an oval cross-sectional area and an oval surface according to at least one embodiment.

[0085] Figure 27H It is a perspective view of an exemplary light guide having a triangular cross-sectional area and a triangular face according to at least one embodiment.

[0086] Figure 27I It is a perspective view of an exemplary light guide having a semi-circular cross-sectional area and a semi-circular surface according to at least one embodiment.

[0087] Figure 27J It is a perspective view of an exemplary light guide with a different cross-sectional area and surface according to at least one embodiment.

[0088] Figure 28A It is a side view of an exemplary light guide having similar surfaces according to at least one embodiment.

[0089] Figure 28B This is a side view of an exemplary light guide with different faces according to at least one embodiment.

[0090] Figure 28C This is a side view of an exemplary light guide with an irregularly shaped surface according to at least one embodiment.

[0091] Figure 28D This is a side view of an exemplary light guide having a conical surface according to at least one embodiment.

[0092] Figure 28E This is a side view of an exemplary light guide with multiple facets according to at least one embodiment.

[0093] Figure 28F This is a side view of an exemplary light guide having a flat surface according to at least one embodiment.

[0094] Figure 28G This is a side view of an exemplary light guide with a convex surface according to at least one embodiment.

[0095] Figure 28H This is a side view of an exemplary light guide with a concave surface according to at least one embodiment.

[0096] Figure 28I This is a side view of an exemplary light guide with a circular surface according to at least one embodiment.

[0097] Figure 28J This is a side view of an exemplary light guide with a chamfered surface according to at least one embodiment.

[0098] Figure 28K This is a side view of an exemplary light guide having an angled surface according to at least one embodiment.

[0099] Figure 29A This is another perspective view of an exemplary light guide having a circular cross-sectional area and a circular surface according to at least one embodiment.

[0100] Figure 29B It is a core without cladding according to at least one embodiment. Figure 29A A cross-sectional view of the optical guide.

[0101] Figure 29C It is a perspective view of an exemplary light guide having a square cross-sectional area and a square face according to at least one embodiment.

[0102] Figure 29D It has a non-clad core Figure 29C A cross-sectional view of the light guide.

[0103] Figure 29E This is a cross-sectional view of an exemplary light guide with a cladding core according to at least one embodiment.

[0104] Figure 29F This is another cross-sectional view of an exemplary light guide with a cladding core according to at least one embodiment.

[0105] Figure 30A This is a perspective view of an exemplary multi-core light guide according to at least one embodiment.

[0106] Figure 30B It is based on at least one embodiment. Figure 30A A cross-sectional view of an exemplary multi-core optical guide.

[0107] Figure 30C This is a perspective view of an exemplary flexible light guide according to at least one embodiment.

[0108] Figure 31A This is a side view of an exemplary multi-core light guide according to at least one embodiment.

[0109] Figure 31B It is based on at least one embodiment. Figure 31A A front view of an exemplary construction of a multi-core optical guide.

[0110] Figure 31C It is based on at least one embodiment. Figure 31A A front view of an exemplary construction of a multi-core optical guide.

[0111] Figure 31D It is based on at least one embodiment. Figure 31A A front view of an exemplary construction of a multi-core optical guide.

[0112] Figure 32A It is a cross-sectional view of an exemplary hollow light guide having a circular cross-sectional area according to at least one embodiment.

[0113] Figure 32B It is a cross-sectional view of an exemplary hollow light guide having a rectangular cross-sectional area according to at least one embodiment.

[0114] Figure 32CIt is a cross-sectional view of an exemplary hollow light guide having an elliptical cross-sectional area according to at least one embodiment.

[0115] Figure 32D It is a cross-sectional view of an exemplary hollow light guide having a hexagonal cross-sectional area according to at least one embodiment.

[0116] Figure 33 This is a perspective view of an exemplary hollow light guide according to at least one embodiment.

[0117] Figure 34 This is a perspective view of another exemplary hollow light guide according to at least one embodiment.

[0118] Figure 35 This is a top view of an exemplary U-shaped light guide having an internal reflective surface according to at least one embodiment.

[0119] Figure 36A This is a cross-sectional view of an exemplary light guide with a cap according to at least one embodiment.

[0120] Figure 36B This is a cross-sectional view of an exemplary light guide with an end dome cap according to at least one embodiment.

[0121] Figure 36C This is a cross-sectional view of an exemplary light guide with an end planar cap according to at least one embodiment.

[0122] Figure 36D This is a cross-sectional view of an exemplary light guide with a tapered shield according to at least one embodiment.

[0123] Figure 36E This is a cross-sectional view of an exemplary light guide having an angled conical shield according to at least one embodiment.

[0124] Figure 36F This is a cross-sectional view of an exemplary light guide with a single-sided shield according to at least one embodiment.

[0125] Figure 36G This is a cross-sectional view of an exemplary light guide with a perforated shield according to at least one embodiment.

[0126] Figure 37 This is a block diagram of an exemplary switching mechanism according to some implementation methods.

[0127] Figure 38 It is based on some implementation methods Figure 37 Another block diagram of an exemplary switching mechanism.

[0128] Figure 39 This is a block diagram of an exemplary system for controlling and / or managing lighting fixtures.

[0129] Figure 40 This is a flowchart of an exemplary method for performing phototherapy procedures based on measurements of living tissue, according to some implementations.

[0130] Figure 41 It includes light-shielding light guides according to some implementation methods. Figure 1 Another block diagram of an exemplary lighting device.

[0131] Figure 42 It includes light-shielding light guides according to some implementation methods. Figure 1 Another block diagram of an exemplary lighting device.

[0132] Figure 43 It is based on some implementation methods Figure 1 A side view of an exemplary handheld structure of an exemplary lighting device.

[0133] Figure 44 It is based on some implementation methods Figure 43 A front view of an exemplary handheld construction.

[0134] Figure 45 It is based on some implementation methods Figure 43 A perspective view of an exemplary handheld construction.

[0135] Figure 46 It is based on some implementation methods Figure 43 An exploded view of an exemplary handheld construction.

[0136] Figure 47 It is based on some implementation methods Figure 43 A cross-sectional view of an exemplary handheld construction.

[0137] Figure 48A It is based on some implementation methods Figure 43 A perspective view of an exemplary mouthpiece.

[0138] Figure 48B It is based on some implementation methods Figure 43 Rear view of an exemplary mouthpiece.

[0139] Figure 48C It is based on some implementation methods Figure 43 A side view of an exemplary mouthpiece.

[0140] Figure 48D It is based on some implementation methods Figure 43 A front view of an exemplary mouthpiece.

[0141] Figure 49A It is based on some implementation methods Figure 43 A perspective view of an exemplary light guide.

[0142] Figure 49B It is based on some implementation methods Figure 43 Rear view of an exemplary light guide.

[0143] Figure 49C It is based on some implementation methods Figure 43 A side view of an exemplary light guide.

[0144] Figure 49D It is based on some implementation methods Figure 43 A front view of an exemplary light guide.

[0145] Figure 50A According to some implementation methods, including Figure 43 A perspective view of an exemplary detachable component, including an exemplary nozzle and a light guide.

[0146] Figure 50B It is based on some implementation methods Figure 50A Rear view of an exemplary detachable component.

[0147] Figure 50C It is based on some implementation methods Figure 50A A side view of an exemplary detachable component.

[0148] Figure 50D It is based on some implementation methods Figure 50A A front view of an exemplary detachable component.

[0149] Figure 51A It is based on some implementation methods without Figures 50A-50D Detachable components Figure 43 A side view of an exemplary handheld structure of an exemplary lighting device.

[0150] Figure 51B It is based on some implementation methods without Figures 50A-50D Detachable components Figure 43 A front view of an exemplary handheld construction.

[0151] Figure 51C It is based on some implementation methods without Figures 50A-50D Detachable components Figure 43 A perspective view of an exemplary handheld construction.

[0152] Figure 52 It is based on some implementation methods Figure 1 A side view of another exemplary construction of an exemplary lighting device.

[0153] Figure 53 It is based on some implementation methods Figure 1 A side view of another exemplary construction of an exemplary lighting device.

[0154] Figure 54A This is a front perspective view of an exemplary handheld configuration of a lighting device for delivering light into or near living tissue in the user's mouth, including the oropharynx.

[0155] Figure 54B yes Figure 54A Rear perspective view of the lighting device.

[0156] Figure 54C yes Figure 54A Front view of the lighting device.

[0157] Figure 54D yes Figure 54A A side view of the lighting device.

[0158] Figure 54E yes Figure 54A A top view of the lighting fixture.

[0159] Figure 55 It is a diagram of the oral cavity.

[0160] Figure 56A This is a perspective view of an exemplary cheek retractor according to certain embodiments.

[0161] Figure 56B This is a perspective view of a cheek retractor that includes materials, such as filters, configured to block certain wavelengths of light during phototherapy treatment.

[0162] Figure 57 This is a perspective view of a device used to fix a light source to a user's nostrils.

[0163] Figure 58 This is a diagram illustrating the inactivation of nitric oxide in the active spike (S) protein of the coronavirus, which facilitates endocytosis and entry into human cells.

[0164] Figure 59A This is a graph illustrating the measured spectral flux of different exemplary LED arrays relative to wavelength.

[0165] Figure 59B The illustration shows a perspective view of a test setup used to provide light from one or more LED arrays to a biological test article.

[0166] Figure 60A This is a graph showing the percentage survival rate at a peak wavelength of 385 nm for a series of doses.

[0167] Figure 60B The diagram is for Figure 60A A graph showing the percentage survival rate at the same dose and peak wavelength of 405 nm.

[0168] Figure 60CThe diagram is for Figure 60A A graph showing the percentage survival rate at the same dose and peak wavelength of 425 nm.

[0169] Figure 61A The figure shows the percentage survival of Vero E6 cells in antiviral assays performed at different cell seeding densities in 96-well plates.

[0170] Figure 61B The figure shows the percentage survival of Vero E6 cells in antiviral assays performed at different cell seeding densities in 48-well plates.

[0171] Figure 61C The figure shows the percentage of survival of Vero E6 cells in antiviral assays performed at different cell seeding densities in 24-well plates.

[0172] Figure 62A This shows the tissue culture infection dose (TCID) of 425 nm light at various dose ranges for Vero E6 cells infected for 1 hour with the SARS-CoV-2 isolate USA-WA1 / 2020 at an MOI of 0.001. 50 A graph showing the percentage of milliliters (ml).

[0173] Figure 62B The diagram shows the percentage reduction in SARS-CoV-2 replication compared to... Figure 62A The graph shows the percentage of cytotoxicity at the indicated light dose.

[0174] Figure 63A The figure illustrates the TCID values ​​of Vero E6 cells infected 1 hour after infection with the SARS-CoV-2 isolate USA-WA1 / 2020 at various dose ranges at 425 nm light. 50 The image is in the format of / ml.

[0175] Figure 63B The diagram shows the percentage reduction in SARS-CoV-2 replication compared to... Figure 63A The graph shows the percentage of cytotoxicity at the indicated light dose.

[0176] Figure 63C This indicates that reverse transcription polymerase chain reaction (rRT-PCR) was used to... Figures 63A-63B TCID 50 A table showing the SARS-CoV-2 RNA assessment performed on the collected samples.

[0177] Figure 64A This shows the TCID of Vero 76 cells infected with SARS-CoV-2 at various dose ranges at 425 nm light. 50 The image is in the format of / ml.

[0178] Figure 64B This shows the percentage reduction in SARS-CoV-2 replication compared to... Figure 64A The graph shows the percentage of cytotoxicity at the indicated light dose.

[0179] Figure 65 This shows that for Vero E6 cells infected with an MOI of 0.01, TCID 50 / ml relative to different doses of 625nm red light.

[0180] Figure 66A This shows the result via TCID. 50 A graph showing the assay of SARS-CoV-2 virus in Vero E6 cells from the first laboratory.

[0181] Figure 66B This shows the result via TCID. 50 A graph showing the assay of SARS-CoV-2 virus in Vero E6 cells from the first laboratory.

[0182] Figure 67A This indicates that it is within the range of 0-180 J / cm 2 Under 530 nm light within the dose range, Vero E6 cells did not show a decrease in viability.

[0183] Figure 67B This indicates that it is within the range of 0-240 J / cm 2 Under 625nm light, Vero E6 cells did not show a decrease in viability.

[0184] Figure 68A This shows the density of Vero E6 cells at different seeding levels and different light doses (J / cm²). 2 A graph of the raw emission value (RLU) of ).

[0185] Figure 68B It is a display Figure 68A A graph showing the percentage survival of Vero E6 cells at different seeding densities and different light doses.

[0186] Figure 68C This is a graph comparing RLU with total cell count, indicating that CTG is a measurement of 10 6 An effective reagent for achieving a cell density of more than one Vero E6 cell.

[0187] Figure 69A Calu-3 cells infected with SARS-CoV-2 showed TCID levels at 24 and 48 hours post-infection. 50 A graph of / ml relative to dose.

[0188] Figure 69B The graph shows for Figure 69A Calu-3 cells, the percentage reduction in SARS-CoV-2 compared to the percentage of cytotoxicity.

[0189] Figure 70A This is a graph showing the percentage reduction in SARS-CoV-2 replication relative to the percentage of cytotoxicity in Vero E6 cells infected with an MOI of 0.01 after irradiation with different doses of 425nm light.

[0190] Figure 70B This is a graph showing the percentage reduction in SARS-CoV-2 replication relative to the percentage of cytotoxicity in Vero E6 cells infected with an MOI of 0.001 after irradiation with different doses of 425nm light.

[0191] Figure 70C The figure shows the percentage of survival of primary human tracheal / bronchial tissue from a single donor at different doses of 425nm light irradiation.

[0192] Figure 71A This is a graph showing the percentage reduction in SARS-CoV-2 replication relative to the percentage of cytotoxicity in Vero E6 cells infected with an MOI of 0.01 after irradiation with different doses of 450 nm light.

[0193] Figure 71B This is a graph showing the percentage reduction in SARS-CoV-2 replication relative to the percentage of cytotoxicity in Vero E6 cells infected with an MOI of 0.001 after irradiation with different doses of 450 nm light.

[0194] Figure 71C The figure shows the percentage of survival of primary human tracheal / bronchial tissue from a single donor at different doses of 450nm light irradiation.

[0195] Figure 72 It is a summary Figures 70A-70C The results are shown in tables in 71A-71C.

[0196] Figure 73A The figure shows the WT-influenza A virus titer, which is based on the residual viral load after different initial viral doses of treatment with different doses of 425nm light.

[0197] Figure 73B The figure shows the titer of Tamiflu-resistant influenza A virus, based on the residual viral load of a single initial viral dose after treatment with different doses of 425nm light.

[0198] Figure 74AThe figure shows the TCID of WT-A influenza treated with different doses of 425nm light. 50 The relationship between / ml and energy dose, with the MOI for WT-A influenza being 0.01.

[0199] Figure 74B The figure shows the percentage reduction in viral load and percentage of cytotoxicity to treated cells when Madin-Darby canine kidney (MDCK) cells infected with influenza A were exposed to different doses of 425 nm light and the MOI of WT-A influenza was 0.01.

[0200] Figure 74C The illustration shows the TCID of cells infected with WT-A influenza and treated with different doses of 425nm light. 50 The MOI for WT-H1 influenza was 0.1.

[0201] Figure 74D The figure shows the percentage reduction in viral load and percentage of cytotoxicity to treated cells when Madin-Darby canine kidney (MDCK) cells infected with influenza A were exposed to different doses of 425 nm light and the MOI of WT-A influenza was 0.1.

[0202] Figure 75A The graph shows the exposure time in hours after exposure, at 58.5 J / cm³. 2 The effectiveness of doses of 405, 425, 450, and 470 nm light in killing Pseudomonas aeruginosa.

[0203] Figure 75B The graph shows the exposure time in hours after exposure, at 58.5 J / cm³. 2 The effectiveness of doses of 405, 425, 450, and 470 nm light in killing Staphylococcus aureus.

[0204] Figure 76A The figure shows the values ​​from 1 to 1000 J / cm 2 The effectiveness of 425nm light applied within the dosage range in killing Pseudomonas aeruginosa.

[0205] Figure 76B The figure shows the values ​​from 1 to 1000 J / cm 2 The effectiveness of 425nm light applied within a dose range in killing Staphylococcus aureus.

[0206] Figure 77A The figure shows the values ​​from 1 to 1000 J / cm 2 The effectiveness of 405nm light applied within the dosage range in killing Pseudomonas aeruginosa.

[0207] Figure 77BThe figure shows the values ​​from 1 to 1000 J / cm 2 The effectiveness of 405nm light applied within a dose range in killing Staphylococcus aureus.

[0208] Figure 78 This is a graph showing the toxicity of 405nm and 425nm light to primary human aortic endothelial cells (HAEC).

[0209] Figure 79A The figure illustrates the exposure of tissues to 4 to 512 J / cm². 2 After exposure to 405nm light within the light dose range, the bacterial log of the infected AIR-100 tissue... 10 Reduction and loss of vitality%.

[0210] Figure 79B The figure illustrates the exposure of tissues to 4 to 512 J / cm². 2 After exposure to 425nm light within the light dose range, the bacterial log of the infected AIR-100 tissue... 10 Reduction and loss of vitality%.

[0211] Figure 79C The figure illustrates the exposure of tissue to 4 to 512 J / cm². 2 After exposure to 405 nm light in the light dose range, bacterial logs of infected AIR-100 tissue containing Gram-negative bacteria (e.g., Pseudomonas aeruginosa) were observed. 10 Reduction and loss of vitality%.

[0212] Figure 79D The figure illustrates the exposure of tissue to 4 to 512 J / cm². 2 After exposure to 425 nm light within the light dose range, bacterial logs of infected AIR-100 tissue containing Gram-negative bacteria (e.g., Pseudomonas aeruginosa) were observed. 10 Reduction and loss of vitality%.

[0213] Figure 79E The figure illustrates the exposure of tissue to 4 to 512 J / cm². 2 After exposure to 405 nm light within the light dose range, bacterial logs of infected AIR-100 tissue containing Gram-positive bacteria (e.g., Staphylococcus aureus) were observed. 10 Reduction and loss of vitality%.

[0214] Figure 79F The figure illustrates the exposure of tissue to 4 to 512 J / cm². 2 After exposure to 425nm light within the light dose range, bacterial logs of infected AIR-100 tissue containing Gram-positive bacteria (e.g., Staphylococcus aureus) were observed. 10 Reduction and loss of vitality%.

[0215] Figure 80A-80J It is a series of graphs showing the bacterial survival rate versus dose (J / cm²). 2 Regarding the effects of 405nm and 425nm light at different dose levels on Pseudomonas aeruginosa and Staphylococcus aureus, this study investigated the effects of 405nm and 425nm light on Pseudomonas aeruginosa and Staphylococcus aureus.

[0216] Figure 81 It is a summary of the Light Therapy Index (LTI) calculation and Figure 79A-8 Table of corresponding bactericidal doses for bacterial experiments shown in Figure 0.

[0217] Figure 82 The figure shows the effect of different doses of 425nm light on killing Pseudomonas aeruginosa over time periods of 0, 2, 4, and 22.5 hours.

[0218] Figure 83 The graph shows the results at 8 and 48 hours after application, regardless of the light intensity (J / cm²). 2 Whether administered as a single dose or in a series of smaller doses, the antibacterial effect (mean CFU / ml) versus the dose (J / cm³) 2 The number of processing times (X) is roughly the same.

[0219] Figure 84A This shows the effect of various drug-resistant cell types (mean CFU / ml) on the dose (J / cm²) at 24 hours post-exposure. 2 (The image is shown.)

[0220] Figure 84B It is a table summarizing the types and strains of bacteria tested.

[0221] Figure 84C A table summarizing the efficacy of twice-daily application of 425nm light against difficult-to-treat clinical pulmonary pathogens.

[0222] Figure 85 It is similar to Figure 39 The system is a schematic diagram of a system for providing phototherapy, including more details on providing tailored phototherapy to induce any number of biological effects on body tissues.

[0223] Figure 86A This is a perspective view of a phototherapy device that includes a shape factor for a mouthpiece used to position itself within the user's mouth during operation.

[0224] Figure 86B yes Figure 86A A top view of the phototherapy device.

[0225] Figure 86C yes Figure 86A An end view of one of the ends of the housing of the phototherapy device.

[0226] Figure 87A It is possible Figure 86A The cross-section of the portion of the phototherapy device that is implemented in all or part of the device to deliver emission to the target tissue.

[0227] Figure 87B It is possible Figure 86A A cross-section of a device portion implemented in all or part of a phototherapy device for delivering emission to target tissue, wherein one or more optical ports include an outwardly curved outer surface.

[0228] Figure 87C It is possible Figure 86A A cross-section of a device portion implemented in all or part of a phototherapy device for delivering emission to target tissue, wherein one or more optical ports include an inwardly curved outer surface.

[0229] Figure 87D It is possible Figure 86A A cross-section of a device portion implemented in all or part of a phototherapy device, which is used to provide emission to target tissue and / or capture images and other sensor data from target tissue.

[0230] Figure 88A It is similar to Figure 86A A perspective view of a phototherapy device, showing the arrangement for attaching the electrical module to the housing rather than incorporating it into the housing.

[0231] Figure 88B yes Figure 88A A top view of the phototherapy device.

[0232] Figure 89A It is possible Figure 88A The cross-section of the portion of the phototherapy device that is implemented in all or part of the device to deliver emission to the target tissue.

[0233] Figure 89B It is possible Figure 88A A cross-section of a device portion implemented in all or part of a phototherapy device to deliver emission to target tissue, wherein one or more optical ports include an outwardly curved outer surface.

[0234] Figure 89C It is possible Figure 88A A cross-section of a device portion implemented in all or part of a phototherapy device to deliver emission to target tissue, wherein one or more optical ports include an inwardly curved outer surface.

[0235] Figure 89D It is possible Figure 88A A cross-section of a device portion implemented in all or part of a phototherapy device, which is used to deliver emission to target tissue and / or capture images and other sensor data from target tissue.

[0236] Figure 90A This is a graph showing the induced expression of interleukin-1α (IL-1α) molecules in AIR-100 tissue in response to light at wavelengths of 385 nm, 425 nm, and 625 nm, compared to unirradiated control tissue samples.

[0237] Figure 90B This shows the comparison with control tissue samples. Figure 90A A diagram showing IL-1α expression induced only by light at a wavelength of 385 nm.

[0238] Figure 90C This shows the comparison with control tissue samples. Figure 90A A diagram showing IL-1α expression induced only by light at a wavelength of 425 nm.

[0239] Figure 90D Figure 90 shows the expression of IL-1α induced only by light at a wavelength of 625 nm, compared to the control tissue sample.

[0240] Figure 90E This is a graph showing the induced expression of interleukin-1β (IL-1β) molecules in AIR-100 tissue in response to light at wavelengths of 385 nm, 425 nm, and 625 nm, compared to unirradiated control tissue samples.

[0241] Figure 90F This is a graph showing the induced expression of interleukin-6 (IL-6) molecules in AIR-100 tissue in response to light at wavelengths of 385 nm, 425 nm, and 625 nm, compared to unirradiated control tissue samples.

[0242] Figure 90G This is a graph showing the induced expression of lactate dehydrogenase B (LDH-B) protein in AIR-100 tissue in response to light at wavelengths of 385 nm and 425 nm, compared to unirradiated control tissue samples.

[0243] Figure 90H This is a graph showing the induced expression of caspase-3 in AIR-100 tissue in response to light at wavelengths of 385 nm and 425 nm, compared to unirradiated control tissue samples.

[0244] Figure 91 It is displayed during operation. Figures 54A-54E A cross-sectional view of the part where the lighting device is placed.

[0245] Figure 92 The table shown summarizes the first Phase I studies used in humans to evaluate the use of [the drug / treatment]. Figure 91 The acute safety and tolerability (e.g., local reactiveness) of the illumination device used for phototherapy.

[0246] Figure 93A The table displays demographic data of the study population used in Phase I / II clinical trials, which is used to assess the use of, for example... Figure 91 The safety and efficacy of the lighting device shown for phototherapy in outpatients with SARS-CoV-2 infection for COVID-19.

[0247] Figure 93B This is a graph showing the viral load of SARS-CoV-2 in saliva during Phase I / II clinical trials.

[0248] Figure 93C This shows the Log for all subjects with a positive baseline value. 10 The average change in SARS-CoV-2 viral load relative to baseline.

[0249] Figure 93D This is a daily summary log of Phase I / II clinical trials. 10 A table of SARS-CoV-2 viral load efficacy data (mean + / - SE).

[0250] Figure 93E This is a graph showing the Kaplan-Meier event time analysis for sustained symptom resolution in a Phase I / II clinical trial.

[0251] Figure 93F This is a table summarizing other key efficacy observations between the active treatment group and the sham treatment group in Phase I / II clinical trials.

[0252] Figure 93G It is a table showing the incidence and severity of any diary symptom scores that occurred on or after day 4 of a phase I / II clinical trial, which were higher than baseline. Detailed Implementation

[0253] The embodiments described below represent the information necessary to enable those skilled in the art to implement the embodiments and to illustrate the best mode of implementation. Upon reading the following description in conjunction with the accompanying drawings, those skilled in the art will understand the concepts of this disclosure and will recognize the application of these concepts not specifically mentioned herein. It should be understood that these concepts and applications fall within the scope of this disclosure and the appended claims.

[0254] It should be understood that although the terms first, second, etc., may be used herein to describe various elements, these elements should not be limited by these terms. These terms are used only to distinguish one element from another. For example, the first element may be referred to as the second element, and similarly, the second element may be referred to as the first element, without departing from the scope of this disclosure. As used herein, the term "and / or" includes any and all combinations of one or more of the related listed items.

[0255] It should be understood that when an element such as a layer, region, or base is described as "on" or "extending" to another element, it may be directly on or directly extending to the other element, or there may be intermediate elements. Conversely, when an element is described as "directly on" or "directly extending" to another element, there are no intermediate elements. Similarly, it should be understood that when an element such as a layer, region, or base is described as extending "above" or "on" another element, it may be directly above or directly extending above the other element, or there may be intermediate elements. Conversely, when an element is described as "directly on" or "directly extending" to another element, there are no intermediate elements. It should also be understood that when an element is described as "connected" or "coupled" to another element, it may be directly connected to or coupled to the other element, or there may be intermediate elements. Conversely, when an element is described as "directly connected" or "directly coupled" to another element, there are no intermediate elements.

[0256] It should be understood that although the terms “upper,” “lower,” “bottom,” “middle,” “center,” “top,” etc., may be used herein to describe various elements, these elements should not be limited by these terms. These terms are used only to distinguish one element from another. For example, a first element may be referred to as an “upper” element, and similarly, a second element may be referred to as an “upper” element based on the relative orientation of these elements, without departing from the scope of this disclosure.

[0257] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that, when used herein, the terms “comprises,” “comprising,” “includes,” and / or “including” expressly indicate the presence of features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0258] Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. It should also be understood that the terms used herein are to be interpreted as having the same meaning as they have in the context of this specification and related art, and are not to be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0259] This document describes embodiments with reference to schematic diagrams illustrating embodiments of the present disclosure. Therefore, the actual dimensions of layers and elements may differ, and differences from the illustrated shapes are expected due to factors such as manufacturing techniques and / or tolerances. For example, areas shown or described as squares or rectangles may have circular or curved features, while areas shown as straight lines may have some irregularities. Therefore, the areas shown in the figures are schematic, and their shapes are not intended to illustrate the precise shapes of the areas of the device and are not intended to limit the scope of this disclosure. Furthermore, for illustrative purposes, the dimensions of structures or areas may be exaggerated relative to other structures or areas; therefore, the general structures provided to illustrate the subject matter may or may not be drawn to scale. Common elements between the figures may be indicated herein by common element numbers and may not be repeated subsequently.

[0260] This disclosure relates to apparatus and methods for irradiating light onto mammalian tissue (e.g., within a patient's body and / or body cavity), wherein the light may include at least one property that applies or induces at least one biological effect within or on the tissue. The biological effect may include at least one combination of inactivating and inhibiting the growth of microorganisms and pathogens (including, but not limited to, viruses, bacteria, fungi, and other microorganisms). The biological effect may also include one or more of the following: upregulating local immune responses, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, releasing nitric oxide from endogenous nitric oxide storage, and inducing anti-inflammatory effects. The wavelength of the light may be selected based on at least one expected biological effect on one or more targeted tissues and on targeted microorganisms or pathogens. In some aspects, the wavelength of the light may include visible light within any number of wavelength ranges based on the expected biological effect. Further aspects relate to irradiating tissue with light for biological effects on multiple microorganisms and / or multiple pathogens, using light with a single peak wavelength or a combination of light having more than one peak wavelength. Devices and methods for phototherapy are disclosed, which provide light doses to induce biological effects on various targeted pathogens and tissues with enhanced efficacy and reduced cytotoxicity. The light dose can include various combinations of irradiance, wavelength, and exposure time, and can be applied continuously or intermittently via multiple pulsed exposures.

[0261] Microorganisms, including pathogenic agents, typically invade human tissues through two main routes: mucosal surfaces within body cavities, such as the mucous membranes of the respiratory tract, and epithelial surfaces outside the body. Many respiratory infections are associated with pathogens, including viruses and bacteria. Examples include orthomyxoviridae (e.g., influenza), the common cold, coronaviruses (e.g., coronaviruses) and piconemavirus infections, tuberculosis, pneumonia, and bronchitis. Most infections begin with the subject's exposure to pathogen particles, which enter the body through the mouth, nose, and ears. For viral infections, three requirements must generally be met to ensure successful infection in a single host: there must be a sufficient quantity of virus to trigger infection, the cells at the site of infection must be accessible, susceptible, and permissible to the virus, and the local host's antiviral defense system must be absent or initially ineffective.

[0262] Conventional treatment of respiratory infections typically involves systemic administration of antibiotics, which unfortunately can lead to drug resistance and gastrointestinal discomfort. In contrast, devices and methods for treating, preventing, or reducing the bioactivity of pathogens in the mouth, nose, and / or ears, and before they spread to the lungs or other parts of the body, would be particularly beneficial. Specifically, such devices and methods can prevent infection by reducing the microbial load before pathogens enter the lungs, decreasing the ability of the infection site to penetrate cells, and enhancing the host's defense system—all of which can minimize or avoid the need for conventional antibiotics.

[0263] This disclosure generally relates to lighting devices, apparatus, and methods for irradiating living tissue with light to induce one or more therapeutic biological effects. In various aspects, the induced biological effects may include at least one of the following: inactivating microorganisms in a cell-free environment, inhibiting the replication of microorganisms in a cell-associated environment, upregulating local immune responses, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, releasing nitric oxide from endogenous nitric oxide storage, and inducing anti-inflammatory effects. In some aspects, the light may be referred to as nitric oxide-modulated light to increase the concentration of unbound nitric oxide within the living tissue. As will be explained in more detail below, embodiments of this disclosure may apply light of one or more wavelengths as pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) to (1) eliminate pathogens in or on tissues of the ear, nose, mouth, throat, or other body cavities and / or (2) enhance the host's defense system. Embodiments of this disclosure may be used for the prevention and / or treatment of respiratory infections and other infectious diseases. For example, in one embodiment, the handheld lighting device may apply light of one or more wavelengths as a preventative measure to reduce viral infectivity and COVID-19 morbidity in individuals who are infected or believed to have been exposed to the SARS-CoV-2 virus. In some aspects, the lighting device of this disclosure may be provided or referred to as a phototherapy and / or phototherapy device.

[0264] The term "phototherapy" refers to the therapeutic use of light. As used in this article, phototherapy is used to treat or prevent microbial infections, including viral infections of the mucosal epithelial tissues of the body, including the vaginal cavity, anal canal, oral cavity, ear canal, upper respiratory tract, and esophagus.

[0265] The effective mechanisms of light wavelengths can vary depending on the wavelength applied. Biological effects, including antibacterial effects, can be provided across a wide range of wavelengths, including the UV, visible, and infrared ranges. The effects vary depending on the antibacterial mechanism of the light and the wavelength at which these mechanisms are produced.

[0266] Illumination devices for treating pathogen-infected tissues and / or for inducing one or more biological effects can take any form suitable for delivering light to infected tissues. The device will include a light source capable of emitting a suitable light distribution that can provide one or more direct or indirect biological effects. The light distribution can be represented by a graph of the emission intensity versus the wavelength of any particular light source. Light sources with a light distribution in the visible spectrum are disclosed herein, for example, light emission with peak wavelengths primarily in the range of 400 nm to 700 nm. Depending on the target application, the light distribution may also include infrared or near-infrared peak wavelengths of 700 nm or higher, or ultraviolet peak wavelengths of 400 nm or lower. In some embodiments, the light emission may have a single peak wavelength in the range of 200 nm to 900 nm, or in the range of 400 nm to 490 nm, or in the range of 400 nm to 435 nm, or in the range of 400 nm to 420 nm, or in the range of 410 nm to 440 nm, or in the range of 420 nm to 440 nm, or in the range of 450 nm to 490 nm, or in the range of 500 nm to 900 nm, or in the range of 490 nm to 570 nm, or in the range of 510 nm to 550 nm. Within the range, specifically 520nm to 540nm, 525nm to 535nm, 528nm to 532nm, 320nm to 400nm, 350nm to 395nm, 280nm to 320nm, 320nm to 350nm, 200nm to 280nm, 260nm to 270nm, 240nm to 250nm, or 200nm to 225nm. In a further embodiment, the light emission may include multiple peak wavelengths selected from any of the above ranges, depending on the target application and desired biological effect. Depending on the target application, the full width at half maximum (FWHM) value of any of the above peak wavelength ranges may be less than or equal to 100nm, or less than or equal to 90nm, or less than or equal to 40nm, or less than or equal to 20nm. In some implementations, lower FWHM values ​​are typically associated with single-emission color LEDs in any of the aforementioned wavelength bands. Larger FWHM values ​​(e.g., 40 nm to 100 nm) may be associated with phosphor-converted LEDs, where the spectral bandwidth is a combination of LED emission and phosphor-converted emission. Exemplary phosphor-converted LEDs applicable to this disclosure are phosphor-converted amber LEDs with peak wavelengths in the range of 585 nm to 600 nm and FWHM values ​​in the range of 70 nm to 100 nm, and phosphor-converted mint and / or lime-green LEDs with peak wavelengths in the range of 520 nm to 560 nm.Additional embodiments of this disclosure can also be applied to broad-spectrum white LEDs, which may include LEDs with peak wavelengths in the range of 400 nm to 470 nm, and one or more phosphors to provide a broad emission spectrum. In such embodiments, the broad-spectrum LED can provide wavelengths that induce one or more biological effects, while also providing broad-spectrum emission to a target region for illumination. In this regard, tissue illumination targeting single and / or multiple microorganisms and / or multiple pathogenic biological effects can provide light with a single peak wavelength or a combination of light with more than one peak wavelength.

[0267] The light dose that induces one or more biological effects can be applied in conjunction with one or more light properties, including peak wavelength, radiant flux, and irradiance to the target tissue. The provided irradiance to the target tissue can be as low as 0.1 milliwatts per square centimeter (mW / cm²). 2 Up to 200mW / cm 2 Within the range, or at 5mW / cm 2 Up to 200mW / cm 2 Within the range, or at 5mW / cm 2 Up to 100mW / cm 2 Within the range, or at 5mW / cm 2 Up to 60mW / cm 2 Within the range, or at 60mW / cm 2 Up to 100mW / cm 2 Within the range, or at 100mW / cm 2 Up to 200mW / cm 2Within a certain range. Such an irradiance range can be applied in one or more of continuous wave and pulsed configurations, including LED-type photonic devices configured with suitable power (radiant flux) to irradiate target tissue with any of the aforementioned ranges. A light source providing such an irradiance range can be configured to provide at least 5 mW, or at least 10 mW, or at least 15 mW, or at least 20 mW, or at least 30 mW, or at least 40 mW, or at least 50 mW, or at least 100 mW, or at least 200 mW, or in the range of 5 mW to 200 mW, or in the range of 5 mW to 100 mW, or in the range of 5 mW to 60 mW, or in the range of 5 mW to 3 ... The radiant flux values ​​are within the ranges of mW to 20mW, or 5mW to 10mW, or 10mW to 60mW, or 20mW to 60mW, or 30mW to 60mW, or 40mW to 60mW, or 60mW to 100mW, or 100mW to 200mW, or 200mW to 500mW, or another range specified herein. Depending on one or more of the configurations of the light source, the corresponding illumination device, and the distance from the target tissue, the radiant flux value of the light source may be higher than the irradiance value at the tissue.

[0268] Although some peak wavelengths used for certain target tissue types can reach up to 1 W / cm 2 While applying irradiance at certain peak wavelengths may not cause significant tissue damage, safety considerations for other peak wavelengths and corresponding tissue types may necessitate lower irradiance levels, particularly in continuous wave applications. In some embodiments, pulsed irradiance can be applied, allowing for the safe application of significantly higher irradiance levels. Pulsed irradiance can be characterized as an average irradiance within a safe range, resulting in minimal or no damage to the tissue to which it is applied. In some embodiments, 0.1 W / cm² is used. 2 Up to 10W / cm 2 Irradiance within the range can be safely pulsed to the target tissue.

[0269] In some aspects, the dose of light applied, or light intensity, may be referred to as a therapeutic dose of light. A light intensity may include various suitable combinations of peak wavelength, irradiance to the target tissue, and exposure time. Specific doses of light are disclosed, tailored to provide safe and effective light to induce one or more biological effects in various types of pathogens and corresponding tissue types. In some aspects, the light intensity may be applied continuously or in a pulsed manner over a single time period. In a further aspect, the light intensity may be applied repeatedly to provide a cumulative or total dose over a cumulative time period. For example, a single dose of light as disclosed herein may be provided over a single time period, such as from 10 microseconds to no more than one hour, or from 10 seconds to no more than one hour, while a single dose may be repeated at least twice to provide a cumulative dose over a cumulative time period, such as a 24-hour time period. In some embodiments, the described light intensity may be 0.5 joules per square centimeter (J / cm²). 2 Up to 100 J / cm 2 Within the range, or at 0.5 J / cm 2 Up to 50J / cm 2 Within the range, or at 2J / cm 2 Up to 80J / cm 2 Within the range, or at 5J / cm 2 Up to 50J / cm 2 It is available within the range of 1J / cm 2 Up to 1000 J / cm 2 Within the range, or at 1J / cm 2 Up to 500J / cm 2 Within the range, or at 1J / cm 2 Up to 200J / cm 2 Within the range, or at 1J / cm 2 Up to 100J / cm 2 Within the range, or at 4J / cm 2 Up to 160J / cm 2 Within the range, or at 10 J / cm 2 Up to 100J / cm 2 The corresponding cumulative dose is provided within the specified range. In a specific example, it can be applied at 10 J / cm². 2 Up to 20J / cm 2 A single dose within the range, and this single dose can be repeated twice daily for four consecutive days to provide at 80 J / cm². 2 Up to 160J / cm 2 The cumulative dose within the range. In another specific example, it can be around 30 J / cm². 2 A single dose is administered, and this single dose can be repeated twice daily for seven consecutive days to provide 420 J / cm². 2The cumulative dose.

[0270] In a further aspect, light used to induce one or more biological effects may include applying different doses of light to a target tissue to induce one or more biological effects against different target pathogens. As disclosed herein, biological effects may include altering the concentration of one or more pathogens in the body and altering the growth of one or more pathogens in the body. Biological effects may include at least one of the following: inactivating a first pathogen in a cell-free environment, inhibiting the replication of a first pathogen in a cell-associated environment, upregulating local immune responses in mammalian tissues, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide stores in mammalian tissues, releasing nitric oxide from endogenous nitric oxide stores in mammalian tissues, and inducing anti-inflammatory effects in mammalian tissues. As further disclosed herein, pathogens may include viruses, bacteria, and fungi, or any other type of microorganism that can cause infection. Notably, the light doses disclosed herein can provide non-systemic and durable effects to the target tissue. Light can be applied locally without producing off-target tissue effects or systemic effects associated with conventional drug therapies that can spread throughout the body. In this respect, phototherapy can induce biological effects and / or responses in the target tissue without triggering the same or other biological responses in other parts of the body. As described in this article, phototherapy can be administered in a sustained, safe, and effective dose. For example, a dose can be applied for several minutes at a time, once or several times a day, and the beneficial effects of phototherapy can continue between treatments.

[0271] The light source may include one or more of LEDs, OLEDs, lasers, and other lamps according to this disclosure. Lasers may be combined with optical fibers or other delivery mechanisms for irradiation. One disadvantage of using lasers is that they may require highly skilled professionals to operate complex equipment to ensure proper laser radiation protection, increasing cost and reducing accessibility. LEDs are solid-state electronic devices capable of emitting light when electrically activated. LEDs can be configured for many different target emission spectral bands, offering high efficiency and relatively low cost. In this respect, LEDs are relatively simple devices that can operate over a wider range of current and temperature, thus providing an effective alternative to expensive laser systems. Therefore, LEDs can be used as light sources in photonic devices for phototherapy applications. Light from LEDs is applied using devices capable of delivering the required power to the target treatment area or tissue. Devices based on high-power LEDs can be employed to meet the diverse spectral and power requirements of various medical applications. The LED-based photonic devices described herein can be configured with suitable power to provide up to 100 mW / cm² within the desired wavelength range. 2 Or 200mW / cm 2The irradiance is [specifically, the LED array in the device]. The LED array can be integrated into the irradiation head, handheld device, and / or used as an external unit. When integrated into the handheld device or irradiation head, the risk of exposure to harmful radiation to the eyes or other organs can be avoided.

[0272] According to aspects of this disclosure, exemplary target tissue and cell phototherapy may include one or more of the following: epithelial tissue, mucosal tissue, connective tissue, muscle tissue, cervical tissue, dermal tissue, vaginal mucosal epithelial tissue, anal canal, oral cavity, ear canal, upper respiratory tract and esophagus, keratinocytes, fibroblasts, blood, sputum, saliva, cervical fluid and mucus. Phototherapy may also be applied to organs and / or internal and external body surfaces, as well as to any mammalian body and / or body cavities, such as the oral cavity, esophageal cavity, larynx and vaginal cavity.

[0273] Based on the general principles described herein, features from any of the embodiments described herein can be combined with each other. These and other embodiments, features, and advantages will be more fully understood upon reading the following detailed description in conjunction with the accompanying drawings and claims.

[0274] Figure 1 This is an illustration of an exemplary configuration 100 of an illumination device 102 for delivering light 130 to body tissue 104 to induce at least one biological effect. As previously described, the induced biological effect may include at least one of the following: inactivation of microorganisms in a cell-free environment, inhibition of microbial replication in a cell-associated environment, upregulation of local immune responses, stimulation of enzymatic production of nitric oxide to increase endogenous nitric oxide storage, release of nitric oxide from endogenous nitric oxide storage, and induction of anti-inflammatory effects. In some aspects, the lamp 130 may be configured to modulate nitric oxide light to increase the concentration of unbound nitric oxide within body tissue 104. Figure 1 As shown, the illumination device 102 may include one or more light emitters 120 operable to emit light 130 onto a treatment area 140 of body tissue 104. The light emitters 120 may be positioned such that one or more portions of the light 130 illuminate the treatment area 140 at an angle of incidence of 90 degrees and a tolerance of ±10 degrees, although other angles of incidence may also be used. The light emitters 120 may also be configured to provide a beam uniformity of light 130 at the treatment area 140 of no more than about 20%, or no more than about 15%, or no more than about 10% of the average range. Such beam uniformity values ​​may be determined based on the selection of optics and / or waveguides for the light emitters 120. In some embodiments, when positioned at a distance of about 96 mm from the treatment area 140, the light emitters 120 may provide an irradiance to the treatment area 140 of up to about 45 mW / cm². 2 Or at a distance of approximately 83 mm from the treatment area, up to approximately 60 mW / cm 2Or at a distance of approximately 70 mm from the treatment area, up to approximately 80 mW / cm 2 The irradiance values ​​described above are provided as examples only. In practice, irradiance values ​​may be in other ranges depending on the application configuration. The light emitter 120 may include any light source capable of emitting or stimulating one or more biological effects. Examples of the light emitter 120 may include, but are not limited to, light-emitting diodes (LEDs), organic light-emitting diodes (OLEDs), superluminescent diodes (SLDs), lasers, and / or any combination thereof. Where the light emitter is described as emitting light of a certain wavelength or wavelength range, and where the light is referred to as having a certain wavelength (e.g., a wavelength of 415 nanometers (nm), it should be understood that wavelength values ​​may refer to the dominant wavelength of light, the peak wavelength of light, the centroid wavelength of light, and / or wavelengths within 3 nm that constitute at least 50% of the light emission spectrum. Unless otherwise stated in this disclosure, various embodiments are provided below with reference to the peak wavelength.

[0275] The lighting device 102 may further include (1) an emitter drive circuit 110 operable to control the output of the light emitter 120 and (2) one or more sensors (e.g., sensors 115 and 125) operable to sense or measure properties of the lighting device 102, the light emitter 120, the nitric oxide modulated light 130, the treatment area 140, the body tissue 104, and / or the environment in which the lighting device 102 operates. As will be explained in more detail below, the emitter drive circuit 110 may control the output of the light emitter 120 based on information collected by the sensors 115 and 125. Examples of sensors 115 and 125 include, but are not limited to: temperature sensors, light sensors, image sensors, proximity sensors, blood pressure or other pressure sensors, chemical sensors, biosensors (e.g., heart rate sensors, body temperature sensors, sensors that detect the presence or concentration of chemical or biological species or other conditions), accelerometers, humidity sensors, pulse oximeters (e.g., pulse oximeters), current sensors, voltage sensors, etc. In some embodiments, the operation of the methods disclosed herein may be in response to one or more signals generated by one or more sensors 115 and / or 125 or other elements.

[0276] Figure 2This is an illustration of an exemplary configuration 200 of an illumination device 102 for delivering two types of light 230, 240 to body tissue 104. The two types of light 230, 240 can be configured to induce at least two biological effects, such as at least two of the following: inactivating microorganisms in a cell-free environment, inhibiting the replication of microorganisms in a cell-associated environment, upregulating local immune responses, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, releasing nitric oxide from endogenous nitric oxide storage, and inducing anti-inflammatory effects. The two types of light 230, 240 can also be configured to provide similar biological effects, such as two different types of nitric oxide modulated light to increase the concentration of unbound nitric oxide within body tissue 104. Additionally, the two types of light 230, 240 can be configured to provide the same or different biological effects for different types of microorganisms and / or pathogens that may be present in body tissue 104.

[0277] In some embodiments, light emitter 120 may include one or more light emitters 210 operable to emit endogenous storage increase light 230 and one or more light emitters 220 operable to emit endogenous storage release light 240. Light emitters 210 and 220 may include any light source capable of emitting suitable light. Examples of light emitters 210 and 220 may include, but are not limited to, LEDs, OLEDs, SLDs, lasers, and / or any combination thereof.

[0278] Figure 3 It is a display Figure 1 The exemplary light 130 is a spectrum of intensity versus wavelength, which can be configured to induce any of the aforementioned biological effects, including nitric oxide modulated light. Figure 4 It is a display Figure 2 The exemplary light 230, 240 are shown as intensity versus wavelength spectra, which can be configured to induce any of the aforementioned biological effects, such as endogenous storage-increasing light 230 and endogenous storage-releasing light 240. For example, light 130 is shown having a peak intensity 308 at a peak wavelength 304, light 230 is shown having a peak intensity 414 at a peak wavelength 404, and light 230 is shown having a peak intensity 414 at a peak wavelength 410. In these examples, peak wavelength 304 can be any wavelength in the range from wavelength 302 to wavelength 306, peak wavelength 404 can be any wavelength in the range from wavelength 402 to wavelength 406, and peak wavelength 410 can be any wavelength in the range from wavelength 408 to wavelength 412.

[0279] Figure 3 and Figure 4 The specific peak wavelengths shown are provided as examples without limitation. In practice, depending on the target application, one or more target microorganisms and / or pathogens, and the target tissue type, Figure 1 Light 130 and Figure 3 and 4 The light 230 and 240 can be provided within a wide range of peak wavelengths. Exemplary wavelength ranges include 200 nm to 900 nm, or 400 nm to 900 nm, or 400 nm to 700 nm, or 400 nm to 450 nm, or 400 nm to 435 nm, or 400 nm to 420 nm, or 420 nm to 440 nm, or 450 nm to 490 nm, or 500 nm to 900 nm, or 490 nm to 570 nm, or 510 nm to 550 nm, or 520 nm to 540 nm, or 525 nm to 540 nm. The wavelength ranges are 535 nm to 528 nm to 532 nm, or 200 nm to 280 nm, or 260 nm to 270 nm, or 280 nm to 320 nm, or 320 nm to 350 nm, or 320 nm to 400 nm, or 350 nm to 395 nm, or 600 nm to 900 nm, or 600 nm to 700 nm, or 620 nm to 670 nm, or 630 nm to 660 nm, depending on the target application and target tissue type. Specific exemplary wavelength ranges are provided below in the context of specific target applications in accordance with the principles of this disclosure.

[0280] As used herein, the term "light" generally refers to electromagnetic radiation of any wavelength or any combination of wavelengths and / or to one or more photons. Therefore, as used herein, the term "light" can refer to visible or invisible light (particularly ultraviolet or infrared light). As used herein, the term "light" can refer to a single photon of a single wavelength, or it can refer to multiple photons that may have the same wavelength, or one or more photons having each of two or more wavelengths. In the context of light impinging on an object (e.g., in the statement "at least one first solid-state light-emitting device is configured to impinge / irradiate light having a first peak wavelength onto skin tissue"), the term "irradiate" may indicate that light is incident on the object.

[0281] The term "peak wavelength" is generally used in this document to refer to the wavelength of light emitted by a light emitter at its maximum irradiance. The term "dominant wavelength" is generally used in this document to refer to the perceived color of a spectrum, that is, the wavelength of a single light source that produces a color sensation most similar to the perceived color sensation of light emitted from the observed light source (i.e., it is roughly similar to a "hue"), as opposed to the "peak wavelength," which generally refers to the spectral line with the highest power in the power distribution of the light source's spectrum. Because the human eye cannot perceive all wavelengths equally (e.g., it perceives yellow and green light better than red and blue light), and because the light emitted by many solid-state light emitters (e.g., LEDs) is actually a range of wavelengths, the perceived color (i.e., the dominant wavelength) is not necessarily equal to (and often differs from) the wavelength with the highest power (the peak wavelength). True monochromatic light (e.g., laser light) may have both a dominant wavelength and a peak wavelength.

[0282] As used herein, the term "nitric oxide modulated light" generally refers to light that increases the concentration of unbound nitric oxide in a living tissue when irradiated. The term "nitric oxide modulated light" can include endogenous nitric oxide-increasing light and / or endogenous nitric oxide-releasing light. The term "nitric oxide modulated light" can also refer to light that stimulates the natural production of nitric oxide (e.g., through methods similar to...). Figure 5A and 5B The process shown) and / or the transient release of nitric oxide reserves found in living tissue (e.g., through processes similar to those described) Figure 6A and 6B The term "nitric oxide modulated light" may also refer to any light capable of stimulating at least one of the following: (1) the enzymatic generation of unbound nitric oxide in living tissue (e.g., by means of a process similar to...). Figure 5A and 5B (as shown in the process) or (2) release nitric oxide from the endogenous storage of nitric oxide bound in living tissue (e.g., via a process similar to...) Figure 6A and 6B (The process shown).

[0283] Figure 5A and 5B The illustration depicts a reaction sequence showing photo-activated upregulation (e.g., using light 230) of inducible nitric oxide synthase (iNOS) expression, followed by iNOS catalysis to produce unbound nitric oxide, which is then bound to CCO. Nitric oxide can be covalently bound (in a “bound” state) in vivo when it is autoxidized to nitrosation intermediates (e.g., endogenous stores of nitric oxide, including nitrosoglutathione, nitrosoalbumin, nitrosohemoglobin, nitrosothiols, nitrosamines, and / or metal nitroso complexes). Figure 5CThe figure illustrates the enzymatic production of nitric oxide (in keratinocytes) to the percentage of cells expressing iNOS 24 hours after exposure to light (no light, blue light, red light of the first wavelength, red light of the second wavelength, and infrared radiation) in keratinocytes after 10 minutes of radiation exposure.

[0284] Figure 6A This is a graph showing the amount of nitric oxide (μmol / s) released by the GSNO photoreceptor relative to time (minutes) when exposed to blue, green, and red wavelengths of light. Figure 6B This is a diagram illustrating the attachment of nitric oxide to the photoreceptor CCO to form a complex CCO-NO, and the subsequent release of NO from this complex upon exposure to endogenous storage release light 240.

[0285] As used herein, the term "endogenous storage-enhancing light" generally includes light of wavelengths or wavelength ranges that induce an increase in bound nitric oxide in endogenous storage and / or stimulate the enzymatic production of unbound nitric oxide that can be naturally covalently bound in endogenous storage. Examples of endogenous storage-enhancing light include, but are not limited to, blue light, light having a peak wavelength in the range of about 410 nm to about 440 nm, light having a peak wavelength in the range of about 400 nm to about 490 nm, light having a peak wavelength in the range of about 400 nm to about 450 nm, light having a peak wavelength in the range of about 400 nm to about 435 nm, light having a peak wavelength in the range of about 400 nm to about 420 nm, light having a peak wavelength in the range of about 420 nm to about 440 nm, light having a peak wavelength in the range of about 400 nm to about 500 nm, light having a peak wavelength in the range of about 400 nm to about 430 nm, light with a peak wavelength of about 415 nm, light with a peak wavelength equal to about 405 nm, and / or any combination thereof.

[0286] As used herein, the term "endogenous storage release light" generally includes light of wavelengths or wavelength ranges that photoinitiate the release of unbound nitric oxide from an endogenous nitric oxide store. Examples of endogenous storage release light include, but are not limited to, green light, light having a peak wavelength in the range of about 500 nm to about 540 nm, light having a peak wavelength in the range of about 500 nm to about 900 nm, light having a peak wavelength in the range of about 490 nm to about 570 nm, light having a peak wavelength in the range of about 510 nm to about 550 nm, light having a peak wavelength in the range of about 520 nm to about 540 nm, light having a peak wavelength in the range of about 525 nm to about 535 nm, light having a peak wavelength in the range of about 528 nm to about 532 nm, light with a peak wavelength equal to about 530 nm, and / or any combination thereof.

[0287] As used herein, the term "endogenous nitric oxide increase and / or endogenous nitric oxide emission light" includes light of wavelengths or wavelength ranges that increase the rate of endogenous nitric oxide production, light of wavelengths or wavelength ranges that increase the rate of endogenous nitric oxide emission, light of wavelengths or wavelength ranges that increase both the rate of endogenous nitric oxide production and the rate of endogenous nitric oxide emission, and a combination of light from at least one first group of light emitters (which emits light of wavelengths or wavelength ranges that increase the rate of endogenous nitric oxide production) and light from at least one second group of light emitters (which emits light of wavelengths or wavelength ranges that increase the rate of endogenous nitric oxide emission).

[0288] return Figure 2 In some embodiments, light 240 may have a first peak wavelength and a first radiant flux to include one or more biological effects, and light 230 may have a second peak wavelength and a second radiant flux to include one or more biological effects.

[0289] In some embodiments, the second peak wavelength may be at least 25 nm, at least 40 nm, at least 50 nm, at least 60 nm, at least 75 nm, at least 85 nm, at least 100 nm, or another threshold specified herein, greater than the first peak wavelength. Such a peak wavelength difference may exist to induce any of the aforementioned biological effects, including embodiments where light 230 is endogenous storage-enhancing light and light 240 is endogenous storage-releasing light.

[0290] Exemplary implementations are provided below in the context of nitric oxide-modulated light, including light that increases endogenous storage and light that releases endogenous storage. It should be understood that any of the following implementations can similarly relate to any light and / or combination of light that induces one or more of the previously described biological effects, including inactivating microorganisms in cell-free environments, inhibiting microbial replication in cell-associated environments, upregulating local immune responses, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, releasing nitric oxide from endogenous storage, and inducing anti-inflammatory effects in tissues. Different combinations of light and induced biological effects can be tailored to different body tissues and different target microorganisms and / or pathogens.

[0291] In some embodiments, each of the endogenous storage-increasing light 230 and the endogenous storage-releasing light 240 (and / or light 130) may have a power range of at least 5 mW, or at least 10 mW, or at least 15 mW, or at least 20 mW, or at least 30 mW, or at least 40 mW, or at least 50 mW, or at least 100 mW, or at least 200 mW, or at least 500 mW, or at least 2500 mW, or at least 5000 mW, or in the range of 5 mW to 200 mW, or in the range of 5 mW to 100 mW, or in the range of 5 mW to 60 mW, or in the range of 5 mW to 60 mW. Radiation flux within the range of 30 mW, or within the range of 5 mW to 20 mW, or within the range of 5 mW to 10 mW, or within the range of 10 mW to 60 mW, or within the range of 20 mW to 60 mW, or within the range of 30 mW to 60 mW, or within the range of 40 mW to 60 mW, or within the range of 60 mW to 100 mW, or within the range of 100 mW to 200 mW, or within the range of 200 mW to 500 mW, or within the range of 5 mW to 5000 mW, or within the range of 5 mW to 2500 mW, or within another range specified herein. Higher fluxes (e.g., between 0.1 W and 10 W, or between 10 W and 10 GW, including those using pulsed light) may be used to increase penetration and achieve microbial decontamination, if desired, within another range specified herein.

[0292] Each of the endogenous storage-increasing light 230 and the endogenous storage-releasing light 240 (and light 130) can be at 0.1 mW / cm 2 Up to 200mW / cm 2 Within the range, or at 5mW / cm 2 Up to 200mW / cm 2 Within the range, or at 5mW / cm 2 Up to 100mW / cm 2 Within the range, or at 5mW / cm 2 Up to 60mW / cm 2 Within the range, or at 60mW / cm 2 Up to 100mW / cm 2 Within the range, or at 100mW / cm 2 Up to 200mW / cm 2Irradiance within a certain range is applied to the target tissue. This irradiance range can be applied in one or more of continuous wave and pulsed configurations, including LED-based photonic devices configured with appropriate power (radiant flux) to irradiate the target tissue with any of the aforementioned ranges. Depending on the configuration of one or more of the light source, the corresponding illumination device, and the distance from the target tissue, the radiant flux value of the light source can be higher than the irradiance value at the tissue. In some embodiments, the radiant flux value can be configured to be greater than the irradiance value on the tissue. For example, the radiant flux can be in the range of 5 to 20 times greater than the irradiance, or in the range of 5 to 15 times greater than the irradiance, etc., depending on the implementation.

[0293] In some embodiments, the endogenous storage-enhancing light 230 may have a greater radiative flux than the endogenous storage-emitting light 240.

[0294] In some embodiments, one or both of the endogenous storage-enhancing light 230 and the endogenous storage-releasing light 240 may have a radiant flux distribution that is substantially constant during the treatment window. In some embodiments, at least one of the endogenous storage-enhancing light 230 and the endogenous storage-releasing light 240 may have a radiant flux distribution that increases over time during the treatment window. In some embodiments, at least one of the endogenous storage-enhancing light 230 and the endogenous storage-releasing light 240 may have a radiant flux distribution that decreases over time during the treatment window. In some embodiments, one of the endogenous storage-enhancing light 230 or the endogenous storage-releasing light 240 may have a radiant flux distribution that decreases over time during the treatment window, while the other of the endogenous storage-enhancing light 230 or the endogenous storage-releasing light 240 may have a radiant flux distribution that increases over time during the treatment window.

[0295] In some embodiments, endogenous storage release light 240 may be applied to the tissue during a first time window, and endogenous storage enhancement light 230 may be applied to the tissue during a second time window, and the second time window may overlap with the first time window. In other embodiments, endogenous storage release light 240 may be applied to the tissue during the first time window, and endogenous storage enhancement light 230 may be applied to the tissue during the second time window, and the second time window may not overlap with the first time window or may only partially overlap. In some embodiments, the second time window may begin more than one minute, more than five minutes, more than ten minutes, more than 30 minutes, or more than one hour after the end of the first time window. In some embodiments, endogenous storage release light 240 may be applied to the tissue during the first time window, and endogenous storage enhancement light 230 may be applied to the tissue during the second time window, and the first and second time windows may be substantially the same. In other embodiments, the second time window may be longer than the first time window. Aspects of these embodiments are also contemplated, wherein UVA / UVB / UVC light is applied in the same or different time windows, or applied to the same or different tissues.

[0296] In some implementations, one or both of the endogenous storage increase light 230 and the endogenous storage release light 240 may be provided by a steady-state source that provides a radiative flux that can be substantially constant and not pulsed over an extended period of time.

[0297] In some embodiments, one or both of the endogenous storage-enhancing light 230 and the endogenous storage-releasing light 240 may include more than one discrete light pulse (e.g., multiple pulses). In some embodiments, during a first time window, more than one discrete endogenous storage-releasing light 240 pulse may be applied to the tissue, and / or during a second time window, more than one discrete endogenous storage-enhancing light 230 pulse may be applied to the tissue. In some embodiments, the first and second time windows may be co-extended, may overlap but not co-extended, or may not overlap.

[0298] In some embodiments, during a portion of the first time window, at least one of the radiant flux and pulse duration of the endogenous storage release light 240 may decrease from a maximum value to a non-zero decrease. In some embodiments, during a portion of the first time window, at least one of the radiant flux and pulse duration of the endogenous storage release light 240 may increase from a non-zero value to a higher value. In some embodiments, during a portion of the second time window, at least one of the radiant flux and pulse duration of the endogenous storage increase light 230 may decrease from a maximum value to a non-zero decrease. In some embodiments, during a portion of the second time window, at least one of the radiant flux and pulse duration of the endogenous storage increase light 230 may increase from a non-zero value to a higher value.

[0299] In some embodiments, each of the endogenous storage-increasing light 230 and the endogenous storage-releasing light 240 may consist of incoherent light. In some embodiments, each of the endogenous storage-increasing light 230 and the endogenous storage-releasing light 240 may consist of coherent light. In some embodiments, one of the endogenous storage-increasing light 230 or the endogenous storage-releasing light 240 may consist of incoherent light, and the other of the endogenous storage-increasing light 230 or the endogenous storage-releasing light 240 may consist of coherent light.

[0300] In some embodiments, the endogenous storage release light 240 may be provided by at least one first light-emitting device, and the endogenous storage increase light 230 may be provided by at least one second light-emitting device. In some embodiments, the endogenous storage release light 240 may be provided by a first array of light-emitting devices, and the endogenous storage increase light 230 may be provided by a second array of light-emitting devices.

[0301] In some embodiments, at least one of the internally stored light-increasing (ESI) 230 or internally stored light-releasing (ESI) 240 may be provided by at least one solid-state light-emitting device. Examples of solid-state light-emitting devices include (but are not limited to) light-emitting diodes, lasers, thin-film electroluminescent devices, powder electroluminescent devices, field-induced polymer electroluminescent devices, and polymer light-emitting electrochemical cells. In some embodiments, ESI 240 may be provided by at least one first solid-state light-emitting device, and ESI 230 may be provided by at least one second solid-state light-emitting device. In some embodiments, ESI 230 and ESI 240 may be generated by different emitters included in a single solid-state emitter package, wherein close spacing between adjacent emitters can provide overall color mixing. In some embodiments, ESI 240 may be provided by a first array of solid-state light-emitting devices, and ESI 230 may be provided by a second array of solid-state light-emitting devices. In some embodiments, a solid-state emitter package array may be provided, each including at least one first emitter and at least one second emitter, wherein the solid-state emitter package array is embodied as a first array of solid-state emitters arranged to generate endogenous storage release light 240, and as a second array of solid-state emitters arranged to generate endogenous storage increase light 230. In some embodiments, the solid-state emitter package array may embody a package further including a third, fourth, and / or fifth solid-state emitter, such that a single solid-state emitter package array may embody three, four, or five solid-state emitter arrays, wherein each array may be arranged to generate emission with different peak wavelengths.

[0302] In some embodiments, at least one of the endogenous storage-increasing light 230 or the endogenous storage-releasing light 240 may be provided by at least one light-emitting device without wavelength-converting material. In other embodiments, at least one of the endogenous storage-increasing light 230 or the endogenous storage-releasing light 240 may be provided by at least one light-emitting device arranged to excite wavelength-converting material (such as phosphor material, fluorescent dye material, quantum dot material, and fluorophore material).

[0303] In some embodiments, the endogenous storage-enhancing light 230 and the endogenous storage-releasing light 240 may consist of substantially monochromatic light. In some embodiments, the endogenous storage-releasing light 240 may include a first spectral output having a first full width at half maximum (WHM) of less than 25 nm (or less than 20 nm, or less than 15 nm, or in the range of 5 nm to 25 nm, or in the range of 10 nm to 25 nm, or in the range of 15 nm to 25 nm), and / or the endogenous storage-enhancing light 230 may include a second spectral output having a second WHM of less than 25 nm (or less than 20 nm, or less than 15 nm, or in the range of 5 nm to 25 nm, or in the range of 10 nm to 25 nm, or in the range of 15 nm to 25 nm). In some embodiments, less than 5% of the first spectral output may be in a wavelength range of less than 400 nm, and less than 1% of the second spectral output may be in a wavelength range of less than 400 nm.

[0304] In some embodiments, the endogenous storage release light 240 may be generated by one or more first light emitters having a single first peak wavelength, and the endogenous storage increase light 230 may be generated by one or more second light emitters having a single second peak wavelength. In other embodiments, the endogenous storage increase light 230 may be generated by at least two light emitters having different peak wavelengths (e.g., differing by at least 5 nm, at least 10 nm, at least 15 nm, at least 20 nm, or at least 25 nm), and / or the endogenous storage release light 240 may be generated by at least two light emitters having different peak wavelengths (e.g., differing by at least 5 nm, at least 10 nm, at least 15 nm, at least 20 nm, or at least 25 nm).

[0305] Ultraviolet light (e.g., UV-A light with peak wavelengths in the range of 350 nm to 395 nm, and UV-B light with peak wavelengths in the range of 320 nm to 350 nm) can be effective as ES-enhancing light; however, excessive exposure to UV light may lead to harmful health effects, including premature skin aging and an increased potential risk of certain types of cancer. UVC light is also particularly effective in treating microbial infections. While damage to tissues exposed to these wavelengths should be minimized during antimicrobial treatment, some adverse effects may occur with prolonged exposure. Therefore, it may be desirable to use UV light cycles that are shorter than those of non-UV light. In some implementations, UV light (e.g., with peak wavelengths in the range of 320 nm to 399 nm) can be used as ES-enhancing light; however, in other implementations, UV light can be avoided. Combining these (UVA, UVB, and / or UVC) wavelengths with anti-inflammatory light can minimize these effects.

[0306] In some embodiments, the endogenous storage-enhancing light 230 and the endogenous storage-releasing light 240 may be substantially free of UV light. In some embodiments, less than 5% of the endogenous storage-enhancing light 230 may be in a wavelength range of less than 400 nm, and less than 1% of the endogenous storage-releasing light 240 output may be in a wavelength range of less than 400 nm. In some embodiments, the endogenous storage-enhancing light 230 includes a peak wavelength in the range of 400 nm to 490 nm, or 400 nm to 450 nm, or 400 nm to 435 nm, or 400 nm to 420 nm, or 410 nm to 440 nm, or 420 nm to 440 nm.

[0307] In some embodiments, the endogenous storage-enhancing light 230 may include wavelength ranges and irradiance capable of altering the presence, concentration, or growth of pathogens (e.g., bacteria, viruses, fungi, protozoa, and / or other microorganisms) in or on the light-receiving mammalian living tissue. UV and near-UV light are particularly likely to affect microbial growth. The effect on microbial growth may depend on the wavelength range and dose. In some embodiments, the ES-enhancing or endogenous storage-releasing light 240 may include near-UV light with a peak wavelength in the range of 400 nm to 420 nm to provide antibacterial effects (e.g., using irradiance <9 mW / cm²). 2 Pulsed light), providing a bactericidal effect (e.g., using pulsed light with 9mW / cm²). 2 Up to 17mW / cm 2 (basic steady-state light of irradiance), or to provide antibacterial effects (e.g., using light with an irradiance greater than 17 mW / cm²). 2 The basic steady-state irradiance, for example, 18 mW / cm². 2 Up to 60mW / cm 2 In some embodiments, the irradiance values ​​and ranges can be extended to approximately 60 to approximately 100 mW / cm². 2 Or approximately 100 to 200 mW / cm 2 .

[0308] For certain tissues and certain wavelengths, up to 1 W / cm can be applied. 2 Irradiance can be applied at a level that does not cause significant damage to tissue. If the light is pulsed, irradiance can be applied over a significantly higher range, provided the average irradiance is within these ranges and causes minimal damage to the tissue being treated. Irradiance in a pulsed setting can be as low as 0.1 W / cm². 2 Up to 10W / cm 2 , or even higher.

[0309] In some embodiments, near-UV range light (e.g., 400 nm to 420 nm) may also affect microbial growth (whether within the antibacterial, bactericidal, or antimicrobial range) for purposes such as wound healing, reducing acne blemishes, or treating atopic dermatitis. Such functionality could complement the function of endogenous storage-enhancing light 230, which increases the endogenous storage of nitric oxide in living tissue.

[0310] An equal combination of 410nm and 530nm light may be as effective as using 530nm light alone. This combination may be beneficial because a 410nm blue LED may be significantly more effective than a 530nm green LED, such that when operating to provide the same radiant flux, an equal combination of 410nm and 530nm LED emission can use 26% less power than a single 530nm LED emission.

[0311] In terms of NO release from Hb-NO, 660 nm light may be significantly less efficient than 530 nm green light. For 530 nm green light, 660 nm red light, and combinations of 530 nm green light and 660 nm light, the NO release from Hb-NO appears to be the same over a time window from 0 seconds to approximately 2000 seconds, but the efficiency varies between different sources thereafter. Without being bound by any particular theory or explanation for this phenomenon, it is suggested that NO binds to Hb-NO at multiple sites, and that removing a second or subsequent NO molecule from Hb-NO may require more energy than removing the first NO molecule, possibly due to the change in shape of Hb-NO after the removal of the first NO molecule.

[0312] In some embodiments, anti-inflammatory light having a first peak wavelength is irradiated onto the living tissue, and ES-enhancing or ES-emitting light, including light having a second peak wavelength, is irradiated onto the living tissue. Furthermore, light having a third peak wavelength (i.e., ES-emitting or ES-enhancing light) can be irradiated onto the living tissue. In some embodiments, light having a third peak wavelength can be provided substantially simultaneously with (or within a time window overlapping with at least one of the anti-inflammatory light and ES-enhancing and / or ES-emitting light) one or both.

[0313] In some embodiments, the light having a third peak wavelength differs from each of the first and second peak wavelengths by at least 10 nm. In some embodiments, the light having a third peak wavelength exceeds the second peak wavelength by at least 20 nm. In some embodiments, the light having a third peak wavelength provides an irradiance of 5 mW / cm². 2 Up to 60mW / cm 2 Within the range, or 60 to 100 mW / cm 2 Or 100 to 200 mW / cm2 Or even higher. For certain tissues and certain wavelengths, up to 1 W / cm can be applied. 2 Irradiance can be applied at a level that does not cause significant damage to tissue. If the light is pulsed, irradiance can be applied over a significantly higher range, provided the average irradiance is within these ranges and causes minimal damage to the tissue being treated. Irradiance in pulsed settings can be as low as 0.1 W / cm². 2 Up to 10W / cm 2 , or even higher.

[0314] In some implementations, anti-inflammatory light in the range of about 630 nm to 670 nm (e.g., specific wavelengths including about 630 nm and about 660 nm) may help provide anti-inflammatory effects and / or promote vasodilation. The anti-inflammatory effect can be used to treat conditions, particularly microbial conditions causing inflammation of the nasal cavity or oral cavity.

[0315] It can be 5mW / cm 2 Up to 60mW / cm 2 Approximately 60 to approximately 100 mW / cm 2 Or approximately 100 to approximately 200 mW / cm 2 The range of light doses used to administer antiviral therapy is as follows. For certain tissues and at certain wavelengths, up to 1 W / cm² can be applied. 2 Irradiance can be applied at a level that does not cause significant damage to tissue. If the light is pulsed, irradiance can be applied over a significantly higher range, provided the average irradiance is within these ranges and causes minimal damage to the tissue being treated. Irradiance in pulsed settings can be as low as 0.1 W / cm². 2 Up to 10W / cm 2 , or even higher.

[0316] For visible light in the range of approximately 400 to 700 nm, phototherapy is recommended to provide therapeutic benefits, including increased circulation (e.g., by increasing the formation of new capillaries); stimulation of collagen production; stimulation of adenosine triphosphate (ATP) release; enhanced porphyrin production; reduced excitability of nervous system tissues; regulation of fibroblast activity; increased phagocytosis; induction of thermal effects; stimulation of tissue granulation and connective tissue projection; reduction of inflammation; and stimulation of acetylcholine release.

[0317] In some embodiments, the peak wavelength of the endogenous storage-enhancing light 230 may be in the range of 500 nm to 900 nm, or in the range of 490 nm to 570 nm, or in the range of 510 nm to 550 nm, or in the range of 520 nm to 540 nm, or in the range of 525 nm to 535 nm, or in the range of 528 nm to 532 nm, or in the range of approximately 530 nm. A wavelength of 660 nm can both have anti-inflammatory effects and release NO.

[0318] Figure 7 This is an illustration of an exemplary configuration 700 of an illumination device 102 operable to induce biological effects in overlapping treatment zones 730 and 740 of body tissue 104 via light modulation. For example, a light emitter 120 may provide photons of a first energy and / or peak wavelength (e.g., light 710) to the body tissue 104 to stimulate enzymatic production of nitric oxide to increase endogenous storage of nitric oxide in treatment zone 730, and the light emitter 120 may also provide photons of a second energy and / or peak wavelength (e.g., light 720) within or in overlapping areas of treatment zone 730 to trigger the release of nitric oxide from endogenous storage, thereby creating treatment zone 740. In some embodiments, sequential or simultaneous irradiation with light of increasing wavelengths (e.g., nitric oxide modulated light 710 and / or nitric oxide modulated light 720) can be used to “push” a nitric oxide diffusion zone deeper within body tissue 104 than might be achieved using a single (e.g., long) wavelength of light. As shown, treatment zones 730 and 740 can be provided at different depths within body tissue 104. Light emitter 120 can further provide additional energy and / or peak wavelength photons to the same or different treatment zones (including at different depths within body tissue 104). As with previous embodiments, although an example is provided in the context of nitric oxide modulated light, illumination device 102 can be configured to induce any previously described biological effects in treatment zones 730, 740. At this point, light 710 can be provided at a first depth, and light 720 can be provided at a second depth greater than the first depth within body tissue 104. One or more additional light emissions can be further provided at deeper depths within body tissue 104. In some embodiments, treatment zones 730 and 740 can be provided at substantially different depths within body tissue 104. In further embodiments, light 710 can be configured to provide a first biological effect, light 720 can be configured to provide a second biological effect, and any additional light can be configured to provide the same or different biological effect as the first or second biological effect.

[0319] Figure 8This is a spectrum showing the intensity versus wavelength of exemplary nitric oxide modulated light 710 and 720. In this example, nitric oxide modulated light 710 is shown as having a peak intensity 814 at a peak wavelength 804, and nitric oxide modulated light 720 is shown as having a peak intensity 814 at a peak wavelength 810. In these examples, peak wavelength 804 can be any wavelength in the range from wavelength 802 to wavelength 806, and peak wavelength 810 can be any wavelength in the range from wavelength 808 to wavelength 812.

[0320] Figure 9 This is an illustration of an exemplary configuration 900 of an illumination device 102, which has an additional light emitter 910 operable to emit light 920. As shown, the additional light emitter 910 can be configured to provide emission to the treatment area 140 from a different emission angle than the light emitter 120. For example, the light emitter 120 can be configured to have an emission angle of approximately 90 degrees relative to the surface of the treatment area 140, while the light emitter 910 can be configured to have any emission angle other than 90 degrees. In other configurations, the light emitter 910 can be positioned in the same location to provide the same emission angle to the treatment area 140 as the light emitter 120. In some embodiments, light 920 can represent light that substantially does not modulate nitric oxide within the body tissue 104. Examples of light 920 may include, but are not limited to, vascular system control light for controlling blood flow within body tissue 104, microbial control light for controlling the bioactivity of microorganisms on body tissue 104 (including inactivating microorganisms in cell-free environments and / or inhibiting the replication of microorganisms in cell-associated environments), anti-inflammatory light for reducing inflammation in body tissue 104, upregulating local immune responses, and / or any combination thereof.

[0321] Figure 10 This is an illustration of an exemplary configuration 1000 of the illumination device 102, which has a camera sensor 1010 for acquiring images of the treatment area 140 at one or more wavelengths. In some embodiments, the images may be analyzed to (1) monitor how the treatment area 140 responds to phototherapy, (2) monitor how much light the treatment area 140 is exposed to, (3) monitor inflammation in the treatment area 140, and / or (4) track which parts of the body tissue 104 have been or are being treated. Figure 10 In the illustrated embodiment, camera 1010 can acquire an image of the treatment area 140 at the same wavelength as light 130. Figure 11In the alternative configuration 1100 shown, the illumination device 102 may include an additional light emitter 1110 for illuminating the treatment area 140 with imaging light 1120, the wavelength of which may differ from that of light 130. As shown, the additional light emitter 1110 may be configured to provide emission to the treatment area 140 from a different emission angle than that of light emitter 120. In other configurations, the additional light emitter 1110 may be positioned in the same location to provide the same emission angle to the treatment area 140 as light emitter 120.

[0322] The systems and apparatus described herein can be configured to treat tissues within various body cavities. For example, the systems and apparatus described herein can be configured to treat, prevent, and / or reduce the bioactivity of pathogens present in the oral cavity and / or ear canals (i.e., mouth, nose, and ears) and the throat, larynx, pharynx, oropharynx, trachea, and / or esophagus. Representative types of light delivery devices and / or light delivery devices described herein that can be used to perform the methods described herein include devices that can be used to deliver light to (and / or may be located in or through) any part of a patient's mouth, nose, ear, and pharynx, larynx, pharynx, oropharynx, trachea, and / or esophagus. In some embodiments, exemplary illumination devices are provided configured to emit safe visible light, including but not limited to light having a peak wavelength in the range of 400 nm to 490 nm, to eliminate invading respiratory pathogens in and around the oropharynx and to stimulate host defenses in surrounding tissues.

[0323] Examples include, but are not limited to, light-emitting devices (e.g., shaped and sized to be inserted into or usable into a patient's oral cavity, such as the nasal cavity and / or ear canal), observation instruments with light-emitting elements and / or light delivery components, such as ophthalmoscopes, tubes with light-emitting elements and / or light delivery components, etc. In various embodiments, the light source may be a barcode scanner, a flashlight, an ophthalmoscope, or a light plate.

[0324] Light-emitting devices, shaped and sized for insertion into or suitable for insertion into a patient's oral cavity and / or nasal cavity, typically include any device adapted for insertion into the patient's oral cavity and / or nasal cavity and capable of emitting light with desired characteristics. Examples include panels (which can be flat or curved), barcode scanners, flashlights, headphones that have a light source in addition to or in place of a speaker, observation instruments, tubes, and intraoral devices. Each of these devices may include a light source, such as LEDs, OLEDs, SLDs, lasers, and combinations thereof, to illuminate the oral cavity, ear canal, etc.

[0325] Figure 12 This is an illustration of an exemplary configuration 1200 of the lighting device 102. In this configuration, the size and shape of the lighting device 102 may be partially or completely fitted within the body cavity 1210. Figure 13An exemplary configuration 1300 of an illumination device 102 with a light guide 1320 is shown. In this embodiment, a light emitter 120 is operable to generate light 130 outside a body cavity 1310, and the light guide 1320 can deliver light 130 from the light emitter 120 to a treatment area 140 within the body cavity 1310. The light guide 1320 may include any light delivery component (e.g., fiber optic cable, waveguide, lens, etc.) operable to deliver light to living tissue within the body cavity. The light guide 1320 may be made of a thermally and / or electrically insulating material. In some embodiments, the light guide 1320 may be configured to minimize internal light absorption, maximize efficient light transmission, and / or maximize internal light reflection.

[0326] The light guide 1320 can be appropriately shaped according to the body cavity to which it is to be inserted. For example, the light guide 1320 can be shaped to conform to or be adapted to at least one of the following cavities: nasal cavity, ear cavity, larynx, pharynx, trachea, esophagus, urethra, vagina, or cervix. In one embodiment, the body cavity 1310 can be the oral cavity, and the light guide 1320 can be shaped to guide light 130 through the mouth to living tissue within the oral cavity. In at least one embodiment, the light guide 1320 can have a length ranging from about 85 mm to about 115 mm and a width ranging from about 10 mm to about 20 mm. As with the previous embodiments, although examples are provided against a background of light, the illumination device 102 and the light guide 1320 can be configured to induce any of the aforementioned biological effects in the treatment area 140 within the body cavity 1310.

[0327] Some embodiments of the apparatus used to perform the methods described herein (and some embodiments of the apparatus described herein) may include one or more features and / or components to scatter or enhance the scattering of light. Representative examples of such features and components include (1) a digital optical processor (e.g., which may be positioned at the end of an optical fiber element and propagate light leaving the optical fiber element, e.g., a 320-degree sphere), (2) light-diffusing and / or scattering materials (e.g., zinc oxide, silicon dioxide, titanium dioxide, etc.), (3) textured light-scattering surfaces, (4) patterned light-scattering surfaces, and / or (5) phosphors or other wavelength-converting materials (which tend to spherically re-emit light). In some embodiments, low-absorption light-scattering particles, liquids, and / or gases may be placed within a low-absorption element to prevent the escape of particles, liquids, and / or gases.

[0328] Figure 14 and 15Side and front views of an exemplary handheld configuration 1400 of an illumination device 102 are shown, respectively. The illumination device 102 is used to deliver light into or near a user's oral cavity (including the oropharynx) and living tissue. In various aspects, the light can be configured to induce one or more of the aforementioned biological effects in or near the user's oral cavity, including at least one of the following: inactivating microorganisms in a cell-free environment, inhibiting the replication of microorganisms in a cell-associated environment, upregulating local immune responses, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, releasing nitric oxide from endogenous nitric oxide storage, and inducing anti-inflammatory effects. Figure 14 and 15 In this embodiment, the lighting device 102 may include a housing 1402 for housing and protecting one or more light emitters, emitter drive circuitry, and / or one or more sensors as described above. In some embodiments, the housing 1402 may include a handle 1404, a button 1406 for energizing the lighting device 102 and / or the light emitter 120, and a port 1408 for charging the lighting device 102 and / or accessing or updating data stored in the lighting device 102. Figure 14 As shown, the light guide 1320 may have a curved profile suitable for insertion into a user's oral cavity. In some embodiments, the length of the light guide 1320 may be sufficient to transmit light from outside the user's oral cavity to the back of the user's oral cavity and / or oropharynx or nearby. In some embodiments, a conical shield 1410 having an oval opening 1502 may be fixedly or removably attached to the light-emitting end 1504 of the light guide 1320. In some embodiments, the illumination device 102 may include a positioning plate 1412, which the user of the illumination device 102 can use to measure the correct insertion attempt of the light guide 1320, and / or upper and lower mouthguards 1414, which are used to protect the light guide 1410 and / or allow the user to hold the light guide 1320 by biting down on the upper mouthguard 1414. In some embodiments, when in contact with the outer surface of the user's mouth, the positioning plate 1412 may help index the light-transmitting surface of the light guide 1320 at the appropriate depth within the user's oral cavity. In one embodiment, the positioning plate 1412 can index the light guide 1320 at a depth within the user's oral cavity, where the tissue area exposed to the light 130 at this depth is approximately 25 cm². 2 In one embodiment, the positioning plate 1412 can deliver an irradiance of less than about 160 mW / cm² to the tissue from the light 130. 2 The optical guide 1320 is indexed at a depth within the user's oral cavity.

[0329] Figure 16-18 Another exemplary handheld configuration 1600 of the lighting device 102 is shown for delivering light into or near the user's oral cavity (including the oropharynx) and living tissue. Figure 16These are side views of the lighting device 102. In these figures, the lighting device 102 may include a housing 1602 for housing and protecting one or more light emitters, emitter drive circuitry, and / or one or more sensors. In some embodiments, the lighting device 102 may include a handle 1604 and / or a button 1606 for energizing the lighting device 102 and / or the light emitter 120. Figure 16-18 As shown, the lighting device 102 may include a straight light guide assembly 1608, the size and shape of which are adapted for insertion into the user's mouth. Figure 17 As shown in the exploded diagram. Figure 16 The light guide assembly 1608 may include a mouthpiece housing 1610 surrounding and protecting the light guide 1320. The mouthpiece housing 1610 may be formed of any suitable transparent or opaque material. The mouthpiece housing 1610 may have a hexagonal hollow core 1702 shaped to receive the light guide 1320 having a similar cross-sectional shape. In some embodiments, a retaining collar 1704 may be secured to the light guide 1320. In some embodiments, the illumination device 102 may include an adjustable positioning plate 1612, which the user of the illumination device 102 can use to measure the appropriate insertion depth of the light guide 1320. In some embodiments, the positioning plate 1612 may be repositioned at any of the notches 1614 integrated into the mouthpiece housing 1610. In some embodiments, the positioning plate 1612 may help index the light-transmitting surface of the light guide 1320 at an appropriate depth within the user's oral cavity when in contact with the outer surface of the user's mouth. Figure 18 As shown in the front view, the handle 1604 may be removable and may allow access to the battery 1802 within the lighting unit 102.

[0330] Figure 19 Another exemplary handheld configuration 1900 of the lighting device 102 is illustrated for delivering light into or near living tissue in a user's mouth (including the oropharynx). In this figure, the lighting device 102 may include a housing 1902 for housing and protecting one or more light emitters, emitter driving circuitry, and / or one or more sensors as described above. In this embodiment, the light guide 1320 may have a tapered profile and may include a circular light-emitting tip 1904 and an exposed light-emitting side 1906.

[0331] Figure 20Another exemplary handheld configuration 2000 of the lighting device 102 is illustrated for delivering light to living tissue in or near a user's mouth (including the oropharynx). In this embodiment, the lighting device 102 may include one or more housings 2002 for housing and protecting a light emitter 120, a light emitter driving circuitry 110, a fan 2004, and a heat sink 2006 connected to the light emitter. In some embodiments, the housing 2002 may include one or more vents 2008 through which the fan 2004 draws air into the heat sink 2006. Figure 20 As shown, the light guide 1320 may have a curved profile, its size and shape adapted for insertion into a user's oral cavity. In some embodiments, the length of the light guide 1320 may be sufficient to deliver light from outside the user's oral cavity to the back of the user's oral cavity and / or to the oropharynx. In some embodiments, the illumination device 102 may include an end dome cap 2010.

[0332] Figures 21A-21E Other exemplary configurations of the lighting device 102 are shown for delivering light to tissues within a patient's internal cavity (e.g., the vaginal cavity). Figure 21A In the illustrated embodiment, the illumination device 102 may include a body 2101, which may be rigid, semi-rigid, or articulated. The treatment head 2103 may include one or more light-emitting features 2105 therein or on it, which may be formed or encapsulated therein by silicone or another suitable light-transmitting material. In some embodiments, the light-emitting feature 2105 may represent a light emitter 120 encapsulated within the treatment head 2103. In an alternative embodiment, the light emitter 120 may be external to the body 2101, and the body 2101 and the treatment head 2103 may form all or part of a light guide 1320. In this embodiment, light emission from the light emitter 120 may be transmitted within the body 2101 and may exit the treatment head 2103 at a hole or location corresponding to the light-emitting feature 2105.

[0333] exist Figure 21BIn the illustrated embodiment, according to one implementation, the illumination device 102 may include a concave light-emitting surface 2114, which includes one or more light-emitting features 2115 for delivering light to the patient's cervical tissue. In this embodiment, the illumination device 102 may include a body 2111, which may be rigid, semi-rigid, or articulated. A connector 2112 may be disposed between the body 2111 and the treatment head 2113. The treatment head 2113 may have one or more light-emitting features 2115 disposed therein or thereon, which may be formed or encapsulated therein by silicone or another suitable light-transmitting material. In some embodiments, the light-emitting feature 2115 may represent a light emitter 120 encapsulated within the treatment head 2113. In an alternative embodiment, the light emitter 120 may be external to the body 2111, and the body 2111, connector 2112, and treatment head 2113 may form all or part of a light guide 1320. In this embodiment, the light emission from the light emitter 120 can be transmitted through the body 2111, connector 2112 and treatment head 2113 and can exit the treatment head 2113 at a hole or position corresponding to the light-emitting feature 2115. Figure 21C The illustration shows the insertion of 2150 into the vaginal cavity. Figure 21B The illumination device 102 is used to deliver light to patient cervical tissue 2155 near the cervical opening 2156. The concave light-emitting surface 2114 can be configured to approximately match the convex contour of the cervical tissue 2155.

[0334] exist Figure 21D In the illustrated embodiment, the illumination device 102 may include a light-emitting surface 2124 having a protruding probe portion 2126 for delivering light to the patient's cervical tissue. The probe portion 2126 may include a light-emitting feature 2125 arranged to deliver light into the cervical opening. In this embodiment, the illumination device 102 may include a body 2121, which may be rigid, semi-rigid, or articulated. A connector 2122 may be disposed between the body 2121 and the treatment head 2123. The treatment head 2123 may have one or more light-emitting features 2125 disposed therein or thereon, which may be formed or encapsulated in silicone or another suitable light-transmitting material. In some embodiments, the light-emitting feature 2125 may represent a light emitter 120 encapsulated within the treatment head 2123. In alternative embodiments, the light emitter 120 may be external to the body 2121, and the body 2121, connector 2122, and treatment head 2123 may form all or part of a light guide 1320. In this embodiment, the light emission from the light emitter 120 can be transmitted through the body 2121, connector 2122 and treatment head 2123 and can exit the treatment head 2123 at a hole or position corresponding to the light-emitting feature 2125. Figure 21E The insertion into the vaginal cavity 2150 is shown. Figure 21DThe illumination device 102 is used to deliver light to the cervical tissue 2155 of a patient that is close to and located within the cervical opening 2156. The main light-emitting surface 2124 can be arranged to illuminate the cervical tissue defining the vaginal cavity 2150, while the probe portion 2126 can be inserted into the cervical opening 2156 to deliver additional light therein to increase the amount of cervical tissue receiving light, thereby addressing one or more conditions, including the neutralization of pathogens (e.g., HPV).

[0335] The optical guide based on the principles of this disclosure can be shaped in various ways according to the application. (See also...) Figure 22A and 22B The 1320 optical guide can have various profiles and cross-sectional areas. Figure 22A In the illustrated embodiment, the light guide 1320 may have a straight profile that allows at least some light from the light emitter 120 to enter and exit the hexagonal end face 2202 and hexagonal end face 2204 without being internally reflected. Figure 22B In the illustrated embodiment, the light guide 1320 may have a curved profile. In this embodiment, the light guide 1320 may have a bend 2210, which causes all light entering and exiting the circular end face 2206 and 2208 from the light emitter 120 to be internally reflected. In some embodiments, the bend 2210 may allow light 130 to exit the light guide 1320 in a mixed and / or homogeneous state.

[0336] See Figures 23A-23E The 1320 optical guide can have various profiles. Figure 23A In the illustrated embodiment, the light guide 1320 may have a straight profile that allows at least some light from the light emitter 120 to enter end face 2302 and exit end face 2304 without being internally reflected. Figure 23B In the illustrated embodiment, the light guide 1320 may have a curved profile. In this embodiment, the light guide 1320 may have a bend 2306, which causes all light entering from the light emitter 120 at end face 2308 and exiting at end face 2310 to be internally reflected. Figure 23C In the illustrated embodiment, the light guide 1320 may have a tapered profile with an end face 2312 through which light from the light emitter 120 enters the light guide 1320. This end face 2312 is relatively larger than the end face 2314 through which light from the light emitter 120 exits the light guide 1320. Figure 23D In the illustrated embodiment, the light guide 1320 may have a tapered profile with an end face 2316 through which light from the light emitter 120 enters the light guide 1320. This end face 2316 is relatively smaller than the end face 2318 through which light from the light emitter 120 exits the light guide 1320. Figure 23EIn the illustrated embodiment, the light guide 1320 may have a 90-degree curved profile. In this embodiment, the light guide 1320 may have a 90-degree bend 2320, which causes all light from the light emitter 120 entering end face 2322 and exiting end face 2324 to be internally reflected.

[0337] See Figures 24A-24C The optical guide 1320 can have various other profiles. Figure 24A In the illustrated embodiment, the light guide 1320 may have a curved profile. In this embodiment, the light guide 1320 may have multiple bends (e.g., bends 2402, 2404, and 2406), which cause all light entering end face 2408 and exiting end face 2410 from the light emitter 120 to be internally reflected. Figure 24B In the illustrated embodiment, the light guide 1320 may have a bulbous profile with a flat end face 2412 through which light from the light emitter 120 enters the light guide 1320. This end face 2412 is relatively smaller than the bulbous end face 2414 through which light from the light emitter 120 exits the light guide 1320. Figure 24C In the illustrated embodiment, the light guide 1320 may have a curved profile. In this embodiment, the light guide 1320 may have a uniform curvature, which causes all light from the light emitter 120 entering end face 2416 and exiting end face 2418 to be internally reflected.

[0338] See Figures 25A-25C The light guide 1320 can gradually taper and / or taper upwards in multiple dimensions. In this embodiment, the light guide 1320 may have... Figure 25A The conical profile in the dimensions shown and Figure 25C The upward conical profile in the dimension shown. In some embodiments, the circular surface area of ​​end face 2502 may be greater than, less than or equal to the elliptical surface area of ​​end face 2504.

[0339] In some embodiments, the light guide 1320 may have a split structure. In these embodiments, the light guide 1320 may have different numbers of incident light end faces and exit light end faces. For example, in Figures 26A-26C In the illustrated embodiment, the light guide 1320 may include a single light-incident end face 2602 and two light-exit end faces 2604. In some embodiments, the surface area of ​​the light-incident end face 2602 may be greater than, less than, or equal to the surface area of ​​the light-exit end face 2604.

[0340] The optical guide disclosed herein may include cross-sectional areas and / or end faces of various shapes. For example, in Figure 27A In the illustrated embodiment, the light guide 1320 may have a circular cross-sectional area and a circular end face 2702. Figure 27BIn the illustrated embodiment, the light guide 1320 may have a hexagonal cross-sectional area and a hexagonal end face 2704. Figure 27C In the illustrated embodiment, the light guide 1320 may have an elliptical cross-sectional area and an elliptical end face 2706. Figure 27D In the illustrated embodiment, the light guide 1320 may have a rectangular cross-sectional area and a rectangular end face 2708. Figure 27E In the illustrated embodiment, the light guide 1320 may have a pentagonal cross-sectional area and a pentagonal end face 2710. Figure 27F In the illustrated embodiment, the light guide 1320 may have an octagonal cross-sectional area and an octagonal end face 2712. Figure 27G In the illustrated embodiment, the light guide 1320 may have an oval cross-sectional area and an oval end face 2714. Figure 27H In the illustrated embodiment, the light guide 1320 may have a triangular cross-sectional area and a triangular end face 2716. Figure 27I In the embodiment shown, the light guide 1320 may have a semi-circular cross-sectional area and a semi-circular end face 2718.

[0341] The optical guide disclosed herein can have a uniform cross-sectional area and a similarly shaped end face. For example, in Figure 28A In the illustrated embodiment, the light guide 1320 may have circular end faces 2802 and 2804 with similar shapes and sizes. In other embodiments, the light guide 1320 may have cross-sectional areas of different shapes and end faces of different shapes. For example, in Figure 27J and 28B In the illustrated embodiment, the light guide 1320 may have a hexagonal end face 2720 and a circular end face 2722. In this embodiment, the cross-sectional area of ​​the light guide 1320 may be hexagonal, circular, and / or a combination of hexagonal and circular.

[0342] The optical guide disclosed herein may include end faces having various types of surfaces. For example, in Figure 28A and 28B In the illustrated embodiment, the light guide 1320 may have a substantially flat end face. Figure 28C In the illustrated embodiment, the light guide 1320 may have an end face with an irregularly shaped surface 2806. Figure 28D In the illustrated embodiment, the light guide 1320 may have an end face with a tapered surface 2808. Figure 28E In the illustrated embodiment, the light guide 1320 may have an end face with a multifaceted surface 2810. Figure 28F In the illustrated embodiment, the light guide 1320 may have an end face with a flat surface 2812. Figure 28G In the illustrated embodiment, the light guide 1320 may have an end face with a convex surface 2814. Figure 28H In the illustrated embodiment, the light guide 1320 may have an end face with a concave surface 2816. Figure 28I In the illustrated embodiment, the light guide 1320 may have an end face with a circular surface 2818. Figure 28J In the illustrated embodiment, the light guide 1320 may have an end face with a chamfered surface 2820. Figure 28K In the embodiment shown, the light guide 1320 may have an end face with an angled surface 2822.

[0343] The light guide disclosed herein may have one or more cores, and each core of the light guide 1320 may be clad or unclad and / or buffered or unbuffered. For example, in Figure 29A and 29B In the illustrated embodiment, the light guide 1320 may include a single unclad and unbuffered circular core 2902 having a circular cross-sectional area 2904. In at least one embodiment, the refractive index of the light guide 1320 may be uniform across the cross-sectional area 2904. Figure 29C In the illustrated embodiment, the light guide 1320 may include an unclad and unbuffered square core 2906 having a square cross-sectional area 2908. In at least one embodiment, the refractive index of the light guide 1320 may be uniform across the cross-sectional area 2908. Figure 29E In the illustrated embodiment, the light guide 1320 may include a circular core 2910 surrounded by a cladding 2912. In at least one embodiment, the circular core 2910 may be designed to have a higher refractive index than the cladding 2912, which results in total internal reflection of light within the circular core 2910. Figure 29F In the illustrated embodiment, the light guide 1320 may include a circular core 2914 surrounded by a cladding 2916. In at least one embodiment, the cladding 2916 may be surrounded by an additional cladding or buffer 2918. In some embodiments, the circular core 2914 may be designed to have a higher refractive index than the cladding 2916. Furthermore, the cladding 2916 may be designed to have a higher refractive index than the cladding 2918, which can result in more efficient total internal reflection of light in the circular core 2914.

[0344] exist Figures 30A-30C In the illustrated embodiment, the optical guide 1320 may include multiple fibers 3002. In some embodiments, the multiple fibers 3002 may be encapsulated in a flexible or rigid buffer 3004. If the buffer 3004 is formed of a flexible material and the multiple fibers 3002 are flexible, the optical guide 1320 may also be flexible and capable of assuming various curved shapes (e.g., Figure 30C(The curved shape shown). In some embodiments, each of the plurality of fibers 3002 may be coupled to a different one of the light emitters 120. In other embodiments, two or more of the plurality of fibers 3002 may be connected to the same light emitter 120. In some embodiments, one or more of the plurality of fibers 3002 may be additionally or alternatively connected to an optical sensor.

[0345] Figure 31A Several exemplary multi-core configurations of the light guide 1320 are shown, wherein one or more cores 3102 are connected to the light emitter 120, while one or more other cores 3104 are connected to the optical sensor 3106. In an alternative embodiment, cores 3102 may be connected to the optical sensor 3106, and cores 3104 may be connected to the light emitter 120. Figure 31B-31D Exemplary cross-sectional areas of cores 3102 and 3104 are shown. Figure 31B In the illustrated embodiment, cross-sectional areas 3108 and 3110 can represent the cross-sectional areas of cores 3102 and 3104, respectively. Figure 31C In the illustrated embodiment, cross-sectional areas 3112 and 3114 can represent the cross-sectional areas of cores 3102 and 3104, respectively. Figure 31D In the embodiment shown, cross-sectional areas 3116 and 3118 can represent the cross-sectional areas of cores 3102 and 3104, respectively.

[0346] In some embodiments, the optical guide of this disclosure may have one or more hollow cores and / or hollow cross-sectional areas. For example, in Figure 32A In the illustrated embodiment, the light guide 1320 may have a circular hollow core 3202 and / or a circular hollow cross-sectional area 3204. Figure 32B In the illustrated embodiment, the light guide 1320 may have a rectangular hollow core 3206 and / or a rectangular hollow cross-sectional area 3208. Figure 32C In the illustrated embodiment, the light guide 1320 may have an elliptical hollow core 3210 and / or an elliptical hollow cross-sectional area 3212. Figure 32D In the embodiment shown, the light guide 1320 may have a hexagonal hollow core 3214 and / or a hexagonal hollow cross-sectional area 3216.

[0347] In some embodiments, hollow cores 3202, 3206, 3210, and / or 3214 may have reflective surfaces, and light guide 1320 may be configured to deliver light through hollow cores 3202, 3206, 3210, and / or 3214. Additionally or alternatively, light guide 1320 may be configured to deliver light through cross-sectional areas 3204, 3208, 3212, or 3216. For example, in Figure 33In the illustrated embodiment, the light guide 1320 can be part of a ventilator and may include a hollow core 3302 through which air 3304 can flow, while light 130 is transmitted from the light emitter 120 through the light guide 1320 to the tissues inside the patient's mouth. Similarly, in Figure 34 In the illustrated embodiment, the light guide 1320 may include a hollow core 3402 through which air 3404 can flow, while light 130 is transmitted from the light emitter 120 to the tissues within the patient's oral cavity via the light guide 1320. In this embodiment, the light guide 1320 may be additionally equipped with a tube 3406, through which fluid 3408 can be aspirated and / or drained when the light guide 1320 is inserted into the patient's mouth (or other body cavity).

[0348] Figure 35 This is an illustration of an exemplary U-shaped configuration 3500 of a light guide 1320 for directing light to a user's cheek when inserted into the user's mouth. As shown, the light guide 1320 may include an inner surface 3502 having a reflective coating 3504. The reflective coating 3504 may reflect light 130 radially from the light guide 1320 and / or reflect light 130 in a direction transverse to the direction in which light 130 enters the light guide 1320.

[0349] In some embodiments, the light guide 1320 may include a cap or shield for protecting the light guide 1320 and / or for protecting tissue near the light guide 1320 from excessive exposure. Figure 36A In the illustrated embodiment, the light guide 1320 may include a cover cap 3602. In Figure 36B In the illustrated embodiment, the light guide 1320 may include an end dome cap 3604. Figure 36C In the illustrated embodiment, the light guide 1320 may include an end flat cap 3606. In Figure 36D In the illustrated embodiment, the light guide 1320 may include a tapered shield 3608 having an opening 3610 through which light can pass. Figure 36E In the illustrated embodiment, the light guide 1320 may include an angled conical shield 3612 having an opening 3614 through which light can pass. Figure 36F In the illustrated embodiment, the light guide 1320 may include a single-sided shield 3616 having an opening 3618 through which light can pass. Figure 36G In the embodiment shown, the light guide 1320 may include a perforated shield 3620 having a plurality of openings 3624 through which light can pass.

[0350] The lighting device according to this disclosure can be controlled in a variety of ways, for example by turning the lighting device on or off by a simple on / off switch or button (e.g., by button 1406 or button 1606 discussed above), although other control mechanisms may also be provided. Figure 37 and 38 An exemplary lever-based switch mechanism 3700 is shown for powering and / or controlling the lighting device 102 after it has been inserted into a user's mouth. In this embodiment, the lighting device 102 may include a power supply 3702 for powering a light emitter 120 and / or an emitter drive circuit 110, a switch 3704 for connecting or disconnecting the power supply 3702 from the light emitter 120 and / or the emitter drive circuit 110, and a pivot 3706 positioned to close or open the switch 3704. A spring 3708 may apply a force to the pivot 3706, which, when not counteracted, causes the pivot 3706 to open the switch 3704. The user may counteract the force applied by the spring 3708 by biting down on the pivot 3706, thereby closing the switch 3704 and enabling the power supply 3702 to power the light emitter 120 and / or the emitter drive circuit 110, as... Figure 38 As shown.

[0351] The lighting device according to this disclosure can be controlled or managed, at least in part, by an application running on another device. In one example, lighting device 102 can be controlled by... Figure 39 The exemplary system 3900 shown is controlled or managed in whole or in part. Figure 39 As shown, system 3900 may include server 3902 communicating with client device 3906 via network 3904. In one example, server 3902 may include server-side application 3908 for managing, controlling, or communicating with lighting device 102. In at least one embodiment, server-side application 3908 may be configured to collect usage data from multiple lighting devices (e.g., as part of a clinical trial).

[0352] Additionally or alternatively, the client device 3906 may include a client application 3910 for managing, controlling, or communicating with the lighting device 102. In at least one embodiment, the client application 3910 may be configured to collect sensor data from the lighting device and / or user feedback (e.g., as part of a clinical trial).

[0353] Server 3902 and client device 3906 generally represent any type or form of computing device capable of reading computer-executable instructions. Examples of server 3902 and client device 3906 include, but are not limited to, laptops, tablets, desktops, servers, cellular phones, personal digital assistants (PDAs), multimedia players, embedded systems, wearable devices (such as smartwatches, smart glasses, etc.), routers, switches, game consoles, one or more combinations thereof, or any other suitable computing device. In at least one example, client device 3906 may represent a user's computing device to which the lighting device 102 has been paired.

[0354] Network 3904 typically represents any medium or architecture capable of facilitating communication or data transmission. Examples of network 3904 include, but are not limited to, intranets, wide area networks (WANs), local area networks (LANs), personal area networks (PANs), the Internet, power line communication (PLC), cellular networks (such as GSM networks), etc. Network 3904 can facilitate communication or data transmission using wireless or wired connections. In one embodiment, network 3904 can facilitate communication between server 3902 and client device 3906 or lighting device 102.

[0355] Figure 40 This is a flowchart of an exemplary computer implementation method 4000 for performing phototherapy operations based on sensor measurements. Figure 40 The steps shown can be performed by any suitable computer-executable code and / or computing system, including Figure 39 The system shown. In one example, Figure 40 Each step shown can represent an algorithm whose structure includes and / or is represented by multiple sub-steps, examples of which will be provided in more detail below.

[0356] like Figure 40 As shown, in step 4010, one or more systems described herein can obtain a first set of measurements of the living tissue. For example, as an illumination device according to any of the foregoing embodiments, the temperature of the target body tissue can be obtained by a temperature sensor and / or one or more images of the target body tissue can be captured by a camera sensor. In at least one embodiment, the illumination device can capture one or more visible light images, one or more infrared images, one or more ultraviolet images, one or more image measurement lights within a predetermined wavelength range, and / or one or more image measurement lights within two or more different predetermined wavelength ranges. In some embodiments, one or more systems described herein can use the first set of measurements to establish baseline measurements from which the safety or effectiveness of subsequent phototherapy treatments can be verified and / or the user's health can be monitored.

[0357] In step 4020, one or more systems described herein may irradiate light onto the living tissue during phototherapy. Then, in step 4030, one or more systems described herein may obtain a second set of measurements of the living tissue. In some embodiments, the second set of measurements may include measurements of the same type as those included in the first set of measurements. While an exemplary computer-implemented method 4000 is provided in the context of light, the disclosed principles are applicable to any light that can induce any of the previously described biological effects.

[0358] In step 4040, one or more systems described herein can perform operations based on at least one of a first set of measurements and a second set of measurements. In one example, the client application (e.g., Figure 39 (3910) can transmit the first set of measurements and the second set of measurements from the lighting device (e.g., Figure 39 102) relay to server-side applications (e.g. Figure 39 (3908) for analysis. In one implementation, the server-side application can use a first set of measurements and / or a second set of measurements to verify the safety or effectiveness of irradiating living tissue based on a comparison of the first set of measurements and the second set of measurements.

[0359] In another example, such as Figure 39 The illumination device 102 and / or client application 3910 shown can adjust parameters of subsequent phototherapy treatments based on a comparison of a first set of measurements and a second set of measurements. For example, the illumination device 102 and / or client application 3910 can adjust the duration of subsequent phototherapy treatments, light intensity, peak wavelength of light, or wavelength range of light.

[0360] In some embodiments, the lighting device 102 may include one or more light-shielding elements that prevent light 130 from reaching portions of body tissue 104 that are not intended to receive light 130 (e.g., any portion of body tissue 104 not considered for treatment area 140, e.g.) Figure 41 and 42 (Central protected area 4150). Figure 41 This is an illustration of an exemplary configuration 4100 of an illumination device 102 having a light-shielding light guide 4120. In this configuration, the size and shape of the illumination device 102 may be partially or completely adapted to fit within a body cavity 4110. In this embodiment, the light emitter 120 is operable to emit light 130 within the body cavity 4110 along one or more paths (e.g., paths 4130 and 4140), and the light-shielding light guide 4120 may be formed to (1) allow light 130 to travel along the guide path 4130 to the treatment area 140, but (2) prevent light 130 from traveling along the blocked path 4140 to the protected area 4150. Figure 42An exemplary configuration 4200 of an illumination device 102 with a light-shielding light guide 4220 is shown. In this embodiment, the light emitter 120 is operable to emit light 130 outside the body cavity 4210 along multiple paths (e.g., paths 4230 and 4240), and the shape of the light-shielding light guide 4220 can be such that (1) the light 130 travels along the guide path 4230 to the treatment area 140 within the body cavity 4210, but (2) the light 130 is prevented from traveling along the blocked path 4240 to the protection zone 4150.

[0361] Light-shielding light guides 4120 and / or 4220 may include any light-shielding component operable to prevent light from reaching certain parts of a user's body by blocking, reflecting, or absorbing large amounts of light. In some examples, light-shielding light guides 4120 and / or 4220 may include one or more hollow or transparent regions that allow light to travel freely through these regions, and / or one or more solid, reflective, or opaque regions that prevent light from traveling freely through these regions. Examples of light-shielding light guides 4120 and / or 4220 include, but are not limited to, hollow cylinders, tubes, pipes, sleeves, funnels, lampshades, and collimators. In some examples, light-shielding light guides 4120 and / or 4220 may perform other functions, such as expanding body cavities or diffusing or displacing tissue. For example, in combination with Figures 43-53 The mouthpiece and / or light guide shown may include one or more light-shielding areas (e.g., to prevent the user's cheeks or tongue from being exposed to light).

[0362] The light-shielding light guide 4220 can be appropriately shaped to fit into the body cavity to which it is to be inserted. For example, the light-shielding light guide 4220 can be shaped to conform to or be suitable for at least one of the following cavities: nasal cavity, ear cavity, larynx, pharynx, trachea, esophagus, urethra, vagina, or cervix. In one embodiment, the body cavity 4110 can be the oral cavity, and the light-shielding light guide 4220 can be shaped to guide light 130 through the mouth to living tissue within the oral cavity.

[0363] Figure 43-52Various views of an exemplary handheld configuration 4300 of a lighting device 102 are shown for delivering light (e.g., nitric oxide-modulated light and / or light inducing any of the aforementioned biological effects) to living tissue in or near the user's mouth, including the oropharynx. As shown, the lighting device 102 may include a housing having (1) a housing 4302 for housing and protecting a light emitter 120, (2) a housing 4304 for housing and protecting at least a light emitter drive circuit 110, a button 4306 for powering the lighting device 102 and / or the light emitter 120, and / or a carrier 4308, and (3) a housing 4310 for housing and protecting at least a battery 4312. In some embodiments, the housing 4304 may be covered by a sleeve or overmolded member 4314 having a tactile element 4316 for engaging the button 4306 and a port 4318 for charging the lighting device 102 and / or accessing data stored in the lighting device 102. Figure 46 In this embodiment, the light emitter 120 can be secured to a printed circuit board 4320, which can be secured to a housing 4302 by screws 4322 (or any other suitable fasteners). Additionally, the illumination device 102 may include a lens 4324 for allowing light 130 to enter and / or approach the user's mouth. In some embodiments, a retaining ring 4326 secures the lens 4324 to the housing 4302. In this example, a lens washer 4328 may be positioned between the retaining ring 4326 and the lens 4324, and a lens spacer 4330 may be positioned between the lens 4324 and the housing 4302. As shown, the illumination device 102 may include a light guide 4332 and a mouthpiece 4334, the size and shape of which are adapted for insertion into the user's mouth.

[0364] like Figures 48A-48D As shown, the mouthpiece 4334 may include an outer surface 4802 for connecting or engaging with a user's oral cavity surface (e.g., the user's lips and cheeks), an occlusal surface 4804 for engaging with the user's teeth, and a protrusion 4806 for engaging the posterior portion of the user's teeth. In some embodiments, the outer surface 4802 may apply outward force to the user's lips and / or cheeks to expand the user's oral cavity during phototherapy. In some embodiments, the occlusal surface 4804 and / or the protrusion 4806 may allow the user to hold the illumination device 102 in their mouth by biting down on the occlusal surface 4804. In some embodiments, the mouthpiece 4334 may help to index the illumination device 102 at an appropriate depth within the user's oral cavity. In one embodiment, the mouthpiece 4334 may index the illumination device 102 at a depth within the user's oral cavity where the tissue area exposed to light 130 is approximately 25 cm². 2In one embodiment, the mouthpiece 4334 can index the light guide 1320 at a depth within the user's oral cavity, where the light irradiance to the tissue is less than approximately 160 mW / cm². 2 In this respect, the mouthpiece 4334 can be referred to as a light guide locator, configured to at least partially position and hold the light guide 4332 within or near the oral cavity to ensure that light emitted from the light emitter 120 exits the light guide 4332 at the appropriate location to irradiate target tissue, such as the oropharynx. In at least one embodiment, the mouthpiece 4334 can serve to block light from reaching the user's oral cavity and can be appropriately adjusted in shape and size for this purpose. In some embodiments, the mouthpiece 4334 can be detached from the illumination device 102.

[0365] like Figures 49A-49D As shown, the light guide 4332 may include a tongue depressor 4900 for depressing the user's tongue when inserted into the user's mouth. In some embodiments, the tongue depressor 4900 may reposition the user's tongue to expose the back of the user's throat, oropharynx (or other treatment areas) to light emitted by the light emitter 120. The tongue depressor 4900 may have any suitable size and shape and may serve to block light from reaching the user's tongue. In some embodiments, the light guide 4332 may include a cylindrical wall 4902 that defines a light transmission path 4904 through which light can pass. In at least some embodiments, the cylindrical wall 4902 may serve to block light from reaching portions of the user's oral cavity and may be suitably shaped and sized for this purpose. In some embodiments, the light guide 4332 may be detachable. Figure 44 In the embodiment shown in A-49D, the light guide 4332 may include a fixing tab 4906, which is shaped to mate with notches 5102 and 5104 of the housing 4302. Figure 52 In the alternative embodiment shown, the light guide 4332 may include a fixing notch (e.g., notch 5204) that is shaped to securely engage a corresponding protrusion (e.g., protrusion 5202) of the housing 4302.

[0366] In some embodiments, the nozzle 4334 (also referred to as a light guide locator) and the light guide 4332 may be a single, indivisible structure. Alternatively, the nozzle 4334 and the light guide 4332 may be separable structures, securely connected together to form a detachable assembly. In each case, the combination of the nozzle 4334 (e.g., a light guide locator) and the light guide 4332 can form an assembly that can be detachably attached to the lighting device 102. Figures 50A-50DAn exemplary detachable assembly 5000 of the mouthpiece 4334 and the light guide 4332 is shown. In this embodiment, the light guide 4332 may include a retaining protrusion 4908 shaped to engage with a corresponding notch in the mouthpiece 4334 to facilitate tool-free separation of the light guide 4332 from the mouthpiece 4334.

[0367] Figure 51A , 51B 51C and 51C are respectively based on some implementation methods Figure 43 The side view, front view, and perspective view of the lighting device 102, which does not have Figures 50A-50D The nozzle 4334 and the light guide 4332 are detachably assembled 5000. In some embodiments, Figures 49A-49D The shown retaining tab 4906 can be configured to snap-fit ​​or otherwise connect to the notches 5102 and 5104 of the housing 4302. In this respect, the nozzle 4334 and the light guide 4332 can be easily removed from the lighting device 102 for cleaning and / or replacement.

[0368] Figure 52 This is a side view of another exemplary configuration 5200 of the exemplary lighting device 102, which is an embodiment in which the mouthpiece 4334 and the light guide 4332 can be easily detached from the lighting device 102. As shown, the light guide 4332 may include a fixing notch (e.g., notch 5204) shaped to securely engage a corresponding protrusion (e.g., protrusion 5202) of the housing 4302.

[0369] Figure 53An exemplary handheld configuration 5300 of the lighting device 102 is illustrated for delivering light to living tissue in or near a user's mouth, including the oropharynx. As shown, the lighting device 102 may include a housing 5302 for housing and protecting one or more light emitters, emitter drive circuitry 110, and / or one or more sensors as described above. In some embodiments, the housing 5302 may include a handle 5304 and a button 5306 for energizing the lighting device 102 and / or the light emitters. In some embodiments, the lighting device 102 may include a mouthpiece 5310 for contact with the user's mouth, cheek, and / or the tips of the teeth, and a tongue depressor 5308 for moving the user's tongue. In some examples, the lighting device 102 may include a positioning plate 5312 that the user of the lighting device 102 can use to measure the appropriate insertion depth of the lighting device 102, and / or upper and lower mouthguards 5314 for enabling the user to secure the lighting device 102 by biting down on the mouthguards 5314. In some embodiments, the positioning plate 5312 can help direct the illumination device 102 at an appropriate depth within the user's oral cavity when it contacts the outer surface of the user's mouth. In one embodiment, the positioning plate 5312 can direct the illumination device 102 at a depth within the user's oral cavity where the tissue area exposed to light is approximately 25 cm². 2 In one embodiment, the positioning plate 5312 can index the light guide 1320 at a depth within the user's oral cavity, where the light irradiance to the tissue is less than approximately 160 mW / cm². 2 .

[0370] Although not shown in the diagram, it should be noted that a properly sized and shaped mouthpiece and / or light guide (similar to a combination) is important. Figures 43-53 The nozzle and light guide can also be integrated into Figure 14-21E The example configuration of the lighting device 102 shown is illustrated. Additionally, in conjunction with… Figures 43-53 The described nozzle and light guide may include some or all of the features of light guide 1320.

[0371] Figures 54A-54E Various views of an exemplary handheld configuration 5400 of the lighting device 102 are shown, which is used to deliver light (such as nitric oxide modulated light and / or light that induces any previously described biological effects) to living tissue in or near the user's mouth, including the oropharynx. Figure 54A It is a front perspective view. Figure 54B It is a rear perspective view. Figure 54C This is the front view. Figure 54D It is a side view, and Figure 54E This is a top view of an exemplary handheld configuration 5400 of the lighting device 102. Figures 54A-54E The exemplary handheld configuration 5400 is similar to that described previously. Figure 43-52An exemplary handheld configuration 4300 is provided, and the tongue depressor 490 further defines a shape in which the width at one end of the tongue depressor 4900 is greater than the corresponding width of the tongue depressor 4900 closer to the housing 4302. In this way, the end of the tongue depressor 4900 can be configured to depress a larger portion of the user's tongue when inserted into the user's mouth. Furthermore, the housing 4302 may form one or more features 4302' that can provide heat dissipation for the housing 4302. Figure 43 A similar feature 4302' is shown, but it is provided in a manner that surrounds multiple sides of the housing 4302, while... Figures 54A-54E In one embodiment, feature 4302' may be disposed along the back side of housing 4302 and surround the housing portion adjacent to light guide 43342.

[0372] Using a suitable device, the phototherapy described herein can be applied to selected portions of the oral cavity, ear canal, pharynx, larynx, pharynx, oropharynx, trachea, and / or esophagus, the choice of which depends on the location of the light exposure. The treatment methods described herein can be performed using any light delivery device capable of delivering light with the desired characteristics (e.g., wavelength characteristics, radiant flux, duration, pulsed or non-pulsed, coherence, etc.) to the desired area.

[0373] In addition to the aforementioned illumination devices, representative types of light delivery devices that can be used for phototherapy, and / or the light delivery devices described herein, include any device that can be used to deliver light to (and / or can be positioned in or through) any part or multiple parts of a patient's mouth, ear canal, etc. Examples include, but are not limited to, light-emitting devices (e.g., those shaped and sized to be inserted into or insertable into a patient's mouth and / or nasal cavity), observation instruments (such as ophthalmoscopes for reaching the mouth, throat, ears, and nose; bronchoscopes for reaching deeper into the pharynx and esophagus, trachea, etc.), tubes with light-emitting elements, and / or light delivery assemblies, etc.

[0374] Examples include, but are not limited to, light-emitting devices (e.g., shaped and sized to be inserted into or accessible into a patient's oral cavity, such as the nasal cavity and / or ear canal), observation instruments (e.g., ophthalmoscopes with light-emitting elements and / or light delivery components), tubes with light-emitting elements and / or light delivery components, etc. In various embodiments, the light source is a scanning gun, a flashlight, an ophthalmoscope, or a light plate.

[0375] Light-emitting devices, shaped and sized to be inserted into or be insertable into a patient's mouth and / or nasal cavity, typically include any device suitable for insertion into a patient's mouth and / or nasal cavity and capable of emitting light with desired characteristics. Examples include panels (which can be flat or curved), barcode scanners, flashlights, headphones that have a light source in addition to or in place of a speaker, observation instruments, tubes, and intraoral devices. Each of them has a light source, such as a light-emitting diode (LED), OLED, superluminescent diode (SLD), laser, or combinations thereof, to illuminate the mouth, ear canal, etc.

[0376] The method described herein may use an observation instrument comprising a light-emitting element and / or a light delivery assembly. Such an observation instrument includes any device suitable for insertion into (and / or through) any region of a patient's airway. At least one light delivery assembly and / or at least one light-emitting element is disposed within and / or supported by the observation instrument.

[0377] Representative examples of suitable observation instruments include bronchoscopes, nasopharyngoscopes, and fiberoptic endoscopes. Representative examples of suitable optical delivery components include fiber optic devices and other waveguides.

[0378] In one particular embodiment, an ophthalmoscope is disclosed that, instead of allowing a doctor to examine a patient's mouth, ears, and nose, is equipped with a light source, such as an LED, OLED, laser, etc., emitting one or more specific antibacterial wavelengths. In this embodiment, the ophthalmoscope has an accessory to focus light onto the ears and / or nose.

[0379] An ophthalmoscope is a handheld, usually battery-powered device containing optics for illuminating and observing the eye's media (cornea, aqueous humor, lens, and vitreous humor) and retina. However, ophthalmoscopes often include various accessories that allow the device to illuminate the ears, nostrils, mouth, and throat.

[0380] One such accessory is an otoscope accessory, which allows users to illuminate the ear canal and eardrum.

[0381] Another type of accessory is a nasal speculum adapter (usually used with an otoscope accessory). When using an otoscope accessory with a nasal speculum adapter, the device can illuminate the nostrils (nasal openings) while maintaining a line of sight through the nasal passages, one passage at a time.

[0382] A curved-arm illuminator is a handheld lamp used to illuminate a patient's mouth and upper throat. It can also be used for transillumination of the sinuses. While typical ophthalmoscopes or bronchoscopes include an on / off switch but not a timer, the bronchoscope described herein may include a timer, allowing the user to know when treatment is complete. The timer may include different treatment times based on the location of the applied light, the wavelength applied, etc.

[0383] Some embodiments of devices that pass through a patient's epiglottis (e.g., devices including observation instruments and tubes that pass through the patient's mouth or nose, through the epiglottis, and into the trachea) may include demand valve-type components. This is similar to a demand valve in scuba diving equipment, which helps prevent the epiglottis from obstructing the insertion of devices (e.g., observation instruments and tubes).

[0384] Tubes having light-emitting elements and / or light delivery components (e.g., LEDs, OLEDs, or laser emitting or delivering components) can be used in the methods described herein. This includes any device suitable for insertion into (and / or through) any region of a patient's oral cavity, wherein at least one light delivery component and / or at least one light-emitting element is disposed within and / or supported by the tube. In another embodiment, the tube includes light sources located at different positions at the front of the tube and around the tube, so as to enable simultaneous illumination of light onto the user's throat, palate, tongue, gums, and cheeks. Representative examples of suitable tubes include tracheostomy tubes, endotracheal tubes, and nasogastric tubes, and representative examples of tubes having light-emitting elements and / or light delivery components. Specifically, this includes tubes in which at least one optical fiber and / or other waveguide is disposed and / or supported, and wherein at least one light-emitting element is positioned and oriented to feed light into the optical fiber and / or other waveguide.

[0385] On the other hand, the light source is a panel (i.e., a light plate), which can be straight or curved, and, for example, a cheek retractor, allows the user to be exposed to light by opening their mouth. Instead of a fixed light source, the panel can be positioned so that the patient can sit or lie down and be exposed to the panel. The panel may include clips or supports to facilitate positioning so that the user's mouth, nose, and / or ears can be exposed to the antibacterial light.

[0386] As described above, the apparatus for performing the method described herein (and certain embodiments thereof) includes at least one light-emitting element capable of delivering light having desired characteristics (e.g., wavelength characteristics, radiant flux, duration, pulsed or non-pulsed, coherence, etc.) to a desired region of a patient's airway. Wavelength characteristics include saturation, wavelength spectrum (e.g., wavelength range, full width at half maximum), dominant wavelength, and / or peak wavelength.

[0387] In some embodiments, at least one of the light-emitting elements is a solid-state light-emitting device. Examples of solid-state light-emitting devices include, but are not limited to, LEDs, OLEDs, SLDs, lasers, thin-film electroluminescent devices, powder electroluminescent devices, field-induced polymer electroluminescent devices, and polymer light-emitting electrochemical cells.

[0388] While both LEDs and lasers are variable-power light sources, LEDs are more flexible in this respect. Lasers have a threshold current below which there is no power output, and above which the current increases exponentially with the application of more drive current. In contrast, LEDs begin to emit light with very low drive current, and then the emission is roughly linear as the drive current increases. This advantage of LEDs over lasers is important for providing sufficient flux to treat the target disease without providing too much to damage tissue. This feature is particularly important in body regions such as the lungs, where the same medical device can be used to address different and complex topologies.

[0389] While not coherent light sources with spectral widths as narrow as lasers, LEDs offer several advantages over lasers in photobiological modulation (PBM). These advantages directly apply to the absorption of one component of PBMs—photoreceptor molecules. LEDs are more readily available across a wide wavelength range, from UV to IR, than lasers. In addition to their wider wavelength range, LEDs are also more readily available at more discrete wavelengths within that range. LEDs are characterized by a wider spectral width than lasers, thus making it less likely that absorption of target molecules will be missed due to an incorrect selection of the emission wavelength of a laser only a few nm wide. LEDs also feature a wider far field than lasers, making more uniform treatment over large areas more direct than with lasers, whether through direct emission or target irradiation by other optical elements. Finally, from a practical standpoint, LEDs are more cost-effective per mW of emission, more readily available, and easier to use in optical systems compared to lasers. Therefore, in one embodiment, the therapeutic method described herein uses LEDs as the light source. In some embodiments, one, some, or all of the light-emitting elements have a full width at half maximum (WWHM) of less than 25 nm (or less than 20 nm, or less than 15 nm, or in the range of 5 nm to 25 nm, or in the range of 10 nm to 25 nm, or in the range of 15 nm to 25 nm).

[0390] In some embodiments, different light-emitting elements are included in a single solid-state emitter package. In some embodiments, the light-emitting elements are arranged in one, two, or more arrays. In some embodiments, the light-emitting elements include one or more wavelength-converting materials, examples of which include phosphor materials, fluorescent dye materials, quantum dot materials, and fluorophore materials.

[0391] Some embodiments of the apparatus for carrying out the methods described herein (and some embodiments of the apparatus herein) may include a power supply circuit arranged to provide at least one regulated power signal for use by at least one of the microcontrollers of the apparatus.

[0392] Some embodiments of the apparatus used to perform the methods described herein (and some embodiments of the apparatus described herein) may include one or more features and / or components for scattering or enhancing light scattering.

[0393] Those skilled in the art are familiar with various such features and components, and any such features and components are within the scope of this specification.

[0394] Representative examples of such features and components include (1) digital optical processors (e.g., which can be placed at the end of an optical fiber and propagate light leaving the fiber, such as a 320-degree sphere), (2) light-diffusing and / or scattering materials (e.g., zinc oxide, silicon dioxide, titanium dioxide, etc.), (3) textured light-scattering surfaces, (4) patterned light-scattering surfaces, and / or (5) phosphors or other wavelength-converting materials (which tend to re-emit light spherically).

[0395] In some embodiments, low-absorption light-scattering particles, liquids, and / or gases may be placed within a low-absorption element to prevent the escape of particles, liquids, and / or gases.

[0396] In some embodiments, light extraction features may be provided and may include different sizes and / or shapes. In some embodiments, light extraction features may be uniformly or non-uniformly distributed on a flexible printed circuit board. In some embodiments, light extraction features may include a tapered surface. In some embodiments, different light extraction features may include one or more connected portions or surfaces. In some embodiments, different light extraction features may be discrete or spatially separated relative to each other. In some embodiments, light extraction features may be arranged in lines, rows, zigzags, or other patterns. In some embodiments, one or more wavelength conversion materials may be disposed on or near one or more light extraction features.

[0397] Some embodiments of the apparatus used to perform the methods described herein (and some embodiments of the apparatus herein) may include one or more sensors of any type. In some embodiments, operation of the methods disclosed herein may be in response to one or more signals generated by one or more sensors or other elements.

[0398] Various types of sensors can be used, including temperature sensors, light sensors, image sensors, proximity sensors, blood pressure or other pressure sensors, chemical sensors, biological sensors (such as heart rate sensors, body temperature sensors, sensors that detect the presence or concentration of chemical or biological species or other conditions), accelerometers, humidity sensors, pulse oximeters such as pulse oximeters, current sensors, voltage sensors, etc.

[0399] Other elements that may affect the light exposure and / or operation of the devices disclosed herein include timers, cycle counters, manually operated control elements such as on / off switches, wireless transmitters and / or receivers (possibly included in a transceiver), laptops or tablets, mobile phones, or other portable digital devices. Wired and / or wireless communication between the devices disclosed herein and one or more signal generating or receiving elements may be provided. In any of these aspects, the user can be exposed to light with sufficient power and for sufficient time to produce the desired antibacterial effect without causing excessive exposure to light.

[0400] In some embodiments, the apparatus for performing the methods described herein (and some embodiments of the apparatus described herein) may include one or more storage elements configured to store information indicating one or more sensor signals or any other information.

[0401] Some embodiments of the apparatus for performing the methods described herein (and some embodiments of the apparatus described herein) may include one or more communication modules configured to communicate electronically with an electronic device external to the apparatus.

[0402] Since users may not be able to see the applied wavelength because they can wear eye protection devices, light sources such as bronchoscopes can provide auditory or tactile signals indicating that phototherapy has ceased. In some aspects of these implementations, the light source can be controlled using an application. In others, the light source itself includes a timer, allowing the user to set the duration of light application.

[0403] When subjects are exposed to light at antibacterial wavelengths, it is important to protect their eyes from these wavelengths. Several methods exist to achieve this. In one embodiment using blue or UV wavelengths, glasses, goggles, or eye shields can be used to protect the subjects' eyes, such as those used in tanning beds, which filter out those wavelengths. In another embodiment, the eyes are covered with an opaque covering, which can be in the form of goggles, eye shields, etc.

[0404] Coatings that prevent users from being affected by specific wavelengths are well known in the art. Examples include UV-protective coatings, anti-blue light coatings, etc. In some embodiments, particularly concerning ophthalmic lenses and goggles, one of the two main surfaces of the lens / goggles may include an optical filter designed to reduce unwanted light, such as blue light, thereby reducing any light-induced phototoxic effects on the wearer's retina. In one aspect, this is defined based on the wavelength range and the angle of incidence. As used herein, "range from x to y" means "within the range from x to y," with limits x and y included in this range.

[0405] Visible light for humans extends across the spectrum from approximately 380 nanometers (nm) to 780 nm. A portion of this spectrum, from approximately 380 nm to approximately 500 nm, corresponds to high-energy, primarily blue light. Numerous studies have shown that blue light has phototoxic effects on human eye health, particularly on the retina. Exposure to these and other wavelengths can be limited using lenses / goggles with appropriate filters, which can prevent or limit the transmission of phototoxic blue light to the retina.

[0406] Other filters can effectively transmit visible light with wavelengths higher than 465 nm, thus maintaining good vision for the wearer without exposing the retina to harmful wavelengths. Therefore, in one embodiment, the lens filters out blue light received by the eye in the 420 nm to 450 nm wavelength range, while achieving excellent transmittance in the 465 nm to 495 nm wavelength range. One way to achieve this is by using a highly selective narrowband filter, which is typically composed of a monolithic thick stack comprising multiple dielectric layers. Such a filter can be applied to the front master surface, where an optical narrowband filter as described above has already been deposited. In this case, the front master surface of the ophthalmic lens is the master surface of the ophthalmic lens, and it is furthest from the wearer's eyes. In contrast, the master surface of the ophthalmic lens closest to the wearer's eyes is the rear master surface.

[0407] Even though direct light incident on the anterior surface of the ophthalmic lens is effectively blocked by reflection from a narrow-band filter deposited on the anterior surface, in some cases, indirect light from the wearer's background is still reflected into the wearer's eyes. For this reason, protective goggles, such as tanning goggles used with a tanning bed, are preferred.

[0408] Ideally, adequate eye protection is matched to the wavelength of the light used, such that the amount of phototoxic light (e.g., phototoxic blue light) reaching the wearer's retina can be significantly reduced to a safe level. In one embodiment, the eyeglasses or goggles include an ophthalmic lens having a front and a rear principal surface, at least one of the principal surfaces including a filter that provides the principal surface including the filter with the following characteristics: an average blue reflectance coefficient (R0) within a wavelength range of 420 nm to 450 nm in the incident angle range of 0° to 15°. m,B A spectral reflectance curve with an incident angle range of 0° to 15° and a reflectance greater than or equal to 5%. This reflectance curve has: maximum reflectance at wavelengths less than 435 nm, full width at half maximum (FWHM) greater than 80 nm, and for incident angles θ from 0° to 15° and θ' from 30° to 45°, the relationship Δ(θ,θ')=1-[R θ' (435nm) / R θ The parameter Δ(θ,θ') is defined as follows: (435nm) is such that Δ(θ,θ') is greater than or equal to 0.6, where: R θ (435nm) represents the reflectance value of the main surface of the filter at an incident angle θ at a wavelength of 435nm, and R θ' (435nm) represents the reflectance value of the main surface of the filter at an incident angle θ' at a wavelength of 435nm.

[0409] In another embodiment, this disclosure relates to an ophthalmic lens having a front main surface and a rear main surface, at least one of the two main surfaces including a filter that provides the main surface including the filter with the following properties: an average blue reflectance coefficient (R0) in the wavelength range of 420 nm to 450 nm with an incident angle range of 0° to 15°. m,BA spectral reflectance profile with an incident angle range of 0° to 15° and a reflectance greater than or equal to 5%, having a maximum reflectance at wavelengths less than 435 nm and a full width at half maximum (FWHM) greater than or equal to 70 nm, preferably greater than or equal to 75 nm. For incident angles θ from 0° to 15° and θ' from 30° to 45°, a parameter Δ(θ,θ') defined by the relation Δ(θ,θ') = 1 - [Rθ'(435nm) / Rθ(435nm)] is such that this parameter Δ(θ,θ') is greater than or equal to 0.5, where Rθ(435nm) represents the main surface of the filter at an incident angle of 0° to 15°. The reflectance value at a wavelength of 435 nm is given by θ, and Rθ'(435 nm) represents the reflectance value of the principal surface including the filter at an incident angle θ' and / or an incident angle ranging from 0° to 15° at a wavelength of 435 nm. The parameter Δspectrum is defined by the relationship Δspectrum = 1 - [R0°-15°(480 nm) / R0°-15°(435 nm)], in such a way that this parameter Δspectrum is greater than or equal to 0.8, where R0°-15°(480 nm) represents the reflectance value of the front principal surface at a wavelength of 480 nm, and R0°-15°(435 nm) represents the reflectance value of the front principal surface at a wavelength of 435 nm. These types of ophthalmic lenses minimize the transmission of phototoxic blue light to the user's retina by providing average reflectance in the wavelength range of 420 nm to 450 nm.

[0410] For devices configured for insertion into the oral cavity, a cheek retractor may be included. A cheek retractor is a medical device used during surgery to pull the cheek away from and hold it in place to expose the mouth. More specifically, the cheek retractor displaces the mucosal-periosteal flap, cheek, lips, and tongue from the treatment area, thereby facilitating phototherapy of the entire mouth / oral cavity. As disclosed herein, the cheek retractor may be incorporated as part of a light guide locator and / or mouthguard for the aforementioned illumination device.

[0411] Figure 56A and 56B An example of a cheek retractor is shown in the image. Figure 56AThis is a perspective view of an exemplary cheek retractor 5600. The cheek retractor 5600 may include a transparent material, such as plastic, designed to provide a sufficiently wide opening for a doctor or dentist to perform surgery in the mouth or other parts of the oral cavity or in the throat. While these can be used, and eye protection can be used to protect the user's eyes from wavelengths passing through the transparent plastic, it is preferable to use a cheek retractor that is opaque to all wavelengths or has a coating that filters harmful wavelengths. This is particularly relevant because the doctor or dentist does not need to use a retractor to access the mouth; all that is required is access to a light source, and it is advantageous to minimize or prevent exposure of the user's eyes to light at these wavelengths.

[0412] Figure 56B This is a perspective view of a cheek retractor 5610, which includes a material, such as a filter, configured to block certain wavelengths of light during phototherapy. For example, if the light involves delivering blue light or light with peak wavelengths in the range of 400 nm to 450 nm to illuminate or near the oropharynx, the cheek retractor 5610 may include a material that filters such blue light or light with peak wavelengths in the range of 400 nm to 450 nm. In other embodiments, the cheek retractor 5610 may include a material that filters and / or blocks any of the aforementioned peak wavelength ranges, depending on the application. In yet another embodiment, the cheek retractor 5610 may include a substantially opaque or even black material configured to block most light from passing through. In some embodiments, the material (e.g., for filtering and / or blocking) may be formed throughout the cheek retractor 5610 and / or the material may be embedded in a body adhesive material, such as plastic. In yet another embodiment, the filtering and / or blocking material may be provided as a coating on the surface of the cheek retractor 5610.

[0413] In some embodiments, the cheek retractor 5610 may also have a centrally formed aperture 5620 adapted to receive a light source (not shown). At this point, one or more light sources may be adapted to be fitted or otherwise positioned at or within the aperture 5620 for delivering light. One or both of the light source and the cheek retractor 5610 may be fitted with gaskets to allow pressure engagement of light into the aperture 5620. Alternatively, the cheek retractor 5610 may be threaded to allow the light source to be screwed into place. In any of these embodiments, the user can use the light without having to hold it in place, and the cheek retractor 5610 can prevent light emission from leaving the user's mouth. On the other hand, the cheek retractor 5610 may be formed into a narrower shape than conventional cheek retractors because it is designed to allow light into the mouth without requiring sufficient opening for dentists or doctors to perform surgical procedures within the mouth. In one embodiment, the cheek retractor 5610 may be adapted to receive a light source so that a user can insert the cheek retractor 5610 into the mouth to hold the light source in place. For example, the cheek retractor 5610 may be adapted to receive a light source through an opening (e.g., a hole 5620) that includes receiving the light source, the light source being adapted to be fitted into the opening. In one aspect, the cheek retractor 5610 may include threads, and the light source is adapted to be screwed into these threads. In this respect, the cheek retractor 5610 may include an opaque, black, and / or light-filtering material provided within the cheek retractor 5610 or as a coating, which minimizes light transmission in unwanted directions. This can be used to protect the user's eyes when the light source is inserted into the mouth, thereby reducing the amount of light passing through the cheek retractor 5610 and leaving the oral cavity. In another aspect, the cheek retractor 5610 is otherwise a solid plastic sheet, but includes an opening sized to accommodate a light source, allowing the user to open their mouth to receive light without having to hold the light source.

[0414] In other embodiments, a set of light sources suitable for transmitting light to the ear is disclosed. In some aspects of these embodiments, to facilitate the illumination of light to the ear, the shape of the light source may be designed to resemble an in-ear headphone or a standard headphone, but instead of emitting sound, the device also emits light of an antimicrobial wavelength. In one aspect of this embodiment, the light source is provided in a form similar to headphones, which, in addition to or instead of transmitting sound, includes a light source for emitting light of an antimicrobial wavelength toward the ear.

[0415] In some implementations, the light source can be adjusted to facilitate light transmission to the nostrils. For example, Figure 57This is a perspective view of a device 5700 for attaching a light source to a user's nostril. The device may include a clip 5710 so that the light source, which is in optical communication with the device 5700, can be clipped onto the nostril. The light source may be included at or away from the device 5700 and connected to the device 5700 via an optical cable and / or light guide at a light receiver 5720. Dual light sources or dual devices 5700 can be used to facilitate the simultaneous application of light to both nostrils. In these embodiments, intranasal phototherapy can be used to eliminate microorganisms in the nasal passages.

[0416] The principles of this disclosure are well-suited for providing phototherapy kits for treating, preventing, or reducing the bioactivity of microorganisms present in the mouth, nose, and / or ear. Such kits may include one or more combinations of any of the aforementioned lighting devices, including a light source for delivering light of antimicrobial wavelengths to the mouth, nose, and / or ear. Such phototherapy kits may also include other devices and accessories such as protective eyewear, goggles, shields, and / or masks to protect the wearer's eyes from antimicrobial wavelengths and / or all wavelengths; the aforementioned cheek retractors to facilitate the application of light to the user's mouth; and / or a pillow designed to arch the user's neck so that light transmitted into the mouth can also propagate linearly to the target infected area, such as the user's throat and / or oropharynx.

[0417] In some implementations, the lighting device and treatment may also be applied to infections and / or other specific lung conditions that have progressed to the lungs. The treatment process can be tracked in various ways after treatment. Treatment or prevention of microbial infections can be tracked, for example, by monitoring the severity of symptoms, the presence of fever, the use of a pulse oximeter, etc. Prevention of inflammatory lung diseases can be tracked by X-rays, pulmonary function tests, etc. Challenge tests are pulmonary function tests used to help confirm an asthma diagnosis, in which a patient inhales a small amount of a substance known to trigger symptoms in asthma patients, such as histamine or methacholine. Lung function is assessed after inhalation of the substance. After light delivery to induce one or more biological effects, it can be determined whether the decline in lung function after inhaling these substances has lessened relative to before the start of phototherapy, indicating that phototherapy is effective for such patients.

[0418] The fear of being diagnosed with coronaviruses, including COVID-19, followed by rapid hospitalization and death due to severe lung dysfunction, is real. However, using the lighting apparatus and method described in this article, infection with coronaviruses and coronaviruses can be avoided, even after exposure to COVID-19, provided that a sufficient number of viral particles do not enter the lungs through the mouth. The same applies to SARS-CoV-2, which infects the mucous membranes of the oropharynx and lungs through the adhesion of its spike protein to host cell receptors.

[0419] The same applies to Orthomyxoviridae viruses (such as influenza viruses), which cause influenza. Coronaviruses and Orthomyxoviridae viruses can cause similar symptoms, and the methods described in this article are effective in preventing these viruses from spreading from the mouth to the lungs in certain applications.

[0420] In one implementation, nitric oxide can be used to prevent coronavirus infectivity. Compared to pharmacological methods, nitric oxide can be produced by stimulating epithelial cells in the mouth, ear canal, larynx, pharynx, oropharynx, trachea, and / or esophagus with visible blue light, for example, in the range of 400 nm to 450 nm, including 425 nm and 430 nm. Photoinduced release of nitric oxide enhances defense against SARS-CoV-2 and other coronaviruses, as well as influenza viruses such as influenza A and influenza B, by preventing entry into human cells and inactivating viral replication. If this can be accomplished after initial infection but before viral particles enter the lungs in sufficient numbers to cause respiratory infection, the result is post-infection prevention of coronavirus or influenza respiratory infection.

[0421] Many widely deployable medical device countermeasures can be envisioned. One specific approach for patients exposed to or believed to be exposed to coronaviruses could utilize a standard bronchoscopic surgical device with a thin blue optical fiber, which reaches the mouth, throat, larynx, pharynx, trachea, and esophagus through the standard working channel of a bronchoscope (HopeScope). This strategy could limit infectivity and prevent coronaviruses such as SARS-CoV-2 and influenza viruses from progressing to lung tissue. Furthermore, any of the previously described illumination devices would be well-suited for delivering light to combat coronaviruses and influenza viruses.

[0422] Nitric oxide (NO) is a natural component of the innate immune response against invading pathogens and is produced at high micromolar concentrations by inducible nitric oxide synthase (iNOS) in epithelial tissues. Preclinical in vitro studies have shown that nitric oxide inhibits the replication of DNA viruses, including herpes simplex virus, Epstein-Barr virus, and vaccinia virus. The infectivity of influenza is also reduced in the presence of nitric oxide; results showed that the infectivity of all three tested strains was completely suppressed when viral particles were exposed to nitric oxide before infection. Nitric oxide-based viral replication inhibition and selective antiviral activity against human raft epithelial cultures infected with HPV-18 have also been demonstrated. The broad-spectrum antiviral activity of nitric oxide has been well documented previously, but not in the oral cavity or ear canal.

[0423] One potentially effective way for nitric oxide is to prevent SARS-CoV from entering human cells. Nitric oxide and its derivatives lead to reduced palmitoylation of newly expressed spike (S) proteins, which affects the fusion between the S protein and its host cell receptor angiotensin-converting enzyme 2. Figure 58 The illustration shows the inactivation of nitric oxide in the active spike (S) protein of the coronavirus, which facilitates endocytosis and entry into human cells.

[0424] Nitric oxide can also inhibit viral replication, including that of SARS-CoV. While not wishing to be limited to any particular theory, one or more of the following mechanisms are considered to be involved in how nitric oxide inhibits viral infection. Following exposure to nitric oxide, a reduction in viral RNA production was observed in the early stages of viral replication due to the effect on one or both cysteine ​​proteases encoded in Orf1a of SARS-CoV. In examining known pathogenic mechanisms utilized by coronaviruses, nitric oxide may also be able to inhibit other key enzymes (e.g., caspases) used by RNA viruses to induce apoptosis and rapidly destroy lung tissue. Inhibition of caspases contributes to lower coronavirus infectivity. Inhibition of caspase-dependent apoptosis, which is essential for viral particle transmission, offers a significant advantage for any nitric oxide-based therapeutic or preventative approach. Although endogenous inhibitors of caspase activation and activity have been described, none are more prevalent than NO. All caspase proteases contain a single cysteine ​​residue at their catalytic site, which can be efficiently S-nitrosylated in the presence of NO. Evidence has been confirmed regarding the S-nitrosylation of caspase-3 and caspase-1 in vivo.

[0425] Another mechanism of nitric oxide's antiviral activity is through the inhibition of NF-κB, thereby suppressing the immune response. NF-κB proteins are a family of transcription factors that regulate gene expression to control a wide range of biological processes and have been shown to play an important role in SARS-CoV infection. Inhibition of NF-κB with nitric oxide can limit the surge of inflammatory cytokines that contribute to the death of COVID-19 patients due to inflammation. Nitric oxide can directly inhibit the DNA-binding activity of NF-κB family proteins, suggesting that intracellular NO provides another control mechanism for regulating the expression of NF-κB response genes.

[0426] Pharmacological approaches to the delivery of nitric oxide have been explored. In China, the safe administration of clinical concentrations of NO gas to SARS patients resulted in observed improvements in (1) time to discharge, (2) reduced need for ventilation support, and (3) improved appearance of lung infection as observed on chest X-rays. However, nitric oxide can be generated by stimulating epithelial cells with visible light of a precise color, as disclosed in, for example, U.S. Patent No. 10,569,097, the entire disclosure of which is incorporated herein by reference. While other wavelengths described herein are effective in generating or releasing nitric oxide, blue light, particularly in the 400-450 nm range, including 425 nm and 430 nm, has been found to be a specific wavelength that both triggers the release of bound NO from endogenous stores and upregulates the enzymatic production of nitric oxide by cells. When nitric oxide is produced naturally, the gas has a half-life of less than 1 second in physiological tissues. Nitric oxide and its metabolites, as nitrosothiols and metal nitrosocenters, maintain persistent concentrations in cells and can be recycled to biologically active NO upon photostimulation. The sustained enzymatic production of nitric oxide was a completely unexpected result. Measured by upregulating iNOS and eNOS proteins in epithelial cells of the culture, a single 10-minute blue light treatment maintained the enzyme production level 10-fold for 24 hours.

[0427] In some implementations, the wavelength of the light may be outside the UV range, and thus separate and different from any disinfection method with UVC or UVB wavelengths, although such wavelengths are indeed taken into account in other implementations described herein.

[0428] This pioneering use of targeted wavelengths of light is a rapidly deployable strategy that can help limit the infectivity of SARS-CoV-2 and its progression into deeper lung tissue. Using the illumination device described herein, or other devices for delivering light at frequencies capable of generating or releasing nitric oxide and other biological effects, light can be delivered to and / or through the oral cavity, including the nasal cavity, oropharynx, etc., to stimulate mucosal epithelial cells, increasing nitric oxide production to combat the coronavirus. This can help inhibit entry into human cells, suppress viral replication, and eliminate or at least reduce the number of viral particles before a sufficient number of viral particles travel down the oral cavity into the lungs.

[0429] A specific device that applies light, particularly to the pharynx, larynx, pharynx, oropharynx, esophagus, and trachea, is the bronchoscope, which is suitable for emitting blue light. Bronchoscopes are readily available, as more than 500,000 bronchoscopy procedures are performed annually in the United States, and such devices are already widely used in medical facilities across the country. Bronchoscopes can be equipped with thin blue light fibers that pass through the standard working channel of the bronchoscope used for fluid delivery / extraction and biopsy.

[0430] Therapeutic light therapy can be beneficial in saving newly infected patients before they reach the “critical point” where the virus invades the lungs and eventually deteriorates into severe acute respiratory syndrome. Because nitric oxide inhibits viral replication and reduces viral proliferation inside or around the mouth, ear canal, etc., the efficacy of blue light against SARS-CoV-2 can be assessed by applying an appropriate dose of light (integral flux = J / cm²). 2 The dosage and frequency of administration are determined to safely stimulate intracellular nitric oxide production. Nitric oxide antiviral activity is dose-dependent, therefore the most appropriate dose is considered to be at or near the maximum amount of phototherapy light without observing significant adverse effects on tissues or an increase in systemic biomarkers of clinical toxicity during routine blood chemistry and hematology tests.

[0431] Representative dose parameters include 5 J / cm² for single and / or multiple exposures. 2 10J / cm 2 20J / cm 2 Or 30J / cm 2 In addition to the other doses mentioned in this article, and repeated exposure once a week, three times a week, or once or twice a day for one or more days, for two weeks or longer.

[0432] Nitric oxide is a well-known and extensively studied naturally occurring molecule in the body. It primarily interacts with hemoglobin to form methemoglobin, which blocks oxygen transport. The known effects of methemoglobinemia and elevated nitrate levels have been routinely observed and monitored in clinical trials of inhalable nitric oxide gas. These biomarkers enable continuous patient safety monitoring. The adverse effects of gaseous nitric oxide are well-known and can be mitigated by reducing the dose when elevated methemoglobin levels (>5%) are observed. Pulse co-oximetry provides a non-invasive, continuous method for measuring methemoglobin in the blood. Serum nitrate levels are also a well-known metabolite of nitric oxide in the human body and can be used to monitor safety and avoid adverse effects. Elevated NO levels have been extensively studied. x Toxicological consequences of species and MetHb.

[0433] The following are the expected clinical endpoints using the methods described in this paper:

[0434] The infection subsided, and the virus was undetectable on day 7, day 14, and / or day 28.

[0435] The proportion of early-stage patients progressing to severe disease forms was reduced. Severe disease forms were defined as: SpO2 <93% without continuous oxygen supplementation for more than 12 hours; or PaO2 / FiO2 ratio <300 mmHg for more than 12 hours; or requiring high-flow nasal cannula oxygen therapy or intubation, as well as mechanical ventilation or ECMO treatment for 7 days, 14 days, or 28 days.

[0436] Reduce the percentage of patients whose symptoms worsen due to viral particles entering the lungs from the mouth.

[0437] Reduce the percentage of patients with SARS.

[0438] Increase overall survival rate on days 7, 14, 28, and 90.

[0439] Based on the above discussion, treatment and / or prevention methods involve applying light of sufficient wavelength and power to one or more areas of the mouth or ear canal, or to the patient's throat, larynx, pharynx, oropharynx, esophagus, and / or trachea for a sufficient duration to kill the coronavirus and thus prevent lung coronavirus infection. The same method can be used to prevent respiratory infections caused by other viruses, such as influenza viruses, which are present in the mouth but not in sufficient numbers to enter the lungs and cause infection.

[0440] In one embodiment, strong blue light, typically between 400 and 500 nm, preferably around 400-430 nm, such as 405 nm or 415 nm, can be used. A combination of 405 nm blue light and 880 nm infrared light can also be used. In one aspect of this embodiment, light with a wavelength of 450-495 nm is used. Although blue light has been primarily discussed above, UVA, UVB, or UVC light can also be effective in treating coronavirus infections, with UVC light being preferred. Prolonged exposure to these wavelengths may damage tissues. Ideally, tissues should not be exposed to these wavelengths for a period that could cause significant damage. That is, because UVA / UVB / UVC light and other wavelengths work through different mechanisms, specific wavelengths of visible light can also be used alone or in combination with UVA / UVB / UVC light.

[0441] Light can be applied anywhere along the mouth, ear canal, or throat, larynx, pharynx, oropharynx, trachea, or esophagus, depending on the patient's infection status. If the virus is not present in large quantities in the lungs and is mainly confined to the patient's mouth, nose, and throat, phototherapy limited to these areas can prevent respiratory infections. This method can also be used prophylactically for patients at risk of developing coronavirus infection because they have been or are suspected of having been in contact with someone infected with coronavirus.

[0442] In addition to applying light at antibacterial wavelengths, anti-inflammatory wavelengths can also be applied, or alternatively, to suppress inflammation in the nasal passages or mouth, which can further help prevent the infection from spreading to the lungs. Anti-inflammatory wavelengths, particularly within the nasal passages, can also help prevent secondary infections, such as sinus infections, which can lead to bronchitis or pneumonia, caused by bacteria and often following viral infections. In some cases, minimizing the risk of secondary infections is even more important than treating the underlying viral infection.

[0443] Tracking the treatment process can be important, especially if the patient has an active infection that hasn't yet reached the lungs in sufficient ways to cause a lung infection. If prevention is unsuccessful, the patient may experience serious adverse consequences, so monitoring disease progression can be crucial.

[0444] Methods for monitoring treatment progress include regularly taking readings using a pulse oximeter and performing regular chest X-rays / ultrasound / CT scans. Residual microbial infections can also be detected, for example, using ELISA tests or other tests to look for antibodies specific to certain microorganisms, and analyzing residual infection in blood or sputum samples. Patient temperature may also be monitored, especially shortly after treatment for a microbial infection.

[0445] Providing safe, visible wavelengths of light could be an effective, pathogen-agnostic antiviral treatment strategy, expanding the current combination of intervention strategies against SARS-CoV-2 and other respiratory viral infections beyond conventional approaches such as vaccines, antibodies, and drug therapies. Using LED arrays, specific wavelengths of visible light can be uniformly transmitted across a variety of target biological surfaces. In certain aspects of this disclosure, primary 3D human tracheal / bronchial epithelial tissue has been demonstrated to exhibit varying light tolerance in a wavelength- and dose-dependent manner. Primary 3D human tracheal / bronchial tissue tolerates high doses of blue light with a peak wavelength of 425 nm. Extending these studies to Vero E6 cells, this study aimed to understand how light affects the viability of mammalian cell lines commonly used to detect SARS-CoV-2. Exposure of a single-cell monolayer of Vero E6 cells to similar doses of 425 nm blue light resulted in dose- and density-dependent survival rates. Vero E6 cells tolerated doses of 425 nm blue light well, with an inhibition rate of over 99% for SARS-CoV-2 replication after a single 5-minute exposure within 24 hours post-infection. Red light at 625 nm had no effect on SARS-CoV replication or cell viability, indicating that the inhibition of SARS-CoV-2 replication is specific to the antiviral environment induced by blue light. Furthermore, 425 nm visible light inactivated up to 99.99% of cell-free SARS-CoV-2 in a dose-dependent manner. Importantly, the dose of 425 nm light that significantly interfered with SARS-CoV-2 infection and replication was also well tolerated by primary human 3D tracheal / bronchial tissue. In this respect, safe and deliverable doses of visible light could be considered part of a strategy to develop SARS-CoV-2 therapeutic countermeasures to prevent coronavirus disease 2019 (COVID-19).

[0446] Among other approaches to treating SARS-CoV-2 infection are nucleoside analogues, such as remdesivir, and convalescent plasma, both of which have been shown to shorten recovery time in Covid-19 patients; and the glucocorticoid dexamethasone has been shown to reduce mortality in individuals receiving only oxygen or mechanical ventilation support. To curb the lengthy timelines associated with clinical safety and efficacy trials of traditional drug therapies, researchers are actively evaluating FDA-approved drug therapies against SARS-CoV-2. While encouraging, many current strategies are SARS-CoV-2 specific and target either external viruses (acellular viruses) or intracellular viruses (cell-associated replicating viruses). Expanding the therapeutic repertoire beyond traditional strategies could accelerate the availability of therapeutic countermeasures with nonspecific antiviral properties that can inactivate both acellular and cell-associated viruses.

[0447] Phototherapy has the potential to inactivate cell-free viruses and cell-associated viruses (including coronaviruses and orthomyxoviruses). Alleviating SARS-CoV-2 infection with phototherapy requires understanding which wavelengths of light are most effective at interfering with viral infection and replication while minimizing damage to host tissues and cells. Extensive literature indicates that ultraviolet light (primarily UVC at a wavelength of 254 nm) is highly effective in inactivating cell-free coronaviruses on surfaces, in atomized forms, or in liquids. UVC absorbs UVC photons through pyrimidines in the RNA backbone, leading to the formation of pyrimidine dimers, which inhibit the replication of the coronavirus genome, thereby inactivating coronaviruses as well as many other RNA and DNA viruses. UVC is also highly destructive to replicating mammalian cells, causing perturbations in genomic DNA and increasing the risk of mutagenic events. Therefore, inactivation of viruses with UV light is primarily limited to applications in cell-free environments. In this disclosure, the use of safe visible light (e.g., above 400 nm) to inactivate coronaviruses is presented as a novel method for interfering with SARS-CoV-2 infection and replication.

[0448] Photobiological modulation (PBM), or phototherapy, is a method for mitigating the consequences of viral infections in mammals such as humans. PBM can also refer to the phototherapy disclosed herein. PBM involves the safe, low-power illumination of cells and tissues using light-emitting diodes (LEDs) or low-level laser therapy (LLLT) within the visible / near-infrared spectrum (400 nm–1050 nm). Importantly, the therapeutic effect is driven by the interaction of light with photoreceptors within the biological system and is not to be confused with photodynamic therapy (PDT), which employs the exogenous addition of photosensitizers or other chemicals to induce reactive oxygen species (although the addition of photosensitizers or other chemicals to induce reactive oxygen species is another implementation within the scope of the methods described herein).

[0449] In the late 1960s, the safe and effective use of blue light PBM in the 450-490 nm range was mainstream clinically used to treat neonatal jaundice caused by hyperbilirubinemia, and continues to be a primary treatment for hyperbilirubinemia in hospitals today. According to aspects of this disclosure, altering the wavelength of visible light based on the target application can broaden the range of therapeutic applications. Studies have also shown that PBM with visible light may have the function of inactivating RNA and DNA viral replication in vitro. Importantly, multiple studies have shown that PBM therapy can be safely applied to the oral and nasal cavities to treat a range of diseases. As disclosed herein, PBM therapy in the oral and nasal cavities, as well as in lung or endothelial tissues, may be an effective means of reducing SARS-CoV-2 replication in the upper respiratory tract, provided it is administered at a dose that does not significantly affect the viability of the treated tissues. Precise selection of light irradiance (e.g., unit: mW / cm²) is required. 2 Further exploration in combination with one or more monochromatic wavelengths of visible light could broaden the scope of its therapeutic applications in respiratory medicine.

[0450] In this regard, embodiments of the present disclosure are provided, which describe for the first time in cell-based in vitro assays at low power (<100mW / cm). 2 Safe, visible wavelength blue light was used to inactivate cell-free and cell-associated SARS-CoV-2. Importantly, the blue light dose that effectively inactivates SARS-CoV-2 was well tolerated by primary human tracheal / bronchial respiratory tissue.

[0451] To evaluate the safety of visible light for in vitro cells and tissues, and its efficacy in the detection of SARS-CoV-2 infectivity, a carefully designed LED array with narrow-band emission spectra at peak wavelengths of 385 nm, 405 nm, 425 nm, and 625 nm is presented and summarized in [the relevant document / concept]. Figure 59A and 59B In this way, LED arrays can be properly calibrated to provide a repeatable and uniform dose of light, enabling reliable illumination in numerous measurements and multiple laboratories. Measuring the complete emission spectrum near the peak emission wavelength is essential to confirm the correct functioning of each LED array and the photon density per nanometer. At this point, such measurements are recommended as an important characterization step to help harmonize the variability of results published in the literature. Figure 59A Figure 5900 illustrates the measured spectral flux of different exemplary LED arrays relative to wavelength. Each LED array is independently characterized by measuring its spectral flux relative to wavelength (nm), which can be measured in W / nm. Figure 59A In the study, LED arrays with a peak wavelength of 385 nm are clearly located within the upper limit of the UVA spectrum (315-400 nm), while only a small portion (e.g., about 10%) of LED arrays with a peak wavelength of 405 nm extend into the UVA spectrum, and 99% of LED arrays with a peak wavelength of 425 nm are within the visible spectrum (400-700 nm). Figure 59B A perspective view of a test apparatus 5910 for providing light from one or more LED arrays 5920 to a biological test article 5930 is shown. Besides the design of the LED arrays 5920, which include the emission spectrum, other important experimental conditions include the distance D (e.g., 90 mm) between the LED arrays 5920 and the biological test article 5930, and the illumination power (e.g., 25 mW / cm²). 2 Or 50mW / cm 2 (This depends on the entire wavelength), and the indicated dose (J / cm²) must be carefully calibrated. 2 This is to reduce any impact of temperature on the biotest articles 5930. Furthermore, each LED array has been validated to ensure uniform light distribution within the multi-well tissue culture plate, so that the biotest articles in each replicate well receive a uniform dose of light.

[0452] Understanding how target tissues in the upper respiratory tract tolerate blue light is crucial for developing luminescent antiviral approaches against SARS-CoV-2. Initial evaluation of the LED array was conducted on a 3D tissue model developed from cells isolated from the bronchial / tracheal region of a single donor. The 3D EpiAirway tissue model consisted of 3–4 cell layers, including a mucociliary epithelial layer with ciliated apical surfaces. To assess the wavelengths and doses of light to which these tissues were most tolerant, replicated tissue samples were exposed to different doses of 385 nm, 405 nm, or 425 nm light. Viability was determined 3 hours post-exposure using the specified light dose and wavelength, and data are expressed as + / - standard deviation. The percentage of tissue survival was assessed using a mature MTT cytotoxicity assay optimized for the 3D EpiAirway tissue model. Figure 60A Figure 6000 shows the dosage range from 0 to 120 J / cm². 2 Survival percentage at the 385nm peak wavelength within the range. Figure 60B Chart 6010 shows the results for... Figure 60A The survival percentage at the same dose with a peak wavelength of 405 nm. Figure 60C Chart 6020 shows the results for... Figure 60A The percentage of survival at the same dose with a peak wavelength of 425 nm. Figure 60A-60C As shown, the survival rate of tissues was significantly affected in both wavelength- and dose-dependent ways. Illumination with 385 nm light showed the most significant loss of activity at 45 J / cm². 2 The dose was reduced by nearly 50% ( Figure 60A ). At 15 J / cm 2 At doses of 385 nm, light actually showed an increase in cell activity. Although less significant, 405 nm showed a dose-dependent decrease in activity at 60 J / cm². 2 The loss exceeds 25% and is below 120 J / cm 2 The loss is about 50% ( Figure 60B It is worth noting that 425nm light can reach up to 120J / cm². 2 It exhibits good tolerance at light doses ( Figure 60C Using a 75% survival rate as the acceptable cytotoxicity threshold, 385nm light can reach up to 30 J / cm². 2 The power level can be safely applied to these tissues; 405nm light can reach up to 45J / cm². 2 The power level can be safely applied to these tissues, and 425nm light can reach up to 120J / cm². 2 The power levels can be safely applied to these tissues at 90 and 120 J / cm².2 Between these values, the loss of vitality is negligible, and at most approximately 75 J / cm². 2 The 425nm dose actually showed increased cell viability.

[0453] At this point, 425 nm blue light had little or no effect on 3D tissue models derived from the human upper respiratory tract. Therefore, longer wavelengths of visible light (e.g., 425 nm or greater) that do not penetrate the UVA spectrum may reduce the impact on tissue viability of primary human tissues derived from the upper respiratory tract. In particular, at higher doses with such longer wavelengths, less than 20% tissue loss can be achieved. Based on these studies, 425 nm visible blue light was selected for subsequent evaluation in the widely available VeroE6 cell line, which is commonly used to assess SARS-CoV-2 infection and replication.

[0454] Vero E6 cells are commonly used to prepare SARS-CoV-2 stockpiles, perform growth curves, and evaluate treatment strategies. Depending on the type of assay performed, the seeding cell density and multi-well tissue culture plate format may need to be varied. Typically, cell viability is assessed to determine whether the antiviral properties of a therapeutic agent can be resolved from potential therapeutic-induced cytotoxicity. Experiments are performed to determine whether cell density and multi-well plate format affect cell viability upon exposure to 425 nm blue light. For efficient assessment of cell viability, cytotoxicity assays are optimized for use up to 1 x 10⁻⁶ cells. 6 Vero E6 cell density per cell. Antiviral assays performed in 96-well plates are typically performed at 1x10⁻⁶ cells / well. 4 and 2x10 4 The evaluation was conducted at a cell seeding density of 1,000 cells.

[0455] Figure 61A Figure 6100 shows the results on a 96-well plate at 1x10... 4 2x10 4 and 4x10 4 The percentage of Vero E6 cells viable in an antiviral assay performed at a cell seeding density of 10 cells. Under these conditions, the survival rate at 30 J / cm² was shown. 2 and 60J / cm 2 Twenty-four hours after illumination at the specified dose, 425nm blue light resulted in a decrease in cell viability (e.g., 25-50%), while 4x10 4 The seeding density of individual cells can withstand high doses of light. Figure 61B Figure 6110 shows the results of using a 2x10 well on a 48-well plate. 4 4x10 4 and 8x10 4The percentage of Vero E6 cells survived in an antiviral assay performed using cell seeding density of 100 cells per well. Surprisingly, 4x100 cells seeded in a 48-well plate... 4 Individual cells showed poor tolerance, compared to 8x10 4 Compared to individual cells, at 60 J / cm 2 At the specified dose, cell viability decreased by approximately 50%. These results indicate that cell seeding density relative to the surface area of ​​the culture wells affects susceptibility to 425 nm light. Figure 61C Figure 6120 shows the application of 5x10 on a 24-well plate. 4 1x10 5 and 2x10 5 The percentage of Vero E6 cells viable in an antiviral assay based on a cell seeding density of 1 x 10⁻⁶ cells. As shown in the figure, the cell seeding density was 1 x 10⁻⁶ cells. 5 and 2x10 5 of Figure 61C The 24-well plate format exhibited acceptable viability at all tested doses. In contrast, illuminating Vero E6 cells to high doses of 625 nm light likely had no effect on cell viability; therefore, it suggests that the cell density-dependent susceptibility of Vero E6 cells to 425 nm light appears to be a characteristic of shorter wavelength light. Higher Vero E6 seeding densities resulted in 100% cell confluence before illumination, exhibiting cell-to-cell contact similar to the 3D EpiAirway model. Therefore, highly confluent Vero E6 cell monolayers and the 3D EpiAirway tissue model are well-tolerant of 425 nm blue light.

[0456] The use of visible light to inactivate cell-free and cell-associated coronaviruses is unprecedented. To evaluate the ability of 425 nm blue light to inactivate SARS-CoV-2, Vero E6 cells were infected for 1 hour with the SARS-CoV-2 isolate USA-WA1 / 2020 with a multiplicity of infection (MOI) of 0.001. One hour post-infection (hpi), cells were inactivated with 7.5 to 60 J / cm² light. 2 A single dose of 425nm blue light was used to irradiate cell-associated viruses. Figure 62A Figure 6200 shows the dose range of 7.5 to 60 J / cm² for Vero E6 cells infected for 1 hour with the SARS-CoV-2 isolate USA-WA1 / 2020 at an MOI of 0.001. 2 425nm light per milliliter (ml) of tissue culture infection dose (TCID) 50 At 24 hours post-infection (hpi), SARS-CoV-2 TCID50... 50 The dose-dependent decrease in 425nm light at 7.5J / cm³ was significant.2 Sufficient to reduce SARS-CoV-2 by at least 2 log, 15 J / cm 2 At least 3 log, and 30 J / cm 2 At least a 5log decrease. A similar trend was observed at 48 h.pi, although continued viral replication may explain the decrease at 7.5 J / cm. 2 and 15J / cm 2 TCID observed at low doses 50 The data shows similarity per ml. This indicates that 425nm blue light interferes with SARS-CoV-2 replication in a dose-dependent manner. Specific TCID values ​​are provided. 50 / ml values ​​are used to show data trends and relationships between data values, while actual values ​​may vary from laboratory to laboratory and do not imply limitations. Figure 62B Chart 6210 shows the percentage reduction in SARS-CoV-2 replication compared to... Figure 62A The relationship between the percentage of cytotoxicity at the light doses shown is illustrated. Light doses that have little effect on Vero E6 cell viability (e.g., 7.5, 15, and 30 J / cm²) are also considered. 2 ), SARS-CoV-2 replication was observed to be reduced to as much as 99.99%. Notably, at 45 J / cm², 2 and 60J / cm 2 At that time, cell viability was slightly lower than Figure 60A-60C The data shown in the figure; however, since the SARS-CoV-2 experiments were conducted in independent laboratories, differences existed in cell seeding, cell passage, and cell culture media, so slight differences in cytotoxicity assays are expected.

[0457] Figure 63A and 63B Indicates and Figure 62A and 62B Similar experimental data, but the MOI increased to 0.01. Figure 63A Figure 6300 shows the results for Vero E6 cells infected for 1 hour with the SARS-CoV-2 isolate USA-WA1 / 2020 at an MOI of 0.01, at 7.5 to 60 J / cm². 2 TCID of 425nm light at the dose 50 / ml. Provide the specific TCID. 50 / ml values ​​are used to show data trends and relationships between data values; actual values ​​may vary by laboratory and do not imply limitations. Figure 63B Chart 6310 shows the decrease in the percentage of SARS-CoV-2 replication compared to... Figure 63A The figure shows the relationship between the light dose and the percentage of cytotoxicity. As shown, increasing the MOI to 0.01 produces the same effect as before. Figure 62A and 62B A dose-dependent reduction in SARS-CoV-2 replication was observed at an MOI of 0.001. Despite a 10-fold increase in the amount of introduced virus (e.g., from MOI 0.001 to MOI 0.01), the dose was 7.5 J / cm³ over a short 2.5-minute interval. 2 The 425nm blue light still showed that at 24h.pi, SARS-CoV-2 replication was reduced by at least 2log.

[0458] Figure 63C Table 6320 shows the results. Figures 63A-63B TCID 50 The collected samples were evaluated for SARS-CoV-2 RNA using reverse transcription polymerase chain reaction (rRT-PCR). The number of cycles detected is a basic test result, referred to as the quantified cycle number (Cq), where a low Cq value represents a higher initial target amount. As shown in the figure, SARS-CoV-2 genomic RNA showed a dose-dependent reduction; further confirming the effect of 425 nm light on SARS-CoV-2. The fold reduction between 425 nm light doses detected by rRT-PCR was lower than that of replicating virus (TCID). 50 The observed fold increases indicate that SARS-CoV-2 viral RNA remains easily detectable despite the reduction in infectious viral particles. These data suggest that 425 nm blue light may have a relatively small impact on viral RNA replication and packaging compared to viral particle inactivation.

[0459] Figure 64A and 64B Display similar to Figure 63A and 63B The experimental data were obtained through a second independent laboratory evaluation using Vero 76 cells infected with an MOI of 0.01 at 48 h pi. Figure 64A Figure 6400 shows the dosage range of 7.5 to 60 J / cm² for Vero 76 cells infected with SARS-CoV-2 at an MOI of 0.01. 2 TCID of 425nm light 50 / ml. Provide the specific TCID. 50 / ml values ​​are used to show data trends and relationships between data values; actual values ​​may vary by laboratory and do not imply limitations. Figure 64B Chart 6440 shows the percentage reduction in SARS-CoV-2 replication compared to... Figure 64A The relationship between the percentage of cytotoxicity at the indicated light dose and the given light dose. Figure 63A and 63B Consistency, in Figure 64A and 64BA similar trend was observed in the dose-dependent effect of 425 nm blue light on SARS-CoV-2 replication. Importantly, despite differences in cell type (Vero 76), SARS-CoV-2 virus stock preparation, cell culture medium, and viability assay, the dose-dependent trend showed a similar logarithmic decrease.

[0460] To investigate whether the antiviral activity of light against SARS-CoV-2 is specific to 425nm blue light, Vero E6 cells infected with an MOI of 0.01 were exposed to a high dose of red light. At this point, Figure 65 Figure 6500 shows the TCID values ​​for Vero E6 cells infected with an MOI of 0.01. 50 Relationship between / ml and various doses of 625nm red light. Provide specific TCID values. 50 The / ml value is intended to illustrate data trends and relationships between data values; actual values ​​may vary by laboratory and do not imply limitations. Dosage range from 15 J / cm³. 2 Up to 240J / cm 2 Extensive exposure time shows TCID at 24h.pi 50 The concentration of SARS-CoV-2 did not decrease; this demonstrates that 425nm blue light induces a unique antiviral environment leading to SARS-CoV-2 inactivation. At this point, 425nm light can be administered at an effective virucidal dose, which is relatively safe in the VeroE6 cell line (e.g., less than 25% cytotoxicity), and at even higher doses in endothelial cells, such as those found in the respiratory tract and all blood vessels. Red light may have little effect on SARS-CoV-2 replication and / or increase viral load, as indicated by TCID50. 50 Measurements were taken over 24 / 48 hours. However, red light can reduce inflammation induced by blue light exposure, which may have a positive effect on cell viability, thereby reducing cytotoxicity. This reduction in inflammation may be beneficial in the treatment of viral infections, particularly when viruses can trigger cytokine storms and / or inflammation may lead to secondary bacterial infections. Therefore, a combination of blue light (e.g., light at approximately 425 nm) and one or more anti-inflammatory wavelengths of red light can provide the desired combination of biological effects.

[0461] The efficacy of 425nm blue light against cell-associated SARS-CoV-2 may be due to a combination of blue light inducing an antiviral environment within cells and inactivating cell-free viral particles. To differentiate these, Figure 66A and 66B This represents cell-free SARS-CoV-2 inactivation evaluated by two independent laboratories. Irradiation with a specified dose of 425nm blue light containing approximately ~10 5 and ~10 6 TCID 50Two different viral suspensions were used per ml. After light exposure, Vero E6 cells were subjected to TCID treatment in the first laboratory. 50 Measurement, such as Figure 66A As shown in Figure 6600, and in the second laboratory, Vero 76 cells were subjected to TCID... 50 Measurement, such as Figure 66B As shown in Chart 6610. Figure 66A As shown, in the first laboratory, a low dose of 425nm light was sufficient to inactivate 10 6 TCID50 / ml SARS-CoV-2, at 7.5 J / cm 2 The reduction should be at least 1 log (or greater than 90%), at 15 J / cm. 2 The reduction should be at least 2 log (or greater than 99%) at 30 J / cm. 2 The reduction should be at least 3 log (or greater than 99.9%), and at 60 J / cm 2 The decrease was at least 4 log (or greater than 99.99%). A similar trend was observed in Vero 76 cells in the second laboratory, such as... Figure 66B As shown. Although the reduction in SARS-CoV-2 inactivation was not significant, at 60 J / cm 2 A reduction of at least 2 log (or at least 99%) was still observed. Technical differences between laboratories (including SARS-CoV-2 virus stock preparation, cell culture media, and cell types used for virus detection) may be factors influencing susceptibility magnitude. Overall, the results from two independent laboratories suggest that low doses of 425 nm blue light (e.g., ≤15 J / cm²) are effective. 2 It effectively inhibited the infection and replication of cell-free and cell-associated SARS-CoV-2 with minimal impact on cell viability. Specific TCID values ​​are provided. 50 The / ml value is intended to show data trends and relationships between data values; actual values ​​may vary from laboratory to laboratory and do not imply limitations.

[0462] To ensure the integrity of the collected data, the following measures were provided: Figure 67A and 67B This was to demonstrate that Vero E6 cells did not exhibit a decrease in survival percentage when exposed to green or red light doses. Figure 67A and 67B The provided cell count is 2 x 102 5 1 cell, 1 x 10 5 1 cell and 5 x 10 4 Each cell. Figure 67A Figure 6700 shows Vero E6 cells at 0-180 J / cm². 2 No decrease in activity was observed under 530 nm light within the dose range. Figure 67B Figure 6710 shows Vero E6 cells at 0-240 J / cm². 2 No decrease in activity was observed under 625 nm light within the dose range.

[0463] The rapid need for therapeutic countermeasures against SARS-CoV-2 and other respiratory viral pathogens has spurred the rapid development of new approaches to complement existing public health measures. As described in this paper, a carefully designed LED array has demonstrated for the first time that safe, visible 425 nm blue light can inhibit cell-free and cell-associated SARS-CoV-2 infection and replication in a dose-dependent manner. Results from two independent laboratories indicate that low doses of 425 nm blue light (e.g., ≤15 J / cm²) can effectively inhibit SARS-CoV-2 infection and replication in a dose-dependent manner. 2 It effectively inhibited SARS-CoV-2 infection and replication (e.g., >99%) with minimal impact on Vero E6 cell viability. Importantly, in a 3D EpiAirway tissue model established from human tracheal / bronchial tissue, the effect was minimal at doses ≤60 J / cm². 2 It has good tolerance to 425nm light.

[0464] The EpiAirway model is a commercially available in vitro organoid model of human mucociliary airway epithelium cultured at the air / liquid interface to provide a differentiated in vivo-like epithelial structure with barrier properties and metabolic functions. There is a strong global trend to replace animal models with relevant in vitro human-derived testing systems to reduce the number of animals used in preclinical testing. Current guidelines for inhalation toxicity testing developed by the OECD (TG403, TG433, and TG436) outline the use of animals to determine LC. 50 (e.g., the concentration required to cause 50% mortality in test animals). The EpiAirway in vitro tissue model can be used to determine the IC50 of test items. 25 The value (the concentration required to reduce tissue viability by 25% relative to the carrier control tissue). This model has been demonstrated to predict respiratory tissue viability using chemicals classified as Acute Inhalation Toxicity Categories 1 and 2 by the Globally Harmonized System (GHS) and Acute Inhalation Toxicity Categories I-II by the Environmental Protection Agency (EPA). Prolonged exposure times to toxic chemicals (e.g., 24 and 72 hours) also reflect in vivo responses, demonstrating the predictive value of the EpiAirway model for human respiratory toxicities. Furthermore, this homogeneous in vitro model is well-suited for assessing safe doses of light applied to a fixed surface area (e.g., units: J / cm²). 2 Instead of trying to scale the optical delivery of light to the appropriate small rodent anatomy.

[0465] As before Figure 60A-60CAs shown, the EpiAirway model was exposed to light at wavelengths of 385 nm, 405 nm, and 425 nm at various dose ranges. When exposed to 385 nm UVA light, the concentration was greater than 45 J / cm². 2 In cases where viability loss exceeded 25%, an IC50 exceeding the threshold for acute cytotoxicity determined in the EpiAirway model was established. 25 Threshold dose. In contrast, higher doses of 425nm blue light reached the validated IC50 for acute airway irritation. 25 Threshold. Using 60 J / cm 2 Following irradiation with a 425nm blue light dose of an antiviral agent (e.g., SARS-CoV-2 reduction >99.99%), greater than 100% tissue viability was observed. Different viability curves observed at 385nm, 405nm, and 425nm indicate that the 3D EpiAirway tissue model is suitable for identifying phototherapy-related acute respiratory effects in a dose- and wavelength-dependent manner. At 425nm, 120 J / cm²... 2 The minimal loss of vitality indicates that the 3D human respiratory tissue model has high tolerance to this wavelength. Figures 61A to 61C In the 2D Vero E6 cell culture, the concentration of J / cm³ is greater than or equal to 15 J / cm³. 2 A 425nm dose exhibited a density-dependent viability response, with lower seeding densities per surface area being more susceptible to photoinduced cytotoxicity. The enhanced tolerance of the 3D EpiAirway tissue model to 425nm blue light compared to 2D Vero E6 cell cultures is not surprising, as cells in 3D cultures are generally more resistant to drug therapy, metabolize drugs more efficiently, and exhibit increased resistance to drug-induced apoptosis. The properties of the 3D tissue model more closely reflect cellular properties observed in the in vivo tissue environment. Developing optimal conditions for SARS-CoV-2 infection and replication in a 3D respiratory tissue model will contribute to elucidating the mechanisms controlling the ability of 425nm blue light to inactivate SARS-CoV-2.

[0466] The potential mechanisms by which 425nm blue light inactivates SARS-CoV-2 are still under investigation; however, a brief overview of the putative molecular contributors is relevant. The molecular mechanisms controlling the effects of blue light on non-pigmented cells are only beginning to be elucidated. The effects of blue light should follow the first law of photochemistry, namely that light must be absorbed to have an effect. A few blue light photoreceptors have been identified in non-pigmented cells, including cytochrome c oxidase, flavin, porphyrin, opsins, and nitrosamines. Light absorption by these photoreceptors can lead to the release of reactive oxygen species (ROS) and / or nitric oxide (NO), which may inactivate SARS-CoV-2 in cell-free or cell-associated environments. ROS and / or bioactive NO can trigger the activation of transcription factors involved in immune signaling, such as nuclear factor κ-light chain enhancer (NF-κB) and mitogen-activated protein kinase (MAPK) signaling in activated B cells. The NF-κB and MAPK pathways can lead to the transcriptional activation of innate and inflammatory immune response molecules that may interfere with SARS-CoV-2 replication. Nitric oxide can also mediate cell-associated SARS-CoV-2 inactivation via S-nitrosylation of cysteine ​​residues in the active site of viral encoding enzyme proteins. Reactive oxygen species (ROS) and / or nitrogen (NO) may play a role in inactivating cell-free viral particles. Photosensitizers present in cell culture media can promote the production of ROS and / or NO, directly affecting viral particle proteins and / or viral RNA to prevent infection and replication. It has also been demonstrated that inactivation of cell-free feline calicivirus (FCV) by 405 nm light depends on naturally occurring photosensitizers in the culture medium. Importantly, FCV was inactivated by 4 log in artificial saliva and plasma, indicating that photo-induced cell-free virus inactivation can be achieved under biologically relevant conditions. Evidence demonstrating that SARS-CoV can be inactivated by exogenous addition of NO donor molecules or possibly by nitric oxide confirms the potential of nitric oxide inactivation of SARS-CoV-2.

[0467] In the above experiments, the materials and methods are provided in more detail below for reference. Regarding cells, tissues, and viruses, Vero E6 cells were purchased from ATCC and maintained in DMEM (Sigma-Aldrich) supplemented with 10% FetalClone II (HyClone) and 1% antibiotic-antifungal agent (Gibco). Vero76 cells (ATCC CRL-1587) were maintained in MEM supplemented with 2 ml of glutamine and 5% FBS. Primary human airway epithelium (EpiAirway AIR-100, MatTek Corporation) was cultured for 28 days in transwell inserts from MatTek Corporation. Cultured tissues were transported to 24-well plates with agarose embedded in the basal compartment. Upon arrival, the transwell inserts were removed and placed in 6-well plates with cold maintenance medium in the basal compartment; no medium was added to the top surface. Cells were incubated overnight at 37°C and 5% CO2 prior to experimental use. All live virus work was conducted in two separate Biosafety Level 3 (BSL-3) laboratories following established safety guidelines: MRI Global Kansas City facility and Utah State University Antiviral Research. In both laboratories, SARS-CoV-2 (USA_WA1 / 2020) was obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA) and propagated with slight modifications. At MRI Global, Vero E6 cells were cultured overnight in DMEM (Gibco; 12320-032) supplemented with 10% FBS (Avantor, 97068-085), 1% non-essential amino acids (Corning 25-025-Cl), and 1% penicillin / streptomycin (VWR 97063-708). To generate a stock solution, cells were infected with infection medium (as above, with 5% FBS) at an MOI of 0.08 prior to infection, with cytopathic effects monitored daily, and harvested 4 days post-infection as CPE approached 100%. The working stock was cultured in Vero E6 cells at an MOI of 0.005 in DMEM / F12 medium (Gibco; 11330-032) supplemented with 10% FBS and 1% penicillin / streptomycin. Cell CPE was monitored and harvested two days post-infection, as CPE approached 70%. Cell culture debris was precipitated by centrifugation at 500 x g for 5 min, and the viral stock was stored at -80°C. The virus was then analyzed by TCID45. 50 The infectivity of the viral reservoir was determined. At Utah State University, SARS-CoV-2 (USA_WA1 / 2020) multiplied in Vero 76 cells. The infection medium was a basic essential medium supplemented with 2 mM L-glutamine, 2% FBS, and 50 μg / mL gentamicin.

[0468] For cytotoxicity assays of human tissues, the maintenance medium on the human tissue transfer chamber inserts was replaced before illumination. The tissues were irradiated with 385 nm, 405 nm, or 425 nm light and incubated at 37 °C and 5% CO2 for 3 hours. Cytotoxicity was determined using the EpiAirway MTT assay according to the manufacturer's instructions. Briefly, the tissues were rinsed with TEER buffer and placed in preheated MTT reagent, incubated at 37 °C and 5% CO2 for 90 minutes. The MTT solution was extracted with MTT extraction solvent solution with shaking for 2 hours. The tissue inserts were discarded, and the extraction solvent solution was added to 96-well plates for reading at 570 nm. The extraction solvent solution served as an experimental blank, and cell viability was calculated for unilluminated plates.

[0469] For cytotoxicity assays of cell lines, Vero E6 cells were incubated overnight at 37°C and 5% CO2 in clear 24-well, 48-well, and 96-well plates (Corning) at different seeding densities. Cells were irradiated with 385 nm, 405 nm, or 425 nm light and then incubated at 37°C and 5% CO2 for 24 hours. After 24 hours, cytotoxicity was measured using a modified CellTiterGloOne solution (Promega). The amount of CellTiterGloOne solution (“CTG”) was optimized in preliminary experiments. 100 μl of solution was used for 24-well plates, and 60 μl for 48 and 96-well plates. Cells were placed on a track-mounted oscillator for 2 minutes to allow the chemiluminescence signal to stabilize for 10 minutes, and then 50 μl of solution was added to black-bottomed 96-well plates and read using the CellTiterGlo program on GloMax (Promega). CellTiterGloOne solution was used as a blank, and cell viability was calculated relative to unilluminated plates.

[0470] Cytotoxicity analysis was performed 48 hours after light exposure. Cells were treated with 0.01% neutral red for 2 hours to detect cytotoxicity. Excess dye was washed away from the cells with PBS. The absorbed dye was eluted from the cells with 50% Sorensen citrate buffer / 50% ethanol for 30 minutes. Buffer was added to 10 wells for each repetition. Optical density was measured at 560 nm, and cell viability was calculated relative to unilluminated cells.

[0471] Antiviral assays were performed in a separate, modified laboratory. At MRI Global, cells were infected with SARS-CoV-2 at multiples of infection (MOI) of 0.01 and 0.001, in triplicate. One hour post-infection, infected cells were irradiated with 425 nm light at a specified dose. Cell culture supernatants were collected at 24 and 48 hours post-infection for TCID. 50 Assay and qPCR analysis were performed. A no-light control and a virus-free control were included as positive controls for virus growth and cytotoxicity, respectively. Cytotoxicity analysis was performed 24 hours after irradiation, as described above.

[0472] Vero 76 cells were infected with SARS-CoV-2 at MOIs of 0.01 and 0.001. One hour post-infection, infected cells were irradiated with 425 nm light at a specified dose. Cell culture supernatant was collected for TCID at 48 hours post-infection. 50 Assays were performed. A no-light control and a virus-free control were included as positive controls for virus growth and cytotoxicity, respectively. Cytotoxicity analysis was conducted 48 hours after light exposure.

[0473] Virus-killing assays were performed in parallel in different laboratories. In one laboratory, the virus-killing agent was irradiated with different doses of light containing 10... 5 and 10 6 TCID 50 1 mL of solution per ml. Then via TCID. 50 The virus was titrated on Vero E6 cells in triplicate. A dark control was used as a positive control for virus growth.

[0474] In the second laboratory, light containing 10 was irradiated with different doses. 5 and 10 6 TCID 50 1 mL of solution per ml. Then via TCID. 50 The virus was titrated on Vero 76 cells in triplicate. A dark control was used as a positive control for virus growth.

[0475] Viral RNA levels in SARS-CoV-2 samples were determined by quantitative RT-PCR using the CDC N1 assay. Samples used for the RT-PCR reaction were live virus in culture supernatant without nucleic acid extraction. Primers and probes for the N1 nucleocapsid gene target region were from Integrated DNA Technologies (2019-nCoV CDC RUO Kit, No. 10006713). TaqPath 1-Step RT-qPCR Master Mix, CG sourced from ThermoFisher (No. A15299), was used. Reaction volume and thermal cycling parameters followed those published in the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel: Instructions for Use. For the RT-PCR reaction, 15 mL of the prepared premix was added to each well, followed by 5 mL of sample, for a final total volume of 20 mL per well. The reaction was run on a Bio-rad CFX real-time PCR instrument.

[0476] TCID 50 The assays were performed in two laboratories, with slight modifications. In one laboratory, Vero E6 cells were seeded at 10,000 cells / well in 0.1 ml / well of complete medium (DMEM / F12 with 10% fetal bovine serum and 1X penicillin / streptomycin) in 96-well plates and incubated overnight at 37°C with 5% CO2 humidification. The next day, virus samples were serially diluted 1:10 to unreplenished DMEM / F12 medium by adding 0.1 ml of virus to 0.9 ml of diluent, briefly vortexing and repeating until the desired number of dilutions was reached. The medium was poured out of the 96-well plates, and 0.1 ml of each virus dilution was aliquoted into 5 or 8 wells. After incubation at 37°C with 5% CO2 for 4 days, the plates were scored for cytopathic effects. TCID was prepared using the Reed & Muench method. 50 / ml. In the second laboratory, cell culture samples were serially diluted and seeded in quadruplicates onto fresh Vero 76 cells. CPE of the plates was visually examined 6 days post-infection. Wells were indicated as positive or negative, and viral titers were calculated using the Reed-Muench endpoint dilution method.

[0477] Figure 68A Figure 6800 shows the Vero E6 cell density at different seedings and various light doses (J / cm²). 2 The raw emission value (RLU) of ). Figure 68B Figure 6810 shows the density of Vero E6 cells at different seeding levels and Figure 68A Survival percentages for various light doses. Figure 68B This indicates that when the cell density is higher than 106 Before reaching saturation, Vero E6 cell viability may not be fully saturated. RLU and survival percentage based on different light doses indicate that 100 μL and 200 μL of CellTiter-Glo (CTG) are effective volumes for measuring cell viability after seeding different Vero E6 cell densities. Figure 68A and 68B The cell density was shown to be 2 x 10⁻⁶. 5 One cell was treated with 100 μL CTG and 1 x 10⁻⁶ CTG. 5 One cell was mixed with 100 μL CTG, 5 x 10 4 One cell was treated with 100 μL CTG, 2 x 10 5 One cell was mixed with 200 μL CTG and 1X10 5 One cell was treated with 200 μL CTG and 5 x 10⁻⁶ cells. 4 One cell with 200 μL CTG. Figure 68C This is a graph 6820 comparing RLU with total cell count to show that CTG is used to measure values ​​above 10. 6 An effective reagent for cell density of Vero E6 cells. The relationship between RLU values ​​and total cell number for 500 μL CTG, 250 μL CTG, and 100 μL CTG is provided, with data expressed as + / - standard deviation.

[0478] Figure 69A Calu-3 cells infected with SARS-CoV-2 showed TCID levels at 24 and 48 hours post-infection. 50 Figure 6900 shows the ratio of / ml to dose. Figure 69B It is chart 6910, showing the relationship with Figure 69A The percentage reduction in cytotoxicity in Calu-3 cells compared to SARS-CoV-2. Specific TCID values ​​are provided. 50 The / ml value is intended to illustrate data trends and relationships between data values; actual values ​​may vary by laboratory and do not imply limitations. For Figure 69B ,based on Figure 69A The doses shown are presented as graphs of the percentage reduction in SARS-CoV-2 and the percentage of cytotoxicity in the form of nonlinear regression curves. As shown, 425 nm visible light inhibited viral replication of SARS-CoV-2 in the human respiratory cell line Calu-3. Calu-3 cells were infected with SARS-CoV-2 at an MOI of 0.1 and exposed to the specified dose of 425 nm light 1 hour post-infection. SARS-CoV-2 samples were collected at 24 and 48 hours post-infection for TCID. 50 Measurement. At 15 J / cm² 2A single treatment with the specified dose resulted in a viral reduction of greater than 99%. The percentage reduction in SARS-CoV-2 virus was calculated for each dose and time point, as shown below. Figure 69B As shown above, SI (selectivity index) can be defined as the CC of the treated cells. 50 With EC 50 The ratio. For example... Figure 69B As shown, at relatively low dose values, SARS-CoV-2 was reduced by 50% at 24 and 48 hours post-infection. At this point, the light doses that inhibited viral replication had the desired selectivity index (SI) values, greater than 100 at 24 hours post-infection and greater than 25 when taking into account the cell viability of uninfected Calu-3 cells.

[0479] Figure 70A Figure 7000 shows the percentage reduction in SARS-CoV-2 replication and the percentage of cytotoxicity in Vero E6 cells infected with an MOI of 0.01. Figure 70B Figure 7010 shows the percentage reduction in SARS-CoV-2 replication and the percentage of cytotoxicity in Vero E6 cells infected with an MOI of 0.001. Figure 70A and 70B In this study, a specified dose of light was applied 1 hour post-infection, and the dose-response was determined 24 hours post-infection. This was achieved by applying an irradiance of 50 mW / cm². 2 The 425nm light duration was 2.5 minutes (for 7.5 J / cm²). 2 ), 5 minutes (for 15J / cm) 2 ), 10 minutes (for 30J / cm) 2 ), 15 minutes (for 45J / cm) 2 ) and 20 minutes (for 60 J / cm 2 The dosage was determined by the amount of light applied. Consistent with previously provided charts, a similar trend was observed for both MOI values ​​regarding the dose-dependent effect of 425 nm blue light on SARS-CoV-2 replication. The cytotoxicity curves indicated that CC... 50 It is approximately 30.2. In Figure 70A In the middle, for as low as 7.5 J / cm 2 At the given dose, the reduction percentage of SARS-CoV-2 was close to 100%, and the corresponding nonlinear regression curve was at or near 0 J / cm². 2 The dose decreases sharply. For SI calculation purposes, EC is used. 50 The value was chosen to be a conservative 1, to give an SI value of approximately 30 (e.g., CC). 50 / EC 50 ).exist Figure 70B In the middle, for 7.5J / cm 2The dose resulted in a percentage reduction in SARS-CoV-2 far from 100%, thus providing a corresponding nonlinear regression curve at slightly above 0 J / cm². 2 The dose decreases towards 0%. In this way, EC... 50 The value can be indicated as approximately 3.4 to give an SI value of approximately 9 (e.g., CC). 50 / EC 50 Due to the variability of the experiment, the dataset may differ slightly. At this point, Figure 70A and 70B The results shown can be considered similar and within the normal range of experimental variation.

[0480] Although Figure 70A and 70B Provided a percentage reduction in SARS-CoV-2 at the cellular level to determine EC 50 Value, but requires IC of the target tissue 25 The value is used to determine the appropriate LTI treatment value. Figure 70C Figure 7020 shows the percentage of primary human tracheal / bronchial tissue from a single donor that survived at different doses of 425 nm light. Tissue viability was determined 3 hours post-exposure by the MTT assay, a method for measuring cell viability by assessing the enzymatic activity of NAD(P)H-dependent cellular oxidoreductases that reduce MTT dye to formazan. From Figure 7020, IC 25 The value corresponds to a dose at which the viability curve reaches 75% (e.g., a 25% reduction in tissue viability). Figure 70C In China, IC 25 The value is approximately 157, as shown by the superimposed dashed line. (Combined with...) Figure 70A and 70B EC 50 The value, the corresponding LTI value can be determined as Figure 70A Approximately 157 and Figure 70B It is approximately 46.

[0481] Figures 71A-71C Repeated Figures 70A-70C The experiment was conducted using light with a peak wavelength of 450 nm. Figure 71A Figure 7100 shows the percentage reduction in SARS-CoV-2 replication versus the percentage of cytotoxicity in Vero E6 cells infected with 0.01 MOI. Figure 71BFigure 7110 shows the percentage reduction in SARS-CoV-2 replication and the percentage of cytotoxicity in Vero E6 cells infected with 0.001 MOI. Consistent with previously provided figures, a similar trend was observed for the dose-dependent effect of 450 nm blue light on SARS-CoV-2 replication for both MOI values. The cytotoxicity curves indicate CC 50 Greater than 60, because the curve did not extend to 50% cytotoxicity. Conversely, based on CC values ​​greater than 60... 50 The SI value can also be considered to be greater than a specific SI value. Figure 71A In this context, an EC50 value of approximately 7.2 can be used to indicate an SI value greater than 8 (e.g., CC). 50 / EC 50 ).exist Figure 71B In China, it can be instructed by the EC 50 A value of approximately 4.1 is used to give an SI value (e.g., CC) greater than 15. 50 / EC 50 As before, due to the variability of the experiments, the dataset can be expected to differ slightly. At this point, Figure 71A and 71B The results shown can be considered similar and within the normal range of experimental variation.

[0482] Figure 71C Figure 7120 shows the survival percentage of primary human tracheal / bronchial tissue from a single donor at different doses at 450 nm. Figure 70C Similarly, tissue viability was determined 3 hours post-exposure by MTT assay. According to Figure 7120, IC... 25 The value can be determined to be approximately 330. (Combined with...) Figure 71A and 71B EC 50 The value, and the corresponding LTI value can be determined as Figure 71A For approximately 46 and Figure 71B It is approximately 80. Although Figure 71C Displayed at 360J / cm 2 At this dose, the survival rate is approximately 63%, and at this dose, the variability between biological replicates is high. At this point, IC... 25 The value may even be greater than the approximate value of 330, indicating that very high doses can be administered before significant toxicity is observed.

[0483] Figure 72 It is a summary Figures 70A-70C Table 7200 of the 71A-71C experiments. The higher SI and LTI values ​​at 450 nm light are primarily a result of lower cytotoxicity relative to 425 nm light. Lower EC 50The values ​​at 425 nm showed more effective viral inhibition, but this may be related to the higher cytotoxicity values ​​at lower light doses compared to 450 nm. Ideally, phototherapy could include lower EC50 values. 50 Value and the highest possible CC 50 Values. Different target pathogens and tissue types may provide different LTI values. At this point, depending on the application, the LTI values ​​according to this disclosure can be greater than or equal to 2, or in the range of 2 to 100,000, or in the range of 2 to 1,000, or in the range of 2 to 250. Taking into account experimental differences, exemplary data provided for the treatment of SARS-CoV-2 using light in the range of 425 nm to 450 nm show that LTI values ​​within any of the above ranges can be achieved.

[0484] Using a technique similar to that described above for measuring the antiviral activity of 425 to 450 nm light against SARS-CoV-2, the antiviral activity of 425 nm light against wild-type (WT) and Tamiflu-resistant influenza A virus was investigated. Figure 73A Figure 7300 shows the titer of WT influenza A virus, based on the residual viral load after different initial viral doses following treatment with different doses of 425nm light. The initial viral dose was set to 1 x 10⁻⁶. 4 and 1X10 5 It also showed that using 425nm light at 0J / cm 2 60J / cm 2 and 120J / cm 2 Residual viral load (e.g., copy number) after dose treatment. Data indicate that when 60 J / cm² is administered... 2 Or 120J / cm 2 At the specified dose, the viral load of wild-type influenza A virus was significantly reduced, and an additional reduction of approximately 0.5-log was observed at higher doses.

[0485] Figure 73B Figure 7310 shows the titers of Tamiflu-resistant influenza A virus based on a single initial viral dose, representing the residual viral load after treatment with different doses of 425nm light. The initial viral dose was set to 1 x 10⁻⁶. 4 It shows the effect of using 425nm light at 0J / cm 2 60J / cm 2 and 120J / cm 2 Residual viral load (e.g., copy number) after dose treatment. Approximately 1 x 10-1 4 An initial dose was provided, and it was shown that 0 J / cm² light was used with 425 nm light. 2 30J / cm 2 60J / cm 2120J / cm 2 180J / cm 2 and 240J / cm 2 Residual viral load (e.g., copy number) after dose treatment. Data showed that viral load increased when no light was applied, and decreased in a dose-dependent manner to up to approximately 180 J / cm³. 2 The total viral load decreased by approximately 2 log.

[0486] Figure 74A Figure 7400 shows the TCID of WT influenza A virus treated with various doses of 425nm light. 50 The relationship between / ml and energy dosage. The MOI for WT influenza A was 0.01. (Based on 0 J / cm³) 2 3J / cm 2 7.5J / cm 2 15J / cm 2 30J / cm 2 45J / cm 2 60J / cm 2 and 90J / cm 2 Provide the selected dose. Collect results at 24 and 48 hours. When no light is applied (e.g., dose of 0 J / cm²), [following the previous instructions]. 2 The viral load increased to 10 in 24 hours. 3 One copy, and increased to 10 within 48 hours. 5 One copy. At approximately 7.5 J / cm 2 and 60J / cm 2 At doses between these ranges, a dose-dependent decrease in viral load was observed within 24 hours, but the virus rebounded significantly after 48 hours. However, at 90 J / cm²... 2 At the specified dose, viral load decreased significantly within 24 hours and did not increase significantly within 48 hours. Specific TCID values ​​are provided. 50 The / ml value is intended to show data trends and relationships between data values; actual values ​​may vary from laboratory to laboratory and do not imply limitations.

[0487] Figure 74B Figure 7410 shows the percentage reduction in viral load and percentage of cytotoxicity of WT influenza A virus when Madin-Darby canine kidney (MDCK) cells infected with influenza A virus were exposed to different doses of 425 nm light. The MOI for WT influenza A was 0.01. As shown in the figure, at 0 J / cm²... 2 7.5J / cm 2 15J / cm 2 30J / cm 2 45J / cm2 60J / cm 2 and 90J / cm 2 Dose was administered. Viral load and cytotoxicity reduction were monitored at 24 and 48 hours post-irradiation. For any dose, minimal cytotoxicity was observed at any time point. The reduction in viral load was dose-dependent at a dose of 45 J / cm². 2 60J / cm 2 and 90J / cm 2 The viral load was shown to have almost completely decreased.

[0488] Figure 74C It is similar to Figure 74A The chart is 7420, but the initial MOI is 0.1. At this point, Figure 74C The results showed that the influenza A infection was caused by WT and that the concentration of 0 J / cm³ was 0 J / cm³ 2 3J / cm 2 7.5J / cm 2 15J / cm 2 30J / cm 2 45J / cm 2 60J / cm 2 and 90J / cm 2 TCID of cells treated with 425nm light 50 Results were collected after 24 and 48 hours. For values ​​from 0 to 15 J / cm³. 2 At this dose, the viral load remained fairly constant over 24 hours, and increased to 90 J / cm². 2 Viral load decreased in a dose-dependent manner. Over the next 24 hours (i.e., a total of 48 hours post-exposure), viral load remained below 90 J / cm³. 2 Significant rebound was observed at all doses other than those specified.

[0489] Figure 74D It is similar to Figure 74B The chart is 7430, but the initial MOI is 0.1. At this point, Figure 74D The figure shows the percentage reduction in viral load and cytotoxicity of WT influenza A cells when infected with influenza A were exposed to different doses of 425 nm light. The MOI for WT influenza A was 0.1. As shown in the figure, at 0 J / cm²... 2 7.5J / cm 2 15J / cm 2 30J / cm 2 45J / cm 2 60J / cm 2 and 90J / cm 2Administer the dose. Monitor viral load and cytotoxicity reduction at 24 and 48 hours post-irradiation. (As...) Figure 74B At any dose, virtually no cytotoxicity was observed at any time, and the reduction in viral load was dose-dependent, with the dose being 45 J / cm³. 2 60J / cm 2 and 90J / cm 2 This indicates a high or almost complete reduction in viral load. Specific TCID is provided. 50 The / ml value is intended to show data trends and relationships between data values; actual values ​​may vary from laboratory to laboratory and do not imply any limitation.

[0490] In summary, therapeutic phototherapy can be selected from optimal doses, including various combinations of wavelengths, irradiance, and treatment durations as discussed above for various viruses, including SARS-CoV-2 and influenza. Ideally, phototherapy can induce a dual mechanism of action against the virus, involving the disruption of lipid membranes using only oxygen and / or nitric oxide. These treatments have demonstrated efficacy both extracellularly, where cells were absent before infection, and intracellularly, where cells were present after infection. Antiviral effects can be very rapid. For example, inactivation of SARS-CoV-2 virus was confirmed within 24 to 48 hours, compared to the clinically observed reduction in viral load, as SARS-CoV-2 virus cleared the bodies of untreated patients and even those treated with remdesivir.

[0491] It is important to consider the "phototherapy index" or "LTI," which is the IC (internal capacity) of light applied to cells and tissues. 25 and EC 50 The ratio of values. Ideally, phototherapy at a power level without excessive cytotoxicity will effectively kill one or more target viruses. Preferably, IC 25 / EC 50 The proportion should be as high as possible, including greater than 2. Each viral cell system has many variables (e.g., cell density, different cell types used for productive infection, culture medium, etc.), making it difficult to provide a single LTI for all cell types. An important aspect of evaluating cell line LTIs for all viruses (especially respiratory viruses) includes assessing the types of human tissues these viruses may infect, such as EpiAirway from large airway (AIR-100) and nasal cavity (NAS-100) tissues. EpiAirway is a ready-to-use 3D mucociliated tissue model composed of normal human tracheal / bronchial epithelial cells and can also be used as a system for co-culturing with normal human matrix fibroblasts (EpiAirwayFT). At 50 mW / cm² 2A reduction of up to 75-fold was observed after 2.5 minutes of treatment at the specified dose. Phototherapy demonstrated significant antiviral activity post-infection, inhibiting approximately 50% of viral replication. Furthermore, this treatment showed efficacy at doses greater than 8.5 J / cm². 2 Complete log inactivation of WT-type influenza A virus. 8.5 J / cm³ 2 The dosage is an IC50 that provides anti-influenza agents after infection. 50 The dosage. At this point, less than 10 J / cm. 2 The dosage can provide multi-pathogen treatment, eliminating different viruses through one or more different mechanisms. In a specific example, 425nm light was used for 5 minutes of multi-pathogen treatment at 50mW / cm². 2 Irradiation levels of approximately 60 J / cm² can be effective in treating SARS-CoV-2 and influenza A. Furthermore, at approximately 60 J / cm²... 2 At a dose of 425nm light at 50mW / cm 2 After 20 minutes of exposure, a decrease in antiviral activity of more than 2 logs was observed.

[0492] Considering that LTI calculations (e.g., IC50) are performed only at 425 nm in antiviral analyses of SARS-CoV-2 and influenza-specific tissues. 25 / EC 50 The ratio of light used in this study was used to observe a safe and effective dose of light that could be applied. Because other respiratory viruses have similar viral membranes, it is believed (based on successful results with SARS-CoV-2 and influenza A) that this type of treatment is effective against all respiratory viruses. When comparing results from 425 nm light with those from 405 nm or 385 nm, the LTI may be smaller, but this is expected to vary depending on tissue type. Extrapolating the data obtained in this paper, relatively high-power light (e.g., doses of hundreds of J / cm²) previously used for surface disinfection... 2 It cannot be safely used in the body. Importantly, the light dose (J / cm²) is crucial. 2 It must be sufficiently non-cytotoxic (i.e., non-cytotoxic in causing EC) 50 At the recommended dose, survival rates will not be reduced to more than 25%. The resulting LTI is expected to vary depending on the cell type exposed to phototherapy, but ideally, there is an effective therapeutic window for a given cell type, such as at least 2, or an LTI in the range of 2 to 100,000, or 2 to 1,000, or 2 to 250, depending on the application. Since SARS-CoV-2, influenza, and other viruses have lipid membranes, and part of the way phototherapy kills viruses is believed to be through oxidative damage to these membranes, it is believed that this treatment will also be effective against other respiratory viruses. Additionally, the treatment method described in this article may also be effective against viruses that do not have lipid membranes, such as rhinoviruses, which cause the most common cold.

[0493] As disclosed in this article, phototherapy can be combined with conventional drugs, such as antiviral agents, anticoagulants, and anti-inflammatory agents. Furthermore, antiviral wavelengths can be combined with anti-inflammatory wavelengths to reduce inflammatory damage caused by viruses, viral-induced cytokine storms, and / or by phototherapy at antiviral NO production / NO release / singlet oxygen production wavelengths.

[0494] While the examples provided above are in the context of viral applications, the principles of this disclosure are also applicable to the treatment of bacterial infections. A current problem in the treatment of bacterial respiratory infections is AMR and refractory lung infections. Antibiotic resistance results in many patients having lung infections caused by bacteria resistant to many common antibiotics. As new antibiotics are developed, bacterial resistance quickly emerges. One potential solution to this problem is the use of visible light, as described herein, which has effective antimicrobial wavelengths and dosages, and can be used alone or in combination with conventional antibiotic therapy. While bacteria can develop resistance to antibiotics, they are less likely to develop resistance to antimicrobial treatment using visible light. The potential applications are far-reaching; a wide range of respiratory microbial infections, such as tuberculosis, Mycobacterium avium complex, etc., can be effectively treated, especially those caused by spore-forming bacteria, provided that light is delivered at a safe therapeutic dose. Bacterial infections caused by spore-forming bacteria can be particularly difficult to treat with conventional antibiotics because antibiotics only kill bacteria that are not in spore form. As disclosed in this article, certain wavelengths of light can effectively kill spore-forming microorganisms, whether the microorganism is in its active form or in its spore form.

[0495] As discussed below, not all blue wavelengths of light are equivalent. Some have high cytotoxicity to infected tissues, while others have high antibacterial efficacy. Consideration is needed regarding the phototherapy index (LTI), which is a combination of antibacterial activity and the safety of exposed tissues. Therefore, a series of experiments were conducted to determine appropriate wavelengths and dose levels to provide safe and effective antibacterial therapy.

[0496] For the experiments, bacterial cultures were prepared at 10⁶ CFU / ml in 1X phosphate-buffered saline (PBS) or CAMHB, and 200 μl were aliquoted into the wells of a 96-well microtiter plate. The covered plate was rotated under a white illumination box with an LED array placed on top to direct light onto the bacteria. A fan blew through vents in the illumination box to minimize heat generated by the LEDs. All setup was performed within a Class II biosafety cabinet. The lights were turned on for a given time, and then the bacteria were sampled, serially diluted, and plated onto MHA for counting.

[0497] The strains used in this study were obtained from the American Type Culture Collection (ATCC), the Antimicrobial Resistance Bank (AR-BANK) of the CDC-FDA, Dr. John LiPuma of the Burkholderia Cepacia Research Laboratory and Repository (BcRLR) at the University of Michigan, and the laboratory of Dr. Mark Schoenfisch of the University of North Carolina Chapel Hill. The BcRLR strain was confirmed as *Pseudomonas aeruginosa* by 16S sequencing, and other strains were also confirmed as *Pseudomonas aeruginosa* by growth on *Pseudomonas* isolation agar. The strains were stored at -80°C in 20% glycerol stock. The strains were cultured on trypsin-soybean agar (TSA) at 30°C or 37°C for 1–2 days, or in cationic-regulated Mueller-Hinton broth. *Streptococcus pyogenes* and *Haemophilus influenzae* were grown using brain-heart infusion in a chamber containing a 5% CO2 pack. All bacteria were incubated at 37°C. Cytotoxicity was measured as described above regarding antiviral data.

[0498] Figure 75A Chart 7500 shows a value of 58.5 J / cm². 2 The efficacy of doses of 405, 425, 450, and 470 nm light in killing *Pseudomonas aeruginosa* (CFU / ml) (in hours post-exposure). Data showed that at wavelengths of 405 nm or 425 nm, a concentration reduction of 5-log was observed almost instantaneously, and this effect persisted for four hours post-exposure.

[0499] Figure 75B Figure 7510 shows the result at 58.5 J / cm². 2 The efficacy of dosed 405, 425, 450, and 470 nm light in killing Staphylococcus aureus (CFU / ml) (in hours post-exposure). Data showed that at 405 nm, a 3-log decrease was observed within half an hour post-exposure, increasing to a 4-log decrease within two hours. At 425 nm, a 2-log decrease was observed within two hours, increasing to a 4-log decrease within four hours. At 450 nm, a 2-log decrease was observed within three hours, increasing to a 4-log decrease within four hours. 470 nm light was almost ineffective.

[0500] Figure 76A Chart 7600 shows values ​​from 1 to 1000 J / cm².2 The effectiveness of 425nm light at killing Pseudomonas aeruginosa (CFU / ml) was assessed. Data showed that at a wavelength of 425nm, the effective dose was approximately 60 J / cm³. 2 At the dose, a 4-log decrease in concentration was observed, while at 100 J / cm 2 At or higher doses, a 5-log reduction was observed.

[0501] Figure 76B Figure 7610 shows the values ​​from 1 to 1000 J / cm². 2 The effectiveness of 425nm light at killing Staphylococcus aureus (CFU / ml) was assessed. Data showed that at a wavelength of 425nm, the effective concentration was approximately 100 J / cm². 2 At higher doses, a 4-log or even 5-log decrease in concentration was observed.

[0502] Figure 77A Figure 7700 shows the values ​​from 1 to 1000 J / cm². 2 The effectiveness of 405 nm light at killing Pseudomonas aeruginosa (CFU / ml) was assessed. Data showed that at a wavelength of 405 nm, the effective concentration was approximately 60 J / cm³. 2 At the dose, a 4-log decrease in concentration was observed, while at 100 J / cm 2 At or higher doses, a 5-log reduction was observed.

[0503] Figure 77B Figure 7710 shows the values ​​from 1 to 1000 J / cm². 2 The effectiveness of 405 nm light in killing Staphylococcus aureus (CFU / ml) was assessed. Data showed that at a wavelength of 405 nm, at approximately 100 J / cm², [the effectiveness was determined]. 2 At higher doses, a 5-log decrease in concentration was observed.

[0504] Figure 78 Figure 7800 shows the toxicity of 405nm and 425nm light to primary human aortic endothelial cells (HAECs). The provided data show the effects of various indicated doses of 405nm and 425nm light, even at up to 99 J / cm². 2 At the specified dosage, cell viability never decreased to below 75%, which is a useful threshold for determining treatment safety.

[0505] Figure 79A Chart 7900 shows the bacterial log. 10 Red...

Claims

1. A lighting device, comprising: At least one light source is arranged to irradiate light onto tissues within a body cavity, the light being configured to induce a biological effect, the biological effect including at least one of the following: altering the concentration of one or more pathogens within the body cavity and altering the growth of one or more pathogens within the body cavity; The light guide includes a hollow core, wherein the light guide is configured to receive light from the at least one light source, and the hollow core defines a guiding path such that at least some of the light travels completely through the light guide without being reflected internally; and A light guide locator configured to at least partially fix the light guide within the body cavity to provide light to the tissue within the body cavity, wherein the light guide locator includes a mouthpiece configured to engage with one or more surfaces of a user's oral cavity, and wherein the mouthpiece includes one or more mouthguards for protecting and fixing the light guide.

2. The lighting device according to claim 1, wherein, The biological effects include altering the concentration of one or more pathogens within the body cavity and altering the growth of one or more pathogens within the body cavity.

3. The lighting device according to claim 1, wherein, The one or more pathogens include at least one of viruses, bacteria, and fungi.

4. The lighting device according to claim 1, wherein, The one or more pathogens mentioned include those from the Coronaviridae family.

5. The lighting device according to claim 4, wherein, The coronavirus family includes SARS-CoV-2.

6. The lighting device according to claim 1, wherein, The biological effects further include at least one of the following: upregulating local immune responses within the body cavity, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, and releasing nitric oxide from endogenous nitric oxide storage.

7. The lighting device according to claim 1, wherein, The biological effects include inactivating one or more pathogens in the cell-free environment within the body cavity.

8. The lighting device according to claim 1, wherein, The biological effects include inhibiting the replication of one or more pathogens in the cell-associated environment within the body cavity.

9. The lighting device of claim 1, further comprising a tongue depressor configured to depress the user's tongue to provide light to the oropharynx.

10. The lighting device according to claim 9, wherein, The tongue depressor is formed from a portion of the light guide.

11. The lighting device of claim 1, further comprising a housing containing the at least one light source, wherein the light guide and the light guide locator are configured to be detachably attached to the housing.

12. The lighting device of claim 1, further comprising a port configured to charge the lighting device and access at least one of the data stored in the lighting device.

13. The lighting device according to claim 1, wherein, The light includes a first optical characteristic, which includes a peak wavelength in the range of 410 nanometers (nm) to 440 nm.

14. The lighting device according to claim 1, wherein, Irradiating the tissue within the body cavity with light includes applying light at a concentration of 0.5 joules per square centimeter (J / cm²). 2 Up to 100 J / cm 2 Light dose within the range.

15. The lighting device according to claim 1, wherein, Irradiating the tissue within the body cavity with light includes applying a light dose with a phototherapy index in the range of 2 to 250, wherein the phototherapy index is defined as a dose concentration that reduces tissue viability by 25% divided by a dose concentration that reduces the cellular percentage of the one or more pathogens by 50%.

16. The lighting device according to claim 1, wherein, The optical guide and the optical guide positioner form a single, indivisible structure.

17. A lighting device, comprising: At least one light source is arranged to irradiate light onto tissues in the user's oropharynx to induce a biological effect, said biological effect including at least one of the following: altering the concentration of one or more pathogens and altering the growth of one or more pathogens. and A mouthpiece configured to engage with one or more surfaces of a user's oral cavity; and A light guide, the light guide including a light-shielding wall defining the boundary of a hollow light-transmitting path that provides a guiding path for light to pass through the light guide, wherein a portion of the light guide forms a tongue depressor configured to press down the user's tongue to provide light to the oropharynx.

18. The lighting device according to claim 17, wherein, The biological effects include altering the concentration of the one or more pathogens and altering the growth of the one or more pathogens.

19. The lighting device according to claim 17, wherein, The one or more pathogens include at least one of viruses, bacteria, and fungi.

20. The lighting device according to claim 17, wherein, The one or more pathogens mentioned include those from the Coronaviridae family.

21. The lighting device according to claim 20, wherein, The coronavirus family includes SARS-CoV-2.

22. The lighting device according to claim 17, wherein, The biological effects further include at least one of the following: upregulating local immune responses, stimulating enzymatic production of nitric oxide to increase endogenous nitric oxide storage, and releasing nitric oxide from endogenous nitric oxide storage.

23. The lighting device according to claim 17, wherein, The mouthpiece is configured to expand the user's oral cavity.

24. The lighting device according to claim 17, wherein, The nozzle is configured to be detachably attached to the light guide.

25. The lighting device according to claim 17, wherein, The nozzle and the light guide form a single, inseparable structure.

26. The lighting device according to claim 17, wherein, The mouthpiece includes one or more mouthguards for protecting and securing the light guide.

27. The lighting device according to claim 17, wherein, The light includes a peak wavelength in the range of 410 nanometers (nm) to 440 nm, and irradiating the oropharyngeal tissue with the light includes applying a concentration of 0.5 joules per square centimeter (J / cm²). 2 Up to 100 J / cm 2 Light dose within the range.

28. The lighting device according to claim 17, wherein, The one or more pathogens include those of the Coronaviridae family, and irradiating the oropharyngeal tissue with light includes applying a light dose with a phototherapy index in the range of 2 to 250, wherein the phototherapy index is defined as a dose concentration that reduces tissue viability by 25% divided by a dose concentration that reduces the cellular percentage of the one or more pathogens by 50%.

Images