Patent Application
20090192437
Infectious keratitis is probably one of the most feared diseases of the cornea. Depending on the pathogen responsible of the infection, the prognosis for visual rehabilitation may be poor. Topical antibiotics and anti-infectives are prone to resistance development, since microorganisms have mechanisms to transform and avoid the effects of these medications. Systemic administration of anti-infective agents is virtually useless, as therapeutic levels are not reached in the area where the infection develops. Therefore, the cornea constitutes an ideal tissue to harbor living microorganisms, as it is bathed by the tear film with nutrients, and lacks of vessels to allow the protective systems of the body react against pathogenic microorganisms.
Recently, several outbreaks of infectious keratitis have been reported in the U.S. and worldwide (CDC Health Advisory. Early Report of Serious Eye Infections Associated with Soft Contact Lens Solution. (http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00260) and Singapore Ministry of Health. Increasing incidence of contact lens related fungal corneal infections (update 3). Feb. 21, 2006 http://www.moh.gov.sg/corp/about/newsroom/pressreleases/details.do?id=36077601). Paradoxically, some of them have been related to the use of contact lens disinfecting solutions, and have been particularly resilient to traditional treatment.
The invention provides a wearable ocular photoactivator device. The device to be worn by a subject includes a frame and a light source that is directed towards the eye of the subject when the subject is wearing the device. The light source is contained within a housing is connected to the frame. The housing includes the light source contained within the housing, and one or more lenses that can be aligned with emitted light from the light source. The lenses focus the light onto the cornea of the eye, providing a spot of light of a defined, predetermined size at a particular distance from the eye. The spot of light can be directed to a specific portion of the eye, e.g., the cornea, while avoiding other parts of the eye, preventing, or limiting the damage to the eye. The device also includes a power source operably connected to the light source to provide power to the device. In an embodiment, the device includes a structure for attachment of the frame a head of the subject, such as arms or bands or both.
The invention provides an adjustable mount for the light assembly housing. In various embodiments of the invention, the housing can be adjusted in one, two, or three dimensions relative to the eye of the subject to be treated. In certain embodiments, the housing can be rotated within the mount. The device can include a measuring device or distance gauge to facilitate the adjustment of the device on the face of the subject.
The invention provides the use of any light source that can provide the appropriate wavelength and power to practice the methods of the invention. For example, lights for use with the device of the invention include, but are not limited to light emitting diodes (LED), laser diodes, frequency tripled Nd:Yag solid state lasers, dye lasers, quartz lamps, fluorescent lamps, Nernst glowers, Tungsten-Halogen lamps, and discharge lamps. The wavelength of emitted light for use in the invention includes ultraviolet, visible, infrared, and x-ray. In a preferred embodiment, the wavelength of light emitted is UV-A (380 nm -315 nm).
The invention provides a light source housing having one or more lenses. In some embodiments, the housing includes lenses of more than one size. Such lens housings can be rotated to allow for the alignment of the desired lens(es) with the light source(s). In alternative embodiments, the lens housing attached to the proximal end of the housing can be easily exchanged to provide lenses of the desired size. In an embodiment, the angle of the lenses can be adjusted in the lens housing. The housing can also include an opening that can serve one or more purposes. The opening can be used by an ophthalmologist to align the housing with the appropriate portion of the eye of the subject. The ophthalmologist can introduce the photoactive therapeutic agent through the opening in the housing, using an automated dropper device, or manually using, for example, a medicine dropper. The opening can also be used by the subject to allow the subject to watch television or other form of visual entertainment during the treatment. The eye of the subject not being treated can be covered with an occluder that optionally includes an opening for use by the ophthalmologist, the subject, or both.
The invention further provides a wearable ocular photoactivator device having a NIR source and a phototransistor to detect light emitted by the light source. This allows for the device to detect if the lens(es) and light source(s) are in proper alignment, and/or to detect the size lens aligned with the light source.
The invention further provides the use of the devices of the invention for the treatment of ocular disorders or diseases, particularly diseases and disorders of the cornea such as infections, corneal dystrophies, and corneal neoplasia. The methods include exposing the eye of a subject to light using the device of the invention by positioning the device on the face of the subject to direct light onto the eye, preferably onto the cornea of the subject, and providing power to a device of the invention such that light of the desired wavelength and power is provided to the eye, preferably the cornea for the desired amount of time. In a preferred embodiment, the eye of the subject is contacted with at least one photoactive therapeutic agent prior to exposure to light of the desired power and wavelength. Preferably, the photoactive agent is delivered topically to the surface of the eye. In certain embodiments, the invention includes repeated administration of the phototherapeutic agent with multiple rounds of light administration between the repeated administrations of the agent. In an embodiment, the subject is selected for having an ocular disease, particularly a corneal disease. In an embodiment, the subject is monitored for amelioration of at least one sign or symptom of the disease or disorder.
The invention provides for the use of essentially any photoactive therapeutic agent with the desired activity, e.g., cell killing activity, including anti-pathogen activity and anti-neoplastic activity, and/or cross-linking activity to rigidify the cornea. In a preferred embodiment, the activity of the photoactive therapeutic agent is a result of the activity of the agent as a crosslinking agent, or the activity of the agent as a generator of singlet oxygen species. Agents for use in the methods of the invention include, but are not limited to, riboflavin, psoralen, lumiflavin, lumichrome, rose Bengal, eosin, courmarin, sparfloxacin, fluorescein, ficusin, psoberan, Toluidine Blue O, methylene blue, and thionin.
The invention further provides kits for practicing the methods of the invention. Kits of the invention include, for example, a device of the invention and a photoactive therapeutic agent. Kits can further include instructions for use and appropriate packaging.
By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease. Amelioration can require administration of more than one dose.
By “diagnosing” as used herein refers to a clinical or other assessment of the having a disease, disorder, or condition based on the presence of at least one sign or symptom of the disease, disorder, or condition. Typically, diagnosing using the method of the invention includes the observation of the subject for other signs or symptoms of the disease, disorder, or condition in addition to detection of a loss-of-function mutation in a gene that makes the subject susceptible to a particular disease or condition.
“Distal” is meant the end or portion of the device furthest away from the subject, particularly the eye of the subject, when worn. It is understood that distal can be a relative term that one portion of the device is further away, i.e., more distal, from the subject than another portion of the device.
By “effective dose” is meant a sufficient amount of light exposure, with or without administration of a sufficient amount of one or more photoactive therapeutic agent(s), to result in a decrease of the incidence of a disease or disorder, or to result in a decrease of at least one sign or symptom of a disease or disorder. The effective dose of each light and photoactive therapeutic agent in the methods of the invention can readily be determined by one of skill in the art, such as an ophthalmologist. An effective dose is a sufficient dose to ameliorate at least one sign or symptom of a disease or condition to be treated using a device or method of the invention.
As used herein, “fluence” or “integrated flux” is defined as the number of particles that intersect a unit area . Its units are m−2 (number of particles per meter squared). In particular, it is used to describe the strength of a radiation field, in which case the unit used is J/m2. It is considered one of the fundamental units in dosimetry. In laser medicine, the fluence usually refers to the “Power Density” or “Energy Density” of a laser at the emitter tip. The higher the fluence, the more “cutting power” a laser has.
As used herein, “infection” is understood as the state produced by the establishment of an infective or pathogenic organism in or on a suitable host or subject; or a disease resulting from infection.
As used herein, “infectious keratitis” is understood to be any infection of the cornea, i.e., the front part of the eye, including, but not limited to, amoebic keratitis, usually caused by Acanthamoeba; bacterial keratitis, usually caused by Staphylococcus aureus or Pseudomonas aeruginosa; fungal keratitis, for example caused by Fusarium; and viral keratitis which can be caused by a Herpes virus such as Herpes simplex or Herpes zoster.
As used herein, “keratoconus” is understood as a degenerative non-inflammatory disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve. Keratoconus can cause substantial distortion of vision, with multiple images, streaking and sensitivity to light all often reported by the patient. Keratoconus is the most common dystrophy of the cornea. Other corneal dystrophies include, but are not limited to the anterior part of the cornea (map-dot-fingerprint dystrophy, Meesman dystrophy, Reis-Bucklers dystrophy, Thiel-Behnke dystrophy), the intermediate part of the cornea (macular dystrophy, granulardystrophy, lattice dystrophy, Schnyder dystrophy) and the posterior part of the cornea (posterior polymorphous dystrophy, farinata dystrophy, Fuchs dystrophy).
As used herein, “light source” and the like are understood as a device that provides light energy in a visible (400-750 nm) or invisible (e.g., UV-A, UVB, infrared, x-ray) range. In certain embodiments, the power, and wavelength of the light energy provided can be modulated or operate in a continuous mode. In certain embodiments, the wavelength or range of wavelengths of light provided is fixed for a specific light source. In certain embodiments, the power of the light source is fixed. In certain embodiments, the light source is a light emitting diode (LED), laser diode, frequency tripled Nd:Yag solid state lasers, dye lasers, quartz lamps, fluorescent lamps, Nernst glowers (ceramic) and Tungsten-Halogen lamps, discharge lamps (e.g. carbon arcs, high pressure Xenon arc lamps or Krypton arc lamps). Any light source that provides an appropriate wavelength, or range of wavelength, and an appropriate power can be used in the device and methods of the invention.
As used herein, “obtaining” means purchasing, making, or otherwise coming into possession of.
By “ocular” is meant of or relating to the eye.
By “pathogen” is meant an organism (e.g., bacteria, virus, mycoplasm, parasite, yeast, fungus, aeomeba) that is not normally present in or on a subject, particularly a human subject, and the presence of the organism is detrimental or potentially detrimental to the subject.
As used herein, “photoactive therapeutic agent” is understood as a compound that upon exposure to an appropriate wavelength of light is “activated” and gains a new function not present in the molecule, or present at a much lower level in the molecule, prior to light exposure. For example, riboflavins, eosin, courmarin, sparfloxacin, fluorescein, lumichrome, lumiflavin, ficusin, psoberan, or tricyclic furocoumarins such as psoralen, etc. that absorb light in the UV-A range, activating anti-pathogenic activity in the compounds, are referred to herein as UV-A photoactive therapeutic agents. For example, exposure of a photoactive therapeutic agent to an appropriate wavelength of light can result in the release of free radicals that can have anti-pathogenic activity, or promote cross-linking of proteins and/or nucleic acids providing anti-pathogenic activity. Photoactive agents can intercalate bonds in collagen fibers producing cross-links upon activation of the compounds with light, stiffening the cornea. Photoactive agents that can be excited by light in the visible spectrum include rose Bengal (PolySciences), Toluidine Blue O (Sigma-Aldrich, molecular formula: C15H16ClN3S), methylene blue, and fluorescent polyimides such as thionin (Sigma-Aldrich) producing singlet oxygen (active oxygen species). Such photoactive therapeutic agents can also produce free radicals that cause damage to the pathogens. As used herein, a photoactive therapeutic agent is a pharmaceutically acceptable compound that is safe for administration to a mammal, preferably a human, for the route of administration (e.g., topical, ocular administration). Photoactive therapeutic agents for use with the method of the invention are well known and include, for example, the light activated antimicrobial and antiviral agents provided in U.S. Pat. No. 6,239,048 (incorporated herein by reference). The therapeutic agent is in a pharmaceutically acceptable carrier for ocular administration (e.g., normal saline, water, buffered phosphate solution, dextran 500, hypertonic saline, hypotonic saline, hyaluronic acid, polyvinyl acid, glycerine, methylcellulose, etc.). Methods to test and confirm antimicrobial activity in response to activation by light is well within the ability of those of skill in the art.
Examples of wavelengths for excitation of various photoactive therapeutic agents are in the table below:
It is understood that the wavelength of light absorption and emission is dependent, for example, on pH and other conditions. Such considerations are well understood by those of skill in the art.
“Providing,” refers to obtaining, by for example, buying or making the, e.g., device or photoactive therapeutic agent. The material provided may be made by any known or later developed biochemical or other technique.
By “proximal” is meant the end or portion of the device closest to the subject, particularly the eye of the subject, when worn. It is understood that proximal can be a relative term that one portion of the device is closer, i.e., more proximal, to the subject than another portion of the device.
The term “subject” includes organisms which are capable of suffering from a disease of interest that could otherwise benefit from a treatment using the devices and/or methods of the instant invention. The term “non-human animals” of the invention includes all vertebrates, e.g., mammals, e.g., sheep, dog, cow, and primates including non-human primates; e.g., rodents, e.g., mice, , and non-mammals, e.g., chickens, amphibians, reptiles, etc. A human subject can be referred to as a patient.
As used herein, “susceptible to” or “prone to” or “predisposed to” a specific disease or condition and the like refers to an individual who based on genetic, environmental, health, and/or other risk factors is more likely to develop a disease or condition than the general population. An increase in likelihood of developing a disease may be an increase of about 10%, 20%, 50%, 100%, 150%, 200%, or more.
By “selecting” for example “selecting a subject in need of treatment” is meant identifying an individual for treatment using devices and/or methods of the instant invention by the presence of one or more signs or symptoms of a disease or disorder amenable to treatment with the devices or methods of the instant invention. Selecting can also include identification of an appropriate photosensitive therapeutic agent, light exposure time, wavelength of light, light exposure power, etc for use with the devices and methods of the instant invention.
The term “treated,” “treating” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder, condition, or disease being treated. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder. Treatment can also include prophylaxis (i.e., prevention). Treatment can result in amelioration of a disease. Treatment and prophylaxis can require administration of more than one dose.
As used herein, “ultraviolet light” or “UV light” is light energy that is within the range of wavelengths in the ultraviolet range. Wavelengths for various types of UV light are presented in the table below.
It is understood that the wavelength of light is selected based on the wavelength or wavelengths of light absorbed by the photoactive therapeutic agent.
Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.
Unless specifically stated or obvious from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural.
As used herein, “about” is understood to mean approximately or reasonably close to, and within the tolerances generally accepted in the specific experiment or result, for example within two standard deviations of the mean of a specific result. For example, about can be understood as a variation of 10% or less, 7% or less, 5% or less, 2% or less, or 1% or less.
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
Each patent, patent application, or reference cited herein is hereby incorporated by reference as if each were incorporated by reference individually.
The invention provides devices and methods for treatment of diseases and disorders of the eye, particularly the cornea. The device to be worn by a subject includes a frame to which a light source contained in a housing is connected. The light source can be adjusted for delivery of a specific wavelength or range of wavelengths of light to the cornea of the same subject, to either the surface of the cornea, or an internal layer of the eye. The light is delivered to the eye at a specific power over a specific area, typically a round area.
The invention provides a device and therapeutic method using a combination of light and a photoactive molecule for the treatment of infectious keratitis. The invention includes the use of a photoactive therapeutic agent such as riboflavin (Vitamin B-2), combined with the UV-A exposure directly to the cornea. This treatment is similar to an approach to induce corneal stiffening by means of chemically binding collagen bands within the cornea in a process called cross-linking. Using this method, ophthalmologists have been able to stop the progression of keratoconus and other corneal ectasias, inducing more rigidity to the cornea to avoid the corneal deformation on these conditions (Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Opthalmol. 2006; 17:356-60, incorporated herein by reference). On the other hand, using a similar approach, researchers have been able to sterilize biological fluids using the oxidative byproducts of photoactivated riboflavin after UV-A light exposure. Riboflavin degrades to free-radicals, which affect DNA and RNA present in cells and viral particles (Ruane P H, Edrich R, Gampp D, Keil S D, Leonard R L, Goodrich R P. Photochemical inactivation of selected viruses and bacteria in platelet concentrates using riboflavin and light. Transfusion. 2004; 44:877-85, incorporated herein by reference). In one study, this method was effective against a parasite (Leishmania donovani) that infect humans (Cardo L J, Rentas F J, Ketchum L, Salata J, Harman R, Melvin W, Weina P J, Mendez J, Reddy H, Goodrich R. Pathogen inactivation of Leishmania donovani infantum in plasma and platelet concentrates using riboflavin and ultraviolet light. Vox Sang. 2006; 90:85-91, incorporated herein by reference). In this invention riboflavin and UV-A combination is a treatment method for a variety of infections of the cornea. Due to the universal nature of the target in this technology affecting DNA and RNA, the device and method can be used for the treatment of essentially any corneal infection as all infectious agents include nucleic acids. The device and method can also be used for neoplastic diseases of the cornea by focusing the light at the appropriate portion of the cornea, damage to adjacent tissues can be mitigated.
Light can be administered alone for therapeutic purposes. Alternatively, the light can be used in conjunction with a photoactive therapeutic agent which can be activated by light of different wavelengths, for example UV-A in the case of UV-A photoactive therapeutic agents such as riboflavin, or psoralen or other tricyclic furocoumarins. Such agents can be used as broad spectrum anti-pathogen agents as their action is dependent on intercalation in nucleic acid of the organisms, and/or by the generation of free radicals that destroy the pathogens by causing structural damage to macromolecules in the cells. Although the method can result in damage of the corneal epithelium, the high rate of turnover of the cells prevents any significant or long term damage of the eye.
It is understood that the photoactive agents for use in the methods of the invention can be unstable upon exposure to light. The invention includes readministration of the photoactive agent at one or more times during a treatment. The frequency of readministration required can depend on the energy of light administered and the area over which the light is administered. The invention also includes the use of components and methods to protect the photoactive agents from light, e.g., opaque tubing, agent reservoirs, drippers, etc. Such considerations are well understood by those of skill in the art.
UV-A photoactive agents can also be used for the treatment of corneal dystrophies, especially those which may have a component related to deposition of material produced by keratocytes, since the treatment can be adjusted in such a way that a controlled removal of keratocytes from the corneal stroma can be achieved. The depth of the effect can be adjusted by changes in the concentration of the photochemical and/or the fluence of the light. The effective dose of the photoactive agent and/or the light will need to be greater (e.g., higher concentration of photoactive agent, longer or higher power light exposure) for the treatment of corneal dystrophies as compared to infections. The dose of agent and light is limited by the posterior layer of the cornea (endothelium), which needs to be protected from the toxic radicals. Damage to endothelium results in serious damage to the cornea. It is possible that higher concentrations of agent may actually be protective of the eye by absorbing more of the light, particularly UV light, when used with the device and methods of the invention. Such considerations and variations in the use of the device would be well understood by those of skill in the art.
Moreover, due to the universal nature of the target in this technology affecting DNA and RNA, this treatment may also be used for neoplastic diseases by focalized exposure of the treatment to the tumor area. There is no selectivity, the treatment may also destroy healthy cells, but in this case the focal exposure will warrant the destruction of the targeted cells. In treatment of neoplasia, the damage of tissue adjacent to treatment areas can be an acceptable mode of treatment (e.g., radiation therapy).
The cornea is a is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, and as a result helps the eye to focus, accounting for approximately 80% of the eye's optical power. The clarity and rigidity of the cornea are essential for its function.
The human cornea, like that of other primates, has five layers. The structural rigidity, shape, and clarity of the cornea are required for site and visual acuity.
The outer layer of the cornea is the corneal epithelium. It is a thin epithelial multicellular tissue layer (stratified squamous epithelium) of fast-growing and easily-regenerated cells, kept moist with tears. Irregularity or edema of the corneal epithelium disrupts the smoothness of the air-tear film interface, the most significant component of the total refractive power of the eye, thereby reducing visual acuity. It is continuous with the conjunctival epithelium is composed of about 6 layers of cells which are shed constantly on the exposed layer and are regenerated in the basal layer.
Adjacent to the corneal epithelium is Bowman's layer, a tough layer that protects the corneal stroma, consisting of irregularly-arranged collagen fibers, essentially a type of stroma. It is eight to 14 microns thick.
Corneal stroma (or substantia propria) is a thick, transparent middle layer, consisting of regularly-arranged collagen fibers along with sparsely populated keratocytes. The corneal stroma consists of approximately 200 layers of type I collagen fibrils. Ninety percent of the corneal thickness is composed of stroma.
Descemet's membrane is a thin acellular layer that serves as the modified basement membrane of the corneal endothelium.
Corneal endothelium is a simple squamous or low cuboidal monolayer of mitochondria-rich cells responsible for regulating fluid and solute transport between the aqueous and corneal stromal compartments.
The wearable photoactivator device of the invention allows for the delivery of light to the cornea particularly for prevention or treatment of a disease or condition of the eye, particularly the cornea. The device allows for the positioning of a light source over the eye of a subject. The device can be secured to the subject's face and adjusted to provide light at the appropriate spot or spots on the cornea. The light is focused to a desired spot on the cornea. The therapeutic agent preferentially absorbs this light, preventing any light from penetrating to or being transmitted to other areas of the eye. In addition, in the methods of the invention, the therapeutic agent will release reactive oxygen species including singlet oxygen which is one acknowledged mechanism for destroying microbes and simultaneously forming new molecular bi-products which tend to mask the light from penetrating to internal structures of the eye, thereby protecting the eye. However, the invention can include the use of masks or other barriers to protect portions of the eye depending on the portion of the cornea that needs to be treated and its proximity to other parts of the eye (e.g., iris).
It is understood that the device can be made in various sizes for use on subjects of different sizes, e.g., human adults and children, or animals. The specific working distance of the housing to the eye is a matter of choice by the user within a range, for example, within about 1-5 cm, about 1.5-4 cm, about 2-3 cm from the eye. The specific working distance can be adjusted for the comfort of the subject. It is understood that the device of the invention can be used for applications other than those specifically provided herein wherein the application includes the exposure of the eye to specific wavelength or range of wavelengths of light, particularly exposure of the cornea to a specific wavelength or range of wavelengths of light for a period of time, particularly a period of time longer than is convenient to have a subject remain sufficiently still, e.g. more than about 10 seconds, more than about 20 seconds, more than about 30 seconds, more than about 1 minute, more than about 2 minutes.
The device is easy to use by a user, such ophthalmologists, is relatively simple and compact, and may have reduced cost as compared to other light delivery devices. The apparatus may also facilitate a reduced patient recovery time. The device may also be more comfortable and convenient for both the patient and the ophthalmologist by allowing the patient to move his/her head during the period of light exposure of the cornea, which may be extensive (from about 1 minute, 2 minutes, 5 minutes to about at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, or 90 minutes, or more).
The light may be delivered continuously or intermittently (i.e., in pulses). Pulsing the light device may have advantage over continuous operation because pulsed peak power is higher as compared to cw (average) power and may be useful to break-down the microbe cellular wall. As UV light light interacts with tissue/chromophores to stimulate electron transfer, forming complexes and molecular fragments without generating any heat as contrasted to near and mid IR, pulsing is not required to prevent overheating in the UV range. It is understood that variation in the power of the light source to provide the desired dose to the eye is within the ability of those of skill in the art. For example, dosing can be determined by observing the eye and changes in at least one sign or symptom of the disease or disorder indicating amelioration of the disease or condition. The device can be worn by the subject when standing or sitting. However, it is preferred that the patient is prone during administration of the photoactive agent to the eye. Such considerations are well understood by those of skill in the art.
Representative embodiments of the invention are shown in the figures. Additional features are described in the following description in which embodiments are set forth in detail in conjunction with the accompanying drawings. Numbers on the figures indicate parts in the drawings to which the specification refers.
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The light source drive currents are typically selected to produce the desired power density for each selected spot size. Known in the art, each light source may have a rear facet photodetector or other light sensing device. The photodetector output signal can provide feedback to maintain a constant power output. The light source can have a constant current drive source to maintain a constant and stable power output.
The invention further provides kits for practicing the methods of the invention. Kits of the invention include, for example, a device of the invention and a photoactive therapeutic agent. Kits can further include instructions for use and appropriate packaging. Kits of the invention can include replacement bulbs, interchangeable lens housings, various size supports to allow the device to be adjustable, and other components for practicing the methods of the invention.
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the assay, screening, and therapeutic methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention.
This invention is further illustrated by the following examples, which should not be construed as limiting.
A patient presents with acanthamoebic keratitis in one eye. A lid speculum is used to hold the patient's eye open. The recumbent patient is fitted with a wearable photoactivator of the invention having a UV-A light source. The housing of the light source is adjusted to provide light over 3 to 10 mm spot size on the eye, depending on the area to be exposed, based on the extent of the infection. The fluence of the light is such that it warrants its absorption in the layers of the cornea before penetrating into other ocular structures, thereby reducing the exposure of other structures to the light. A dropper is inserted through an opening in the housing to apply riboflavin to the eye in the form of drops and the riboflavin solution concentration is in the range of about 0.1% to 5% to completely bathe the eye in riboflavin.
The riboflavin is instilled in the eye every 5 minutes for 15 minutes in the form of eyedrops or soaked in a filter paper disc placed on the surface of the cornea in order to impregnate the stroma with the photochemical substance. The light source is then turned on for a period of 30 minutes, with continuous instillation of riboflavin eyedrops every 5 minutes. The fluence used is in the range of 3 to 20 mW/cm2. The spot of UV-A light is adjusted according to the size of the ulcer, and centered in the area of infection to cover the entirety of the corneal infiltrate caused by the keratitis. The limbal area can be protected by a mask to avoid exposure of this area and prevent further damage in the limbal stem cell pool.
A patient presents with keratoconus in one eye. A lid speculum is used to hold the patient's eye open. The recumbent patient is fitted with a wearable photoactivator of the invention having a UV-A light source. The optical system for the light source is adjusted to provide light of 8-9 mm spot size on the eye. The fluence of the light is such that it warrants its absorption in the layers of the cornea before penetrating into other ocular structures. A dropper is inserted through an opening in the housing to apply riboflavin to the eye in the form of drops and the riboflavin solution concentration is in the range of 0.1% to 5% to completely bathe the eye in riboflavin.
The riboflavin is instilled in the eye every 5 minutes for 15 minutes in the form of eyedrops or soaked in a filter paper disc placed on the surface of the cornea to impregnate the sroma with the photochemical substance. The light source is then turned on for a period of 30 minutes, with continuous instillation of riboflavin eyedrops every 5 minutes. The fluence used is in the range of 3 to 20 mW/cm2, and the riboflavin solution concentration is in the range of 0.1% to 5%. The spot of UV-A light will be adjusted according to the size of the ulcer, and centered in the cornea to cover the majority of the corneal area. The limbal area may be protected by a mask to avoid exposure of this area and prevent further damage in the limbal stem cell pool.
This application claims priority to U.S. Provisional Patent Application Ser. No. 60/994,979 filed on Sep. 24, 2007, which is incorporated by reference herein in its entirety.
This work was supported in part by the National Eye Institute grant numbers 1R43 EY 015055. The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 60994979 | Sep 2007 | US |
