CN110582238A

CN110582238A - System and method for treating myopia

Info

Publication number: CN110582238A
Application number: CN201780090319.XA
Authority: CN
Inventors: J·K·卢特鲁勒; D·B·昌; B·W·L·马戈利斯
Original assignee: Ojai Retinal Technology LLC
Current assignee: Ojai Retinal Technology LLC
Priority date: 2017-05-01
Filing date: 2017-12-05
Publication date: 2019-12-17
Also published as: EP3618923A1; SG11201909214YA; JP2022184907A; JP2020518317A; BR112019023061A2; AU2017412681B2; AU2017412681A1; CA3058891A1; EP3618923A4; WO2018203930A1

Abstract

A method of preventing or treating myopia includes applying pulsed energy, such as a pulsed laser beam, to tissue of an eye that has or is at risk of developing myopia. The pulsed energy source has energy parameters including wavelength or frequency, duty cycle, and pulse train duration selected to elevate ocular tissue temperature to eleven degrees celsius to achieve a therapeutic or prophylactic effect, such as stimulating heat shock protein activation in the ocular tissue. The average temperature rise of the ocular tissue is maintained at or below a predetermined level over a period of several minutes so as not to permanently damage the ocular tissue.

Description

System and method for treating myopia

RELATED APPLICATIONS

This application is a partial continuation of U.S. application serial No. 15/583,096 filed on day 5/1 in 2017, U.S. application serial No. 15/583,096 is a partial continuation of U.S. application serial No. 15/214,726 filed on day 7/20 in 2016, U.S. application serial No. 15/214,726 is a partial continuation of U.S. application serial No. 14/922,885 (now patent No. 9,427,602) filed on day 26 in 10/2015 (which claims priority to U.S. provisional application No. 62/153,616 filed on day 28 in 4/2015), U.S. application serial No. 14/922,885 is a partial continuation of U.S. application serial No. 14/607,959 (now patent No. 9,168,174) filed on day 28 in 1/2015, U.S. application serial No. 14/607,959 is a partial continuation of U.S. application serial No. 13/798,523 filed on day 13 in 3/2013, U.S. application serial No. 13/798,523 is U.S. application serial No. 13/481,124 filed on day 25 in 2012 (13/481,124) ((U Current patent No. 9,381,115), this application is also a partial continuation of U.S. application serial No. 15/232,320 filed on 8/9/2016, U.S. application serial No. 15/232,320 is a partial continuation of U.S. application serial No. 15/188,608 filed on 21/6/2016, U.S. application serial No. 15/188,608 is a partial continuation of U.S. application serial No. 15/148,842 filed on 6/5/2016, U.S. application serial No. 15/148,842 is a partial continuation of U.S. application serial No. 14/921,890 (now patent No. 9,381,116) filed on 23/10/2015, and U.S. application serial No. 14/921,890 is a partial continuation of U.S. application serial No. 14/607,959 (now patent No. 9,168,174) filed on 28/1/2015. This application is also a partial continuation of U.S. application serial No. 15/460,821 filed on 3/16/2017, U.S. application serial No. 15/460,821 is a partial continuation of U.S. application serial No. 15/214,726 filed on 20/2016, U.S. application serial No. 15/214,726 is a partial continuation of U.S. application serial No. 14/922,885 (now U.S. patent No. 9,427,602) filed on 26/10/2015 (which claims the benefit of U.S. application serial No. 62/153,616 filed on 28/4/2015), U.S. application serial No. 14/922,885 is a partial continuation of U.S. application serial No. 14/607,959 (now U.S. patent No. 9,618,174) filed on 28/1/2015, U.S. application serial No. 13/798,523 filed on 13/3/2013, U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 (filed on 25/5/2012) (U.S. application serial No. 14/607,959 is filed Current us patent No. 9,381,115), this application is also a partial continuation of us application No. 15/148,842 filed on 6/5/2016, this us application No. 15/148,842 is a partial continuation of us application No. 14/921,890 (current us patent No. 9,381,116) filed on 23/10/2015, this us application No. 14/921,890 is a partial continuation of us application No. 14/607,959 (current us patent No. 9,168,174) filed on 28/1/2015, this us application No. 14/607,959 is a partial continuation of us application No. 13/798,523 filed on 13/3/2013, this us application No. 13/798,523 is a partial continuation of us application No. 13/481,124 (current us continuation patent No. 9,381,115) filed on 25/5/2012, and this application is also a partial continuation of us application No. 15/075,432 filed on 21/3/2016, the U.S. application serial No. 15/075,432 is a continuation of U.S. application serial No. 13/798,523 filed on 3/13/2013, and the U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 (now U.S. patent No. 9,831,115) filed on 25/5/2012. This application is also a partial continuation of U.S. application serial No. 15/332,132 filed on 24/10/2016, U.S. application serial No. 15/332,132 is a division of U.S. application serial No. 15/232,320 filed on 9/8/2016, U.S. application serial No. 15/232,320 is a partial continuation of U.S. application serial No. 15/148,842 filed on 6/5/2016, U.S. application serial No. 15/148,842 is a partial continuation of U.S. application serial No. 14/921,890 (now U.S. patent No. 9,381,116) filed on 23/10/2015, U.S. application serial No. 14/921,890 is a partial continuation of U.S. application serial No. 14/607,959 (now U.S. patent No. 9,168,174) filed on 28/1/2015, U.S. application serial No. 14/607,959 is a partial continuation of U.S. application serial No. 13/798,523 filed on 13/3/2013, this U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 (now U.S. patent No. 9,381,115) filed on 25/5/2012, and this application is also a partial continuation of U.S. application serial No. 15/188,608 filed on 21/6/2016, 15/188,608 being a partial continuation of U.S. application serial No. 13/481,124 (now U.S. patent No. 9,381,115) filed on 25/5/2012, and this application is also a partial continuation of U.S. application serial No. 13/798,523 filed on 3/13/2013, 13/798,523 being a partial continuation of U.S. application serial No. 13/481,124 (now U.S. patent No. 9,381,115) filed on 25/5/2012. This application is also a partial continuation of U.S. application serial No. 15/291,796 filed on 12/10/2016, U.S. application serial No. 15/291,796 being a division of U.S. application serial No. 15/148,842 filed on 6/5/2016, U.S. application serial No. 15/148,842 being a partial continuation of U.S. application serial No. 14/921,890 filed on 23/10/2015, and U.S. application serial No. 14/921,890 being a partial continuation of U.S. application serial No. 14/607,959 (now U.S. patent No. 9,168,174) filed on 28/1/2015. The U.S. application serial No. 14/607,959 is a partial continuation of U.S. application serial No. 13/798,523 filed on 3/13/2013, the U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 filed on 5/25/2012, and the present application is also a partial continuation of U.S. application serial No. 15/075,432 filed on 21/2016, the U.S. application serial No. 15/075,432 is a continuation of U.S. application serial No. 13/798,523 filed on 3/13/2013, and the U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 filed on 25/5/2012. This application is also a partial continuation of U.S. application serial No. 15/232,320 filed on 8/9/2016, U.S. application serial No. 15/232,320 is a partial continuation of U.S. application serial No. 15/148,842 filed on 6/5/2016, U.S. application serial No. 15/148,842 is a partial continuation of U.S. application serial No. 14/921,890 (now U.S. patent No. 9,381,116) filed on 23/10/2015, U.S. application serial No. 14/921,890 is a partial continuation of U.S. application serial No. 14/607,959 (now U.S. patent No. 9,168,174) filed on 28/1/2015, U.S. application serial No. 14/607,959 is a partial continuation of U.S. application serial No. 13/798,523 filed on 13/3/2013, U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 (now U.S. patent No. 9,381,115) filed on 25/2012, and this application is also a partial continuation of U.S. application serial No. 15/188,608 filed on 21/6/2016, 15/188,608 being a continuation of U.S. application serial No. 13/481,124 (now U.S. patent No. 9,381,115) filed on 25/5/2012, and this application is a partial continuation of U.S. application serial No. 13/798,523 filed on 13/3/2013, 13/798,523 being a partial continuation of U.S. application serial No. 13/481,124 (now U.S. patent No. 9,381,115) filed on 25/5/2012. This application is also a partial continuation of U.S. application serial No. 15/214,726 filed on 20/7/2016, 15/214,726 being a partial continuation of U.S. application serial No. 14/922,885 filed on 26/10/2015 (which claims the benefit of U.S. application serial No. 62/153,616 filed on 28/4/2015), 14/922,885 being a partial continuation of U.S. application serial No. 14/607,959 filed on 28/2015 (now patent No. 9,168,174), 14/607,959 being a partial continuation of U.S. application serial No. 13/798,523 filed on 13/3/2013, 13/798,523 being a partial continuation of U.S. application serial No. 13/481,124 filed on 25/2012 (now U.S. patent No. 9,381,115). This application is also a partial continuation of U.S. application serial No. 15/188,608 filed on 21/6/2016, and U.S. application serial No. 15/188,608 is a continuation of U.S. application serial No. 13/481,124 filed on 25/5/2012. This application is also a partial continuation of U.S. application serial No. 15/148,842 filed on day 5/6 2016, U.S. application serial No. 15/148,842 is a partial continuation of U.S. application serial No. 14/921,890 filed on day 10/23 in 2015, U.S. application serial No. 14/921,890 is a partial continuation of U.S. application serial No. 14/607,959 (now US9,168,174) filed on day 1/28 in 2015, U.S. application serial No. 14/607,959 is a partial continuation of U.S. application serial No. 13/798,523 filed on day 3/13 in 2013, U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 filed on day 5/25 in 2012, and this application is also a partial continuation of U.S. application serial No. 15/075,432 filed on day 21 in 2016, U.S. application serial No. 15/075,432 is a continuation of U.S. application serial No. 13/798,523 filed on day 3/13 in 2013, this U.S. application serial No. 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 filed on 25/5/2012. This application is also a partial continuation of U.S. application serial No. 15/075,432 filed on 21/3/2016, 15/075,432 is a continuation of U.S. application serial No. 13/798,523 filed on 13/3/2013, 13/798,523 is a partial continuation of U.S. application serial No. 13/481,124 filed on 25/5/2012.

Technical Field

the present invention relates generally to systems and methods for treating ocular diseases. In particular, the present invention relates to systems and methods for preventing or treating myopia by applying pulse energy to tissue of an eye that is suffering from or at risk of developing myopia to raise the temperature of the eye tissue sufficiently to provide a therapeutic benefit without permanently damaging the eye tissue.

Background

myopia is a condition known as "myopic eye" in which the image in front of the eye is focused in front of the retina, rather than being precisely located on the retina. This focusing of the image on the retina is also referred to as "emmetropia". Images in myopia may be focused in front of the retina for one or both of the following reasons: refractive power in the anterior portion of the eye at the cornea and lens is excessive; and/or the axial length of the eye is too long so that the retina is behind the image focus, causing blurred vision. To counteract this blurred vision, the affected persons are close to the object to be observed. This moves the focus of the image back and near the retina, thus making vision more clear.

According to common medical definitions, myopia is prevalent, affecting as many as 50% of adults, with an increased incidence of 200% or more in children of the near-age school. This rapid increase and popularity is attributed to improved educational opportunities, increased reading times, and increased use of electronic devices and media.

the causes of typical myopia appear to be genetic as well as environmental. Higher education and the time it takes to do near work and read are known to be risk factors for myopia. Stimulation of near work causing myopia has been shown to affect (possibly in part through accommodation by the lens) the nerves and/or chemical mediators of eye growth, thereby increasing the axial length of the eye. Evidence for this phenomenon is that topical atropine for children can reduce the extent and incidence of acquired myopia by allowing accommodation paralysis.

The "emmetropia" factors that promote normal eye growth and formation and eye axis length and are eliminated, blocked or inhibited by near work result in increased eye length, most likely in the central retina or "macula" where visual images are usually focused. The near vision condition is increased by interfering with the autoregulation of eye growth through hard-wired nerves and/or diffusion chemical feedback mechanisms, by actively encouraging or depriving emmetropic stimuli to passively allow the axial length of the eye to increase to accommodate the eye to the near vision focus.

Retinal dysfunction and alterations in retinal autoregulation in response to environmental factors are common phenomena and findings in most chronic progressive retinopathies, including age-related macular degeneration and diabetic retinopathy, optic nerve diseases such as chronic open angle glaucoma, and hereditary retinopathies, including retinitis pigmentosa and Stargardt's Disease. In glaucoma, an environment similar to the development of myopia, selective complementary preservation of visual field defects shows direct and neurological and/or chemical communication between the contralateral eye mediated by the central nervous system to minimize total visual disability. In response to ocular hypertension in glaucoma, optic nerve tissue is sacrificed to increase the likelihood of preserved visual field in one eye, thereby covering the lost visual field in the other eye to maximize overall visual function when both eyes are used together. Thus, there is a clear anatomical response mediated by retinal signals that alters the retina and neural structures to accommodate the quality of visual stimuli and maximize visual function.

Pediatric myopia appears to develop and progress in the same manner and by similar mechanisms as other chronic progressive eye diseases. Thus, abnormal stimuli (long-term near work and lens accommodation) causing a change in retinal function and autoregulation in response to abnormal circumstances become abnormal and cause elongated growth of the eye, thereby restoring sharp near vision with less accommodation, and thus, a near vision condition develops.

Although typical axial or refractive myopia can be corrected by spectacles, contact lenses or refractive surgery, myopia is also often associated with reduced visual function and increases the risk of vision loss due to retinal detachment, choroidal neovascularization, macular atrophy and glaucoma. In summary, the need for refractive correction of myopia, as well as medical consequences, constitute a serious public health problem and socio-economic burden.

accordingly, there is a continuing need for systems and methods that can prevent and/or treat myopic eye conditions. Such systems or methods should be capable of altering biological factors that may cause acquired myopia to slow or prevent acquired myopia. Such treatment systems and methods should be relatively easy to perform and harmless. The present invention fulfills these needs and provides other related advantages.

Disclosure of Invention

The present invention relates to a method for preventing or treating myopia. A pulsed energy source is provided having energy parameters including wavelength or frequency, duty cycle, and pulse duration. The energy parameter is selected to raise the temperature of the ocular tissue to 11 ℃ to obtain a therapeutic or prophylactic effect. The average temperature rise of the ocular tissue is maintained at or below a predetermined level over a period of several minutes so as not to permanently damage the ocular tissue. It may be determined that the eye has or is at risk of developing myopia. The pulse energy is applied to tissue of the eye that is or is at risk of myopia to stimulate heat shock protein activation in the eye tissue.

The pulsed energy may comprise a pulsed light beam having a wavelength between 530 nanometers and 1300 nanometers, particularly between 80 nanometers and 1000 nanometers. The light beam may have a duty cycle of less than 10%, preferably between 2.0% and 5%. The pulsed light beam may have a power between 0.5 and 74 watts. The pulsed light beam may have a pulse train duration between 0.1 and 0.6 seconds.

Typically, the ocular tissue to which the pulse energy is applied includes the retina and/or foveal tissue. The pulsed energy source energy parameter is selected to elevate the ocular tissue temperature between 6 ℃ and 11 ℃ during at least the application of the pulsed energy source. However, the average temperature rise of the ocular tissue is maintained at about 1 ℃ or less over a period of several minutes, for example over a six minute period.

The pulse energy may be applied to a plurality of ocular tissue regions, wherein adjacent ocular tissue regions are separated by at least a predetermined distance to avoid thermal tissue damage. The pulse energy may be applied to a first ocular tissue region and reapplied to the first ocular tissue region after a predetermined length of time within a single treatment session. The pulse energy is applied to the second ocular tissue region during an interval between the application of the pulse energy to the first ocular tissue region.

Other features and advantages of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, illustrating by way of example the principles of the invention.

Drawings

the drawings are intended to illustrate the invention. In these drawings:

FIG. 1 is a graph showing the average power of a laser source having one wavelength compared to the source radius and pulse train duration of the laser;

FIG. 2 is a graph similar to FIG. 1 showing the average power of a laser source having a higher wavelength compared to the source radius and pulse train duration of the laser;

FIG. 3 is a schematic view showing a system for treating an eye in accordance with the present invention;

FIG. 4 is a schematic view of an exemplary optical lens or mask used to generate a geometric pattern in accordance with the present invention;

FIG. 5 is a schematic view showing an alternative embodiment of a system for treating ocular tissue in accordance with the present invention;

FIG. 6 is a schematic view showing another alternative embodiment of a system for treating ocular tissue in accordance with the present invention;

FIG. 7 is a front view of a camera of the present invention including an iris diaphragm;

FIG. 8 is a front view of a camera including an LCD aperture according to the present invention;

FIG. 9 is a top view of an optical scanning mechanism used in accordance with the present invention;

FIG. 10 is a partially exploded view of the optical scanning mechanism of FIG. 9, showing various components thereof;

FIG. 11 is a schematic view showing controlled offset of irradiation of an exemplary geometric pattern grid laser spot used to treat ocular tissue in accordance with the present invention;

FIG. 12 is a schematic view showing controllable scanning of a geometric object element in the form of a line for treating a region of ocular tissue in accordance with the present invention;

FIG. 13 is a schematic view similar to FIG. 12 but showing the geometric line or strip being rotated to treat an area of the retina in accordance with the present invention;

FIGS. 14A-14D are schematic views showing the application of laser light to different treatment areas during predetermined time intervals and the reapplication of the laser light to the previous treatment areas during a single treatment session in accordance with the present invention; and

Fig. 15-17 are graphs showing treatment power versus time according to embodiments of the present invention.

Detailed Description

As shown in the drawings, and as more fully described herein, the present invention relates to a method for preventing or treating myopia. This is achieved by providing a pulsed energy source with energy parameters selected to increase the temperature of the ocular tissue sufficiently to achieve a therapeutic or prophylactic effect while maintaining the average temperature rise of the ocular tissue at or below a predetermined level over time so as not to permanently damage the ocular tissue.

as mentioned above, the prevalence of myopia worldwide has increased dramatically over the last few decades. Recent studies have shown that refractive development or myopia is affected by environmental, behavioral and genetic factors. The inventors believe that there are changeable biological factors behind the back of simple acquired myopia. The inventors have demonstrated that low intensity and high density sub-threshold diode micro-pulse lasers (SDMs) improve the physical and psychophysical functions of the eye and optic nerve in a variety of chronic progressive retinal diseases and open angle glaucoma. Studies have shown that SDM achieves this goal by normalizing retinal function and autoregulation by a mechanism called by the inventors as a "reset to default" effect or homotrophy (homeotropy). By selectively targeting and normalizing the function of the Retinal Pigment Epithelium (RPE), which is the primary driving force for retinal function and autoregulation, the biological function of the RPE (if abnormal due to environmental or other reasons) is reset to default, or returned to normal function. By doing so, the progression of the disease is slowed, stopped, or even reversed. The inventors believe that by restoring normal retinal physiology and autoregulation, SDM cotrophic treatment should slow, stop or even reverse the progression of myopia, particularly pediatric myopia, in the same manner it performs for other chronic progressive retinopathies and glaucoma. Clinical experience and use in other eye diseases including diabetic retinopathy, age-related macular degeneration, glaucoma, and hereditary retinopathy indicate that effective SDM homeopathic treatment should be both robust and sustainable through periodically repeated treatments.

The inventors have found that electromagnetic radiation, for example in the form of laser light of various wavelengths, can be applied to retinal tissue in a manner that does not damage or damage the retinal tissue while obtaining beneficial effects on ocular disease. It is believed that this may be due, at least in part, to stimulation and activation of heat shock proteins and promotion of protein repair in tissues. It is believed that the creation of a thermal time course stimulates heat shock protein activation or production and promotes repair without causing any damage.

The inventors have discovered that a laser beam can be generated that is therapeutic, is sub-lethal to retinal tissue cells, thereby avoiding damaging photocoagulation in the retinal tissue, and thereby providing a prophylactic and protective treatment of the retinal tissue of the eye. The various parameters of the beam must be considered and selected so that the combination of selected parameters achieves a therapeutic effect without permanently damaging the tissue. These parameters include the laser wavelength, the radius of the laser source, the average laser power, the total pulse duration, and the duty cycle of the pulse train. While a laser beam is used in certain preferred embodiments, other pulsed energy sources including ultrasound, ultraviolet frequencies, microwave frequencies, and the like, with appropriately selected energy parameters may be used, but are not as convenient as other diseases in treating eye diseases, including myopia.

The choice of these parameters can be determined by requiring an Arrhenius score for HSP activation of greater than 1 or one. Arrhenius integration was used to analyze the effect on biological tissue. See, e.g., The CRC Handbook of thermal Engineering, ed.Frank Kreith, Springer Science and Business Media (2000). At the same time, the selected parameters must not permanently damage the tissue. Therefore, Arrhenius integrals for lesions can also be used, wherein the solved Arrhenius integral is smaller than 1 or one.

Alternatively, FDA/FCC limits in terms of energy deposition and temperature rise per unit gram of tissue measured over a period of several minutes are met to avoid permanent tissue damage. FDA/FCC requirements for energy deposition and temperature rise are widely used and can be referenced, for example, in www.fda.gov/media/devices/requirements for regulation and regulation/regulation documents/ucm073817.htm # attacha for electromagnetic sources, and danasosto and p.larivero, ed., emissive Imaging technologies.crc Press (2012), for ultra sources.

In general, a tissue temperature rise between 6 ℃ and 11 ℃ may result in a therapeutic effect, e.g., by activation of heat shock proteins, while keeping the average tissue temperature below a predetermined temperature (e.g., 6 ℃ and even 1 ℃ or less in certain cases) for a long period of time, e.g., for a period of several minutes, e.g., 6 minutes, will not permanently damage the tissue.

The sub-threshold retinal photocoagulation (sometimes referred to as "true sub-threshold") of the present invention is defined as the application of retinal laser light that is invisible to the biomicroscope at the time of treatment. As a result of the present invention, a "true subthreshold" photocoagulation is invisible and includes laser treatments that are not recognizable by any other known method, such as FFA, FAF, or even SD-OCT. Thus, "true subthreshold" photocoagulation is defined as laser treatment that absolutely does not produce any retinal damage detectable by any means at the time of treatment or by any known means of detection at any later time. Thus, the "true subthreshold" is free of damage and other tissue damage and destruction. Since there is no typical photocoagulation damage, the present invention may be more accurately referred to as photostimulation rather than photocoagulation.

Various parameters are determined to obtain "true subthreshold" or "low intensity" effective photocoagulation. These include providing sufficient power to produce effective therapeutic retinal laser irradiation, but not so high as to cause tissue damage or destruction. True subthreshold laser applications can be applied alone or to create geometric objects or patterns of arbitrary size and configuration to minimize heat build up, but ensure uniform heat distribution and maximize heat dissipation, for example, by using low duty cycles. The inventors have found how to achieve a therapeutically effective and harmless true subthreshold retinal laser treatment. The inventors have also found that arranging the true subthreshold laser application fusibly and proximally to the retinal surface improves and maximizes the therapeutic benefit of the treatment without harm or retinal damage.

it has been found that a low duty cycle 810 nanometer laser beam intensity or power of between 100 watts per square centimeter and 590 watts is effective and safe. For a 810 nm micropulsed diode laser, a particularly preferred intensity or power of the laser beam is about 250 to 350 watts per square centimeter.

The power limitations of current micro-pulsed diode lasers require longer illumination durations. The longer the laser irradiation, the more important the ability of the heat sink to the central spot towards the unirradiated tissue at the edge of the laser spot and towards the underlying choriocapillaris. Accordingly, the radiation beam of a 810 nm diode laser should have an illumination envelope duration of 500 milliseconds or less, preferably about 100 to 300 milliseconds. Of course, if the micro-pulse diode laser is changed to more power, the irradiation duration will be correspondingly reduced. It will be appreciated that the duration of the illumination envelope is the duration of exposure of the micro-pulse laser beam to the same point or location of the retina, although the actual time of tissue exposure to the laser is much less because the duration of the laser pulse is less than 1 millisecond, typically between 50 microseconds and 100 microseconds.

Invisible phototherapy or true subthreshold photocoagulation in accordance with the present invention may be performed at various laser wavelengths, for example, ranging from 532 nanometers to 1300 nanometers. The use of different wavelengths may affect the preferred intensity or power of the laser beam and the duration of the illumination envelope so as not to damage the retinal tissue, but still achieve a therapeutic effect.

another parameter of the invention is the duty cycle (the frequency of the micro-pulse train, or the length of the thermal relaxation time between successive pulses). It has been found that the use of 10% duty cycle or higher duty cycle of a micro-pulsed laser adjusted to deliver similar irradiance at similar MPE levels significantly increases the risk of lethal cell damage, especially at darker ocular fundus. However, duty cycles of less than 10% and preferably about 5% or less have been demonstrated to have sufficient heat rise and treatment at the RPE cell level to stimulate a biological response, but remain below levels expected to produce lethal cell damage even at dark fundus. Also, if the duty cycle is less than 5%, in some cases, the illumination envelope duration may exceed 500 milliseconds.

In a particularly preferred embodiment, a small retinal laser spot is used. This is because a larger spot may result in uneven heat distribution and insufficient heat dissipation within the large retinal laser spot, potentially leading to tissue damage or even tissue destruction toward the center of the larger laser spot. In this usage, "small" is generally applicable to retinal spots that are less than 3 millimeters in diameter. However, the smaller the retinal spot, the more desirable the heat dissipation and uniform energy application becomes. Therefore, at the above power intensities and illumination durations, small spots, e.g., 25 to 300 microns in diameter, or small geometric lines or other objects, are preferred to maximize uniform heat distribution and dissipation, thereby avoiding tissue damage.

Thus, the following key parameters have been found to create a harmless "true subthreshold" sublethal micropulse laser beam to achieve the objectives of the present invention, including wavelength or frequency, duty cycle, and pulse duration. The laser beam should have a wavelength greater than 532 nm to avoid cytotoxic photochemical benefits, such as a wavelength between 550 nm and 1300 nm, and in a particularly preferred embodiment, between 810 nm and 1000 nm. The duty cycle should be less than 10%, preferably between 2.5% and 5%. The pulse train duration or illumination time should be between 100 and 600 milliseconds. The intensity or power of the laser beam should be between 100 and 590 watts per square centimeter at the retina, or about 1 watt per laser spot for each treatment spot at the retina. This power is sufficient to produce retinal laser shots between 18 and 55 times the maximum allowable shot (MPE), and at 100 to 590W/cm²Retinal irradiance in between. Preferably, a small spot size is used to minimize heat build-up and ensure uniform heat distribution within a given laser spot, thereby maximizing heat dissipation.

By using the above parameters, a harmless but therapeutically effective "true subthreshold" or invisible phototherapy treatment may be obtained, in which retinal light stimulation of all areas of the RPE may be exposed to laser radiation and maintained and may be used to facilitate treatment. The present invention has been found to produce the benefits of conventional photocoagulation and phototherapy, but avoids the disadvantages and complications of conventional phototherapy. In accordance with the present invention, a physician can apply a laser beam to treat the entire retina, including sensitive areas such as the macula and even the fovea, without causing vision loss or other damage. This is not possible with traditional phototherapy because it may cause damage to the eyes or even cause blindness.

the traditional thinking has been that tissue damage and lesions must be created to achieve a therapeutic effect. However, the inventors have found that this is not the case. In the absence of laser-induced retinal damage, there is no loss of functional retinal tissue and no inflammatory response to treatment. Thus, the adverse therapeutic effects are completely eliminated and the functional retina is retained rather than sacrificed. This can produce superior visual acuity results compared to traditional photocoagulation therapy.

The present invention preserves the neurosensory retina and is selectively absorbed by the RPE. The current theories regarding the pathogenesis of retinal vascular disease are, among other things, the use of cytokines (a potent extracellular vasoactive factor produced by RPE) as important mediators of retinal vascular disease. The present invention both selectively targets and avoids lethal accumulation within the RPE. Thus, by the present invention, the ability of treated RPEs to participate in therapeutic responses is preserved, even enhanced, rather than eliminated by their destruction of RPEs in traditional photocoagulation therapy.

It has been noted that the clinical effect of cytokines may follow a "U-shaped curve", where small physiological changes in cytokine production (represented by the left side of the curve) may have a large clinical effect comparable to high dose (pharmacological) treatment (represented by the right side of the curve). The use of sublethal laser irradiation according to the present invention may work on the left side of the curve, where the treatment response may be more similar to the "on/off" phenomenon, rather than the dose response. This may explain the clinical effectiveness of the invention observed at low reported irradiance. This is also consistent with clinical experience and in vitro studies of laser-tissue interactions, where increased irradiance may simply increase the risk of thermal retinal damage without improving the therapeutic effect.

Another mechanism by which SDM works is thought to be the activation of Heat Shock Proteins (HSPs). Despite the almost limitless variety of possible cellular abnormalities, all types of cells share a common and highly conserved repair mechanism: heat Shock Proteins (HSPs). Almost any type of cellular stress or injury will almost immediately trigger HSPs in seconds to minutes. HSPs are extremely effective in repairing and restoring living cells to a more normal functional state in the absence of lethal cell injury. Although HSPs are transient, typically peaking within hours and lasting for days, their effects may persist for long periods of time. HSPs reduce inflammation, a common factor that contributes to many retinal diseases, including Diabetic Retinopathy (DR) and AMD.

Laser treatment induces HSP activation and, in the case of retinal treatment, thus alters and normalizes retinal cytokine expression. The more sudden and severe the non-lethal cellular stress (e.g., laser radiation), the more rapid and robust HSP production. Thus, bursts of repetitive low temperature thermal peaks with very high rates of change (rise of about 7 ℃, or 70,000 ℃/sec per 100 microsecond micropulse) generated by each SDM irradiation are particularly effective in stimulating HSP production, especially compared to non-lethal irradiation with sub-threshold treatment with continuous wave laser (which can replicate only low average tissue temperature rise).

laser wavelengths below 532 nm produce a progressively increasing cytotoxic photochemical effect. SDM produces photothermal (rather than photochemical) cellular stress at 532 nm to 1300 nm, particularly 880 nm to 1000 nm. Thus, SDM can affect tissue, including RPE, without damaging it. Consistent with HSP activation, SMD produces rapid clinical effects such as rapid and significant improvement in retinal electrophysiology, visual acuity, contrast visual acuity, and improved macular sensitivity as measured by microperimetry, and long-term effects such as DME reduction and retinal neovascular regression.

Thus, in the retina, the clinical benefit of SDM is produced by sub-lethal photothermal RPE HSP activation. In dysfunctional RPE cells, HSP stimulation by SDM results in normalized cytokine expression, and thus improved retinal structure and function. The therapeutic effect of this "low intensity" laser/tissue interaction is then amplified by the application of a "high intensity" laser, characterizing all dysfunctional RPEs in the targeted area, thereby maximizing the therapeutic effect. These principles define the therapeutic strategy for SDM as described herein. The ability of SDM to produce therapeutic effects similar to drugs and photocoagulation indicates that laser-induced retinal damage (effects other than burning) is unnecessary and non-therapeutic; and, in fact, is harmful because of loss of retinal function and stimulation of inflammation.

HSP stimulation in normal cells often has no significant clinical effect, as normally functioning cells do not require repair. The "pathological selectivity" of the near-infrared laser effect, e.g., SDM, affects diseased cells of various cell types without affecting normal cells consistent with clinical observations of SDM. This function is critical for the applicability of SDM for early and prophylactic treatment of eyes with chronic progressive disease as well as eyes with mild retinal abnormalities and mild dysfunction. Finally, SDM has been reported to have a clinically broad therapeutic range, unique in retinal laser mode, consistent with the american national standards institute "maximum allowable irradiance" prediction. While SDM can cause direct photothermal effects such as entropy protein unfolding and breakdown, SDM appears to be optimized for clinical safety and effective stimulation of HSP-mediated retinal repair.

since SDM does not produce laser-induced retinal damage (photocoagulation) and has no known adverse therapeutic effects, and have been reported to be effective in treating several retinal diseases (including diabetic macular edema; DME) proliferative diabetic retinopathy (proliferative diabetic retinopathy; PDR), retinal vein occlusion due to branching (branch retinal vein occlusion; BRVO), central serous chorioretinopathy (central serous chorioretinopathy; CSR), reversal of drug resistance, and prophylactic treatment of progressive degenerative retinopathies, such as age-related macular degeneration, Stargardt's disease, cone dystrophy, SDM's safety allows it to be used transfoveally in eyes with 20/20 visual acuity to reduce the risk of vision loss due to early involvement of the foveal DME.

as noted above, although SDM stimulation of HSPs is not specific to the disease process, the consequences of HSP-mediated repair are essentially directed to dysfunctional states. HSPs tend to solve problems, whatever the problem is. Thus, the effectiveness of SDM was observed in radically different retinal conditions such as BRVO, DME, PDR, CSR, age-related and hereditary retinopathy, and drug-resistant NAMD. Conceptually, this function can be considered as a "reset to default" mode of SDM action. For a variety of diseases where cellular function is critical, SDM normalizes cellular function by triggering a "reset" (to a "factory default setting") by HSP-mediated cellular repair.

The inventors have found that SDM treatment of patients with age-related macular degeneration (AMD) can slow progression or even stop progression of AMD. Following this SDM treatment, most patients see a significant improvement in median visual acuity versus median contrast visual acuity for the dynamically functioning logMAR. SDM is believed to work by targeting, maintaining, and "normalizing" (to normal) the function of retinal pigment epithelial cells (RPEs).

while systemic diabetes persists, SDM has been shown to prevent or reverse the manifestation of diabetic retinopathy disease states without the damage or adverse effects associated with treatment. On this basis, it is assumed that SDM can work by inducing a restoration to more normal cell functions and cytokine expression in RPE cells affected by diabetes, similar to clicking a "reset" button of an electronic device to restore factory default settings. Based on the above information and studies, SDM treatment can directly affect cytokine expression through Heat Shock Protein (HSP) activation in target tissues.

As shown above, sub-threshold diode micropulse laser (SDM) light stimulation is effective in stimulating the direct repair of slightly misfolded proteins in ocular tissues. Another route that may occur in addition to HSP activation is because the temperature spike caused by the micropulse in the form of a thermal time-course allows water to diffuse inside the protein, and this breaks the peptide-peptide hydrogen bonds that prevent the protein from returning to its original state. Diffusion of water into proteins results in an increase in the number of inhibitory hydrogen bonds of the order of a thousand fold. Thus, it is believed that this process may also be advantageously applied to other diseases.

as noted above, the energy source to be applied to the target tissue will have energy and operating parameters that must be determined and selected to achieve a therapeutic effect without permanently damaging the tissue. For example, in the case of using a beam energy source, such as a laser beam, the laser wavelength, duty cycle, and total pulse train duration parameters must be considered. Other parameters that may be considered include the radius of the laser source and the average laser power. Adjusting or selecting one of these parameters may affect at least one other parameter.

figures 1 and 2 show graphs of average power in watts compared to the laser source radius (between 0.1 cm and 0.4 cm) and the pulse train duration (between 0.1 and 0.6 seconds). Fig. 1 shows a wavelength of 880 nanometers, while fig. 2 has a wavelength of 1000 nanometers. It can be seen that in these figures, the required power decreases monotonically with decreasing source radius, with increasing total column duration, and with decreasing wavelength. The preferred parameter for the radius of the laser source is 1 mm to 4 mm. For a wavelength of 880 nanometers, the minimum power value is 0.55 watts with a laser source radius of 1 millimeter and a total pulse train duration of 600 milliseconds. The maximum power value for a wavelength of 880 nanometers is 52.6 watts when the laser source radius is 4 millimeters and the total pulse train duration is 100 milliseconds. However, when a laser having a wavelength of 1000 nm is selected, the minimum power value is 0.77 watts with a laser source radius of 1 mm and a total pulse train duration of 600 msec, and the maximum power value is 73.6 watts when the laser source radius is 4 mm and the total pulse train duration is 100 msec. The corresponding peak power during a single pulse is obtained by dividing the average power by the duty cycle.

the volume of the tissue region to be heated is determined by the wavelength, the absorption length in the relevant tissue, and the beam width. The total pulse duration and average laser power determine the total energy delivered to heat the tissue, and the duty cycle of the pulse train gives the peak power that is related to the average laser power. Preferably, the pulsed energy source energy parameters are selected to absorb between about 20 and 40 joules per cubic centimeter of target tissue.

It has been determined that the target tissue can be heated up to about 11 ℃ for a short period of time, e.g., less than 1 second, to produce the therapeutic effect of the present invention, while maintaining the average temperature of the target tissue in a lower temperature range, e.g., less than 6 ℃ or even 1 ℃ or less, for a long period of time, e.g., several minutes. The selection of the duty cycle and the total pulse train duration provides a time interval over which heat can be dissipated. It has been found that a duty cycle of less than 10% and preferably between 2.5% and 5% is effective with a total pulse duration between 100 and 600 milliseconds.

it has been found that an increase in the average temperature rise of the desired target area of at least 6 ℃ and up to 11 ℃, and preferably about 10 ℃, during total irradiation results in HSP activation. Control of target tissue temperature is determined by selecting source and target parameters such that Arrhenius score for HSP activation is greater than 1 while ensuring compliance with conservative FDA/FCC requirements to avoid injury or injury Arrhenius score less than 1.

To meet conservative FDA/FCC limits to avoid permanent tissue damage, the average temperature rise of the target tissue is 1 ℃ or less for any 6 minute period for the beam and other electromagnetic radiation sources. Typical decay time required to reduce the temperature of the heated target region from a temperature rise of about 10 ℃ to 1 ℃ by thermal diffusion is 16 seconds when the wavelength is 880 nanometers and the source diameter is 1 millimeter. The temperature decay time was 107 seconds when the source diameter was 4 mm. The temperature decay time was 18 seconds for a source diameter of 1 mm at a wavelength of 1000 nm and 136 seconds for a source diameter of 4 mm. This is well within the time to maintain the average temperature rise over the course of several minutes, e.g. 6 minutes or less. Although the temperature of the target tissue is raised, for example, to about 10 ℃ very quickly (e.g., within a fraction of a second) during application of the energy source to the tissue, the lower duty cycle provides a longer period of time between energy pulses applied to the tissue and the shorter pulse train duration ensures sufficient temperature diffusion and decay over a shorter period of time including minutes, for example, 6 minutes or less, so that there is no permanent tissue damage.

The pulse train energy delivery pattern has distinct advantages over either a single pulse or a progressive energy delivery pattern in terms of remedial HSP activation and promotion of protein repair. There are two considerations that make this advantageous: first, one major advantage of HSP activation and protein repair in SDM energy delivery modes comes from the generation of peak temperatures on the order of 10 ℃. Such a large temperature rise has a large impact on the Arrhenius score, which quantifies the number of activated HSPs and the rate of diffusion of water into the protein that promotes protein repair. This is because the temperature constitutes an index having an amplifying effect. Secondly, it is important that the temperature rise does not remain high (10 ℃ or higher) for a long time, since that would violate FDA and FCC requirements that the average temperature rise must be less than 1 ℃ (or 6 ° in the case of ultrasound) over a period of minutes.

SDM energy delivery mode uniquely satisfies both of these considerations by judicious selection of power, pulse time, pulse spacing, and volume of the target region to be treated. The volumetric inclusion of the treatment zone is due to the fact that the temperature must decay fairly quickly from its high value, on the order of 10 c, so that the long-term average temperature rise does not exceed the long-term FDA/FCC limit (6 c for ultrasound frequencies and 1 c or less for electromagnetic radiation energy sources).

Referring now to FIG. 3, a schematic diagram of a system for implementing the method of the present invention is shown. The system, generally indicated by reference numeral 30, includes a laser console 32, such as a 810 nanometer near infrared micro-pulse diode laser in the preferred embodiment. The laser generates a laser beam that is passed through optical means, such as an optical lens or mask, or a plurality of optical lenses and/or masks 34, as desired. The laser projector optics 34 deliver the shaped beam to an on-axis wide-area untouched digital optical viewing system/camera 36 to project the laser beam light onto the patient's eye 38. It should be understood that block 36 may represent both a laser beam projector and a viewing system/camera, which may actually comprise two distinct components when in use. The viewing system/camera 36 provides feedback to a display monitor 40, which may also include necessary computerized hardware, data input and control, etc., to operate the laser 32, the optical device 34, and/or the projection/viewing assembly 36.

As mentioned above, current treatments require the application of a large number of individual laser beam spots individually to the target tissue to be treated. These may be hundreds or even thousands for the desired treatment area. This is very time consuming and laborious.

Referring now to FIG. 4, in one embodiment, a laser beam 42 is passed through a collimator lens 44 and then through a mask 46. In a particularly preferred embodiment, the mask 46 comprises a diffraction grating. The mask/diffraction grating 46 produces a geometric object, or more typically, a geometric pattern made up of multiple laser spots or other geometric objects generated simultaneously. This is represented by a plurality of laser beams 48. Alternatively, the plurality of laser spots may be generated by a plurality of fiber optic lines. Both methods of generating laser spots allow for the simultaneous creation of extremely large numbers of laser spots over an extremely wide treatment field, for example, consisting of the entire retina. In practice, a very high number of laser spots (perhaps hundreds or even thousands or more) may cover the entire fundus and the entire retina, including the macula and fovea, retinal blood vessels, and the optic nerve. The aim of the method of the invention is to better ensure complete and complete coverage and treatment, by laser without leaving any part of the retina, thus improving vision.

by using optical features with feature sizes comparable to the wavelength of the laser light employed, for example by using diffraction gratings, it is possible to exploit quantum mechanical effects, which allow for the simultaneous application of very large numbers of laser spots to very large target areas. The individual spots produced by such diffraction gratings all have similar optical geometries as the input beam, with each spot having minimal power variation. The result is multiple laser spots with sufficient irradiance simultaneously producing harmless but effective therapeutic applications over a large target area. The present invention also contemplates the use of other geometric objects and patterns generated by other diffractive optical elements.

laser diffraction through mask 46 produces a periodic pattern at a distance from mask 46, as shown by laser beam 48 in FIG. 4. A single laser beam 42 is thus formed into multiple (up to hundreds or even thousands) of individual laser beams 48 to create a desired pattern of spots or other geometric objects. These laser beams 48 may be passed through additional lenses, collimators, etc. 50 and 52 to transmit the laser beams and form the desired pattern on the patient's retina. Such additional lenses, collimators, etc. 50 and 52 may also convert and redirect the laser beam 48 as desired.

Any pattern may be constructed by controlling the shape, spacing, and pattern of the optical mask 46. The pattern and the illumination spot can be created and modified arbitrarily, as required by the application requirements of experts in the field of optical engineering. Photolithography techniques, particularly those developed in the semiconductor manufacturing field, can be used to create simultaneous geometric patterns of spots or other objects.

Although hundreds or even thousands of simultaneous laser spots may be generated and created and formed into a pattern to be applied to eye tissue, there is a limit to the number of treatment spots or beams that may be used simultaneously in accordance with the present invention due to the requirement that eye tissue, and particularly the eye lens, not be overheated. Each individual laser beam or spot requires a minimum average power effective during the column duration. At the same time, however, the eye tissue cannot exceed a certain temperature rise without being damaged. For example, there is a 4 ℃ limit to the temperature rise of the eye's lens, which will set an upper limit on the average power that can be sent through the lens without overheating and damaging the eye's lens. For example, for the use of a 810 nm wavelength laser, the number of simultaneous spots generated and used can range from only 1 up to about 100 when using a 0.04 (4%) duty cycle and a total column duration of 0.3 seconds (300 milliseconds) for panretinal coverage. Water absorption increases with increasing wavelength, resulting in heating over a long path length through the anterior vitreous of the retina. For shorter wavelengths, such as 577 nanometers, the absorption coefficient of melanin of the RPE may be higher and thus the laser power may be lower. For example, at 577 nm, the power can be reduced by a factor of 4 for the present invention to be effective. Accordingly, when using a 577 nm wavelength laser, it is possible to have only a single laser spot or up to about 400 laser spots without damaging or injuring the eye.

The present invention can use multiple simultaneously generated treatment beams or spots, such as tens or even hundreds, because the parameters and methods of the present invention create a therapeutically effective but non-destructive and non-permanently damaging treatment that allows laser spots to be applied to any portion of the retina, including the fovea, whereas conventional techniques cannot use a large number of simultaneous laser spots, and are often limited to only one treatment laser beam, to avoid accidentally illuminating sensitive areas of the retina, such as the fovea, because these areas will be damaged by the illumination of conventional laser beam methods, which can cause vision loss or other complications.

FIG. 5 schematically illustrates a system for coupling a plurality of light sources into the pattern generating optical subassembly described above. Specifically, the system 30' is similar to the system 30 described above in FIG. 3. The primary difference between the alternative system 30' and the earlier described system 30 is the inclusion of a plurality of laser consoles 32, the outputs of which are each input into a fiber coupler 54. The fiber coupler produces a single output that is delivered to the laser projector optics 34 as described in earlier systems. Coupling multiple laser consoles 32 into a single fiber is accomplished by fiber couplers 54 as is known in the art. Other known mechanisms for combining multiple light sources are available and can be used in place of the fiber optic couplers described herein.

In this system 30', the plurality of light sources 32 follow similar paths as described earlier in system 30, namely collimation, diffraction, re-collimation, and directing into the retina by a directing mechanism. In this alternative system 30', depending on the wavelength of light passed through, the diffractive element must act in a different manner than described earlier, resulting in a slightly varying pattern. The variation is linear with the wavelength of the diffracted light source. In general, the difference in diffraction angles is small enough that different overlapping patterns can be directed along the same optical path through the directing mechanism 36 toward the retina 38 for treatment. A slight difference in diffraction angle will affect how the guide pattern achieves coverage of the retina.

Since the resulting pattern will vary slightly for each wavelength, the sequential shift to achieve full coverage will be different for each wavelength. This sequential shift can be implemented in two modes. In the first mode, light of all wavelengths is applied simultaneously without the same coverage. An offset guide pattern is used that achieves full coverage for one of the plurality of wavelengths. Thus, while light of selected wavelengths achieves complete coverage of the retina, application of other wavelengths achieves incomplete or overlapping coverage of the retina. The second mode sequentially applies varying or different wavelengths of light sources with appropriate guide patterns to achieve complete coverage of the retina for that particular wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve the same coverage for each wavelength. This avoids incomplete or overlapping coverage for arbitrary wavelengths of light.

These patterns may also be mixed and matched. For example, two wavelengths may be applied simultaneously, one wavelength achieving full coverage and the other achieving incomplete or overlapping coverage, followed by a sequential application of a third wavelength and achieving full coverage.

Fig. 6 schematically shows another alternative embodiment of the inventive system 30 ". This system 30 "is configured substantially the same as the system 30 shown in fig. 3. The main difference is the inclusion of a plurality of pattern generating subassembly channels tuned to the particular wavelength of the light source. A plurality of laser consoles 32 are arranged in parallel, each directly leading to its own laser projector optics 34. The laser projector optics of each channel 58a, 58b, 58c include a collimator 44, a mask or diffraction grating 48, and a re-collimator 50, 52, as described above in connection with fig. 4-the entire set of optics is tuned for the particular wavelength generated by the corresponding laser console 32. The outputs of each set of optics 34 are then directed to a beam splitter 56 for combination with other wavelengths. As known to those skilled in the art, a reverse-use beam splitter may be used to combine multiple beams into a single output.

The combined channel output from the final beamsplitter 56c is then directed through the camera 36, which applies a directing mechanism to allow complete coverage of the retina 38.

In this system 30 ", the optical elements of each channel are tuned to produce a precise specific pattern for the wavelength of the channel. Thus, when all channels are combined and properly aligned, a single guide pattern can be used to achieve complete coverage of the retina for all wavelengths.

System 30 "may use as many channels 58a, 58b, 38c, etc. as there are wavelengths of light used in the treatment, as well as beamsplitters 56a, 56b, 56c, etc.

Implementations of the system 30 "may utilize different symmetries to reduce the number of alignment constraints. For example, the proposed grid pattern is periodic in two dimensions and directed along two dimensions to achieve full coverage. Thus, if the pattern and designation of each channel is the same, the actual pattern of each channel will not need to be aligned for the same guide pattern to achieve complete coverage for all wavelengths. Only optical alignment of the channels will be required to achieve effective combining.

In system 30 ", the channels begin with a light source 32, which may be from an optical fiber as in other embodiments of the pattern generation subassembly. The light source 32 is directed to an optical assembly 34 to collimate, diffract, re-collimate and direct to the beam splitter, which combines the channels with the primary output.

The field of photobiology indicates that different biological effects can be obtained by exposing target tissue to laser light of different wavelengths. The same effect can also be obtained by applying a plurality of lasers with different or the same wavelength sequentially and successively at variable intervals and/or with different radiant energies. The present invention contemplates the simultaneous or sequential application of multiple laser, light or radiation wavelengths (or modes) to maximize or customize the desired therapeutic effect. This approach also minimizes potential harmful effects. The optical methods and systems shown and described above provide for the simultaneous or sequential application of multiple wavelengths.

The invention described herein is generally safe for panretinal and/or transfoveal treatment. However, it is possible that the user, e.g., a surgeon, is prepared to limit treatment to a particular area of the retina where disease markers are located, or to prevent treatment of a particular area with darker pigmentation, e.g., from scar tissue. In this case, the camera 36 may be equipped with an iris diaphragm 72 configured to selectively enlarge or narrow an opening through which light is directed into the patient's eye 38. Fig. 7 shows an opening 74 on the camera 36 fitted with such an iris diaphragm 72. Alternatively, the iris diaphragm 72 may be replaced or supplemented by a Liquid Crystal Display (LCD) 76. The LCD76 acts as a dynamic aperture to allow each pixel in the display to transmit or block light passing through it. Such an LCD76 is shown in fig. 8.

Preferably, any of the inventive systems 30, 30', 30 "includes displaying a real-time image of the retina as seen by the camera 36 on the user interface. The user interface may include an overlay of this real-time image of the retina to select the area where therapeutic light will be limited or excluded by the iris diaphragm 72 and/or the LCD 76. The user may draw the outline on the real-time image as on a touch screen and then choose to have limited or excluded coverage inside or outside the outline.

For example, if the user identifies scar tissue on the retina that should be excluded from treatment, the user will draw a contour around the scar tissue and then mark the interior of the contour for removal from laser treatment. The control system and user interface will then send appropriate control signals to the LCD76 to block the projection of therapeutic light by selecting pixels above the scar tissue. The LCD76 provides the added benefit of facilitating attenuation of the areas of the projected pattern. This feature may be used to limit the peak power output of a particular spot within a pattern. Limiting the peak power of a particular spot in the pattern at the highest power output can be used to make the therapeutic power more uniform across the retina.

alternatively, the surgeon may use the fundus monitor to outline the area of the retina to be treated or avoided; and then the designated area to be treated or avoided is treated or avoided by software directing a treatment beam to treat or avoid the area without the need or use of a blocking LCD76 aperture.

Generally, the system of the present invention comprises a guidance system to ensure a complete and comprehensive retinal treatment by retinal light stimulation. This guidance system is distinguished from conventional retinal laser guidance systems which are not only used to guide therapy to a specific retinal location, but also to guide therapy away from sensitive locations such as the fovea which can be damaged by conventional laser therapy, and therefore can treat the entire retina, including the fovea and even the optic nerve, since the treatment method of the present invention is harmless. Also, preventing accidental visual loss caused by accidental patient movement is not a concern. Instead, patient motion will primarily affect the guidance of the tracking of the laser application to ensure adequate coverage. A fixation/tracking/registration system consisting of a fixation target, tracking mechanism and operatively linked to the system is common in many ophthalmic diagnostic systems and may be incorporated into the present invention.

In a particularly preferred embodiment, the geometric patterns of simultaneous laser spots are sequentially offset to achieve fusion and complete treatment of the retinal surface. Although a portion of the retina may be treated according to the present invention, it is more desirable to treat the entire retina within one treatment session. This is performed in a time-saving manner by arranging a plurality of light spots over the entire fundus at once. This simultaneous pattern of spots is sequentially scanned, shifted or redirected as a complete array to cover the entire retina during a single treatment session.

This may be performed in a controlled manner by using the optical scanning mechanism 60. Fig. 9 and 10 show an optical scanning mechanism 60 that may be used in the form of a MEMS mirror having a base 62 with electronically actuated controls 64 and 66 for tilting and moving a mirror 68 when power is applied to and removed from the electronically actuated controls. Power to the controllers 64 and 66 moves the mirror 68 and thus the simultaneous pattern of laser spots or other geometric objects reflected thereon correspondingly on the patient's retina. This may be performed in an automated manner, for example, by using an electronic software program to adjust the optical scanning mechanism 60 until the retina is completely covered or at least a portion of the retina in need of treatment is exposed to phototherapy. The optical scanning mechanism may also be a small beam diameter scanning galvanometer system, or similar systems, such as those distributed by Thorlabs, Inc. Such a system is capable of scanning the laser in a desired offset pattern.

since the parameters of the present invention determine that the applied radiant energy or laser is not destructive or damaging, the geometric patterns of the laser spots, for example, can be superimposed without damaging the tissue or forming any permanent damage. However, in a particularly preferred embodiment, as shown in FIG. 11, each shot shifts the pattern of the spot, thereby creating a space from the previous shot to allow for heat dissipation and prevent the possibility of thermal damage or tissue damage. Thus, as shown in fig. 11, each shot offset is illustrated as a pattern of a grid of sixteen spots, so that the laser spot occupies a different space than the previous shot. It should be understood that the schematic use of circles or open dots and solid dots is for illustrative purposes only to illustrate the prior and subsequent illumination of the area by the spot pattern in accordance with the present invention. The spacing of the laser spots prevents overheating and damage to the tissue. It will be appreciated that this occurs until the entire retina (preferred method) has received phototherapy or until the desired effect is achieved. This may be performed, for example, by a scanning mechanism, such as by applying a static electric torque to the micro-machined mirror, as shown in fig. 9 and 10. By combining the use of small laser spots (to prevent heat build-up) separated by non-illuminated areas with a grid with a large number of spots on each side, it is possible to treat large target areas non-invasively and invisibly with short illumination durations at speeds much faster than existing methods.

by rapidly and sequentially repeating the simultaneous application of reorientations or shifts of the entire grid array of spots or geometric objects, complete coverage of a target, such as a human retina, can be rapidly achieved without thermal tissue damage. Depending on the laser parameters and the desired application, this offset can be determined by an algorithm to ensure the fastest treatment time and minimal risk of damage due to thermal tissue. Modeling is performed by using Fraunhoffer Approximation as follows. With a nine by nine square mask, a hole radius of 9 microns, a hole pitch of 600 microns, using an 890 nm wavelength laser, a mask-lens spacing of 75 mm, and a secondary mask size of 2.5 mm by 2.5 mm, the following parameters will produce a grid of nineteen spots on each side spaced 133 microns with a spot size radius of 6 microns. Given the desired region side length "a", given the output pattern spots "n" per square edge, the spacing between spots "R", the spot radius "R" and the desired square side length "a" to the treatment region, the number of shots "m" required for treatment (fusion coverage applied in small spots) can be given by:

Through the arrangement, the operation times m required for treating different irradiation fields can be calculated. For example, a 3 mm x 3 mm area favorable for treatment would require 98 deflection operations, requiring a treatment time of about thirty seconds. Another example is a 3 cm x 3 cm area, representing the entire human retinal surface. For such large treatment areas, a larger secondary mask size of 25 mm by 25 mm may be used, resulting in a treatment grid of 190 spots per side spaced 133 microns with a spot size radius of 6 microns. Since the secondary mask size is increased by the same factor as the required treatment area, the number of shift operations of about 98 and thus the treatment time of about 30 seconds is constant. These treatment times represent at least a ten to thirty-fold reduction in treatment time compared to prior sequential laser spot-alone application methods. A field size of 3 mm would, for example, allow treatment of the entire human macula in a single irradiation, facilitating the treatment of common blinding conditions such as diabetic macular edema and age-related macular degeneration. Performing all 98 sequential shifts will ensure complete coverage of the macula.

of course, the number and size of retinal spots generated in a simultaneous pattern array is variable and varied, so that the number of sequential offset operations required to complete a treatment can be easily adjusted according to the treatment needs of a given application.

furthermore, with the help of small holes employed in the diffraction grating or mask, quantum mechanical behavior can be observed, which allows arbitrary distribution of the laser input energy. This would allow the generation of multiple spots in any geometric shape or pattern, for example in a grid pattern, lines or any other desired pattern. Other methods of generating the geometry or pattern, such as using a plurality of optical fibers or microlenses, may also be used in the present invention. The time savings from using simultaneous projection geometries or patterns allows for a treatment field of novel size, e.g., 1.2 square centimeter area, to achieve the entire retinal treatment during a single clinical setting or treatment.

referring now to fig. 12 and 13, instead of using a geometric pattern of small laser spots, the present invention contemplates the use of other geometric objects or patterns. For example, a single laser line 70 may be created that is continuous or formed by a series of closely spaced spots. The line may be sequentially scanned over the area using an offset optical scanning mechanism, as indicated by the downward arrow in fig. 12. Referring now to fig. 13, the same geometric objects of line 70 may be rotated, as indicated by the arrows, to create a circular phototherapy field. However, a potential negative effect of this approach is that the central area will be repeatedly irradiated and may reach unacceptable temperatures. However, this disadvantage can be overcome by increasing the time between irradiations or by forming voids in the line so that the central region is not irradiated.

Power limitations in current micro-pulsed diode lasers require a rather long illumination duration. The longer the illumination, the more important the heat sink capability of the center-spot towards the unirradiated tissue at the edge of the laser spot and towards the underlying choriocapillaris layer in the retina. Thus, the pulsed laser beam of a 810 nm diode laser should have an illumination envelope duration of 500 milliseconds or less, and preferably about 300 milliseconds. Of course, if the micro-pulse diode laser is changed to a higher power, the irradiation duration should be reduced accordingly.

In addition to the power limit, another parameter of the present invention is the duty cycle, or the frequency of the micro-pulse train, or the length of the thermal relaxation time between successive pulses. It has been found that the use of 10% duty cycle or higher duty cycle of a micro-pulsed laser adjusted to deliver similar irradiance at similar MPE levels significantly increases the risk of lethal cell damage, especially at darker ocular fundus. However, duty cycles of less than 10% and preferably about 5% or less demonstrate sufficient heat rise and treatment at the MPE cell level to stimulate a biological response, but remain below levels expected to produce lethal cell damage even at dark fundus. However, the lower the duty cycle, the illumination envelope duration increases, and in some cases may exceed 500 milliseconds.

Each micropulse lasts a fraction of a millisecond, typically between 50 microseconds and 100 microseconds in duration. Thus, for illumination envelope durations of 300 to 500 milliseconds, and less than a 5% duty cycle, there is a significant amount of wasted time between micropulses to allow for thermal relaxation time between successive pulses. Typically, a thermal relaxation time delay of between 1 and 3 milliseconds, preferably about 2 milliseconds, is required between successive pulses. For adequate treatment, retinal cells are typically subjected to between 50 and 200 laser shots or impacts, and preferably between 75 and 150 at each location. With a relaxation or separation time of 1 to 3 milliseconds, the total time to treat a given area (or location on the retina especially exposed to the laser spot) according to the above-described embodiments is on average between 200 and 500 milliseconds. Thermal relaxation times are required to avoid overheating the cells in the location or spot and to prevent damage or destruction of the cells. Although the period of 200 to 500 milliseconds does not appear to be long, given the small size of the laser spot and the need to treat a large area of the retina, treating the entire macula or the entire retina can take a significant amount of time, especially from the perspective of the patient being treated.

Thus, the present invention may use the interval between successive laser applications for the same location (typically between 1 and 3 milliseconds) to apply laser light to a second or additional region of the retina and/or fovea that is spaced from the first treatment region. The laser beam is returned to the first treatment position or previous treatment position within a predetermined time interval to provide sufficient thermal relaxation time between successive pulses, but also to adequately treat the cells in these positions or regions (by repeatedly applying laser light to the position to sufficiently increase the temperature of these cells over time) to achieve the desired therapeutic benefits of the present invention.

it is important to return to the previously treated position within 1 to 3 milliseconds, preferably about 2 milliseconds, to allow the region to cool sufficiently during this time and treat it within the necessary time window. For example, an individual may not be able to wait one or two seconds and then return to a previously treated area that has not received the necessary overall treatment because the treatment will not be effective or may not be effective at all. However, during that time interval, typically about 2 milliseconds, at least one other region, typically a plurality of regions, may be treated by the laser application, since the duration of the laser pulses is typically 50 microseconds to 100 microseconds. The number of additional zones that can be treated is limited only by the duration of the micropulses and the ability to controllably move the laser beam from one zone to another. Currently, about four additional regions that are sufficiently spaced apart from each other can be treated during the thermal relaxation interval beginning with the first treatment region. Thus, during the 200 to 500 millisecond illumination envelope for the first region, multiple regions may be at least partially treated. Thus, instead of applying only 100 simultaneous spots to the treatment area during a single time interval, about 500 spots may be applied during that time interval in different treatment areas. This would be the case, for example, for a laser beam having a wavelength of 810 nanometers. For shorter wavelengths, such as 570 nanometers, even more individual locations may be exposed to the laser beam to create a spot. Thus, instead of up to about 400 simultaneous spots, about 2000 spots may be covered during the interval between micro-pulse treatments for a given area or location.

As mentioned above, during the duration of the illumination envelope (typically 200 to 500 milliseconds), each position typically has a light application applied thereto of between 50 and 200, more typically between 75 and 150, to achieve the desired treatment. According to one embodiment of the invention, the application of the laser to the previously treated region is repeated sequentially during the relaxation time interval for each region or position. This will occur repeatedly until a predetermined number of laser applications to each area to be treated are achieved.

This is schematically shown in fig. 14A to 14D. Fig. 14A shows in solid circles that the first area has laser light applied to it as the first application. Shifting or micro-shifting the laser beam to the second irradiation region, followed by the third irradiation region and the fourth irradiation region, as shown in fig. 14B, until a position in the first irradiation region needs to be retreated by having the laser applied thereto again within the thermal relaxation time interval. Then, a location within this first shot area will have laser light reapplied to it, as shown in FIG. 14C. Secondary or subsequent irradiation will occur at each irradiated region as shown in fig. 14D by the shaded dots or circles until the desired number of shots or impacts or light applications are achieved to therapeutically treat these regions, as schematically shown by the black circles in irradiated region 1 in fig. 14D. This enables the system to add additional shot areas when the first or previous shot area treatment is completed, repeating the process until the entire retinal area to be treated is completely treated. It should be understood that the use of solid, dashed, partially shaded, and fully shaded circles is for illustrative purposes only, as in fact the illumination of laser light in accordance with the present invention is invisible and undetectable to the human eye and known detection devices and techniques.

Adjacent illuminated areas must be separated by at least a predetermined minimum distance to avoid tissue damage. Such distances are at least 0.5 diameter from the immediately preceding treatment location or area, preferably between 1 and 2 diameters. Such spacing is correlated to the actual treatment location in the previously irradiated region. The present invention contemplates that the larger area may actually include multiple illumination areas therein, which are offset in a different manner than shown in fig. 14. For example, the irradiation region may include thin lines as shown in fig. 12 and 13, which will be irradiated repeatedly in sequence until all necessary regions are sufficiently irradiated and treated. This may include, in accordance with the present invention, a limited area of the retina, the entire macula or the whole macula treatment, or the entire retina, including the fovea. However, because of the method of the present invention, the time required to treat the area of the retina to be treated or the entire retina is significantly reduced, e.g., by a factor of 4 or 5, so that a single treatment session takes less time for the medical provider and the patient does not have to be uncomfortable for a long period of time.

This embodiment of the invention, which is based on applying one or more treatment beams to the retina at a time and moving the treatment beam to a series of new positions, and then returning the beam to repeatedly re-treat the same position or area, has also been found to require less power than a method that maintains the laser beam at the same position or area during the entire duration of the illumination envelope. Referring to fig. 15-17, there is a linear relationship between pulse length and required power, and a logarithmic relationship between generated heat.

Referring to fig. 15, a graph is provided in which the x-axis represents the logarithm of the average power in watts and the y-axis represents the treatment time in seconds. The lower curve is for total macular treatment and the upper curve is for total retinal treatment. This would be for a laser beam with a micropulse time of 50 microseconds, a time period of 2 milliseconds between pulses, and a column duration on the spot of 300 milliseconds. The area of each retinal spot is 100 microns and the laser power for these 100 micron retinal spots is 0.74 watts. The total macular area is 0.55cm²a total of 7,000 total macular spots are required, and the total retinal area is 3.30cm²Full coverage requires 42,000 full macular spots. In accordance with the present invention, each RPE spot requires a minimum energy to have its resetting mechanism fully activated, i.e., 38.85 joules for the full macula and 233.1 joules for the full retina. As expected, the shorter the treatment time, the greater the average power required. However, the allowable average power has an upper limit that limits how short the treatment time can be.

As described above, there are limits not only with respect to the laser light that can be obtained and used, but also with respect to the amount of power that can be applied to the eye without damaging the eye tissue. For example, the temperature rise of the lens of the eye is limited, for example, to between 4 ℃ in order to avoid overheating and damaging the lens, for example, causing cataracts. Thus, an average power of 7.52 watts can raise the lens temperature to about 4 ℃. This power limitation increases the minimum treatment time.

However, referring to fig. 16, the total power required for each pulse is small with a slight offset that repeats and sequentially moves the laser spot back to the previous treatment position, so that the total energy and total average power delivered during treatment is the same. Figures 16 and 17 show how the total power depends on the treatment time. Shown in fig. 16 for total macular treatment and in fig. 17 for total retinal treatment. The upper solid line or curve represents embodiments in which no thermal relaxation time interval is utilized for micro-migration, such as described and illustrated in fig. 11, while the lower dashed line represents the situation for such micro-migration, as described and illustrated in fig. 14. Figures 16 and 17 show that for a given treatment time, the total peak power is less with a micro-excursion than without. This means that by using the micro-offset embodiments of the present invention, less power is required for a given treatment time. Alternatively, the allowable peak power may be advantageously used to reduce the total treatment time.

Thus, according to fig. 15-17, a log power of 1.0 (10 watts) would require a total treatment time of 20 seconds, as described herein, by using the micro-offset embodiments of the present invention. Without a micro-offset, but having the micro-pulse beam at the same location or region during the entire treatment envelope time, a 2 minute time would be required. With a minimum treatment time in terms of wattage. However, this treatment time is much shorter in the case of a slight offset than in the case without a slight offset. When the required laser power is small with a slight offset, it may be possible in some cases to increase the power to reduce the treatment time for a given required retinal treatment area. The product of treatment time and average power is fixed for a given treatment area to achieve therapeutic treatment in accordance with the present invention. This may be implemented, for example, by applying a higher number of therapeutic laser beams or spots simultaneously at a reduced power. Of course, since the parameters of the laser are selected to be therapeutically effective rather than destructive or permanently damaging to the cells, there is no need to direct or track the beam, only a treatment beam is required, and all areas of the retina, including the fovea, can be treated in accordance with the invention. Indeed, in certain preferred embodiments, the entire retina, including the fovea, is treated in accordance with the present invention, which is not possible at all using conventional techniques.

Due to the unique characteristics of the present invention, a single set of optimized laser parameters that are not significantly affected by media turbidity, retinal thickening, or fundus pigmentation is allowed, thus allowing for a simplified user interface. While operational controls can be presented and acted upon in many different ways, the system allows for an extremely simplified user interface that can employ only two control functions. That is, an "activate" button, wherein a single press of this button while in "standby" will activate and initiate the treatment. Pressing this button during treatment will allow early termination of treatment and return to "standby" mode. For example, the activity of the machine may be identified and displayed by an LED located adjacent to or within the button. The second control function may be a "field size" knob. A single press of this button can program the unit to produce, for example, a 3 mm focal spot or "macular" field spot. Pressing this knob a second time programs the cell to produce a 6 mm or "rear pole" spot. A third press of this knob may program the cell to produce a "pan retinal" or approximately 160 ° to 220 ° pan retinal spot or coverage area. Manual rotation of this knob can produce various spot field sizes therebetween. Within each field size, the density and intensity of treatment will be the same. The change in field size will be produced by an optical or mechanical mask or aperture, such as an aperture described below or an LCD aperture.

the fixation software can monitor the display image of the fundus. Before initiating treatment of the fundus marker, for example, the optic nerve, or any part or feature of either eye of the patient (assuming the visual axis is normal) may be marked on the display screen by the operator. The treatment may be initiated and the software will monitor the fundus image or any other image registered to any part of any one of the patient's eyes (assuming the visual axis is normal) to ensure adequate fixation. A fixed disconnection will automatically interrupt the treatment. The fixed disconnection may be optically detected; or by interrupting a low energy infrared beam projected parallel to and at the outer edge of the treatment beam by the edge of the pupil. Once fixation is established, the treatment will automatically revert to completion. At the end of the treatment (determined by the completion of the delivery of the required laser energy to the target fusion), the unit will automatically terminate the irradiation and default to a "start" or "standby" mode. Due to the unique nature of this treatment, a fixed interruption will not risk injury or injury to the patient, but merely extend the treatment period.

The laser light may be projected through a wide field non-contact lens to the fundus. Custom orientation of a particular target or region of the fundus outside of the laser field or central region may be achieved by the operator's joystick or an off-center patient gaze. The laser delivery optics may be coaxially coupled to a wide-field contactless digital fundus viewing system. The generated fundus image may be displayed on a video monitor visible to the laser operator. Maintaining a clear and focused fundus image may be aided by a joystick on the camera assembly that is manually guided by the operator. Alternatively, adding a target registration and tracking system to the camera software would result in a fully automated treatment system.

A fixed image may be displayed coaxially to the patient to facilitate eye alignment. During treatment, this image will change shape and size, color, intensity, rate of flashing or oscillation, or other periodic or continuous modification to avoid photoreceptor exhaustion, patient fatigue, and promote good fixation.

In addition, results or images from other retinal diagnostic modes, such as OCT, retinal angiography, and automated fluorography, may be displayed in parallel or superimposed on the displayed image of the patient's fundus to guide, assist, or otherwise facilitate treatment. This parallel or superimposed image may help identify disease, injury or scar tissue on the retina.

The inventors have found that treatment of patients with age-related macular degeneration (AMD) according to the invention may slow progression or even arrest progression of AMD. Further evidence for this restorative therapeutic effect is that the inventors found that treatment can uniquely reduce the risk of vision loss in AMD due to choroidal neovascularization by 80%. After treatment according to the invention, most patients see a significant improvement in the dynamic functional logMAR visual acuity versus the contrast visual acuity, some experience better vision. It is believed that this works by targeting, maintaining, and "normalizing" (to normal) the function of the retinal pigment epithelial cells (RPEs).

While systemic diabetes persists, treatment according to the present invention has been shown to prevent or reverse the manifestation of diabetic retinopathy disease states without the damage or adverse effects associated with treatment. The studies published by the inventors show that the restorative effect of the treatment can uniquely reduce the risk of progression of diabetic retinopathy by 85%. On this basis, it is assumed that the present invention can work by inducing a restoration to more normal cell functions and cytokine expression in RPE cells affected by diabetes, similar to clicking a "reset" button of an electronic device to restore factory default settings.

Based on the above information and studies, SDM treatment can directly affect cytokine expression and Heat Shock Protein (HSP) activation in target tissues, particularly in the Retinal Pigment Epithelial (RPE) layer. The inventors have noted that whole retina and whole macula SDMs reduce the rate of progression of many retinal diseases, including severe non-proliferative and proliferative diabetic retinopathy, AMD, DME, and the like. The known therapeutic benefits of these retinal disease patients combined with the absence of known adverse therapeutic effects allow for early and prophylactic treatment, liberal application, and re-treatment if necessary. This theory of replacement also suggests that the present invention is applicable to many different types of RPE-mediated retinal diseases. Indeed, the inventors have recently demonstrated that total macular treatment can significantly improve dry age-related macular degeneration, retinitis pigmentosa, cone rod retinal degeneration, and retinal function and health, retinal sensitivity, as well as dynamic logMAR visual acuity and contrast visual acuity in Stargardt's disease (no other treatment has been previously found to do so).

Currently, retinal imaging and visual acuity testing guide the management of chronic progressive retinal disease. Since tissue and/or organ structural damage and vision loss are late stage disease manifestations, treatment initiated at this time must be intensive, often long and expensive, and often fails to improve visual acuity and rarely restores normal vision. Since the present invention has proven to be an effective treatment for several retinal diseases without adverse therapeutic effects, and because of its safety and effectiveness, it can also be used to treat the eye, to prophylactically prevent or delay the onset or symptoms of retinal diseases, or as a prophylactic treatment for such retinal diseases. Any treatment that improves retinal function and thus improves health should also reduce disease severity, progression, adverse events, and vision loss. By initiating treatment early, before pathological structural changes, and maintaining therapeutic benefit through periodic, function-guided re-treatment, structural degeneration and vision loss can thus be delayed, if not prevented. Even a less dramatic reduction in the rate of disease progression in the early stages can lead to significant long-term reductions in visual loss and complications. By alleviating the consequences of the primary defect, the course of the disease can be reduced, progression can be slowed, and complications and visual loss can be reduced. This is reflected in the inventors' studies, where treatment was found to reduce the risk of progression of diabetic retinopathy and vision loss by 85% and to reduce the risk of progression of AMD and vision loss by 80%.

Since SDM has been successfully used in eutrophy or "reset to default" by normalizing RPE function, retinal function and autoregulation, and biological function of RPE, it is believed that the use of SDM can restore normal retinal physiology and autoregulation to slow, stop, or even reverse the progression of myopia, particularly pediatric myopia, in the same manner as it does for other chronically progressive retinopathies.

generating a laser beam that is sub-lethal and creates a true sub-threshold photocoagulation or photostimulation of retinal tissue, and exposing at least a portion of the retinal tissue to the generated laser beam without damaging the exposed retina or foveal tissue, thereby providing a prophylactic and protective treatment of the retinal tissue of the eye. The retina being treated may include the fovea, Retinal Pigment Epithelium (RPE), choroid, choroidal neovascular membrane, subretinal fluid collection, macula, macular edema, parafovea, and/or perifoveal area. The laser beam may be directed to only a portion of the retina, or substantially the entire retina and fovea, or other ocular tissue. This process is applied to the tissues of the eye, such as the retina and/or foveal tissue of an eye that has or is at risk of developing myopia.

Although most therapeutic effects appear to be long-term (if not permanent), clinical observations suggest that it appears to occasionally disappear. Accordingly, the retina is periodically retreated. This may be performed on a planned basis or when it is determined that the patient's retina needs to be retreated, for example by periodically monitoring the patient's vision and/or retinal function or condition.

Although specific embodiments have been described in detail herein for purposes of illustration, various modifications may be made without deviating from the scope and spirit of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

1. A method of preventing or treating myopia comprising the steps of:

Providing a pulsed energy source having energy parameters including wavelength or frequency, duty cycle, and pulse train duration selected to elevate ocular tissue temperature to eleven degrees celsius to achieve a therapeutic or prophylactic effect, wherein the average temperature rise of the ocular tissue over a period of minutes is maintained at or below a predetermined level so as not to permanently damage the ocular tissue; and

The pulse energy is applied to tissue of the eye that is or is at risk of myopia to stimulate heat shock protein activation in the eye tissue.

2. The method of claim 1, wherein the ocular tissue comprises retina and/or foveal tissue.

3. The method of claim 1, comprising the step of determining that the eye has or is at risk of developing myopia.

4. The method of claim 1, comprising the steps of: the pulsed energy source energy parameter is selected to elevate the temperature of the ocular tissue to between six degrees celsius and eleven degrees celsius at least during application of the pulsed energy source.

5. The method of claim 1, wherein the average temperature rise of the ocular tissue is maintained at about one degree celsius or less over a period of minutes.

6. The method of claim 5, wherein the average temperature of the ocular tissue is maintained at one degree Celsius or less during a six minute time period.

7. The method of claim 1, wherein the pulse energy is applied to a plurality of ocular tissue regions, and wherein adjacent ocular tissue regions are separated by at least a predetermined distance to avoid thermal tissue damage.

8. The method of claim 7, wherein the pulse energy is applied to a first ocular tissue region and reapplied to the first ocular tissue region after a predetermined length of time within a single treatment session, and the pulse energy is applied to a second ocular tissue region during an interval between pulse energy applications to the first ocular tissue region.

9. The method of claim 1, wherein the pulsed energy source comprises a pulsed light beam having a wavelength between 530 nanometers and 1300 nanometers, a duty cycle of less than 10%, and a pulse train duration between 0.1 and 0.6 seconds.

10. The method of claim 9, wherein the pulsed light beam has a wavelength between 880 nanometers and 1000 nanometers and a duty cycle between 2.5% and 5%.

11. The method of claim 9, wherein the pulsed light beam has a power between 0.5 and 74 watts.

12. A method of preventing or treating myopia comprising the steps of:

Providing a pulsed energy source having energy parameters including wavelength or frequency, duty cycle, and pulse train duration selected to achieve a therapeutic or prophylactic effect without permanently damaging ocular tissue;

Determining that the eye has or is at risk of developing myopia; and

Applying the pulse energy to the retina and/or foveal tissue of the eye determined to be or at risk of developing myopia to stimulate heat shock protein activation in the eye tissue;

Wherein the pulse energy is applied to a plurality of ocular tissue regions, and wherein adjacent ocular tissue regions are separated by at least a predetermined distance to avoid thermal tissue damage; and

Wherein the pulsed energy source comprises a pulsed light beam having a wavelength between 530 nanometers to 1300 nanometers, a duty cycle of less than 10%, and a pulse train duration between 0.1 and 0.6 seconds.

13. The method of claim 12, wherein the applying step comprises the steps of: the eye tissue temperature is increased between six degrees Celsius and eleven degrees Celsius at least during the application of the pulsed energy source while maintaining the average eye tissue temperature below a predetermined level for a period of minutes.

14. The method of claim 12, wherein the average temperature rise of the ocular tissue is maintained at about one degree celsius or less over a period of minutes.

15. The method of claim 14, wherein the average temperature of the ocular tissue is maintained at one degree celsius or less during a six minute time period.

16. The method of claim 12, wherein the pulse energy is applied to a first ocular tissue region and reapplied to the first ocular tissue region after a predetermined length of time within a single treatment session, and the pulse energy is applied to a second ocular tissue region during an interval between pulse energy applications to the first ocular tissue region.

17. The method of claim 12, wherein the pulsed light beam has a duty cycle between 2.5% and 5%, a wavelength between 880 nanometers and 1000 nanometers.

18. The method of claim 17, wherein the pulsed light beam has a power between 0.5 and 74 watts.

19. A method of preventing or treating myopia comprising the steps of:

Determining that the eye has or is at risk of developing myopia; and

Wherein the pulse energy is applied to a plurality of ocular tissue regions, and wherein adjacent ocular tissue regions are separated by at least a predetermined distance to avoid thermal tissue damage;

Wherein the pulse energy is applied to a first ocular tissue region and reapplied to the first ocular tissue region after a predetermined length of time within a single treatment session, and the pulse energy is applied to a second ocular tissue region during an interval between pulse energy applications to the first ocular tissue region;

Wherein the applying step comprises the step of increasing the eye tissue temperature by between six and eleven degrees Celsius at least during the applying of the pulsed energy source while maintaining an average eye tissue temperature increase of about one degree Celsius or less for a period of minutes; and

Wherein the pulsed energy source comprises a pulsed light beam having a wavelength between 530 nanometers to 1300 nanometers, a duty cycle between 2.5% and 5%, a power between 0.5 and 74 watts, and a pulse train duration between 0.1 and 0.6 seconds.