BR112021009787A2 - process to deliver retinal phototherapy safely - Google Patents

Abstract

PROCESS TO SAFELY PROVIDE RETINA PHOTOTHERAPY. A process for safely providing retinal phototherapy, characterized in that it includes the generation of an interferometric signal or pattern by applying a beam of infrared light close to a retinal pigment epithelium of a retina of an eye. Level or concentration of melanin in the retinal pigment epithelium of the retina of the eye, characterized by the fact that it is elevated compared to a normal level or concentration using the detected interferometric signal or pattern. One or more treatment parameters of retinal phototherapy, characterized in that they are adjusted if the level or concentration of melanin in the retinal pigment epithelium of the eye exceeds the normal level or concentration by a predetermined amount.

Description

PROCESS TO SAFELY PROVIDE RETINA PHOTOTHERAPY DESCRIPTION FIELD OF THE INVENTION

[0001] The present invention generally relates to a process for safely providing retinal phototherapy. More particularly, the present invention is directed to a process for safely providing retinal phototherapy by adjusting the treatment parameters of retinal phototherapy based on the determination of an elevated content of retinal pigment epithelium (RPE) melanin.

FUNDAMENTALS OF THE INVENTION

[0002] The importance of macular pigment to eye health has sparked the development and interest in methods to measure its density or concentration in the retina. Previous systems and methods, however, were based on equipment that is not commonly available, time-consuming, or complicated and expensive.

[0003] Referring now to FIG. 1, a diagrammatic view of an eye, generally referred to by reference numeral 10, is shown. The eye 10 includes a cornea 12 which is a transparent front part of the eye that covers the iris and the pupil 14 which is the variable-sized or slit-shaped black circular opening in the center of the iris that regulates the amount of light entering the eye. eye. Lens 16 is a clear biconvex structure in the eye that, together with cornea 12, helps refract light to be focused onto retina 18. The retina is a thin layer of neural cells lining the back of the eyeball, which captures light and turns it into electrical signals for the brain. She has a lot of blood vessels 20 to nourish her. The fovea and macular region, referred to by the reference number 22, is a part of the eye used for color vision and fine detail vision. The retinal pigment epithelium (RPE) 24 is the layer of pigmented cells just outside the sensorineural retina 18 that nourishes the visual cells of the retina. It is firmly attached to an underlying choroid 26 which is a vascular layer of the eye 10 coated between the retina 18 and the sclera. The choroid 26 provides oxygen and nutrition to the outer layers of the retina 18.

[0004] Many eye diseases are related to the retina and methodologies have been developed to treat them. Some forms of phototherapy, such as photostimulation and photocoagulation, rely on heating retinal tissue to create their therapeutic effects. Excessive heating can damage or even destroy retinal tissue, which in some treatment methodologies is intentional, but in others is avoided. It has been observed that abnormal levels of pigmentation, particularly melanin levels or concentrations in the RPE, can cause unexpected excessive heat during such treatments and potentially damage retinal tissue.

[0005] Melanin in the eye has many important functions that are not yet fully understood. Melanin in the eye provides eye protection by absorbing harmful ultraviolet radiation. Melanin promotes visual acuity by scattering stray light away from rods and cones and absorbing reflected light at the back of the eye. Melanin also serves as an antioxidant to help prevent retinal diseases such as age-related macular degeneration.

[0006] Many of these properties result from the fact that the absorption spectrum of melanin is very broad. In this respect, it is unique among pigments. Many mechanisms have been suggested for this unique behavior. As examples, broadband absorption has been attributed to chemical heterogeneity, amorphous semiconductor and dispersion. However, it has been shown that dispersion losses represent only a small percentage of broadband attenuation. There are also problems with chemical heterogeneity and the amorphous semiconductor hypothesis. Some have proposed polymeric charge jumps. Others stressed the importance of hydration and the introduction of free radicals into melanin. Still others have suggested that melanin excitons may play a role in its broadband absorption. There does not seem to be universal agreement that any particular explanation can account for all of the electrical and optical properties of melanin.

[0007] As stated above, melanin within the eye serves many important functions. It may be important to ascertain the determination of levels or concentrations of melanin in the eye. For example, phytotherapy laser treatments of eye diseases may be based on inducing temperature increases in the RPE, which activates the eye's natural repair mechanisms. In the near infrared, this results from the absorption of infrared radiation by the melanin pigment in the RPE. Considerable melanin also exists in the choroid behind the RPE, but uptake by melanin in the choroid does not play a significant role in increasing the temperature of the RPE due to lack of diffuse heat transfer to the RPE during relatively short treatment times and due to cooling. convective by blood vessels in the choroid and choriocapillaries.

[0008] In herbal treatments of true subthreshold laser damage of eye diseases, which prevent retinal damage, laser treatment is effective as long as the temperature rise does not exceed the order of 10°C. This temperature rise limitation determines the maximum laser energy that can be absorbed by the RPE during the treatment time. A possible concern, however, is that for laser powers that are adequate for most patients, the temperature rise may exceed the threshold for harm if the melanin content or concentration of the patient's RPE is abnormally large.

[0009] Consequently, there is a continuing need for a simple and relatively inexpensive process to determine melanin levels or concentrations within the eye, and particularly within the RPE of the eye, so that one or more treatment parameters of the phototherapy treatment of retina can be adjusted as necessary to avoid injuring the patient's eyes that have an abnormally high content or concentration of melanin in the RPE. The present invention meets these needs and provides other related advantages.

SUMMARY OF THE INVENTION

[00010] The present invention is directed to a process for safely providing retinal phototherapy by adjusting one or more treatment parameters of retinal phototherapy if the melanin content or concentration in the RPE of the eye exceeds a predetermined amount.

[00011] An interferometric signal or pattern is generated by applying a beam of infrared light close to the retina of an eye. Preferably, the light beam has a wavelength between 600 nm and 1000 nm and a depth resolution on the order of 3 to 10 microns. The light beam is divided into a reference beam and a sample beam which is applied to the retinal pigment epithelium of the eye.

[00012] Interferometric signal or pattern is detected. This may comprise using a photodetector to detect light reflected from the retina. An optical coherence tomography device can be used to apply the light beam to the retina and detect the interferometric signal or pattern.

[00013] It is determined whether a level or concentration of melanin in the retinal pigment epithelium of the retina of the eye is elevated compared to a normal level or concentration using the detected interferometric signal or pattern. This can be done by calculating a ratio between abnormal densities of retinal pigment epithelium melanin and normal retinal pigment epithelium melanin. This can be as per the calculation of: [{Nσs + μbackscat}RPE /{2N(σs +σa) + 2μbackscat}RPE}] times [1 - exp[-2w{N(σs +σa) + μbackscat}RPE ]], where N is the numerical density of the melanin aggregates that absorb and scatter the light beam; σs denotes a cross-section of a backward scattering melanin aggregate; σa denotes a cross-section of an aggregate of melanin for absorption; and μback scat is a coefficient for backscatter of a retinal structural matrix.

[00014] One or more treatment parameters of retinal phototherapy are adjusted if the level or concentration of melanin in the retinal pigment epithelium of the eye exceeds the normal level or concentration by a predetermined amount. One or more treatment parameters can be adjusted when the change in the signal or interferometric pattern is ten percent or more. One or more treatment parameters can be adjusted when the level or concentration of melanin in the retinal pigment epithelium is at least three times higher than the normal level or concentration.

[00015] This adjustment step comprises adjusting at least one of a retinal spot size of a treatment light beam, a pulse train duration of the treatment light beam, a duty cycle of the treatment light beam or a power of the treatment light beam. For example, a retinal spot size of the treatment light beam can be increased. Alternatively, or in addition, a pulse train duration of a treatment light beam can be reduced. Alternatively, or in addition, a duty cycle of a treatment light beam can be reduced. Alternatively, or in addition, the power of the treatment light beam may be reduced.

[00016] One or more treatment parameters of the retina therapy system can be automatically adjusted when the concentration of melanin in the retinal pigment epithelium of the eye exceeds the predetermined amount. A notification may be provided that one or more of the retina care parameters have been automatically adjusted. Other features and advantages of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[00017] The accompanying drawings illustrate the invention. In such drawings:

FIGURE 1 is a schematic view of an eye; FIGURE 2 is a schematic view of a system used in accordance with the present invention to determine melanin levels within an RPE of an eye; FIGURE 3 is a schematic view of an OCT system used in accordance with the present invention; FIGURE 4 are images of retinal layer mappings of an eye using an OCT device; FIGURE 5 is a graph illustrating the wavelength dependence of primary eye pigment absorption; FIGURE 6 is a graph illustrating the wavelength dependence of primary eye pigment absorption over a narrower wavelength range; FIGURE 7 is a graph illustrating the absorbance of eumelanin as a function of wavelength; FIGURE 8 is a graph depicting bidirectional transmission through melanin in the RPE at ordinary concentrations; FIGURE 9 is a graph illustrating the variation of melanin transmission in the RPE at different wavelengths; FIGURE 10 is a graph depicting the percent change in OCT signal representing the ratio of melanosome density in the RPE to normal density; FIGURE 11 is a graph showing the ratio of damage of the melanin content in the abnormal RPE to the melanin content in the normal RPE at which damage may occur compared to a pulse train duration of pulsed light phototherapy; and FIGURE 12 is a graph similar to FIG. 11, which illustrates the damage ratio over a range of 200 milliseconds to 500 milliseconds of phototherapy pulse train duration.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES

[00018] For purposes of illustration, the present invention is directed to a process for safely providing retinal phototherapy by determining melanin concentrations within an eye, and particularly within the retinal pigment epithelium (RPE) of the eye. The determination of melanin concentrations in the RPE of the eye can be important in determining the treatment of eye diseases. For example, if an individual has abnormally high concentrations or levels of melanin within the RPE, this can cause unexpectedly high heating and thus tissue destruction when treating the eye, and particularly the retina, with light sources such as beams of light. infrared or near-infrared laser light, such as those used in retinal phototherapy, such as photocoagulation or photostimulation where tissue is heated as part of the therapy process. It is the level or concentrations of melanin within the RPE that are often important to determine, as this is the layer that can cause excessive heating and damage when the retina is exposed to light sources during photocoagulation or photostimulation treatments.

[00019] Melanin in the eye is mainly eumelanin and its monomer has the chemical formula C18H10N2O4, and a molecular weight of 318.283, with a density of 1.7 g/cc and a refractive index of 1.772. In RPE, melanin is contained in protein-encoded organelles called melanosomes. Within melanosomes, melanin monomers, which have dimensions of less than ten Angstroms, combine to form aggregates. The aggregates have dimensions of several tens of Angstroms and are made up of stacked sheets of covalently bonded monomer, with the sheets having separations of 3.4 Angstroms. The sheets are held together by weaker pi-pi bonding forces.

[00020] The melanin in the RPE is derived from neural ectoderm. In RPE, melanosomes are located primarily in the apical region of RPE cells and are elongated in shape, with the long dimension aligned with the apices to make close contact with the rods and cones. Typical widths of all melanosomes in the extraneous RPE are 250-500 nm and typical lengths are 640-800 nm. This gives 6.5 x 10-14 cubic centimeters for a typical melanosome volume. Melanin is densely packed into melanosomes in the RPE, the density of melanin in a monomer being 1.7 g/cc.

[00021] In RPE, from the previous numbers, the number density of melanin is 3.38x1018 cm-3 with a mass density of 1.8x10-3 g/cc, and since the melanin is all contained in the melanosomes , the corresponding number density of the melanosomes in the RPE is 10x1010 cm-3. This gives a linear separation between the melanosomes in the RPE of 3.68 microns.

[00022] Referring now to FIG. 2, a system 100 is shown that can be used in accordance with the present invention. The laser console 102 generates a beam of light having a wavelength near the infrared. The wavelength range can be between 600 nm and 1000 nm, typically between 600 nm and 850 nm. Wavelengths below the predetermined wavelength range begin to absorb and scatter light from other pigments, and wavelengths above the predetermined wavelength range of the present invention are increasingly absorbed by water. However, the predetermined wavelength range of the present invention, between 600 nm and 1000 nm, is ideal for measuring RPE melanin levels.

[00023] The generated light beam is then passed through optics 104, which can be used to focus the light beam, filter the light beam, generate a plurality of light beams from the first generated light beam, or the like. The light beam is then passed through the projector 106, which may be a retinal camera or the like, for projection onto the eye 10 and more particularly so as to apply the first beam of light to the RPE 24 and the choroid of the eye 10. Additional optics 108, as needed, can be used to direct the light beam to the RPE 24 of the retina. Reflections from the RPE are detected by detector 110. Detector 110, in a particularly preferred embodiment, detects interferometry, such as an Optical Coherence Tomography (OCT) device.

[00024] The amount of light reflected from the RPE by the light beam is measured and then a concentration of melanin within the RPE of the eye is determined using the measured amount of light reflected from the RPE of the light beam. The determined level or concentration of melanin within the RPE can then be compared to normal or average anticipated levels of melanin within the RPE to determine whether melanin levels within the RPE of that eye are elevated or outside the anticipated range or predetermined amount.

[00025] Referring now to FIG. 3 , in a particularly preferred embodiment, an interferometric signal or pattern is generated and detected from which it can be determined whether the level or concentration of melanin within the RPE is dangerously high. This involves generating a beam of infrared light using a light source (LS). As will be described in more detail herein, the light beam has a wavelength between 600 nm and 1000 nm, and more preferably a wavelength between 600 nm and 850 nm. A beam splitter (BS) splits the light beam into a reference beam (REF) and a sample beam (SMP) which is applied to the retina and more particularly to the RPE. Typically, the reference beam is applied to a moving mirror or other reference point.

[00026] Continuing with reference to FIG. 3, the light beam and more particularly the sample beam portion (SMP) of the light beam is focused to a depth resolution on the order of 3 to 10 microns which corresponds to a thickness of the RPE. The light reflected from the RPE comprises an interferometric signal or pattern that is detected, such as using a photodetector (PD). Digital signal processing (DSP) in the form of electronics, including a microcontroller and/or computer, processes the reflections and can create a displayable image (IMAGE) and/or provide the determination if the level or concentration of melanin within the RPE of the retina of the eye is elevated compared to a normal level or concentration.

[00027] Typically, the device or system that generates the near-infrared light beam and detects the interferometric signal or pattern is an optical coherence tomography (OCT) device or system. The principle of OCT is light or low coherence interferometry. The optical configuration typically consists of a low-coherence interferometer and a light source. The light is split and recombined from the reference on the sample arm respectively, as described above. In OCT, interference occurs at a distance of micrometers, due to the use of the light source used. As described above, light in an OCT system is split into two arms, namely a sample arm containing the item of interest and a reference arm, usually a mirror. The combination of light reflected from the sample arm and reference light from the reference arm gives rise to an interference pattern if the light from both arms has shifted approximately the same optical distance. By scanning the mirror on the reference arm, a reflectivity profile of the sample can be obtained, which is a time domain OCT. Areas of the sample that reflect a lot of light will create greater interference than areas that do not. A cross-sectional tomography, as illustrated in FIG. 4, can be obtained by laterally combining a series of these axial depth scans. OCT can be used to obtain subsurface images of translucent or opaque materials at a resolution equivalent to a low power microscope. It will be appreciated that the OCT device generally described in FIG. 3 may have additional components, such as additional optics, cameras, filters, diffraction graduation, and the like, as needed. A benefit of using an OCT device in accordance with the present invention is that they are commonly used in the ophthalmic field and the data obtained from them can be used in accordance with the present invention or the OCT system can be modified as necessary to in order to carry out the present invention.

[00028] OCT is routinely used by retinal specialists to obtain images of the retina. Regardless of the treatment used, OCT is typically used to assess the general condition of the retina before starting treatment. FIG. 4 illustrates two OCT mappings of retinal layers. The OCT image on the left has a depth resolution of ten microns and is obtained with a superluminescent diode (SLD) with a central wavelength of 843 nm. The OCT image on the right has a depth resolution of three microns and is obtained with a TI:AL2O3 laser with a mean wavelength of 800 nm. The RPE in these images is normally the brightest layer.

[00029] Continuing with reference to FIG. 4, an example of in vivo topographic mapping of retinal layers in the central fovea along ~3 mm of the papillomacular axis is shown. The logarithm of the signal is represented in a false color scale shown at the top of the figure. (A) SLD: mean wavelength λ = 843, λ = 30 nm, depth resolution 10 μm. (b) Ti: Al2O3 laser: mean wavelength λ = 800 nm, λnm; 3μm depth resolution. The layers are (top): ILM / NFL = inner limiting membrane / nerve fiber layer; IPL = inner plexiform layer; OPL = outer plexiform layer; ONL = external nuclear level; ELM = outer limiting membrane; PR-IS = internal segment of photoreceptors; PR-OS = outer segment of photoreceptors RPE = retinal pigment epithelium; Ch = choriocapillary and choroid.

[00030] As mentioned above, OCT is based on low-coherence interferometry and typically employs near-infrared light. In its simplest form, in an OCT system, this near IR light is split into two arms: a sample arm that contains the target of interest and a reference arm that contains a moving mirror. An interference pattern arises when light reflected from the sample arm is combined with light reflected from the reference arm, but only if light from both arms has shifted by nearly the same distance. In this document, “close” means that the two paths must be within the “coherence length” of the radiation source. This means that for short coherence lengths, the OCT device can be “focused” to a specific depth of the target simply by adjusting the length of the reference arm by moving its mirror. Hereby, all other target depths are excluded from contributing to the desired signal.

[00031] For an OCT, the depth resolution z is often given as: z = ( 2ln2/π(λ2/λ) = 0.44 (λ2/λ) [2.1]

[00032] This assumes an ideal Gaussian amplitude spectrum. This expression is a limiting case of the more general uncertainty relation estimation for a wave packet: z k ≈ 2π [2.2a] which, with k = 2π / λ, |k| ≈ 2π (λ/λ2 ), [2.2b] Giving: z ≈ (λ2/λ). [2.3]

[00033] For example, for the case λ = 800nm and λ = 260nm of FIG. 7, eq. [23] gives a depth resolution z ≈ 2.5 μm, not very different from the 3 μm resolution obtained from the real Ti:Al2O3 OCT system.

[00034] Treating the total electric field ET(t) at the interferometer detector as a scalar, it can be written as the sum of the field ER(t +t) of the reference arm and the field ES(t) of the reference arm. sample: ET(t) = ER(t+t) + ES(t) [2.4]

[00035] In this expression, a time delay t has been introduced in the reference signal to allow for a difference in the path lengths of the reference and sample arms.

[00036] The intensity I (t) associated with each field E (t) is: I(t) = E*(t)E(t). [2.5]

[00037] We can consider that each electric field has the form: E(t) = A(t) exp[(t) –iωt], [2.6] where A(t) exp[(t)] is the envelope of the field and ω is the average angular frequency of the force spectrum of E(t). For the fields of interest in OCT, the envelope time change rates are small compared to those described by the mean angular frequency ω.

[00038] Then, the average intensity at the interferometer detector is: IT(t) = <ET*(t, t) ET(t, t)>, [2.7] where the angle brackets indicate a mean of the set . The process can be considered ergodic so that the average intensity is independent of t.

[00039] When inserting eqs. [2.4] - [2.6] in eq. [2.7], the results are: IT(t) = IS + IR + GSR(t), [2.8] With : GSR(t) = 2{ISIR]1/2 γSR(t)cos[αSR – δSR(t)]. [2.9]

[00040] The quantity GSR(t) contains the desired interferometric information that provides the target information. In this expression, γSR(t is the complex degree of coherence of the two waves, δSR(t) is the phase delay with the time delay  related to the path difference z between the reference and sample beams by  t = z / c The quantity αSR is a constant phase with no consequence for the determination of information about the target.

[00041] Equation [2.9] was developed for a simple OCT where a difference in path length is introduced between the reference and target arms, say, by a movable mirror on the reference arm. Since it arises from a correlation function between the fields of the reference and target arm, it is simple to apply the Wiener-Khinchine theorem relating a correlation function and a spectral power density to obtain expressions for OCT instruments in the frequency domain. equally. But the basic physics underlying OCT is simply low-coherence interferometry between the signals from a reference arm and a sample arm.

[00042] From the description above, OCT is based on interference between signals in a reference arm and a sample arm that arises from a source with a very short coherence time. Because of the very short coherence time sources used in OCT, the phenomenon is very similar to interference between two short wave packets. Only when the difference between the two paths corresponds to a time difference less than the duration of the wave packet will there be an interference signal. This means that when the coherence time is too short, the peak of the interferometric signal will only emerge from a given depth in the sample. This depth is determined by the movable mirror on the reference arm: the depth is only half the light path length on the Ito reference arm and the mirror). The signal will go to zero when the depth differs from this value by the depth resolution estimate of eq. [2.3].

[00043] The significance for measuring the melanin content of the RPE is that by choosing a source coherence distance comparable to the thickness of the melanin of the RPE (6-8 microns), it is possible to use OCT to isolate the contribution of melanin in the RPE for the OCT signal and thereby determine when the concentration of melanin in the RPE is dangerously high.

[00044] Specifically, for source coherence distances on the order of 6-8 microns, the total OCT interferometric signal from the radiation from the RPE interacting with the signal from the reference arm will be determined by: o Backscatter of the RPE, and o Attenuation by absorption and scatter propagation through the RPE and anterior retina.

[00045] Source coherence distances in OCT are comparable to RPE thickness: sometimes shorter, sometimes longer. For example, in the two cases of FIG. 4, the coherence distances are 3 microns and 10 microns. The approximate equations developed below should suffice to give the dependencies of the results on the melanin content in the RPE: In particular, they should be usable for estimating the relative magnitudes of the expected signals of normal and dangerously abnormal melanin levels.

[00046] Nearby IR radiation in the sample arm experiences absorption and scattering (the latter resulting in reflection of the radiation at the interferometer detector).

[00047] Referring now to FIG. 5, a graph shows the wavelength dependence primarily in the near-infrared of the absorptions of the four primary eye pigments, namely melanin, oxygenated hemoglobin, hemoglobin and water. Lens absorption is also shown. It can be seen that the absorption spectrum of melanin differs from all other pigments in being very broad. However, melanin in RPE absorbs and scatters radiation. In the range of 600-800 nm plus, the absorption of melanin is greater than the absorption of all other pigments in the water in the eye, as shown in FIG. 5.

[00048] Referring now to FIG. 6, the absorption of blood, melanin, macular pigments, the lens, water, long wavelength sensitive visual pigments (LWS) and medium wavelength sensitive visual pigments (MWS) mainly within the visible range of wavelengths is illustrated. wave. The blood layer is 23 microns thick and has an oxygenation of 95%. The melanin density is from 1.32 to 500 nm and the macular density is from 0.54 to 460 nm. Lens density is 0.54 at 420 nm and water density is 0.025 at 740 nm. Visual pigment densities are both 0.57 at their peaks. In the eye, melanin dominates the absorption of laser light in the wavelength range generally between 550 nm and 1000 nm, and more particularly between 600 nm and 850 nm, as shown in FIG. 6.

[00049] Previous modeling of the spectral reflectance of the human eye used values of 3.61-8.05 mmol/L for melanin in the RPE. The thickness of the melanin layer in the RPE is less than 10 microns, typically around 6 microns. It was observed that the melanin content in the RPE generally does not vary much from patient to patient.

[00050] As seen in FIG. 6, the melanin absorption coefficient decreases considerably as the wavelength increases. Thus, at the lower 600 nm end of the melanin-dominated absorption window, the absorption of melanin in the RPE is much greater than at the higher end than 850 nm of a particularly preferred range of wavelengths. However, there is no general agreement on how melanin absorption varies with wavelength.

[00051] FIGURE 7 is a graph illustrating the absorbance of eumelanin as a function of wavelength, particularly between 250 nm and 700 nm. Eumelanin is the dominant component of melanin in the eye. Although there is no general agreement on the variation of optical density with wavelength, the present invention considers exponential dependence of exp [-0.062λ (nm), which is reflected in FIG. 7. If this result is combined with the earlier finding of an optical density of 0.22 at 500 nm, this gives bidirectional transmission through the RPE of: Transmission = exp [-2αL] = exp [-22.72 exp [ -0.0062 λ (nm)]]. [3.1]

[00052] On the other hand, if an optical density of 0.29 at 500 nm is used, then the result will yield: Transmission = exp [-2αL] = exp [-29.973 exp [-0.0062 λ (nm)]] . [3.2]

[00053] Equations [3.1] and [3.2] are graphically represented in FIG. 8, which is a graph depicting bidirectional transmission (as determined by the large absorption cross section) through melanin in the RPE at common concentrations. The upper curve considers the optical density to be 0.22 at 500 nm, while the lower curve considers the optical density at 500 nm to be 0.29. It can be seen that towards the 850 nm limit of the melanin-dominated absorption window, the absorption coefficient of melanin in the RPE is small, allowing the reflected signal from the choroid to pass through detector 110. At high and potentially dangerous levels of melanin in the RPE, the signal reflected from the choroid at 600 nm decreases considerably when passing through the RPE, while at 800 nm it does not decrease as much.

[00054] FIGURE 9 is a graph illustrating the variation of melanin transmission in the RPE (as determined by the large absorption coefficient) at 750 nm (upper curve) and at 600 nm (lower curve), as the concentration of melanin in the RPE ranges from normal (n = 1) to an elevated hazard threshold of three times normal (n = 3). In FIG. 9, the optical density at 500 nm is considered to be 0.22 for a normal concentration of RPE. Continuing with reference to FIG. 9, the graph shows the behavior of melanin transmission in the RPE at 600 nm and 750 nm, as the concentration ranges from normal (n = 1) to a dangerous level of three times normal (n = 3). The graph of FIG. 9 shows that at 600 nm the transmitted signal is decreased by a factor close to 4, while at 750 nm it is decreased by only a factor of approximately 1.5. This big difference, however, can be mitigated somewhat by other factors in the reflectivity expression.

[00055] In addition to being the dominant absorber of radiation in the wavelength range from 600 nm -800 nm plus, melanin also scatters radiation. Melanin is densely packed in melanosomes. As described above, in RPE the melanosomes are elongated in shape and make close contact with the rods and cones. Melanosomes are considered the basic scattering entities. Melanosomes have dimensions comparable to the 600nm-850nm wavelengths of interest. A typical RPE melanosome has dimensions of 250-400 nm (average 300 nm) wide by 640 nm-800 nm (average 720 nm) in length.

[00056] Consequently, the dispersion in this wavelength range is in the Mie dispersion domain. For Mie scattering, the cross-section of asymptotic scattering in the backward direction is approximately proportional to λ2. The resulting cross section for the backward scattering of a melanosome in the RPE is: σsRPE ≈ ≈ 0.05x10-14 λnm 2 cm2 , [3.3] where λnm denotes the wavelength expressed in nanometers.

[00057] Although absorption is dominated by melanin in the wavelength range 600 nm - 800+ nm, scattering can also result from the structural matrix in which the melanosomes are embedded. It was determined that the retinal and choroidal scattering properties of OCT scans for a wavelength of 855 nm on the retina are: o Scatter coefficient 1.64x10-4 λnm2 RPE = 120 cm-1 o Anisotropic Factor gRPE =< cosθ> = 0.97

[00058] The backward scatter coefficient is obtained from the scatter coefficient by multiplying it by (1-g).

[00059] The dispersion occurs due to incompatibilities in the refractive index of different tissue components, ranging from cell membranes to whole cells. Cell nuclei and mitochondria are the most important dispersers. Their dimensions range from 100 nm to 6 μm and thus are within the NIR window. Most of these organelles fall in the Mie region, and exhibit highly anisotropic forward-directed scattering.

[00060] The anterior gives only the scattering coefficient and the anisotropic factor for the entire retina and not for the RPE layer that forms the posterior layer of the retina individually. We should approximate the RPE scattering coefficient and the anisotropic factor using the total retinal quantities.

[00061] We must apply the factor λ2 of eq. [3.3] to determine the dispersion coefficients at other wavelengths, resulting in: μ backscatRPE = (1-0.97) 120 (λnm /855)2 = 4.92 x10-6 λnm2 cm-1 [3.4]

[00062] These can be compared with the melanin scattering coefficients for normal melanosome densities (NRPE = 2x1010 cm-3) μ sRPE = 2x1010 x 0.05x10-14 λnm2 = 1x10-5 λnm2 cm-1[melanin density in normal RPE] [3.5]

[00063] We see that the dispersion of the structural matrix in the RPE is smaller than that of melanin. The scattering coefficients are also smaller than the data above for the absorption coefficient at normal melanin densities: μ aRPE = 2x1010 x 9.47x10-7 exp[-0.0062λnm]= 1.89x104 exp[-0.0062λnm ] [3.6]

[00064] The melanosome number densities and scattering cross-sections indicate that not much scattering occurs when shifting the RPE to radiation with wavelengths in the 600-800+ nm wavelength range. This is much lower than the optical density for absorption by melanin. Optical scattering density in the anterior retina is also small.

[00065] In the RPE with a melanosome density of 2x1010 cm- 3 , the mean free path is: Λmfp = 1 / 9.54 = 0.0.1 cm, that is, 1000 microns. [3.7]

[00066] This is much larger than the 6-10 micron thickness of the RPE, so the probability that a photon will scatter when displacing the RPE is actually very small. The optical density for scattering in RPE is: OD scattering in RPE = μscatw =9.54x0.0006 / 2.303 = 0.004. [3.8]

[00067] This is much lower than the optical density for absorption by melanin. Optical scattering density in the anterior retina is also small. Consequently, in the 600-800 nm wavelength range, absorption is more important than dispersion in the RPE.

[00068] Because the scattering of near IR radiation in the RPE is so small, we will use the transport equations developed by Kubelka and Munk (1931). More exact treatments are possible using numerical Monte Carlo methods [See, for example, Preece and Claridge (2002)], but we use the simple Kubelka-Munk equations in this document to develop a simple intuition for the dependence of OCT results on the parameters.

[00069] The treatment is similar to the calculation of total reflectivity. However, it differs from the latter in that the interference signal for a low coherence source with a time delay corresponding to a point within the RPE and a depth resolution comparable to the thickness of the RPE means that no contribution to the signal will arise from the choroid.

[00070] Furthermore, we have seen that the cross section for absorption is large only for the RPE and therefore we must ignore the attenuation of radiation through the anterior portion of the retina. (This should be enough to show how the relative signals received by the interferometer detector are a normal concentration of melanin in the RPE and a dangerously high level of melanin concentration in the RPE.)

[00071] Consequently, we must consider that the short coherence interferometric signal arises only from the reflected (and attenuated) radiation in the RPE itself. The approximate steady-state transport equations are: dI(+)/dx = -[N(σs +σa)+μback scat] I(+) +[ Nσs +μback scat] I(-) [3.9] dI(- )/dy = -[N(σs +σa)+μback scat] I(-) + [ Nσs +μback scat] I(-) [3.10]

[00072] In this document, the I (+) is the intensity of the incoming radiation as it travels through the RPE; the I (-) is the intensity of the reflected radiation as it travels back through the RPE to the front of the RPE; x is the distance in the RPE measured from the front of the RPE;

o y = w-x, where w is the thickness of the melanin layer in the RPE; N is the numerical density of melanin aggregates that absorb and disperse radiation; the σs denotes the cross section of an aggregate of melanin for backward dispersion; σa denotes the cross section of an aggregate of melanin for absorption; and μbackscat is the backscatter coefficient of the structural matrix.

[00073] It has previously been shown experimentally that σa/(σs +σa) is quite large, the dispersion contributing less than 6% to the total optical attenuation at all wavelengths in the UV and optical range. The amount N(σs +σa) w is simply 2.303 x the total attenuation optical density (absorption plus dispersion) of the melanin layer in the RPE. Equations [3.9] and [3.10] can be further simplified by ignoring the term +Nσs I (-) in eq. [3.9], the rationale for this is that the reflected signal I(-) is much smaller than the input signal I(+). So by requiring that: I (+) at x = 0 is equal to the input intensity Io [3.11] I (-) at x = w is equal to 0 at x = w [3.12]

[00074] The equations can be solved directly to give the output intensity I (-) ax = 0 I(-, x = 0) = I(+,x=0) [{Nσs + μbackscat}RPE /{2N( σs +σa) + 2μbackscat}RPE}] times [1 - exp[-2w{N(σs +σa) + μbackscat}RPE ]] [3.11]

[00075] The subscript “RPE” was added in eq. [3.11] to indicate that the amounts are for the RPE.

[00076] By eq. [2.9], the OCT interferometric signal is proportional to {I(-, x = 0)I(+,x=0)}1/2

[00077] OCT sign = constant x I (+, x = 0) [{Nσs + μbackscat}RPE /{2N(σs +σa) + 2μbackscat}RPE}]1/2 x [1 - exp[-2w{ N(σs +σa) + μbackscat}RPE ]]1/2 [3.12] where the constant is determined by the specifications of the efficiencies and geometry of the system.

[00078] To avoid system specification issues, we should focus our attention on the ratio of OCT signals to abnormal and normal RPE densities: OCT signal (abnormal RPE melanin density) / OCT signal (RPE melanin density) normal = [{Nσs + μbackscat}RPE /{2N(σs +σa) + 2μbackscat}RPE}] times [1 - exp[-2w{N(σs +σa) + μbackscat}RPE ]] [3.13]

[00079] Referring now to FIG. 10, a graph illustrating the percent change in OCT signal given by Eqs. [3.12] and [3.13] as the melanosome density in the RPE increases from its normal value of 2x1010 cm-3 by a factor of n. FIG.10 illustrates the percentage change in OCT signal from equation [3.12] versus n, where n is the ratio of abnormal melanosome density in the RPE to the normal density of 2x1010 cm-3. FIG. 10 shows that a 20% change in the OCT signal results from an increase in melanosome density in the RPE by a factor of about five. Hazard thresholds of normal melanosome densities in the RPE of 3 to 8 times result in a decrease in the OCT signal of the order of 10% and can be reliably measured by photoelectric cells or other similar detectors. Pretreatment low optical coherence (OCT) coherent tomography with central wavelength in the wavelength range of 600 - 900 nm and depth resolution on the order of 3-10 microns can be used to detect dangerous levels of melanin concentrations in the RPE. Photocells are quite capable of detecting the type of changes indicated in FIG. 10. This suggests that a photodetector can be used to obtain reliable detection of hazard threshold percent changes in brightness. This can be done by accessing the photoelectric signal from the OCT detector directly or by using a photocell to measure the brightness of the OCT visual monitor. This can be compared to what would be considered a normal melanin RPE level, which is on the order of 2x1010cm-3 for a normal patient.

[00080] It should be noted that the concentration of melanin in the RPE varies with the lateral position of the eye. It peaks at the center of the macula and then decreases on both sides over a range of approximately 5° to a relatively constant value for about 10° on both sides, before rising again towards the equator at -20°. ° and + 15°. To obtain consistent results, it is best to operate the detector 110 in regions where the concentration is relatively constant, or in other words on the order of approximately 10° away from the center of the macula.

[00081] Table 1 below shows the peak laser power for retinal phototherapy treatment that will keep the Arrhenius integral for HSP activation at a conservative value of unity when the melanin content in the RPE assumes different values. The peak power for different values of point radius, train duration, duty cycle and abnormal melanin rate content in RPE is shown.

The table considers a treatment pulse wavelength at 810 nm.

TABLE 1: R dc α / Psdm (micron) tF (s) (%) αnormal (watts)

100 0.2 2 1 3.44 3 3.14 5 0.69 8 0.43 100 0.2 3 1 2.29 3 0.76 5 0.46 8 0.29 100 0.2 4 1 1, 72 3 0.57 5 0.34 8 0.21 100 0.2 5 1 1.38 3 0.46 5 0.28 8 0.17

100 0.3 2 1 2.68 3 0.89 5 0.54 8 0.33

100 0.3 3 1 1.79 3 0.6 5 0.36 8 0.22

100 0.3 4 1 1.34 3 0.45 5 0.27

8 0.17

100 0.3 5 1 1.07 3 0.36 5 0.21 8 0.14

100 0.4 2 1 2.14 3 0.71 5 0.43

8 0.27

100 0.4 3 1 1.43 3 0.48 5 0.29 8 0.18

100 0.4 4 1 1.07 3 0.36 5 0.21 8 0.13

100 0.4 5 1 0.86 3 0.29 5 0.17 8 0.11

100 0.5 2 1 1.72 3 0.57 5 0.34 8 0.21

100 0.5 3 1 1.15 3 0.38 5 0.23 8 0.14

100 0.5 4 1 0.86

3 0.29 5 0.17 8 0.11

100 0.5 5 1 0.69 3 0.23 5 0.14 8 0.09

200 0.2 2 1 6.88 3 2.29 5 1.38 8 0.86

200 0.2 3 1 4.59 3 1.53 5 0.92 8 0.57

200 0.2 4 1 3.44 3 1.15 5 0.69 8 0.43

200 0.2 5 1 2.75 3 0.92 5 0.55 8 0.34

200 0.3 2 1 5.36 3 1.79 5 1.07 8 0.67

200 0.3 3 1 3.57 3 1.19 5 0.71 8 0.45

200 0.3 4 1 2.68 3 0.89 5 0.54 8 0.33

200 0.3 5 1 2.14 3 0.71 5 0.43 8 0.27

200 0.4 2 1 4.28 3 1.43 5 0.86 8 0.54

200 0.4 3 1 2.85 3 0.95 5 0.57 8 0.36

200 0.4 4 1 2.14 2 0.71 5 0.43 8 0.27

200 0.4 5 1 1.71 3 0.57 5 0.34 8 0.21

200 0.5 2 1 3.44 3 1.15 5 0.69 8 0.43

200 0.5 3 1 2.3 3 0.77 5 0.28 8 0.29

200 0.5 4 1 1.72 3 0.57 5 0.34 8 0.22 200 0.5 5 1 1.38 3 0.46 5 0.28 8 0.17

[00082] As shown in Table 1 above, the range of the ratio of abnormal melanin content in the RPE to the normal melanin content in the RPE was taken to a range between one and eight. The laser peak power depends on the laser spot radius on the retina, the duration of the micropulse train and the duty cycle. For each of these cases, the ratio of abnormal to normal RPE melanin content was considered to be 1, 3, 5, and 8.

[00083] Any abnormal melanin content of the RPE is manifested through a change in the absorption coefficient of the RPE for the incoming laser radiation: the absorption coefficient is proportional to the total melanin content of the RPE. Consequently, in the table, the melanin content in the RPE is represented by four values of the ratio of the absorption coefficient α to the normal absorption coefficient αnormal: α / αnormal = 1, 3, 5, 8.

[00084] The effect of melanin content on Psdm laser peak treatment potency depends on laser retinal spot radius (R), micropulse sequence duration (tF) and sequence duty cycle (dc) micropulse (tF). In the table, examples are given for Psdm (in watts) for all possible combinations of:

R = 100 microns, 200 microns tF = 0.2 s, 0.3 s, 0.4 s and 0.5 s dc = 2%, 3%, 4%, 5% for each of the four values of the α/ αnormal.

[00085] The value of λnm shown is the peak power value that maintains the Arrhenius integral for heat shock protein (HSP) activation Ωhsp at a (conservative) treatment value of unity: Ωhsp = 1.

[00086] And it was considered that the wavelength of the treatment laser is 810 nm - for which αnormal = 104 cm-1.

[00087] For an arbitrary near IR wavelength (in nanometers) λnm, the treatment powers in the table should be multiplied by the factor ξ(λnm): ξ(λnm) = Exp [0.0062 (810-λnm)] , ie Psdm(λnm) = Psdm ξ(λnm) = Psdm (table value) x Exp [0.0062 (810- λnm)].

[00088] From the above, it can be seen that Psdm decreases as α / αnormal increases; the values of Psdm are larger the larger the radius of the point (R); the values of Psdm are higher the shorter the duration of the train tF; and the Psdm values are higher the smaller the duty cycle (dc).

[00089] FIGURES 11 and 12 are graphs showing the ratio of abnormal RPE melanin content to normal RPE melanin content at which damage may occur. These graphs are based on approximate expressions for the Arrhenius integrals for HSP activation and for damage that give surprisingly close matches to the exact expressions. Both graphs represent the ratio rdano vs the duration of the tF pulse train. The graph of FIG. 11 covers the tF range from 0.01 s to 1 s. The graph of FIG. 12 covers a more realistic clinical range of tF from 0.2 to 0.5 s.

[00090] As can be seen in FIGS. 11 and 12, the critical ratio of abnormal melanin content in the RPE to the normal melanin content in the RPE at which damage can occur ranges from 3 to about 8 for pulse train durations ranging from 0.2 to 0 .5 s. Thus, one or more treatment parameters, as described above, are adjusted when the melanin content in the RPE is determined to be at least three times greater than a normal melanin content in the RPE. Thus, considering a normal RPE density of 2x1010 cm-3, one or more treatment parameters are adjusted when the melanin content in the RPE is determined to be greater than 6x1010 cm-3.

[00091] At this critical ratio, damage can be avoided and effective activation of the HSP can be ensured by shifting treatment parameters from their normal values. For example, for most clinical treatment parameters of interest: Peak power P can be reduced from its normal value Pnormal to be in range; Pnormal/ rdano<P Pnormal, if the duty cycle and retinal spot radius are left at their normal values.

[00092] The dc duty cycle can be reduced from its normal dcnormal value to be in the range: dcnormal / rdano<dc dcnormal, if the peak laser power and retinal spot radius are kept at their normal values.

[00093] The radius of the retinal point R can be increased from its normal value Rnormal to be in the range:

Rnormal< RRnormal rdano, if peak laser power and duty cycle are maintained at their normal values.

[00094] Although a single laser phototherapy parameter can be adjusted, it will be understood that more than one of these parameters can also be adjusted simultaneously. For example, the laser spot radius can be increased in diameter and the power reduced, but not decreased to the extent that would be necessary if only the power were reduced. Likewise, all parameters can be adjusted slightly, such as slightly increasing the retinal spot size for the treatment light beam, decreasing the pulse train duration of the treatment light beam, decreasing the duty cycle of the treatment light beam and decreasing the power of the treatment light beam so that unity in the Arrhenius integral is achieved in order to avoid damage to the retina and eye of the patient with an abnormally large concentration or amount of melanin in their RPE .

[00095] While various embodiments have been described in detail for purposes of illustration, various modifications can be made without departing from the scope and spirit of the invention. Consequently, the invention is not to be limited, except for the appended claims.

Claims (28)

- CLAIMS - 1. PROCESS TO SAFELY PROVIDE RETINA PHOTOTHERAPY, characterized in that it comprises the steps of: generating an interferometric signal or pattern including the application of a beam of infrared light close to a retina of an eye; detect the interferometric signal or pattern; determining whether a level or concentration of melanin in the retinal pigment epithelium of the retina of the eye is elevated compared to a normal level or concentration using the detected interferometric signal or pattern; and adjusting one or more treatment parameters of retinal phototherapy if the level or concentration of melanin in the retinal pigment epithelium of the eye exceeds the normal level or concentration by a predetermined amount. 2. Process according to claim 1, characterized in that the light beam has a wavelength between 600nm and 1,000nm and a depth resolution of the order of 3 to 10 microns. 3. Process according to claim 1, characterized in that the light beam is divided into a reference beam and a sample beam applied to the retina. 4. Process according to claim 1, characterized in that the detection step comprises the use of a photodetector to detect light reflected from the retina. 5. Process according to claim 1, characterized in that an optical coherence tomography device is used to apply the light beam to the retina and detect the interferometric signal or pattern. 6. Process according to claim 1, characterized in that one or more treatment parameters are adjusted when the change in the signal or interferometric pattern is ten percent or more. 7. Process according to claim 1, characterized in that one or more treatment parameters are adjusted when the level or concentration of melanin in the retinal pigment epithelium is at least three times higher than the normal level or concentration . 8. Process according to claim 1, characterized in that the determination step comprises calculating a ratio of abnormal retinal pigment epithelium melanin and normal retinal pigment epithelium melanin densities according to the calculation of: [{Nσs + μbackscat}RPE /{2N(σs +σa) + 2μbackscat}RPE}] times [1 - exp[-2w{N(σs +σa) + μbackscat}RPE ]] where N is the numerical density of melanin aggregates that absorb and scatter the light beam; σs denotes the cross section of an aggregate of melanin for backward dispersion; σa denotes the cross section of an aggregate of melanin for absorption; and μbackscat is a coefficient for backscattering of a retinal structural matrix. 9. Process according to claim 1, characterized in that the adjustment step comprises adjusting at least one of a retinal spot size of a treatment light beam, a pulse train duration of the light beam of treatment, a duty cycle of the treatment light beam or a power of the treatment light beam. 10. Process according to claim 9, characterized in that the adjustment step comprises increasing the size of a retinal spot of a treatment light beam. 11. Process according to claim 9, characterized in that the adjustment step comprises decreasing a pulse train duration of a treatment light beam. 12. Process according to claim 9, characterized by the fact that the adjustment step comprises decreasing a work cycle of a treatment light beam. 13. Process according to claim 9, characterized in that the adjustment step comprises decreasing the power of a treatment light beam. 14. Process according to claim 1, characterized in that it includes the step of automatically adjusting one or more treatment parameters of a retinal therapy system when the concentration of melanin in the retinal pigment epithelium of the eye exceeds the predetermined amount. 15. Process according to claim 11, characterized in that it includes the step of notifying one or more retinal treatment parameters that are adjusted. 16. PROCESS TO PROVIDE RETINA PHOTOTHERAPY SAFELY, characterized by the fact that it comprises the steps of: generate an interferometric signal or pattern including splitting a light beam with a wavelength between 600nm and 1000nm into a reference beam and a sample beam with a depth resolution of the order of 3 to 10 microns applied to an epithelium of pigment in the retina of an eye; detect the interferometric signal or pattern; determining whether a level or concentration of melanin in the retinal pigment epithelium of the retina of the eye is elevated compared to a normal level or concentration using the detected interferometric signal or pattern; and adjusting one or more treatment parameters of retinal phototherapy if the level or concentration of melanin in the retinal pigment epithelium of the eye exceeds the normal level or concentration by a predetermined amount. 17. Process according to claim 16, characterized in that the detection step comprises the use of a photodetector to detect light reflected from the retina. 18. Process according to claim 16, characterized in that an optical coherence tomography device is used to apply the light beam to the retina and detect the interferometric signal or pattern. 19. Process according to claim 16, characterized in that one or more treatment parameters are adjusted when the change in the signal or interferometric pattern is ten percent or more. 20. Process according to claim 16, characterized in that one or more treatment parameters are adjusted when the level or concentration of melanin in the retinal pigment epithelium is at least three times higher than the normal level or concentration . 21. Process according to claim 16, characterized in that the determination step comprises calculating a ratio of abnormal retinal pigment epithelium melanin and normal retinal pigment epithelium melanin densities according to the calculation of: [{Nσs + μbackscat}RPE /{2N(σs +σa) + 2μbackscat}RPE}] times [1 - exp[-2w{N(σs +σa) + μbackscat}RPE]], where N is the numerical density of the melanin aggregates that absorb and scatter the light beam; σs denotes the cross section of an aggregate of melanin for backward dispersion; σa denotes the cross section of an aggregate of melanin for absorption; and μbackscat is a coefficient for backscattering of a retinal structural matrix. 22. Process according to claim 16, characterized in that the adjustment step comprises adjusting at least one of a retinal spot size of a treatment light beam, a pulse train duration of the light beam of treatment, a duty cycle of the treatment light beam or a power of the treatment light beam. 23. Process according to claim 22, characterized in that the adjustment step comprises increasing the size of a retinal spot of a treatment light beam. Process according to claim 22, characterized in that the adjustment step comprises decreasing a pulse train duration of a treatment light beam. 25. Process according to claim 22, characterized in that the adjustment step comprises decreasing a work cycle of a treatment light beam. 26. Process according to claim 22, characterized in that the adjustment step comprises decreasing the power of a treatment light beam. 27. Process according to claim 16, characterized in that it includes the step of automatically adjusting one or more treatment parameters of a retinal therapy system when the concentration of melanin in the retinal pigment epithelium of the eye exceeds the predetermined amount. 28. Process according to claim 27, characterized in that it includes the step of notifying one or more retinal treatment parameters that are adjusted.