Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N5/0613—Apparatus adapted for a specific treatment
  • A61N5/0625—Warming the body, e.g. hyperthermia treatment
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
  • A61F9/007—Methods or devices for eye surgery
  • A61F9/008—Methods or devices for eye surgery using laser
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N5/067—Radiation therapy using light using laser light
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
  • A61F9/007—Methods or devices for eye surgery
  • A61F9/008—Methods or devices for eye surgery using laser
  • A61F2009/00861—Methods or devices for eye surgery using laser adapted for treatment at a particular location
  • A61F2009/00863—Retina
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
  • A61F9/007—Methods or devices for eye surgery
  • A61F9/008—Methods or devices for eye surgery using laser
  • A61F2009/00897—Scanning mechanisms or algorithms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
  • A61N2005/0643—Applicators, probes irradiating specific body areas in close proximity
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
  • A61N2005/0659—Radiation therapy using light characterised by the wavelength of light used infrared
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
  • A61N2005/0662—Visible light
  • A61N2005/0663—Coloured light

Definitions

• the present invention is generally directed to systems and processes for treating biological tissue, and particularly retinal tissue. More particularly, the present invention is directed to a process for heat treating retinal or other biological tissue using radiation, such as light beams, which create a
• Retinal photocoagulation is a commonly used procedure for treating retinal diseases, including diabetic retinopathy.
• Retinal photocoagulation involves the use of light to create thermal burns in the retinal tissue. These thermal burns are believed to seal the retina and stop blood vessels from growing and leaking.
• the retinal laser burns are full-thickness in the areas of retinal pathology and visible at the time of treatment as white or gray retinal lesions. With time, these lesions develop into focal areas of chorioretinal scarring and progressive atrophy.
• A“threshold” lesion is one that is barely visible
• A“subthreshold” lesion is one that is not visible at treatment time, but is detectable ophthalmoscopically or angiographically.
• “Suprathreshold” laser therapy is retinal photocoagulation performed to readily visible end point. In all cases, however, it is believed that actual tissue damage and scarring are necessary in order to create the benefits of the procedure. Photocoagulation has been found to be an effective means of producing retinal scars and has become the technical standard for macular photocoagulation for diabetic macular edema and other retinal diseases for many years.
• thermal tissue damage may be the sole source of many potential complications of conventional photocoagulation which may lead to immediate and late visual loss. Such complications include sub-retinal fibrosis, choroidal neovascularization, and progressive expansion of laser scars.
• Inflammation resulting from the tissue destruction may cause or exacerbate macular edema, induced precipitous contraction of fibrovascular proliferation with retinal detachment and vitreous hemorrhage, and cause uveitis, serous choroidal detachment, angle closure or hypotony. While some of these complications are rare, others, including treatment pain, progressive scar expansion, visual field loss, decreased night vision, etc. are so common so as to be accepted as inevitable side effects of conventional laser retinal
• the inventors have discovered that radiation, such as in the form of various wavelengths of light, can be applied to retinal tissue in a manner that does not destroy or permanently damage the retinal tissue, but achieves the beneficial effects on the eye diseases.
• the inventors have found that one or more light beams can be generated and applied to the retinal tissue such that it is therapeutic, yet sublethal to the retinal tissue, and avoids damaging photocoagulation in the retinal tissue, yet provides preventative and protective treatment of the retinal tissue of the eye. It is believed that the process raises the tissue temperature such in a controlled manner to selectively stimulate heat shock protein activation and/or production and facilitation of protein repair, which serves as a mechanism for therapeutically treating the tissue.
• these activated heat shock proteins may reset the diseased retina to its healthy condition by removing and repairing damaged proteins. This then results in improved RPE function, improves retinal function and autoregulation, restorative acute inflammation, reduced chronic inflammation, and systematic immunodulation.
• the effects of the present invention may slow, stop or even reverse retinal diseases and improve visual function and reduce the risk of visual loss. It is believed that raising tissue temperature in such a controlled manner to selectively stimulate heat shock protein activation without damaging or destroying the tissue has benefits in other tissues as well.
• treatment radiation is generated and applied to the biological tissue in such a manner so as to heat stimulate the biological tissue sufficiently to create a therapeutic effect without destroying the tissue.
• treatment radiation is generated having a wavelength between 570 nm and 1 BOO nm and an average power of between 0.0000069 to B7.5 watts.
• Treatment radiation may be generated which has a wavelength between 600 nm - 1 1 00 nm and an average power of between 0.0001 5 and 6.94 watts.
• the treatment radiation is applied to the biological tissue such that at least one treatment spot having a diameter between 1 0-700 microns is formed on the biological tissue. At least one treatment spot having a diameter of between 1 00-500 microns may also be formed.
• the treatment radiation may be pulsed and applied to the tissue for a duration of between 30-800
• the treatment radiation may be applied to retinal tissue of an eye.
• the treatment radiation may be applied to at least a portion of the fovea of the eye.
• the tissue may be heated to between six and eleven degrees Celsius during the application of the treatment radiation to the tissue.
• the average temperature rise of the tissue over several minutes is maintained at approximately one degree Celsius or less. This may stimulate heat shock protein activation in a tissue, and thus create a therapeutic effect, without destroying the tissue.
• a plurality of spaced apart beams of treatment radiation may be generated and simultaneously applied to the tissue to form a plurality of spaced apart treatment spots in a first treatment area.
• the treatment radiation beams may be moved and applied to a second treatment area of the tissue sufficiently spaced apart from the first treatment area of the tissue to avoid thermal tissue damage of the target tissue.
• the treatment radiation beams may be repeatedly applied, in an alternating manner during the same treatment session, to each of the first and second treatment areas of the tissue until a predetermined number of applications to each of the first and second treatment areas of the tissue has been achieved.
• the treatment radiation may be applied to the tissue for a first period of time, such as less than one second, to stimulate heat shock protein activation in the tissue.
• the application of the treatment radiation is halted for an interval of time that exceeds the first period of time, such as several seconds to several minutes.
• the treatment radiation is then reapplied to the tissue after the interval of time, within a single treatment session, so as to controllably raise the temperature of the tissue without destroying the tissue to increase the level of heat shock protein activation in the tissue.
• FIGURE 1 is a graph illustrating absorption of radiation at given wavelengths by blood and ocular tissues
• FIGURE 2 is a graph depicting properties of melanin
• FIGURE B is a graph depicting absorption coefficients of water at various wavelengths
• FIGURES 4A and 4B are graphs depicting radiation-induced temperature rise in the lens of an eye as a function of the average radiation power and time of irradiation;
• FIGURE 5 is a graph depicting the increase in water temperature near the retina as a function of average radiation power for different
• FIGURE 6 is a graph depicting the increase in required power as the radiation wavelength increases for melanin absorption and heat shock protein activation
• FIGURES 7A-7C are graphs depicting average power at retinal spots of varying diameters as a function of the radiation duration for average required treatment power and maximum allowable average treatment power, in accordance with the present invention
• FIGURES 8A-8C are graphs depicting the average power density required for treatment and maximum allowable average treatment power at varying retinal spot diameters, in accordance with the present invention
• FIGURES 9A and 9B are graphs illustrating the average power of a laser source compared to a source radius and pulse train duration of the laser;
• FIGURES 1 0A and 1 OB are graphs illustrating the time for the temperature to decay depending upon the laser source radius and wavelength;
• FIGURE 1 1 is a diagrammatic view illustrating a system used to generate a laser light beam, in accordance with the present invention
• FIGURE 1 2 is a diagrammatic view of optics used to generate a laser light geometric pattern, in accordance with the present invention
• FIGURE 1 B is a top plan view of an optical scanning mechanism, used in accordance with the present invention.
• FIGURE 1 4 is a partially exploded view of the optical scanning mechanism of FIG. 1 3, illustrating the various component parts thereof;
• FIGURE 1 5 illustrates controlled offsets of exposure of an
• FIGURE 1 6 is a diagrammatic view illustrating the use of a
• geometric object in the form of a line or bar controllably scanned to treat an area of the target tissue
• FIGURE 1 7 is a diagrammatic view similar to FIG. 16, but illustrating the geometric line or bar rotated to treat the target tissue;
• FIGURE 1 8 is a diagrammatic view illustrating an alternate embodiment of the system used to generate laser light beams for treating tissue, in accordance with the present invention;
• FIGURE 1 9 is a diagrammatic view illustrating yet another
• FIGURES 20A-20D are diagrammatic views illustrated in the application of micropulsed energy to different treatment areas during a predetermined interval of time, within a single treatment session, and
• FIGURES 21 -23 are graphs depicting the relationship of treatment power and time in accordance with the embodiments of the present invention.
• FIGURES 24A and 24B are graphs depicting the behavior of HSP cellular system components over time following a sudden increase in
• FIGURES 25A-25H are graphs depicting the behavior of HSP cellular system components in the first minute following a sudden increase in
• FIGURES 26A and 26B are graphs illustrating variation in the activated concentrations of HSP and inactivated HSP in the cytoplasmic reservoir over an interval of one minute, in accordance with the present invention.
• FIGURE 27 is a graph depicting the improvement ratios versus interval between treatments, in accordance with the present invention.
• the present invention is directed to a system and method for heat treating biological tissue. This may be done by delivering radiation, such as one or more light beams or the like, having energy and application
• thermal time-course in tissue to raise the tissue temperature over a short period of time to a sufficient level to achieve a therapeutic effect while maintaining an average tissue temperature over a prolonged period of time below a predetermined level so as to avoid permanent tissue damage. It is believed that the creation of the thermal time-course stimulates heat shock protein activation or production and facilitates protein repair without causing any damage.
• a laser light beam can be generated that is therapeutic, yet sublethal to retinal tissue cells and thus avoids damaging photocoagulation in the retinal tissue which provides preventative and protective treatment of the retinal tissue of the eye. It is believed that this may be due, at least in part, to the stimulation and activation of heat shock proteins and the facilitation of protein repair in the retinal tissue.
• parameters include radiation wavelength, radius of the radiation source or spot size formed on the retina, radiation power, application duration, and duty cycle of the pulse train.
• radiation wavelength, average radiation power, spot size formed on the retina by the radiation source, and application duration, such as the train duration of a pulsed radiation source are particularly important parameters when generating and applying the treatment radiation to the retina in order to achieve therapeutic effect without destroying or
• tissue temperature rises are widely used and can be referenced, for example, at www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocument s/ucm07381 7.htm#attacha for electromagnetic sources.
• tissue temperature rises of between 6° C and 1 1 ° C can create therapeutic effect, such as by activating heat shock proteins, whereas maintaining the average tissue temperature over a prolonged period of time, such as over several minutes, such as six minutes, below a predetermined temperature, such as 1 ° C or less, will not permanently damage the tissue.
• wavelength of the treatment radiation is one of the parameters which must be determined and selected.
• the possible wavelength range is determined at the increased absorption by the tissue, such as the retina’s visual pigments, at the lower end and by the decreased melanin absorption coupled with the increased water absorption at the upper end.
• FIG. 1 which illustrates the absorption of radiation along a spectrum of wavelengths by blood, RPE melanin, macular pigments, the lens, water, and long wavelength sensitive (LWS) and medium wavelength sensitive (MWS) visual pigments.
• LWS long wavelength sensitive
• MWS medium wavelength sensitive
• FIG. 1 displays the optical density, or the product of the absorption-per-unit length times the absorption length as a function of wavelength between 400 nm and 750 nm wavelength of the radiation, such as within the light spectrum.
• the lower wavelength limit realistically usable by the process of the present invention is determined by undesirable absorption by the visual pigments and other absorbers.
• a lower extreme wavelength limit would be approximately 570 nm where the melanin and sum of the visual pigment optical densities are comparable.
• a preferable lower wavelength limit would be 600 nm, where the absorption is dominated by the melanin with no visual pigment absorption, and thus avoiding the patient experiencing visual disturbances during treatment.
• the absorption coefficient of water is a function of wavelength (between 49 nm and 1 mm) is shown in FIG. 3.
• the absorption coefficient of water to radiation increases from 0.03 crrr 1 at 81 0 nm to 0.3 crrr 1 at 1 300 nm. This means that as the wavelength increases above 81 0 nm, the temperature of the eye lens and of the vitreous will increase more for a given input laser power.
• cx Water (X)/cx(81 0) « (X/81 0) 5 i.e., cxwa ter (X) « 0.03 [X((nm)/81 0] 5 .
• FIGS. 4A and 4B the radiation-induced temperature rise in the lens of the eye as a function of the average radiation power and time of irradiation for wavelengths of 81 0 nm and 1 300 nm are shown.
• the plot is for powers in the range of 0 to 5 watts and for irradiation times in the range of 0 to 0.8 seconds. It can be seen from FIGS. 4A and 4B that increasing the wavelength from 81 0 nm to 1 300 nm results in an order of magnitude increase in the temperature rise of the lens.
• the resulting temperature rises in the lens for the powers and irradiation times would not result in denaturation of the lens proteins for either wavelength and thus while 810 nm would be a preferable wavelength, it is unlikely that an increase in the wavelength to the order of 1 BOO nm would cause damage to the lens.
• FIGURE 5 illustrates increase in water temperature near the retina as a function of average radiation power, the top curve being at a wavelength of 1 300 nm and the bottom curve for 810 nm radiation wavelengths.
• the power ranges from 0 to 5 watts.
• FIG. 5 shows that at the 810 nm wavelength, the temperature rise is small and should not damage the retina .
• the temperature rise can be quite appreciable as the average power increases.
• the temperature rise is 8 K for a power of 2 watts. Nevertheless, as will be shown more fully below, it is unlikely that the average power levels at this magnitude will be needed. Accordingly, it is unlikely that for average powers of interest in the invention that increasing the radiation wavelength to the order of 1 BOO nm should raise the water
• a reasonable upper limit on the usable wavelength for the process of the present invention is 1 300 nm.
• a more preferable upper limit on wavelength is 1 1 00 nm, where although the power required is still larger than its shorter wavelengths, it is not nearly as much as higher wavelengths.
• the present invention can be performed in a broad range of wavelengths between 570 nm to 1 BOO nm.
• a more preferable range of wavelengths is 600 nm to 1 1 00 nm.
• An even more preferable range of wavelengths is 700 nm to 900 nm, with a particularly preferred operating wavelength at approximately 810 nm.
• the melanin absorption is dominant with the heating primarily in the desired RPE and the wavelength is at a safe distance from the wavelengths where appreciable absorption occurs in the visual pigments at shorter wavelengths or water at longer wavelengths.
• the other parameters that need to be specified in order for one to be able to practice the invention are the duration of the irradiation at a single spot, the single spot radius of the radiation at the retina, and the average power P at the retina.
• the average radiation power density (fluence) Pi at the retina is related to the peak radiation power density at the retina multiplied by the duty cycle dc of the micropulse train.
• FIGURES 7A-7C show the dependence of the required average radiation power on spot size and radiation duration.
• two powers are shown, namely, Preset, the average required treatment power (bottom curve), and Pdamage , the maximum allowable average treatment power above which appreciable damage can occur (top curve).
• the lower curve shows the power which gives a reset Arrhenius integral of 1 .
• the top curve gives a damage threshold Arrhenius integral of 1 .
• the radiation durations range from 0.03 seconds to 0.8 seconds. A radiation wavelength of 81 0 nm is assumed.
• FIG. 7 A illustrates the average power in watts at a retinal spot of diameter 10 microns as a function of the radiation duration.
• FIG. 7 A illustrates the average power in watts at a retinal spot of diameter 10 microns as a function of the radiation duration.
• FIG. 7B illustrates the average power in watts at a retinal spot diameter of 200 microns as a function of the radiation duration.
• FIG. 7C illustrates the average power in watts at a retinal spot diameter of 500 microns as a function of the radiation duration.
• FIGURES 8A-8C illustrate the dependence of the required radiation power density (fluence) at the retina, on spot size and micro train duration. Accordingly, FIG. 8A has a retinal spot diameter of 10 microns, 8B a retinal spot diameter of 200 microns, and 8C a retinal spot diameter of 500 microns. Once again, a radiation wavelength of 810 nm is used. Although FIGS. 8A-8C could be obtained directly from FIGS. 7A-7C simply by dividing the powers of FIGS. 7A-7C by the areas of the spots, they are included for ease of reference. [Para 6B] FIGURES 7 and 8 show that as the treatment duration decreases, the required powers and power densities increase dramatically. Moreover, the larger the retinal spot treated, the larger is the required average power.
• the larger the retinal spot treated the smaller is the required average power density.
• the power at a 500 micron spot is of the order of 75 times larger than the power at a 10 micron spot, the average power does not appear to be excessive.
• the required power density is of the order of B4 times that for a 500 micron spot, but the higher power densities do not seem to be excessive.
• these treatment spot sizes represent an approximate upper and lower end of the sizes used in accordance with the present invention.
• a broad range of treatment times of 0.03 seconds to 0.8 seconds may be used, with a preferred range of treatment times of 0.1 seconds to 0.5 seconds.
• the powers are in watts, the power densities in watts/cm 2 , time is in seconds, and spot diameters are in microns.
• the values of t F are those at the extremes of the suggested treatment ranges.
• Treatment power Preset, damage power Pdamage , treatment power densities at retina Pr eset , and threshold damage power densities at retina Pi damage as a function of irradiation treatment time t F at a retinal radiation spot diameter, for l 600 nm.
• the powers are in watts, the power densities in watts/cm 2 , time is in seconds, and spot diameters are in microns.
• the values of t F are those at the extremes of the suggested treatment ranges.
• tF sec Diameter Preset Pdamage Plreset Pldamage seconds miti watts watts watts/sqcm watts/sqcm
• Pl damage as a function of irradiation treatment time t F at a retinal radiation spot diameter, for l 81 0 nm.
• the powers are in watts, the power densities in watts/cm 2 , time is in seconds, and spot diameters are in microns.
• the values of t F are those at the extremes of the suggested treatment ranges.
• Pi damage as a function of irradiation treatment time t F at a retinal radiation spot diameter, for l 1 1 00 nm.
• the powers are in watts, the power densities in watts/cm 2 , time is in seconds, and spot diameters are in microns.
• the values of t F are those at the extremes of the suggested treatment ranges. tF sec Diameter Preset Pdamage Plreset Pldamage seconds pm watts watts watts/sqcm watts/sqcm
• Pi damage as a function of irradiation treatment time t F at a retinal radiation spot diameter, for l 1 B00 nm.
• the powers are in watts, the power densities in watts/cm 2 , time is in seconds, and spot diameters are in microns.
• the values of t F are those at the extremes of the suggested treatment ranges.
• the inventors have discovered that generating one or more radiation beams, such as coherent (laser) or non-coherent light beams within the range indicated above, with a corresponding appropriate duration, treatment spot size, and average radiation power or average radiation power density at the retina creates desirable retinal photostimulation without any visible burn areas or tissue destruction.
• Appropriate selection of the radiation generation and energy application parameters raises the retinal tissue at least up to a therapeutic level but below a cellular or tissue lethal level so as to avoid destroying, burning or otherwise damaging the retinal tissue.
• subthreshold as used herein in connection with the invention means not only that no visible burn areas or tissue destruction is formed, but that the treated areas show no signs of burns, lesions or tissue damage ophthalmoscopically or
• the present invention can be used to treat the entire retina, including sensitive areas such as the fovea, without the risk of damage or vision loss. This is referred to herein as“subthreshold diode micropulse laser treatment” (SDM).
• SDM subthreshold diode micropulse laser treatment
• DME diabetic macular edema
• PDR proliferative diabetic retinopathy
• BRVO branch retinal vein occlusion
• HSPs heat shock proteins
• HSPs are elicited almost immediately, in seconds to minutes, by almost any type of cell stress or injury. In the absence of lethal cell injury, HSPs are extremely effective at repairing and returning the viable cell toward a more normal functional state. Although HSPs are transient, generally peaking in hours and persisting for a few days, their effects may be long lasting. HSPs reduce inflammation, a common factor in many disorders.
• 70,000°C/sec produced by each SDM exposure is especially effective in stimulating activation of HSPs, particularly compared to non-lethal exposure to subthreshold treatment with continuous wave lasers, which can duplicate only the low average tissue temperature rise.
• HSP stimulation in normal cells would tend to have no notable clinical effect.
• the “patho-selectivity” of near infrared laser effects, such as SDM, affecting sick cells but not affecting normal ones, on various cell types is consistent with clinical observations of SDM.
• SDM has been reported to have a clinically broad therapeutic range, unique among retinal laser modalities, consistent with American National Standards Institute“Maximum Permissible Exposure” predictions. While SDM may cause direct photothermal effects such as entropic protein unfolding and disaggregation, SDM appears optimized for clinically safe and effective stimulation of HSP-mediated repair.
• HSP mediated repair is by its nature specific to the state of the dysfunction. HSPs tend to fix what is wrong, whatever that might be.
• this facility can be considered a sort of“Reset to Default” mode of SDM action.
• SDM normalizes cellular function by triggering a“reset” (to the“factory default settings”) via HSP- mediated cellular repair.
• SDM treatment of patients suffering from age-related macular degeneration can slow the progress or even stop the progression of AMD.
• Most of the patients have seen significant improvement in dynamic functional logMAR mesoptic visual acuity and mesoptic contrast visual acuity after the SDM treatment. It is believed that SDM works by targeting, preserving, and“normalizing” (moving toward normal) function of the retinal pigment epithelium (RPE).
• RPE retinal pigment epithelium
• SDM has also been shown to stop or reverse the manifestations of the diabetic retinopathy disease state without treatment-associated damage or adverse effects, despite the persistence of systemic diabetes mellitus.
• SDM might work by inducing a return to more normal cell function and cytokine expression in diabetes-affected RPE cells, analogous to hitting the“reset” button of an electronic device to restore the factory default settings.
• SDM treatment may directly affect cytokine expression via heat shock protein (HSP) activation in the targeted tissue.
• HSP heat shock protein
• SDM subthreshold diode micropulse light
• the energy source to be applied to the target tissue will have energy and operating parameters which must be determined and selected so as to achieve the therapeutic effect while not permanently damaging the tissue.
• a light beam energy source such as a laser light beam
• the laser wavelength, the radius of the laser treatment spot, the average laser power and total pulse train duration parameters must be taken into account. Adjusting or selecting one of these parameters can have an effect on at least one other parameter.
• FIGS. 9A and 9B illustrate graphs showing the average power in watts as compared to the laser source radius (between 0.1 cm and 0.4 cm) and pulse train duration (between 0.1 and 0.6 seconds).
• FIG. 9A shows a
• FIG. 10B has a wavelength of 1000 nm. It can be seen in these figures that the required power decreases monotonically as the radius of the source decreases, as the total train duration increases, and as the wavelength decreases.
• the preferred parameters for the radius of the laser source is 1 mm-4 mm.
• the minimum value of power is 0.55 watts, with a radius of the laser source being 1 mm, and the total pulse train duration being 600 milliseconds.
• the maximum value of power for the 880 nm wavelength is 52.6 watts when the laser source radius is 4 mm and the total pulse drain duration is 1 00 milliseconds.
• the minimum power value is 0.77 watts with a laser source radius of 1 mm and a total pulse train duration of 600 milliseconds, and a maximum power value of 73.6 watts when the laser source radius is 4 mm and the total pulse duration is 1 00 milliseconds.
• corresponding peak powers, during an individual pulse are obtained from the average powers by dividing 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 by the beam width.
• the total pulse duration and the average laser power determine the total energy delivered to heat up the tissue, or power density per area of tissue, and the duty cycle of the pulse train gives the associated spike, or peak, power associated with the average laser power.
• the pulsed energy source energy parameters are selected so that approximately 20 to 40 joules of energy is absorbed by each cubic centimeter of the target tissue.
• the absorption length is very small in the thin melanin layer in the retinal pigmented epithelium. In other parts of the body, the absorption length is not generally that small.
• the penetration depth and skin is in the range of 0.5 mm to 3.5 mm.
• the penetration depth into human mucous tissues is in the range of 0.5 mm to 6.8 mm.
• the heated volume will be limited to the exterior or interior surface where the radiation source is placed, with a depth equal to the penetration depth, and a transverse dimension equal to the transverse dimension of the radiation source. Since the light beam energy source is used to treat diseased tissues near external surfaces or near internal accessible surfaces, a source radii of between 1 mm to 4 mm and operating a wavelength of 880 nm yields a penetration depth of approximately 2.5 mm and a
• the target tissue can be heated to up to approximately 1 1 ° C for a short period of time, such as less than one second, to create the therapeutic effect of the invention while maintaining the target tissue average temperature to a lower temperature range, such as less than 6° C or even G C or less over a prolonged period of time, such as several minutes.
• the selection of the duty cycle and the total pulse train duration provide time intervals in which the heat can dissipate.
• a duty cycle of less than 10%, and preferably between 2.5% and 5%, with a total pulse duration of between 100 milliseconds and 600 milliseconds has been found to be effective.
• 1 0A and 10B illustrate the time to decay from 1 0° C to 1 ° C for a laser source having a radius of between 0.1 cm and 0.4 cm with the wavelength being 880 nm in FIG. 1 0A and 1000 nm in FIG. 1 0B. It can be seen that the time to decay is less when using a wavelength of 880 nm, but either wavelength falls within the acceptable requirements and operating parameters to achieve the benefits of the present invention while not causing permanent tissue damage.
• the control of the target tissue temperature is determined by choosing source and target parameters such that the Arrhenius integral for HSP activation is larger than 1 , while at the same time assuring compliance with the conservative FDA/FCC requirements for avoiding damage or a damage
• Arrhenius integral being less than 1 .
• FIGS. 10A and 1 OB above illustrate the typical decay times required for the temperature in the heated target region to decrease by thermal diffusion from a temperature rise of approximately 1 0° C to 1 ° C as can be seen in FIG. l OA when the wavelength is 880 nm and the source diameter is 1 millimeter, the temperature decay time is 1 6 seconds. The temperature decay time is 107 seconds when the source diameter is 4 mm. As shown in FIG.
• the temperature decay time is 1 8 seconds when the source diameter is 1 mm and 1 B6 seconds when the source diameter is 4 mm. This is well within the time of the average temperature rise being maintained over the course of several minutes, such as 6 minutes or less.
• the target tissue’s temperature is raised, such as to approximately 10° C, very quickly, such as in a fraction of a second during the application of the energy source to the tissue
• the relatively low duty cycle provides relatively long periods of time between the pulses of energy applied to the tissue and the relatively short pulse train duration ensure sufficient temperature diffusion and decay within a relatively short period of time comprising several minutes, such as 6 minutes or less, that there is no permanent tissue damage.
• tissue water content can vary from one tissue type to another, however, there is an observed uniformity of the properties of tissues at normal or near normal conditions which has allowed publication of tissue parameters that are widely used by clinicians in designing treatments.
• Table 6 relating to muscle, skin and tissues with high water content
• Table 7 relating to fat, bone and tissues with low water content.
• FIG. 1 1 a schematic diagram is shown of a system for generating electromagnetic energy radiation, such as laser light, embodying SDM.
• the system generally referred to by the reference number 20, includes a treatment radiation generator 22, such as for example the 810 nm near infrared micropulsed diode laser in the preferred embodiment.
• the treatment radiation may comprise electromagnetic radiation having a wavelength between 570 nm and 1 300 nm, and as such may comprise coherent or non-coherent light beams.
• a coherent laser beam is particularly preferred and used in the description herein as an example.
• the laser generates a laser light beam which is passed through optics, such as an optical lens and/or mask or a plurality of optical lenses and/or masks 24, as needed.
• the laser projector optics 24 pass the shaped light beam to a delivery device 26, for projecting the laser beam light onto the target tissue of the patient.
• the box labeled 26 can represent both the laser beam projector or delivery device as well as a viewing system/camera, such as an endoscope, or comprise two different components in use.
• the viewing system/camera 26 provides feedback to a display monitor 28, which may also include the necessary computerized hardware, data input and controls, etc. for manipulating the laser 22, the optics 24, and/or the projection/viewing components 26.
• a plurality of radiation light beams are generated, each of which has parameters selected so that a target tissue temperature may be controllably raised to therapeutically treat the target tissue without destroying or permanently damaging the target tissue.
• This may be done, for example, by passing the laser light beam 30 through optics which diffract or otherwise generate a plurality of laser light beams from the single laser light beam 30 having the selected parameters.
• the laser light beam 30 may be passed through a collimator lens 32 and then through a mask 34.
• the mask 34 comprises a diffraction grating.
• the mask/diffraction grating 34 produces a geometric object, or more typically a geometric pattern of simultaneously produced multiple laser spots or other geometric objects. This is represented by the multiple laser light beams labeled with reference number 36.
• the multiple laser spots may be generated by a plurality of fiber optic waveguides.
• therapeutic light beams or spots such as numbering in the dozens or even hundreds, as the parameters and methodology of the present invention create therapeutically effective yet non-destructive and non-permanently damaging treatment.
• a wide array of simultaneously applied small separated laser spot applications may be desirable as such avoids certain disadvantages and treatment risks known to be associated with large laser spot applications.
• the single laser beam 30 has thus been formed into dozens or even hundreds of individual laser beams B6 so as to create the desired pattern of spots or other geometric objects.
• These laser beams B6 may be passed through additional lenses, collimators, etc. 38 and 40 in order to convey the laser beams and form the desired pattern.
• additional lenses, collimators, etc. 38 and 40 can further transform and redirect the laser beams 36 as needed.
• Arbitrary patterns can be constructed by controlling the shape, spacing and pattern of the optical mask 34.
• the pattern and exposure spots can be created and modified arbitrarily as desired according to application requirements by experts in the field of optical engineering. Photolithographic techniques, especially those developed in the field of semiconductor
• manufacturing can be used to create the simultaneous geometric pattern of spots or other objects.
• the number of simultaneous spots generated and used could number from as few as 1 and up to approximately 1 00 when a 0.04 (4%) duty cycle and a total train duration of 0.3 seconds (BOO milliseconds) is used.
• the water absorption increases as the wavelength is increased.
• the laser power can be lower.
• the power can be lowered by a factor of 4 for the invention to be effective. Accordingly, there can be as few as a single laser spot or up to approximately 400 laser spots when using the 577 nm wavelength laser light, while still not harming or damaging the tissue.
• the system of the present invention incorporates a guidance system to ensure complete and total retinal treatment with retinal photostimulation.
• Fixation/tracking/registration systems consisting of a fixation target, tracking mechanism, and linked to system operation can be incorporated into the present invention.
• fixation/tracking/registration systems consisting of a fixation target, tracking mechanism, and linked to system operation can be incorporated into the present invention.
• the geometric pattern of simultaneous laser spots is sequentially offset so as to achieve confluent and complete treatment of the surface.
• FIGS. 1 3 and 1 4 illustrate an optical scanning mechanism 50 in the form of a MEMS mirror, having a base 52 with electronically actuated controllers 54 and 56 which serve to tilt and pan the mirror 58 as electricity is applied and removed thereto. Applying electricity to the controller 54 and 56 causes the mirror 58 to move, and thus the simultaneous pattern of laser spots or other geometric objects reflected thereon to move accordingly on the retina of the patient. This can be done, for example, in an automated fashion using electronic software program to adjust the optical scanning mechanism 50 until complete coverage of the retina, or at least the portion of the retina desired to be treated, is exposed to the phototherapy.
• the optical scanning mechanism may also be a small beam diameter scanning galvo mirror system, or similar system, such as that distributed by Thorlabs. Such a system is capable of scanning the lasers in the desired offsetting pattern.
• the pattern illustrated for exemplary purposes as a grid of sixteen spots, is offset each exposure such that the laser spots occupy a different space than previous exposures. It will be understood that the diagrammatic use of circles or empty dots as well as filled dots are for diagrammatic purposes only to illustrate previous and subsequent exposures of the pattern of spots to the area, in accordance with the present invention.
• the spacing of the laser spots prevents overheating and damage to the tissue.
• the treatment spots are spaced apart from one another by a distance of at least one-half diameter of the treatment spot, and more preferably between at least one and two diameters away from one another to prevent overheating and damage. It will be understood that this occurs until the entire target tissue to be treated has received phototherapy, or until the desired effect is attained. This can be done, for example, by applying electrostatic torque to a micromachined mirror, as illustrated in FIGS. 1 S and 1 4.
• a micromachined mirror as illustrated in FIGS. 1 S and 1 4.
• Another example would be a 3 cm x 3 cm area, representing the entire human retinal surface.
• a much larger secondary mask size of 25mm by 25mm could be used, yielding a treatment grid of 1 90 spots per side separated by 1 33pm with a spot size radius of 6pm. Since the secondary mask size was increased by the same factor as the desired treatment area, the number of offsetting operations of approximately 98, and thus treatment time of approximately thirty seconds, is constant.
• simultaneous pattern array can be easily and highly varied such that the number of sequential offsetting operations required to complete treatment can be easily adjusted depending on the therapeutic requirements of the given application.
• An offsetting optical scanning mechanism can be used to sequentially scan the line over an area, illustrated by the downward arrow in FIG. 16.
• FIGURE 1 8 illustrates diagrammatically a system which couples multiple treatment light sources into the pattern-generating optical
• this system 20' is similar to the system 20 described in FIG. 1 1 above.
• the primary differences between the alternate system 20' and the earlier described system 20 is the inclusion of a plurality of laser consoles, the outputs of which are each fed into a fiber coupler 42.
• Each laser console may supply a laser light beam having different
• the fiber coupler produces a single output that is passed into the laser projector optics 24 as described in the earlier system.
• the coupling of the plurality of laser consoles 22 into a single optical fiber is achieved with a fiber coupler 42 as is known in the art.
• Other known mechanisms for combining multiple light sources are available and may be used to replace the fiber coupler described herein.
• the diffractive element functions differently than described earlier depending upon the wavelength of light passing through, which results in a slightly varying pattern.
• the variation is linear with the wavelength of the light source being diffracted.
• the difference in the diffraction angles is small enough that the different, overlapping patterns may be directed along the same optical path through the projector device 26 to the tissue for treatment.
• a sequential offsetting to achieve complete coverage will be different for each wavelength.
• This sequential offsetting can be accomplished in two modes. In the first mode, all wavelengths of light are applied simultaneously without identical coverage. An offsetting steering pattern to achieve complete coverage for one of the multiple wavelengths is used. Thus, while the light of the selected wavelength achieves complete coverage of the tissue, the application of the other wavelengths achieves either incomplete or overlapping coverage of the tissue.
• the second mode sequentially applies each light source of a varying wavelength with the proper steering pattern to achieve complete coverage of the tissue for that particular wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve identical coverage for each wavelength. This avoids either incomplete or overlapping coverage for any of the optical wavelengths.
• FIGURE 1 9 illustrates diagrammatically yet another alternate embodiment of the inventive system 20".
• This system 20" is configured generally the same as the system 20 depicted in FIG. 1 1 .
• the main difference resides in the inclusion of multiple pattern-generating subassembly channels tuned to a specific wavelength of the light source.
• Multiple laser consoles 22 are arranged in parallel with each one leading directly into its own laser projector optics 24.
• each channel 44a, 44b, 44c comprise a collimator B2, mask or diffraction grating B4 and recollimators 38, 40 as described in connection with FIG. 1 2 above - the entire set of optics tuned for the specific wavelength generated by the corresponding laser console 22.
• the output from each set of optics 24 is then directed to a beam splitter 46 for combination with the other wavelengths. It is known by those skilled in the art that a beam splitter used in reverse can be used to combine multiple beams of light into a single output.
• the combined channel output from the final beam splitter 46c is then directed through the projector device 26.
• the system 20" may use as many channels 44a, 44b, 44c, etc. and beam splitters 46a, 46b, 46c, etc. as there are wavelengths of light being used in the treatment.
• Implementation of the system 20" may take advantage of different symmetries to reduce the number of alignment constraints. For example, the proposed grid patterns are periodic in two dimensions and steered in two dimensions to achieve complete coverage. As a result, if the patterns for each channel are identical as specified, the actual pattern of each channel would not need to be aligned for the same steering pattern to achieve complete coverage for all wavelengths. Each channel would only need to be aligned optically to achieve an efficient combination.
• each channel begins with a light source 22, which could be from an optical fiber as in other embodiments of the pattern
• This light source 22 is directed to the optical assembly 24 for collimation, diffraction, recollimation and directed into the beam splitter which combines the channel with the main output.
• FIGS. 1 1 -1 9 are exemplary. Other devices and systems can be utilized to generate a source of SDM light which can be operably passed through to a projector device.
• the proposed treatment with a train of electromagnetic pulses has two major advantages over earlier treatments that incorporate a single short or sustained (long) pulse.
• the short (preferably subsecond) individual pulses in the train activate cellular reset mechanisms like HSP activation with larger reaction rate constants than those operating at longer (minute or hour) time scales.
• the repeated pulses in the treatment provide large thermal spikes (on the order of 10,000) that allow the cell’s repair system to more rapidly surmount the activation energy barrier that separates a dysfunctional cellular state from the desired functional state.
• the net result is a“lowered therapeutic threshold” in the sense that a lower applied average power and total applied energy can be used to achieve the desired treatment goal.
• the micropulsed laser light beam of an 81 0 nm diode laser should have an exposure envelope duration of 500 milliseconds or less, and preferably approximately 300 milliseconds.
• the exposure duration should be lessened accordingly.
• duty cycle or the frequency of the train of micropulses, or the length of the thermal relaxation time between consecutive pulses. It has been found that the use of a 1 0% duty cycle or higher adjusted to deliver micropulsed laser at similar irradiance at similar MPE levels significantly increase the risk of lethal cell injury. However, duty cycles of less than 10%, and preferably 5% or less demonstrate adequate thermal rise and treatment at the level of the MPE cell to stimulate a biological response, but remain below the level expected to produce lethal cell injury. The lower the duty cycle, however, the exposure envelope duration increases, and in some instances can exceed 500 milliseconds.
• Each micropulse lasts a fraction of a millisecond, typically between 50 microseconds to 1 00 microseconds in duration. Thus, for the exposure envelope duration of 300-500 milliseconds, and at a duty cycle of less than 5%, there is a significant amount of wasted time between micropulses to allow the thermal relaxation time between consecutive pulses. Typically, a delay of between 1 and 3 milliseconds, and preferably approximately 2 milliseconds, of thermal relaxation time is needed between consecutive pulses.
• the cells are typically exposed or hit between 50-200 times, and preferably between 75-1 50 at each location, and with the 1 -3 milliseconds of relaxation or interval time, the total time in accordance with the embodiments described above to treat a given area which is being exposed to the laser spots is usually less than one second, such as between 100 milliseconds and 600 milliseconds on average.
• the thermal relaxation time is required so as not to overheat the cells within that location or spot and so as to prevent the cells from being damaged or destroyed. While time periods of 1 00-600 milliseconds do not seem long, given the small size of the laser spots and the need to treat a relatively large area of the target tissue, treating the entire target tissue take a significant amount of time, particularly for a patient who is undergoing treatment.
• the present invention may utilize the interval between consecutive applications to the same location to apply energy to a second treatment area, or additional areas, of the target tissue that is spaced apart from the first treatment area.
• the pulsed energy is returned to the first treatment location, or previous treatment locations, within the predetermined interval of time so as to provide sufficient thermal relaxation time between consecutive pulses, yet also sufficiently treat the cells in those locations or areas properly by sufficiently increasing the temperature of those cells over time by repeatedly applying the energy to that location in order to achieve the desired therapeutic benefits of the invention.
• At least one other area, and typically multiple areas can be treated with a laser light application as the laser light pulses are typically 50 seconds to 1 00 microseconds in duration. This is referred to herein as microshifting.
• the number of additional areas which can be treated is limited only by the micopulse duration and the ability to controllably move the light beams from one area to another. [Para 1 BO]
• approximately four additional areas which are sufficiently spaced apart from one another can be treated during the thermal relaxation intervals beginning with a first treatment area.
• multiple areas can be treated, at least partially, during the 200-500 millisecond exposure envelope for the first area.
• approximately 500 light spots can be applied during that interval of time in different treatment areas. This would be the case, for example, for a laser light beam having a wavelength of 81 0 nm. For shorter wavelengths, such as 572 nm, even a greater number of individual locations can be exposed to the laser beams to create light spots. Thus, instead of a maximum of approximately 400
• each location has between 50-200, and more typically between 75-1 50, light applications applied thereto over the course of the exposure envelope duration (typically 200-500 milliseconds) to achieve the desired treatment.
• the exposure envelope duration typically 200-500 milliseconds
• the light would be reapplied to previously treated areas in sequence during the relaxation time intervals for each area or location. This would occur repeatedly until a
• the pulsed energy could be reapplied to a previously treated area in sequence during the relaxation time intervals for each area or location until a desired number of applications has been achieved to each treatment area.
• the treatment areas must be separated by at least a predetermined minimum distance to enable thermal relaxation and heat dissipation and avoid thermal tissue damage.
• the pulsed energy and application parameters are selected so as to raise the target tissue temperature up to 1 1 ° C, such as between
• the cells of the target tissue must be given a period of time to dissipate the heat such that the average temperature rise of the tissue over several minutes is maintained at or below a
• predetermined level 1 ° C or less over several minutes, so as not to permanently damage the target tissue.
• FIGS. 20A-20D This is diagrammatically illustrated in FIGS. 20A-20D.
• FIG. 20A illustrates with solid circles a first area having energy beams, such as laser light beams, applied thereto as a first application.
• the beams are controllably offset or microshifted to a second exposure area, followed by a third exposure area and a fourth exposure area, as illustrated in FIG. 20B, until the locations in the first exposure area need to be re-treated by having beams applied thereto again within the thermal relaxation time interval.
• the locations within the first exposure area would then have energy beams reapplied thereto, as illustrated in FIG. 20C.
• Secondary or subsequent exposures would occur in each exposure area, as illustrated in FIG. 20D by the increasingly shaded dots or circles until the desired number of exposures or hits or applications of energy to the target tissue area has been achieved to therapeutically treat these areas,
• Such distance is at least 0.5 diameter away from the immediately preceding treated location or area, and more preferably between 1 -2 diameters away.
• Such spacing relates to the actually treated locations in a previous exposure area. It is contemplated by the present invention that a relatively large area may actually include multiple exposure areas therein which are offset in a different manner than that illustrated in FIG. 20.
• the exposure areas could comprise the thin lines illustrated in FIGS. 16 and 1 7, which would be
• the time required to treat that area to be treated is significantly reduced, such as by a factor of 4 or 5 times, such that a single treatment session takes much less time for the medical provider and the patient need not be in discomfort for as long of a period of time.
• a graph is provided wherein the x-axis represents the Log of the average power in watts of a laser and the y-axis represents the treatment time, in seconds.
• the lower curve is for panmacular treatment and the upper curve is for panretinal treatment.
• the areas of each retinal spot are 1 00 microns, and the laser power for these 1 00 micron retinal spots is 0.74 watts.
• the panmacular area is 0.55 2 , requiring 7,000 panmacular spots total, and the panretinal area is 3.30 2 , requiring 42,000 laser spots for full coverage.
• Each RPE spot requires a minimum energy in order for its reset mechanism to be adequately activated, in accordance with the present invention, namely, 38.85 joules for panmacular and 233.1 joules for panretinal.
• the shorter the treatment time the larger the required average power.
• there is an upper limit on the allowable average power which limits how short the treatment time can be.
• FIGS. 22 and 23 show how the total power depends on treatment time. This is displayed in FIG. 22 for panmacular treatment, and in FIG. 23 for panretinal treatment.
• the upper, solid line or curve represents the embodiment where there are no microshifts taking advantage of the thermal relaxation time interval, such as described and illustrated in FIG. 1 5, whereas the lower dashed line represents the situation for such microshifts, as described and illustrated in FIG. 20.
• FIGS. 22 and 23 show how the total power depends on treatment time. This is displayed in FIG. 22 for panmacular treatment, and in FIG. 23 for panretinal treatment.
• the upper, solid line or curve represents the embodiment where there are no microshifts taking advantage of the thermal relaxation time interval, such as described and illustrated in FIG. 1 5, whereas the lower dashed line represents the situation for such microshifts, as described and illustrated in FIG. 20.
• the peak total power is less with microshifts than without microshifts. This means that less power is required for a given treatment time using the microshifting embodiment of the present invention.
• the allowable peak power can be advantageously used, reducing the overall treatment time.
• a log power of 1 .0 (10 watts) would require a total treatment time of 20 seconds using the microshifting embodiment of the present invention, as described herein. It would take more than 2 minutes of time without the microshifts, and instead leaving the micropulsed light beams in the same location or area during the entire treatment envelope duration. There is a minimum treatment time according to the wattage. However, this treatment time with microshifting is much less than without microshifting. As the laser power required is much less with the microshifting, it is possible to increase the power in some instances in order to reduce the treatment time for a given desired retinal treatment area.
• the product of the treatment time and the average power is fixed for a given treatment area in order to achieve the therapeutic treatment in accordance with the present invention.
• the parameters of the laser light are selected to be therapeutically effective yet not destructive or permanently damaging to the cells, no guidance or tracking beams are required, only the treatment beams as all areas can be treated in accordance with the present invention.
• the shifting or steering of the pattern of light beams may be done by use of an optical scanning mechanism, such as that illustrated and described in
• the target tissue is heated by the pulsed energy for a short period of time, such as ten seconds or less, and typically less than one second, such as between 100 milliseconds and 600 milliseconds.
• the time that the energy is actually applied to the target tissue is typically much less than this in order to provide intervals of time for heat relaxation so that the target tissue does not overheat and become damaged or destroyed.
• laser light pulses may last on the order of microseconds with several milliseconds of intervals of relaxed time.
• E is the activation energy
• T(t) is the temperature of the thin RPE layer, including the laser-induced temperature rise
• HSFs (trimer) heat shock factor capable of binding to DNA, formed from HSF
• HSE heat shock element a DNA site that initiates transcription of
• mRNA messenger RNA molecule for producing HSP S substrate for HSP binding a damaged protein
• HSP HSP a complex of HSP bound to HSF (unactivated HSPs)
• HSF 3 HSF 3 .
• HSE a complex of HSF 3 bound to HSE, that induces transcription and the creation of a new HSP mRNA molecule
• HSP HSP actively repairing the protein
• HSP denatured or damaged proteins that are as yet unaffected by HSPs
• HSP denotes free (activated) heat shock proteins
• HSP:S denotes activated HSPs that are attached to the damaged proteins and performing repair
• HSP:HSF denotes (inactive) HSPs that are attached to heat shock factor monomers
• HSF denotes a monomer of heat shock factor
• HSF3 denotes a trimer of heat shock factor that can penetrate the nuclear membrane to interact with a heat shock element on the DNA molecule
• HSE:HSF3 denotes a trimer of heat shock factor attached to a heat shock element on the DNA molecule that initiates transcription of a new mRNA molecule
• mRNA denotes the messenger RNA molecule that results from the HSE:HSF3, and that leads to the production of a new (activated) HSP molecule in the cell’s cytoplasm.
• FIGURE 24 shows that initially the concentration of activated HSPs is the result of release of HSPs sequestered in the molecules HSPHSF in the cytoplasm, with the creation of new HSPs from the cell nucleus via mRNA not occurring until 60 minutes after the temperature rise occurs.
• FIG. 24 also shows that the activated HSPs are very rapidly attached to damaged proteins to begin their repair work. For the cell depicted, the sudden rise in temperature also results in a temporary rise in damaged protein concentration, with the peak in the damaged protein concentration occurring about SO minutes after the temperature increase.
• FIGURE 24 shows what the Rybinski et al equations predict for the variation of the 10 different species over a period of 350 minutes.
• the present invention is concerned with SDM application is on the variation of the species over the much shorter O(minute) interval between two applications of SDM at any single retinal locus. It will be understood that the preferred embodiment of SDM in the form of laser light treatment is analyzed and described, but it is applicable to other sources of energy as well.
• FIGS. 25A-25H the behavior of HSP cellular system components during the first minute following a sudden increase in temperature from 37° C to 42° C using the Rybinski et al. (201 3) equations with the initial values and rate constants of Tables 9 and 10 are shown.
• the abscissa denotes time in minutes, and the ordinate shows concentration in the same arbitrary units as in FIG. 25.
• FIGURE 25 shows that the nuclear source of HSPs plays virtually no role during a 1 minute period, and that the main source of new HSPs in the cytoplasm arises from the release of sequestered HSPs from the reservoir of HSPHSF molecules. It also shows that a good fraction of the newly activated HSPs attach themselves to damaged proteins to begin the repair process.
• Table 1 1 Equilibrium values of species in arbitrary units [Rybinski et al (201 3)] corresponding to the rate constants of Table 10.
• the arbitrary units are those chosen by Rybinski et al for computational convenience: to make the quantities of interest in the range of 0.01 -10.
• a first treatment to the target tissue may be performed by repeatedly applying the pulsed energy (e.g., SDM) to the target tissue over a period of time so as to controllably raise a temperature of the target tissue to therapeutically treat the target tissue without destroying or permanently damaging the target tissue.
• the pulsed energy e.g., SDM
• A“treatment” comprises the total number of applications of the pulsed energy to the target tissue over a given period of time, such as dozens or even hundreds of light or other energy applications to the target tissue over a short period of time, such as a period of less than ten seconds, and more typically a period of less than one second, such as 100 milliseconds to 600 milliseconds.
• This“treatment” controllably raises the temperature of the target tissue to activate the heat shock proteins and related components.
• the first treatment creates a level of heat shock protein activation of the target tissue
• the second treatment increases the level of heat shock protein activation in the target tissue above the level due to the first treatment.
• This technique may be referred to herein as“stair-stepping” in that the levels of activated HSP production increase with the subsequent treatment or treatments within the same office visit treatment session.
• This“stair stepping” technique may be described by a combination of the Arrhenius integral approach for subsecond phenomena with the Rybinski et al. (201 B) treatment of intervals between repeated subsecond applications of the SDM or other pulsed energy.
• SDM can be applied prophylactically to a healthy cell, but oftentimes SDM will be applied to a diseased cell. In that case, the initial concentration of damaged proteins [S(0)] can be larger than given in Table 1 1 . We shall not attempt to account for this, assuming that the qualitative behavior will not be changed.
• the duration of a single SDM application is only subseconds, rather than the minutes shown in Figure 24.
• the Rybinski et al rate constants are much smaller than the Arrhenius constants: the latter give Arrhenius integrals of the order of unity for subsecond durations, whereas the Rybinski et al rate constants are too small to do that.
• the Rybinski et al rate constants apply to
• [HSP(SDM2)] [HSP( t)] + [HSPHSF( t)](l -exp[-Q])
• [HSF(SDM2)] [HSF( t)] + [HSPHSF t)](l -exp[-Q])
• [HSP( t)], [HSF( t)], and [HSPHSF( t)] are the values determined from the Rybinski et al (201 S) equations at the time l ⁇ .
• FIGURES 26A and 26B illustrate the variation in the activated concentrations [HSP] and the unactivated HSP in the cytoplasmic reservoir
• the activation Arrhenius integral W depends on both the treatment parameters (e.g., laser power, duty cycle, total train duration) and on the RPE properties (e.g., absorption coefficients, density of HSPs).
• the cell is taken to have the Rybinski et al (201 3) equilibrium concentrations for the ten species involved, given in Table 1 1 .
• Table 1 2 shows four HSP concentrations (in the Rybinski et al arbitrary units) each corresponding to four different times:
• Table 14 is the same as the Tables 12 and 1 B, except that the treatments are separated by one minute, or sixty seconds.
• [HSPHSF(SDM1 )] is much smaller than [HSPHSF(equil)] • [HSP] decreases appreciably in the interval l ⁇ between the two SDM treatments, with the decrease being larger the larger l ⁇ is.
• the decrease in [HSP] is accompanied by an increase in both [HSPHSF] - as shown in Figure 26 and in [HSPS] during the interval l ⁇ - indicating a rapid replenishment of the cytoplasmic reservoir of unactivated HSP’s and a rapid attachment of HSP’s to the damaged proteins.
• performing multiple intra-sessional treatments on a single target tissue location or area, such as a single retinal locus, with the second and subsequent treatments following the first after an interval anywhere from three seconds to three minutes, and preferably ten seconds to ninety seconds, should increase the activation of HSPs and related components and thus the efficacy of the overall treatment of the target tissue.
• the resulting“stair-stepping” effect achieves incremental increases in the number of heat shock proteins that are activated, enhancing the therapeutic effect of the treatment. However, if the interval of time between the first and subsequent treatments is too great, then the“stair-stepping” effect is lessened or not achieved.
• the technique of the present invention is especially useful when the treatment parameters or tissue characteristics are such that the associated Arrhenius integral for activation is low, and when the interval between repeated applications is small, such as less than ninety seconds, and preferably less than a minute. Accordingly, such multiple treatments must be performed within the same treatment session, such as in a single office visit, where distinct treatments can have a window of interval of time between them so as to achieve the benefits of the technique of the present invention.

Landscapes

• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pathology (AREA)
• Radiology & Medical Imaging (AREA)
• Physics & Mathematics (AREA)
• Optics & Photonics (AREA)
• Ophthalmology & Optometry (AREA)
• Surgery (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Radiation-Therapy Devices (AREA)
• Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
• Cultivation Of Seaweed (AREA)

Priority Applications (6)

Applications Claiming Priority (6)

Publications (1)

Family

ID=66538738

Family Applications (1)

Country Status (7)

Cited By (2)

Citations (3)

Family Cites Families (13)

• 2018
  • 2018-07-19 EP EP18877518.3A patent/EP3703815A1/en active Pending
  • 2018-07-19 JP JP2020507031A patent/JP7130271B2/ja active Active
  • 2018-07-19 AU AU2018369022A patent/AU2018369022B2/en active Active
  • 2018-07-19 BR BR112020009238-0A patent/BR112020009238A2/pt unknown
  • 2018-07-19 CN CN201880073796.XA patent/CN111343936B/zh active Active
  • 2018-07-19 WO PCT/US2018/042833 patent/WO2019099068A1/en active Application Filing
  • 2018-07-19 CA CA3071937A patent/CA3071937A1/en active Pending

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events