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
  • A61N5/067—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
• • 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
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
  • A61B2017/00017—Electrical control of surgical instruments
  • A61B2017/00137—Details of operation mode
  • A61B2017/00154—Details of operation mode pulsed
• • 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
  • A61F2009/00844—Feedback systems
• • 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
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N2005/0626—Monitoring, verifying, controlling systems and methods
• • 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
  • A61N2005/0645—Applicators worn by the patient
  • A61N2005/0647—Applicators worn by the patient the applicator adapted to be worn on the head
  • A61N2005/0648—Applicators worn by the patient the applicator adapted to be worn on the head the light being directed to the eyes
• • 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

Definitions

• the present invention is generally directed to retinal phototherapy or photostimulation. More particularly, the present invention is directed to a retinal phototherapy or photostimulation system and method wherein parameters of one or more treatment beams are selected and fixed so as not to be alterable by a medical provider to ensure the retinal target tissue is photostimulated or treated while not permanently damaging the retinal tissue.
• parameters of one or more treatment beams are selected and fixed so as not to be alterable by a medical provider to ensure the retinal target tissue is photostimulated or treated while not permanently damaging the retinal tissue.
• Photocoagulation With visible end point photocoagulation, laser light absorption heats pigmented tissue at the laser sight. Heat conduction spreads this temperature increase from the retinal pigment epithelium (RPE) and choroid to overlying non-pigmented and adjacent unexposed tissues. Laser lesions become visible so as to track the treated areas. In fact, it has been believed that actual tissue damage and scarring are necessary in order to create the benefits of traditional photocoagulation. Photocoagulation has been found to be an effective means of producing retinal scars, it has become the technical standard for treatment of various retinal diseases, including macular photocoagulation for diabetic macular edema and other retinal diseases for decades.
• the fovea/macula region is a portion of the eye used for color vision and fine detail vision.
• the fovea is at the center of the macula, where the concentration of the cells needed for central vision is the highest. Although it is the area where diseases such as age-related macular degeneration are so damaging, this is the area where conventional photocoagulation phototherapy cannot be used as damaging the cells in the foveal area can significantly damage the patient’s vision. Thus, with current conventional photocoagulation therapies, the foveal region is avoided.
• HSPs heat shock proteins
• subthreshold photocoagulation treatment can be, and may ideally be, applied to the entire retina, including sensitive areas such as the fovea, without visible tissue damage or the resulting drawbacks or complications of conventional visible retinal photocoagulation treatments. It is believed that raising tissue temperature in such a controlled manner to selectively stimulate heat shock protein activation has benefits in other tissues as well.
• the selection of the proper operating parameters, including wavelength, power, pulse train duration and duty cycle of the laser treatment beam is important to provide the therapeutic or stimulation benefit while not damaging the retinal tissue to which the laser light is applied. Selecting and using laser beam generation and application parameters outside of the acceptable ranges can result in damage to the patient’s retina. Moreover, improperly selecting the combination of laser treatment light beam parameters, even within the safely-determined parameters, can result in less than ideal treatment or photostimulation. [Para 8] Accordingly, there is a continuing need for a retinal phototherapy or photostimulation system which generates one or more laser treatment beams having operating and application parameters selected so as to treat or photostimulate retinal tissue while not permanently damaging the retinal tissue.
• the present invention resides in a retinal phototherapy or photostimulation system and related method.
• the system generally comprises a laser console generating at least one pulsed treatment beam.
• the at least one treatment beam has parameters of wavelength, power, pulse train duration and duty cycle to photostimulate or treat a retinal target tissue while not permanently damaging the retinal target tissue.
• the parameters of the at least one treatment beam are fixed so as not to be alterable by a medical provider.
• the at least one treatment beam has a wavelength between 530 nm to 1300 nm, a duty cycle of less than 10%, and a pulse train duration between 0.1 and 0.6 seconds.
• the at least one treatment beam may have a wavelength between 750 nm and 850 nm, a duty cycle between 2% and 5%, and a pulse train duration of between 0.15 and 0.5 seconds.
• the laser console has a power output of between 1.0-3.0 watts.
• a projector or camera projects the at least one treatment beam onto at least a portion of a retina.
• the at least one treatment beam may create a treatment spot on the retina having a size of between 100-1000 micrometers.
• a scanning mechanism controllably directs the at least one treatment beam to treatment areas of the retina.
• the at least one treatment beam may be applied to a plurality of target tissue areas, wherein adjacent target tissue areas are separated to avoid thermal tissue damage.
• the at least one treatment beam stimulates heat shock protein activation in the target tissue.
• the at least one treatment beam raises a target tissue temperature to a desired level while maintaining an average temperature rise of the target tissue over a period of time at or below a predetermined level so as not to permanently damage the target tissue.
• the at least one treatment beam may raise a target tissue temperature to no greater than 11° C to achieve a therapeutic or prophylactic effect.
• the at least one treatment beam may raise the target tissue temperature between 6° C to 11° C at least during application of the pulse energy source to the target tissue.
• the average temperature rise of the target tissue over several minutes is maintained at or below a predetermined level so as not to permanently damage the target tissue.
• the average temperature rise of the target tissue over several minutes, such as six minutes or less, may be maintained at 1° C or less.
• FIG. 5 is a diagrammatic view of optics used to generate a laser light geometric pattern, in accordance with the present invention
• FIG. 6 is a top plan view of an optical scanning mechanism, used in accordance with the present invention
• FIG. 7 is a partially exploded view of the optical scanning mechanism of FIG. 6, illustrating the various component parts thereof
• FIG. 8 illustrates controlled offsets of exposure of an exemplary geometric pattern grid of laser spots to treat the target tissue, in accordance with an embodiment of the present invention
• FIG. 9 is a diagrammatic view illustrating the use of a geometric object in the form of a line controllably scanned to treat an area of the target tissue
• FIG. 25 FIG.
• FIG. 10 is a diagrammatic view similar to FIG. 9, but illustrating the geometric line or bar rotated to treat the target tissue;
• FIG. 11 is a diagrammatic view illustrating an alternate embodiment of the system used to generate treatment laser light beams for treating tissue, in accordance with the present invention;
• FIG. 12 is a diagrammatic view illustrating yet another embodiment of a system used to generate treatment laser light beams to treat tissue in accordance with the present invention;
• FIGS. 13A and 13B are graphs depicting the behavior of HSP cellular system components over time following a sudden increase in temperature; [Para 29] FIGS.
• FIGS. 14A-14H are graphs depicting the behavior of HSP cellular system components in the first minute following a sudden increase in temperature;
• FIGS. 15A and 15B are graphs illustrating variation in the activated concentrations of HSP and unactivated HSP in the cytoplasmic reservoir over an interval of one minute, in accordance with the present invention; and
• FIG. 16 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 delivering a pulsed energy, such as one or more light beams having energy parameters selected to cause a 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 pulsed energy such as one or more light beams having energy parameters selected to cause a 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.
• 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.
• Various parameters of the light beam must be taken into account and selected so that the combination of the selected parameters achieve the therapeutic effect while not permanently damaging the tissue.
• Arrhenius integrals are used for analyzing the impacts of actions on biological tissue. At the same time, the selected parameters must not permanently damage the tissue. Thus, the Arrhenius integral for damage may also be used, wherein the solved Arrhenius integral is less than 1 or unity.
• the FDA/FCC constraints on energy deposition per unit gram of tissue and temperature rise as measured over periods of minutes be satisfied so as to avoid permanent tissue damage.
• tissue temperature rises of between 6° C and 11 ° 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 6° C and even 1° C or less in certain circumstances, will not permanently damage the tissue.
• a predetermined temperature such as 6° C and even 1° C or less in certain circumstances.
• a predetermined intensity or power such as between 100- 590 watts per square centimeter at the retina or approximately 1 watt per laser spot for each treatment spot at the retina
• a predetermined pulse length or exposure time such as between 100 and 600 milliseconds
• SDM subthreshold diode micropulse laser treatment
• SDM does not produce laser-induced retinal damage (photocoagulation), and has no known adverse treatment effect, and has been reported to be an effective treatment in a number of retinal disorders (including diabetic macular edema (DME) proliferative diabetic retinopathy (PDR), macular edema due to branch retinal vein occlusion (BRVO), central serous chorioretinopathy (CSR), reversal of drug tolerance, and prophylactic treatment of progressive degenerative retinopathies such as dry age-related macular degeneration, Stargardts' disease, cone dystrophies, and retinitis pigmentosa.
• DME diabetic macular edema
• PDR proliferative diabetic retinopathy
• BRVO branch retinal vein occlusion
• CSR central serous chorioretinopathy
• reversal of drug tolerance and prophylactic treatment of progressive degenerative retinopathies such as dry age-related macular degeneration, Stargardts' disease, cone
• HSPs heat shock proteins
• 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.
• Laser treatment can induce HSP production or activation and alter cytokine expression. The more sudden and severe the non-lethal cellular stress (such as laser irradiation), the more rapid and robust HSP activation.
• a burst of repetitive low temperature thermal spikes at a very steep rate of change (-7° C elevation with each 100 ⁇ s micropulse, or 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.
• Laser wavelengths below 530 nm produce increasingly cytotoxic photochemical effects. Between 530 nm and 1310 nm and particularly around 810 nm, SDM produces photothermal, rather than photochemical, cellular stress. Thus, SDM is able to affect the tissue without damaging it.
• HSP stimulation by SDM results in normalized cytokine expression, and consequently improved structure and function.
• the therapeutic effects of this "low-intensity" laser/tissue interaction are then amplified by "high-density” laser application, recruiting all the dysfunctional cells in the targeted tissue area by densely/confluently treating a large tissue area, including all areas of pathology, thereby maximizing the treatment effect.
• 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.
• AMD age-related macular degeneration
• SDM retinal pigment epithelium
• SDM treatment may directly affect cytokine expression via heat shock protein (HSP) activation in the targeted tissue.
• HSP heat shock protein
• SDM photostimulation has been effective in stimulating direct repair of slightly misfolded proteins in eye tissue.
• SDM subthreshold diode micropulse laser
• another way this may occur is because the spikes in temperature caused by the micro­pulses in the form of a thermal time-course allows diffusion of water inside proteins, and this allows breakage of the peptide-peptide hydrogen bonds that prevent the protein from returning to its native state. The diffusion of water into proteins results in an increase in the number of restraining hydrogen bonds by a factor on the order of a thousand.
• 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, duty cycle and total pulse train duration parameters must be taken into account.
• Other parameters which can be considered include the radius of the laser source as well as the average laser power. Adjusting or selecting one of these parameters can have an effect on at least one other parameter.
• a retinal phototherapy or photostimulation system embodying the present invention has the at least one treatment parameters, including wavelength, power, pulse train duration and duty cycle, preselected and fixed so as not to be alterable by a medical provider or other end user.
• the pulsed energy generator such as a laser console, will generate a pulsed energy source, such as a pulsed treatment laser light beam, having a combination of parameters selected so as to photostimulate and/or treat the retinal tissue without destroying, permanently damaging, or even damaging the retinal tissue whatsoever.
• the proper or most beneficial preselected parameters of wavelength, power, pulse train duration and duty cycle of the at least one treatment beam may be selected and fixed before delivery to the medical care provider or other end user.
• the combination of preselected parameters will be safe and can be optimized.
• the at least one treatment beam may have a wavelength selected between 530 nm to 1300 nm, a duty cycle of less than 10% and a pulse train duration of between 0.1 and 0.6 seconds.
• the duty cycle may be between 2% and 5%.
• the peak laser power output may be between 0.5 and 3.0 watts.
• a treatment spot size on the retinal tissue formed by the one or more treatment beams may be between 100-1000 micrometers. More particularly, the at least one treatment beam may have a wavelength between 750 nm and 850 nm, a duty cycle between 2% and 5%, and a pulse train duration of between 0.15 and 0.5 seconds.
• the system may have the fixed parameters of 810 nm, a duty cycle of 5%, a pulse train duration of 0.3 seconds, a power of 1.8 watts, and a resulting spot size of 500 micrometers.
• FIGS. 1A and 1B 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. 1A shows a wavelength of 880 nm
• FIG. 1B 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 100 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 100 milliseconds.
• the 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, 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.
• the target tissue can be heated to up to approximately 11° 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 1° 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.
• FIGS. 2A and 2B illustrate the time to decay from 10° 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. 2A and 1000 nm in FIG. 2B. 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.
• FIG. 2A and 2B 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 10° C to 1 ° C as can be seen in FIG. 2A when the wavelength is 880 nm and the source diameter is 1 millimeter, the temperature decay time is 16 seconds. The temperature decay time is 107 seconds when the source diameter is 4 mm. As shown in FIG. 2B, when the wavelength is 1000 nm, the temperature decay time is 18 seconds when the source diameter is 1 mm and 136 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 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.
• the pulse train mode of energy delivery has a distinct advantage over a single pulse or gradual mode of energy delivery, as far as the activation of remedial HSPs and the facilitation of protein repair is concerned.
• a light generating unit 10 such as a laser having a desired wavelength and/or frequencies and other operating parameters is used to generate electromagnetic radiation, such as laser light, in a controlled, pulsed manner to be delivered through a light tube or pipe 12 to a projector.
• the light generating unit 10 such as comprising a laser console, will generate one or more pulsed energy sources, such as a pulsed laser light beam, having the operating parameters discussed above preselected and fixed so as to be unalterable by a medical care provider or other end user.
• pulsed energy sources such as a pulsed laser light beam
• the light tube 12 could be connected to a camera, projector, or the light transmitted by the light generating unit 10 could be directly transmitted to such projector, camera or the like without the need of a light tube or pipe or the like.
• FIG. 4 a schematic diagram is shown of a system for generating electromagnetic energy radiation, such as laser light, including SDM.
• the system includes a laser console 22, such as for example the 810 nm near infrared micropulsed diode laser in the preferred embodiment.
• the laser generates a laser light beam which may be passed through optics, such as an optical lens 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, 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 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. Either method of generating laser spots allows for the creation of a very large number of laser spots simultaneously over a very wide treatment field. In fact, a very high number of laser spots, perhaps numbering in the hundreds even thousands or more could be simultaneously generated to cover a given area of the target tissue, or possibly even the entirety of the target tissue.
• 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 individual spots produced by such diffraction gratings are all of a similar optical geometry to the input beam, with minimal power variation for each spot. The result is a plurality of laser spots with adequate irradiance to produce harmless yet effective treatment application, simultaneously over a large target area.
• the present invention also contemplates the use of other geometric objects and patterns generated by other diffractive optical elements.
• the laser light passing through the mask 34 diffracts, producing a periodic pattern a distance away from the mask 34, shown by the laser beams labeled 36 in FIG. 21.
• the single laser beam 30 has thus been formed into hundreds or even thousands of individual laser beams 36 so as to create the desired pattern of spots or other geometric objects.
• These laser beams 36 may be passed through additional lenses, collimators, etc. 38 and 40 in order to convey the laser beams and form the desired pattern. Such 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 present invention can use a multitude of simultaneously generated 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. Although hundreds or even thousands of simultaneous laser spots could be generated and created and formed into patterns to be simultaneously applied to the tissue, due to the requirements of not overheating the tissue, there are constraints on the number of treatment spots or beams which can be simultaneously used in accordance with the present invention.
• Each individual laser beam or spot requires a minimum average power over a train duration to be effective.
• tissue cannot exceed certain temperature rises without becoming damaged.
• the number of simultaneous spots generated and used could number from as few as 1 and up to approximately 100 when a 0.04 (4%) duty cycle and a total train duration of 0.3 seconds (300 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.
• the system of the present invention incorporates a guidance system to ensure complete and total retinal treatment with retinal photostimulation of the entire retina, or the selected portion of the retina.
• 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 may be sequentially offset so as to achieve con­fluent and complete treatment of the surface.
• FIGS. 6 and 7 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 of spots are offset at each exposure so as to create space between the immediately previous expo­sure to allow heat dissipation and prevent the possibility of heat damage or tissue destruction.
• 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.
• 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.
• This offsetting can be determined algorithmically to ensure the fastest treatment time and least risk of damage due to thermal tissue, depending on laser parameters and desired application.
• quantum mechanical behavior may be observed which allows for arbitrary distribution of the laser input energy. This would allow for the generation of any arbitrary geometric shapes or patterns, such as a plurality of spots in grid pattern, lines, or any other desired pattern. Other methods of generating geometric shapes or patterns, such as using multiple fiber optical fibers or microlenses, could also be used in the present invention.
• Time savings from the use of simultaneous projection of geometric shapes or patterns permits the treatment fields of novel size, such as the 1.2 cm 2 area to accomplish whole-retinal treatment, in a single clinical setting or treatment session.
• generation and application of a plurality of laser light beams to simultaneously create a corresponding plurality of target tissue treatment spots has its advantages, it will be understood that the present invention could be utilized with only a single treatment laser light beam which is controllably moved over a desired treatment area of the retina.
• the present invention contemplates use of other geometric objects or patterns. For example, a single line 60 of laser light, formed by the continuously or by means of a series of closely spaced spots, can be created.
• An offsetting optical scanning mechanism can be used to sequentially scan the line over an area, illustrated by the downward arrow in FIG. 9.
• the same geometric object of a line 60 can be rotated, as illustrated by the arrows, so as to create a circular field of phototherapy.
• the potential negative of this approach is that the central area will be repeatedly exposed, and could reach unacceptable temperatures. This could be overcome, however, by increasing the time between exposures, or creating a gap in the line such that the central area is not exposed.
• the field of photobiology reveals that different biologic effects may be achieved by exposing target tissues to lasers of different wavelengths.
• FIG. 11 illustrates diagrammatically a system which couples multiple treatment light sources into the pattern-generating optical subassembly described above. Specifically, this system 20' is similar to the system 20 described in FIG. 4 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 parameters, such as of a different wavelength.
• 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.
• This sequential offsetting can be accomplished in two modes.
• 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.
• 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.
• These modes may also be mixed and matched.
• FIG. 12 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. 4. 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 32, mask or diffraction grating 34 and recollimators 38, 40 as described in connection with FIG. 11 above--the entire set of optics tuned for the specific wavelength generated by the corresponding laser console 22.
• each set of optics 24 is then directed to a beam splitter 46 for combination with the other wavelengths.
• 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 optical elements for each channel are tuned to produce the exact specified pattern for that channel's wavelength. Consequently, when all channels are combined and properly aligned a single steering pattern may be used to achieve complete coverage of the tissue for all wavelengths.
• the system 20'' may use as many channels 44a, 44b, 44c, etc. and beam splitters 46a, 46b, 46c, etc.
• each channel begins with a light source 22, which could be from an optical fiber as in other embodiments of the pattern- generating subassembly.
• 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.
• the laser light generating systems illustrated in FIGS. 4-12 are exemplary. Other devices and systems can be utilized to generate a source of SDM laser 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. First, 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.
• Power limitations in current micropulsed diode lasers require fairly long exposure duration. The longer the exposure, the more important the center-spot heat dissipating ability toward the unexposed tissue at the margins of the laser spot.
• the micropulsed laser light beam of an 810 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.
• another parameter of the present invention is the 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 10% duty cycle or higher adjusted to deliver micropulsed laser at similar irradiance at similar MPE levels significantly increase the risk of lethal cell injury.
• 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 100 microseconds in duration.
• 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 75-150 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. [Para 88] Adjacent exposure areas must be separated by at least a predetermined minimum distance to avoid thermal tissue damage.
• 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.
• a continuous wave laser could potentially be used instead of a micropulsed laser.
• the continuous wave laser there is concern of overheating as the laser is moved from location to location in that the laser does not stop and there could be heat leakage and overheating between treatment areas.
• the controlled manner of applying energy to the target tissue is intended to raise the temperature of the target tissue to therapeutically treat the target tissue without destroying or permanently damaging the target tissue. It is believed that such heating activates HSPs and that the thermally activated HSPs work to reset the diseased tissue to a healthy condition, such as by removing and/or repairing damaged proteins. It is believed by the inventors that maximizing such HSP activation improves the therapeutic effect on the targeted tissue.
• HSPs and HSP system species their generation and activation, temperature ranges for activating HSPs and time frames of the HSP activation or generation and deactivation can be utilized to optimize the heat treatment of the biological target tissue.
• 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.
• HSF a complex of HSP bound to HSF (unactivated HSPs) HSF 3 .
• HSE a complex of HSF 3 bound to HSE, that induces transcription and the creation of a new HSP mRNA molecule HSP.S a complex of HSP attached to damaged protein (HSP actively repairing the protein) [Para 100]
• the coupled simultaneous mass conservation equations for these 10 species are summarized below as eqs.
• 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
• HSF 3 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:HSF 3 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:HSF 3 , and that leads to the production of a new (activated) HSP molecule in the cell's cytoplasm.
• FIG. 13 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. 13 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 30 minutes after the temperature increase.
• FIG. 13 shows what the Rybinski et al equations predict for the variation of the 10 different species over a period of 350 minutes.
• FIG. 15 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.
• 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.
• performing multiple treatments to the target tissue of the patient within a single treatment session or office visit enhances the overall treatment of the biological tissue so long as the second or additional treatments are performed after an interval of time which does not exceed several minute but which is of sufficient length so as to allow temperature relaxation so as not to damage or destroy the target tissue.
• 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.
• the first SDM application is taken to reduce the cytoplasmic reservoir of unactivated HSPs in the initial HSPHSF molecule population from [HSPHSF(equil)] to [HSPHSF(equil)]exp[- ⁇ ] , • and to increase the initial HSP molecular population from [HSP(equil)] to [HSP(equil)] + [HSPHSF(equil)](1-exp[- ⁇ ]) • as well as to increase the initial HSF molecular population from [HSF(equil)] to [HSF(equil)] + [HSPHSF(equil)](1-exp[- ⁇ ]) •
• the equilibrium concentrations of all of the other species will be assumed to remain the same after the first SDM application •
• the HSP and HSPHSF concentrations can vary quite a bit in the interval t between SDM applications.
• HSP activated concentration
• cytoplasmic reservoir [HSPHSF] cytoplasmic reservoir
• the activation Arrhenius integral ⁇ 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 (2013) equilibrium concentrations for the ten species involved, given in Table 4.
• Table 7 is the same as the Tables 5 and 6, except that the treatments are separated by one minute, or sixty seconds.
• Table 7 is the same as the Tables 5 and 6, except that the treatments are separated by one minute, or sixty seconds.
• Tables 5-7 show that: • The first treatment of SDM increases [HSP] by a large factor for all three ⁇ ’s, although the increase is larger the larger ⁇ .
• [HSP] comes at the expense of the cytoplasmic reservoir of sequestered (unactivated) HSP’s: [HSPHSF(SDM1)] is much smaller than [HSPHSF(equil)] • [HSP] decreases appreciably in the interval ⁇ t between the two SDM treatments, with the decrease being larger the larger ⁇ t is.

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