WO2024118164A1 - Système et procédé d'utilisation d'énergie pour la neurorégénération - Google Patents

Système et procédé d'utilisation d'énergie pour la neurorégénération Download PDF

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Publication number
WO2024118164A1
WO2024118164A1 PCT/US2023/035408 US2023035408W WO2024118164A1 WO 2024118164 A1 WO2024118164 A1 WO 2024118164A1 US 2023035408 W US2023035408 W US 2023035408W WO 2024118164 A1 WO2024118164 A1 WO 2024118164A1
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target tissue
para
tissue
pulsed energy
energy
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PCT/US2023/035408
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English (en)
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Jeffrey K. LUTTRULL
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Ojai Retinal Technology, Llc
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Priority claimed from US18/072,889 external-priority patent/US20230103544A1/en
Application filed by Ojai Retinal Technology, Llc filed Critical Ojai Retinal Technology, Llc
Publication of WO2024118164A1 publication Critical patent/WO2024118164A1/fr

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    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
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    • 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
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    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
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    • A61B2018/2255—Optical elements at the distal end of probe tips
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    • A61N2007/0095—Beam steering by modifying an excitation signal

Definitions

  • the present invention is generally directed to systems and processes for treating biological tissue, such as diseased or damaged biological tissue. More particularly, the present invention is directed to a process for heat treating biological tissue using energy having parameters and applied such so as to create a therapeutic effect to a target tissue without destroying or permanently damaging the target tissue.
  • biological tissue such as diseased or damaged biological tissue.
  • the present invention is directed to a process for heat treating biological tissue using energy having parameters and applied such so as to create a therapeutic effect to a target tissue without destroying or permanently damaging the target tissue.
  • BACKGROUND OF THE INVENTION [Para 2]
  • the chronic progressive retinopathies (CPRs) are the most important causes of irreversible visual loss worldwide.
  • Open angle glaucoma is a chronic progressive disease that affects approximately 6% of the population over thirty-five years of age. OAG is one of the few ocular diseases that can lead to absolute blindness. Historically, OAG has been attributed to abnormally elevated intraocular pressures (IOP). Thus, conventional treatment of OAG has been directed to lowering IOP.
  • IOP intraocular pressures
  • Chronic progressive retinopathies may either be partially caused by, or result in, associated progressive optic neuropathy and atrophy or degeneration of neural elements, including the optic nerve, retinal nerve fiber layers, ganglion cells, and the like. It is also believed that many diseases and ailments throughout the body similarly have a neural component to them, wherein either atrophied or degenerated neural elements contribute to the disease or ailment, or the chronic disease or ailment results in degeneration and atrophy of the underlying neural elements within the associated tissue.
  • HSPs are a family of proteins that are produced by cells in response to exposure to stressful conditions.
  • Heat shock proteins can be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the Page 2 of 128 ORTLLC-61843 PCT App cell to toxins, oxidants, heavy metals, starvation, hypoxia, water deprivation and tissue trauma.
  • environmental stress conditions such as infection, inflammation, exercise, exposure of the Page 2 of 128 ORTLLC-61843 PCT App cell to toxins, oxidants, heavy metals, starvation, hypoxia, water deprivation and tissue trauma.
  • heat shock proteins play a role in responding to a large number of abnormal conditions in body tissues, including viral infection, inflammation, malignant transformations, exposure to oxidizing agents, cytotoxins, and anoxia.
  • Several heat shock proteins function as intra-cellular chaperones for other proteins and members of the HSP family are expressed or activated at low to moderate levels because of their essential role in protein maintenance and simply monitoring the cell's proteins even under non- stressful conditions.
  • Heat shock proteins are found in nearly every cell and tissue-type of multicellular organisms as well as in explanted tissues and in cultured cells.
  • the HSPs typically comprise 3%-10% of a cell’s proteins, although when under stress the percentage can rise to 15%.
  • the density of proteins of a mammalian cells has been found to be in the range of (2-4) x 10 18 CM -3 .
  • the aforementioned percentages mean that the density of HSPs is normally (1-4) x 10 17 CM -3 , while under stress the density can rise to (3-6) x 10 17 CM -3 .
  • Heat shock proteins are typically named according to their molecular weight, and act in different ways.
  • An especially ubiquitous heat shock protein is Hsp70, a protein with a molecular weight of 70 killodaltons. It plays a particularly significant role in protecting proteins that are just being formed and in rescuing damaged proteins. It contains a groove with an affinity for Page 3 of 128 ORTLLC-61843 PCT App neutral, hydrophobic amino acid residues that can interact with peptides up to 7 residues in length.
  • Hsp70 has peptide-binding and ATPase domains that stabilize protein structures in unfolded and assembly-competent states.
  • Hsp70 plays a role in preventing aggregation of misfolded proteins, many of which have exposed hydrophobic portions, and a facilitating the refolding of proteins into their proper conformations.
  • Hsp70 accomplishes this by first binding to the misfolded or fragmented protein, a binding that is made energetically possible by a site that binds ATP and hydrolyzes it into ADP.
  • Hsp70 heat shock proteins are a member of extracellular and membrane bound heat-shock proteins which are involved in binding antigens and presenting them to the immune system. Hsp70 has been found to inhibit the activity of influenza A virus ribonucleoprotein and to block the replication of the virus. Heat shock proteins derived from tumors elicit specific protective immunity.
  • a light beam can be generated and applied to the retinal tissue cells such that it 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.
  • the treatment typically entails applying a train of laser micropulses to radiate a portion of a diseased retina for a total duration of less than a second. Each micropulse is on the order of tens to hundreds of microseconds long, with the microseconds being separated by one to several milliseconds, which raises the tissue temperature in a controlled manner.
  • the present invention is directed to a process for heat treating biological tissues by applying treatment energy to a target tissue to therapeutically treat the target tissue. More particularly, the present invention is directed to a process for providing neuroprotection and neuroregeneration to biological tissue.
  • a first treatment to the target tissue is performed by generating treatment energy and repeatedly applying the treatment energy 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 generated treatment energy may be pulsed or rapidly applied in succession.
  • Page 6 of 128 ORTLLC-61843 PCT App More particularly, the process of the present invention provides a pulsed energy having energy parameters including a wavelength or frequency, a duty cycle of less than 10% and a pulse train duration of less than one second.
  • the pulsed energy is applied to neural elements of a target tissue having a chronic progressive disease or at a risk of having a chronic progressive disease, to provide neuroprotection or neuroregeneration to the neural elements of the target tissue.
  • the energy parameters are selected so as to apply the pulsed energy to the target tissue for a total pulse duration of less than one second and raise a target tissue temperature up to 11° C. to achieve a therapeutic effect, wherein the average temperature rise of the tissue over several minutes is maintained at or below a predetermined level so as not to permanently damage the target tissue.
  • the energy parameters may be selected so that the target tissue temperature is raised between approximately 6° C. to 11° C. at least during application of the energy to the target tissue. The average temperature rise of the target tissue over several minutes is maintained at 6° C.
  • the pulsed energy source energy parameters may be selected so that 20 to 40 joules of energy is absorbed by each cubic centimeter of the target tissue. This may result in raising the target tissue temperature, as described above.
  • the target tissue may comprise retinal tissue.
  • the neural elements may comprise a nerve fiber and ganglion cell layers of the retina.
  • the pulsed energy which may be in the form of a plurality of simultaneously applied pulsed energy spaced apart beams, may be moved in a selected manner so as to cover the entirety of the retina, including the fovea.
  • the treatment energy and application parameters are selected such so as to therapeutically treat the target tissue without destroying or permanently damaging the target tissue.
  • the selected energy and application parameters may comprise tissue application spot size or area, average power or average power density, and exposure duration. Other parameters which may be selected include wavelength or frequency and duty cycle.
  • the treatment energy and application parameters may be selected to have an average power density of 100-590 watts per square centimeter of target tissue, a target tissue application spot size between 100-500 microns, and a train exposure duration of 500 milliseconds or less.
  • the treatment energy may comprise a light beam, a microwave, a radiofrequency or an ultrasound.
  • a device may be inserted into a cavity of the body in order to apply the treatment energy to the tissue.
  • the treatment energy Page 8 of 128 ORTLLC-61843 PCT App may be applied to an exterior area of a body which is adjacent to the target tissue, or has a blood supply close to a surface of the exterior area of the body.
  • the treatment energy may comprise a radiofrequency between approximately 3 to 6 megahertz (MHz). It may have a duty cycle of between approximately 2.5% to 5%. It may have a pulsed train duration of between approximately 0.2 to 0.4 seconds.
  • the radiofrequency may be generated with a device having a coil radii of between approximately 2 and 6 mm and approximately 13 and 57 amp turns.
  • the treatment energy may comprise a microwave frequency of between 10 to 20 gigahertz (GHz).
  • the microwave may have a pulse train duration of approximately between 0.2 and 0.6 seconds.
  • the microwave may have a duty cycle of between approximately 2% and 5%.
  • the microwave may have an average power of between approximately 8 and 52 watts.
  • the treatment energy may comprise a pulsed light beam, such as one or more laser light beams.
  • the light beam may have a wavelength of between approximately 570 nm to 1300 nm, and more preferably between 600 nm and 1000 nm.
  • the pulsed light beam may have a power of between approximately 0.5 and 74 watts.
  • the pulsed light beam has a duty cycle of less than 10%, and preferably between 2.5% and 5%.
  • the pulsed light beam may have a pulse train duration of approximately 0.1 and 0.6 seconds.
  • the treatment energy may comprise a pulsed ultrasound, having a frequency of between approximately 1 and 5 MHz.
  • the ultrasound has a train duration of approximately 0.1 and 05 seconds.
  • the ultrasound may have a duty Page 9 of 128 ORTLLC-61843 PCT App cycle of between approximately 2% and 10%.
  • the ultrasound has a power of between approximately 0.46 and 28.6 watts.
  • the pulsed energy may be applied to a plurality of target tissue areas.
  • Adjacent target tissue areas are separated by at least a predetermined distance to avoid thermal tissue damage.
  • a plurality of pulsed energy beams may be simultaneously applied to the target tissue in sufficiently spaced apart relation so as not to damage the target tissue.
  • the pulsed energy may be moved from a first treatment area after a pulse and applied to one or more additional treatment areas of the target tissue.
  • the pulsed energy is then returned to the first treatment area before a next sequential pulse of the pulse train during the space of time between pulses of the pulse train, comprising less than one second. This is repeated until a predetermined number of pulses of the pulsed energy have been applied to the first and additional treatment areas.
  • the treatment energy may be applied to a second area of the target tissue sufficiently spaced apart from the first area of the target tissue to avoid thermal tissue damage of the target tissue.
  • the treatment energy is repeatedly applied, in an alternating manner during the same treatment session, to each of the first and second areas of the target tissue until the Page 10 of 128 ORTLLC-61843 PCT App predetermined number of energy applications to each of the first and second areas of the target tissue has been achieved.
  • the first treatment comprises applying the treatment energy to the target tissue for a period of less than ten seconds, and more typically less than one second.
  • the first treatment creates a level of heat shock protein activation in the target tissue.
  • the application of the treatment energy to the target tissue is halted for an interval of time that preferably exceeds the period of time of the first treatment.
  • the interval of time may comprise several seconds to several minutes, such as three seconds to three minutes, or preferably between ten seconds to ninety seconds.
  • a second treatment is performed to the target tissue by repeatedly reapplying the treatment energy to the target tissue so as to controllably raise the temperature of the target tissue to therapeutically treat the target tissue without destroying or permanently damaging the target tissue.
  • a system for providing neuroprotection or neuroregeneration to biological tissue in accordance with the present invention generally comprises a pulsed energy generator that generates a pulsed energy having energy parameters including a wavelength or frequency, a duty cycle of less than 10% and a pulse train duration of less than one second.
  • a delivery device that applies the pulsed energy to neural elements of a target tissue having a chronic Page 11 of 128 ORTLLC-61843 PCT App progressive disease or at a risk of having a chronic progressive disease.
  • the delivery device applies the total pulse train duration of less than one second such that the target tissue temperature is raised between 6° and 11° C at least during application of the pulsed energy to the target tissue to provide neuroprotection or neuroregeneration to the neural elements of the target tissue, while maintaining the average temperature rise of the target tissue at or below a predetermined level of 6° C or less for several minutes so as not to permanently damage the target tissue.
  • the delivery device may comprise an endoscope or other device insertable into a cavity of the body to apply the pulsed energy source to the target tissue.
  • the treatment energy may be applied to an exterior of a body which is adjacent to a target tissue. This may be by means of a laser generating laser light, or a device which creates microwaves, radiofrequency waves or ultrasound.
  • the delivery device may apply the pulsed energy to nerve fiber and ganglion cell layers of a retina.
  • Such an energy device may comprise one or more lasers creating one or more treatment laser light beams which are applied to the retina.
  • Means may be provided for creating a plurality of pulsed energy beams and simultaneously applying the plurality of pulsed energy beams to the target tissue in sufficiently spaced apart relation so as not to damage the target tissue.
  • Page 12 of 128 ORTLLC-61843 PCT App [Para 35]
  • the means for creating a plurality of pulsed energy beams may comprise an optical mask that splits the pulsed energy into a plurality of beams.
  • the optical mask may comprise diffraction grating.
  • the means for creating a plurality of pulsed energy beams may comprise a plurality of pulsed energy generators.
  • a plurality of lasers may be used to create a plurality of laser light beams.
  • the emitters may comprise RF emitters.
  • the treatment energy is applied to the target tissue, wherein the treatment energy has energy and application parameters selected so as to raise the target tissue temperature sufficiently to create a therapeutic effect while maintaining an average temperature of the target tissue over several minutes at or below a predetermined temperature so as not to destroy or permanently damage the target tissue.
  • the system may also include means for moving the pulsed energy from a first treatment area after a pulse to one or more additional treatment areas of the target tissue and return the pulsed energy to the first treatment area before a next sequential pulse of the pulse train duration during the space of time between pulses of the pulse train duration of less than a second, repeated until a predetermined number of pulses of the pulsed energy have been applied to the first and additional treatment areas.
  • a phase delay in the activation of the energy emitters of the array may be introduced to generate treatment energy in Page 13 of 128 ORTLLC-61843 PCT App a phased manner using a predetermined delay of activation in order to apply treatment energy to each of the first and second areas of the target tissue.
  • the energy emitters of the array may be activated sequentially in order to apply treatment energy to each of the first and second areas of the target tissue.
  • FIGURE 1 is a table illustrating a comparison of rates of average nerve fiber layer trend improvement between different groups receiving treatment in accordance with the present invention and without treatment;
  • FIGURE 2 is a table illustrating comparison of rates of ganglion cell complex layer trend improvement between groups;
  • FIGURE 3 is a table illustrating comparison of rates of average retinal thickness trend improvement between two diseased groups receiving treatment in accordance with the present invention;
  • FIGURES 4A and 4B are graphs illustrating the average power of a laser source compared to a source radius and pulse train duration of the laser;
  • FIGURES 5A and 5B are graphs illustrating the time for the temperature to decay depending upon the laser source radius and wavelength;
  • FIGURES 6-9 are graphs illustrating the peak ampere turns for various radiofrequencies, duty cycles, and coil radii;
  • FIGURE 10 is a graph depicting the time for temperature rise to decay compared to radiofrequency coil radius
  • FIGURE 27 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
  • FIGURE 28 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
  • FIGURE 29 is a diagrammatic view similar to FIG.
  • FIGURE 30 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 31 is a diagrammatic view illustrating yet another embodiment of a system used to generate laser light beams to treat tissue in accordance with the present invention
  • FIGURE 32 is a cross-sectional and diagrammatic view of an end of an endoscope inserted into the nasal cavity and treating tissue therein, in accordance with the present invention
  • FIGURE 33 is a diagrammatic and partially cross-sectioned view of a bronchoscope extending through the trachea and into the bronchus of a lung and providing treatment thereto, in accordance with the present invention
  • FIGURE 34 is a diagrammatic view of a colonoscope providing photostimulation to an intestinal or colon area
  • FIGURE 49 is another graph depicting the width of individual lines of the pattern of FIG. 47; [Para 82] FIGURE 49 is another graph depicting the width of individual lines of the pattern of FIG. 47; [Para 83] FIGURE 50 is a plot graph depicting the determinant of the line separation; [Para 84] FIGURE 51 is a block diagram of components of a steerable array system; [Para 85] FIGURE 52 is a plot graph showing induced tissue temperature rise and drops; [Para 86] FIGURES 53-55 are graphs depicting variables of three different coils, in accordance with the present invention; Page 19 of 128 ORTLLC-61843 PCT App [Para 87] FIGURE 56 is a graph depicting the plots of FIGS.
  • FIGURE 57 is a block diagram for an induction array which can be used in accordance with the present invention
  • FIGURES 58A and 58B are graphs depicting the behavior of HSP cellular system components over time following a sudden increase in temperature
  • FIGURES 59A-59H are graphs depicting the behavior of HSP cellular system components in the first minute following a sudden increase in temperature
  • FIGURES 60A and 60B 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
  • FIGURE 61 is a graph depicting the improvement ratios versus interval between treatments, in accordance with the present invention.
  • the present invention is directed to systems and methods for delivering a pulsed energy, such as ultrasound, radiofrequency, microwave, one or more light beams, and the like, having energy parameters selected to cause a thermal time-course in tissue to raise the tissue temperature over a short Page 20 of 128 ORTLLC-61843 PCT App 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 ultrasound, radiofrequency, microwave, one or more light beams, and the like
  • 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.
  • Arrhenius integrals are used for analyzing the impacts of actions on biological tissue. See, for instance, The CRC Handbook of Thermal Engineering, ed. Frank Kreith, Springer Science and Business Media (2000). At the same time, the selected parameters must not permanently damage the tissue. Thus, the Arrhenius integral for damage may also be used, wherein the solved Arrhenius integral is less than 1 or unity. Alternatively, 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.
  • Page 22 of 128 ORTLLC-61843 PCT App [Para 97] The inventors have discovered that generating a subthreshold, sublethal micropulse laser light beam which has a wavelength greater than 532 nm and a duty cycle of less than 10% at a predetermined intensity or power and a predetermined pulse length or exposure time creates desirable retinal photostimulation without any visible burn areas or tissue destruction.
  • a predetermined average power or power intensity 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 train length or exposure time such as between 100 and 600 milliseconds or less
  • 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 Page 23 of 128 ORTLLC-61843 PCT App 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, Stargardt’s disease, cone dystrophies, and retinitis pigmentosa.
  • DME App diabetic macular edema
  • PDR proliferative diabetic retinopathy
  • BRVO branch retinal vein occlusion
  • CSR central serous chorioretinopathy
  • prophylactic treatment of progressive degenerative retinopathies such as dry age-related macular degeneration, Star
  • 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 70,000oC/sec) produced by each SDM exposure is especially effective in stimulating activation Page 24 of 128 ORTLLC-61843 PCT App 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 550 nm produce increasingly cytotoxic photochemical effects.
  • the lower wavelength limit realistically usable by the process of the present invention is determined by the undesirable absorption by the visual pigments and other absorbers, including blood, the lens of the eye, etc.
  • the absorption is dominated by melanin between 570 nm and 650 nm, where above 650 nm the absorption is practically all due to the melanin in the RPE.
  • the melanin absorbance is only 0.048 of what it is at 810 nm, and the radiation power due to this effect alone would have to be increased by a factor of 20 compared to the power at 810 nm to achieve the same temperature increase. Accordingly, the present invention can be performed at a broad range of wavelengths between 570 nm to 1300 nm, with the more preferable range of wavelengths being 600 nm to 1100 nm, and an even more preferable range of wavelengths of 650 nm to 900 nm, with the particularly preferred operating wavelength at approximately 810 nm.
  • the melanin absorption is dominant and the heating primarily in Page 25 of 128 ORTLLC-61843 PCT App the desired RPE and the wavelength is at a safe distance from the wavelengths where appreciable absorption occurs in the visual pigments as shorter wavelengths or water at longer wavelengths, which will create undesirable heating of the eye and other tissues.
  • SDM produces photothermal, rather than photochemical, cellular stress.
  • SDM is able to affect the tissue without damaging it.
  • the average required treatment power between tissue reset and tissue damage can be calculated with the wavelength used, the radiation train duration, preferably being between 0.03 and 0.8 seconds and a retinal application spot by the radiation being between 10 and 500 microns .
  • 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.
  • the corresponding peak powers, during the individual pulse, are obtained from the average powers by dividing by the duty cycle.
  • the average power can vary between 0.0000069 to 37.5 watts within a wavelength between 570 nm – 1300 nm, a pulse train duration between 30–800 milliseconds, and a treatment spot between 10-700 microns.
  • 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. [Para 105] As noted above, while SDM stimulation of HSPs is non-specific with regard to the disease process, the result of 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.
  • SDM retinal disease 2019
  • 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.
  • Page 27 of 128 ORTLLC-61843 PCT App [Para 106] The inventors have found that SDM treatment of patients suffering from age-related macular degeneration (AMD) can slow the progress or even stop the progression of AMD.
  • 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
  • the present invention is directed to the controlled application of ultrasound or electromagnetic radiation to treat abnormal conditions including inflammations, autoimmune conditions, and cancers that are accessible by means of fiber optics of endoscopes or Page 28 of 128 ORTLLC-61843 PCT App surface probes as well as focused electromagnetic/sound waves.
  • SDM subthreshold diode micropulse laser
  • SDM when applied to eye tissue, uses one or more laser light beams selectively targeting the retinal pigment epithelium (RPE) which causes photothermal activation of RPE heat shock proteins (HSPs) at energy levels sublethal to the RPE, enhancing HSP protein repair kinetics and upregulating the endoplasmic reticulum (ER) unfolded protein response (UPR) to improve a normal eye cell function and inhibit apoptosis.
  • RPE retinal pigment epithelium
  • HSPs heat shock proteins
  • SDM Low-intensity/high-density subthreshold microsecond pulsed diode laser (SDM) has been shown to clinically improve all measures of retinal and visual function in all CPRs studied, including AMD, OAG, DR, IRDs, including Stargardt’s Disease and retinitis pigmentosa.
  • ROAG is characterized by GON as the only evidence of a retinopathy, unlike the other CPRs which have characteristic retinal abnormalities and only secondary, if ever, optic nerve involvement.
  • ROAG appears to be characterized by either a hyponeurotropism, or excessive production of neurotoxic factors from the abnormal RPE – or both.
  • Page 30 of 128 ORTLLC-61843 PCT App [Para 113] Because the retina is neural tissue that is part of the central nervous system, these effects are also neurotropic and neuroprotective. This has been confirmed by a study, the results of which are illustrated in FIGS. 1-3.
  • the study is the result of clinical observation in eyes with CPRs treated with regular periodic panmacular SDM laser, sometimes referred to herein as vision protection therapy or VPT.
  • the clinical observation is that the longitudinal trends of key spectral-domain optical coherence tomography (OCT) indices of glaucoma disease progression appear to be improving, rather than worsening, over time.
  • OCT optical coherence tomography
  • a study was undertaken to compare the changes in average nerve fiber layer trends (NFLT) and ganglion cell complex layer trends (GCCT) over time in three groups of eyes, namely, OAG without VPT, OAG with VPT, and AMD with VPT.
  • NFLT average nerve fiber layer trends
  • GCCT ganglion cell complex layer trends
  • the findings of the study suggest a neuroprotective effect of SDM in CPRs, with also the possibility of neuroregeneration.
  • FIG. 3 illustrates the average retinal thickness trends for the OAG with VPT and AMD with VPT.
  • Inclusion criteria for all eyes were the useful OCT data, treatment with VPT for neuroprotection throughout the period of OCT analysis, and complete data in the electronic medical record (EMR) over the same period.
  • EMR electronic medical record
  • the diagnosis and treatment for OAG were required.
  • an indication for VPT of intermediate AMD without OAG was required.
  • a third group consisting of eyes with OAG that were not managed with VPT were then identified. These eyes were drawn from the same glaucoma subspecialty practice experiencing similar glaucoma management. Spectral-domain OCT data of the VPT untreated OAG eyes was obtained from the Optovue Angiovue system.
  • VPT describes a strategy of regular periodic SDM intended to maintain neuroprotection over time. As all CPRs are neurodegenerations, the neuroprotective effects of SDM apply and are relevant to all, although the manifestations of each are different, reflecting the nature of the underlying disease process.
  • HSP activation is a catalytic reaction that accelerates protein repair in dysfunctional cells that are characterized by high levels of misfolded proteins and failing proteostasis.
  • HSP normalize cell function by restoring proteostasis and inhibiting apoptosis through upregulation of the endoplasmic reticular (ER) unfolded protein response (UPR).
  • ER endoplasmic reticular
  • RPE HSP activation and normalization of retinal function including normalized retinal cytokine expression and response leading to homeotrophic retinal microglia M2 and astrocyte A2 activation may account for the findings of a progressive thickening of NFL and GCC in eyes with both Page 35 of 128 ORTLLC-61843 PCT App OAG and AMD.
  • the anatomic thickening of NFL and GCC suggests the possibility of not only neuroprotection, but also neuroregeneration, as a result of SDM therapy.
  • new retinal nerve cells including regeneration of retinal ganglion cells and other neural elements in OAG, AMD, and other progressive retinopathies.
  • the effect appears to begin with the first treatment, and gradually continues and improves with periodic repeated treatment/maintenance treatment. It is believed that neuroprotection, or even neuroregeneration, of other tissues within the body, other than the retina, will occur when the treatment in accordance with the present invention is applied to such tissues. Such could be for neuroprotection, or in some cases even neuroregeneration.
  • 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.
  • FIGS. 4A and 4B 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. 4A shows a Page 36 of 128 ORTLLC-61843 PCT App wavelength of 880 nm
  • FIG.4B 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.
  • Page 37 of 128 ORTLLC-61843 PCT App [Para 127]
  • the absorption length is very small in the thin melanin layer in the retinal pigmented epithelium.
  • 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. Accordingly, 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.
  • 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 wavelength of 1000 nm yields a penetration depth of approximately 3.5 mm.
  • 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.
  • FIGS. 5A and 5B illustrate the time to decay from 10°C to 1°C for a laser source Page 38 of 128 ORTLLC-61843 PCT App having a radius of between 0.1 cm and 0.4 cm with the wavelength being 880 nm in FIG. 5A and 1000 nm in FIG. 5B.
  • 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. 5A and 5B 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. 5A 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. 5A 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.
  • the temperature decay time is 18 seconds Page 39 of 128 ORTLLC-61843 PCT App 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. While 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.
  • the parameters differ for the individual energy sources, including microwave, infrared lasers, radiofrequency and ultrasound, because the absorption properties of tissues differ for these different types of energy sources.
  • the 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 1 relating to muscle, skin and tissues with high water content
  • Table 2 relating to fat, bone and tissues with low water content.
  • Page 40 of 128 ORTLLC-61843 PCT App [Para 132] Table 1.
  • the heated region is determined by the dimensions of the coil that is the source of the radiofrequency energy rather than by absorption lengths.
  • the electric and magnetic fields can be expressed in terms of the vector magnetic potential, which in turn can be expressed in closed form in terms of elliptic integrals of the first and second kind.
  • the heating occurs only in a region that is comparable in size to the dimensions of the coil source itself. Accordingly, if it is desired to preferentially heat a region characterized by a radius, the source coil will be chosen to have a similar radius.
  • the heating drops off very rapidly outside of a hemispherical region of radius because of the 1/r 3 drop off of the magnetic field. Since it is proposed to use the radiofrequency the diseased tissue accessible only externally or from inner cavities, it is reasonable to consider a coil radii of between approximately 2 to 6 mm. [Para 135]
  • the radius of the source coil(s) as well as the number of ampere turns (NI) in the source coils give the magnitude and spatial extent of the magnetic field, and the radiofrequency is a factor that relates the magnitude of the electric field to the magnitude of the magnetic field.
  • the heating is proportional to the product of the conductivity and the square of the electric field. For target tissues of interest that are near external or internal surfaces, the conductivity is that of skin and mucous tissue.
  • the duty cycle of the pulse train as well as the total train duration of a pulse train are factors which affect how much total energy is delivered to the tissue.
  • Preferred parameters for a radiofrequency energy source have been determined to be a coil radii between 2 and 6 mm, radiofrequencies in the range of 3-6 MHz, total pulse train durations of 0.2 to 0.4 seconds, and a duty Page 42 of 128 ORTLLC-61843 PCT App cycle of between 2.5% and 5%.
  • FIGS. 6-9 show how the number of ampere turns varies as these parameters are varied in order to give a temperature rise that produces an Arrhenius integral of approximately one or unity for HSP activation.
  • the peak ampere turns (NI) is 13 at the 0.6 cm coil radius and 20 at the 0.2 cm coil radius.
  • the peak ampere turns is 26 when the pulse train duration is 0.4 seconds and the coil radius is 0.6 cm and the duty cycle is 5%.
  • the peak ampere turns is 40 when the coil radius is 0.2 cm and the pulse train duration is 0.2 seconds.
  • a duty cycle of 2.5% is used in FIGS. 8 and 9. This yields, as illustrated in FIG.
  • the temperature decay time is approximately 37 seconds when the radiofrequency coil radius is 0.2 cm, and approximately 233 seconds when the radiofrequency Page 43 of 128 ORTLLC-61843 PCT App coil radius is 0.5 cm. When the radiofrequency coil radius is 0.6 cm, the decay time is approximately 336 seconds, which is still within the acceptable range of decay time, but at an upper range thereof.
  • Microwaves are another electromagnetic energy source which can be utilized in accordance with the present invention. The frequency of the microwave determines the tissue penetration distance. The gain of a conical microwave horn is large compared to the microwave wavelength, indicating under those circumstances that the energy is radiated mostly in a narrow forward load.
  • a microwave source used in accordance with the present invention has a linear dimension on the order of a centimeter or less, thus the source is smaller than the wavelength, in which case the microwave source can be approximated as a dipole antenna.
  • Such small microwave sources are easier to insert into internal body cavities and can also be used to radiate external surfaces.
  • the heated region can be approximated by a hemisphere with a radius equal to the absorption length of the microwave in the body tissue being treated.
  • frequencies in the 10-20 GHz range are used, wherein the corresponding penetration distances are only between approximately 2 and 4 mm.
  • the temperature rise of the tissue using a microwave energy source is determined by the average power of the microwave and the total pulse train duration.
  • the duty cycle of the pulse train determines the peak power in a single pulse in a train of pulses.
  • the radius of the source is taken to be less Page 44 of 128 ORTLLC-61843 PCT App than approximately 1 centimeter, and frequencies between 10 and 20 GHz are typically used, a resulting pulse train duration of 0.2 and 0.6 seconds is preferred.
  • the required power decreases monotonically as the train duration increases and as the microwave frequency increases. For a frequency of 10 GHz, the average power is 18 watts when the pulse train duration is 0.6 seconds, and 52 watts when the pulse train duration is 0.2 seconds.
  • a graph depicts the average microwave power in watts of a microwave having a frequency of 10 GHz and a pulse train duration from between 0.2 seconds and 0.6 seconds.
  • FIG. 12 is a similar graph, but showing the average microwave power for a microwave having a frequency of 20 GHz.
  • the average microwave source power varies as the total train duration and microwave frequency vary.
  • Arrhenius integral for HSP activation in the heated region is approximately 1.
  • a graph illustrates the time, in seconds, for the temperature to decay from approximately 10°C to 1°C compared to microwave frequencies between 58 MHz and 20000 MHz.
  • the minimum and maximum temperature decay for the preferred range of microwave frequencies Page 45 of 128 ORTLLC-61843 PCT App are 8 seconds when the microwave frequency is 20 GHz, and 16 seconds when the microwave frequency is 10 GHz.
  • Utilizing ultrasound as an energy source enables heating of surface tissue, and tissues of varying depths in the body, including rather deep tissue. The absorption length of ultrasound in the body is rather long, as evidenced by its widespread use for imaging.
  • ultrasound can be focused on target regions deep within the body, with the heating of a focused ultrasound beam concentrated mainly in the approximately cylindrical focal region of the beam.
  • the heated region has a volume determined by the focal waist of the airy disc and the length of the focal waist region, that is the confocal parameter. Multiple beams from sources at different angles can also be used, the heating occurring at the overlapping focal regions.
  • the relevant parameters for determining tissue temperature are frequency of the ultrasound, total train duration, and transducer power when the focal length and diameter of the ultrasound transducer is given.
  • the frequency, focal length, and diameter determine the volume of the focal region where the ultrasound energy is concentrated. It is the focal volume that comprises the target volume of tissue for treatment.
  • Transducers having a diameter of approximately 5 cm and having a focal length of approximately 10 cm are readily available.
  • Favorable focal dimensions are achieved when the ultrasound frequency is between 1 and 5 MHz, and the total train duration is 0.1 to 0.5 seconds.
  • the focal volumes are 0.02 cc at 5 MHz and 2.36 cc at 1 MHz.
  • FIG. 14 a graph illustrates the average source power in watts compared to the frequency (between 1 MHz and 5 MHz), and the pulse train duration (between 0.1 and 0.5 seconds).
  • a transducer focal length of 10 cm and a source diameter of 5 cm have been assumed.
  • the required power to give the Arrhenius integral for HSP activation of approximately 1 decreases monotonically as the frequency increases and as the total train duration increases.
  • the minimum power for a frequency of 1 GHz and a pulse train duration of 0.5 seconds is 5.72 watts, whereas for the 1 GHz frequency and a pulse train duration of 0.1 seconds the maximum power is 28.6 watts.
  • 0.046 watts is required for a pulse train duration of 0.5 seconds, wherein 0.23 watts is required for a pulse train duration of 0.1 seconds.
  • the corresponding peak power during an individual pulse is obtained simply by dividing by the duty cycle.
  • FIGURE 15 illustrates the time, in seconds, for the temperature to diffuse or decay from 10°C to 6°C when the ultrasound frequency is between 1 and 5 MHz.
  • FIG. 16 illustrates the time, in seconds, to decay from approximately 10°C to approximately 1°C for ultrasound frequencies from 1 to 5 MHz.
  • the maximum time for temperature decay is 366 seconds when the ultrasound frequency is 1 MHz
  • the minimum temperature decay is 15 Page 47 of 128 ORTLLC-61843 PCT App seconds when the microwave frequency is 5 MHz.
  • FIGS. 15 and 16 illustrate the volume of focal heated region, in cubic centimeters, as compared to ultrasound frequencies from between 1 and 5 MHz. Considering ultrasound frequencies in the range of 1 to 5 MHz, the corresponding focal sizes for these frequencies range from 3.7 mm to 0.6 mm, and the length of the focal region ranges from 5.6 cm to 1.2 cm.
  • the corresponding treatment volumes range from between approximately 2.4 cc and 0.02 cc.
  • Examples of parameters giving a desired HSP activation Arrhenius integral greater than 1 and damage Arrhenius integral less than 1 is a total ultrasound power between 5.8-17 watts, a pulse duration of 0.5 seconds, an interval between pulses of 5 seconds, with total number of pulses 10 within the total pulse stream time of 50 seconds.
  • the target treatment volume would be approximately 1 mm on a side. Larger treatment volumes could be treatable by an ultrasound system similar to a laser diffracted optical system, by applying ultrasound in multiple simultaneously applied adjacent but separated and spaced columns.
  • the multiple focused ultrasound beams converge on a very small treatment target within the body, the convergence allowing for a minimal heating except at the overlapping beams at the target.
  • This area would be Page 48 of 128 ORTLLC-61843 PCT App heated and stimulate the activation of HSPs and facilitate protein repair by transient high temperature spikes.
  • the treatment is in compliance with FDA/FCC requirements for long term (minutes) average temperature rise ⁇ 1K.
  • An important distinction of the invention from existing therapeutic heating treatments for pain and muscle strain is that there are no high T spikes in existing techniques, and these are required for efficiently activating HSPs and facilitating protein repair to provide healing at the cellular level.
  • the volume of the treatment region enters because the temperature must decay from its high value of the order of 10°C fairly rapidly in order for the long term average temperature rise not to exceed the long term FDA/FCC limit of 6°C for ultrasound frequencies and 1°C or less for electromagnetic radiation energy sources.
  • L linear dimension
  • D 0.00143 cm 2 /sec is the typical heat diffusion coefficient.
  • L 1 mm
  • the decay time is roughly 0.4 sec.
  • a train consisting of 10 pulses each of duration 0.5 seconds, with an interval between pulses of 5 second can achieve the desired momentary high rise in temperature while still not exceeding an average long term temperature rise of 1°C. This is demonstrated further below.
  • the limitation of heated volume is the reason why RF electromagnetic radiation is not as good of a choice for SDM-type treatment of regions deep with the body as ultrasound.
  • [7] is provided by: dT(t) ⁇ dT o (t p /t) 3/2 [9] as can be seen in FIG. 18, which is a comparison of eqs. [7] and [9] for dT(t)/ dT o at the target treatment zone.
  • the bottom curve is the approximate expression of eq [9].
  • the Arrhenius integral for a train of N pulses can now be evaluated with the temperature rise given by eq. [9].
  • dT N (t) ⁇ dT(t-nt I ) [11]
  • dT(t-ntI) is the expression of eq. [9] with t replaced by t-ntI .
  • the Arrhenius integral can be evaluated approximately by dividing the integration interval into the portion where the temperature spikes occur and the portion where the temperature spike is absent.
  • the summation over the temperature spike contribution can be simplified by applying Laplace’s end point formula to the integral over the temperature spike.
  • the integral over the portion when the spikes are absent can be simplified by noting that the non-spike temperature rise very rapidly reaches an asymptotic value, Page 53 of 128 ORTLLC-61843 PCT App so that a good approximation is obtained by replacing the varying time rise by its asymptotic value. When these approximations are made, eq.
  • Logarithm of Arrhenius integrals [eq.
  • the pulsed energy source may be directed to an exterior of a body which is adjacent to the target tissue or has a blood supply close to the surface of the exterior of the body.
  • a device may be inserted into a cavity of a body to apply the pulsed energy source to the target tissue. Whether the energy source is applied outside of the body or inside of the body and what type of device is utilized depends upon the energy source selected and used to treat the neural elements of the target tissue.
  • Photostimulation in accordance with the present invention, can be effectively transmitted to an internal surface area or tissue of the body utilizing an endoscope, such as a bronchoscope, proctoscope, colonoscope or the like.
  • an endoscope such as a bronchoscope, proctoscope, colonoscope or the like.
  • one of the internal tubes comprises a light pipe or multi-mode optical fiber which conducts light down the scope to illuminate the region of interest and enable the doctor to see what is at the illuminated end.
  • Another internal tube could consist of wires that carry an electrical current to enable the doctor to cauterize the illuminated tissue.
  • Yet another internal tube might consist of a biopsy tool that would enable the doctor to snip off and hold on to any of the illuminated tissue.
  • one of these internal tubes is used as an electromagnetic radiation pipe, such as a multi-mode optical fiber, to transmit Page 56 of 128 ORTLLC-61843 PCT App the SDM or other electromagnetic radiation pulses that are fed into the scope at the end that the doctor holds.
  • a light generating unit 10 such as a laser having a desired wavelength and/or frequency 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 distal end of the scope 14, illustrated in FIG. 22, which is inserted into the body and the laser light or other radiation 16 delivered to the target tissue 18 to be treated.
  • electromagnetic radiation such as laser light
  • FIG. 23 a schematic diagram is shown of a system for generating electromagnetic energy radiation, such as laser light, including SDM.
  • the system generally referred to by the reference number 20, 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 is 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, such as an endoscope, for projecting the laser beam light onto the target tissue of the patient.
  • a delivery device 26 such as an endoscope
  • 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 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 optical 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 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 Page 59 of 128 ORTLLC-61843 PCT App 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.
  • 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. 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. 25 and 26 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.
  • the optical scanning mechanism 50 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.
  • 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. 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. 25 and 26.
  • a much larger secondary mask size of 25mm by 25mm could be used, yielding a treatment grid of 190 spots per side separated by 133 ⁇ m with a spot size radius of 6 ⁇ m. Since the secondary mask size was increased by the same factor as the desired treatment Page 63 of 128 ORTLLC-61843 PCT App area, the number of offsetting operations of approximately 98, and thus treatment time of approximately thirty seconds, is constant. [Para 180] Of course, the number and size of spots produced in a 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.
  • a geometric pattern of small laser spots instead of a geometric pattern of small laser spots, the present invention contemplates use of other geometric objects or patterns.
  • a single line 60 of laser light formed by the continuously or by means of a series of closely spaced spots, can be created.
  • Page 64 of 128 ORTLLC-61843 PCT App An offsetting optical scanning mechanism can be used to sequentially scan the line over an area, illustrated by the downward arrow in FIG. 28.
  • FIG. 29 With reference now to FIG. 29, 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.
  • FIGURE 30 illustrates diagrammatically a system which couples multiple treatment light sources into the pattern-generating optical subassembly described above.
  • this system 20 ⁇ is similar to the system 20 described in FIG. 23 above.
  • the primary differences between the Page 65 of 128 ORTLLC-61843 PCT App 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.
  • the multiple light sources 22 follow a similar path as described in the earlier system 20, i.e., collimated, diffracted, recollimated, and directed to the projector device and/or tissue.
  • the diffractive element must function 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 Page 66 of 128 ORTLLC-61843 PCT App 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.
  • These modes may also be mixed and matched. For example, two wavelengths may be applied simultaneously with one wavelength achieving complete coverage and the other achieving incomplete or overlapping coverage, followed by a third wavelength applied sequentially and achieving complete coverage.
  • FIGURE 31 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. 23.
  • 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.
  • the laser projector optics of each channel 44a, 44b, 44c comprise a collimator 32, mask or diffraction grating 34 and recollimators 38, Page 67 of 128 ORTLLC-61843 PCT App 40 as described in connection with FIG. 24 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.
  • 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. as there are wavelengths of light being used in the treatment.
  • 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. 23-31 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, typically in the form of an endoscope having a light pipe or the like. Also, other forms of electromagnetic radiation may also be generated and used, including ultraviolet waves, microwaves, other radiofrequency waves, and laser light at predetermined wavelengths.
  • ultrasound waves may also be generated and used to create a thermal time- course temperature spike in the target tissue sufficient to activate or produce heat shock proteins in the cells of the target tissue without damaging the target tissue itself.
  • a pulsed source of ultrasound or electromagnetic radiation energy is provided and applied to the target tissue in a manner which raises the target tissue temperature, such as between 6°C and 11°C, transiently while only 6°C or 1°C or less for the long term, such as over several minutes.
  • the viruses Page 69 of 128 ORTLLC-61843 PCT App that cause colds primarily affect a small port of the respiratory epithelium in the nasal passages and nasopharynx. Similar to the retina, the respiratory epithelium is a thin and clear tissue.
  • FIG. 32 a cross- sectional view of a human head 62 is shown with an endoscope 14 inserted into the nasal cavity 64 and energy 16, such as laser light or the like, being directed to tissue 18 to be treated within the nasal cavity 64.
  • the tissue 18 to be treated could be within the nasal cavity 64, including the nasal passages, and nasopharynx.
  • the wavelength can be adjusted to an infrared (IR) absorption peak of water, or an adjuvant dye can be used to serve as a photosensitizer.
  • treatment would then consist of drinking, or topically applying, the adjuvant, waiting a few minutes for the adjuvant to permeate the surface tissue, and then administering the laser light or other energy source 16 to the target tissue 18 for a few seconds, such as via optical fibers in an endoscope 14, as illustrated in FIG. 32.
  • the endoscope 14 could be inserted after application of a topical anesthetic. If necessary, the procedure could be repeated periodically, such as in a day or so.
  • the treatment would stimulate the activation or production of heat shock proteins and facilitate protein repair without damaging the cells and tissues being treated.
  • certain heat shock proteins have been found to play an important role in the immune response as well as the well-being of the targeted cells and tissue.
  • the source of energy could be Page 70 of 128 ORTLLC-61843 PCT App monochromatic laser light, such as 810 nm wavelength laser light, administered in a manner similar to that described in the above-referenced patent applications, but administered through an endoscope or the like, as illustrated in FIG. 32.
  • the adjuvant dye would be selected so as to increase the laser light absorption.
  • the flexible light tube 12 of a bronchoscope 14 is inserted through the individual's mouth 66 through the throat and trachea 68 and into a bronchus 70 of the respiratory tree.
  • the laser light or other energy source 16 is administered and delivered to the tissue in this area of the uppermost segments to treat the tissue and area in the same manner described above with respect to FIG. 32.
  • a wavelength of laser or other energy would be selected so as to match an IR absorption peak of the water resident in the mucous to heat the tissue and Page 71 of 128 ORTLLC-61843 PCT App stimulate HSP activation or production and facilitate protein repair, with its attendant benefits.
  • a colonoscope 14 could have flexible optical tube 12 thereof inserted into the anus and rectum 72 and into either the large intestine 74 or small intestine 76 so as to deliver the selected laser light or other energy source 16 to the area and tissue to be treated, as illustrated. This could be used to assist in treating colon cancer as well as other gastrointestinal issues.
  • the procedure could be performed similar to a colonoscopy in that the bowel would be cleared of all stool, and the patient would lie on his/her side and the physician would insert the long, thin light tube portion 12 of the colonoscope 14 into the rectum and move it into the area of the colon, large intestine 74 or small intestine 76 to the area to be treated.
  • the physician could view through a monitor the pathway of the inserted flexible member 12 and even view the tissue at the tip of the colonoscope 14 within the intestine, so as to view the area to be treated.
  • the tip 78 of the scope would be directed to the tissue to be treated and the source of laser light or other radiation 16 would be delivered through one of the light tubes of the colonoscope 14 to treat the area of tissue to be treated, as described above, in order to stimulate HSP activation or production in that tissue 18.
  • Page 72 of 128 ORTLLC-61843 PCT App is what is frequently referred to Page 72 of 128 ORTLLC-61843 PCT App as "leaky gut” syndrome, a condition of the gastrointestinal (GI) tract marked by inflammation and other metabolic dysfunction. Since the GI tract is susceptible to metabolic dysfunction similar to the retina, it is anticipated that it will respond well to the treatment of the present invention. This could be done by means of subthreshold, diode micropulse laser (SDM) treatment, as discussed above, or by other energy sources and means as discussed herein and known in the art.
  • SDM diode micropulse laser
  • the flexible light tube 12 of an endoscope or the like is inserted through the patient's mouth 66 through the throat and trachea area 68 and into the stomach 80, where the tip or end 78 thereof is directed towards the tissue 18 to be treated, and the laser light or other energy source 16 is directed to the tissue 18.
  • a colonoscope could also be used and inserted through the rectum 72 and into the stomach 80 or any tissue between the stomach and the rectum.
  • a chromophore pigment could be delivered to the GI tissue orally to enable absorption of the radiation.
  • the pigment would have an absorption peak at or near 810 nm.
  • the wavelength of the energy source could be adjusted to a slightly longer wavelength at an absorption peak of water, so that no externally applied chromophore would be required.
  • Page 73 of 128 ORTLLC-61843 PCT App [Para 204] It is also contemplated by the present invention that a capsule endoscope 82, such as that illustrated in FIG. 36, could be used to administer the radiation and energy source in accordance with the present invention. Such capsules are relatively small in size, such as approximately one inch in length, so as to be swallowed by the patient.
  • the capsule or pill 82 when at the appropriate location, the capsule or pill 82 could receive power and signals, such as via antenna 84, so as to activate the source of energy 86, such as a laser diode and related circuitry, with an appropriate lens 88 focusing the generated laser light or radiation through a radiation-transparent cover 90 and onto the tissue to be treated.
  • the location of the capsule endoscope 82 could be determined by a variety of means such as external imaging, signal tracking, or even by means of a miniature camera with lights through which the doctor would view images of the GI tract through which the pill or capsule 82 was passing through at the time.
  • the capsule or pill 82 could be supplied with its own power source, such as by virtue of a battery, or could be powered externally via an antenna, such that the laser diode 86 or other energy generating source create the desired wavelength and pulsed energy source to treat the tissue and area to be treated.
  • the radiation would be pulsed to take advantage of the micropulse temperature spikes and associated safety, and the power could be adjusted so that the treatment would be completely harmless to the tissue. This could involve Page 74 of 128 ORTLLC-61843 PCT App adjusting the peak power, pulse times, and repetition rate to give spike temperature rises on the order of 10°C, while maintaining the long term rise in temperature to be less than the FDA mandated limit of 1°C.
  • the device could be powered by a small rechargeable battery or over wireless inductive excitation or the like.
  • the heated/stressed tissue would stimulate activation or production of HSP and facilitate protein repair, and the attendant benefits thereof.
  • the technique of the present invention is limited to the treatment of conditions at near body surfaces or at internal surfaces easily accessible by means of fiber optics or other optical delivery means.
  • the reason that the application of SDM to activate HSP activity is limited to near surface or optically accessibly regions of the body is that the absorption length of IR or visible radiation in the body is very short. However, there are conditions deeper within tissue or the body which could benefit from the present invention.
  • the present invention contemplates the use of ultrasound and/or radio frequency (RF) and even shorter wavelength electromagnetic (EM) radiation such as microwave which have relatively long absorption lengths in body tissue.
  • RF radio frequency
  • EM electromagnetic
  • the use of pulsed ultrasound is preferable to RF electromagnetic radiation to activate remedial HSP activity in abnormal tissue that is inaccessible to surface SDM or the like.
  • a light pipe may not be an effective means of delivering the pulsed energy.
  • pulsed Page 75 of 128 ORTLLC-61843 PCT App low frequency electromagnetic energy or preferably pulsed ultrasound can be used to cause a series of temperature spikes in the target tissue.
  • a source of pulsed ultrasound or electromagnetic radiation is applied to the target tissue in order to stimulate HSP production or activation and to facilitate protein repair in the living animal tissue.
  • electromagnetic radiation may be ultraviolet waves, microwaves, other radiofrequency waves, laser light at predetermined wavelengths, etc.
  • absorption lengths restrict the wavelengths to those of microwaves or radiofrequency waves, depending on the depth of the target tissue.
  • ultrasound is to be preferred to long wavelength electromagnetic radiation for deep tissue targets away from natural orifices.
  • the ultrasound or electromagnetic radiation is pulsed so as to create a thermal time-course in the tissue that stimulates HSP production or activation and facilitates protein repair without causing damage to the cells and tissue being treated.
  • the area and/or volume of the treated tissue is also controlled and minimized so that the temperature spikes are on the order of several degrees, e.g. approximately 10°C, while maintaining the long-term rise in temperature to be less than the FDA mandated limit, such as 1°C. It has been found that if too large of an area or volume of tissue is treated, the increased temperature of the tissue cannot be diffused sufficiently quickly enough to meet the FDA requirements.
  • an ultrasound transducer 92 or the like generates a plurality of ultrasound beams 94 which are coupled to the skin via an acoustic-impedance-matching gel, and penetrate through the skin 96 and through undamaged tissue in front of the focus of the beams 94 to a target organ 98, such as the illustrated liver, and specifically to a target tissue 100 to be treated where the ultrasound beams 94 are focused.
  • a target organ 98 such as the illustrated liver
  • the pulsating heating will then only be at the targeted, focused region 100 where the focused beams 94 overlap.
  • the tissue in front of and behind the focused region 100 will not be heated or affected appreciably.
  • the present invention contemplates not only the treatment of surface or near surface tissue, such as using the laser light or the like, deep tissue using, for example, focused ultrasound beams or the like, but also Page 77 of 128 ORTLLC-61843 PCT App treatment of blood diseases, such as sepsis.
  • focused ultrasound treatment could be used both at surface as well as deep body tissue, and could also be applied in this case in treating blood.
  • the SDM and similar treatment options which are typically limited to surface or near surface treatment of epithelial cells and the like be used in treating blood diseases at areas where the blood is accessible through a relatively thin layer of tissue, such as the earlobe.
  • treatment of blood disorders simply requires the transmission of SDM or other electromagnetic radiation or ultrasound pulses to the earlobe 102, where the SDM or other radiation source of energy could pass through the earlobe tissue and into the blood which passes through the earlobe. It would be appreciated that this approach could also take place at other areas of the body where the blood flow is relatively high and/or near the tissue surface, such as fingertips, inside of the mouth or throat, etc.
  • a clamp device 104 configured to transmit SDM radiation or the like.
  • Power could be provided, for example, by means of a lamp drive 108.
  • the lamp drive 108 could be the actual source of laser light, which would be transmitted through the appropriate optics and electronics to the earlobe 102.
  • the clamp device 104 would merely be used to Page 78 of 128 ORTLLC-61843 PCT App clamp onto the patient's earlobe and cause that the radiation be constrained to the patient's earlobe 102. This may be by means of mirrors, reflectors, diffusers, etc.
  • the proposed treatment with a train of electromagnetic or ultrasound 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 810nm 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 Page 80 of 128 ORTLLC-61843 PCT App 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.
  • Other pulsed energy sources including microwave, radio frequency and ultrasound is also preferably pulsed in nature and have duty cycles and/or pulse trains and thus lag time or intervals between micropulse energy applications to the target tissue.
  • the target tissue previously treated with the micropulse of the energy must be allowed to dissipate the heat created by the energy application in order not to exceed a predetermined upper temperature level which could permanently damage or even destroy the cells of the target tissue.
  • the area or volume of target tissue to be treated is much larger than the area or volume of target tissue which is treated at any given moment by the energy sources, even if multiple beams of energy are created and applied to the target tissue.
  • 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 Page 81 of 128 ORTLLC-61843 PCT App 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.
  • the laser light is returned to the previously treated location within one to three milliseconds, and preferably approximately two milliseconds, as one cannot wait one or two seconds and then return to a previously treated area that has not yet received the full treatment necessary, as the treatment will not be as effective or perhaps not effective at all.
  • 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 100 microseconds in duration. This is referred to herein as microshifting.
  • the number of additional areas which can be treated is limited only by the micropulse duration and the ability to controllably move the light beams from one area to another.
  • each location has between 50-200, and more typically between 75-150, light applications applied thereto over the course of the exposure envelope duration (typically 200-500 milliseconds) to achieve the desired treatment.
  • the laser 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 predetermined number of laser light applications to each area to be treated have been achieved.
  • the one or more beams of microwave, radiofrequency and/or ultrasound could be applied to second, or additional treatment areas of Page 83 of 128 ORTLLC-61843 PCT App the target tissue that is spaced apart from the first treatment area, and after a predetermined interval of time returning, if necessary, to the first treatment area of the target tissue to reapply the pulsed energy thereto.
  • 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 dissipation and avoid thermal tissue damage.
  • the pulsed energy parameters including wavelength or frequency, duty cycle and pulse train duration are selected so as to raise the target tissue temperature up to 11°C, such as between approximately 6°-11°C, during application of the pulsed energy source to the target tissue to achieve a therapeutic effect, such as by stimulating HSP production within the cells.
  • 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, such as 6°C or less, or even 1°C or less, over several minutes so as not to permanently damage the target tissue.
  • a predetermined level such as 6°C or less, or even 1°C or less
  • FIG. 40A 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. 40B, until the locations in the first exposure area need to be re-treated by having beams applied thereto Page 84 of 128 ORTLLC-61843 PCT App 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. 40C. Secondary or subsequent exposures would occur in each exposure area, as illustrated in FIG.
  • 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 in a different manner than that illustrated in FIG. 40.
  • the exposure areas could Page 85 of 128 ORTLLC-61843 PCT App comprise the thin lines illustrated in FIGS. 28 and 29, which would be repeatedly exposed in sequence until all of the necessary areas were fully exposed and treated.
  • 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 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.
  • each retinal spot The areas of each retinal spot are 100 microns, and the laser power for these 100 micron retinal spots is 0.74 watts.
  • the panmacular area is Page 86 of 128 ORTLLC-61843 PCT App 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. As would be expected, the shorter the treatment time, the larger the required average power. However, there is an upper limit on the allowable average power, which limits how short the treatment time can be.
  • FIGS. 42 and 43 show how the total power depends on treatment time. This is displayed in FIG. 42 for panmacular treatment, and in FIG. 43 for panretinal treatment.
  • the upper, solid line or curve represents the embodiment where there are no microshifts taking advantage of the thermal relaxation time Page 87 of 128 ORTLLC-61843 PCT App interval, such as described and illustrated in FIG. 27, whereas the lower dashed line represents the situation for such microshifts, as described and illustrated in FIG. 40.
  • FIGS. 42 and 43 show that for a given treatment time, 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. Alternatively, 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.
  • This could be implemented, for example, by applying a higher number of therapeutic laser light beams or spots simultaneously at a reduced power.
  • the parameters of the laser light are selected to be therapeutically effective yet not destructive or permanently damaging to Page 88 of 128 ORTLLC-61843 PCT App 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 present invention is described for use in connection with a micropulsed laser, theoretically a continuous wave laser could potentially be used instead of a micropulsed laser.
  • 41-43 is derived from observations and calculations of laser light beams as the energy source applied to retinal eye tissue, it is believed that applying such pulsed light beams to other tissue will achieve similar results in that moving the treatment beams to a series of new locations, then bringing the beams back to re-treat the same location or area repeatedly will not only save time but also require less power compared to the methodology of keeping the beams in the same location or area during the entire exposure envelope duration. Similarly, it is believed that such power conservation will also be achieved with other sources of pulsed energy, including coherent and non- coherent light, microwave, radiofrequency and ultrasound energy sources.
  • the shifting or steering of the pattern of light beams may be done by use of an Page 89 of 128 ORTLLC-61843 PCT App optical scanning mechanism, such as that illustrated and described in connection with FIGS. 25 and 26.
  • the steering can be accomplished by using phased arrays.
  • the illumination or energy in this case is said to be the “far field”.
  • Phased arrays can be used for the microwave and ultrasound illumination application or even for the laser light beam source.
  • Steering for microwave, ultrasound and even for laser energy sources may be done by use of multiple sources which provide an “array”.
  • the wavelength of the radiation is much larger than body dimensions.
  • the wavelengths range from 10,000 cm to 5000 cm.
  • the target region in the body is in the” near field” of the source, i.e. the target distance and dimensions are much Page 92 of 128 ORTLLC-61843 PCT App less than the wavelength of the RF radiation.
  • the relevant treatment fields are not radiation fields (as they were in the case of microwave, ultrasound, and laser treatments), but are instead induction fields.
  • the induction field from an RF coil is only large over dimensions comparable to the coil dimension. The induction magnetic fields drop off rapidly as 1/r3 for distances larger than this.
  • the treatment volume for a coil at the surface of the body, we can picture the treatment volume as roughly a hemisphere with radius equal to that of the coil.
  • the treatment volumes for these coils are rather close to the surface (distances comparable to the coil dimensions). Larger coils can be used for deeper targets. In keeping with the spacing criteria discussed earlier, the spacing between the coils in a surface array would be chosen to be comparable to the individual coil dimensions.
  • the wavelengths are much less than the distances from the sources to the target tissue. For these sources, then, the intensity distributions from the arrays can be calculated in the “far field” approximation.
  • the wavelength is much larger than the distances between the sources to the target tissue.
  • the intensity distribution be calculated in the “near field” approximation.
  • the wavelengths are much less than the distance between the sources and target tissue; however, at low microwave frequencies, the wavelengths can be larger than the distance between the sources and the target tissues. (Thus, at 1 and 100 GHz , the Page 93 of 128 ORTLLC-61843 PCT App wavelengths are 30 cm and 3 mm, respectively). Accordingly, at high microwave frequencies, the “far field” approximation applies, while at low microwave frequencies, the “near field” approximation applies.
  • Each antenna has a side of length 5A, and the shortest distance between the centers of adjacent antennas is 2d. There are a total of N antennas along a line in the x direction and N antennas along the y-direction, for a total of N 2 antennas.
  • FIG. 46 is a plot of a typical radiation pattern from a square array. (Anomalies in the plot appear due to the plotting routine employed.
  • FIGURE 47 is the form of a typical radiation pattern along the X- axis for a typical radiation pattern from a “far field” array. The pattern results from the individual features shown in FIGS. 48-50.
  • the lines occur every time the function has a zero, i.e. whenever the argument of the function is some multiple of ⁇ .
  • the function is plotted in FIG. 50.
  • the widths of the individual lines and the envelope are determined by the half-widths of the Sin 2 (Nk ⁇ d) and Sinc 2 (k ⁇ a) functions, respectively, and the spacing between the lines is determined by the zeros of the Sin 2 ((k ⁇ d) function.
  • a field array such as that illustrated in FIG. 45, can be selectively and controllably steered.
  • the position of the peaks can be changed by introducing a phase delay in the excitation of the antennas.
  • the direction in the X direction can be changed by introducing a phase delay ⁇ n in the nth antenna in the X-direction, that is proportional to n.
  • FIG. 51 a block diagram of its system for exciting the antennas in the array, such as that illustrated in FIG. 45, to irradiate a target tissue is shown.
  • the array system of FIG. 51 is applicable for the light beam, ultrasound and high frequency microwave arrays.
  • the computer controller provides the desired power excitation and phase delays for steering the array.
  • the computer-controlled oscillator source activates the antennas with appropriate phase delays to steer the antenna array peaks, as described above.
  • a near field (induction) array, and particularly the steering of such near field arrays, for low frequency microwaves and RF differs markedly from the far field arrays discussed above.
  • FIG. 52 it is shown that the induced tissue temperature rise drops off rapidly as the axial distance from the coil increases.
  • the tissue between the coil and about an axial distance equal to the Page 98 of 128 ORTLLC-61843 PCT App radius of the coil divided by 2 can be expected to experience a temperature rise.
  • the coil should be approximately 10 cm in diameter.
  • FIG. 52 also shows that the main heating will occur in a circular ring equal in radius to the coil radius. [Para 273] To illustrate the latter point, FIGS.
  • FIGURE 56 shows the plots of FIGS.
  • the computer-controlled powered oscillating current source selects the coils sequentially in order to treat different transverse tissue positions.
  • coils 1-N are powered sequentially in order to steer the induction fields.
  • a different steering mechanism or system is utilized in order to treat the desired tissue at a desired depth.
  • 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.
  • HSP activation improves the therapeutic effect on the targeted tissue.
  • understanding the behavior and activation of HSPs and HSP system species, their generation and activation, temperature ranges for activating HSPs and time frames of the HSP activation or Page 100 of 128 ORTLLC-61843 PCT App 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.
  • laser light pulses may last on the order of microseconds with several milliseconds of intervals of relaxed time. [Para 279]
  • the laser-induced temperature rise – and therefore 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).
  • HSF a complex of HSP bound to HSF (unactivated HSPs) HSF3.
  • HSE a complex of HSF3 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 285]
  • 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.
  • FIGURE 58 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. 58 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.
  • FIGURE 58 shows what the Rybinski et al equations predict for the variation of the 10 different species over a period of 350 minutes. However, 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. [Para 298] With reference now to FIGS. 59A-59H, 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.
  • FIGURE 59 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.
  • the initial concentrations in Table 5 are not the equilibrium values of the species, i.e.
  • 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 Page 109 of 128 ORTLLC-61843 PCT App 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
  • Page 110 of 128 ORTLLC-61843 PCT App and 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 Page 112 of 128 ORTLLC-61843 PCT App 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 HSP and HSPHSF concentrations can vary quite a bit in the interval ⁇ t between SDM applications.
  • [Para 311] Although only a single repetition (one-step) is treated here, it is apparent that the procedure could be repeated to provide a multiple stair- stepping events as a means of improving the efficacy of SDM, or other therapeutic method involving activation of tissue HSPs.
  • the cell is taken to have the Rybinski et al (2013) equilibrium concentrations for the ten species involved, given in Table 7.
  • Table 10 is the same as the Tables 8 and 9, except that the treatments are separated by one minute, or sixty seconds. Page 116 of 128 ORTLLC-61843 PCT App [Para 321] Table 10.
  • Tables 8-10 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.
  • the decrease in [HSP] is accompanied by an increase in both [HSPHSF] – as shown in FIG.
  • 61 should be taken as representative rather than absolute. However, they are not anticipated to be significantly different. Thus, performing multiple intra-sessional treatments on a single target tissue location or area, such as a Page 118 of 128 ORTLLC-61843 PCT App 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.

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Abstract

L'invention concerne un système qui fournit une neuroprotection ou une neurorégénération à un tissu biologique qui comprend une énergie pulsée ayant des paramètres d'énergie comprenant une longueur d'onde ou une fréquence, un cycle de service et une durée de train d'impulsions. Un dispositif d'administration applique l'énergie pulsée à des éléments neuronaux du tissu cible présentant une maladie évolutive chronique ou à risque de présenter une maladie évolutive chronique. Le dispositif d'administration applique l'énergie pulsée pendant une durée de train d'impulsions totale prédéterminée de telle sorte que la température du tissu cible est suffisamment accrue pour fournir une neuroprotection ou une neurorégénération aux éléments neuronaux du tissu cible, tout en maintenant l'élévation de température moyenne du tissu cible au niveau ou au-dessous d'un niveau prédéterminé de façon à ne pas endommager de façon permanente le tissu cible.
PCT/US2023/035408 2022-12-01 2023-10-18 Système et procédé d'utilisation d'énergie pour la neurorégénération WO2024118164A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6259952B1 (en) * 1996-06-27 2001-07-10 Radionics, Inc. Method and apparatus for altering neural tissue function
US20170232269A1 (en) * 2012-05-25 2017-08-17 Ojai Retinal Technology, Llc Process for providing protective therapy for biological tissues or fluids
US20180200532A1 (en) * 2012-05-25 2018-07-19 Ojai Retinal Technology, Llc Process utilizing pulsed energy to heat treat biological tissue

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6259952B1 (en) * 1996-06-27 2001-07-10 Radionics, Inc. Method and apparatus for altering neural tissue function
US20170232269A1 (en) * 2012-05-25 2017-08-17 Ojai Retinal Technology, Llc Process for providing protective therapy for biological tissues or fluids
US20180200532A1 (en) * 2012-05-25 2018-07-19 Ojai Retinal Technology, Llc Process utilizing pulsed energy to heat treat biological tissue

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