WO2018169560A1 - Système et procédé utilisant une énergie pulsée pour traiter un tissu biologique - Google Patents

Système et procédé utilisant une énergie pulsée pour traiter un tissu biologique Download PDF

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WO2018169560A1
WO2018169560A1 PCT/US2017/044337 US2017044337W WO2018169560A1 WO 2018169560 A1 WO2018169560 A1 WO 2018169560A1 US 2017044337 W US2017044337 W US 2017044337W WO 2018169560 A1 WO2018169560 A1 WO 2018169560A1
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tissue
pulsed energy
approximately
para
target tissue
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PCT/US2017/044337
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English (en)
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Jeffrey K. LUTTRULL
David B. Chang
Benjamin W. L. Margolis
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Ojai Retinal Technology, Llc
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Priority claimed from US15/460,821 external-priority patent/US20170203132A1/en
Application filed by Ojai Retinal Technology, Llc filed Critical Ojai Retinal Technology, Llc
Publication of WO2018169560A1 publication Critical patent/WO2018169560A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
    • A61N1/403—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals for thermotherapy, e.g. hyperthermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/02—Radiation therapy using microwaves
    • A61N5/022—Apparatus adapted for a specific treatment
    • A61N5/025—Warming the body, e.g. hyperthermia treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/0625—Warming the body, e.g. hyperthermia treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A61F2009/00861—Methods or devices for eye surgery using laser adapted for treatment at a particular location
    • A61F2009/00863—Retina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A61N2005/0608—Rectum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A61N2005/0609—Stomach and/or esophagus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
    • A61N2005/0643—Applicators, probes irradiating specific body areas in close proximity
    • A61N2005/0645—Applicators worn by the patient
    • A61N2005/0647—Applicators worn by the patient the applicator adapted to be worn on the head
    • A61N2005/0648—Applicators worn by the patient the applicator adapted to be worn on the head the light being directed to the eyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0659—Radiation therapy using light characterised by the wavelength of light used infrared
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light

Definitions

  • the present invention is generally directed to systems and processes for treating biological tissue, such as diseased biological tissue. More
  • the present invention is directed to a process for heat treating biological tissue using pulsed energy that creates a therapeutic effect to a target tissue without destroying or permanently damaging the target tissue.
  • the inventors have discovered that electromagnetic radiation, such as in the form of various wavelengths of laser light, can be applied to retinal tissue in a manner that does not destroy or damage the retinal tissue while achieving beneficial effects on eye diseases.
  • electromagnetic radiation such as in the form of various wavelengths of laser light
  • a laser 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.
  • Heat shock proteins are a family of proteins that are produced by cells in response to exposure to stressful conditions. Production of high levels of heat shock proteins can be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to toxins, starvation, hypoxia, or water deprivation.
  • 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. These activities are part of a cell's own repair system, called the cellular stress response or the heat-shock response.
  • Heat shock proteins are typically named according to their molecular weight.
  • Hsp60, Hsp70 and Hsp80 refer to the families of heat shock proteins on the order of 60, 70 and 80 kilodaltons in size, respectively. They act in a number of different ways.
  • Hsp70 has peptide- binding and ATPase domains that stabilize protein structures in unfolded and assembly-competent states.
  • Mitochondrial Hsp60s form ring-shaped structures facilitating the assembly of proteins into native states.
  • Hsp90 plays a
  • Hsp27 suppresses protein aggregation.
  • Hsp70 heat shock proteins are a member of extracellular and
  • 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. Experimental and clinical observations have shown that heat shock proteins are involved in the regulation of autoimmune arthritis, type 1 diabetes, mellitus, arterial sclerosis, multiple sclerosis, and other autoimmune reactions.
  • the present invention fulfills these needs, and provides other related advantages.
  • the present invention is directed to a process for heat treating biological tissues by applying pulsed energy to a target tissue to therapeutically treat the target tissue.
  • a pulsed energy is generated that creates a therapeutic effect to the target tissue exposed to the pulsed energy without destroying or permanently damaging the target tissue.
  • the pulsed energy is applied to a first treatment area of the target tissue. After a predetermined interval of time, within a single treatment session, the pulsed energy is reapplied to the first treatment area of the target tissue. During the interval of time between the pulsed energy applications to the first treatment area, the pulsed energy is applied to a second treatment area of the target tissue that is spaced apart from the first treatment area.
  • pulsed energy is applied to other treatment areas of the target tissue.
  • adjacent areas are separated by at least a predetermined minimum distance to avoid thermal tissue damage.
  • the pulsed energy application may comprise a pulse train duration of less than one second. [Para 1 0]
  • the pulsed energy is reapplied to a treatment area withi n a predeterm ined interval of ti me from the i mmediately prior pulsed energy appl ication to that treatment area.
  • the pulsed energy may be reappl ied to previously treated areas i n seq uence. It is bel ieved that applying the pulsed energy sti mu lates heat shock protei n activation i n the target tissue.
  • the pulsed energy has energy parameters includ ing wavelength or frequency, duty cycle and pulse trai n duration.
  • the energy parameters are selected so as to raise a target tissue tem perature up to 1 1 ° C. to achieve a therapeutic effect, wherein the average tem perature rise of the tissue over several mi nutes is mai ntained at or below a predeterm ined level so as not to permanently damage the target tissue.
  • the pulsed energy parameters may be selected so that the target tissue temperature is raised between approximately 6° C. to 1 1 ° C. at least during application of the pulsed energy to the target tissue.
  • the average temperature rise of the target tissue over several m inutes is mai ntained at 6° C. or less, such as at approxi mately 1 ° C. or less over several m inutes.
  • the pulsed energy may com prise laser light, m icrowave,
  • a device may be i nserted into a cavity of the body i n order to apply the pulsed energy to the tissue.
  • the pulsed energy 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 pulsed energy may com prise a rad iofrequency 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
  • the pulsed energy may comprise a microwave frequency of between 1 0 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 pulsed energy may comprise a pulsed light beam, such as a laser light.
  • the light beam may have a wavelength of between approximately 530 nm to 1 300 nm, and more preferably between 800 nm and 1 000 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 1 0%, 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 pulsed 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 cycle of between approximately 2% and 1 0%.
  • the ultrasound has a power of between approximately 0.46 and 28.6 watts.
  • FIGURES 1 A and 1 B are graphs illustrating the average power of a laser source compared to a source radius and pulse train duration of the laser;
  • FIGURES 2A and 2 B are graphs illustrating the time for the temperature to decay depending upon the laser source radius and wavelength;
  • FIGURES 3-6 are graphs illustrating the peak ampere turns for various radiofrequencies, duty cycles, and coil radii ;
  • FIGURE 7 is a graph depicting the time for temperature rise to decay compared to radiofrequency coil radius
  • FIGURES 8 and 9 are graphs depicting the average microwave power compared to microwave frequency and pulse train durations
  • FIGURE 1 0 is a graph depicting the time for the temperature to decay for various microwave frequencies
  • FIGURE 1 1 is a graph depicting the average ultrasound source power compared to frequency and pulse train duration ;
  • FIGURES 1 2 and 1 3 are graphs depicting the time for temperature decay for various ultrasound frequencies;
  • FIGURE 1 4 is a graph depicting the volume of focal heated region compared to ultrasound frequency;
  • FIGURE 1 5 is a graph comparing equations for temperature over pulse durations for an ultrasound energy source
  • FIGURES 1 6 and 1 7 are graphs illustrating the magnitude of the logarithm of damage and HSP activation Arrhenius integrals as a function of temperature and pulse duration;
  • FIGURE 1 8 is a diagrammatic view of a light generating unit that produces timed series of pulses, having a light pipe extending therefrom, in accordance with the present invention
  • FIGURE 1 9 is a cross-sectional view of a photostimulation delivery device delivering electromagnetic energy to target tissue, in accordance with the present invention.
  • FIGURE 20 is a diagrammatic view illustrating a system used to generate a laser light beam, in accordance with the present invention.
  • FIGURE 21 is a diagrammatic view of optics used to generate a laser light geometric pattern, in accordance with the present invention.
  • FIGURE 22 is a top plan view of an optical scanning mechanism, used in accordance with the present invention.
  • FIGURE 23 is a partially exploded view of the optical scanning mechanism of FIG. 22, illustrating the various component parts thereof;
  • FIGURE 24 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 25 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 26 is a diagrammatic view similar to FIG. 25 , but illustrating the geometric line or bar rotated to treat the target tissue;
  • FIGURE 27 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 28 is a diagrammatic view illustrating yet another
  • FIGURE 29 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 30 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 31 is a diagrammatic view of a colonoscope providing photostimulation to an intestinal or colon area of the body, in accordance with the present invention
  • FIGURE 32 is a diagrammatic view of an endoscope inserted into a stomach and providing treatment thereto, in accordance with the present invention
  • FIGURE 33 is a partially sectioned perspective view of a capsule endoscope, used in accordance with the present invention ;
  • FIGURE 34 is a diagrammatic view of a pulsed high intensity focused ultrasound for treating tissue internal the body, in accordance with the present invention.
  • FIGURE 35 is a diagrammatic view for delivering therapy to the bloodstream of a patient, through an earlobe, in accordance with the present invention
  • FIGURE 36 is a cross-sectional view of a stimulating therapy device of the present invention used in delivering photostimulation to the blood, via an earlobe, in accordance with the present invention
  • FIGURES 37A-37D are diagrammatic views illustrated in the application of micropulsed energy to different treatment areas during a predetermined interval of time, within a single treatment session, and
  • FIGURES 38-40 are graphs depicting the relationship of treatment power and time in accordance with the embodiments of the present invention.
  • the present invention is directed to a system and method for delivering a pulsed energy, such as laser, ultrasound, ultraviolet
  • radiofrequency microwave radiofrequency and the like, having energy
  • thermal time-course in tissue to raise the tissue temperature over a short period of time to a sufficient level to achieve a therapeutic effect while maintaining an average tissue temperature over a prolonged period of time below a predetermined level so as to avoid permanent tissue damage. It is believed that the creation of the thermal time-course stimulates heat shock protein activation or production and facilitates protein repair without causing any damage.
  • a laser light beam can be generated that is therapeutic, yet sublethal to retinal tissue cells and thus avoids damaging photocoagulation in the retinal tissue which provides preventative and protective treatment of the retinal tissue of the eye. It is believed that this may be due, at least in part, to the stimulation and activation of heat shock proteins and the facilitation of protein repair in the retinal tissue.
  • This is disclosed in United States patent application serial numbers 1 4/607,959 filed January 28, 201 5 , 1 3 / 798, 523 filed March 1 3, 201 3, and 1 3/481 , 1 24 filed May 25, 201 2 , the contents of which are hereby incorporated by reference as if made in full.
  • Various parameters of the light beam must be taken into account and selected so that the combination of the selected parameters achieve the therapeutic effect while not permanently damaging the tissue.
  • parameters include laser wavelength, radius of the laser source, average laser power, total pulse duration, and duty cycle of the pulse train.
  • 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.
  • tissue temperature rises of between 6°C and 1 1 °C can create therapeutic effect, such as by activating heat shock proteins, whereas maintaining the average tissue temperature over a prolonged period of time, such as over several minutes, such as six minutes, below a predetermined temperature, such as 6°C and even 1 °C or less in certain circumstances, will not permanently damage the tissue.
  • SDM subthreshold diode micropulse laser treatment
  • DME diabetic macular edema
  • PDR proliferative diabetic retinopathy
  • BRVO branch retinal vein occlusion
  • CSR chorioretinopathy
  • prophylactic treatment of progressive degenerative retinopathies such as dry age-related macular degeneration, Stargardts' disease, cone dystrophies, and retinitis pigmentosa.
  • SDM chorioretinopathy
  • HSPs heat shock proteins
  • SDM 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 surface probes as well as focused electromagnetic/sound waves.
  • abnormal conditions including inflammations, autoimmune conditions, and cancers that are accessible by means of fiber optics of endoscopes or surface probes as well as focused electromagnetic/sound waves.
  • cancers on the surface of the prostate that have the largest threat of
  • metastasizing can be accessed by means of fiber optics in a proctoscope.
  • Colon tumors can be accessed by an optical fiber system, like those used in colonoscopy.
  • the energy source to be applied to the target tissue will have energy and operating parameters which must be determined and selected so as to achieve the therapeutic effect while not permanently damaging the tissue.
  • a light beam energy source such as a laser light beam
  • the laser wavelength, duty cycle and total pulse train duration parameters must be taken into account.
  • Other parameters which can be considered include the radius of the laser source as well as the average laser power. Adjusting or selecting one of these parameters can have an effect on at least one other parameter.
  • FIGS. 1 A and 1 B 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. 1 A shows a
  • FIG. l B has a wavelength of 1 000 nm. It can be seen in these figures that the required power decreases monotonically as the radius of the source decreases, as the total train duration increases, and as the wavelength decreases.
  • the preferred parameters for the radius of the laser source is 1 mm-4 mm.
  • the minimum value of power is 0.55 watts, with a radius of the laser source being 1 mm, and the total pulse train duration being 600 milliseconds.
  • the maximum value of power for the 880 nm wavelength is 52.6 watts when the laser source radius is 4 mm and the total pulse drain duration is 1 00 milliseconds.
  • the minimum power value is 0.77 watts with a laser source radius of 1 mm and a total pulse train duration of 600 milliseconds, and a maximum power value of 73.6 watts when the laser source radius is 4 mm and the total pulse duration is 1 00 milliseconds.
  • corresponding peak powers, during an individual pulse are obtained from the average powers by dividing by the duty cycle.
  • the volume of the tissue region to be heated is determined by the wavelength, the absorption length in the relevant tissue, and by the beam width.
  • the total pulse duration and the average laser power determine the total energy delivered to heat up the tissue, and the duty cycle of the pulse train gives the associated spike, or peak, power associated with the average laser power.
  • the pulsed energy source energy parameters are selected so that approximately 20 to 40 joules of energy is absorbed by each cubic centimeter of the target tissue.
  • the absorption length is very small in the thin melanin layer in the retinal pigmented epithelium. In other parts of the body, the absorption length is not generally that small.
  • the penetration depth and skin is in the range of 0.5 mm to 3.5 mm.
  • the penetration depth into human mucous tissues is in the range of 0.5 mm to 6.8 mm.
  • the heated volume will be limited to the exterior or interior surface where the radiation source is placed, with a depth equal to the penetration depth, and a transverse dimension equal to the transverse dimension of the radiation source. Since the light beam energy source is used to treat diseased tissues near external surfaces or near internal accessible surfaces, a source radii of between 1 mm to 4 mm and operating a wavelength of 880 nm yields a penetration depth of approximately 2.5 mm and a
  • wavelength of 1 000 nm yields a penetration depth of approximately 3.5 mm.
  • the target tissue can be heated to up to approximately 1 1 °C for a short period of time, such as less than one second, to create the therapeutic effect of the invention while maintaining the target tissue average temperature to a lower temperature range, such as less than 6°C or even 1 °C or less over a prolonged period of time, such as several minutes.
  • the selection of the duty cycle and the total pulse train duration provide time intervals in which the heat can dissipate.
  • a duty cycle of less than 1 0%, and preferably between 2.5% and 5%, with a total pulse duration of between 1 00 milliseconds and 600 milliseconds has been found to be effective.
  • FIG. 2A and 2B illustrate the time to decay from 1 0°C to 1 °C for a laser source having a radius of between 0.1 cm and 0.4 cm with the wavelength being 880 nm in FIG. 2A and 1 000 nm in FIG. 2 B. It can be seen that the time to decay is less when using a wavelength of 880 nm, but either wavelength falls within the acceptable requirements and operating parameters to achieve the benefits of the present invention while not causing permanent tissue damage.
  • the control of the target tissue temperature is determined by choosing source and target parameters such that the Arrhenius integral for HSP activation is larger than 1 , while at the same time assuring compliance with the conservative FDA/ FCC requirements for avoiding damage or a damage Arrhenius integral being less than 1 .
  • FIGS. 2A and 2B above illustrate the typical decay times required for the temperature in the heated target region to decrease by thermal diffusion from a temperature rise of approximately 1 0°C to 1 °C as can be seen in FIG. 2A when the wavelength is 880 nm and the source diameter is 1 millimeter, the temperature decay time is 1 6 seconds. The temperature decay time is 1 07 seconds when the source diameter is 4 mm. As shown in FIG.
  • the temperature decay time is 1 8 seconds when the source diameter is 1 mm and 1 36 seconds when the source diameter is 4 mm. This is well within the time of the average temperature rise being maintained over the course of several minutes, such as 6 minutes or less.
  • the target tissue's temperature is raised, such as to approximately 1 0°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.
  • Wavelength Dielectric Conductivity Wavelength ⁇ n e p P t ra t °n n Air-Fat Interface Fat-Muscle Interface Frequency in Air Constant ⁇ _, XL
  • 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.
  • the radius of the source coil(s) as well as the number of ampere turns (Nl) 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.
  • 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 cycle of between 2.5% and 5%.
  • FIGS. 3-6 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 (Nl) is 1 3 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. 5 and 6. This yields, as illustrated in FIG.
  • the time, in seconds, for the temperature rise to decay from approximately 1 0°C to approximately 1 °C for coil radii between 0.2 cm and 0.6 cm is illustrated for a radiofrequency energy source in FIG. 7.
  • the temperature decay time is approximately 37 seconds when the radiofrequency coil radius is 0.2 cm, and approximately 233 seconds when the radiofrequency coil radius is 0.5 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.
  • the microwaves are used to treat tissue near external surfaces or surfaces accessible from internal cavities, frequencies in the 1 0-20 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 than approximately 1 centimeter, and frequencies between 1 0 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.
  • the average power is 1 8 watts when the pulse train duration is 0.6 seconds, and 52 watts when the pulse train duration is 0.2 seconds.
  • an average power of 8 watts is used when the pulse train is 0.6 seconds, and can be 26 watts when the pulse train duration is only 0.2 seconds.
  • the corresponding peak power are obtained from the average power simply by dividing by the duty cycle.
  • FIG. 9 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.
  • the governing condition is that the 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 1 0°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 are 8 seconds when the microwave frequency is 20 GHz, and 1 6 seconds when the microwave frequency is 1 0 GHz.
  • 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
  • Multiple beams from sources at different angles can also be used, the heating occurring at the overlapping focal regions.
  • tissue temperature For ultrasound, 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 1 0 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. 1 1 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 1 0 cm and a source diameter of 5 cm have been assumed.
  • 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 1 2 illustrates the time, in seconds, for the temperature to diffuse or decay from 1 0°C to 6°C when the ultrasound frequency is between 1 and 5 MHz.
  • FIG. 1 3 illustrates the time, in seconds, to decay from
  • the maximum time for temperature decay is 366 seconds when the ultrasound frequency is 1 MHz
  • the minimum temperature decay is 1 5 seconds when the microwave frequency is 5 MHz.
  • the 366 second decay time at 1 MHz to get to a rise of 1 °C over the several minutes is
  • FIGURE 1 4 illustrates 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- 1 7 watts, a pulse duration of 0.5 seconds, an interval between pulses of 5 seconds, with total number of pulses 1 0 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 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 ⁇ 1 K.
  • 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.
  • electromagnetic radiation is not as good of a choice for SDM-type treatment of regions deep with the body as ultrasound.
  • the long skin depths (penetration distances) and Ohmic heating all along the skin depth results in a large heated volume whose thermal inertia does not allow both the attainment of a high spike temperature that activates HSPs and facilitates protein repair, and the rapid temperature decay that satisfies the long term FDA and FCC limit on average temperature rise.
  • Bone 1 .1 5 [Para 1 01 ] Assuming that the geometric variation of the incoming radiation due to the focusing dominates any variation due to attenuation, the intensity of the incoming ultrasound at a distance r from the focus can be written
  • dT(tp) Patp / (4nC v r 2 ) [2] where ex is the absorption coefficient and C v is the specific volume heat capacity. This will be the case until the r is reached at which the heat diffusion length at t becomes comparable to r, or the diffraction limit of the focused beam is reached. For smaller r, the temperature rise is essentially independent of r. As an example, suppose the diffraction limit is reached at a radial distance that is smaller than that determined by heat diffusion. Then
  • dT(t) [dTo/ ⁇ (l / 2)+(TTI /2/6) ⁇ ][(1 / 2)(t p /t)3/2 + (TTi /2/6)(tp/t)] [7] with
  • dT N (t) ⁇ dT(t-nti) [1 1 ]
  • dT(t-nti) is the expression of eq. [9] with t replaced by t-nti-and with ti designating the interval between pulses.
  • 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, so that a good approximation is obtained by replacing the varying time rise by its asymptotic value.
  • ⁇ AN[ ⁇ tp(2 k B To 2 /(3 EdTo) ⁇ exp[-(E/k B )l /(T 0 + dT 0 + dT N (Nt,))]
  • the graphs in FIGS. 1 6 and 1 7 show that Qdamage does not exceed 1 until d ⁇ T 0 exceeds 1 1 .3 K, whereas Qhs P is greater than 1 over the whole interval shown, the desired condition for cellular repair without damage.
  • 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 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.
  • Each of these consist essentially of a flexible tube that itself contains one or more internal tubes.
  • 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 the SDM or other electromagnetic radiation pulses that are fed into the scope at the end that the doctor holds.
  • a light generating unit 1 0, 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 1 2 to a distal end of the scope 1 4, illustrated in FIG. 1 9, which is inserted into the body and the laser light or other radiation 1 6 delivered to the target tissue 1 8 to be treated.
  • the system for generating electromagnetic energy radiation, such as laser light, including SDM.
  • the system includes a laser console 22, such as for example the 81 0 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.
  • 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
  • the laser light beam 30 may be passed through a collimator lens 32 and then through a mask 34.
  • the mask 34 comprises a
  • 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.
  • wavelength of the laser employed for example using a diffraction grating
  • the individual spots produced by such diffraction gratings are all of a similar optical geometry to the input beam, with minimal power variation for each spot.
  • the result is a plurality of laser spots with adequate irradiance to produce harmless yet effective treatment application, simultaneously over a large target area.
  • the present invention also contemplates the use of other geometric objects and patterns generated by other diffractive optical elements.
  • the laser light passing through the mask 34 diffracts, producing a periodic pattern a distance away from the mask 34, shown by the laser beams labeled 36 in FIG.21.
  • the single laser beam 30 has thus been formed into hundreds or even thousands of individual laser beams 36 so as to create the desired pattern of spots or other geometric objects.
  • These laser beams 36 may be passed through additional lenses, collimators, etc. 38 and 40 in order to convey the laser beams and form the desired pattern. Such additional lenses, collimators, etc. 38 and 40 can further transform and redirect the laser beams 36 as needed.
  • Arbitrary patterns can be constructed by controlling the shape, spacing and pattern of the optical mask 34.
  • the pattern and exposure spots can be created and modified arbitrarily as desired according to application requirements by experts in the field of optical engineering. Photolithographic techniques, especially those developed in the field of semiconductor
  • manufacturing can be used to create the simultaneous geometric pattern of spots or other objects.
  • the present invention can use a multitude of simultaneously generated therapeutic light beams or spots, such as numbering in the dozens or even hundreds, as the parameters and methodology of the present invention create therapeutically effective yet non-destructive and non-permanently damaging treatment.
  • hundreds or even thousands of simultaneous laser spots could be generated and created and formed into patterns to be applied to the tissue, due to the requirements of not overheating the tissue, there are constraints on the number of treatment spots or beams which can be simultaneously used in accordance with the present invention.
  • Each individual laser beam or spot requires a minimum average power over a train duration to be effective. However, at the same time, 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 1 00 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. Accordingly, there can be as few as a single laser spot or up to approximately 400 laser spots when using the 577 nm wavelength laser light, while still not harming or damaging the tissue.
  • the system of the present invention incorporates a guidance system to ensure complete and total retinal treatment with retinal photostimulation.
  • Fixation/tracking/registration systems consisting of a fixation target, tracking mechanism, and linked to system operation can be incorporated into the present invention.
  • the geometric pattern of simultaneous laser spots is sequentially offset so as to achieve confluent and complete treatment of the surface.
  • FIGS. 22 and 23 illustrate an optical scanning mechanism 50 in the form of a MEMS mirror, having a base 52 with electronically actuated controllers 54 and 56 which serve to tilt and pan the mirror 58 as electricity is applied and removed thereto. Applying electricity to the controller 54 and 56 causes the mirror 58 to move, and thus the simultaneous pattern of laser spots or other geometric objects reflected thereon to move accordingly on the retina of the patient. This can be done, for example, in an automated fashion using electronic software program to adjust the optical scanning mechanism 50 until complete coverage of the retina, or at least the portion of the retina desired to be treated, is exposed to the phototherapy.
  • the optical scanning mechanism may also be a small beam diameter scanning galvo mirror system, or similar system, such as that distributed by Thorlabs. Such a system is capable of scanning the lasers in the desired offsetting pattern.
  • the pattern of spots are offset at each exposure so as to create space between the immediately previous exposure to allow heat dissipation and prevent the possibility of heat damage or tissue destruction.
  • the pattern illustrated for exemplary purposes as a grid of sixteen spots, is offset each exposure such that the laser spots occupy a different space than previous exposures.
  • the diagrammatic use of circles or empty dots as well as filled dots are for diagrammatic purposes only to illustrate previous and subsequent exposures of the pattern of spots to the area, in accordance with the present invention.
  • the spacing of the laser spots prevents overheating and damage to the tissue. 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.
  • Another example would be a 3 cm x 3 cm area, representing the entire human retinal surface.
  • a much larger secondary mask size of 25mm by 25mm could be used, yielding a treatment grid of 1 90 spots per side separated by 1 33 ⁇ with a spot size radius of 6 ⁇ . Since the secondary mask size was increased by the same factor as the desired treatment area, the number of offsetting operations of approximately 98, and thus treatment time of approximately thirty seconds, is constant.
  • simultaneous pattern array can be easily and highly varied such that the number of sequential offsetting operations required to complete treatment can be easily adjusted depending on the therapeutic requirements of the given application.
  • quantum mechanical behavior may be observed which allows for arbitrary distribution of the laser input energy. This would allow for the generation of any arbitrary geometric shapes or patterns, such as a plurality of spots in grid pattern, lines, or any other desired pattern.
  • Other methods of generating geometric shapes or patterns, such as using multiple fiber optical fibers or microlenses, could also be used in the present invention. Time savings from the use of simultaneous projection of geometric shapes or patterns permits the treatment fields of novel size, such as the 1 .2 cm A 2 area to accomplish whole-retinal treatment, in a single clinical setting or treatment session.
  • FIG. 25 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.
  • An offsetting optical scanning mechanism can be used to sequentially scan the line over an area, illustrated by the downward arrow in FIG. 25.
  • FIGURE 27 illustrates diagrammatically a system which couples multiple light sources into the pattern-generating optical subassembly described above.
  • this system 20' is similar to the system 20 described in FIG. 20 above.
  • the primary differences between the alternate system 20' and the earlier described system 20 is the inclusion of a plurality of laser consoles, the outputs of which are each fed into a fiber coupler 42.
  • the fiber coupler produces a single output that is passed into the laser projector optics 24 as described in the earlier system.
  • the coupling of the plurality of laser consoles 22 into a single optical fiber is achieved with a fiber coupler 42 as is known in the art.
  • Other known mechanisms for combining multiple light sources are available and may be used to replace the fiber coupler described herein.
  • the diffractive element 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 identical coverage. An offsetting steering pattern to achieve complete coverage for one of the multiple wavelengths is used. Thus, while the light of the selected wavelength achieves complete coverage of the tissue, the application of the other wavelengths achieves either incomplete or overlapping coverage of the tissue.
  • the second mode sequentially applies each light source of a varying wavelength with the proper steering pattern to achieve complete coverage of the tissue for that particular wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve identical coverage for each wavelength. This avoids either incomplete or overlapping coverage for any of the optical wavelengths.
  • FIGURE 28 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. 20. 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, 40 as described in connection with FIG. 21 above - the entire set of optics tuned for the specific wavelength generated by the corresponding laser console 22.
  • each set of optics 24 is then directed to a beam splitter 46 for combination with the other wavelengths. It is known by those skilled in the art that a beam splitter used in reverse can be used to combine multiple beams of light into a single output.
  • the combined channel output from the final beam splitter 46c is then directed through the projector device 26. [Para 1 33] In this system 20" the optical elements for each channel are tuned to produce the exact specified pattern for that channel's wavelength.
  • 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.
  • each channel begins with a light source 22 , which could be from an optical fiber as in other embodiments of the pattern- generating subassembly.
  • This light source 22 is directed to the optical assembly 24 for collimation, diffraction, recollimation and directed into the beam splitter which combines the channel with the main output.
  • FIGS. 20-28 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
  • 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 1 1 °C, transiently while only 6°C or 1 °C or less for the long term, such as over several minutes.
  • a light pipe is not an effective means of delivering the pulsed energy.
  • pulsed 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 1 0°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.
  • limiting the area and/or volume of the treated tissue as well as creating a pulsed source of energy accomplishes the goals of the present invention of stimulating HSP activation or production by heating or otherwise stressing the cells and tissue, while allowing the treated cells and tissues to dissipate any excess heat generated to within acceptable limits.
  • the viruses 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. 29 a cross- sectional view of a human head 62 is shown with an endoscope 1 4 inserted into the nasal cavity 64 and energy 1 6, such as laser light or the like, being directed to tissue 1 8 to be treated within the nasal cavity 64.
  • the tissue 1 8 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 1 6 to the target tissue 1 8 for a few seconds, such as via optical fibers in an endoscope 1 4, as illustrated in FIG. 29.
  • the endoscope 1 4 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 monochromatic laser light, such as 81 0 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. 29.
  • the adjuvant dye would be selected so as to increase the laser light absorption. While this comprises a particularly preferred method and embodiment of performing the invention, it will be appreciated that other types of energy and delivery means could be used to achieve the same objectives in accordance with the present invention.
  • the flexible light tube 1 2 of a bronchoscope 1 4 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 1 6 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. 29.
  • 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 stimulate HSP activation or production and facilitate protein repair, with its attendant benefits.
  • a colonoscope 1 4 could have flexible optical tube 1 2 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 1 6 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.
  • 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 1 2 of the colonoscope 1 4 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 1 2 and even view the tissue at the tip of the
  • colonoscope 1 4 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 1 6 would be delivered through one of the light tubes of the
  • colonoscope 1 4 to treat the area of tissue to be treated, as described above, in order to stimulate HSP activation or production in that tissue 1 8.
  • FIG. 32 Another example in which the present invention can be advantageously used is what is frequently referred to as "leaky gut” syndrome, a condition of the gastrointestinal (Gl) tract marked by inflammation and other metabolic dysfunction. Since the Gl 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 1 2 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 1 8 to be treated, and the laser light or other energy source 1 6 is directed to the tissue 1 8.
  • 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 Gl tissue orally to enable absorption of the radiation. If, for instance, unfocused 81 0 nm radiation from a laser diode or LED were to be used, the pigment would have an absorption peak at or near 81 0 nm. Alternatively, 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.
  • a capsule endoscope 82 such as that illustrated in FIG. 33, 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. As the capsule or pill 82 is swallowed and enters into the stomach and passes through the Gl tract, when at the
  • 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 Gl 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 adjusting the peak power, pulse times, and repetition rate to give spike temperature rises on the order of 1 0°C, while maintaining the long term rise in temperature to be less than the FDA mandated limit of 1 °C. If the pill form 82 of delivery is used, 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.
  • the present invention contemplates the use of ultrasound and/or radio frequency (RF) and even shorter wavelength
  • EM radiation such as microwave which have relatively long absorption lengths in body tissue.
  • EM radiation such as microwave which have relatively long absorption lengths in body tissue.
  • 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.
  • Pulsed ultrasound sources can also be used for abnormalities at or near surfaces as well.
  • 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 1 00 to be treated where the ultrasound beams 94 are focused.
  • the pulsating heating will then only be at the targeted, focused region 1 00 where the focused beams 94 overlap. The tissue in front of and behind the focused region 1 00 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 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.
  • SDM or other electromagnetic radiation or ultrasound pulses simply requires the transmission of SDM or other electromagnetic radiation or ultrasound pulses to the earlobe 1 02, 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.
  • an earlobe 1 02 is shown adjacent to a clamp device 1 04 configured to transmit SDM radiation or the like.
  • This could be, for example, by means of one or more laser diodes 1 06 which would transmit the desired frequency at the desired pulse and pulse train to the earlobe 1 02.
  • Power could be provided, for example, by means of a lamp drive 1 08.
  • the lamp drive 1 08 could be the actual source of laser light, which would be transmitted through the appropriate optics and
  • the clamp device 1 04 would merely be used to clamp onto the patient's earlobe and cause that the radiation be constrained to the patient's earlobe 1 02. This may be by means of mirrors, reflectors, diffusers, etc. This could be controlled by a control computer 1 1 0, which would be operated by a keyboard 1 1 2 or the like.
  • the system may also include a display and speakers 1 1 4, if needed, for example if the procedure were to be performed by an operator at a distance from the patient.
  • 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.
  • 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 1 0,000) that allow the cell's repair system to more rapidly surmount the activation energy barrier that separates a dysfunctional cellular state from the desired functional state.
  • the net result is a "lowered therapeutic threshold" in the sense that a lower applied average power and total applied energy can be used to achieve the desired treatment goal.
  • the micropulsed laser light beam of an 81 Onm diode laser should have an exposure envelope duration of 500 milliseconds or less, and preferably approximately 300 milliseconds. Of course, if micropulsed diode lasers become more powerful, the exposure duration should be lessened accordingly.
  • duty cycle or the frequency of the train of micropulses, or the length of the thermal relaxation time between consecutive pulses. It has been found that the use of a 1 0% duty cycle or higher adjusted to deliver micropulsed laser at similar irradiance at similar MPE levels significantly increase the risk of lethal cell injury. However, duty cycles of less than 1 0%, and preferably 5% or less demonstrate adequate thermal rise and treatment at the level of the MPE cell to stimulate a biological response, but remain below the level expected to produce lethal cell injury. The lower the duty cycle, however, the exposure envelope duration increases, and in some instances can exceed 500 milliseconds.
  • Each micropulse lasts a fraction of a millisecond, typically between 50 microseconds to 1 00 microseconds in duration. Thus, for the exposure envelope duration of 300-500 milliseconds, and at a duty cycle of less than 5%, there is a significant amount of wasted time between micropulses to allow the thermal relaxation time between consecutive pulses. Typically, a delay of between 1 and 3 milliseconds, and preferably approximately 2 milliseconds, of thermal relaxation time is needed between consecutive pulses.
  • the cells are typically exposed or hit between 50-200 times, and preferably between 75-1 50 at each location, and with the 1 -3 milliseconds of relaxation or interval time, the total time in accordance with the embodiments described above to treat a given area which is being exposed to the laser spots is between 200 milliseconds and 500 milliseconds on average.
  • the thermal relaxation time is required so as not to overheat the cells within that location or spot and so as to prevent the cells from being damaged or destroyed. While time periods of 200-500 milliseconds do not seem long, given the small size of the laser spots and the need to treat a relatively large area of the target tissue, treating the entire target tissue take a significant amount of time, particularly for a patient who is undergoing treatment.
  • 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 in a particularly preferred embodiment utilizes the interval between consecutive applications to the same location to apply energy to a second treatment area, or additional areas, of the target tissue that is spaced apart from the first treatment area.
  • the pulsed energy is returned to the first treatment location, or previous treatment locations, within the predetermined interval of time so as to provide sufficient thermal relaxation time between consecutive pulses, yet also sufficiently treat the cells in those locations or areas properly by sufficiently increasing the temperature of those cells over time by repeatedly applying the energy to that location in order to achieve the desired therapeutic benefits of the invention.
  • each location has between 50-200, and more typically between 75-1 50, light applications applied thereto over the course of the exposure envelope duration (typically 200-500 milliseconds) to achieve the desired treatment.
  • the 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 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 1 1 °C, such as between approximately 6°-l 1 °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.
  • FIGS. 37A-37D This is diagrammatically illustrated in FIGS. 37A-37D.
  • FIG. 37A illustrates with solid circles a first area having energy beams, such as laser light beams, applied thereto as a first application.
  • the beams are offset or
  • FIG. 37B microshifted to a second exposure area, followed by a third exposure area and a fourth exposure area, as illustrated in FIG. 37B, until the locations in the first exposure area need to be re-treated by having beams applied thereto again within the thermal relaxation time interval.
  • the locations within the first exposure area would then have energy beams reapplied thereto, as illustrated in FIG. 37C.
  • Secondary or subsequent exposures would occur in each exposure area, as illustrated in FIG. 37D by the increasingly shaded dots or circles until the desired number of exposures or hits or applications had been achieved to therapeutically treat these areas, diagrammatically illustrated by the blackened circles in exposure area 1 in FIG. 37D.
  • 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. 37.
  • the exposure areas could comprise the thin lines illustrated in FIGS. 25 and 26, which would be
  • the time required to treat that area to be treated is significantly reduced, such as by a factor of 4 or 5 times, such that a single treatment session takes much less time for the medical provider and the patient need not be in discomfort for as long of a period of time.
  • the lower curve is for panmacular treatment and the upper curve is for panretinal treatment.
  • the areas of each retinal spot are 1 00 microns, and the laser power for these 1 00 micron retinal spots is 0.74 watts.
  • the panmacular area is 0.55 2 , requiring 7,000 panmacular spots total, and the panretinal area is 3.30 2 , requiring 42,000 laser spots for full coverage.
  • Each RPE spot requires a minimum energy in order for its reset mechanism to be adequately activated, in accordance with the present invention, namely, 38.85 joules for panmacular and 233.1 joules for panretinal.
  • the shorter the treatment time the larger the required average power.
  • there is an upper limit on the allowable average power which limits how short the treatment time can be.
  • FIGS. 39 and 40 show how the total power depends on treatment time. This is displayed in FIG. 39 for panmacular treatment, and in FIG. 40 for panretinal treatment.
  • the upper, solid line or curve represents the embodiment where there are no microshifts taking advantage of the thermal relaxation time interval, such as described and illustrated in FIG. 24, whereas the lower dashed line represents the situation for such microshifts, as described and illustrated in FIG. 37.
  • FIGS. 39 and 40 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
  • the allowable peak power can be advantageously used, reducing the overall treatment time.
  • a log power of 1 .0 (1 0 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 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.
  • the target tissue may be periodically re-treated. This may be done according to a set schedule or when it is determined that the target tissue of the patient is to be re-treated, such as by periodically monitoring the condition of the patient, based upon test results, etc.
  • the known therapeutic benefits of the methodology of the present invention coupled with the absence of known adverse treatment effects, allows for consideration of early and preventative treatment, liberal application and re-treatment as necessary.

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Abstract

La présente invention concerne un procédé de traitement thermique de tissu biologique, le procédé comprenant l'application d'une énergie pulsée à une première zone de traitement d'un tissu cible pour créer un effet thérapeutique sur le tissu cible, sans détruire ni endommager de façon permanente le tissu cible. Après un laps de temps prédéterminé, dans le courant d'une même session de traitement, l'énergie pulsée est réappliquée à la première zone de traitement. Pendant le laps de temps entre les applications d'énergie pulsée à la première zone de traitement, l'énergie pulsée est appliquée à une seconde zone de traitement du tissu cible qui est espacée de la première zone de traitement. L'énergie pulsée est appliquée de façon répétée pour chacune des zones à traiter, jusqu'à ce qu'un nombre prédéterminé d'applications d'énergie pulsée ait été effectué sur chaque zone à traiter.
PCT/US2017/044337 2017-03-16 2017-07-28 Système et procédé utilisant une énergie pulsée pour traiter un tissu biologique WO2018169560A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6599246B1 (en) * 2002-01-25 2003-07-29 Kenneth W. Coffey Apparatus and method for substantially stationary transducer therapeutic ultrasound treatment
US20090048586A1 (en) * 2007-08-15 2009-02-19 The Cleveland Clinic Foundation Precise disruption of tissue in retinal and preretinal structures
US20140194958A1 (en) * 2007-12-07 2014-07-10 Carewave, Inc. Devices and methods for therapeutic heat treatment
US20150157498A1 (en) * 2012-05-25 2015-06-11 Ojai Retinal Technology, Llc Process for restoring responsiveness to medication in tissue of living organisms
US20160082294A1 (en) * 2012-05-25 2016-03-24 Ojai Retinal Technology, Llc Pulsating electromagnetic and ultrasound therapy for stimulating targeted heat shock proteins and facilitating protein repair

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6599246B1 (en) * 2002-01-25 2003-07-29 Kenneth W. Coffey Apparatus and method for substantially stationary transducer therapeutic ultrasound treatment
US20090048586A1 (en) * 2007-08-15 2009-02-19 The Cleveland Clinic Foundation Precise disruption of tissue in retinal and preretinal structures
US20140194958A1 (en) * 2007-12-07 2014-07-10 Carewave, Inc. Devices and methods for therapeutic heat treatment
US20150157498A1 (en) * 2012-05-25 2015-06-11 Ojai Retinal Technology, Llc Process for restoring responsiveness to medication in tissue of living organisms
US20160082294A1 (en) * 2012-05-25 2016-03-24 Ojai Retinal Technology, Llc Pulsating electromagnetic and ultrasound therapy for stimulating targeted heat shock proteins and facilitating protein repair

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