EP3595775A1 - Méthode utilisant une énergie pulsée pour traiter thermiquement un tissu biologique - Google Patents

Méthode utilisant une énergie pulsée pour traiter thermiquement un tissu biologique

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Publication number
EP3595775A1
EP3595775A1 EP18766907.2A EP18766907A EP3595775A1 EP 3595775 A1 EP3595775 A1 EP 3595775A1 EP 18766907 A EP18766907 A EP 18766907A EP 3595775 A1 EP3595775 A1 EP 3595775A1
Authority
EP
European Patent Office
Prior art keywords
target tissue
para
tissue
approximately
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18766907.2A
Other languages
German (de)
English (en)
Other versions
EP3595775A4 (fr
Inventor
Jeffrey K. LUTTRULL
David B. Chang
Benjamin W. L. Margolis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ojai Retinal Technology LLC
Original Assignee
Ojai Retinal Technology LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/460,821 external-priority patent/US20170203132A1/en
Priority claimed from US15/583,096 external-priority patent/US10953241B2/en
Priority claimed from US15/629,002 external-priority patent/US10278863B2/en
Priority claimed from US15/918,487 external-priority patent/US10874873B2/en
Application filed by Ojai Retinal Technology LLC filed Critical Ojai Retinal Technology LLC
Publication of EP3595775A1 publication Critical patent/EP3595775A1/fr
Publication of EP3595775A4 publication Critical patent/EP3595775A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • 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
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0082—Scanning transducers

Definitions

  • the present invention is generally directed to systems and processes for treating biological tissue, such as diseased biological tissue. More particularly, 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.
  • 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.
  • 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.
  • HSPs heat shock proteins
  • RPE retinal pigment epithelium
  • HSPs 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, 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. 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 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%- l 0% of a cell's proteins, although when under stress the percentage can rise to 1 5%.
  • the density of proteins of a mammalian cells has been found to be in the range of (2-4) x 1 0 1 8 CM "3 .
  • the aforementioned percentages mean that the density of HSPs is normally (1 -4) x 1 0 1 7 CM- 3 , while under stress the density can rise to (3-6) x 1 0 1 7 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 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 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
  • 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 first treatment to the target tissue is performed by generating a pulsed energy and repeatedly applying the pulsed 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 target tissue may comprise retinal tissue.
  • the pulsed energy has energy parameters including wavelength or frequency, duty cycle and pulse train duration.
  • the energy parameters are selected so as to raise a target tissue temperature up to 1 1 ° 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 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 a l ight beam, a microwave, a radiofreq uency or an ultrasound.
  • a device may be i nserted i nto 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 trai n duration of between approximately 0.2 to 0.4 seconds.
  • the radiofrequency may be generated with a device having a coil rad ii of between approximately 2 and 6 mm and
  • the pulsed energy may com prise a m icrowave freq uency of between 1 0 to 20 gigahertz (GHz).
  • the m icrowave may have a pulse trai n duration of approxi mately between 0.2 and 0.6 seconds.
  • the m icrowave may have a duty cycle of between approxi mately 2% and 5%.
  • the microwave may have an average power of between approximately 8 and 52 watts.
  • the pulsed energy may com prise a pulsed l ight beam, such as one or more laser l ight beams.
  • the l ight beam may have a wavelength of between approximately 530 n m to 1 300 n m, 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 l ight beam has a duty cycle of less than 1 0%, and preferably between 2.5% and 5%.
  • the pulsed l ight beam may have a pulse trai n duration of approxi mately 0.1 and 0.6 seconds.
  • the pulsed energy may com prise a pulsed ultrasound , havi ng a frequency of between approximately 1 and 5 MHz.
  • the ultrasound has a train duration of approxi mately 0.1 and 05 seconds.
  • the ultrasound may have a duty cycle of between approxi mately 2% and 1 0%.
  • the ultrasound has a power of between approxi mately 0.46 and 28.6 watts.
  • the first treatment comprises applying the pulsed energy to the target tissue for a period of less than ten seconds, and more typical ly less than one second.
  • the first treatment creates a level of heat shock protein activation in the target tissue.
  • a second treatment is performed to the target tissue by repeatedly reapplyi ng the pulsed energy to the target tissue so as to control lably raise the tem perature of the target tissue to therapeutically treat the target tissue without destroying or permanently damaging the target tissue.
  • the second treatment increases the level of heat shock protein activation in the target tissue such that it is at a level which is higher than the level after the first treatment.
  • 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 2B are graphs illustrating the time for the
  • 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
  • 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.
  • FIGURE 41 is a graph depicting wavefront from two sources separated by a distance
  • FIGURES 42A and 42 B are graphs depicting the behavior of HSP cellular system components over time following a sudden increase in
  • FIGURES 43A-43 H are graphs depicting the behavior of HSP cellular system components in the first minute following a sudden increase in
  • FIGURES 44A and 44B 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 45 is a graph depicting the improvement ratios versus interval between treatments, in accordance with the present invention.
  • the present invention is directed to a system and method for delivering a pulsed energy, such as ultrasound, ultraviolet radiofrequency, microwave radiofrequency, 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 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, ultraviolet radiofrequency, microwave radiofrequency, 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.
  • 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.
  • a predetermined temperature such as 6°C and even 1 °C or less in certain circumstances.
  • 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 treatment of patients suffering from age-related macular degeneration can slow the progress or even stop the progression of AMD.
  • Most of the patients have seen significant improvement in dynamic functional logMAR mesoptic visual acuity and mesoptic contrast visual acuity after the SDM treatment. It is believed that SDM works by targeting, preserving, and "normalizing" (moving toward normal) function of the retinal pigment epithelium (RPE).
  • RPE retinal pigment epithelium
  • SDM has also been shown to stop or reverse the manifestations of the diabetic retinopathy disease state without treatment-associated damage or adverse effects, despite the persistence of systemic diabetes mellitus.
  • SDM might work by inducing a return to more normal cell function and cytokine expression in diabetes-affected RPE cells, analogous to hitting the "reset" button of an electronic device to restore the factory default settings.
  • SDM treatment may directly affect cytokine expression via heat shock protein (HSP) activation in the targeted tissue.
  • HSP heat shock protein
  • 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.
  • SDM subthreshold diode micropulse laser
  • 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.
  • 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.
  • 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.
  • 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 parameter. 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.
  • 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.
  • dT(t) [dT 0 / ⁇ (l / 2)+( ⁇ ⁇ /2/6) ⁇ ][(1 / 2)(t p /t)3/2 + (TTi /2/6)(t p /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. 16 and 17 show that Qdamage does not exceed 1 until dT 0 exceeds 11.3 K, whereas Qhsp is greater than 1 over the whole interval shown, the desired condition for cellular repair without damage.
  • a SAPRA system can be used.
  • 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.
  • FIG. 20 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 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
  • a plurality of light beams are generated, each of which has parameters selected so that a target tissue temperature may be controllably raised to therapeutically treat the target tissue without destroying or permanently damaging the target tissue.
  • This may be done, for example, by passing the laser light beam 30 through optics which diffract or otherwise generate a plurality of laser light beams from the single laser light beam 30 having the selected parameters.
  • the laser light beam 30 may be passed through a collimator lens 32 and then through a mask 34.
  • the mask 34 comprises a diffraction grating.
  • the mask/diffraction grating 34 produces a geometric object, or more typically a geometric pattern of simultaneously produced multiple laser spots or other geometric objects. This is represented by the multiple laser light beams labeled with reference number 36.
  • the multiple laser spots may be generated by a plurality of fiber optic waveguides.
  • Either method of generating laser spots allows for the creation of a very large number of laser spots simultaneously over a very wide treatment field.
  • 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.
  • manufacturing can be used to create the simultaneous geometric pattern of spots or other objects.
  • the present invention can use a multitude of simultaneously generated therapeutic light beams or spots, such as numbering in the dozens or even hundreds, as the parameters and methodology of the present invention create therapeutically effective yet non-destructive and non-permanently damaging treatment. Although hundreds or even thousands of simultaneous laser spots could be generated and created and formed into patterns to be simultaneously applied to the tissue, due to the requirements of not
  • 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 1 00 when a 0.04 (4%) duty cycle and a total train d uration 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
  • the system of the present invention incorporates a guidance system to ensure complete and total retinal treatment with retinal photostimulation.
  • Fixation/tracking/ registration systems consisting of a fixation target, tracking mechanism, and linked to system operation can be incorporated into the present invention.
  • fixation/tracking/ registration systems consisting of a fixation target, tracking mechanism, and linked to system operation can be incorporated into the present invention.
  • the geometric pattern of simultaneous laser spots is sequentially offset so as to achieve confluent and complete treatment of the surface.
  • FIGS. 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 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. 22 and 23.
  • 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 25 mm 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.
  • 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 treatment light sources into the pattern-generating optical
  • 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.
  • Each laser console may supply a laser light beam having different
  • the fiber coupler produces a single output that is passed into the laser projector optics 24 as described in the earlier system.
  • the coupling of the plurality of laser consoles 22 into a single optical fiber is achieved with a fiber coupler 42 as is known in the art.
  • Other known mechanisms for combining multiple light sources are available and may be used to replace the fiber coupler described herein.
  • the diffractive element 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.
  • 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.
  • 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.
  • the treatment would stimulate the activation or production of heat shock proteins and facilitate protein repair without damaging the cells and tissues being treated. As discussed above, 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,
  • 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.
  • 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. It is contemplated that 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
  • 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.
  • the pill form 82 of delivery 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
  • electromagnetic (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.
  • 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 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.
  • 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.
  • a target organ 98 such as the illustrated liver
  • 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
  • Each micropulse lasts a fraction of a millisecond, typically between 50 microseconds to 1 00 microseconds in duration. Thus, for the exposure envelope duration of 300-500 milliseconds, and at a duty cycle of less than 5%, there is a significant amount of wasted time between micropulses to allow the thermal relaxation time between consecutive pulses. Typically, a delay of between 1 and 3 milliseconds, and preferably approximately 2 milliseconds, of thermal relaxation time is needed between consecutive pulses.
  • the cells are typically exposed or hit between 50-200 times, and preferably between 75-1 50 at each location, and with the 1 -3 milliseconds of relaxation or interval time, the total time in accordance with the embodiments described above to treat a given area which is being exposed to the laser spots is usually less than one second, such as between 1 00 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.
  • Pulse 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
  • 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 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 pulses are typically 50 seconds to 1 00 microseconds in duration. This is referred to herein as microshifting.
  • the number of additional areas which can be treated is limited only by the micopulse duration and the ability to controllably move the light beams from one area to another.
  • 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.
  • a predetermined level such as 6°C or less, or even 1 °C or less
  • 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 controllably offset or 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 of energy to the target tissue area has been achieved to therapeutically treat these areas,
  • Adjacent exposure areas must be separated by at least a
  • 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.
  • a graph is provided wherein the x-axis represents the Log of the average power in watts of a laser and the y-axis represents the treatment time, in seconds.
  • the lower curve is for panmacular treatment and the upper curve is for panretinal treatment.
  • the areas of each retinal spot are 1 00 microns, and the laser power for these 1 00 micron retinal spots is 0.74 watts.
  • the panmacular area is 0.55 2 , requiring 7,000 panmacular spots total, and the panretinal area is 3.30 2 , requiring 42,000 laser spots for full coverage.
  • Each RPE spot requires a minimum energy in order for its reset mechanism to be adequately activated, in accordance with the present invention, namely, 38.85 joules for panmacular and 233.1 joules for panretinal.
  • the shorter the treatment time the larger the required average power.
  • there is an upper limit on the allowable average power which limits how short the treatment time can be.
  • FIGS. 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.
  • the parameters of the laser light are selected to be therapeutically effective yet not destructive or permanently damaging to the cells, no guidance or tracking beams are required, only the treatment beams as all areas can be treated in accordance with the present invention.
  • the shifting or steering of the pattern of light beams may be done by use of an optical scanning mechanism, such as that illustrated and described in connection with FIGS. 22 and 23.
  • an optical scanning mechanism such as that illustrated and described in connection with FIGS. 22 and 23.
  • 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.
  • FIG. 41 depicts the wavefront originating from two adjacent sources.
  • a commercially available microwave standard gain horn source operating at 1 40-220 GHz has transverse dimensions of 1 3.9mm by 1 0.8 mm and a depth dimension of 32.2 mm.
  • the wavelength is 0.1 5 cm
  • eq. [6] then gives 9 cm.
  • the wavelength of the radiofrequency radiation is typically much larger than a human body
  • the treatment volume is said to be in the "near field" of the radiofrequency source. Phased arrays are not useful in near field, and a different method of steering is required.
  • the wavelength of the radiation is much larger than body dimensions. Thus, for 3-6 MHz, the wavelengths range from 1 0,000 cm to 5000 cm. Accordingly, the target region in the body is in the" near field" of the source, i.e. the target distance and dimensions are much 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 controlled manner of applying energy to the target tissue is intended to raise the temperature of the target tissue to therapeutically treat the target tissue without destroying or permanently damaging the target tissue. It is believed that such heating activates HSPs and that the thermally activated HSPs work to reset the diseased tissue to a healthy condition, such as by removing and/or repairing damaged proteins. It is believed by the inventors that maximizing such HSP activation improves the therapeutic effect on the targeted tissue.
  • 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 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 1 00 milliseconds and 600 milliseconds.
  • the time that the energy is actually applied to the target tissue is typically much less than this in order to provide intervals of time for heat relaxation so that the target tissue does not overheat and become damaged or destroyed.
  • laser light pulses may last on the order of microseconds with several milliseconds of intervals of relaxed time.
  • E is the activation energy
  • T(t) is the temperature of the thin RPE layer, including the laser-induced temperature rise [Para 206]
  • Rybinski, Z.Szymanska, S. Lasota, A. Gambin (201 3) Modeling the efficacy of hyperthermia treatment. Journal of the Royal Society Interface 1 0, No. 88, 201 30527 (Rybinski et al (201 3)). The species considered in Rybinski et al (201 3) are shown in Table 1 .
  • HSFs (trimer) heat shock factor capable of binding to DNA, formed from HSF
  • HSE heat shock element a DNA site that initiates transcription of
  • S substrate for HSP binding a damaged protein
  • HSP HSP a complex of HSP bound to HSF (unactivated HSPs)
  • HSF3 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)
  • HSP denatured or damaged proteins that are as yet unaffected by HSPs
  • HSP denotes free (activated) heat shock proteins
  • HSP:S denotes activated HSPs that are attached to the damaged proteins and performing repair
  • HSP:HSF denotes (inactive) HSPs that are attached to heat shock factor monomers
  • HSF denotes a monomer of heat shock factor
  • HSF3 denotes a trimer of heat shock factor that can penetrate the nuclear membrane to interact with a heat shock element on the DNA molecule
  • HSE: HSF3 denotes a trimer of heat shock factor attached to a heat shock element on the DNA molecule that initiates transcription of a new mRNA molecule
  • mRNA denotes the messenger RNA molecule that results from the HSE: HSF3, and that leads to the production of a new (activated) HSP molecule in the cell's cytoplasm.
  • FIGURE 42 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. 42 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 42 shows what the Rybinski et al equations predict for the variation of the 1 0 different species over a period of 350 minutes.
  • the present invention is concerned with SDM application is on the variation of the species over the much shorter O(minute) interval between two applications of SDM at any single retinal locus. It will be understood that the preferred embodiment of SDM in the form of laser light treatment is analyzed and described, but it is applicable to other sources of energy as well.
  • FIGURE 43 shows that the nuclear source of HSPs plays virtually no role during a 1 minute period, and that the main source of new HSPs in the cytoplasm arises from the release of sequestered HSPs from the reservoir of HSPHSF molecules. It also shows that a good fraction of the newly activated HSPs attach themselves to damaged proteins to begin the repair process.
  • a first treatment to the target tissue may be performed by repeatedly applying the pulsed energy (e.g., SDM) to the target tissue over a period of time so as to controllably raise a temperature of the target tissue to therapeutically treat the target tissue without destroying or permanently damaging the target tissue.
  • 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 1 00 milliseconds to 600 milliseconds. This "treatment” controllably raises the temperature of the target tissue to activate the heat shock proteins and related components.
  • the first treatment creates a level of heat shock protein activation of the target tissue
  • the second treatment increases the level of heat shock protein activation in the target tissue above the level due to the first treatment.
  • This technique may be referred to herein as "stair-stepping” in that the levels of activated HSP production increase with the subsequent treatment or treatments within the same office visit treatment session.
  • This "stairstepping” technique may be described by a combination of the Arrhenius integral approach for subsecond phenomena with the Rybinski et al. (201 3) treatment of intervals between repeated subsecond applications of the SDM or other pulsed energy.
  • [HSP(SDM l )] [HSP(equil)] + [HSPHSF(equil)](l -exp[-Q])
  • [HSF(SDM l )] [HSF(equil)] + [HSPHSF(equil)](l -exp[-Q])
  • [HSP(SDM2)] [HSP(Xt)] + [HSPHSF(Xt)](l -exp[-Q])
  • [HSF(SDM2)] [HSF(Xt)] + [HSPHSF(Xt)](l -exp[-Q])
  • [HSP(Xt)], [HSF(Xt)] , and [HSPHSF( t)] are the values determined from the Rybinski et al (201 3) equations at the time t.
  • FIGURES 44A and 44B illustrate the variation in the activated concentrations [HSP] and the unactivated HSP in the cytoplasmic reservoir
  • the activation Arrhenius integral ⁇ depends on both the treatment parameters (e.g., laser power, duty cycle, total train duration) and on the RPE properties (e.g., absorption coefficients, density of HSPs).
  • the cell is taken to have the Rybinski et al (201 3) equilibrium concentrations for the ten species involved, given in Table 4.
  • Table 5 shows four HSP concentrations (in the Rybinski et al arbitrary units) each corresponding to four different times:
  • Table 7 is the same as the Tables 5 and 6, except that the
  • [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 Figure 44 and in [HSPS] during the interval t - indicating a rapid replenishment of the cytoplasmic reservoir of unactivated HSP's and a rapid attachment of HSP's to the damaged proteins.
  • results of Tables 5-7 and FIG. 45 are for the Rybinski et al. (201 3) rate constants of Table 3 and the equilibrium concentrations of Table 4.
  • the actual concentrations and rate constants in a cell may differ from these values, and thus the number results in Tables 5-7 and FIG. 45 should be taken as representative rather than absolute. However, they are not anticipated to be significantly different.
  • performing multiple intra-sessional treatments on a single target tissue location or area, such as a single retinal locus with the second and subsequent treatments following the first after an interval anywhere from three seconds to three minutes, and preferably ten seconds to ninety seconds, should increase the activation of HSPs and related components and thus the efficacy of the overall treatment of the target tissue.
  • the resulting "stair-stepping” effect achieves incremental increases in the number of heat shock proteins that are activated, enhancing the therapeutic effect of the treatment. However, if the interval of time between the first and subsequent treatments is too great, then the "stair-stepping" effect is lessened or not achieved.
  • the technique of the present invention is especially useful when the treatment parameters or tissue characteristics are such that the associated Arrhenius integral for activation is low, and when the interval between repeated applications is small, such as less than ninety seconds, and preferably less than a minute. Accordingly, such multiple treatments must be performed within the same treatment session, such as in a single office visit, where distinct

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Abstract

L'invention concerne un procédé de traitement thermique de tissu biologique consistant à appliquer de façon répétée une énergie pulsée à un tissu cible sur une période de temps de façon à élever de manière régulable une température du tissu cible pour créer un effet thérapeutique sur le tissu cible sans détruire ou endommager de façon permanente le tissu cible. Une fois que le premier traitement est terminé, l'application de l'énergie pulsée au tissu cible est arrêtée pendant un intervalle de temps. Au cours d'une seule session de traitement, un second traitement est effectué sur le tissu cible après l'intervalle de temps en réappliquant de manière répétée l'énergie pulsée au tissu cible de façon à élever de manière régulable la température du tissu cible pour traiter thérapeutiquement le tissu cible sans détruire ou endommager de façon permanente le tissu cible.
EP18766907.2A 2017-03-16 2018-03-13 Méthode utilisant une énergie pulsée pour traiter thermiquement un tissu biologique Withdrawn EP3595775A4 (fr)

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US15/460,821 US20170203132A1 (en) 2015-10-26 2017-03-16 System and process utilizing pulsed energy to treat biological tissue
US15/583,096 US10953241B2 (en) 2012-05-25 2017-05-01 Process for providing protective therapy for biological tissues or fluids
US15/629,002 US10278863B2 (en) 2016-03-21 2017-06-21 System and process for treatment of myopia
US15/918,487 US10874873B2 (en) 2012-05-25 2018-03-12 Process utilizing pulsed energy to heat treat biological tissue
PCT/US2018/022201 WO2018169969A1 (fr) 2017-03-16 2018-03-13 Méthode utilisant une énergie pulsée pour traiter thermiquement un tissu biologique

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US5445146A (en) * 1995-03-31 1995-08-29 Bellinger; Gary J. Biological tissue stimulation by low level optical energy
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WO2007146342A2 (fr) * 2006-06-12 2007-12-21 Ivivi Technologies, Inc. Appareil électromagnétique de prophylaxie et réparation de tissu opthalmique et procédé
EP2207595A4 (fr) * 2007-10-19 2012-10-24 Lockheed Corp Système et procédé de conditionnement de tissu animal par rayon laser
US8141557B2 (en) * 2008-10-22 2012-03-27 Peyman Gholam A Method of oscillatory thermotherapy of biological tissue
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US9427602B2 (en) * 2012-05-25 2016-08-30 Ojai Retinal Technology, Llc Pulsating electromagnetic and ultrasound therapy for stimulating targeted heat shock proteins and facilitating protein repair
US9962291B2 (en) * 2012-05-25 2018-05-08 Ojai Retinal Technology, Llc System and process for neuroprotective therapy for glaucoma
US9381115B2 (en) * 2012-05-25 2016-07-05 Ojai Retinal Technology, Llc System and process for retina phototherapy
US10531908B2 (en) * 2012-05-25 2020-01-14 Ojai Retinal Technology, Llc Method for heat treating biological tissues using pulsed energy sources
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