EP3250139A1 - Thérapie électromagnétique pulsée et par ultrasons pour stimuler des protéines de choc thermique ciblées et faciliter une réparation de protéine - Google Patents

Thérapie électromagnétique pulsée et par ultrasons pour stimuler des protéines de choc thermique ciblées et faciliter une réparation de protéine

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Publication number
EP3250139A1
EP3250139A1 EP15880628.1A EP15880628A EP3250139A1 EP 3250139 A1 EP3250139 A1 EP 3250139A1 EP 15880628 A EP15880628 A EP 15880628A EP 3250139 A1 EP3250139 A1 EP 3250139A1
Authority
EP
European Patent Office
Prior art keywords
tissue
target tissue
para
radiation energy
lai
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.)
Pending
Application number
EP15880628.1A
Other languages
German (de)
English (en)
Other versions
EP3250139A4 (fr
Inventor
Jeffrey K. LUTTRULL
Benjamin W. L. Margolis
David B. Chang
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 US14/607,959 external-priority patent/US9168174B2/en
Priority claimed from US14/922,885 external-priority patent/US9427602B2/en
Application filed by Ojai Retinal Technology LLC filed Critical Ojai Retinal Technology LLC
Publication of EP3250139A1 publication Critical patent/EP3250139A1/fr
Publication of EP3250139A4 publication Critical patent/EP3250139A4/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/0625—Warming the body, e.g. hyperthermia treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61B18/14—Probes or electrodes therefor
    • A61B18/1492—Probes or electrodes therefor having a flexible, catheter-like structure, e.g. for heart ablation
    • 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
    • A61B2018/2065—Multiwave; Wavelength mixing, e.g. using four or more wavelengths
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/063—Radiation therapy using light comprising light transmitting means, e.g. optical fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
    • A61N2005/0642—Irradiating part of the body at a certain distance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0661—Radiation therapy using light characterised by the wavelength of light used ultraviolet
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0043—Ultrasound therapy intra-cavitary
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities

Definitions

  • the present invention is generally directed to the activation of heat shock proteins and the facilitation of protein repair. More particularly, the present invention is directed to a system and method for selectively stimulating targeted heat shock protein activation or production and facilitating protein repair utilizing a pulsating electromagnetic or ultrasound energy source.
  • Heat shock proteins are a family of proteins that are produced by cells in response to exposure to stressful conditions. Production of high levels of heat shock proteins can be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to toxins, starvation, hypoxia, or water deprivation.
  • heat shock proteins play a role in responding to a large number of abnormal conditions in body tissues, including viral infection, inflammation, malignant transformations, exposure to oxidizing agents, cytotoxins, and anoxia.
  • Several heat shock proteins function as intra-cellular chaperones for other proteins and members of the HSP family are expressed or activated at low to moderate levels because of their essential role in protein maintenance and simply monitoring the cell's proteins even under non- stressful conditions. These activities are part of a cell's own repair system, called the cellular stress response or the heat-shock response.
  • Heat shock proteins are typically named according to their molecular weight.
  • Hsp60, Hsp70 and Hsp80 refer to the families of heat shock proteins on the order of 60, 70 and 80 kilodaltons in size, respectively. They act in a number of different ways.
  • Hsp70 has peptide- binding and ATPase domains that stabilize protein structures in unfolded and assembly-competent states.
  • Mitochondrial Hsp60s form ring-shaped
  • Hsp90 plays a suppressor regulatory role by associating with cellular tyrosine kinases, transcription factors, and glucocorticoid receptors.
  • Hsp27 suppresses protein aggregation.
  • Hsp70 heat shock proteins are a member of extracellular and
  • heat shock proteins which are involved in binding antigens and presenting them to the immune system.
  • Hsp70 has been found to inhibit the activity of influenza A virus ribonucleoprotein and to block the replication of the virus.
  • Heat shock proteins derived from tumors elicit specific protective immunity. Experimental and clinical observations have shown that heat shock proteins are involved in the regulation of autoimmune arthritis, type 1 diabetes, mellitus, arterial sclerosis, multiple sclerosis, and other autoimmune reactions.
  • the present invention is directed to a method for stimulating heat shock protein activation in tissue without damaging the target tissue.
  • the method comprises the steps of providing a source of pulsed ultrasound or electromagnetic energy.
  • the electromagnetic energy may comprise ultraviolet waves, microwaves, radio frequency waves or laser light at a predetermined wavelength.
  • the laser light may have a wavelength between 530nm to 1 300 nm, a duty cycle of less than 1 0% and a pulse length of 500 milliseconds or less.
  • the pulsed ultrasound or electromagnetic radiation energy is applied to the target tissue to create a thermal time-course that stimulates cells of the target tissue to activate heat shock proteins without damaging the target tissue. This includes raising the target tissue temperature to at least 1 0 ° C transiently, while only 1 ° C or less over several minutes.
  • a plurality of laser light spots are
  • a device may be inserted into a cavity of the body in order to apply the pulsed ultrasound or electromagnetic radiation energy to the tissue.
  • the device may comprise an endoscope.
  • the pulsed ultrasound or electromagnetic radiation 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 body area may comprise an earlobe and the pulse electromagnetic radiation energy is applied to the blood flowing through the earlobe.
  • FIGURE 1 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 2 is a cross-sectional view of a photostimulation delivery device delivering electromagnetic energy to target tissue, in accordance with the present invention
  • FIGURE 3 is a diagrammatic view illustrating a system used to generate a laser light beam, in accordance with the present invention
  • FIGURE 4 is a diagrammatic view of optics used to generate a laser light geometric pattern, in accordance with the present invention.
  • FIGURE 5 is a diagrammatic view illustrating an alternate
  • FIGURE 6 is a diagrammatic view illustrating yet another
  • FIGURE 7 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 8 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 9 is a diagrammatic view of a colonoscope providing photostimu lation to an intestinal or colon area of the body, in accordance with the present invention.
  • FIGURE 1 0 is a diagrammatic view of an endoscope inserted into a stomach and providing treatment thereto, in accordance with the present invention
  • FIGURE 1 1 is a partially sectioned perspective view of a capsule endoscope, used in accordance with the present invention
  • FIGURE 1 2 is a diagrammatic view of a pulsed high intensity focused ultrasound for treating tissue internal the body, in accordance with the present invention
  • FIGURE 1 3 is a diagrammatic view for delivering therapy to the bloodstream of a patient, through an earlobe, in accordance with the present invention.
  • FIGURE 1 4 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.
  • the present invention is directed to a system and method for delivering an energy source, such as laser, ultrasound, ultraviolet
  • radiofrequency microwave radiofrequency and the like, to cause a pulsing thermal time-course in tissue that stimulates heat shock protein activation or production and facilitates protein repair without causing any damage.
  • a subthreshold, sublethal micropulse laser light beam which has a wavelength greater than 532 nm and a duty cycle of less than 1 0% at a predetermined intensity or power and a predetermined pulse length or exposure time creates desirable retinal photostimulation without any visible burn areas or tissue destruction.
  • a laser light beam having a wavelength of between 550nm- l 300nm, and in a particularly preferred embodiment 81 Onm, having a duty cycle of approximately 5% or less and a predetermined intensity or power (such as between 1 00-590 watts per square centimeter at the retina or approximately 1 watt per laser spot for each treatment spot at the retina) and a predetermined pulse length or exposure time (such as 500 milliseconds or less) creates a sublethal, "true subthreshold" retinal photostimulation in which all areas of the retinal pigment epithelium exposed to the laser irradiation are preserved and available to contribute therapeutically.
  • 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 has been reported to have a clinically broad therapeutic range, unique among retinal laser modalities, consistent with American National Standards Institute "Maximum Permissible Exposure” predictions. While SDM may cause direct photothermal effects such as entropic protein unfolding and disaggregation, SDM appears optimized for clinically safe and effective stimulation of HSP-mediated repair.
  • 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, autoimmu ne conditions, and cancers that are accessible by means of fiber optics of endoscopes or surface probes as well as focused electromagnetic/sou nd waves.
  • abnormal conditions including inflammations, autoimmu ne conditions, and cancers that are accessible by means of fiber optics of endoscopes or surface probes as well as focused electromagnetic/sou nd 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 tu mors can be accessed by an optical fiber system, like those used in colonoscopy.
  • 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 tu bes 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. 2, 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. 3 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 Onm 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 projection /viewing components 26.
  • the laser light beam 30 may be passed through a collimator lens 32 and then through a mask 34.
  • the mask 34 comprises a
  • the mask/diffraction grating 34 produces a geometric object, or more typically a geometric pattern of simultaneously produced multiple laser spots or other geometric objects. This is represented by the multiple laser light beams labeled with reference number 36.
  • the multiple laser spots may be generated by a plurality of fiber optic waveguides. Either method of generating laser spots allows for the creation of a very large number of laser spots simultaneously over a very wide treatment field. In fact, a very high number of laser spots, perhaps numbering in the hu ndreds even thousands or more could be simultaneously generated to cover a given area of the target tissue, or possibly even the entirety of the target tissue. A wide array of simultaneously applied small separated laser spot applications may be desirable as such avoids certain disadvantages and treatment risks known to be associated with large laser spot applications.
  • the 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. 4.
  • the single laser beam 30 has thus been formed into hundreds or even thousands of individual laser beams 36 so as to create the desired pattern of spots or other geometric objects.
  • These laser beams 36 may be passed through additional lenses, collimators, etc. 38 and 40 in order to convey the laser beams and form the desired pattern. Such additional lenses, collimators, etc. 38 and 40 can further transform and redirect the laser beams 36 as needed.
  • Arbitrary patterns can be constructed by controlling the shape, spacing and pattern of the optical mask 34.
  • the pattern and exposure spots can be created and modified arbitrarily as desired according to application requirements by experts in the field of optical engineering.
  • Photolithographic techniques especially those developed in the field of semiconductor
  • manufacturing can be used to create the simultaneous geometric pattern of spots or other objects.
  • FIG. 5 illustrates diagrammatically a system which couples multiple light sources into the pattern-generating optical subassembly described above.
  • this system 20' is similar to the system 20 described in FIG. 3 above.
  • the primary differences between the alternate system 20' and the earlier described system 20 is the inclusion of a plurality of laser consoles, the outputs of which are each fed into a fiber coupler 42.
  • the fiber coupler produces a single output that is passed into the laser projector optics 24 as described in the earlier system.
  • the coupling of the plurality of laser consoles 22 into a single optical fiber is achieved with a fiber coupler 42 as is known in the art.
  • Other known mechanisms for combining multiple light sources are available and may be used to replace the fiber coupler described herein.
  • the diffractive element must function differently than described earlier depending upon the wavelength of light passing through, which results in a slightly varying pattern.
  • the variation is linear with the wavelength of the light source being diffracted.
  • the difference in the diffraction angles is small enough that the different, overlapping patterns may be directed along the same optical path through the projector device 26 to the tissue for treatment.
  • a sequential offsetting to achieve complete coverage will be different for each wavelength.
  • This sequential offsetting can be accomplished in two modes. In the first mode, all wavelengths of light are applied simultaneously without identical coverage. An offsetting steering pattern to achieve complete coverage for one of the multiple wavelengths is used. Thus, while the light of the selected wavelength achieves complete coverage of the tissue, the application of the other wavelengths achieves either incomplete or overlapping coverage of the tissue.
  • the second mode sequentially applies each light source of a varying wavelength with the proper steering pattern to achieve complete coverage of the tissue for that particular wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve identical coverage for each wavelength. This avoids either incomplete or overlapping coverage for any of the optical wavelengths.
  • FIG. 6 illustrates diagrammatically yet another alternate
  • This system 20" is configured generally the same as the system 20 depicted in FIG. 3. The main difference resides in the inclusion of multiple pattern-generating subassembly channels tu ned 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. 4 above - the entire set of optics tuned for the specific wavelength generated by the corresponding laser console 22.
  • the output from each set of optics 24 is then directed to a beam splitter 46 for combination with the other wavelengths. It is known by those skilled in the art that a beam splitter used in reverse can be used to combine multiple beams of light into a single output.
  • the 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. 3-6 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. 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 at least 1 0 ° C, transiently while only 1 ° C or less for the long term, such as over several minutes, such as two or more minutes.
  • a light pipe is not an effective means of delivering the pulsed energy.
  • pulsed low frequency electromagnetic energy or preferably pulsed ultrasound can be used to cause a series of temperature spikes in the target tissue.
  • 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 of 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.
  • epithelium is a thin and clear tissue.
  • a cross-sectional view of a human head 48 is shown with an endoscope 1 4 inserted into the nasal cavity 50 and energy 1 6, such as laser light or the like, being directed to tissue 1 8 to be treated within the nasal cavity 50.
  • energy 1 6, such as laser light or the like being directed to tissue 1 8 to be treated within the nasal cavity 50.
  • the tissue 1 8 to be treated could be within the nasal cavity 50, 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 su rface 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. 7.
  • the endoscope 1 4 could be inserted after application of a topical anesthetic. If necessary, the procedure could be repeated periodically, such as in a day or so.
  • the source of energy could be monochromatic laser light, such as 81 Onm wavelength laser light, administered in a manner similar to that described in the above- referenced patent applications, but administered through an endoscope or the like, as illustrated in FIG. 7.
  • the adjuvant dye would be selected so as to increase the laser light absorption. While this comprises a particularly
  • 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. 7. 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 58 and into either the large intestine 60 or small intestine 62 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
  • 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 tu be portion 1 2 of the colonoscope 1 4 into the rectu m and move it into the area of the colon, large intestine 60 or small intestine 64 to the area to be treated.
  • the physician could view through a monitor the pathway of the inserted flexible member 1 2 and even view the tissue at the tip of the colonoscope 1 4 within the intestine, so as to view the area to be treated.
  • the tip 64 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. 1 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 tu be 1 2 of an endoscope or the like is inserted through the patient's mouth 52 through the throat and trachea area 54 and into the stomach 66, where the tip or end 64 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 58 and into the stomach 66 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 Onm radiation from a laser diode or LED were to be used, the pigment would have an absorption peak at or near 81 Onm.
  • the wavelength of the energy source could be adjusted to a slightly longer wavelength at an
  • a capsule endoscope 68 such as that illustrated in FIG. 1 1 , 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 68 is swallowed and enters into the stomach and passes through the Gl tract, when at the
  • the capsule or pill 68 could receive power and signals, such as via antenna 70, so as to activate the source of energy 72, such as a laser diode and related circuitry, with an appropriate lens 74 focusing the generated laser light or radiation through a radiation-transparent cover 76 and onto the tissue to be treated.
  • the location of the capsule endoscope 68 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 68 was passing through at the time.
  • the capsule or pill 68 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 72 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 68 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 which have relatively long absorption lengths in body tissue.
  • RF radio frequency
  • EM electromagnetic
  • Pulsed ultrasound is preferable to RF electromagnetic radiation to activate remedial HSP activity in abnormal tissue that is inaccessible to surface SDM or the like.
  • Pulsed ultrasound sources can also be used for abnormalities at or near surfaces as well.
  • a specific region deep in the body can be specifically targeted by using one or more beams that are each focused on the target site.
  • the pulsating heating will then be largely only in the targeted region where the beams are focused and overlap.
  • an ultrasound transducer 78 or the like generates a plurality of ultrasound beams 80 which are coupled to the skin via an acoustic-impedance-matching gel, and penetrate through the skin 82 and through undamaged tissue in front of the focus of the beams 80 to a target organ 84, such as the illustrated liver, and specifically to a target tissue 86 to be treated where the ultrasound beams 80 are focused.
  • a target organ 84 such as the illustrated liver
  • the pulsating heating will then only be at the targeted, focused region 86 where the focused beams 80 overlap. The tissue in front of and behind the focused region 86 will not be heated or affected appreciably.
  • 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 u ltrasound system similar to the laser diffracted optical system (described in paragraph 45), by applying ultrasound in multiple simultaneously applied adjacent but separated and spaced columns.
  • the multiple focused ultrasound beams converge on a very small treatment target within the body, the convergence allowing for a minimal heating except at the overlapping beams at the target. This area would be heated and stimulate the activation of HSPs and facilitate protein repair by transient high temperature spikes.
  • the treatment is in compliance with FDA/FCC requirements for long term (minutes) average temperature rise ⁇ 1 K.
  • FDA/FCC requirements for long term (minutes) average temperature rise ⁇ 1 K An important distinction of the invention from existing therapeutic heating treatments for pain and muscle strain is that there are no high T spikes in existing techniques, and these are required for efficiently activating HSPs and facilitating protein repair to provide healing at the cellular level.
  • electromagnetic radiation is not as good of a choice for SDM-type treatment of regions deep with the body.
  • 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(tp) Pcxtp / (4nC v r2) [2] where a is the absorption coefficient and C v is the specific volume heat capacity This will be the case until the r is reached at which the heat diffusion length at t becomes comparable to r, or the diffraction limit of the focused beam is reached. For smaller r, the temperature rise is essentially independent of r. As an example, suppose the diffraction limit is reached at a radial distance that is smaller than that determined by heat diffusion. Then
  • dT(t) [dTo/ ⁇ (l /2)+(TTI/2/6) ⁇ ][(1 /2)(t P /t)3/2 + (ni/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 /(3EdTo) ⁇ exp[-(E/ kB)l /(T 0 + dT 0 + dT N (Nti))]
  • This simple example demonstrates that focused ultrasou nd shou ld be usable to stimulate reparative HSP's deep in the body with easily attainable equipment:
  • a SAPRA system can be used.
  • 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 ultrasou nd pulses simply requires the transmission of SDM or other electromagnetic radiation or ultrasou nd pulses to the earlobe 88, 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 88 is shown adjacent to a clamp device 90 configured to transmit SDM radiation or the like.
  • This could be, for example, by means of one or more laser diodes 92 which would transmit the desired frequency at the desired pulse and pulse train to the earlobe 88.
  • Power could be provided, for example, by means of a lamp drive 94.
  • the lamp drive 94 could be the actual source of laser light, which would be transmitted through the appropriate optics and electronics to the earlobe 88.
  • the clamp device 90 would merely be used to clamp onto the patient's earlobe and cause that the radiation be constrained to the patient's earlobe 88.
  • the system may also include a display and speakers 1 00, 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.

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Abstract

L'invention concerne un système et un procédé pour stimuler l'activation de protéines de choc thermique et faciliter une réparation de protéine dans des cellules et des tissus de façon à tirer profit de la nature de correction et de restauration de l'activation ou production de protéine de choc thermique accrue et de la facilitation de réparation de protéine, tout en n'endommageant pas les cellules et tissus. Ce procédé consiste à traiter une zone cible spécifiée avec une source de rayonnement ultrasonore ou électromagnétique qui est pulsée et appliquée ou concentrée sur une ou plusieurs petites zones de façon à obtenir l'augmentation de température nécessaire ou contraindre suffisamment les cellules et tissus pour stimuler la production ou activation de protéine de choc thermiques et faciliter une réparation de protéine, tout en permettant à la température de diminuer suffisamment rapidement pour ne pas endommager ou détruire le tissu traité.
EP15880628.1A 2015-01-28 2015-11-16 Thérapie électromagnétique pulsée et par ultrasons pour stimuler des protéines de choc thermique ciblées et faciliter une réparation de protéine Pending EP3250139A4 (fr)

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US14/607,959 US9168174B2 (en) 2012-05-25 2015-01-28 Process for restoring responsiveness to medication in tissue of living organisms
US201562153616P 2015-04-28 2015-04-28
US14/922,885 US9427602B2 (en) 2012-05-25 2015-10-26 Pulsating electromagnetic and ultrasound therapy for stimulating targeted heat shock proteins and facilitating protein repair
PCT/US2015/060893 WO2016122752A1 (fr) 2015-01-28 2015-11-16 Thérapie électromagnétique pulsée et par ultrasons pour stimuler des protéines de choc thermique ciblées et faciliter une réparation de protéine

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