WO2018031255A1 - Processus destiné à fournir une thérapie protectrice pour des tissus ou de fluides biologiques - Google Patents

Processus destiné à fournir une thérapie protectrice pour des tissus ou de fluides biologiques Download PDF

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WO2018031255A1
WO2018031255A1 PCT/US2017/044319 US2017044319W WO2018031255A1 WO 2018031255 A1 WO2018031255 A1 WO 2018031255A1 US 2017044319 W US2017044319 W US 2017044319W WO 2018031255 A1 WO2018031255 A1 WO 2018031255A1
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Prior art keywords
target
tissue
target tissue
energy source
para
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PCT/US2017/044319
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English (en)
Inventor
Jeffrey K. LUTTRULL
Benjamin W. L. Margolis
David B. Chang
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Ojai Retinal Technology, Llc
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Priority claimed from US15/232,320 external-priority patent/US9962291B2/en
Priority claimed from US15/583,096 external-priority patent/US10953241B2/en
Application filed by Ojai Retinal Technology, Llc filed Critical Ojai Retinal Technology, Llc
Priority to BR112019001348A priority Critical patent/BR112019001348A2/pt
Priority to AU2017308587A priority patent/AU2017308587A1/en
Priority to CA3030483A priority patent/CA3030483A1/fr
Priority to JP2018565035A priority patent/JP2019524179A/ja
Priority to EP17840010.7A priority patent/EP3496810A4/fr
Priority to CN201780047506.XA priority patent/CN109562272A/zh
Publication of WO2018031255A1 publication Critical patent/WO2018031255A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/02—Radiation therapy using microwaves
    • 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
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/04—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor combined with photographic or television appliances
    • A61B1/041—Capsule endoscopes for imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/233—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the nose, i.e. nasoscopes, e.g. testing of patency of Eustachian tubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/267—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the respiratory tract, e.g. laryngoscopes, bronchoscopes
    • A61B1/2676—Bronchoscopes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/273—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the upper alimentary canal, e.g. oesophagoscopes, gastroscopes
    • A61B1/2736—Gastroscopes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/31—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the rectum, e.g. proctoscopes, sigmoidoscopes, colonoscopes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00137—Details of operation mode
    • A61B2017/00154—Details of operation mode pulsed
    • A61B2017/00172—Pulse trains, bursts, intermittent continuous operation
    • 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
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00482—Digestive system
    • A61B2018/00494—Stomach, intestines or bowel
    • 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
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00589—Coagulation
    • A—HUMAN NECESSITIES
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    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
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    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A61N2005/0604—Lungs and/or airways
    • A—HUMAN NECESSITIES
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    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A61N2005/0607—Nose
    • A—HUMAN NECESSITIES
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    • 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
    • A61N2005/0659—Radiation therapy using light characterised by the wavelength of light used infrared
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0004—Applications of ultrasound therapy

Definitions

  • the present invention generally relates to processes for treating biological tissues or fluids. More particularly, the present invention relates to a process for providing protective therapy for biological tissues or fluids having a chronic progressive disease, or a risk for a chronic progressive disease.
  • CPDs Chronic progressive diseases
  • IPF Idiopathic Pulmonary Fibrosis
  • Chronic progressive diseases may have any number of underlying causes, including infectious, genetic, multi-factorial and immune. While there are many different causes of CPDs, they share fundamental commonalities.
  • a unifying feature of all CPDs is the accumulation of abnormal intracellular proteins.
  • Another common feature of all CPDs is increasing cellular and organ dysfunction, leading to failure.
  • Yet another common and unifying feature of CPDs is cellular and organ dysfunction that causes and promotes chronic inflammation.
  • CPDs non-specific and antiinflammatory treatments. These include various steroidal and non-steroidal anti-inflammatory agents and immunosuppressive drugs.
  • antiinflammatory drugs have many drawbacks in CPDs. As they do not address the underlying cause of the disease, they must be used long-term and have limited effectiveness. Because of their modes of action and necessity of long-term use, the side effects and complications of treatment limit their usefulness.
  • Immunosuppressive drugs have the same limitations as anti-inflammatory drugs. However, as they alter the normal function of the immune system apart from the disease process, they can cause further complications including other disease syndromes and neoplasia.
  • Radiation therapy such as using x-ray radiation, is another treatment for CPDs.
  • manager protein therapy attempts to address the problems presented by gene, drug, and antiinflammatory/immunosuppression therapy by finding proteins or enzymes which are both key and common to several disease states, regardless of the underlying cause, and inhibiting them in various ways. As a single manager protein may be central to the development of a number of disease conditions, such as various and otherwise unrelated cancers, blocking this key protein could have wider therapeutic application than more disease-targeted therapies.
  • manager protein therapy shares the general limitation of targeted drug therapy if the protein itself is targeted, with the additional problem of triggering compensatory mechanisms such as up-regulation leading to permanent insensitivity to a drug action.
  • manager protein therapy shares the general limitations of gene therapy if the transcriptional and translational mechanisms that produce the protein are targeted. Such manager protein therapy also shares the problems targeted drug therapy has, as mentioned above.
  • SCT Stem cell transplantation
  • SCT attempts to replace dead or dysfunctional tissue with new functional tissue by transplanting stem cells into the tissue or area surrounding the tissue.
  • SCT is highly complex and expensive, with significant risks and adverse treatment effects. Despite much public interest, SCT has been thus far ineffective.
  • the present invention is generally directed to a process for providing protective therapy for biological tissues or fluids which have a chronic progressive disease or a risk for chronic progressive disease.
  • the present invention applies a pulsed energy source to a biological tissue or fluid which raises the temperature of the targeted tissue or targeted fluid and stimulates activation of heat shock proteins, which facilitate protein repair without damaging the tissue.
  • a pulsed energy source having energy parameters including wavelength or frequency, duty cycle and pulse train duration.
  • the pulsed energy source may comprise laser light, microwave, radiofrequency or ultrasound.
  • the energy parameters are selected so as to raise the target tissue or bodily target fluid temperature up to 1 1 ° C, typically between 6° C to 1 1 ° C at least during the application of the pulsed energy source to the target tissue or target fluid, to achieve a
  • the average temperature rise of the tissue or target fluid over several minutes is maintained at or below a predetermined level so as to not permanently damage the target tissue or target fluid.
  • the average temperature rise of the target tissue or target fluid over several minutes may be maintained at 6° C or less. More often, the average temperature rise of the target tissue or target fluid is maintained at
  • the pulsed energy source may comprise a radiofrequency.
  • the radiofrequency is typically between 3-6 megahertz (MHz), and has a duty cycle of between 2.5% to 5%, and a pulse train duration between 0.2 to 0.4 seconds.
  • the radiofrequency may be generated with a device having a coil radii between 2 and 6 mm and between 1 3 and 57 amp turns.
  • the pulsed energy source comprises a microwave frequency
  • the frequency is typically between 1 0 to 20 gigahertz (GHz), a pulse train duration between 0.2 and 0.6 seconds, and a duty cycle between 2% and 5%.
  • the microwave may have an average power between 8 and 52 watts.
  • the pulsed energy source is a pulsed light beam
  • the light beam may have a wavelength of between 530 nm to 1 300 nm, a duty cycle of less than 1 0% and a pulse train duration between 0.1 and 0.6 seconds.
  • the pulsed light beam preferably has a wavelength of between 800 nm and 1 000 nm, and a power between 0.5 and 74 watts.
  • the pulsed energy source comprises pulsed ultrasound
  • it typically has a frequency between 1 MHz and 5 MHz, a train duration between 0.1 and 0.5 seconds and a duty cycle between 2% to 1 0%.
  • the ultrasound may have a power between 0.46 and 28.6 watts.
  • the pulsed energy source is applied to the target tissue or target fluid having the chronic progressive disease or risk of having a chronic progressive disease to therapeutically or prophylactically treat the target tissue or target fluid.
  • the pulsed energy source energy parameters may be selected so that 20 to 40 joules of energy is absorbed by each cubic centimeter of the target tissue or target fluid.
  • the pulsed energy may be applied by inserting a device into a cavity of a body to apply the pulsed energy source to the target tissue or target fluid.
  • the pulsed energy source is directed to an exterior of a body which is adjacent to the target tissue or has a target bodily fluid supply close to the surface of the exterior of the body.
  • the pulsed energy source may be applied to a plurality of target tissue areas. Adjacent target tissue areas are separated by at least a predetermined distance to avoid thermal tissue damage.
  • beneficial effects may be caused by inducing a heat shock response in order to increase the number or activity of heat shock proteins in body tissue or fluid in response to infection or other abnormalities.
  • the present invention performs this in a controlled manner in order not to damage or destroy the tissue, fluid or the area of the body being treated.
  • FIGURE 1 is a diagrammatic view illustrating a system used to generate a pulsed energy source in the form of a laser light beam, in
  • FIGURE 2 is a diagrammatic view of optics used to generate a laser light geometric pattern, in accordance with the present invention
  • FIGURE 3 is a diagrammatic view illustrating an alternate
  • FIGURE 4 is a diagrammatic view illustrating yet another
  • FIGURE 5 is a top plan view of an optical scanning mechanism, used in accordance with the present invention.
  • FIGURE 6 is a partially exploded view of the optical scanning mechanism of FIG. 5 , illustrating various component parts thereof;
  • FIGURE 7 illustrates controlled offset of exposure of an exemplary geometric pattern grid of laser spots to treat a target tissue, in accordance with the present invention;
  • FIGURE 8 is a diagrammatic view illustrating a geometric object in the form of a line controllably scanned to treat a target tissue, in accordance with the present invention
  • FIGURE 9 is a diagrammatic view similar to FIG. 8, but illustrating the geometric line or bar rotated to treat an area, in accordance with the present invention
  • FIGURES 1 0 and 1 1 are graphs illustrating the average power of a laser source compared to a source radius and pulse train duration of the laser;
  • FIGURES 1 2 and 1 3 are graphs illustrating the time for the temperature for decay depending upon the laser source radius and wavelength;
  • FIGURE 1 4- 1 7 are graphs illustrating peak ampere turns for various radiofrequencies, duty cycles and coil radii;
  • FIGURE 1 8 is a graph depicting the time for temperature rise to decay compared to radiofrequency coil radius
  • FIGURE 21 is a graph depicting the time for the temperature to decay for various microwave frequencies
  • FIGURE 22 is a graph depicting the average ultrasound source power compared to frequency and pulse train duration ;
  • FIGURES 23 and 24 are graphs depicting the time for temperature decay for various ultrasound frequencies;
  • FIGURE 25 is a graph depicting the volume of focal heated region compared to ultrasound frequency
  • FIGURE 26 is a graph comparing equations for temperature over pulse durations for an ultrasound energy source
  • FIGURES 27 and 28 are graphs illustrating the magnitude of the logarithm of damage and HSP activation Arrhenius integrals as a function of temperature and pulse duration;
  • FIGURE 29 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 30 is a cross-sectional view of a photostimulation delivery device delivering electromagnetic energy to target tissue, in accordance with the present invention
  • FIGURE 31 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 32 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 33 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 34 is a diagrammatic view of an endoscope inserted into a stomach and providing treatment thereto, in accordance with the present invention
  • FIGURE 35 is a partially sectioned perspective view of a capsule endoscope, used in accordance with the present invention ;
  • FIGURE 36 is a diagrammatic view of a pulsed high intensity focused ultrasound for treating tissue internal the body, in accordance with the present invention.
  • FIGURE 37 is a diagrammatic view for delivering therapy to the bloodstream of a patient, through an earlobe, in accordance with the present invention
  • FIGURE 38 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.
  • FIGURE 39 is a diagrammatic and perspective view of a device for treating multiple areas or an entire body of an individual, in accordance with the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • a pulsed energy source having energy parameters including wavelength or frequency, duty cycle and pulse train duration selected so as to raise a target tissue or bodily target fluid temperature up to eleven degrees Celsius for a short period of time of seconds or less, while maintaining an average
  • the pulsed energy source is applied to the target tissue or target fluid which is either determined to have a chronic progressive disease or at a risk of having a chronic progressive disease. This determination may be made before imaging, serologic, immunologic, or other abnormalities are detectable and may be done prophylactically. The determination may be accomplished by ascertaining if the patient is at risk for the chronic progressive disease.
  • results of an examination or test of the patient may be abnormal.
  • a specific test such as a genetic test, may be conducted to establish that the patient has a risk for the chronic progressive disease.
  • HSPs Heat shock proteins
  • HSPs are ubiquitous in highly conserved families of enzymes present in all cells of all creatures. This may account for as much as 40% of all proteins present in a given cell. HSPs are active and essential in maintenance of normal cell function and homeostasis. HSPs have many critical functions, one of which is to protect the cell from lethal injury of any kind and repair sublethal injuries.
  • Chronic inflammation While chronic inflammation is pathologic and destructive, acute inflammation can be reparative. Acute inflammation may occur in response to an acute injury. Common injuries requiring repair are typically associated with cellular and tissue damage, such as a wound. Depending upon the severity of injury and the functional sensitivity of the tissue, loss of key functions may result despite wound repair. Incomplete repair or continued or repeated injury may lead to chronic inflammation, as in CPDs.
  • HSPs are the first step in the acute inflammatory process.
  • HSPs Activation of HSPs by a threat initiates a cascade of subsequent events leading to improved cell function, reduced chronic inflammation, and reparative immunomodulation.
  • the effective HSP activations preserve the life of the cell and normalize cell function, also referred to as homeotrophy. Sudden and severe stimuli are the most potent stimulators of homeotrophic HSP activation. Slowly progressive and chronic stimuli are not effective activators HSP response. Thus, CPDs do not stimulate a repairative response of the HSP activation. In some CPDs, like diabetes and Alzheimer disease, HSP function itself can become abnormal.
  • HSPs normalize cell function independent of the cause of abnormality by identifying and repairing abnormal cell proteins without regard to what made them abnormal, thus normalizing cell function. HSPs have an ability to restore every protein to its correct state or eliminate the irreparable, leading to replacement. As the HSP response is physiologic and thus perfect and without adverse effects, fixing what is broken without regard to the cause of the breakage, the repair response of HSPs is exactly tailored to the disease process. Homeotrophic HSP activation is thus a non-specific trigger of disease-specific repair.
  • PEMR pulsed electromagnetic radiation
  • the inventors surmised that the therapeutic alterations in the retinal pigment epithelium (RPE) cytokine production elicited by conventional photocoagulation comes from cells at the margins of traditional laser burns which were affected but not killed by the laser exposure.
  • the inventors created energy parameters which created "true subthreshold photocoagulation", which is invisible and includes laser treatment non-discernable by any known means such as FFA, FAF, retrograde FAF, or even SD-OCT and produces absolutely no retinal damage detectible by any means at the time of treatment or any time thereafter by any known means of detection, but still yields the benefits of conventional retinal photocoagulation. This is discussed in U.S. Publication No. 201 6/03461 26 Al , the contents of which are hereby incorporated by reference.
  • subthreshold effective photocoagulation including providing sufficient power to produce effective treatment but not too high to create tissue damage or destruction. It has been found that the intensity or power of a low duty cycle 81 0 nm laser beam between 1 00 watts to 590 watts per square centimeter is effective yet safe. A particularly preferred intensity or power of the laser light beam is approximately 250-350 watts per square centimeter for an 81 0 nm micropulsed diode laser.
  • invisible phototherapy or true subthreshold photocoagulation in accordance with the present invention can be performed at various laser light wavelengths, such as from a range of 532 nm to 1 300 nm.
  • Use of a different wavelength can impact the preferred intensity or power of the laser light beam and the exposure envelope duration in order that the retinal tissue is not damaged, yet therapeutic effect is achieved.
  • the laser light pulse is less than a millisecond in duration, and typically between 50 microseconds to 1 00 microseconds in duration.
  • Duty cycle Another parameter of the present invention when utilizing laser light is the duty cycle, or the frequency of the train of micropulses or the length of the thermal relaxation time in between consecutive pulses. It has been found that the use of a 1 0% duty cycle or higher can increase the risk of lethal cell injury. Thus, duty cycles less than 1 0%, and preferably approximately 5% duty cycle or less are used as this parameter has been demonstrated to provide adequate thermal rise in treatment that remains below the level expected to produce lethal cell injury. The less the duty cycle, the longer the exposure envelope duration can be. For example, if the duty cycle is less than 5%, the exposure envelope duration in some instances can exceed 500 milliseconds.
  • low duty cycle such as less than 1 0% and preferably 5% or less
  • FIG. 1 a schematic diagram is shown of a system for realizing the process of the present invention.
  • the system generally referred to by the reference number 1 0, includes a laser console 1 2, 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 1 4 as needed.
  • the laser projector optics 1 4 pass the shaped light beam to a coaxial wide-field non-contact digital optical viewing system/camera 1 6 for projecting the laser beam light onto the eye 1 8 of the patient, or other biological target tissue or bodily fluid as more fully discussed herein.
  • the box labeled 1 6 can represent both the laser beam projector as well as a viewing system/camera, which might in reality comprise two different components in use.
  • the viewing system/camera 1 6 provides feedback to a display monitor 20, which may also include the necessary computerized hardware, data input and controls, etc. for manipulating the laser 1 2, the optics 1 4, and/or the projection/viewing components 1 6.
  • the laser light beam 22 is passed through a collimator lens 24 and then through a mask 26.
  • the mask 26 comprises a diffraction grating.
  • the mask/diffraction grating 26 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 28.
  • the multiple laser spots may be generated by a plurality of fiber optic wires. Either method of generating laser spots allows for the creation of a very large number of laser spots
  • a very wide treatment field such as consisting of the entire retina.
  • a very high number of laser spots perhaps numbering in the hundreds even thousands or more could cover the entire ocular fundus and entire retina, including the macula and fovea, retinal blood vessels and optic nerve.
  • the intent of the process in the present invention is to better ensure complete and total coverage and treatment of the target area, which may comprise a retina, and sparing none of the retina by the laser so as to improve vision.
  • 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 26 diffracts, producing a periodic pattern a distance away from the mask 26, shown by the laser beams labeled 28 in FIG. 2.
  • the single laser beam 22 has thus been formed into multiple, up to hundreds or even thousands, of individual laser beams 28 so as to create the desired pattern of spots or other geometric objects.
  • These laser beams 28 may be passed through additional lenses, collimators, etc. 30 and 32 in order to convey the laser beams and form the desired pattern on the patient's retina.
  • additional lenses, collimators, etc. 30 and 32 can further transform and redirect the laser beams 28 as needed.
  • Arbitrary patterns can be constructed by controlling the shape, spacing and pattern of the optical mask 26.
  • 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. 3 illustrates diagrammatically a system which couples multiple light sources into the pattern-generating optical subassembly described above.
  • this system 1 0' is similar to the system 1 0 described in FIG. 1 above.
  • the primary differences between the alternate system 1 0' and the earlier described system 1 0 is the inclusion of a plurality of laser consoles 1 2, the outputs of which are each fed into a fiber coupler 34.
  • the fiber coupler produces a single output that is passed into the laser projector optics 1 4 as described in the earlier system.
  • the coupling of the plurality of laser consoles 1 2 into a single optical fiber is achieved with a fiber coupler 34 as is known in the art.
  • 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 area to be treated, 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 or different wavelength with the proper steering pattern to achieve complete coverage of the tissue for that particular
  • 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. 4 illustrates diagrammatically yet another alternate
  • This system 1 0" is configured generally the same as the system 1 0 depicted in FIG. 1 .
  • 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 1 2 are arranged in parallel with each one leading directly into its own laser projector optics 1 4.
  • the laser projector optics of each channel 38a, 38b, 38c comprise a collimator 24, mask or diffraction grating 28 and recollimators 30, 32 as described in connection with FIG. 2 above— the entire set of optics tuned for the specific wavelength generated by the corresponding laser console 1 2.
  • the output from each set of optics 1 4 is then directed to a beam splitter 36 for combination with the other wavelengths.
  • the system 1 0" may use as many channels 38a, 38b, 38c, etc. and beam splitters 36a, 36b, 36c, etc. as there are wavelengths of light being used in the treatment.
  • each channel begins with a light source 1 2, which could be from an optical fiber as in other embodiments of the pattern- generating subassembly.
  • This light source 1 2 is directed to the optical assembly 1 4 for collimation, diffraction, recollimation and directed into the beam splitter which combines the channel with the main output.
  • the system of the present invention incorporates a guidance system to ensure complete and total treatment with photostimulation.
  • Fixation/tracking/ registration systems consisting of a fixation target, tracking mechanism, and linked to system operation can be incorporated into the present invention.
  • the geometric pattern of simultaneous laser spots is sequentially offset so as to achieve confluent and complete treatment of the target tissue. This is done in a time-saving manner by placing a plurality of spots over the target tissue at once. This pattern of simultaneous spots is scanned, shifted, or redirected as an entire array sequentially, so as to cover the entire target tissue in a single treatment session.
  • FIGS. 5 and 6 illustrate an optical scanning mechanism 40 which may be used in the form of a MEMS mirror, having a base 42 with electronically actuated controllers 44 and 46 which serve to tilt and pan the mirror 48 as electricity is applied and removed thereto. Applying electricity to the controller 44 and 46 causes the mirror 48 to move, and thus the
  • the optical scanning mechanism 40 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 geometric pattern of laser spots can be overlapped without destroying the tissue or creating any permanent damage.
  • the pattern of spots are offset at each exposure so as to create space between the immediately previous exposure to allow heat dissipation and prevent the possibility of heat damage or tissue destruction.
  • the pattern illustrated for exemplary purposes as a grid of sixteen spots, is offset each exposure such that the laser spots occupy a different space than previous exposures.
  • Field sizes of 3 mm would, for example, allow treatment of the entire human macula in a single exposure, useful for treatment of common blinding conditions such as diabetic macular edema and age- related macular degeneration. Performing the entire 98 sequential offsettings would ensure entire coverage of the macula.
  • 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.
  • FIGS. 8 and 9 instead of a geometric pattern of small laser spots, the present invention contemplates use of other geometric objects or patterns.
  • a single line 50 of laser light formed 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. 8.
  • FIG. 9 the same geometric object of a line 50 can be rotated, as illustrated by the arrows, so as to create a circular field of phototherapy.
  • the potential negative of this approach is that the central area will be repeatedly exposed, and could reach unacceptable temperatures. This could be overcome, however, by increasing the time between exposures, or creating a gap in the line such that the central area is not exposed.
  • the micropulsed laser light beam of an 81 0 nm diode laser should have an exposure envelope duration of 500 milliseconds or less, and preferably approximately 300 milliseconds. Of course, if micropulsed diode lasers become more powerful, the exposure duration should be lessened accordingly.
  • duty cycle or the frequency of the train of micropulses, or the length of the thermal relaxation time between consecutive pulses. It has been found that the use of a 1 0% duty cycle or higher adjusted to deliver micropulsed laser at similar irradiance at similar MPE levels significantly increase the risk of lethal cell injury. However, duty cycles of less than 1 0%, and preferably 5% or less demonstrate adequate thermal rise and treatment at the level of the MPE cell to stimulate a biological response, but remain below the level expected to produce lethal cell injury. The lower the duty cycle, however, the exposure envelope duration increases, and in some instances can exceed 500 milliseconds.
  • Each micropulse lasts a fraction of a millisecond, typically between 50 microseconds to 1 00 microseconds in duration. Thus, for the exposure envelope duration of 300-500 milliseconds, and at a duty cycle of less than 5%, there is a significant amount of 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. For adequate treatment, the cells are typically exposed or hit by the laser light between 50-200 times, and preferably between 75- 1 50 at each location.
  • the total time in accordance with the embodiments described above to treat a given area, or more particularly the locations of the target tissue which are being exposed to the laser spots is between 200 milliseconds and 500 milliseconds on average.
  • the thermal relaxation time is required so as not to overheat the cells within that location or spot and so as to prevent the cells from being damaged or destroyed.
  • RPE retinal pigment epithelium
  • the invention 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 and heat shock protein (HSP) activation in the targeted tissue, particularly the retinal pigment epithelium (RPE) layer.
  • HSP heat shock protein
  • Panretinal and panmacular SDM has been noted by the inventors to reduce the rate of progression of many retinal diseases, including severe non-proliferative and proliferative diabetic retinopathy, AMD, DME, etc.
  • the reset theory also suggests that the invention may have application to many different types of RPE-mediated retinal disorders.
  • panmacular treatment can significantly improve retinal function and health, retinal sensitivity, and dynamic logMAR visual acuity and contrast visual acuity in dry age-related macular degeneration, retinitis pigmentosa, cone-rod retinal degenerations, and Stargardt's disease where no other treatment has previously been found to do so.
  • a patient such as an eye of the patient, has a risk for a disease. This may be before imaging abnormalities are detectable. Such a determination may be accomplished by ascertaining if the patient is at risk for a chronic progressive disease, such as retinopathy, including diabetes, a risk for age-related macular degeneration or retinitis pigmentosa. Alternatively, or additionally, results of an examination or test of the patient may be abnormal. A specific test, such as a physiology test or a genetic test, may be conducted to establish that the patient has a risk for a disease.
  • a chronic progressive disease such as retinopathy, including diabetes, a risk for age-related macular degeneration or retinitis pigmentosa.
  • results of an examination or test of the patient may be abnormal.
  • a specific test such as a physiology test or a genetic test, may be conducted to establish that the patient has a risk for a disease.
  • a laser light beam that is sublethal and creates true subthreshold photocoagulation and retinal tissue, is generated and at least a portion of the retinal tissue is exposed to the generated laser light beam without damaging the exposed retinal or foveal tissue, so as to provide preventative and
  • the treated retina may comprise the fovea, foveola, retinal pigment epithelium (RPE), choroid, choroidal neovascular membrane, subretinal fluid, macula, macular edema, parafovea, and/or perifovea.
  • the laser light beam may be exposed to only a portion of the retina, or substantially the entire retina and fovea.
  • tissue is periodically retreated. This may be done according to a set schedule or when it is determined that the tissue of the patient is to be retreated, such as by periodically monitoring visual and/or retinal function or condition of the patient.
  • the present invention is particularly suited for treatment of retinal diseases, such as diabetic retinopathy and macular edema, it has been found that it can be used for other diseases as well.
  • the system and process of the present invention could target the trabecular mesh work as treatment for glaucoma, accomplished by another customized treatment field template.
  • SDM intraocular pressure
  • the mechanism of the retinal laser treatment is sometimes referred to herein as "reset to default" theory, which postulates that the primary mode of retinal laser action is sublethal activation of the retinal pigment epithelial (RPE) heat shock proteins.
  • RPE retinal pigment epithelial
  • the laser light beam to the retinal and/or foveal tissue of an eye having glaucoma or a risk of glaucoma creates a therapeutic effect to the retinal and/or foveal tissue exposed to the laser light beam without destroying or permanently damaging the retinal and/or foveal tissue and also improves function or condition of an optic nerve and/or retinal ganglion cells of the eye.
  • Retinal ganglion cells and the optic nerve are subject to the health and function of the retinal pigment epithelium (RPE). Retinal homeostasis is principally maintained by the RPE via still the poorly understood but extraordinarly complex interplay of small proteins excreted by the RPE into the intercellular space called "cytokines". Some RPE-derived cytokines, like pigment epithelial derived factor (PEDF) are neuroprotective. Retinal laser treatment may alter RPE cytokine expression, including, but not limited to, increasing expression of PEDF. Absent retinal damage, the effect of SDM, in accordance with the present invention, is "homeotrophic", moving retinal function toward normal. By normalizing RPE function, it follows that retinal autoregulation and cytokine expression is also normalized. This suggests the normalization of retinal cytokine expression may be the source of the neuroprotective effects from SDM in OAG.
  • RPE retinal pigment epithelium
  • retinal CPDs are also like CPDs elsewhere.
  • CPDs including type II diabetes, Alzheimer disease, idiopathic pulmonary fibrosis (IPF) and ischemic heart disease and various cardiomyopathies
  • IPF idiopathic pulmonary fibrosis
  • ischemic heart disease ischemic heart disease
  • various cardiomyopathies abnormalities of the HSP system has been recognized and stimulation found to be beneficial.
  • SDM in connection with eye diseases suggests that appropriately designed PEMR should effectively and safely treat any CPDs affecting any other part of the body.
  • endoscopes or surface probes as well as focused electromagnetic/sound waves For example, 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.
  • a pulsed energy source such as laser, ultrasound, ultraviolet, radiofrequency, microwave radiofrequency and the like, having energy
  • the parameters of the pulsed energy source and its application to the target tissue or target bodily fluid is important in creating the thermal time-course so as to have a therapeutic effect without causing damage.
  • 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 for a short period of time, such as seconds or fractions of a second, 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.
  • 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.
  • FIGURES 1 0 and 1 1 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 0 shows a wavelength of 880 nm
  • FIG. 1 1 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
  • 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 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.
  • 1 2 and 1 3 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. 1 2 and 1 000 nm in FIG. 1 3. It can be seen that the time to decay is less when using a wavelength of 880 nm, but either wavelength falls within the acceptable requirements and operating parameters to achieve the benefits of the present invention while not causing permanent tissue damage.
  • the control of the target tissue temperature is determined by choosing source and target parameters such that the Arrhenius integral for HSP activation is larger than 1 , while at the same time assuring compliance with the conservative FDA/ FCC requirements for avoiding damage or a damage Arrhenius integral being less than 1 .
  • FIGS. 1 2 and 1 3 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. 1 2 when the wavelength is 880 nm and the source diameter is 1 millimeter, the temperature decay time is 1 6 seconds. The temperature decay time is 1 07 seconds when the source diameter is 4 mm. As shown in FIG.
  • the temperature decay time is 1 8 seconds when the source diameter is 1 mm and 1 36 seconds when the source diameter is 4 mm. This is well within the time of the average temperature rise being maintained over the course of several minutes, such as 6 minutes or less.
  • the target tissue's temperature is raised, such as to approximately 1 0°C, very quickly, such as in a fraction of a second during the application of the energy source to the tissue, the relatively low duty cycle provides relatively long periods of time between the pulses of energy applied to the tissue and the relatively short pulse train duration ensure sufficient temperature diffusion and decay within a relatively short period of time comprising several minutes, such as 6 minutes or less, that there is no permanent tissue damage.
  • the parameters differ for the individual energy sources, including microwave, infrared lasers, radiofrequency and ultrasound, because the absorption properties of tissues differ for these different types of energy sources.
  • the tissue water content can vary from one tissue type to another, however, there is an observed uniformity of the properties of tissues at normal or near normal conditions which has allowed publication of tissue parameters that are widely used by clinicians in designing treatments.
  • Table 1 relating to muscle, skin and tissues with high water content
  • Table 2 relating to fat, bone and tissues with low water content.
  • Wavelength Dielectric Conductivity Wavelength p P ⁇ J ⁇ t f n ,- Air-Fat Interface Fat-Muscle Interface
  • the electric and magnetic fields can be expressed in terms of the vector magnetic potential, which in turn can be expressed in closed form in terms of elliptic integrals of the first and second kind.
  • the heating occurs only in a region that is
  • 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.
  • FIGS. 1 4- 1 7 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. 1 6 and 1 7. This yields, as illustrated in FIG.
  • the peak ampere turns is 36 when the pulse train duration is 0.4 seconds and the coil radius is 0.6 cm, and 57 amp turns when the pulse train duration is 0.2 seconds and the coil radius is 0.2 cm.
  • 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.
  • FIG. 1 a graph depicts the average microwave power in watts of a microwave having a frequency of 1 0 GHz and a pulse train duration from between 0.2 seconds and 0.6 seconds.
  • FIG. 20 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. 22 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 23 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. 24 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 25 illustrates the volume of focal heated region, in cubic centimeters, as compared to ultrasound frequencies from between 1 and 5 MHz. Considering ultrasound frequencies in the range of 1 to 5 MHz, the corresponding focal sizes for these frequencies range from 3.7 mm to 0.6 mm, and the length of the focal region ranges from 5.6 cm to 1 .2 cm. The
  • corresponding treatment volumes range from between approximately 2.4 cc and 0.02 cc.
  • Examples of parameters giving a desired HSP activation Arrhenius integral greater than 1 and damage Arrhenius integral less than 1 is a total ultrasound power between 5.8- 1 7 watts, a pulse duration of 0.5 seconds, an interval between pulses of 5 seconds, with total number of pulses 1 0 within the total pulse stream time of 50 seconds.
  • the target treatment volume would be approximately 1 mm on a side. Larger treatment volumes could be treatable by an ultrasound system similar to a laser diffracted optical system, by applying ultrasound in multiple simultaneously applied adjacent but separated and spaced columns. The multiple focused ultrasound beams converge on a very small treatment target within the body, the convergence allowing for a minimal heating except at the overlapping beams at the target.
  • This area would be heated and stimulate the activation of HSPs and facilitate protein repair by transient high temperature spikes.
  • the treatment is in compliance with FDA/FCC requirements for long term (minutes) average temperature rise ⁇ 1 K.
  • An important distinction of the invention from existing therapeutic heating treatments for pain and muscle strain is that there are no high T spikes in existing techniques, and these are required for efficiently activating HSPs and facilitating protein repair to provide healing at the cellular level.
  • electromagnetic radiation is not as good of a choice for treatment of regions deep with the body as ultrasound.
  • the long skin depths (penetration distances) and Ohmic heating all along the skin depth results in a large heated volume whose thermal inertia does not allow both the attainment of a high spike temperature that activates HSPs and facilitates protein repair, and the rapid temperature decay that satisfies the long term FDA and FCC limit on average temperature rise.
  • Bone 1 .1 5 [Para 1 50] Assuming that the geometric variation of the incoming radiation due to the focusing dominates any variation due to attenuation, the intensity of the incoming ultrasound at a distance r from the focus can be written
  • dT(tp) Patp / (4nC v r 2 ) [2] where ex is the absorption coefficient and C v is the specific volume heat capacity. This will be the case until the r is reached at which the heat diffusion length at t becomes comparable to r, or the diffraction limit of the focused beam is reached. For smaller r, the temperature rise is essentially independent of r. As an example, suppose the diffraction limit is reached at a radial distance that is smaller than that determined by heat diffusion. Then
  • dT(t) [dTo/ ⁇ (l / 2)+(TTI /2/6) ⁇ ][(1 / 2)(t p /t)3/2 + (ni /2/6)(tp/t)] [7] with
  • FIG. 26 is a comparison of eqs. [7] and [9] for dT(t)/ dTo at the target treatment zone.
  • the bottom curve is the approximate expression of eq [9] .
  • 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.
  • the graphs in FIGS. 27 and 28 show that Qdamage does not exceed 1 until d ⁇ T 0 exceeds 1 1 .3 K, whereas Qhs P is greater than 1 over the whole interval shown, the desired condition for cellular repair without damage.
  • 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 52 to a distal end of the scope 54, illustrated in FIG. 30, which is inserted into the body and the laser light or other radiation 56 delivered to the target tissue 58 to be treated.
  • the light generator unit 1 0 of FIG. 29 could comprise the light generator units discussed above with respect to FIGS. 1 -6.
  • the delivery device or component could comprise an endoscope, bronchoscope, with the generated laser light beam passed through a light tube or pipe 52.
  • the system could include both a laser beam projector or delivery device, such as a scope, as well as a viewing system/camera will comprise two different components in use.
  • the viewing system/camera could provide feedback to a display monitor which may also include the necessary computerized hardware, data input and controls, for manipulating the optics, delivered laser light or other pulsed energy source and/or the projection/viewing components.
  • patterns can be generated which may be offset, as described above.
  • the laser light generating systems of FIGS. 1 -6 are exemplary, and other devices and systems can be utilized to generate a source of laser light or other pulsed electromagnetic radiation which can be operably passed through a projector device, such as the endoscope or light pipe or the like illustrated in FIGS. 29 and 30.
  • a projector device such as the endoscope or light pipe or the like illustrated in FIGS. 29 and 30.
  • Other forms of electromagnetic radiation may also be generated and used, including ultraviolet waves, microwaves, other radiofrequency waves, and laser light at predetermined wavelengths.
  • ultrasound waves may also be generated and used to create a thermal time-course temperature spike in the target tissue sufficient to activate or produce heat shock proteins in the cells of the target tissue without damaging the target tissue itself.
  • a pulsed source of ultrasound or electromagnetic radiation energy is provided and applied to the target tissue in a manner which raises the target tissue temperature, such as between 6°C and 1 1 °C, transiently while only 6°C or 1 °C or less for the long term, such as over several minutes.
  • a light pipe is not an effective means of delivering the pulsed energy.
  • pulsed low frequency electromagnetic energy or preferably pulsed ultrasound can be used to cause a series of temperature spikes in the target tissue.
  • a source of pulsed ultrasound or electromagnetic radiation is applied to the target tissue or fluid 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.
  • epithelium is a thin and clear tissue.
  • a cross-sectional view of a human head 60 is shown with an endoscope 54 inserted into the nasal cavity 62 and energy 56, such as laser light or the like, being directed to tissue 58 to be treated within the nasal cavity 62.
  • the tissue 58 to be treated could be within the nasal cavity 62, 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 56 to the target tissue 58 for a few seconds, such as via optical fibers in an endoscope 54, as illustrated in FIG. 31 .
  • the endoscope 54 could be inserted after application of a topical anesthetic. If necessary, the procedure could be repeated periodically, such as in a day or so.
  • the treatment would stimulate the activation or production of heat shock proteins and facilitate protein repair without damaging the cells and tissues being treated.
  • certain heat shock proteins have been found to play an important role in the immune response as well as the well-being of the targeted cells and tissue.
  • the source of energy could be monochromatic laser light, such as 81 0 nm wavelength laser light,
  • the adjuvant dye would be selected so as to increase the laser light absorption. While this comprises a particularly preferred method and embodiment of performing the invention, it will be appreciated that other types of energy and delivery means could be used to achieve the same objectives in accordance with the present invention.
  • the flexible light tube 52 of a bronchoscope 54 is inserted through the individual's mouth 64 through the throat and trachea 66 and into a bronchus 68 of the respiratory tree.
  • the laser light or other energy source 56 is administered and delivered to the tissue in this area of the uppermost segments to treat the tissue and area in the same manner described above with respect to FIG. 32.
  • a wavelength of laser or other energy would be selected so as to match an IR absorption peak of the water resident in the mucous to heat the tissue and stimulate HSP activation or production and facilitate protein repair, with its attendant benefits.
  • a colonoscope 54 could have flexible optical tube 52 thereof inserted into the anus and rectum 70 and into either the large intestine 72 or small intestine 74 so as to deliver the selected laser light or other energy source 56 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 52 of the colonoscope 54 into the rectum and move it into the area of the colon, large intestine 72 or small intestine 74 to the area to be treated.
  • the physician could view through a monitor the pathway of the inserted flexible member 52 and even view the tissue at the tip of the
  • the colonoscope 54 within the intestine so as to view the area to be treated.
  • the tip 76 of the scope would be directed to the tissue to be treated and the source of laser light or other radiation 56 would be delivered through one of the light tubes of the
  • colonoscope 54 to treat the area of tissue to be treated, as described above, in order to stimulate HSP activation or production in that tissue 58.
  • Gl gastrointestinal
  • SDM diode micropulsed laser
  • the flexible light tube 52 of an endoscope or the like is inserted through the patient's mouth 64 through the throat and trachea area 66 and into the stomach 78, where the tip or end 64 thereof is directed towards the tissue 58 to be treated, and the laser light or other energy source 56 is directed to the tissue 58.
  • a colonoscope could also be used and inserted through the rectum 70 and into the stomach 78 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
  • a capsule endoscope 80 such as that illustrated in FIG. 35, could be used to administer the radiation and energy source in accordance with the present invention.
  • Such capsules are relatively small in size, such as approximately one inch in length, so as to be swallowed by the patient.
  • the capsule or pill 80 could receive power and signals, such as via antenna 82, so as to activate the source of energy 84, such as a laser diode and related circuitry, with an appropriate lens 86 focusing the generated laser light or radiation through a radiation-transparent cover 88 and onto the tissue to be treated.
  • the location of the capsule endoscope 80 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 80 was passing through at the time.
  • the capsule or pill 80 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 84 or other energy generating source create the desired wavelength and pulsed energy source to treat the tissue and area to be treated.
  • the radiation would be pulsed to take advantage of the micropulse temperature spikes and associated safety, and the power could be adjusted so that the treatment would be completely harmless to the tissue. This could involve adjusting the peak power, pulse times, and repetition rate to give spike temperature rises on the order of 1 0°C, while maintaining the long term rise in temperature to be less than the FDA mandated limit of 1 °C. If the pill form 80 of delivery is used, the device could be powered by a small rechargeable battery or over wireless inductive excitation or the like. The heated/stressed tissue would stimulate activation or production of HSP and facilitate protein repair, and the attendant benefits thereof.
  • the technique of the present invention is limited to the treatment of conditions at near body surfaces or at internal surfaces easily accessible by means of fiber optics or other optical delivery means.
  • the reason that the application of SDM or PEMR 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.
  • RF radio frequency
  • EM electromagnetic
  • ultrasound sources can also be used for abnormalities at or near surfaces as well.
  • an ultrasound transducer 90 or the like generates a plurality of ultrasound beams 92 which are coupled to the skin via an acoustic-impedance-matching gel, and penetrate through the skin 94 and through undamaged tissue in front of the focus of the beams 92 to a target organ 96, such as the illustrated liver, and specifically to a target tissue 98 to be treated where the ultrasound beams 92 are focused.
  • a target organ 96 such as the illustrated liver
  • the pulsating heating will then only be at the targeted, focused region 98 where the focused beams 92 overlap.
  • the tissue in front of and behind the focused region 98 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 RF, or microwave beams or the like, but also treatment of blood diseases, and other bodily fluid 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 PEMR treatment options which are typically limited to surface or near surface treatment of epithelial cells and the like be used in treating blood or fluid diseases at areas where the blood or fluid is accessible through a relatively thin layer of tissue, such as the earlobe.
  • an earlobe 1 00 is shown adjacent to a clamp device 1 02 configured to transmit SDM radiation or the like. This could be, for example, by means of one or more laser diodes 1 04 which would transmit the desired frequency at the desired pulse and pulse train to the earlobe 1 00. Power could be provided, for example, by means of a lamp drive 1 06. Alternatively, the lamp drive 1 06 could be the actual source of laser light, which would be transmitted through the appropriate optics and
  • the clamp device 1 02 would merely be used to clamp onto the patient's earlobe and cause that the radiation be constrained to the patient's earlobe 1 00. This may be by means of mirrors, reflectors, diffusers, etc. This could be controlled by a control computer 1 08, which would be operated by a keyboard 1 1 0 or the like.
  • the system may also include a display and speakers 1 1 2 , if needed, for example if the procedure were to be performed by an operator at a distance from the patient.
  • FIGS. 37 and 38 illustrate, for exemplary purposes, the treatment of a bodily fluid, namely blood, through a readily accessible external earlobe 1 00
  • the pulsed energy source of the present invention can be applied to other external areas of the body, internal areas of the body, and utilize a wide variety of energy sources, including laser light, radiofrequency, microwave, and ultrasound.
  • the present invention is not only limited to the treatment of blood and blood diseases, but can also be applied to other bodily fluids, such as lymph fluid, etc.
  • bodily fluids such as lymph fluid, etc.
  • the type of bodily fluid treated may dictate the area where the treatment occurs, such as applying the energy source in an armpit, tonsil, etc. when treating lymph fluid.
  • IPF may be treated by PEMR infrared laser locally via bronchoscopic application.
  • Heart disease due to the heart being located near the bronchial tree and lungs, could also be treated via bronchoscopy.
  • PEMR radiofrequency, ultrasound or microwave may be used to treat the heart, lungs, etc.
  • An additional advantage would be not requiring the discomfort of a bronchoscope being inserted into the lungs of the patient.
  • the selected treatment type and operating procedure and parameters could change depending upon the location of the chronic progressive disease.
  • Alzheimer disease may be treated by RF application to the brain.
  • a person having cancer, or a risk for cancer could have the energy source in accordance with the present invention applied to the organ(s) or area of the body in question, whether it be a tissue or blood (generally not the cancer itself, as activation of HSPs in cancer cells may enhance the survival and growth of the cancer; but to treat components of the immune system to enhance their effectiveness against the cancer).
  • Even mental conditions, such as depression, could potentially be treated in accordance with the present invention.
  • the present invention also contemplates that the time course, and possibly powers, and other energy and operating parameters may need to be changed depending upon the tissue, organ, or area of the body to be treated. For example, for idiopathic pulmonary fibrosis and other lung diseases, such parameters may need to be changed due to the convective air flow which can cool the lung tissue. Having the individual exhale and hold his or her breath for a couple of seconds can also alter these energy parameters as an inflated lung has a conductivity of 0.2 S/ m while a deflated lung has a conductivity twice as large, 0.41 S/ m, and the absorption length is inversely proportional to the square root of the conductivity.
  • tissue or bodily fluid is heated very quickly up to approximately 1 1 °C while maintaining a much lower temperature, such as below 6°C or even 1 °C over several minutes, such as 6 minutes. This will provide the therapeutic benefit, such as activating HSPs, while not damaging the bodily fluid, cells and tissue.
  • diabetes may be treated by microwave, RF application or the like to many areas of the body, and potentially the entire body.
  • the individual may either have multiple chronic
  • progressive diseases or may be at a risk of having multiple chronic progressive diseases which could require treatment of various areas of the body.
  • a device 1 1 4 is contemplated by the present invention which can hold and/or support an entire body 1 1 6, such as by means of a platform 1 1 8 upon which the individual lies. It will be understood, however, that the individual could be in different positions, such as standing, and not necessarily need to lie down.
  • the device 1 1 4 would include a pulsed energy emitter 1 20 which could emit a pulsed energy source having the parameters discussed above so as to treat various types of tissue, organs, bodily fluids, etc. of the individual. This could be, for example, by means of microwave, radiofrequency (RF) and/or ultrasound, or even light sources used to treat external portions of the individual's body or bodily fluids passing adjacent to such surfaces.
  • RF radiofrequency
  • the fluid, organs in question or other tissue could be treated accordingly.
  • the entire body could be treated as the emitter 1 20 is moved, such as along track 1 22, to different areas of the body, either progressively or in a predetermined pattern, in such a manner so as to fairly quickly treat the desired areas of target tissue or target bodily fluid and/or the entire body by heating up the areas to the predetermined temperature while maintaining the predetermined lower temperature over a more prolonged period of time.
  • the whole body treatment could be a sum of the localized treatments. This could be a way, for example, to treat diabetes and other similar diseases which affect the entire body or multiple areas of the body. This could also be, for example, a system and method for protectively and prophylactically treating the whole body of an individual, such as on a period basis.

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Abstract

L'invention concerne un processus qui fournit une thérapie protectrice pour des tissus ou des fluides biologiques consiste à appliquer une source d'énergie pulsée à un tissu cible ou à un fluide cible ayant une maladie progressive chronique ou un risque d'avoir une maladie progressive chronique pour traiter de manière thérapeutique ou prophylactique le tissu cible ou le fluide cible. La source d'énergie pulsée possède des paramètres d'énergie choisis de manière à augmenter la température de tissu cible ou la température du fluide cible corporel jusqu'à une température prédéterminée pendant une courte période de temps pour obtenir un effet thérapeutique ou prophylactique, tandis que l'élévation de température moyenne du tissu cible ou du fluide cible sur une période de temps plus longue est maintenue à un niveau prédéterminé ou au-dessous de celui-ci de façon à ne pas endommager de manière permanente le tissu cible ou le fluide cible.
PCT/US2017/044319 2016-08-09 2017-07-28 Processus destiné à fournir une thérapie protectrice pour des tissus ou de fluides biologiques WO2018031255A1 (fr)

Priority Applications (6)

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BR112019001348A BR112019001348A2 (pt) 2016-08-09 2017-07-28 processo para fornecer terapia protetora a tecidos ou fluidos biológicos
AU2017308587A AU2017308587A1 (en) 2016-08-09 2017-07-28 Process for providing protective therapy for biological tissues or fluids
CA3030483A CA3030483A1 (fr) 2016-08-09 2017-07-28 Processus destine a fournir une therapie protectrice pour des tissus ou de fluides biologiques
JP2018565035A JP2019524179A (ja) 2016-08-09 2017-07-28 生体組織または生体液のための保護療法を提供するためのプロセス
EP17840010.7A EP3496810A4 (fr) 2016-08-09 2017-07-28 Processus destiné à fournir une thérapie protectrice pour des tissus ou de fluides biologiques
CN201780047506.XA CN109562272A (zh) 2016-08-09 2017-07-28 用于向生物组织或流体提供保护性治疗的方法

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US15/232,320 US9962291B2 (en) 2012-05-25 2016-08-09 System and process for neuroprotective therapy for glaucoma
US15/232,320 2016-08-09
US15/583,096 US10953241B2 (en) 2012-05-25 2017-05-01 Process for providing protective therapy for biological tissues or fluids
US15/583,096 2017-05-01

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CN109562272A (zh) 2019-04-02
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JP2019524179A (ja) 2019-09-05

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