Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
• • 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
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
  • A61N1/403—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals for thermotherapy, e.g. hyperthermia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/02—Radiation therapy using microwaves
  • A61N5/022—Apparatus adapted for a specific treatment
  • A61N5/025—Warming the body, e.g. hyperthermia treatment

Definitions

• the present invention generally relates to a system and process for treating biological tissues. More particularly, the present invention relates to a system and process for preventing or treating Alzheimer's and other neurodegenerative diseases.
• CPDs Chronic progressive diseases
• IPF Idiopathic Pulmonary Fibrosis
• Chronic progressive diseases may have any number of underlying causes, including age, infectious, genetic, multi-factorial and immune. The progressive nature of these disorders implies that all worsen with age. 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. These features of all CPDs create a vicious cycle leading to the disease worsening over time.
• CPDs chronic obstructive pulmonary disease
• anti-inflammatory 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. It has effects similar to using anti- inflammatory and immunosuppressive drugs. However, it can also present more problematic side effects that worsen with time even after cessation of treatment, often making it unacceptable if long-term survival is anticipated.
• manager protein therapy attempts to address the problems presented by gene, drug, and anti- inflammatory/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.
• 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 common to targeted therapies 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. Although implicated in the disease process, such proteins virtually always have key roles in normal physiology which may lead to problems if inhibited generally or indiscriminately. Thus, such manager protein therapy also shares the problems targeted drug therapy has, as mentioned above.
• SCT Stem cell transplantation
• CPDs CPDs. 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 largely ineffective.
• Alzheimer's disease, and other neurodegenerative diseases are chronic progressive diseases.
• researchers have been attempting to find treatments or cures to
• Alzheimer's and other degenerative diseases but with little success. It is believed that the potentially disease-modifying drugs which could arrest or reverse severe memory impairment and other such aspects of Alzheimer's and other degenerative diseases may not be effective as they have difficulty in crossing the blood-brain barrier and entering the brain's neurons.
• Transcranial stimulation such as using electromagnetic energy sources, including radiofrequency, has been found to enable treatment of tissue and fluids at the blood-brain barrier and beyond the barrier and into the tissues of the brain.
• the present invention is directed to a system and method for preventing and treating chronic progressive diseases, including Alzheimer's and other degenerative diseases.
• a pulsed electromagnetic energy source comprising radiofrequency or microwave having selected energy parameters, including wavelength or frequency, duty cycle and pulse train duration is applied to the brain of the individual so as to prevent or treat the Alzheimer's or other degenerative disease.
• the pulsed electromagnetic energy may be directed to one or more of the leaky blood- brain barrier, inflamed portions of the brain, junk proteins of the brain, beta amyloid proteins of the brain, and/or tangled tau proteins of the brain.
• the pulsed energy source parameters may be selected so as to raise a temperature of the treated tissue sufficiently to stimulate heat shock protein activation in the treated tissue or fluid.
• the energy parameters are selected so as to raise the target tissue or bodily target fluid temperature up to 11 ° C., typically between 6° C. to 11 ° C. at least during the application of the pulsed energy source to the target tissue or target fluid, to achieve a therapeutic or prophylactic effect.
• 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. For example, 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 approximately V C. or less over several minutes, such as over a six-minute period of time.
• the radiofrequency may be 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 13 and 57 amp turns.
• the pulsed electromagnetic energy parameters may be selected and applied to the brain to cause resonant interactions within biomolecules within and around brain tissue.
• the pulsed energy parameters may be selected and applied to the brain so as to disrupt the structural integrity of the beta amyloid molecules. More particularly, the pulsed energy parameters may be selected so as to interact resonantly with the pi electron stacks in the beta amyloid and other biomolecules.
• a plurality of spaced-apart radiofrequency emitters may be disposed adjacent to a head of an individual to be treated.
• the radiofrequency fields of the spaced-apart radiofrequency emitters preferably do not overlap.
• the power level of each emitter may be set so that a specific absorption rate in the brain is between 1.0 W/kg and 2.0 W/kg.
• Each emitter may transmit a radiofrequency field at 850-950 megahertz every 4 to 5 milliseconds.
• the radiofrequency energy source may be applied to the brain at a given interval over a given period of time.
• the radiofrequency may be applied to the brain for two spaced-apart one-hour treatment periods each day. This may occur over several days, weeks or even months.
• 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 accordance with the present invention
• 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 embodiment of the system to use to generate laser light beams for treating tissue and fluid, in accordance with the present invention
• FIGURE 4 is a diagrammatic view illustrating yet another embodiment of a system used to generate laser light beams to treat tissue in accordance with the present invention
• FIGURE 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 control lably 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 10 and 11 are graphs illustrating the average power of a laser source compared to a source radius and pulse train duration of the laser;
• FIGURES 12 and 13 are graphs illustrating the time for the temperature for decay depending upon the laser source radius and wavelength;
• FIGURES 14-17 are graphs illustrating peak ampere turns for various radiofrequencies, duty cycles and coil radii;
• FIGURE 18 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.
• FIGURE 40 is a diagrammatic perspective view of a plurality of spaced-apart radiofrequency emitters disposed adjacent to a head of an individual to be treated;
• FIGURE 41 is a diagrammatic view illustrating the emitters emitting electromagnetic energy into the head and brain of the individual, in accordance with the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
• the present invention resides in processes and systems that provides protective therapy for biological tissues or fluids having a chronic progressive disease or at a risk of having a chronic progressive disease. More particularly, the present invention is directed to a system and method for preventing or treating Alzheimer's disease or other neurodegenerative diseases.
• 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 temperature rise of the tissue or target fluid over several minutes at or below a predetermined level so as not to permanently damage the target tissue or target fluid.
• 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. Alternatively, or additionally, 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.
• MRI or CAT scans of the brain may be performed, cognitive or memory tests may be administered, inheritance factors or genetics, such as a genetic test, may be utilized, or any other test which can determine that the individual is at a risk of acquiring or has Alzheimer's disease or another neurodegenerative 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 or infection. 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 a first step in the acute inflammatory process. Activation of HSPs by a threat initiates a cascade of subsequent events leading to improved cell function, reduced chronic inflammation, and reparative immunomodulation locally and system! cal ly.
• the effective HSP activations preserve the life of the cell and normalize cell function, also referred to as homeotrophy. Sudden and severe yet sublethal (to the cell) stimuli are the most potent stimulators of homeotrophic HSP activation. Slowly progressive and chronic stimuli are not effective activators HSP response. Thus, insidiously developing and progressing CPDs do not stimulate a reparative response of the
• HSP activation In some CPDs, like diabetes and Alzheimer disease, HSP function itself can become abnormal to the point of failure.
• 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.
• the repair response of HSPs is exactly tailored to the disease process. Agnostic to the cause of protein misfolding and consequent cellular dysfunction, homeotrophic HSP activation is thus a non- specific trigger of disease-specific repair.
• Pulsing allows significant increases in the abruptness and severity of the threat stimulus without killing the target cell to maximize HSP activation in the homeotrophic healing response.
• the various types of PEMR are best suited to different biological applications include light, laser, radio wave and microwave and ultrasound.
• CPDs of the retina may serve as a model for CPDs elsewhere in the body.
• PEMR in the form of low-intensity/high-density subthreshold diode micropulsed laser treatment (SDM) has been shown to effectively treat, prevent, slow, reverse or stop the progression of every major chronic progressive disease of the retina, without regard to the cause.
• SDM subthreshold diode micropulsed laser treatment
• 810 nm laser beam between 100 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 810 nm micropulsed diode laser.
• micropulsed diode lasers become more powerful, the exposure duration can be lessened accordingly. It has been found that 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 1300 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. Typically, the laser light pulse is less than a millisecond in duration, and typically between
• 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 10% duty cycle or higher can increase the risk of lethal cell injury in the retina. Thus, duty cycles less than 10%, 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 lower 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
• [Para 67] a) light beam having a wavelength of at least 532 nm, and preferably between 532 nm to 1300 nm; [Para 68] b) low duty cycle, such as less than 10% and preferably 5% or less;
• HSP stimulation by SDM results in normalized cytokine expression and consequently improved retinal structure and function.
• HSP stimulation in normal cells would tend to have no notable clinical effect.
• the "patho-selectivity" of near infrared laser effects, such as SDM affecting sick cells but not affecting normal ones on various cell types, is consistent with clinical observations of SDM. This facility is key to the suitability of SDM for early and preventative treatment of eyes with chronic progressive disease and eyes with minimal retinal abnormality and minimal dysfunction.
• 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 10, includes a laser console 12, such as for example the 810 nm near infrared micropulsed diode laser in the preferred embodiment.
• the laser generates a laser light beam which is passed through optics, such as an optical lens or mask, or a plurality of optical lenses and/or masks 14 as needed.
• the laser projector optics 14 pass the shaped light beam to a coaxial wide-field non-contact digital optical viewing system/camera 16 for projecting the laser beam light onto the eye 18 of the patient, or other biological target tissue or bodily fluid as more fully discussed herein.
• box labeled 16 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 16 provides feedback to a display monitor 20, which may also include the necessary computerized hardware, data input and controls, etc. for manipulating the laser 12, the optics 14, and/or the projection/viewing components 16.
• 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 simultaneously over 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.
• 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. Such 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.
• the invention can be effective. Accordingly, there can be as few as a single laser spot or up to approximately 400 laser spots when using the 577 nm wavelength laser light, while still not harming or damaging the eye or other tissue.
• the present invention can use a multitude of simultaneously generated therapeutic light beams or spots, such as numbering in the dozens or even hundreds, as the parameters and methodology of the present invention create therapeutically effective yet non-destructive and non-permanently damaging treatment.
• FIG. 3 illustrates diagrammatically a system which couples multiple light sources into the pattern-generating optical subassembly described above.
• this system 10' is similar to the system 10 described in FIG. 1 above.
• the primary differences between the alternate system 10' and the earlier described system 10 is the inclusion of a plurality of laser consoles 12, 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 14 as described in the earlier system.
• a fiber coupler 34 as is known in the art.
• Other known mechanisms for combining multiple light sources are available and may be used to replace the fiber coupler described herein.
• the multiple light sources 12 follow a similar path as described in the earlier system 10, i.e., collimated, diffracted, recollimated, and directed into the retina with a steering mechanism.
• the diffractive element functions 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 steering mechanism 16 to the retina 18 for treatment. The slight difference in the diffraction angles will affect how the steering pattern achieves coverage of the retina.
• 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 wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve identical coverage for each wavelength. This avoids either incomplete or overlapping coverage for any of the optical wavelengths.
• FIGURE 4 illustrates diagrammatically yet another alternate embodiment of the inventive system 10".
• This system 10" is configured generally the same as the system 10 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 12 are arranged in parallel with each one leading directly into its own laser projector optics 14.
• the laser projector optics of each channel 38a, 38b, 38c comprise a collimator 24, mask or diffraction grating 28 and recollimators 30,
• each set of optics 14 is then directed to a beam splitter 36 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 10 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 12, which could be from an optical fiber as in other embodiments of the pattern- generating subassembly.
• This light source 12 is directed to the optical assembly 14 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 simultaneous pattern of laser spots or other geometric objects reflected thereon to move accordingly on the target tissue of the patient. This can be done, for example, in an automated fashion using an electronic software program to adjust the optical scanning mechanism 40 until complete coverage of the target tissue, or at least the portion of the target tissue desired to be treated, is exposed to the phototherapy.
• the optical scanning mechanism may also be a small beam diameter scanning galvo mirror system, or similar system, such as that distributed by Thorlabs. Such a system is capable of scanning the lasers in the desired offsetting pattern.
• the 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.
• FIGS. 8 and 9 instead of a geometric pattern of small laser spots, the present invention contemplates use of other geometric objects or patterns. For example, 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.
• 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 810 nm diode laser should have an exposure envelope duration of 500 milliseconds or less, and preferably approximately 300 milliseconds.
• the exposure duration should be lessened accordingly.
• duty cycle or the frequency of the train of micropulses, or the length of the thermal relaxation time between consecutive pulses. It has been found that the use of a 10% duty cycle or higher adjusted to deliver micropulsed laser at similar irradiance at similar MPE levels significantly increase the risk of lethal cell injury. However, duty cycles of less than 10%, and preferably 5% or less demonstrate adequate thermal rise and treatment at the level of the MPE cell to stimulate a biological response, but remain below the level expected to produce lethal cell injury. The lower the duty cycle, however, the exposure envelope duration increases, and in some instances can exceed 500 milliseconds.
• Each micropulse lasts a fraction of a millisecond, typically between
• 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.
• 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.
• 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 protective treatment of the retinal tissue of the eye.
• 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 to maintain maximum effects and treatment benefits. 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
• Panmacular SDM treatment in accordance with the present invention, in eyes with advanced open-angle glaucoma (OAG) improved key measures of optic nerve and ganglion cell function, indicating a significant neuroprotective effective treatment.
• OAG open-angle glaucoma
• generating a micropulsed laser light beam having characteristics and parameters discussed above and applying 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
• CPDs elsewhere In all CPDs including type II diabetes, Alzheimer disease, idiopathic pulmonary fibrosis (IPF) and ischemic heart disease and various cardiomyopathies, abnormalities of the HSP system has been recognized.
• IPF idiopathic pulmonary fibrosis
• the present invention is also directed to the controlled application of pulsed ultrasound or electromagnetic radiation to treat abnormal conditions including inflammations, autoimmune conditions, and cancers that are accessible by means of fiber optics of endoscopes or surface probes as well as focused electromagnetic/sound waves.
• abnormal conditions including inflammations, autoimmune conditions, and cancers that are accessible by means of fiber optics of endoscopes or surface probes as well as focused electromagnetic/sound waves.
• cancers on the surface of the prostate that have the largest threat of metastasizing can be accessed by means of fiber optics in a proctoscope.
• Colon tumors can be accessed by an optical fiber system, like those used in colonoscopy.
• a burst of repetitive low temperature thermal spikes at a very steep rate of change ( ⁇ 7° C elevation with each 100 ⁇ s micropulse, or 70,000°C/sec) produced by each SDM exposure is especially effective in stimulating activation of HSPs, particularly compared to non-lethal exposure to subthreshold treatment with continuous wave lasers, which can duplicate only the low average tissue temperature rise.
• a pulsed energy source such as laser, ultrasound, ultraviolet, radiofrequency, microwave radiofrequency and the like, having energy parameters selected to cause a thermal time-course in tissue or bodily fluid to raise the target tissue or bodily fluid temperature over a short period of time to a sufficient level to achieve a therapeutic effect while maintaining average tissue temperature over a prolonged period of time below a predetermined level so as to avoid permanent tissue damage. It is believed that the creation of the thermal time-course stimulates heat shock protein activation or production and facilitates protein repair without causing any cellular damage.
• 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
• the selected parameters must not permanently damage the tissue.
• 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 11 °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 10 and 11 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. 10 shows a wavelength of 880 nm
• FIG. 11 has a wavelength of 1000 nm. It can be seen in these figures that the required power decreases monotonically as the radius of the source decreases, as the total train duration increases, and as the wavelength decreases.
• the preferred parameters for the radius of the laser source is 1 mm-4 mm. For a wavelength of 880 nm, the minimum value of power is 0.55 watts, with a radius of the laser source being 1 mm, and the total pulse train duration being 600 milliseconds.
• the maximum value of power for the 880 nm wavelength is 52.6 watts when the laser source radius is 4 mm and the total pulse drain duration is 100 milliseconds.
• the minimum power value is 0.77 watts with a laser source radius of 1 mm and a total pulse train duration of 600 milliseconds, and a maximum power value of 73.6 watts when the laser source radius is 4 mm and the total pulse duration is 100 milliseconds.
• the corresponding peak powers, during an individual pulse, are obtained from the average powers by dividing by the duty cycle. [Para 125]
• 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. In wavelengths ranging from 400 nm to 2000 nm, 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. Accordingly, the heated volume will be limited to the exterior or interior surface where the radiation source is placed, with a depth equal to the penetration depth, and a transverse dimension equal to the transverse dimension of the radiation source.
• a source radii of between 1 mm to 4 mm and operating a wavelength of 880 nm yields a penetration depth of approximately 2.5 mm and a wavelength of 1000 nm yields a penetration depth of approximately 3.5 mm.
• the target tissue can be heated to up to approximately 11 °C for a short period of time, such as less than one second, to create the therapeutic effect of the invention while maintaining the target tissue average temperature to a lower temperature range, such as less than 6°C or even 1°C or less over a prolonged period of time, such as several minutes.
• 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 10%, and preferably between 2.5% and 5%, with a total pulse duration of between 100 milliseconds and 600 milliseconds has been found to be effective.
• FIG. 13 illustrate the time to decay from 10°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.
• 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
• FIGS. 12 and 13 above illustrate the typical decay times required for the temperature in the heated target region to decrease by thermal diffusion from a temperature rise of approximately 10°C to 1°C as can be seen in FIG. 12 when the wavelength is 880 nm and the source diameter is 1 millimeter, the temperature decay time is 16 seconds. The temperature decay time is 107 seconds when the source diameter is 4 mm. As shown in FIG. 13, when the wavelength is 1000 nm, the temperature decay time is 18 seconds when the source diameter is 1 mm and 136 seconds when the source diameter is 4 mm.
• the relatively low duty cycle provides relatively long periods of time between the pulses of energy applied to the tissue and the relatively short pulse train duration ensure sufficient temperature diffusion and decay within a relatively short period of time comprising several minutes, such as 6 minutes or less, that there is no permanent tissue damage.
• tissue water content can vary from one tissue type to another, however, there is an observed uniformity of the properties of tissues at normal or near normal conditions which has allowed publication of tissue parameters that are widely used by clinicians in designing treatments.
• the electric and magnetic fields can be expressed in terms of the vector magnetic potential, which in turn can be expressed in closed form in terms of elliptic integrals of the first and second kind.
• the heating occurs only in a region that is comparable in size to the dimensions of the coil source itself. Accordingly, if it is desired to preferentially heat a region characterized by a radius, the source coil will be chosen to have a similar radius. The heating drops off very rapidly outside of a hemispherical region of radius because of the 1 /r 3 drop off of the magnetic field. Since it is proposed to use the radiofrequency the diseased tissue accessible only externally or from inner cavities, it is reasonable to consider a coil radii of between approximately 2 to 6 mm.
• the radius of the source coil(s) as well as the number of ampere turns (Nl) in the source coils give the magnitude and spatial extent of the magnetic field, and the radiofrequency is a factor that relates the magnitude of the electric field to the magnitude of the magnetic field.
• the heating is proportional to the product of the conductivity and the square of the electric field.
• the conductivity is that of skin and mucous tissue.
• the duty cycle of the pulse train as well as the total train duration of a pulse train are factors which affect how much total energy is delivered to the tissue.
• Preferred parameters for a radiofrequency energy source have been determined to be a coil radii between 2 and 6 mm, radiofrequencies in the range of 3-6 MHz, total pulse train durations of 0.2 to 0.4 seconds, and a duty cycle of between 2.5% and 5%.
• FIGS. 14-17 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 13 at the 0.6 cm coil radius and 20 at the 0.2 cm coil radius.
• the peak ampere turns is 26 when the pulse train duration is 0.4 seconds and the coil radius is 0.6 cm and the duty cycle is 5%. However, with the same 5% duty cycle, 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. 16 and 17. This yields, as illustrated in FIG. 16, 18 amp turns for a 6 MHz radiofrequency having a coil radius of 0.6 cm and a pulse train duration of 0.4 seconds, and 29 amp turns when the coil radius is only 0.2 cm and the pulse train duration is 0.2 seconds.
• 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.
• the time, in seconds, for the temperature rise to decay from approximately 10°C to approximately 1°C for coil radii between 0.2 cm and 0.6 cm is illustrated for a radiofrequency energy source in FIG. 18.
• the temperature decay time is approximately 37 seconds when the radiofrequency coil radius is
• the decay time is approximately 336 seconds, which is still within the acceptable range of decay time, but at an upper range thereof.
• Microwaves are another electromagnetic energy source which can be utilized in accordance with the present invention.
• the frequency of the microwave determines the tissue penetration distance.
• the gain of a conical microwave horn is large compared to the microwave wavelength, indicating under those circumstances that the energy is radiated mostly in a narrow forward load.
• a microwave source used in accordance with the present invention has a linear dimension on the order of a centimeter or less, thus the source is smaller than the wavelength, in which case the microwave source can be approximated as a dipole antenna.
• Such small microwave sources are easier to insert into internal body cavities and can also be used to radiate external surfaces.
• the heated region can be approximated by a hemisphere with a radius equal to the absorption length of the microwave in the body tissue being treated.
• the microwaves are used to treat tissue near external surfaces or surfaces accessible from internal cavities, frequencies in the 10-20 GHz range are used, wherein the corresponding penetration distances are only between approximately 2 and 4 mm.
• the temperature rise of the tissue using a microwave energy source is determined by the average power of the microwave and the total pulse train duration.
• the duty cycle of the pulse train determines the peak power in a single pulse in a train of pulses.
• the radius of the source is taken to be less than approximately 1 centimeter, and frequencies between 10 and 20 GHz are typically used, a resulting pulse train duration of 0.2 and 0.6 seconds is preferred.
• the average power is 18 watts when the pulse train duration is 0.6 seconds, and 52 watts when the pulse train duration is 0.2 seconds.
• FIG. 19 a graph depicts the average microwave power in watts of a microwave having a frequency of 10 GHz and a pulse train duration from between 0.2 seconds and 0.6 seconds.
• FIG. 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 10°C to 1°C compared to microwave frequencies between 58 MHz and 20000 MHz.
• the minimum and maximum temperature decay for the preferred range of microwave frequencies are 8 seconds when the microwave frequency is 20 GHz, and 16 seconds when the microwave frequency is 10 GHz.
• the absorption length of ultrasound in the body is rather long, as evidenced by its widespread use for imaging. Accordingly, 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 10 cm are readily available.
• Favorable focal dimensions are achieved when the ultrasound frequency is between 1 and 5 MHz, and the total train duration is 0.1 to 0.5 seconds.
• the focal volumes are 0.02 cc at 5 MHz and 2.36 cc at 1 MHz.
• a graph illustrates the average source power in watts compared to the frequency (between 1 MHz and 5 MHz), and the pulse train duration (between 0.1 and 0.5 seconds).
• a transducer focal length of 10 cm and a source diameter of 5 cm have been assumed.
• the required power to give the Arrhenius integral for HSP activation of approximately 1 decreases monotonically as the frequency increases and as the total train duration increases.
• the minimum power for a frequency of 1 GHz and a pulse train duration of 0.5 seconds is
• FIGURE 23 illustrates the time, in seconds, for the temperature to diffuse or decay from 10°C to 6°C when the ultrasound frequency is between 1 and 5 MHz.
• FIG. 24 illustrates the time, in seconds, to decay from approximately 10°C to approximately 1°C for ultrasound frequencies from 1 to
• the maximum time for temperature decay is 366 seconds when the ultrasound frequency is 1 MHz
• the minimum temperature decay is 15 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 allowable.
• the decay times to a rise of 6°C are much smaller, by a factor of approximately 70, than that of 1 °C.
• FIGURE 25 illustrates the volume of focal heated region, in cubic centimeters, as compared to ultrasound frequencies from between 1 and 5
• the corresponding focal sizes for these frequencies range from 3.7 mm to 0.6 mm, and the length of the focal region ranges from 5.6 cm to 1.2 cm.
• the corresponding treatment volumes range from between approximately 2.4 cc and 0.02 cc.
• Examples of parameters giving a desired HSP activation Arrhenius integral greater than 1 and damage Arrhenius integral less than 1 is a total ultrasound power between 5.8-17 watts, a pulse duration of 0.5 seconds, an interval between pulses of 5 seconds, with total number of pulses 10 within the total pulse stream time of 50 seconds.
• the target treatment volume would be approximately 1 mm on a side. Larger treatment volumes could be treatable by an ultrasound system similar to a laser diffracted optical system, by applying ultrasound in multiple simultaneously applied adjacent but separated and spaced columns. The multiple focused ultrasound beams converge on a very small treatment target within the body, the convergence allowing for a minimal heating except at the overlapping beams at the target.
• This area would be 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.
• PEMR energy delivery mode comes from producing a spike temperature of the order of 10°C. This large rise in temperature has a big impact on the Arrhenius integrals that describe quantitatively the number of HSPs that are activated and the rate of water diffusion into the proteins that facilitates protein repair. This is because the temperature enters into an exponential that has a big amplification effect.
• 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 p (r) ⁇ P ⁇ t p /(4 ⁇ Cv ⁇ [(6/r dif 2)U ⁇ r dif -r) +(1 /r 2 )U(r-r dif )] [5]
• Arrhenius integral for a train of N pulses can now be evaluated with the temperature rise given by eq. [9].
• dT N (t) ⁇ dT(t-nt I ) [11]
• dT(t-nt I ) is the expression of eq. [9] with t replaced by t-nt I ⁇ and with t I 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.
• 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[ ⁇ t p (2k B To 2 /(3EdT o ) ⁇ exp[-(E/k B )1/(T o + dT o + dT N (Nt I ))]
• FIGURES 27 and 28 show the magnitude of the logarithm of the
• FIG. 28 shows the logarithm of the
• 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 10 such as a laser having a desired wavelength and/or frequency is used to generate electromagnetic radiation, such as laser light, in a controlled, pulsed manner to be delivered through a light tube or pipe 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 10 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.
• Other forms of electromagnetic radiation may also be generated and used, including ultraviolet waves, microwaves, other radiofrequency waves, and laser light at predetermined wavelengths.
• ultrasound waves may also be generated and used to create a thermal time-course temperature spike in the target tissue sufficient to activate or produce heat shock proteins in the cells of the target tissue without damaging the target tissue itself.
• a pulsed source of ultrasound or electromagnetic radiation energy is provided and applied to the target tissue in a manner which raises the target tissue temperature, such as between 6°C and 11°C, transiently while only
• 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 10°C, while maintaining the long-term rise in temperature to be less than the FDA mandated limit, such as 1°C. It has been found that if too large of an area or volume of tissue is treated, the increased temperature of the tissue cannot be diffused sufficiently quickly enough to meet the FDA requirements.
• 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.
• tissue 58 to be treated within the nasal cavity 62 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 elevate intracellular temperatures, and this temperature elevation in itself would be anti -viral in the same way as the fever response to viral infections is anti-viral.
• treatment would thermally 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 810 nm wavelength laser light, administered in a manner similar to that described in the above-referenced patent applications, but administered through an endoscope or the like, as illustrated in FIG. 31.
• the adjuvant dye would be selected so as to increase the laser light absorption. While this comprises a particularly preferred method and embodiment of performing the invention, it will be appreciated that other types of energy and delivery means could be used to achieve the same objectives in accordance with the present invention.
• laser light or other energy source 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. 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 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.
• the procedure could be performed similar to a colonoscopy in that the bowel would be cleared of all stool, and the patient would lie on his/her side and the physician would insert the long, thin light tube portion 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 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.
• FIG. 34 Another example in which the present invention can be advantageously used in the Gl tract, for example 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 micropulsed laser (SDM) treatment, as discussed above, or by other energy sources and means as discussed herein and known in the art.
• 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
• 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 or other light-absorbing material such as metallic nanoparticles could be delivered to the Gl tissue orally to enable absorption of the radiation. If, for instance, unfocused 810 nm radiation from a laser diode or LED were to be used, the pigment would have an absorption peak at or near 810 nm. Alternatively, the wavelength of the energy source could be adjusted to a slightly longer wavelength at an absorption peak of water, so that no externally applied chromophore would be required.
• a capsule endoscope 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 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 10°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
• the use of pulsed ultrasound is often 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 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 100 is shown adjacent to a clamp device 102 configured to transmit SDM radiation or the like.
• This could be, for example, by means of one or more laser diodes 104 which would transmit the desired frequency at the desired pulse and pulse train to the earlobe 100.
• Power could be provided, for example, by means of a lamp drive 106.
• the lamp drive 106 could be the actual source of laser light, which would be transmitted through the appropriate optics and electronics to the earlobe 100.
• the clamp device 102 would merely be used to damp onto the patient's earlobe and cause that the radiation be constrained to the patient's earlobe 100.
• the system may also include a display and speakers 112, 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 100
• 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 or microwave 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.
• tissue or bodily fluid is heated very quickly up to approximately 11°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 114 is contemplated by the present invention which can hold and/or support an entire body 116, such as by means of a platform 118 upon which the individual lies.
• the device 114 would include a pulsed energy emitter 120 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.
• a pulsed energy emitter 120 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 120 is moved, such as along track 122, 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 away, 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.
• the repeated pulses in the treatment provide large thermal spikes (on the order of 10,000) that allow the cell's repair system to more rapidly surmount the activation energy barrier that separates a dysfunctional cellular state from the desired functional state.
• the net result is a
• lowered therapeutic threshold in the sense that a lower applied average power and total applied energy can be used to achieve the desired treatment goal.
• the present invention has been found to also prevent or treat neurodegenerative diseases, including Alzheimer’s disease. It is determined that an individual has a neurodegenerative disease, such as Alzheimer's, or is at a risk of developing a neurodegenerative disease. This could be determined, for example, by genetic testing, cognitive testing, blood or cerebral spinal fluid testing, inheritance determinations, or any other available test which could lead a medical professional to determine that the individual either has a neurodegenerative disease or is at risk of developing a neurodegenerative disease.
• a pulsed electromagnetic energy typically either radiofrequency or microwave, having selected energy parameters, including wavelength or frequency, duty cycle and pulse train duration, is provided and applied to the brain of the individual so as to prevent or treat the neurodegenerative disease.
• the pulsed electromagnetic energy may be directed to one or more of a leaky blood-brain barrier, inflamed portions of the brain, junk proteins of the brain, beta amyloid proteins of the brain, or tangled tau proteins of the brain, or any other portion of the brain, brain tissue, or cerebral spinal fluid or the like to provide treatment.
• the energy parameters and application parameters may be selected to either create thermal interactions with such tissue, proteins or other molecules, or resonant interactions.
• the pulsed energy could be applied to the individual's brain tissue by means of the device 114 illustrated in FIG. 39, which would selectively apply the pulsed energy just to the brain or area of interest of the patient 116.
• Other devices or means of applying the pulsed energy are also contemplated by the present invention, such as disposing a plurality of spaced-apart transmitters 124 disposed adjacent to a head 126 of the individual to be treated, as illustrated in FIGS. 40 and 41 .
• the invention contemplates using a single electromagnetic emitter which would emit the electromagnetic energy, such as radiofrequency or microwave energy, to the individual's brain, through his or her head, and moving the emitter, as necessary.
• the “head cap” 130 having an array of emitters 124 interconnected by electrical leads 128 which can be placed over or on the head of the individual is particularly convenient as it is easily worn and places the emitters 124 in close proximity to the brain 136.
• the head cap 130 illustrated in FIG. 40 has eight emitters 124, although the number, size, and configuration can be adjusted as needed.
• the emitters 124 are sufficiently spaced apart from one another such that the electromagnetic energy 134 emitted by the emitters 124 do not overlap.
• the configuration of the emitters 124 in the head cap 130 illustrated in FIGS. 40 and 41 could be used to treat substantially the entire brain of the individual. However, it may be more desirable to treat only a portion of the brain, and thus a head cap of a different configuration with a different number of emitters could be utilized, or some emitters 124 could be deactivated, as deemed necessary.
• a power and control device 132 could be operably connected to the head cap 130 and/or emitters 124.
• the control box 132 could provide the power necessary for the emitters 124 to emit their electromagnetic waves, and could also include electronics so as to control the intensity, timing, and the like of the emitters 124. It will be understood that the control box 132 could vary in size depending upon power and control requirements.
• control and power device 132 are to emit relatively large frequencies and/or power, the control and power device 132 may be somewhat large and substantially non-portable.
• the power and control device 132 could be quite small and be carried by the user to allow the user to be mobile during treatment.
• the pulsed energy parameters are selected so as to raise a temperature of treated tissue sufficiently to stimulate heat shock protein activation in the treated tissue or fluid.
• the pulsed energy may comprise a radiofrequency between
• the radiofrequency may be generated with a coil having a radii between 2 mm and 6 mm.
• the coil may have between 13 and 45 amp turns.
• a non-invasive electromagnetic treatment more particularly a transcranial electromagnetic treatment (TEMT) has been found to provide statistically significant improvement in the individual's cognitive enhancement, changes to cerebral spinal fluid and blood markers for
• Alzheimer's disease and evidence of enhanced brain connectivity.
• the emitter coils 124 are spaced sufficiently far apart that their fields 134 extend through the individual's skull and into the brain tissue 136, but the fields do not substantially overlap or more preferably do not overlap.
• the power level of each emitter is set so that the specific absorption rate (SAR) in the brain is between 1.0 and 2.0 W/kg.
• the pulsed energy is applied to the individual's brain for multiple, spaced-apart treatments each day.
• the patient could be treated for one hour period in the morning and another hour period in the afternoon.
• Such treatment is applied in such a manner over a prolonged period of time, comprising weeks or even months.
• the treatment could occur for a period of sixty days.
• CSF p-tau protein/amyloid beta ratio CSF p-tau protein/amyloid beta ratio
• reduced levels of oligometric amyloid beta in plasma Enhanced glucose utilization and increased functional connectivity in the brain has also been found.
• ⁇ SAR ⁇ ( ⁇ t/C v ) [1 5] where ⁇ denotes the density.
• the specific heat capacity of brain tissue is 3630 joules/ kg/degC , compared to 41 78 joules/kg/degC for water and p is about 1 gm/cc.
• A[r,z] ( ⁇ l/2) ⁇ acos ⁇ d ⁇ [a 2 + r 2 +z 2 -2arcos ⁇ ]- 1/2 [22] where the integral is from 0 to ⁇ , and r and z are the radius and axial distance in cylindrical coordinates.
• the emitters 124 as illustrated in FIGS. 40 and 41 collectively provide both global and penetrating TEMT to the human forebrain, including the cerebral cortex and underlying structures of the brain.
• the success of the treatment is not due to a thermal effect.
• the successful treatment also does not appear to be due to large induced electric fields, induced charge or current densities, mechanical stresses, or appreciable changes in membrane potentials.
• the radiofrequency, or other pulsed energy is directly acting on the biomolecules in the cells. From the magnitudes of the fields in the induced charge and current densities, it appears that the effect would most likely involve a resonance interaction with a collective mode.
• the TEMT can be used to prevent or even reverse both oligomeric and insoluble amyloid-beta aggregation, both inside and outside neurons.
• the TEMT cannot only disaggregate amyloid-beta oligomers, but also disaggregate tau and ⁇ - synuclein oligomers. It is believed that this is due to the excitation of resonant cooperative oscillations within the brain cells.
• eq. [34] describes a charge that is free to move anywhere under the influence of an electric field, subject only to a drag due to collisions. In an insulator, the charges are not free to move anywhere, but are constrained.
• the collision frequency is proportional to the viscosity, and since the mass of the charge is proportional to the cube of the radius of the mass, the collision frequency is inversely proportional to the square of the mass's radius.
• the distribution of parameters in the Drude expressions means that in biological tissues it is possible to observe the desired resonances at several frequencies rather than at just one frequency.
• ⁇ ⁇ is the plasma frequency defined by eq.
• v is the collision frequency of the charges
• ⁇ ext is the dielectrtic constant of the region surrounding the conductor
• the collision frequency v can be related to viscosity ⁇ [Cf. eq. 52] when the charge moves through a viscous medium (such as the cell electrolyte).
• TEMT is effective in treating Alzheimer's because its applied GHz fields are interacting resonantly with internal biomolecular electrons.
• ⁇ is the (angular) frequency and v is the electron collision frequency.
• K is a restoring force constant
• v is the collisional frequency of the electrons.
• ⁇ o 2 is non- zero.
• ⁇ o 2 0.
• Tables 4 and 5 also show that when the shapes of the complexes cause the resonant frequencies to decrease from the plasma frequency (at which resonance occurs for bulk dielectrics), the magnitude of the field amplification also decreases.
• the decrease in amplification is proportional to 1 / ⁇ ext 1 /2 .
• a reduction depending on the ratio of the thickness to the large dimensions also enters.
• the largest amplification occurs for the case of randomly oriented thin oblate ellipsoids (discs): there the amplification is directly proportional to the large ⁇ ext . Large amplification is all cases also depends on the conduction electron collision frequency v being small.
• the conductivities depend strongly on the doping of the doping of the polymer: e.g. polymers in a NaCI electrolyte can have a very respectable 10
• Amyloid fibril formation is a common characteristic of a variety of unrelated diseases, including Alzheimer's disease, diabetes mellitus, prion diseases, and familial amyloidosis. It is believed that pi-stacking may play an important role in amyloid fibril formation.
• the attractive non-bonded conjugated pi electron systems tend to hold the fibrils together in different, typically four, configurations. Three aromatic residues are the most frequent ones present, namely, tryptophan, tyrosine, and phenylalanine.
• Alzheimer's disease and other neurodegenerative diseases, with low power electromagnetic fields, such as in the radiofrequency range of frequencies, is believed to involve resonant interaction with conjugated pi electron systems in the biomolecules surrounding or within the brain tissue, such as in the beta amyloid protein present in brains of Alzheimer's patients.
• Other targets include tau proteins, particularly tangled tau proteins, which are present in the brain cells of
• Alzheimer's patients Other areas which could be targeted include a leaky blood-brain barrier, inflamed portions of the brain, and junk proteins of the brain.
• the low power resonant treatment of Alzheimer's and other neurodegenerative diseases could be for molecular and tissue targets in which the electromagnetic fields which are applied interact resonantly with the pi electron stacks in these target biomolecular complexes and tissues, including beta amyloids, which are a characteristic of Alzheimer's brains. This interaction disrupts the structural integrity of the beta amyloid, or other molecular complexes.
• the resonant frequency for the interaction is shown to depend on several factors, including the number density of electrons, whether the electrons are conducting or insulating, the shape of the region containing the electrons, and the surrounding dielectric.
• the width of the resonant frequency is shown to depend strongly on the collision frequency of the electrons.
• the usable electromagnetic fields have been found to be in the frequency range of both radiofrequencies and microwaves as mentioned above.

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